Medical Tribune July 2012 HK

July 2012
www.medicaltribune.com
OSA can be successfully managed in primary care
FORUM Surviving the approaching tsunami of diabetes
IN PRACTICE Therapeutics in osteoporosis
CONFERENCE Promising drug combination for breast cancer
AFTER HOURS Chengdu Land of Tea, Tao and Pandas
July 2012
OSA can be successfully managed in primary care

Rajesh Kumar
atients with obstructive sleep apnea (OSA) can be successfully managed in primary care by suitably trained GPs and nurses, according to Australian researchers. Previous studies have shown that ambulatory models of care for OSA in specialist clinics can produce patient outcomes comparable to laboratory-based management. However, this is the first randomized controlled study to be conducted in primary care. Researchers randomized 155 patients with OSA to either primary care-based management or usual care in a specialist sleep center. At 6 months, mean change in Epworth sleepiness scale (ESS) scores, the primary outcome measure of the study, was similar in the two groups (4.9 in the primary care group vs. 5.1 in the specialist group). GPs identified patients with symptomatic, moderate-to-severe OSA using a four-item screening tool, the ESS, and home oximetry. Primary care-based management was led by the patients GP and a community-based nurse and involved use of home auto-titrating of continuous positive airway pressure (CPAP). Usual care in a specialist sleep center involved management by a sleep physician and laboratory-based testing. In addition to similar changes in ESS scores at 6 months, mean change in Functional Outcomes of Sleep Questionnaire (FOSQ) score was similar in the two groups (2.3 in the primary care group vs. 2.7 in the specialist group), as was compliance with CPAP. Mean daily use of
A randomized study involving 155 patients with OSA has shown that a primary care-based management approach can produce outcomes comparable to usual specialist care.
CPAP was 4.8 hours in the primary care group and 5.4 hours in the specialist group. Within-study costs for primary care management were lower than those for specialist care, with significant savings of A$2,157 (95% CI: A$1,293 to A$3,114) per patient. With the rise in demand and growing waiting lists for sleep physician consultation and laboratory-based sleep services, there has been increasing interest in development of ambulatory strategies for the diagnosis and management of OSA involving home sleep monitoring and auto-titrating CPAP, said lead author Dr. Ching Li Chai-Coetzer of the Adelaide Institute for Sleep Health at Repatriation General Hospital, Adelaide, Australia. The results showed that a simplified approach for the treatment of OSA in primary care was not clinically inferior to manage-
July 2012 betes were treated only by specialists, but are now commonly managed in primary care. Dr. Ong Thun How, director of the sleep disorders unit at Singapore General Hospital, agreed a greater role for GPs could be feasible, but said the awareness of OSA among them is still not very good due to insufficient exposure to various aspects of sleep medicine at undergraduate and postgraduate level. In an attempt to fill some gap, Ongs unit is organizing a sleep symposium on 13-14 October this year focusing on management and diagnosis of OSA and will also run a concurrent CPAP workshop that will help GPs learn how to manage patients on CPAP. The study findings may not be applicable to all as the participants were relatively well, community-screened patients. Those with more complicated disease, eg, respiratory failure and/or concomitant heart disease, will still probably need specialist care, Ong added.
ment of these patients in a specialist sleep center. These were recently presented at the American Thoracic Society international conference 2012 in San Francisco, California, US. This approach also offers a lower cost alternative to usual care. In addition, waiting lists for specialist sleep centers are long, and home care may be preferred by patients, said Chai-Coetzer. Rather than a move to transfer the management of OSA from specialist to primary care, he envisioned GP model of care to be complimentary to specialist care, with GPs working alongside specialists to help relieve the excess burden of untreated disease in the community and to expedite treatment. This would be particularly beneficial for rural and remote regions, as well as developing nations, where access to specialist services may be limited, he said, adding that historically, chronic conditions like asthma and dia-
July 2012
International diabetes research prize announced

Rajesh Kumar
sian biomedical researchers racing to find a cure for diabetes can vie for the US$250,000 international research prize if they make a scientific breakthrough. The award was recently established by the prestigious Harold Hamm Diabetes Center (HHDC) at the University of Oklahoma in Oklahoma, US, to spur global research. HHDC is a center of excellence integrating novel research, patient care and large-scale prevention programs. It will award and administer the prize, one of the largest of its kind in the world, to recognize and promote lasting achievements in diabetes research. The prize hopes to encourage research toward a cure for diabetes on all continents, including Asia. Researchers from Asia qualify and will be considered by the selection jury at its discretion, said Dr. Thomas White, the centers assistant director for advancement. Mr. Harold G. Hamm, chairman and chief executive officer of Continental Resources, who helped institute the prize, hopes it will light a worldwide fire of scientific innovation toward finding a cure for diabetes within this generation. Im excited to be part of this next chapter in the fight against diabetes and to see the outstanding new research the prize search will encourage and recognize, he said. A rotating jury of national and international leaders in the field of diabetes will
A biennial prize of US$250,000 is being offered to recongnize breakthroughs in diabetes research.
award the prize biennially, solely on the basis of scientific merit, recognizing scientific breakthroughs in the field of diabetes, either type 1 or type 2 (or both), with special emphasis on progress towards a cure. Individual researchers, teams and research institutions are eligible for nomination by the jury. See www.HaroldHammPrize.org for details.
July 2012
Forum
Surviving the approaching tsunami of diabetes

Excerpt from a speech by Ms. Geralyn R Spollett, American Diabetes Association (ADA) president of health care and education, during the ADAs 72nd scientific sessions held recently in Philadelphia, Pennsylvania, US. ne person is diagnosed with diabetes every 17 seconds. This one person could be your family member, your child, or the man that rides next to you on the train to work each morning. For many of us, diabetes has been our lives work. Unfortunately, there is enough work in this field to last for generations to come. My fondest dream is to hold high the vial of a miraculous serum as Jonas Salk did when he announced the polio vaccine, and tell you that I and my colleagues have found a cure for diabetes and our mission is fulfilled: a life free of diabetes and all its burdens! However, lately I have been having two recurring nightmares. In one, there are lines and lines of people, all with diabetes, who are typing their name into a vast computer program. They fill out a questionnaire and then download a list of lab work to be done prior to their 3-minute telephone or online appointment time. The lucky ones will talk with a real person. The unlucky ones will get an automated response from a very clever program that allows them to select options, similar to the one employed by airlines. But instead of a voice asking you if you want flight information, it will ask you to click 1 if you need insulin or dietary adjustments. My second nightmare, unfortunately, is real. It is the story of a village in the Middle
Around 380 million people globally are expected to have diabetes by 2025.
East where persons with diabetes can buy only one vial of insulin. Each person gets their share of 20 units; just enough to keep them alive and functioning. When I hear that 380 million people in the world are expected to have diabetes by 2025, I dont see a number. I see people like my patients and these villagers who struggle everyday to live a life with a disease that demands so much and gives back so little. We are currently in the midst of a tsunami of diabetes. Its first wave is the ever rising wave of obesity, the underlying current of the increase in diabetes. Worldwide, 2.8 million people die as a result of being overweight or obese and the prevalence of obesity has doubled between 1980 and 2008. North America leads the trend with more than 30
July 2012
Forum
clinicians and educators to help reduce the impact of diabetes by supporting research into prevention, cure and care of those already affected, and by increasing the resources devoted to research. Research shows that despite comparable diabetes care, some groups have poorer health outcomes than others. Factors such as physician interaction, prevalence of undiagnosed or untreated depression, fewer resources, greater stress associated with socioeconomically deprived neighborhoods and out of pocket costs are important for determining outcomes. Improved healthcare delivery systems must, therefore, focus on making it more cost effective and easier to deliver diabetes care within primary care settings, with easier access to self care plans. Ongoing support for self-care in the form of newsletters, email, social media, community board postings, access to information lines and diabetes educators is absolutely necessary. Currently, access to these programs is limited in the government and private sectors. The next step is to take to the higher ground, ie, making change happen. That is the ethical and the right thing to do. If every single one of us was able to inform the public and heighten the awareness of the dangers of a growing diabetes epidemic, just think what we could accomplish. We are all stakeholders in our healthcare system: whether researcher, educator or clinician. The current healthcare systems respond best to acute and episodic care. But that model will not address the burgeoning needs of a population requiring chronic care. Change must start here and now, with those of us who are touched by diabetes and have made it our lives work.
percent people being obese, closely followed by the tip of Africa and the Middle East. Asia and Europe are close behind, with a prevalence of between 20 to 29 percent obesity. The second wave is hyperglycemia. Worldwide, the alarming rise in the incidence of hyperglycemia closely follows the obesity trend and these show no signs of abatement. According to the International Diabetes Federation, there were 284.6 million people with diabetes worldwide in 2010, which is expected to grow to 438.4 million by 2030. The greatest increases will occur in Africa and the Middle East. In North Africa, greater than 90 percent increase is expected, followed by South East Asia and South and Central America. Not only is diabetes a healthcare crisis, it is also an economic one since it will send destructive shockwaves through economies. Diabetes affects the most productive age group of 40 to 59, which in turn affects gross national productivity. We must take the necessary steps to survive this tsunami by first sounding the alarm to warn the public of the dangers to come, preparing ourselves and the healthcare system to reduce the impact and, ultimately, taking to the higher ground. There is false information, misconceptions and myths about diabetes in every sector of our society, including amongst healthcare professionals. Diabetes is a disease without a face. Theres little recognition of its potentially life threatening nature or the demands of daily care. For the public, it is: Dont eat your sugar and take those (insulin) shots every day. But it is much more than just that. We must convince the public that diabetes is a serious disease, with serious personal and societal consequences. Next step is for
July 2012
Hong Kong Focus
17th Hong Kong Medical Forum (HKMF)*, 12-13 May 2012 Sue Mulley reports
Anabolic therapy improves functioning in osteoporosis

nabolic therapy with recombinant human parathyroid hormone 1-34 (teriparatide or PTH 1-34) appears to significantly improve back pain and mobility in patients with severe osteoporosis. Of all the osteoporosis drugs, this is the one thats truly life altering, said Professor Jonathan Derrick Jun Adachi of St Josephs Hospital, McMaster University, Canada. Unlike other osteoporosis therapies, which inhibit bone turnover, PTH 1-34 is able to stimulate bone formation, leading to increased bone mass and improved microarchitecture, he explained. In severe osteoporosis, preventing further bone loss may not be enough to stop further fractures. In these cases, you need to build bone up and then use an antiresorptive agent to prevent it breaking down, Adachi noted. Using a clinical case to demonstrate teriparatides benefits in severe osteoporosis patients, Adachi described a 75-year-old woman who presented with a fractured L3, two pelvic and three sacral fractures. She had been home-managed for a pelvic fracture sustained 12 months previously, and was taking a bisphosphonate. Her baseline pain score was 9/10, and she could barely walk to the bathroom, Adachi said. She was prescribed salmon calcitonin but the drug was stopped after 2 days because she developed nausea, vomiting and diarrhea.
Within 2 days of commencing PTH therapy, her pain score dropped to 3/10 and she was able to walk around the ward. A week later, she was able to manage the hospital stairs, he reported. Teriparatide also appears to be effective in men, said Adachi, describing a 63-yearold male patient who presented with suddenonset, progressively worsening back pain due to L1-L3 fractures. He had purchased a motor scooter to get around, had a wheelchair and put himself on a list for a nursing home bed His pain score was 56/70. He was diagnosed with primary osteoporosis and started on PTH therapy, said Adachi. At a follow-up 3 months later, his pain score had dropped to 10/70, and he got rid of his wheelchair. He had become completely independent. Conceding that evidence from these case histories was anecdotal, he said the benefits of PTH
July 2012
Hong Kong Focus

dronic acid and denosumab had the highest probabilities of reducing vertebral fractures. [BMC Musculoskelet Disord 2011;12:209] Occasional side-effects of PTH 1-34 include muscle cramping (often avoided by abdominal administration) and headache (alleviated by taking the drug every other day for 2 weeks, then increasing to daily administration). Ive treated more than 500 patients with PTH and the vast majority tolerate their medication even with these side-effects, said Adachi.
1-34 were substantiated in clinical trials involving patients with severe osteoporosis, including those with glucocorticoid-induced disease. Postmenopausal women treated with 20 g teriparatide were 35 percent less likely to have 1 nonvertebral fracture and 53 percent less likely to have 1 new nonvertebral fragility fracture after a mean duration of 18 months PTH 1-34 treatment vs placebo. Further, in a systematic review of nine osteoporosis medicines, PTH 1-34 and etidronate had the highest probability of reducing non-vertebral fractures, while PTH 1-34, zole-
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July 2012
Hong Kong Focus
Call for more aggressive therapy in RA

arly intervention, especially with biological therapies, has significantly improved outcomes for rheumatoid arthritis (RA) patients during the past decade. Data indicate that remission rates for patients with earlystage disease (<2 years) are double those for patients with established disease (>10 years). However, translating this evidence into widespread clinical practice is proving challenging, according to Professor Hisashi Yamanaka, Director of the Institute of Rheumatology at Tokyo Womens Medical University, Japan. Yamanaka and colleagues have been collecting data on more than 7,000 RA patients for 12 years in the ongoing Institute of Rheumatology Rheumatoid Arthritis (IORRA) study. The patients were evaluated for swollen/ painful joints, underwent blood tests and answered a 30-page questionnaire bi-annually. From 2000 to 2006, disease activity score (DAS28) significantly improved from 4.15 to 3.63, and the proportion of patients in remission (DAS <2.6) increased from 8.5 to 21.5 percent. [Mod Rheumatol 2007;17:283-289] Today, more than 30 percent of our patients are in remission. The proportion of methotrexate [MTX] users has increased from 33 percent to over 70 percent. Nowadays, about 15 percent of patients receive biological therapies, which were first introduced in Japan in 2003, he noted, adding that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and steroids has decreased strikingly. Treatment focus has changed from maintaining patients current functioning to more
aggressive treatment aiming to completely control disease activity and prevent joint destruction. The problem is that early diagnosis is not easy, he said, noting that the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA should be applied. Until a couple of years ago, wed been using diagnostic criteria drawn up 25 years ago. With the new classification, general practitioners can target patients who have just one swollen joint, and if synovitis cannot be explained by another disease, commence treatment, Yamanaka advised. In a separate presentation, Dr. Tak-Cheong Cheung, Specialist in Rheumatology in private practice in Hong Kong, pointed out that clear outcome targets and tight disease control have to be integrated into standard practice. Its the strategy rather than the drug thats important, he said. If patients dont achieve remission or a low disease activity within 3 months, therapy should be escalated, because joint damage may occur within 4 months of initial symptoms. For patients who cannot tolerate or fail MTX, another disease modifying anti-rheumatic drug or biological therapy can be added, depending on disease severity. Disease activity correlates with progression of joint damage, and there is a small window of opportunity to prevent radiologic deterioration, Cheung emphasized.
*Organized by the University of Hong Kong (HKU)
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July 2012
Hong Kong Focus
Tighter checks on adverts for oral products

Wey-Feng Ong
s of June 1, the government has imposed more stringent restrictions on health claims of orally consumed products under the Undesirable Medical Advertisements (Amendment) Ordinance. According to the amendment, advertising of six groups of health claims of orally consumed products, except those customarily consumed as food or drink, will be prohibited/restricted. The Undesirable Medical Advertisements Ordinance (UMAO) was first enacted in 1953, aiming to protect public health through restricting advertisements which may promote products with unsubstantiated medical claims, resulting in improper management of certain health conditions. Specifically, advertisements likely to lead to the use of any medicine, surgical appliance or treatment for the purpose of treating human beings, or preventing them from contracting diseases or conditions are not allowed, a Department of Health (DH) spokesman stressed. With an ever increasing number of orally consumed products with various health claims on the local market, and rising concerns about their impact on public health, the Ordinance was amended in June 2005. A new Schedule 4 on prohibition/restriction of six groups of health claims for orally con-
sumed products has been added to curb the threat. To promote implementation of these regulations, the DH has initiated various education and publicity activities for stakeholders. In particular, a set of guidelines on the Amendment Ordinance has been prepared for the trade, while briefings and seminars have been organized to provide platforms for interactive communication between stakeholders and the regulatory authority. In addition to the existing UMAO requirements, as of June 2012, no person shall publish an advertisement for an orally consumed product which makes a claim as specified in Schedule 4 of the Ordinance, or any similar claim, except as allowed under the provisions of that Schedule, the spokesman said. Other major amendments include increasing the penalty for breach of the UMAO, and empowering the Director of Health to appoint inspectors to enforce the Ordinance. According to the Amendment, any person who contravenes the provisions commits an offence and will be liable to a maximum fine of HK$50,000 and 6 months imprisonment at the first conviction, and a maximum fine of $100,000 and 1 years imprisonment upon any subsequent conviction.
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July 2012
Hong Kong Focus
Experts advocate home-based NIV for respiratory failure

Naomi Rodrig
ome-based noninvasive ventilation (NIV) can successfully replace the conventional invasive ventilation procedure for selected patients with chronic respiratory failure, an expert argued. According to Dr. Chung-Ming Chu, Governor of the Hong Kong and Macau Chapter of the American College of Chest Physicians (ACCP) and representative of the Hong Kong Thoracic Society, mortality from respiratory failure in Hong Kong is quite high. In 2011, there were about 8,000 cases, mostly related to pneumonia and COPD [chronic obstructive pulmonary disease], he reported. While conventional positive pressure ventilation can effectively treat respiratory failure, it requires intubation, causing significant discomfort and often leading to complications. For acute respiratory failure, patients typically need to be intubated for 3 to 5 days; for complicated COPD, the hospitalization and intubation period could take weeks to months, said Chu. Highlighting the hazards of nosocomial infections, he warned, there is a high chance of bacteria from the hospital environment entering the lungs via the endotracheal tube, which can lead to life-threatening hospital-acquired pneumonia. The longer the period of hospitalization, the higher the chance of infection. Although invasive positive pressure ventilation is also possible at home, it is impractical for most patients. In the past, patients with severe chronic respiratory failure requir-
ing tracheostomy would need a complex machine and technical support at home, effectively turning their home into a mini-ICU, he noted. Currently, NIV is the first-line treatment option for acute respiratory failure in COPD, minimizing the need for intubation. Patients with chronic respiratory failure can also benefit from NIV. A metaanalysis of multinational trials demonstrated that using NIV in COPD-related respiratory failure reduced the need for intubation by 58 percent and shortened hospital stay by 2 to 4 days. Importantly, there was a 59 percent reduction in mortality and 49 percent reduction in treatment failure, noted Chu. Home-based NIV setting is simple, involving a small device operated by pressing the on/off button. Caretakers can easily assist the patient to properly fit the face mask, he explained. Apart from improving respiratory function, NIV improves patients emotions and physical activities. Chu stressed that successful disease management with home-based NIV requires appropriate support and follow-up. Remote monitoring systems that detect abnormalities in patients condition and provide emergency support are now available. The Hong Kong Thoracic Society and the Hong Kong and Macau Chapter of the ACCP are committed to promoting the appropriate use of NIV, and will continue to provide training and support to medical workers and patients, so more patients can benefit from NIV in the future, he remarked.
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Hong Kong Focus

Case Study
Tocilizumab monotherapy in rheumatoid arthritis

Dr Lee Ka-Wing Gavin Consultant Rheumatologist Union Hospital Hong Kong Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease; without proper treatment it results in pain and joint destruction, which in turn have a major impact on patients functional performance and quality of life. With the advances in the understanding of RA, various effective therapeutic options have become available. Methotrexate (MTX) is the mainstay of treatment in most situations. However, patients may not respond to MTX or not tolerate it well. On the other hand, biologic disease modifying antirheumatic drugs (Bio-DMARDs) such as tumor necrosis factor antagonists (anti-TNF) have an established role in the management of moderate-to-severe RA. Nevertheless, in principle, anti-TNF agents should be used in combination with MTX, since trials evaluating anti-TNF monotherapy have shown that its efficacy is similar to MTX alone.1-3 The anti-IL6 receptor antagonist, tocilizumab (TCZ), has demonstrated a therapeutic benefit in the treatment of moderate-tosevere, active RA. In the AMBITION study, TCZ monotherapy therapy has shown a significantly better response than MTX monotherapy. (Figure) The safety profile of TCZ was also superior to MTX. In fact, the occurrence of elevated alanine transferase (ALT) levels was lower in the TCZ group than in the MTX group.4 Case 1 A 52-year-old teacher presented with bilateral wrist pain and swelling of finger joints since 2008. She was found to be positive for rheumatoid factor (RF). She was prescribed MTX, which resulted in dyspepsia, and she defaulted her treatment subsequently. She suffered a significant flare of disease in March 2011, and was given leflunomide (LEF). Her erythrocyte sedimentation rate (ESR) was brought down to 35 mm/hour. Unfortunately, she noticed significant alopecia related to the use of LEF. She stopped using LEF and consulted a TCM practitioner in October 2011, but her knee pain increased after 1 month of herbal treatment. In April 2012, she presented again to the rheumatology clinic with polyarthritis, which caused a limping gait and prominent joint stiffness, especially in the morning. Her ESR was 65 mm/hour and disease activity score of 28 joints (DAS-28) was 5.98. Musculoskeletal ultrasound (MSK USG) revealed the presence of active synovitis in her knees and wrists. Bone erosion was evidenced in the right wrist. In view of her previous intolerance of both MTX and LEF, she was suggested to receive a Bio-
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Hong Kong Focus

left knee replacement surgery in May 2011, she had a significant flare of arthritis. At the same time, her liver function was deranged, in particular ALP. Therefore, LEF was withheld since the postoperative period. She had also used herbal medications for the treatment of RA. In August 2011, she presented in a wheelchair because of very active RA, with all joints of the 28-joint count swollen and tender. ESR was 70 mm/hour, and DAS-28 was 8.17. As she was concerned about taking MTX or LEF again, she was given TCZ 8 mg/kg. After the first infusion, her pain was better controlled, and she was able to walk unaided at home slowly and prepare simple meals for herself. After four monthly infusions of TCZ, her ESR was normalized, and she was able to go outdoors by herself. Discussion The two cases described above illustrate some of the limitations of traditional DMARDs: Many patients either do not respond to these medications or cannot tolerate them. TCZ monotherapy offers a therapeutic advantage when compared head-to-head with MTX monotherapy. Its effectiveness in controlling severe RA and its fast onset of action can potentially have a major positive impact on patients functional status and quality of life. TCZ is an option for those patients who, due to various reasons, need to consider the use of monotherapy in the treatment of moderate-to-severe, active RA.
DMARD, and was started on TCZ 8 mg/kg. At 1-month follow-up, she had a significant improvement in pain and the ESR dropped to 5 mm/hour. Although the number of swollen joints was static, the swelling had decreased. Case 2 A 57-year-old lady suffered from RA for more than 20 years, and underwent C1-2 spinal fusion in 1998 and right knee replacement in November 2010. She was treated with MTX in the past with unsatisfactory response; cyclosporine was also tried but resulted in gum hypertrophy. Eventually, she was stabilized on LEF. However, after her
Figure A) Proportion of methotrexate-nave patients achieving ACR20, ACR50 and ACR70 responses at week 24 (ITT population)
Methotrexate Tocilizumab
B) Time course for achievement of ACR20, ACR50 and ACR70 responses during 24 weeks of treatment with tocilizumab or methotrexate (ITT population)
ate ab
ACR = American College of Rheumatology; ACR 20/50/70 = percent improvement by ACR criteria; ITT = intention to treat Adapted from Ann Reum Dis 2010;69:88-96.
References 1. Arthritis Rheum 2006;54:26-37. 2. N Engl J Med 2000;343:15861593. 3. Lancet 2004;363:675-681. 4. Ann Rheum Dis 2010;69:88-96.
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July 2012
Hong Kong Focus
Adopting a proactive approach in atopic dermatitis

Christina Lau
proactive approach focusing on longterm skin barrier repair is important in treatment of atopic dermatitis, as skin barrier dysfunction is now known to be a primary abnormality in the condition affecting about 15-20 percent of Asians. Skin barrier dysfunction is a primary event in the development of atopic dermatitis. Different phenotypes of the disease seen at the clinic are the result of interaction between the skin barrier and environmental factors, said Dr. Yoke-Chin Giam of the National Skin Center, Singapore, at the Hong Kong Society of Dermatology & Venereology Annual Scientific Meeting 2012. While skin barrier dysfunction can be triggered by excessive production of proteases, changes in stratum corneum pH level, house dust mite, soaps and detergents, Staphylococcus aureus infection, topical steroids, trauma or scratching, or release of cells with structural mimicry of house dust mite, recent studies highlight a strong association between filaggrin (FLG) gene mutations and atopic dermatitis in both Asian and European populations. FLG is one of the most important genes involved in the production of a good skin barrier. Loss-of-function [null] mutations in the gene contribute to pH changes, dehydration, and colonization of the skin by S aureus, which is found in >90 percent of atopic dermatitis patients and contributes to allergic sensitization and inflammation, said Giam.
Recent research by Giam and colleagues suggests that FLG-null mutations are strongly associated with atopic dermatitis as well as increased severity of the condition in Singaporean Chinese patients. [Br J Dermatol 2011;165:106-114] In these patients, there is also a novel association between FLG-null mutations and increased susceptibility to recurrent bacterial skin infection. [Br J Dermatol 2012;166:200-203] To treat atopic dermatitis, clinicians should adopt a proactive approach focusing on long-term repair of the defective skin barrier and prevention of flares, she stressed. In patients with atopic dermatitis, even non-
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important to provide patients with written action plans in simple language, which improves adherence to treatment. This also helps parents decide when milder, safer medications are appropriate and when more potent, potentially risky medications are necessary. For adults and children older than 6 months with mild-to-moderate atopic dermatitis, a non-steroidal anti-inflammatory emollient cream [Atopiclair] has been shown effective in six randomized, double-blind, vehicle-controlled trials. It has also demonstrated an anti-pruritic effect in adult patients, said Dr. Mauro Barbareschi of the University of Milan, Italy. Main constituents of the cream are glycyrrhetinic acid, telmesteine, and Vitis vinifera extracts. It contains no parabens, peanut oil, perfumes and proteins.
lesional, normal-looking skin is characterized by a barrier defect and underlying subclinical eczematous reaction. Thus, it is important to treat both the eczema flare and the normallooking skin. For non-lesional skin in remission, Giam advocates barrier repair with physiologic emollients. Ceramides are the dominant [40-50 percent] lipid on an intact skin barrier. Emollients containing ceramides alleviate childhood atopic dermatitis by restoring barrier lipids, she said. Other physiological ingredients include natural moisturizing factor [NMF] and glycerin. While reactive treatment with topical steroids is required for eczema flares, a stepdown regimen should be adopted once the skin is in remission, stressed Giam. Its also
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July 2012
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Advances in Medicine (AIM)*, 2-3 June 2012 Naomi Rodrig reports
Chronic chest pain evaluation: High-tech or low-tech?

s novel sophisticated modalities for diagnosing coronary artery disease (CAD) become available, physicians should consider their benefits vs risks, as well as applicability in clinical practice, suggested to Dr. Alex Lee, who discussed the pros and cons of functional stress testing vs computed tomography angiogram (CTA). Intuitively, the most accurate way to diagnose CAD is by direct visualization of coronary atherosclerosis with invasive coronary angiography (ICA). However, ICA is not used routinely as first-line test because it is invasive, costly and risky, said Lee, of CUHKs Department of Medicine and Therapeutics. Moreover, anatomic measures of atherosclerosis have limited value in assessing the physiologic implications of the findings. For example, the percentage of stenosis is only a modest surrogate for functional abnormalities. Physiologic factors that affect myocardial perfusion, such as microvascular resistance or vasomotor tone, are also not evaluated by anatomic imaging. According to Lee, randomized trials demonstrated that physiologic approaches to risk stratification and guidance of treatment were superior to anatomic approaches in terms of clinical outcomes and cost effectiveness. Therefore, CAD diagnosis has focused on the detection of physiologic manifestations of myocardial ischemia by functional stress testing rather than anatomic evidence of coronary lesions. ICA has been reserved for confirmation in high-risk patients who may
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conjunction with exercise stress improves the diagnostic accuracy and provides additional prognostic information. Lee suggested that CTA may be particularly helpful in low-risk patients with equivocal results on functional imaging, because a normal CTA is reassuring and may avoid unnecessary invasive investigations in many patients. If CTA demonstrates coronary atherosclerosis, initiation of medical therapy should be strongly considered. The need for revascularization depends on the extent of myocardial damage, left ventricular function and the severity of symptoms. However, a CTA showing intermediate lesions or equivocal result may increase the number of unnecessary revascularizations, he warned. Given that CTA is not without risk (due to radiation and contrast nephrotoxicity), he suggested that CTA imaging is unlikely to replace ICA anytime soon. Most importantly, implementation of new technology however attractive should translate into improved patient outcomes, he argued.
potentially benefit from revascularization, he noted. The recent introduction of multidetector CTA, which enables noninvasive, high-resolution imaging of the coronary arteries, has prompted a re-evaluation, challenging the superiority of the functional approach to diagnosing CAD. While CTA has excellent negative predictive power in excluding CAD, its positive predictive value is limited in elderly and calcified vessels even with state-of-the-art equipment, pointed out Lee. I believe that functional stress test should still be the initial investigation for most patients, as it provides physiologic information about ischemia, indicating whether the patients chronic chest pain is indeed due to CAD. Exercise stress testing is the most widely used method, but a substantial proportion of patients can perform only submaximal exercise stress testing due to various limitations, and the test is often inconclusive. Hence, the addition of myocardial perfusion imaging in
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Advances in Medicine (AIM)*, 2-3 June 2012 Naomi Rodrig reports
New hope for Parkinsons patients
linical trials in Parkinsons disease (PD) focusing on drugs with disease-modifying effects suggest that early treatment with rasagiline may offer neuroprotection and delay disease progression, reported Professor Vincent Mok of the Division of Neurology, CUHK. According to Mok, PD is the second most common neurodegenerative disease after Alzheimers. In Hong Kong, the prevalence of PD is about 0.189 percent, with some 13,000 people diagnosed with the disease, he said. Although it is less common than Alzheimers disease, the mean age of PD onset is 60 years, which is about 15 years younger than for Alzheimers. Therefore, a treatment that can slow down disease progression will be extremely important. He noted that many clinical studies aiming at prevention of disease progression have been conducted in the past few decades. But it is not until recently that the ADAGIO [Attenuation of Disease progression with Azilect Given Once-daily] study showed positive results in this respect, Mok noted. [N Engl J Med 2009;361:1268-1278] ADAGIO was a randomized, multi-center, double-blind, placebo-controlled study prospectively examining rasagilines potential disease-modifying effects in 1,176 patients with early, untreated PD. Patients from 129 centers in 14 countries were randomized to initiate treatment for 72 weeks with rasagiline 1 mg/day or 2 mg/day, or to initiate treatment for 36 weeks with a placebo followed by 36 weeks of rasagiline 1 mg/day or 2 mg/
A Lewy body in a brain cell of the substantia nigra in Parkinsons disease. Brown color indicates positive immunohistochemistry staining for alphasynuclein
day. The prospective delayed-start study design was specifically developed to evaluate the possibility of a disease-modifying effect, he pointed out. The primary analysis included three hierarchical endpoints based on total scores in the Unified Parkinsons Disease Rating Scale (UPDRS). Rasagiline 1 mg/day early-start met all endpoints of the primary analysis: less deterioration in UPDRS score than placebo between weeks 12 and 36; less worsening than delayed-start in UPDRS score between baseline and week 72, despite being on the same medication for the last 9 months; and non-inferiority to delayed-start in rate of deterioration between weeks 48 and 72. Patients who received rasagiline 1 mg/day at the start of the study, experienced superior benefit over 18 months compared with the delayed-start group which started the same treatment 9 months
20
July 2012
Hong Kong Focus

the other reported his gait was steadier. They both didnt have any side effects. Hence, good tolerability is a favorable point for this drug. Additional results and post-hoc analyses of the ADAGIO study published last year showed that rasagiline delayed the need for symptomatic antiparkinsonian drugs. Furthermore, at week 72, patients in the earlystart group who received rasagiline 1 mg/ day had scored better on the activities of daily living (ADL) subscores than those in the delayed-start group. [Lancet Neurology 2011;10:415-423]
later. This supports a possible diseasemodifying effect and the possibility that early treatment with rasagiline may slow the development of disability, commented Mok. It provides new hope for PD sufferers, in particular those whose disease starts at a relatively young age. He noted that rasagiline was registered in Hong Kong less than 1 year ago. To date, I had prescribed it to only two patients, he told Medical Tribune. So far, the patients had slight, yet apparent, improvements after 2 weeks of usage. One patient walked faster and had less mask-like face expression, while
21
July 2012
Hong Kong Focus
Survey: High burnout rates among HA doctors

Naomi Rodrig
more likely to be on call at the hospital than at home. Doctors at this stage of personal development were experiencing changes in their social roles. Many had just married and some might have had children. These personal psychosocial changes were often coupled with the need to sit for professional examinations and strike a balance between professional training, clinical duties, career advancement and family ties, the authors wrote, explaining why the most junior physicians appeared to be less susceptible to high burnout. Despite the heavy burden, the median sick leave taken by high-burnout doctors was only 1 day during the past year, further underscoring the stressful environment and high workload in HA hospitals. Feeling their work was undervalued, excessive stress due to high workload, and poor job security were cited as the main stressors contributing to high burnout. Younger age and shift work were identified as independent risk factors associated with high burnout. Its hardly surprising that 52.2 percent of high-burnout doctors were dissatisfied or very dissatisfied with their jobs. Alarmingly, nearly 10 percent of this group had suicidal thoughts although none had attempted suicide. Stressors identified in this study should be addressed, so as to improve job satisfaction, concluded the authors, suggesting that workshops to develop stress-coping strategies may be useful.
hile burnout due to stress and long working hours is common in the medical profession, a recent survey revealed that local doctors working at public hospitals are particularly prone to work-related exhaustion. [Hong Kong Med J 2012;18:186-192] Burnout defined as exhaustion resulting from excessive demands on energy and resources includes features of emotional exhaustion (EE), depersonalization (DP) and a reduced sense of personal accomplishment (PA). A combination of the three is considered high burnout. The survey included a random sample of 1,000 doctors from the public sector, using a self-administered, standard questionnaire for burnout assessment. A total of 226 valid questionnaires were analyzed, 98.7 percent of them from doctors employed in the Hospital Authority (HA). Overall, 71 respondents (31.4 percent) satisfied the criteria for high burnout, vs 10 and 28 percent reported in USA and New Zealand surveys, respectively. [Acad Med 2007;82:596601; Intern Med J 2005;35:272-278] High-burnout doctors were younger, having worked for a median of 8.5 years. Half of them were still undergoing specialist training and more than one third worked shifts. While their total weekly and weekend working hours did not differ significantly from other respondents, they were
22 HKMF Meeting Higlights
DPP-4 inhibitors: Looking beyond glycemic control

Hypoglycemia is a common side effect of conventional antidiabetic agents. Clinical evidence suggests that hypoglycemia may potentially increase the risk of cardiovascular (CV) events, especially in type 2 diabetes mellitus (T2DM) patients with pre-existing CV disease. At the recent 17th Hong Kong Medical Forum (HKMF), Professor Richard OBrien of the University of Melbourne, Australia, discussed the practical benefits of dipeptidyl-peptidase-4 (DPP-4) inhibitors such as sitagliptin (Januvia), focusing on their renal- and cardio-protective effects. Prof. OBrien
Impact of glycemic control on CV complications Recent clinical trials that evaluated the possible role of hypoglycemia on intensive antidiabetic therapy as a risk factor for CV events found that it was associated with a prolongation of QT interval. A prolonged QT interval can cause arrhythmias and lead to death. Increases in blood coaguability and inflammatory markers may also occur in response to hypoglycemia, explained OBrien. [ Circulation 2011;123:342-348; J Intern Med 1999;246:299-307] Conventional therapy shows good glucose control and a decrease in microvascular complications, but a disappointing reduction in macrovascular complications, he noted. Furthermore, results of the ACCORD (Action to Control CV Risk in Diabetes) trial showed that the use of intensive antidiabetic therapy (incorporating thiazolidinediones, sulfonylureas [SUs], metformin, and insulin) to target normal glycated hemoglobin (HbA1c) levels increased mortality and did not significantly reduce major CV events as compared with standard therapy. [N Engl J Med 2008;358: 2545-2559] A Danish nationwide study also showed
that compared with metformin, most first- and second-generation SUs increased mortality and CV risk. A possible reason is that SUs have been linked to interference with the protective effect of ischemic pre-conditioning of the heart. [Eur Heart J 2011;32:1900-1908; Heart 2004;90:9-12] This is a concern with SUs, and it may be better to avoid drugs that cause hypoglycemia in highrisk patients, remarked OBrien. Sitagliptin in T2DM therapy DPP-4 inhibitors comprise a group of chemically diverse compounds which improve hyperglycemia by regulating levels of the gastrointestinal hormone, glucagon-like peptide (GLP)-1. They have been shown to reduce fasting and postprandial blood glucose, and HbA1c levels in a glucose-dependent manner, with minimal risk of hypoglycemia or weight gain. [Diabetes Obes Metab 2011;13:7-18] Sitagliptin is a highly selective DPP-4 inhibitor indicated for the treatment of T2DM either as monotherapy or in combination with metformin and/or SUs or thiazolidinediones in patients poorly controlled on the maximal doses of these drugs. It can also be used with glitazone, acarbose, and insulin. [Acta Biomed 2008;79:184-191]

Therapeutic efficacy Sitagliptin reduces HbA1c by 0.6-0.8 percent from a baseline of about 8.0 percent. [Diabetologia 2006;49:2564-2571] The data showed that treatment with sitagliptin and metformin as initial combination therapy or sitagliptin as monotherapy provided sustained improvements in glycemic control over 2 years in patients with T2DM and inadequate glycemic control (HbA1c 7.5-11 percent) on diet and exercise. In a recent study in patients with T2DM and chronic renal insufficiency who had inadequate glycemic control, sitagliptin (50 mg once daily for patients with moderate renal insufficiency and 25 mg once daily for patients with severe renal insufficiency) and glipizide (2.5 mg once daily) produced similarly clinically meaningful improvements in glycemic control. Sitagliptintreated patients had a significantly lower incidence of symptomatic hypoglycemia-related adverse effects vs the glipizide group, and a decrease in body weight compared with an increase in body weight with glipizide. (Figure 1) [Proc EASD 2011] Sitagliptin as add-on to insulin In a 24-week, randomized, active-competitor study, subjects using insulin therapy with uncontrolled T2DM (HbA1c 7.5-11 percent) were randomized to receive add-on sitagliptin (100 mg daily, n = 70) or escalating doses of insulin (10 percent at week 12 and 10 percent at week 24, n = 70) while continuing other medications. Interestingly, compared to the insulin-increasing arm, addition of sitagliptin to basal insulin was more effective in lowering HbA1c, and was associated with less hypoglycemia, remarked OBrien. (Figure 2) Sitagliptin resulted in no weight gain, vs 1.2 kg on average in the insulin-escalating group. Given these benefits, addition of sitagliptin to basal insulin may be considered as a potential clinical strategy in uncontrolled T2DM. [Diabetes Obes Metab 2012. Mar 24(Epub ahead of print)] Cardiovascular and renal effects of DPP-4 inhibitors Data from animal and in vitro studies suggest that GLP-1 may have cardioprotective, anti-atherogenic effects and improve myocardial and endothelial function. [J Cardiovasc Pharmacol 2011;58:157-166; Diabetes 2010;59:1063-1073] Reductions in myocardial infarct size and improvements in cardiac function have been reported in animal models with increased GLP-1 levels in the presence of a DPP-4 inhibitor. [Diabetes 2005;54:146-151] A trial including 14 patients with coronary artery disease was carried out to assess the hypothesis that increasing the plasma concentration of GLP-1 by sitagliptin (single dose of 100 mg orally 2 hours before 75 mg oral glucose) would protect the heart from ischemic left ventricular (LV) dysfunction during dobutamine stress echocardiography. The results showed that sitagliptin improves
18 16 14
p=0.001
17
Sitagliptin (n=210) Glipizide (n=212)
Patients (%)
Figure 1. Sitagliptin vs glipizide in T2DM patients with chronic renal insufficiency: 12 Adverse events 10
8 18 6 16 4 14 2 12 0 10
8 6 4 2 0
Abdominal pain Diarrhea
p=0.570 p=0.849
5.2 5.7
p=0.025
p=0.001 6.2
17
Sitagliptin (n=210)
2.8 1.4 0
Patients (%)
2.4
3.3
2.4 0
p=0.568
Glipizide (n=212)
1.4 1.4
2.4
0.5 0.9 Vomiting
Abdominal pain
p=0.570
Diarrhea p=0.849
5.2 5.7
Nausea
p=0.025
Symptomatic Severe Required hypoglycemia hypoglycemia non-medical 6.2 assistance

2.8 1.4 0 Symptomatic Severe Required hypoglycemia hypoglycemia non-medical assistance 1.4
Required medical assistance

1.4 2.4
2.4
3.3
2.4 0 Nausea
p=0.568
0.5 0.9 Vomiting
Required medical assistance
T2DM = type 2 diabetes mellitus
Adapted from Proc EASD 2011.
Figure 2. Add-on sitagliptin vs increasing insulin dose in insulin-treated patients

Sitagliplin adding 10 Insulin increasing 20 *
Event / person-year Event / person-year
Event / person-year Event / person-year
HbA1c
20 15 10 5 20 0 15
10 5 0
HbA1c (%)
9 8
10 7
15 10 Insulin increasing 5 20 * 0 15
10 5 0
Sitagliplin adding
Sitagliptin HbA Insulin

1c
HbA1c (%)
Time (weeks)
12
24
Hypoglycemia
*p<0.05 vs sitagliptin
*p<0.05 vs insulin titration; * p<0.05 vs baseline * 8
Severe hypoglycemia
*
Sitagliptin Insulin Adapted from 7 Diabetes, Obesity and Metabolism, E pub. doi:10.1111/j.1463-1326.2012.01600.x April 2012. 0
Time (weeks)
12
24
Hypoglycemia
*p<0.05 vs sitagliptin
Severe hypoglycemia
*p<0.05 vs insulin titration; p<0.05 vs baseline

global and regional LV performance in response to stress and mitigates post-ischemic stunning. (Figure 3) [Circ Cardiovasc Imaging 2010;3:195-201] Weight gain and hypoglycemia are both associated with risk of vascular events and death. [N Engl J Med 363:1410-1418] Since sitagliptin is weight-neutral and carries a low risk for hypoglycemia, it is a suitable candidate for overweight patients who under conventional therapy suffer from hypoglycemic episodes. A Japanese study found that sitagliptin reduces albuminuria through its antidiabetic and anti-inflammatory actions without decreasing the estimated glomerular filtration rate. Significant reduction in blood pressure with sitagliptin in this study might have contributed to some extent to lowering urinary albumin secretion. [Endocr J 2011;58:69-73] Comparison with SUs SUs have potentially deleterious cellular effects on the CV system and have been shown in some studies to increase the risk of CV events. [Diabetes Care 2004;27:553-591] Conversely, there appears to be a trend of decreased CV events in patients treated with DPP-4 inhibitors, remarked OBrien. Results from three randomized, doubleblind clinical trials comparing sitagliptin and a SU were pooled. They included two add-on to metformin trials (a 104-week trial vs glipizide, and a 30-week trial vs glimepiride), and one monotherapy trial (104 weeks, vs glipizide). Major adverse CV events were assessed, including ischemic events and CV deaths. The incidence of CV-related events and deaths was lower with sitagliptin relative to SU. [Proc IDF, 2011] We cannot discount the fact that severe hypoglycemia is not good for the heart, stressed OBrien.
Figure 3. DPP-4 inhibition with sitagliptin improves myocardial response to dobutamine stress and mitigates stunning
75 70 65 60 55
*p<0.001 vs control
Sitagliptin Control
50
Baseline
Peak stress
Recovery
Adapted from Circ Cardiovasc Imaging 2010;3:195-201.
Differences between DDP-4 inhibitors Sitagliptin was approved by the US FDA in 2006, followed by saxagliptin and linagliptin, while vildagliptin is approved in the EU. Rare cases of liver-enzyme elevation have been reported with vildagliptin; hence, it should not be used in patients with impaired liver function. Saxagliptin is associated with more drug-drug interactions than other DDP-4 inhibitors. Sitagliptin is the only DPP-4 inhibitor approved for use in patients with moderate to severe renal impairment, end-stage renal disease and those on dialysis in Hong Kong, Europe and the USA. For other DPP-4 inhibitors, referral to local prescribing information is advised. Conclusions Intensive control of blood glucose markedly reduces microvascular complications but has less effect on CV disease. DPP-4 inhibitors improve glucose homeostasis in a glucose-dependent manner, thus carrying a low risk of hypoglycemia. Sitagliptin treatment reduces fasting and postprandial blood glucose levels without causing hypoglycemia or weight gain. Sitagliptin has a favorable tolerability profile with minimal gastrointestinal adverse effects. Furthermore, it appears to have cardioprotective properties, thus offering additional potential CV benefits beyond glycemic control.
Evolving concepts in hepatitis C therapy

Recent advances in the field of hepatitis C are leading to a brighter outlook for patients with this chronic disease, especially in Asia. At the 17th Hong Kong Medical Forum (HKMF), Professor Man-Fung Yuen of the Department of Medicine, University of Hong Kong discussed favorable genetic variants affecting response to hepatitis C treatment, and their prevalence in Hong Kong. Professor Lindsay Mollison, Head of Hepatitis Service at the Fremantle Hospital and Health Service, Australia, addressed current and future treatment strategies for hepatitis C, highlighting the future potential of protease inhibitors.
IL28B polymorphisms and treatment response In 2009, three papers independently reported that genetic variations upstream of the human gene encoding interleukin 28B (IL28B) on chromosome 19 Prof. Yuen predicted response to therapy and viral clearance in hepatitis C. [Nature 2009;461:399-401; Nat Genet 2009;41:1105-1109; Nat Genet 2009;41:1100-1104] This important discovery has helped to explain the wide variation observed across ethnic groups in response to treatment with the current standard of care, ie, pegylated interferon alpha 2a or 2b (PegIntron, MSD) plus ribavirin (pegIFN+RBV). The most relevant single nucleotide polymorphism (SNP) upstream of the IL28B gene is rs12979860. For this SNP, the most favorable genotype is CC that is, a homozygous C allele. Conversely, a TT genotype is the least favorable. [Semin Liver Dis 2011;31:375-386] These human genotypes should not be confused with the hepatitis C virus (HCV) genotypes 1 to 6, which also affect response to therapy. Studies have shown that having a favorable IL28B polymorphism is the strongest baseline predictor of sustained virologic response (SVR) to pegIFN+RBV (odds ratio of
5.2 vs 2-3 for other factors such as viral load, fasting serum glucose or ethnicity). [Gastroenterology 2010;139:120-129] Achieving SVR is considered a surrogate for cure in hepatitis C. This is a very good example of genetics explaining why different patients have a different response to treatment, commented Yuen. Favorable C alleles are widespread in Asia The vast majority of hepatitis C patients in Hong Kong and other Asian countries carry C alleles (Table). [Nature 2009;461:798-801]This explains why Asians respond better to treatment, said Yuen. In the past, we thought that Asians responded better to the fixed dose of interferon and ribavirin therapy was because of their lower body weight. But in fact, IL28B explains why the Asian population has a more favorable response to this treatment than the Caucasian population. Predicting treatment success IL28B genotyping allows doctors to predict the likelihood of treatment success for a given patient. However, it is not always necessary to carry out genetic analyses, especially if the patient achieves a rapid virologic response (RVR; ie, negative HCV RNA after 4 weeks of treatment). Patients with RVR are likely to achieve SVR regardless of their IL28B genotype.

However, in HCV genotype 1 patients without RVR (the majority), IL28B type is important as 66 percent of those with CC genotype will eventually attain SVR with continued treatment vs only 24 percent of those with TT genotype. [Gastroenterology 2010;139:120-129] Yuen recommended checking IL28B genotype in patients without RVR, to help determine the subsequent treatment strategy. His team has found that IL28B also predicts response in HCV genotype 6, which is found only in Asia, and affects approximately one quarter of Hong Kong patients. [Am J Gastroenterol 2011;106:1007-1008] About half of Hong Kong patients are infected with genotype 1, and the remaining quarter carry genotype 2 or 3. [J Med Virol 2006;78:574581] Limitations of current treatments The aim of HCV treatment is to achieve SVR, as patients with SVR are no longer infectious. With SVR, liver fibrosis is likely to regress, and progression to cirProf. Mollison rhosis or hepatocellular carcinoma is unlikely. For the past decade, pegIFN+RBV has been the standard of care. Mollison explained that genotype 1 patients typically receive 48 weeks of therapy, and the SVR rates are approximately 40 percent. Genotype 2 and 3 patients receive 24 weeks of therapy and the SVR rates are about 80 percent. However, new drugs are now becoming available that can increase SVR rates and potentially shorten therapy duration. So even though weve had some pretty good success rates in the past, theyre probably going to get even better in the near future, he remarked.
Table. rs12979860 C allele frequency in worldwide populations
Population Region n C allele frequency (%)
Mbuti Pygmies Masai Yoruba Danish Hungarians Irish Russians Roman Jews Sardinians Kuwaitis Indians Cambodians Laotians Chinese, Taiwan Chinese, San Francisco Hakka Japanese Koreans Micronesians Samoans Papua New Guineans Pima, Mexico Mayans
Africa Africa Africa Europe Europe Europe Europe Europe Europe Southwest Asia South Asia Southeast Asia Southeast Asia East Asia East Asia East Asia East Asia East Asia Oceania Oceania Oceania North America North America
39 20 77 51 142 113 32 27 34 16 29 24 118 47 59 40 50 54 36 8 22 99 52
23.1 40.0 31.2 76.5 65.1 73.9 64.1 79.6 52.9 75.0 65.5 97.9 93.6 93.6 97.5 95.0 91.0 93.5 98.6 100.0 70.4 55.5 37.5
Direct antiviral agents Two new direct antiviral agents (DAAs), boceprevir (Victrelis, MSD) and telaprevir, have recently been approved in several countries, but are not yet available in Hong Kong. These protease inhibitors represent a significant treatment advance for genotype-1 hepatitis C patients, when added on to current pegIFN+RBV therapy, although they cannot be used as monotherapy. Recent studies have shown that protease inhibitors provide greatly improved SVR rates compared with pegIFN+RBV alone in both treatment-nave and treatmentexperienced patients. Treatment-experienced patients For difficult-to-treat patients who had previously failed or relapsed after pegIFN+RBV therapy, the addition of boceprevir tripled SVR rates from 21 percent with standard of care to around 60 percent. (Figure 1) [N Engl J Med 2011;364:1207-1217] Similar results have been found with the other DAA, telaprevir.

In treatment-experienced patients, in every case the rate of cure is higher with a protease inhibitor than without a protease inhibitor, noted Mollison. If were going to re-treat previous poor responders, we definitely get a great improvement by adding a DAA. Treatment-nave patients In treatment-nave genotype-1 patients, SVR rate reached nearly 70 percent in boceprevir-treated patients vs 40 percent with standard of care, representing a highly significant improvement. (Figure 2) Mollison observed that protease inhibitors appear to overcome the negative effects of an unfavorable IL28B genotype. They also offer the prospect of shorter therapy in responders. Patients most likely to benefit from DAA therapy are those without favorable IL28B polymorphisms, those with a higher baseline HCV load, or those without an RVR, he said. Future therapies Other promising agents under investigation include interferon , the NS5A inhibitor daclatasvir, the NS3/4 inhibitor anusaprevir, p<0.0001 and the 100 nucleotide polymerase inhibitor p<0.0001 PSI-7977. Combination therapy with some 80 66% 59% of these agents is yielding SVR rates ap60 proaching 40 100 percent, with the prospect of interferon-free regimens becoming 21% a 20 future possibility.
Patients with SVR (%)
0
alleles. In the future, adding a DAA such as boceprevir to pegIFN+RBV therapy could nearly double SVR rates and shorten therapy for responding patients. However, at the moment, if you have a good IL28B genotype and an RVR, then standard of care is still a good approach, suggested Mollison.
Figure 1. Adding boceprevir to pegIFN alfa-2b+RBV: Treatment-experienced genotype-1 patients

100 p<0.0001 p<0.0001 80 60 40 20 0
59%
66%
21%
BOC/RGT n=368
BOC/PR48 n=366
48P/R n=363
SVR = sustained virologic response. All patients received pegIFN+RBV for 4 weeks. Subsequently: BOC/RGT: boceprevir plus pegIFN+RBV for 32 weeks; patients with detectable HCV RNA at week 8 received placebo plus pegIFN+RBV for additional 12 weeks; BOC/PR48: boceprevir plus pegIFN+RBV for 44 weeks; 48P/R: placebo plus pegIFN+RBV for 44 weeks. Adapted from N Engl J Med 2011;364:1207-1217.
Figure 2. Adding boceprevir to pegIFN alfa-2b+RBV: Treatment-nave, non-black, genotype-1 patients

100 p<0.0001 p<0.0001 80 60 40 20 0
67%
68% 40%
Conclusions IL28B polymorphisms predict SVR in chronic hepatitis C infection, and most patients in Hong Kong have favorable SNP
BOC/RGT n=368
BOC/PR48 n=366
48P/R n=363
BOC/RGT n=368
BOC/PR48 n=366
48P/R n=363
SVR = sustained virologic response. All patients received pegIFN+RBV for 4 weeks. Subsequently: BOC/RGT: boceprevir plus pegIFN+RBV for 24 weeks; patients with detectable HCV RNA between weeks 8 and 24 received placebo plus pegIFN+RBV for additional 20 weeks; BOC/PR48: boceprevir plus pegIFN+RBV for 44 weeks; 48P/R: placebo plus pegIFN+RBV for 44 weeks. Adapted from N Engl J Med 2011;364:1195-1206.
Role of a novel continuous erythropoietin receptor activator in diabetes-related renal anemia

Chronic kidney disease (CKD) is a common complication associated with diabetes that leads to cardiovascular (CV) events. Anemia, a clinical manifestation of CKD, is often underestimated, and is a cause for diminished health-related quality of life. Correction of anemia with erythropoietin-stimulating agents (ESAs) has been shown to improve survival rates and is the standard therapy for renal-anemia patients. At the 17th Hong Kong Medical Forum (HKMF), Professor Danilo Fliser of the Department of Internal Medicine, Saarland University Medical Center, Germany, discussed the benefits of methoxy polyethylene glycol-epoetin beta (MPG-EPO) (Mircera, Roche), a novel continuous erythropoietin receptor activator (CERA), for maintenance of stable hemoglobin (Hb) levels in CKD patients. Prof. Fliser
Renal anemia in diabetic patients: Need for early intervention Heart failure is a common cause of kidney problems and is commonly seen in diabetic patients. An important link between CKD and CV complications is anemia, said Fliser. The major causes of anemia in CKD patients are iron and erythropoietin deficiencies and hyporesponsiveness to the actions of erythropoietin. Evidence from clinical trials suggests that deficiency of erythropoietin increases the risk of CV morbidity and mortality. Anemia multiplies the risks of death due to cardiovascular disease (CVD) in diabetes and CKD patients, and its prevalence is higher in diabetic CKD patients than in non-diabetic CKD patients. [Diabetes Care 2009;32:13201326; Am Heart J 1997;133;703-712] In a study from Denmark in patients with type 2 diabetes, about 50 percent of those with stage III CKD and proteinuria were found to have anemia, said Fliser. The prevalence of anemia increased exponentially as renal function fell. (Figure 1) [Diabetologia 2006;49:1151-1157]
However, many patients develop anemia before being diagnosed with CKD. As renal disease often remains asymptomatic until estimated glomerular filtration rate falls well below 60 mL/ min/1.73 m2, CKD and its associated anemia is often under-recognized and undertreated. [Osteopath Med Prim Care 2007;1:14] Association between anemia and outcomes in CKD In patients with stage III or IV CKD who do not require dialysis, untreated anemia increases CV risk, hospitalization, fatigue, dyspnea, and allcause mortality, and diminishes quality of life. [Osteopath Med Prim Care 2007;1:14] The risks of CVD in CKD appear in the early stages before the onset of kidney failure. Left ventricular hypertrophy [LVH] and anemia are both highly prevalent during stages III and IV of CKD, said Fliser. A study that examined the risk of anemia and LVH on the outcomes in CKD showed that both are independent risk factors for CV events and mortality. In particular, anemia was associated with a significantly increased

risk of the composite outcome of MI, stroke and all-cause mortality [adjusted hazard ratio (HR), 1.51 vs no anemia]. CKD patients with anemia also had poorer outcomes following a cardiac event or stroke. (Figure 2) [J Am Soc Nephrol 2005;16:1803-1810] In patients with diabetic nephropathy, even mild anemia (Hb <13.8 g/dL) increases the risk of progression to end-stage renal disease (ESRD). While baseline Hb of 12.5-13.8 g/dL was associated with a HR of 2.36 for progression to ESRD, the HR increased substantially to 4.23 for baseline Hb <11.2 g/dL. [Kidney Int2004;66:1131-1138] These findings highlight the importance of early treatment of renal anemia to improve clinical outcomes. Interventional studies have established that Hb levels can be raised safely with erythropoietin, resulting in improved quality of life, delayed disease progression, and improved survival rates. [Adv Stud Med 2005;5:S715-S719] Benefits of MPG-EPO ESAs are the standard therapy for renal anemia, and are available in short- and long-acting formulations. All ESAs are effective in correcting renal anemia and increasing Hb levels, but the choice of agent should also take into account pharmacokinetics and pharmacodynamics, administration route, and appropriate use. [J Am Med Dir Assoc 2009;10:607-616; Oncologist 2011; 16:19-24] Guidelines of the Kidney Disease: Outcomes Quality Initiative (K/DOQI) and European Best Renal Practice (ERBP) recommend Hb targets of 11-12 g/dL in CKD patients with anemia. Importantly, both guidelines emphasized that attained Hb should not exceed 13 g/dL. [Am J Kidney Dis 2007;50:471-530] Convenient dosing Traditional ESAs have short half-lives and require frequent administration (up to 3 times a week), dose changes, and close monitoring of Hb concentration to maintain target Hb levels. MPG-EPO is structurally different from other ESAs, and provides stable and more constant Hb control than traditional ESAs with once-monthly dosing. This is made possible with MPG-EPOs low affinity for the erythropoietin receptor, which provides continuous stimulation, and its much longer half-life (approximately 130 hours) compared with all other ESAs. [Int J Nephrol Renovasc Dis 2012;5:53-60] The half-life of MPG-EPO is similar for both intravenous and subcutaneous administration. Thus, it has the potential to be just as potent given by either route of administration. [Clin J Am Soc Nephrol 2006;1:12111215] The recommended starting dose for ESA-nave patients is 0.6-0.8 g/kg, administered intravenously or subcutaneously once every 4 weeks to reach a Hb level >11 g/dL. Once the target Hb level is achieved, MPG-EPO is administered once monthly, as compared with a weekly dosing for other ESAs. Patients currently treated with an ESA can be converted to intravenous or subcutaneous MPG-EPO administered once a month. [MIRCERA Summary of Product Characteristics. F. Hoffmann-La Roche Ltd. 2007] Therapeutic efficacy Clinical evidence has demonstrated that MPG-EPO is practical, convenient and offers good control of Hb levels, regardless of the previous type of therapy or dosing frequency. [Curr Med Res Opin 2010;26:10831089] Phase III maintenance studies have

shown that MPG-EPO, administered every 2 or 4 weeks, is comparable to other ESAs in maintaining stable Hb levels over the evaluation period. Target hemoglobin levels were reached in a smooth, steady, and stable manner with MPG-EPO, said Fliser. Targets were achieved in up to 97.5 percent of patients not on dialysis treated with subcutaneous MPG-EPO and in up to 93.3 percent of patients on dialysis with intravenous MPGEPO. The dose for MPG-EPO patients not on dialysis was nearly half of that required for patients who were on dialysis, which shows that there was good control of anemia with this agent, added Fliser. The target levels were maintained over an extended period of time. [Lancet 2007;370:1415-1421; Clin J Am Soc Nephrol 2007;2:637-646; Nephrol Dial Transplant 2008;23:3654-3661; Am J Nephrol 2008;28:280-289] In the CORDATUS (Correction of Renal Anemia in CKD Patients with Subcutaneous Therapy) study of patients with stage III/IV CKD not on dialysis, 94.1 percent of those on once-monthly MPG-EPO achieved Hb response compared with 93.5 percent of patients on a conventional ESA. Patients treated with MPG-EPO showed a steady increase in Hb, with fewer patients overshooting the recommended Hb target of 12 g/dL during the first 8 weeks of treatment. [Nephrol Dial Transplant 2011;26:3980-3986] A new study is underway on stage III CKD patients with near-normal Hb levels of 11-14 g/dL, to determine whether early treatment with MPG-EPO protects against renal function decline, added Fliser. Safety MPG-EPO is generally well tolerated with no major safety concerns. Serious adverse events in clinical trials were mild to moderate
Figure 1. Anemia in CKD patients with diabetes
2258 patients with 2258 patients with type 2 diabetes mellitus type 2 diabetes mellitus 60 60 50 50 40 40 30 30 20 20 10 10 0 0
Prevalence anemia (%) Prevalence ofof anemia (%)
Creatinine clearance (mL/min/1.73 m2) Creatinine clearance (mL/min/1.73 m2)

CKD = chronic kidney disease; AER = albumin excretion rate Adapted from Diabetologia 2006;49:1151-1157.
<30 <30
3060 3060
6090 6090
>90 >90
<20 <20
Urinary AER Urinary AER (g/min) (g/min) >200 >200 20200 20200
Figure 2. Anemia in CKD patients and outcome

1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.1 0.0 0.1 0.0 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.1 0.0 0.1 0.0 0 0
Survival probability Survival probability
Anemia and CKD Anemia CKD Anemia and and no CKD No anemia and CKD Anemia and no CKD No CKD No anemia anemia and and no CKD No anemia and no CKD
Composite event Composite event
1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.1 0.0 0.1 0.0 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.1 0.0 0.1 0.0 0 0
MI / fatal CHD MI / fatal CHD
Stroke Stroke
All-cause mortality All-cause mortality
2 since 4 baseline 6 (years) 8 Time Time since baseline (years)
10 10
2 since 4 6 (years) 8 Time baseline Time since baseline (years)
10 10
CKD = chronic kidney disease; CHD = coronary heart disease
Adapted from J Am Soc Nephrol 2005;16:1803-1810.
and occurred in 37 percent of patients receiving MPG-EPO, compared with 40 percent of patients treated with traditional ESAs. [http://www.accessdata.fda.gov/drugsatfda_ docs/nda/2007/125164s000_ODMemo.pdf (Accessed May 22, 2012)] Conclusion Anemia associated with CKD is a common, often neglected complication of diabetes. MPG-EPO is the most advanced ESA currently available in the market. Subcutaneous or intravenous administration of MPG-EPO results in a smooth and steady increase in Hb levels. MPG-EPO has a major advantage over conventional ESAs as it allows simple, oncemonthly dosing. The agent thus provides a safe, effective and convenient option for the treatment of renal anemia.
31 AIM Meeting Higlights
Towards maximizing bronchodilation in COPD

While airflow limitation in chronic obstructive pulmonary disease (COPD) is caused by a confluence of different airway pathophysiologies, bronchodilation remains the mainstay of its management. At the 15th Advances in Medicine (AIM) conference organized by the Chinese University of Hong Kong, Professor James Donohue, Chairman of the Foundation of the American Thoracic Society, discussed the objectives and rationale of using bronchodilators in COPD management. He highlighted the mechanism of action and clinical benefits of indacaterol (Onbrez, Norvatis) a novel, once-daily, long-acting 2-agonist (LABA) which has demonstrated improvements in lung function and health status of COPD patients.
Prof. Donohue
Pathophysiology and consequences of COPD Airway smooth muscle contraction, increased cholinergic tone, bronchial hyperreactivity, loss of elastic recoil and dynamic hyperinflation are common pathophysiological processes that have been implicated in the development of COPD. COPD is characterized by limitation of expiratory airflow, believed to be caused predominantly by exposure to tobacco smoke, although other common environmental risk factors, such as charcoal smoke, biomass fuels and occupational exposure, may also be involved. COPD patients often experience dyspnea a direct result of airflow limitation, lung hyperinflation and gas trapping which ultimately leads to deterioration in patients health status due to the vicious cycle of decreased exercise tolerance, deconditioning and physical inactivity. In addition, COPD exacerbations cause further decline in lung function and have been associated with increased mortality risk. COPD management: GOLD guideline The 2011 revision of the Global initiative for chronic Obstructive Lung Disease (GOLD) guideline recommends bronchodilators as the backbone of COPD treatment, and
Figure 1. Onset of action: Indacaterol vs other LABAs

120
Airway lumen surface (% of maximum relaxation)
100 80 60 40 20 0 -20 -40

0 5 10
Albuterol Formoterol Indacaterol Salmeterol Time (minutes)
LABA = long-acting 2-agonist Adapted from Pharmacol Exp Ther 2008;324:270-275.
gh FEV1 (L)
considers them central for symptom relief and improving the patients exercise tolerance and health status, said Donohue. Initially, they are given on an as-needed basis to patients with mild disease who are just intermittently short of breath, but should be regularly administered to prevent or reduce Placebosymptoms. Open-label tiotrop The choiceIndacaterol of bronchodilator 150 g od treatments Indacaterol 300 1.55 includes 2-agonists, anticholinergics, the *** *** 1.50 ophylline, and 1.48 a combination of1.46 these *** 1.46 *** *** 1.44 1.45 drugs if 1.43 symptoms are not improved with 1.42
1.40 1.35 1.34

monotherapy. Long-acting, inhaled bronchodilators are the most convenient way of administration; once-daily formulations are better than twice-daily formulations most likely a result of improved treatment adherence by the patient, noted Donohue. Also, the use of combination therapy may improve efficacy and reduce adverse effects caused by higher dosages of monotherapy. [http://www.goldcopd. org/uploads/users/files/GOLD_Report_2011_ Feb21.pdf, Accessed June 18, 2012] Bronchodilators provide symptomatic relief of COPD by relaxing airway smooth muscles, which in turn decreases gas trapping and dynamic hyperinflation, thus improving forced expiratory volume in 1 second (FEV1). Other effects may include increased mucociliary clearance, improved cardiac output and airway/ alveolar mobilization, as well as central nervous system stimulation, added Donohue. Clinically, patients need to achieve reduced breathlessness, increased exercise tolerance and improved sleep quality to have significant improvements in healthrelated quality of life following bronchodilation. The frequency of acute exacerbations should also be reduced, he advised. [J Allergy Clin Immunol 2002;110(6 Suppl): S298-S303; Chest 2004;125:249-259; JAMA 2003;290:2301-2312] Indacaterol: A designer LABA Indacaterol is a novel LABA designed specifically for the physiological and clinical needs of bronchodilation in COPD. Compared with existing LABAs, it has sustained bronchodilatory effects over a 24-hour period to allow once-daily dosing. Indacaterol has a fast onset of action, and is proven to be clinically effective in reducing breathlessness, improving lung function, exercise tolerance and health-related quality of life. It is also safe and well tolerated, remarked Donohue. (Figure 1) [Br J Pharmacol 2008;155: 291-299; Pharmacol Exp Ther 2008;324:270-275] INHANCE: Effective once-daily bronchodilator for COPD patients INdacaterol vs tiotropium to Help Achieve New COPD treatment Excellence (INHANCE) was a two-stage study with an adaptive seamless design. In stage 1, patients were randomized to receive doubleblind indacaterol 75 g, 150 g, 300 g or 600 g once daily, formoterol 12 g twice daily, placebo, or open-label tiotropium 18 g once daily for two weeks. At the end of stage 1, the two most effective doses of indacaterol, the most efficacious active-control agent and the placebo were rolled over into stage 2, lasting up to week 26 from the initial start, to become a four-arm study. Additional patients were recruited and randomized among these treatment arms to complete the 26 week study. Fast onset of action Indacaterol is designed to have high intrinsic efficacy and a fast onset of action, explained Donohue. On day 1, once-daily indacaterol 150 g and 300 g increased FEV1 by 120 mL and 130 mL, respectively, within 5 minutes vs placebo, gradually increasing to 160 mL and 190 mL, respectively, at 1 hour. In patients receiving tiotropium 18 g once daily, the increase in FEV1 was lagging behind that of indacaterol starting from 50 mL at 5 minutes before gradually increasing to 120 mL at 1 hour. [Respir Res 2010;11:135] Other lung function improvements included significant and sustained increases in trough FEV1 over 26 weeks, without the development of drug tolerance. (Figure 2) Indacaterol was also significantly superior to salmeterol and formoterol,

and at least as effective as tiotropium, Donohue pointed out. [Am J Respir Crit Care Med 2010;182: 155-162] Clinical improvements Importantly, patients receiving indacaterol 300 g once daily experienced significant improvements in dyspnea vs placebo and tiotropium, with higher percentage of patients reporting clinically important changes, as measured by the transition dyspnea index (TDI) total score over a 12-week period (p<0.001 vs placebo; p<0.05 vs tiotropium). Other clinically meaningful outcomes included reduced dynamic hyperinflation during exercise, improved exercise endurance time, and improved quality of life as assessed by the St. Georges Respiratory Questionnaire. (Figure 3) [Am J Respir Crit Care Med 2010;182:155-162; COPD 2011;8:340-345] Safety Safety data from INHANCE revealed comparable incidence of any type of adverse events between the four study arms. Indacaterol has safety and tolerability profiles similar to that of placebo. [Am J Respir Crit Care Med 2010;182:155-162] No safety signals were identified despite reviewing the safety data of all 13 clinical trials involving indacaterol, stressed Donohue. [Int J Chron Obstruct Pulmon Dis 2011;6:477-492] Future of COPD management Going forward, in the next decade, many new products for COPD will become available, particularly once-a-day LABAs and long-acting muscarinic antagonists (LAMAs) both as monotherapies or as fixed-drug combinations. I would predict that within the next 2 years, the first breakthrough in COPD management is likely to come from the use of fixed combinations of LABAs and LAMAs, remarked Donohue. Also, prototypes of dual-ligand muscarinic antagonist2-agonist molecules designed to have the ability to react with both receptor classes are currently under testing, and have demonstrated promise in attenuating bronchial hyper-reactivity in COPD and asthma patients. In summary Once-daily indacaterol provides significant, consistent and clinically important improvements in lung function, dyspnea and health status at least comparable to, if not better than, tiotropium, salmeterol and formoterol, Donohue reiterated. It has demonstrated satisfactory safety and tolAlbuterol erability profiles in Formoterol different studies of up Indacaterol Albuterol Salmeterol Formoterol to a years duration, Indacaterol with overall incidence Time (minutes)Salmeterol and pattern of adverse events compaTime (minutes) rable with placebo and/or active controls in moderate-to-severe COPD patients.
120
lumen surface Airway Airway lumen surface (% of maximum relaxation) (% of maximum relaxation)
100 120 80 100 60 80 40 60 20
40 0 20 -20 -40 0 -40
-20 0
10
10
Figure 2. Indacaterol provided significant improvement in trough FEV1 over Placebo Open-label tiotropium 18 g od 26 weeks Indacaterol 150 g od Indacaterol 300 g od
1.55 1.50 1.55 1.45 1.50 1.40 1.45 1.35 1.40 1.30 1.35 1.25 1.30 1.20 1.25 *** *** Placebo Open-label tiotropium 18 g od *** 1.48 Indacaterol 150 g od Indacaterol 300 g od 1.46 1.46 *** *** *** 1.44 1.43 1.44 *** *** 1.42 *** *** 1.41 1.40 *** 1.48 1.46 1.46 *** *** *** 1.44 1.44 *** *** 1.34 1.43 1.42 1.40 1.41
Trough Trough FEV1 (L)FEV1 (L)
1.34
1.28
1.26
1.28
Day 2
Week 12
1.26
Week 26
1.20
Day 2
Week 12
Week 26
***p<0.001 vs placebo; p<0.05, p0.01, p<0.001 vs tiotropium; FEV1 = forced expiratory volume in 1 second; Trough = average of 23 h 10 min and 23 h 45 min post-dose values. Adapted from Am J Respir Crit Care Med 2010;182:155-162.
Figure 3. Indacaterol improved health-related quality of life (SGRQ)

SGRQ total score vs placebo at week 26
0 -0.5 SGRQ total score vs placebo at week 26 -1.0 0 -1.0 -1.5 -0.5 -2.0 -1.0 -2.5 -1.0 -2.4 -1.5 -3.0 ** -2.0 -3.5 -3.3 -2.5 -2.4 -4.0 * -3.0 ** -4.5 -3.5 -3.3 -4.0 Placebo * -4.5 Indacaterol 150 g od Improving Improving
Patients (%) with clinically important change (4 units) in SGRQ

80 60 80 40 60 20 40 0 20
Patients (%) with clinically important change (4 units) in SGRQ

45.0 44.9 *** 51.9 50.1
45.0
44.9
*** 51.9
50.1
Open-label tiotropium 18 g od 0 Indacaterol 300 g od
*p<0.001 vs placebo, **p<0.01 vs placebo, ***p<0.05 vs placebo, p0.01 vs open-label tiotropium; SGRQ = St. Georges Respiratory 150 g od Indacaterol 300 g od Questionnaire. A 4-unit change in Indacaterol SGRQ Total Score is considered to be clinically relevant. Adapted from Am J Respir Crit Care Med 2010;182:155-162 and Eur Respir J 2009;34:2028.
Placebo
Open-label tiotropium 18 g od
Optimizing LDL-C lowering with combination therapy in patients with high CV risk
Despite significant improvements in the lipid lowering efficacy of newer statins, patients at high-risk of cardiovascular (CV) events still commonly fail to achieve their low-density lipoprotein-cholesterol (LDL-C) targets. At the 15th Advances in Medicine (AIM) conference organized by the Chinese University of Hong Kong, Professor Alberto Corsini of the Department of Pharmacological and Biomolecular Sciences, University of Milan, Italy discussed the rationale and clinical evidence for achieving optimal LDL-C control with a combination of ezetimibe (Ezetrol, MSD) and statins. Prof. Corsini
Lowering LDL-C to reduce CV risk Results from a meta-analysis incorporating data from 170,000 patients in 26 randomized trials confirmed the efficacy and safety of intensive LDL-C lowering. Patients receiving statin therapy had significant risk reduction in all-cause and CV mortality vs the control group. Moreover, those receiving more intensive LDL-C lowering therapy were at lower CV risk vs patients on less intensive therapy. Across the analyzed trials, risk of all-cause mortality was reduced by 10 percent for each 1.0 mmol/L reduction in LDL-C. [Lancet 2010;376:1670-1681] Since 2004, dyslipidemia management guidelines in the US, Canada and Europe have recommended progressively lower LDL-C therapeutic targets for patients at high or very high risk of CV events, decreasing from 2.6 mmol/L to 1.8 mmol/L. In 2011, the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) reiterated the importance of LDL-C decrease by 50 percent as an alternative to absolute LDL-C target levels, said Corsini. Generally, dyslipidemia is managed by first-line statin monotherapy, followed, if
need, by second-line combination therapy of statin and another lipid lowering agent of different mechanism of action, such as ezetimibe or fibrates. [Circulation 2004;110:227239; Can J Cardiol 2009;25:567-579; Eur Heart J 2011;32:1769-1818] Challenges of LDL-C lowering in high CV risk patients Despite the proven LDL-C lowering efficacy of statins, lipid abnormalities persist in statin-treated patients particularly in patients with diabetes mellitus (DM), with or without metabolic syndrome; approximately 50 percent of those patients are not at their LDL-C target, emphasized Corsini. [Eur J Clin Pharmacol 2005;61:667674; JAMA 2007;297:177-186; Diabet Med 2011;28:1343-1351] Common factors affecting the LDL-C lowering efficacy in statin-treated patients can be classified into extrinsic and intrinsic factors. Poor tolerability due to lack of dose titration is the main extrinsic factor, whereas rates of cholesterol biosynthesis and absorption are the main contributing intrinsic factors, he explained.

Statin-associated adverse events are also a problem. In contrast with the low rates of adverse events reported in large phase III statin trials, myalgia is commonly encountered in routine clinical practice due to inappropriate dose titration, leading to poor patient adherence and therapy discontinuation, remarked Corsini. Although a substantial proportion of patients are unable achieve their LDL-C goals with statin monotherapy at the initial dose, dose doubling is not recommended due to its disproportionate risk of adverse events, including elevations of liver transaminase and creatine kinase, with concomitant hepatoxicity and myotoxicity. [Cardiovasc Drugs Ther 2005;19:403-414] Furthermore, a recent meta-analysis of randomized controlled trials revealed the association of high-dose statin therapy with increased risk of new-onset diabetes mellitus, leading the US FDA to expand its warning label to include the risk of new-onset diabetes for statins. [JAMA 2011;305:2556-2564; http:// www.fda.gov/Drugs/DrugSafety/ucm293101. htm, Accessed June 10, 2012] Synergistic effects of ezetimibe/statin in LDL-C lowering Intrinsic factors such as genetic mutations or polymorphisms have been shown to affect individuals response to statin therapy, resulting in large variability in the lipid lowering efficacy of statins, said Corsini. [Atherosclerosis 2001;158:183-193] In addition, different lipid lowering strategies have been shown to affect the rates of cholesterol biosynthesis and absorption differently; inhibition of cholesterol absorption is compensated with increased cholesterol synthesis and vice versa. Ezetimibes unique lipid lowering mechanism, which is different to that of statins,
Figure 1. Consistency of ezetimibe in coadministration studies
Lovastatin
0
Pravastatin Simvastatin Atorvastatin Co-administration

Pravastatin Simvastatin Atorvastatin Co-administration
Add-on study
Add-on study
LDL-C (mg/dL) at study end
20 40 60 80 100 120 140

0 20 40 60 80 100 120 140
Lovastatin
23% 21%
21%
23%
23%
19%
19%
23%
21%
21%
Statin alone
Statin + ezetimibe
Statin alone Statin + ezetimibe LDL-C = low-density lipoprotein-cholesterol Adapted from 1) J Am Coll Cardiol 2002;39(9 suppl B):430B; 2) J Am Coll Cardiol 2002;39(suppl B):139B; 3) J Am Coll Cardiol 2002;39(suppl A):226A; 4) J Am Coll Cardiol. 2002;39(5 suppl A):227A; 5) Am J Cardiol 2002;90(suppl):30K-43K.
Figure 2. Postprandial cholesterol, triglyceride and apoB-48 concentrations, and cholesterol:triglyceride ratio in chylomicrons
Chylomicrons
Cholesterol (mg/dL)
Chylomicrons AUC* ezetimibe + simvastatin placebo + simvastatin ezetimibe + simvastatin placebo + simvastatin
Triglycerides (mg/dL)
Cholesterol (mg/dL)
2 1 0 0
Triglycerides (mg/dL)
3 2 1 0 0
AUC*
AUC*
60 40 20 0
60 40 20
AUC*
*
2
*
4
*
0 2 4
*
6
Cholesterol / Triglycerides
0.12 0.08 0.04
*
6
ApoB-48 (mg/L)
* 0 0.16 0
0.12
*
2 4 6
Cholesterol / Triglycerides
0.12 0.08 0.04 0 0
0.16 0.08
ApoB-48 (mg/L)
* *
0 2
*
4
0.12 0.08 0.04 0
0.04 0 0 2
*
4 6
Time after meal (h)
Time after meal (h)

Adapted from Atherosclerosis 2011;217:142-148.
*p<0.05 AUC, postprandial area under curve
*
6
Time after meal (h)

*p<0.05
Time after meal (h)
provides the rationale for combining ezetimibe with statin. While statins inhibit cholesterol synthesis in the liver, ezetimibe inhibits dietary and biliary cholesterol absorption in the intestine. Thus, combining ezetimibe with statin results in an additive and syner25 Placebo gistic effect. Simvastatin + ezetimibe Years of follow-up 20 Rate reduction 17% Indeed, the addition of ezetimibe to 15 10 been shown to provide an added statins has 19 to 23 50percent LDL-C reduction vs statin 0 monotherapy, thus a 60 0 1 achieving 2 3 maximum 4 5 Years of follow-up Number at risk Placebo 4,620 4,204 3,849 3,469 2,566 1,269 percent reduction of LDL-C levels from baseSimvastatin + ezetimibe 4,650 4,271 3,939 3,546 2,655 1,265 line, he reported. (Figure 1) Subgroup analyses of baseline parameters revealed that combination therapy with ezetimibe/simvastatin was also effective in
25 20 15 10 50 0 Placebo Simvastatin + ezetimibe
Rate reduction 17%
Number at risk Placebo 4,620 Simvastatin + ezetimibe 4,650
4,204 4,271
3,849 3,939
3,469 3,546
2,566 2,655
1,269 1,265
0
*p<0.05
Time after meal (h)
Time after meal (h)

patients with DM, and resulted in significantly greater LDL-C reduction than with simvastatin alone. [Mayo Clin Proc 2004;79:620-629] Another study revealed that adding ezetimibe to simvastatin had a beneficial effect on the lipoprotein profiles of DM patients when challenged with a high-fat test meal, compared with those receiving simvastatin alone. Apart from a greater decrease in LDL-C, ezetimibe significantly decreased fasting and postprandial chylomicron lipid content, chylomicron postprandial apoB-48, and fasting and postprandial levels of very low density lipoprotein, intermediate density lipoprotein and LDL. (Figure 2) [Atherosclerosis 2011;217:142-148] The reduced availability of lipids from the intestine to the liver elicited by ezetimibe, together with decreased insulin resistance and reduced lipogenesis in the liver, are the basis for ezetimibes benefit on liver steatosis. [Annu Rev Physiol 2011;73:239-259] Liver steatosis is characterized by fat deposition in the liver and is a strong independent CV risk factor, especially in patients who are obese, and those with metabolic syndrome and/or type II DM. Combination therapy with ezetimibe/rosuvastatin also conferred additional benefits to patients with a history of vascular surgery through further decreases in LDL-C levels and reduction in all-cause mortality compared with rosuvastatin monotherapy. [J Cardiovasc Pharmacol Ther 2012. May 9 (Epub ahead of print)] The SHARP trial (Study of Heart and Renal Protection) also demonstrated the protective effects of ezetimibe/simvastatin in patients with chronic kidney disease, where the use of ezetimibe/simvastatin combination significantly reduced major atherosclerotic events by 17 percent vs placebo. (Figure 3) [Lancet 2011;377:2181-2192]
Figure 3. Effects of allocation to simvastatin plus ezetimibe versus placebo on major atherosclerotic events
25 20 15 10 50 0 0
Number at risk Placebo 4,620 Simvastatin + ezetimibe 4,650
Placebo Simvastatin + ezetimibe

Rate reduction 17%
1
4,204 4,271
Years of follow-up
3,849 3,939 3,469 3,546
4
2,566 2,655
5
1,269 1,265
Adapted from Lancet 2011;377:2181-2192.
Novel approaches to lowering LDL-C Beyond the ezetimibe/statin combination, emerging strategies for lowering LDL-C include pitavastatin, squalene synthase inhibitors, apoB-100 inhibitors, PCSK9 inhibitors, colesevelam, thyroid receptor agonists, microsomal triglyceride transfer protein inhibitors and cholesterol absorption inhibitors. In general, combination therapy should be considered and individualized depending on the patients lipoprotein profile. In addition to statins and ezetimibe, niacin and fibrates can also be considered for increasing high-density lipoproteincholesterol and decreasing triglyceride levels, respectively, suggested Corsini. Conclusion Combination lipid lowering therapy with ezetimibe plus statin is a powerful alternative for patients who are unable to achieve their LDL-C target on high-dose statin monotherapy, especially those at high CV risk. The ezetimibe/statin combination provides a complementary and synergistic mechanism of action, helping patients to achieve their LDL-C goals and reduce CV risks while minimizing the adverse effects associated with high-dose statin monotherapy.
37
July 2012
Hong Kong Focus

Hong Kong Events
Annual Scientific Meeting and Workshop Hong Kong Institute of Musculoskeletal Medicine 21/7-22/7
Info: UBM Medica Pacific Limited Tel: (852) 2155 8557 / 3153 4374 Fax: (852) 2559 6910 E-mail: meeting.hk@ubm.com www.hkimm.hk
12th Asian Conference on Clinical Pharmacy Department of Pharmacy, CUHK 7/7-9/7

Info: UBM Medica Pacific Limited Tel: (852) 2155 8557 / 3153 4374 Fax: (852) 2559 6910 E-mail: info@accp2012.org www.accp2012.org
Chinese Medicine in Geriatrics Hong Kong International Integrative Medicine Conference 2012 Hospital Authority; Hong Kong Association for Integration of Chinese-Western Medicine 7/7-8/7
Tel: (852) 2871 8898 E-mail: hkiic2012@hkam.org.hk
50th Anniversary Multidisciplinary Conference The Evolution and Revolution of Child Health in Hong Kong: Past, Present and the Future Hong Kong Pediatric Society; American Academy of Pediatrics; Hong Kong Pediatric Nurses Association
17/8-19/8 Tel: (852) 2871 8897 Fax: (852) 2871 8898 E-mail: HKPS@hkam.org.hk www.medicine.org.hk/hkps
2012 Conference of Asia Oceania Research Organization on Genital Infection and Neoplasia (AOGIN 2012) Department of Obstetrics and Gynecology, HKU 13/7-15/7
Info: PC Tour and Travel Tel: (852) 2734 3315 Fax: (852) 2367 3375 E-mail: conference@pctourshk.com www.ogshk.org/2011/AOGIN_2012.pdf
5th International Infection Control Conference Hong Kong Infection Control Nurses Association; HKU; Hong Kong College of Radiologists
24/8-26/8 Info: MV Destination Management Ltd. Tel: (852) 2735 8118 Fax: (852) 2735 8282 E-mail: hkicna@mvdmc.com www.mvdmc.com/hkicna/index.html
Hong Kong Surgical Forum Summer 2012 Department of Surgery, HKU 14/7
Tel: (852) 2819 9691 / 2819 9692 Fax: (852) 2818 9249 E-mail: hksf@hku.hk www.surgery.hku.hk/forum.php
International Association of Gerontology and Geriatrics (IAGG) Master Class on Aging International Association of Gerontology and Geriatrics (IAGG); Research Center of Heart, Brain, Hormone & Healthy Aging, HKU; Hong Kong Geriatrics Society
29/8-30/8 E-mail: hbha@hku.hk www.med.hku.hk/hbha/iaggmca2012/index.html
3rd Oncology Forum of Hong Kong Hong Kong College of Radiologists; Hong Kong Society of Clinical Oncology 21/7
Info: PC Tour and Travel Ms. Veronica Cheng Tel: (852) 2734 3312 / 2734 3315 Fax: (852) 2367 3375 / 2367 3375 E-mail: veronica@pctourshk.com www.hkcr.org
2012 FDI Annual World Dental Congress FDI World Dental Federation 29/8-1/9
Tel: (852) 2528 5327 Fax: (852) 2529 0755 E-mail: congress@fdiworldental.org www.fdiworldental.org
38
July 2012
Hong Kong Focus
HK College of Community Medicine Annual Scientific Meeting 2012 15/9

Tel: (852) 2871 8844 / 2871 8745 Fax: (852) 2580 7071 E-mail: yandy_hkccm@hkam.org.hk / hkccm@hkam.org.hk www.hkccm.org.hk/index.php
Update on Osteoporosis Management Osteoporosis Center, Queen Mary Hospital; Research Center of Heart, Brain, Hormone and Healthy Aging, HKU 16/9
Tel: (852) 2255 3577 Fax: (852) 2255 4176 E-mail: osteoctr@hku.hk www.medic.hku.hk/download/2012%20UOM%20flyer.pdf
Transcatheter Renal Denervation (TREND) 2012 Asia-Pacific cme4u GmbH Congresses, Meetings and Education 29/9
Tel: (49) 69 25 61 28 55 Fax: (49) 69 25 62 86 58 E-mail: info@cme4u.org / trend@cvcfrankfurt.de www.csi-trend.org
14th Diabetes and Cardiovascular Risk Factors East Meets West Symposium 1/10-2/10
Info: UBM Medica Pacific Limited Tel: (852) 2155 8557 / 3153 4374 Fax: (852) 2559 6910 E-mail: info@eastmeetswest.org.hk www.eastmeetswest.org.hk
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WWW.HIMSSASIAPAC.ORG/12
LINKING PEOPLE, POTENTIAL AND PROGRESS

On the week of the Singapore F1 we are holding HIMSS AsiaPac12. It is the one healthcare IT event dedicated to connecting people and information in new ways to increase patient care and safety, reduce healthcare costs and improve quality of life across the entire continuum of healthcare.
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39
July 2012
Conference Coverage
48th Annual Meeting of the American Society of Clinical Oncology, 1-5 June, Chicago, Illinois, US
Promising drug combination benefits HER2+ breast cancer patients

Radha Chitale
novel agent linking the antibody trastuzumab (Herceptin) to a potent chemotherapy drug improved progression free survival in women with HER2-positive (HER2+) metastatic breast cancer compared with standard therapy, according to interim results from the phase III EMILIA* trial. The new agent, called T-DM1, may also have positive implication for overall survival. T-DM1 is a brand new way of treating HER2+ breast cancer, said lead researcher Dr. Kimberly Blackwell, Duke University Medical Center in Durham, North Carolina, US. I think it is the first of many antibody drug conjugates to follow that will link a potent anti-cancer agent to the targeted delivery system of an antibody. The trial, supported by Genentech, included 978 women with confirmed HER2+ metastatic breast cancer who were on or had recently been treated with taxane and trastuzumab. Patients were randomized to infusions of the HER2 antibody trastuzumab linked to the microtubule inhibitor emtansine (trastuzumab emtansine, T-DM1) or oral lapatinib plus capecitabine. Median follow-up was just over 1 year for both groups. Median progression free survival improved 35 percent with T-DM1, 9.6 months versus 6.4 months with lapatinib plus capecitabine (P<0.0001). Overall survival at 1 and 2 years was 84.7 percent and 65.4 percent, respectively, in the T-DM1 group and 77 percent and 47.5 percent
in the lapatinib plus capecitabine group. Median overall survival was 23.3 months with standard therapy but was not reached in the trastuzumab group (P=0.0005). The novel trastuzumab emtansine combination appeared to be safe and well tolerated. Emtansine is too toxic to administer systemically and linking it to trastuzumab helps guide it to tumor cells with HER2 receptors. Fewer severe adverse events occurred in the T-DM1 group compared to the lapatinib group (40.8 percent and 50.0 percent, respectively) with thrombocytopenia and increased liver enzymes as the most common adverse events. T-DM1 really works in this patient population, said Dr. Louis Weiner, director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington, D.C., US, and noted the previously limited targeted therapy options for breast cancer patients with progressive disease. The improved survival is particularly notable since effective palliative treatment of metastatic breast cancer has rarely been associated with improved survival in a refractory setting, he said. Blackwell said the novel agent should offer important therapeutic options for HER2+metastatic breast cancer patients.
* EMILIA: An Open-Label Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine+Lapatinib in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer
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Radiation therapy in childhood increases breast cancer risk

Radha Chitale
dult survivors of childhood cancers treated with radiation therapy have an increased risk of breast cancer, similar to that of women who carry BRCA gene mutations, even if the radiation dose was low. Prior studies showed girls treated with radiation to the chest have increased risk of breast cancer, but lead researcher Dr. Chaya Moskowitz, Memorial Sloan-Kettering Cancer Center in New York City, New York, US, said the comparison to risk from BRCA gene mutations is unknown. The researchers compared 1,268 female 5-year cancer survivors from the Childhood Cancer Survivor Study (CCSS) and 4,570 first-degree female relatives of women with breast cancer from the Womens Environmental Cancer and Radiation Epidemiology (WECARE) to estimate the incidence of BRCA-1 and -2 carriers. The rate of breast cancer in the general public was 4 percent by age 50, according to analysis of the Surveillance, Epidemiology, and End Results (SEER) study. Among the WECARE cohort, 324 women were diagnosed with breast cancer by median age 55. Cumulative incidence of breast cancer was 31 percent among those with BRCA-1 mutations and 10 percent among those with BRCA-2 mutations.
In the CCSS cohort, 175 were diagnosed with breast cancer at median age 38 with a median 23 years lag until diagnosis. Median follow up of study participants was 26 years. The overall incidence of breast cancer was 24 percent among girls who survived any type of cancer but the incidence among Hodgkins lymphoma (HL) survivors was 30 percent by age 50, similar to that of women with BRCA-1 mutations. Moskowitz said the discrepancy could be the result of a larger area of the chest exposed to radiation during treatment for HL, which increases the risk of breast cancer. Typically, people who receive radiation doses of 20 Grays (Gy) or more are currently recommended for cancer screening. However, Moskowitz said it was remarkable that women treated for cancers other than HL with moderate doses of radiation (10-19 Gy) to large areas of the chest also have elevated risk of breast cancer similar to that of BRCA-2. These women are not currently recommended for screening but Moskowitz suggested they would benefit from breast cancer surveillance strategies as their risk is higher than previously recognized.
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Newer agents no better than paclitaxel as first-line breast cancer therapy

Elvira Manzano
wo relatively new drugs for patients with recurrent or metastatic breast cancer failed to beat old stand-by paclitaxel in a phase III cooperative group trial. Treatment with paclitaxel resulted in a longer median progression-free survival (PFS) of 10.6 months compared with 9.2 months and 7.6 months for novel nanoparticle albuminbound paclitaxel (nab-paclitaxel) and ixabepilone, respectively. Rates of peripheral neuropathy and hematologic toxicity were also higher with both agents than with paclitaxel. Neither weekly nab-paclitaxel nor ixabepilone is superior to weekly paclitaxel, said study author Dr. Hope Rugo, of the University of California, San Francisco, US. In combination with bevacizumab, weekly paclitaxel is the better tolerated drug. The study involved 799 patients with locally advanced or metastatic breast cancer and no prior chemotherapy randomized to nab-paclitaxel 150 mg/m2, ixabepilone 16 mg/ m2), or paclitaxel 90 mg/m2 (as a control) plus bevacizumab every 2 weeks. Each treatment cycle lasted for 3 weeks, followed by a 1-week break. The primary endpoint was PFS or time from randomization to disease progression or
death from any cause. Median follow-up period was 12 months. The study was powered to detect a hazard ratio of 1.36 (median PFS of 10 vs. 13.6 months). Ixabepilone was dropped earlier from the trial after it demonstrated significantly worse PFS. Our data showed that we should not simply assume that newer drugs are always better than the standard therapies for metastatic breast cancer, said Rugo. She explained that dosing schedules are constantly being examined and refined, new therapies tested, and molecular characteristics of tumors are looked at closely to determine the right treatment for the right patient, with least toxicities. However, she said nab-paclitaxel may be a useful alternative in patients who cannot tolerate paclitaxel or in a setting where paclitaxel is not readily available. The US Food and Drug Administration in November 2011 revoked bevacizumabs conditional approval as a treatment for metastatic breast cancer because of potentially serious side effects such as high blood pressure and hemorrhage. At that time, enrolment for the trial, called CALGB 40502/NCCTG N063H, had already started.
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Afatinib delays progression in advanced lung cancer

Christina Lau
fatinib, an investigational drug that irreversibly blocks EGFR (ErbB1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4), significantly extended progression-free survival (PFS) vs the pemetrexed/cisplatin combination in LUX-Lung3 the largest and most robust phase III trial so far in EGFR mutation positive advanced lung adenocarcinoma. The oral pan-ErbB inhibitor was particularly beneficial for patients with deletion 19 or L858R common mutations that together accounted for 89 percent of all EGFR mutations in the trial. Unlike reversible EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib, afatanib blocks the entire ErbB family of receptors permanently, said lead author Dr. James Yang of the National Taiwan University Hospital. While gefitinib and erlotinib has demonstrated significant benefit vs firstline chemotherapy, LUX-Lung3 is the first trial in EGFR mutation positive lung cancer to use pemetrexed/cisplatin as a chemotherapy comparator. The global trial included 345 treatment-nave patients from 25 countries who had stage IIIB (wet) or IV disease (median age, 61 years; ECOG performance status, 0-1; East Asians, 72 percent; never-smokers, 68 percent). Patients were randomized 2:1 to receive afatinib (40 mg) daily or pemetrexed (500 mg/m2) plus
cisplatin (75 mg/m2) q21d until progression. The trial met its primary endpoint of PFS. After a median follow-up of 8 months, patients receiving afatinib had a significant 4.2-month improvement in PFS. Median PFS was 11.1 months with afatinib vs. 6.9 months with pemetrexed/cisplatin [hazard ratio (HR) 0.58; P=0.0004], Yang reported. The 12-month PFS rate was 47 vs. 22 percent. Importantly, the PFS benefit of afatanib was consistent in all relevant subgroups, including gender, age at baseline, race (Asian or non-Asian), baseline ECOG performance status, and smoking history (never smoked, or smoked <15 pack-years and stopped >1 year). The benefit of afatinib was even greater in patients with deletion 19 or L858R [N=308], he continued. In these patients, afatinib doubled PFS to 13.6 months vs. 6.9 months with pemetrexed/cisplatin [HR 0.47; P<0.0001]. PFS rate at 12 months was 51 vs. 21 percent. Patients treated with afatinib also had a significantly higher objective response rate (56.1 vs. 22.6 percent with pemetrexed/cisplatin; P<0.001), a longer duration of response (11.1 vs. 5.5 months), and a higher disease control rate (90 vs. 81 percent). In patients with deletion 19 or L858R, the objective response rate was 60.8 vs. 22.1 percent (P<0.0001).
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events were as expected with EGFR-targeting therapies, and were manageable and reversible. It is also important to note that patients in the afatinib arm received 16 cycles of therapy, vs. 6 cycles in the pemetrexed/cisplatin arm. In LUX-Lung3, only 7.9 percent of patients discontinued afatinib due to treatment-related adverse events (vs. 11.7 percent with pemetrexed/cisplatin), and only about 1 percent discontinued the drug due to diarrhea.
In addition, afatinib significantly prolonged the time to deterioration of cough (HR 0.6; P=0.007) and dyspnea (HR 0.68; P=0.015). Patients treated with afatinib had better quality of life. Grade 3/4 adverse events that were increased with afatinib include diarrhea [14.4 vs. 0 percent], rash/acne [16.2 vs. 0 percent], stomatitis/mucositis [8.7 vs. 0.9 percent], paronychia [11.4 vs. 0 percent], and dry skin [0.4 vs. 0 percent], said Yang. These adverse
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Regorafenib offers hope for GIST patients failing TKIs

Christina Lau
he multi-kinase inhibitor regorafenib may represent the first targeted treatment option for patients with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) whose disease progressed despite prior use of both imatinib and sunitinib, suggest results of a phase III international trial. The GRID (Regorafenib in Progressive Disease) trial included 199 patients from 17 countries who failed at least imatinib and sunitinib the only two drugs approved for GIST worldwide. Patients were randomized to receive either regorafenib 160mg once daily plus best supportive care (BSC) (N=133), or placebo plus BSC (N=66), on a 3-weeks-on 1-week-off schedule. The trial was unblinded on disease progression, when placebo-treated patients were eligible for crossover to openlabel regorafenib and regorafenib-treated patients were continued on the active treatment. On the next progression, patients were taken off treatment. The trial met its primary endpoint, as progression-free survival (PFS) was significantly and four times longer in the regorafenib arm. Median PFS was 4.8 months for regorafenib vs. 0.9 months for placebo, with a hazard ratio (HR) of 0.27 (P<0.0001), reported Dr. George Demetri of the Dana Farber Cancer Institute in Massachusetts, USA. PFS rates at 3 and 6 months were 60 vs. 11 percent and 38 vs. 0 percent, respectively.
The same PFS benefit was maintained in patients with KIT exon 11 (N=51) or exon 9 (N=15) mutation, the most common mutations in GIST. The HR was 0.212 and 0.239, respectively, he continued. Disease control and objective response were also better with regorafenib, at rates of 52.6 vs. 9.1 percent and 4.5 vs. 1.5 percent, respectively. Although overall survival (OS) favored regorafenib (HR 0.77), the difference between the two arms did not reach statistical significance as 85 percent of patients in the placebo arm crossed over to receive open-label regorafenib, pointed out Demetri. Regorafenib was generally well tolerated in the trial, with side effects similar to those of imatinib and sunitinib. The most common grade 3 adverse events were hand-foot skin reaction (19.7 vs. 1.5 percent), hypertension (22.7 vs. 3 percent) and diarrhea (5.3 vs. 0 percent). The side effects were all manageable with dose modifications. There were no significant differences in grade 4/5 adverse events, he noted. Positive results of the trial were submitted to regulatory authorities in March 2012. If approved, regorafenib will fulfill an urgent unmet need for GIST patients who have exhausted all other treatment options, he suggested. While imatinib and sunitinib have increased patient survival in metastatic GIST
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VEGFR-1, murine VEGFR-2, PDGFR-, RET, BRAF and FGFR-1 that appears to target GIST in a possibly more powerful way, making it a potentially significant new option to help patients.
from 3-6 months to 5 years or more, 85 to 90 percent of patients ultimately develop resistance to these tyrosine kinase inhibitors (TKIs) that target KIT or PDGFRA. Regorafenib is a structurally distinct oral inhibitor of KIT,
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Better strategies needed for ALL in adolescents and young adults

Christina Lau
dolescents and young adults with highrisk acute lymphoblastic leukemia (ALL) have poorer survival and higher toxicity from treatment than their younger counterparts, according to new data from a major phase III study which highlights the need for better treatment strategies for this group of patients. Historically, ALL patients older than 16 years have an inferior outcome compared with patients aged 1 to 15 years because older patients have higher rates of relapse and toxicity, said lead author Dr. Eric Larsen of the Maine Childrens Cancer Program in Scarborough, Maine, US. In the Childrens Oncology Group (COG) study ALL0232, we tested dexamethasone vs. prednisone during induction and high-dose methotrexate vs. escalating Capizzi methotrexate plus PEG asparaginase during interim maintenance 1 in a 2 x 2 factorial design. For the fist time, patients aged 21-30 years were eligible for enrollment in an ALL study. ALL0232 was in patients with newly-diagnosed B-precursor high-risk ALL. Of a total of 2,571 eligible patients in ALL0232, 501 (20 percent) were adolescents and young adults aged 16-30 years. This represents the largest cohort of adolescent and young adult ALL patients to date in a single clinical trial, he said. Previously, observations about ALL outcome were
usually made by comparing one trial with another. In ALL0232, the number of patients receiving the same treatment was large enough to allow comparison within the same trial. At 5 years, ALL0232 patients aged 16-30 years had significantly poorer event-free survival (EFS) and overall survival (OS) than those <16 years (68.0 vs. 80.9 percent and 79.8 vs 88.4 percent, respectively; P<0.0001). Relapses were significantly more frequent in adolescent and young adult patients, primarily due to a higher rate of bone marrow relapse, reported Larsen. The 5-year cumulative relapse rate was 21.3 percent in patients aged 16-30 years, vs. 13.4 percent in those younger than 16 (P=0.002). Marrow relapse at 5 years was 15.3 vs. 9 percent (P=0.0007). Interestingly, central nervous system (CNS) relapse was similar between the two groups, being 5.2 vs. 3.7 percent (P=0.58) at 5 years, he continued. According to the investigators, the treatment strategy of the trial was to try to improve disease control in the CNS. In addition, significantly fewer adolescent and young adult patients achieved remission, defined as <5 percent marrow blasts at the end of induction (97.2 vs. 98.8 percent; P=0.0134). Post-induction remission deaths were significantly higher in those aged 16-30 years vs those <16 years (5 years, 5.5 vs. 2.1 percent;
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pared with previous studies, which showed EFS rates of 50-60 percent, remarked Larsen. However, our results suggest that we need to find novel agents that improve leukemia control with reduced toxicity.
P<0.0001), although there was no significant difference in induction mortality between the two groups (2.4 vs. 1.8 percent; P=0.36). Adolescent and young adult patients treated in ALL0232 had improved outcome com-
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Feeding, not starving, tumors improves response to therapies and overall survival
Radha Chitale
ancer patients may live longer if their tumor microenvironment is normalized, rather than starved of blood and other nutrients, so that therapeutic treatments are more effective, said Professor Rakesh Jain, of the Steele Lab for Tumor Biology, Massachusetts General Hospital, Harvard Medical School in Boston, Massachusetts, US. This approach has implications for the half billion people worldwide with diseases characterized by abnormal vessels, he said. As tumors grow, vessels can become disorganized, misshapen or blocked, creating areas without oxygen. This hypoxic environment creates high interstitial fluid pressure and contributes to genetic instability, angiogenesis, resistance to cell death and metastasis. However, chemotherapy, radiation therapy and immunotherapy are demonstrably more effective when the tumor microenvironment is in a normal state. In a study of 30 patients with recurrent glioblastoma treated with an anti-vascular endothelial growth factor (VEGF), seven had increased tumor blood perfusion for more than 1 month, which was associated with increased survival of 6 months compared to patients in whose tumors blood perfusion remained stable or decreased (P=0.019). [Cancer Res 2012;72:402-407] Normalization induced blood flow has the potential to increase survival in patients,
Normalizing the tumor microenvironment may help enhance the efficacy of therapeutic treatments.
Jain said. However, dose matters when treating with anti-VEGF therapy to improve blood flow to tumors; too little anti-angiogenic agent results in no change to the blood vessels and too much leaves only a small window for normalization before excessive pruning and hypoxia set in. Smaller molecules, about 10 nm, were the optimal size for drug delivery to promote normalization and tumor response. Alleviating hypoxia in tumors makes the mass immunostimulatory, Jain said, and vessels are able to bring more T-cells to the tumor to increase the efficacy of immunotherapy. Five to 10 years from now we would see normalization be combined with a variety of immunotherapies, he said. Jain also noted that a similar normalization strategy could be used for lymphatic vessels and the tumor cellular matrix as well to improve perfusion and improve the efficacy of chemotherapy, radiation therapy and immunotherapy and overall survival.
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Acute cancer drug shortages due to manufacturing, quality control

Radha Chitale
isrupted manufacturing and quality control are the main culprits behind the high volume of drug shortages in the US that have left many cancer patients without necessary treatment. Dr. Richard Schilsky, of the University of Chicago and chair of the ASCO Government Relations Committee, described recent unprecedented shortages of generic injectable drugs such as methotrexate that are mainstays of treatment for many cancers. Were never exactly sure when a generic drug is suddenly going to go out of supply, he said, which creates anxiety for patients and treatment planning difficulty for physicians. Hundreds of drugs have been in short supply in the US over the past year including methotrexate, used frequently for leukaemia, Doxil, which treats ovarian cancer, paclitaxel, used in a variety of cancers including breast cancer, mustargen, used to treat lymphoma, and fluorouracil, given for colorectal and other cancers, and is a key part of adjuvant therapy. Shortages appear to be most acute among community practices, where the majority of adults receive care, said Dr. Michael Link, of the Lucile Packard Childrens Hospital at Stanford University in California, US and ASCO president.
Dr. Sandra Kweder, deputy director of the Office of New Drugs at the US Food and Drug Administration (FDA), said disruptions at large manufacturers of sterile injectable drugs have the most impact. For example, closing a single facility that makes 30 drugs can lead to dozens of shortages. Contamination with glass or metal particles in vials of medicine can also compromise drug availability. Kweder said the FDA works with drug manufacturers to address shortages by encouraging early reporting of production difficulties so that the agency can source the same or alternative drugs from different companies, sometimes from overseas manufacturers in India or Australia, for example. Schilsky noted that cancer drug shortages do not appear to be a problem in overseas markets. Permanent solutions to drug shortages will likely require legislation to make 6 months notice for withdrawals or manufacturing interruption mandatory by drug companies, with penalties for non-reporting, Schilsky said. Dr. W Charles Penley, of Tennessee Oncology in the US and incoming chair of the ASCO Government Relations Committee, noted that drug shortages, particularly of widely used generics, impact clinical research as doctors are unable to use them as standard therapy to measure experimental drugs against. This could really slow down progress if we dont have access to these very standard and vital agents, he said.
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Bevacizumab slows down ovarian cancer progression

Elvira Manzano
dding bevacizumab to standard chemotherapy delayed cancer progression in women with platinum-resistant ovarian cancer, results of a phase III AURELIA* trial showed. Median progression-free survival (PFS) a primary endpoint of the study was 6.7 months for combination therapy compared with 3.4 months for chemotherapy alone. The objective response rate more than doubled with the addition of bevacizumab 12.6 percent to 30.9 percent (P=0.001). For the first-time in platinum-resistant ovarian cancer, we have been able to significantly improve progression-free survival with a combination therapy, said lead study author Dr. Eric Pujade-Lauraine, professor, Universit de Paris Descartes, France and head of the Group dInvestigateurs Nationaux pour lEtude des Cancers Ovariens (GINECO), a clinical trials cooperative group based in France. The risk of the disease getting worse was halved in patients treated with the combination therapy. This is a breakthrough and will definitely change the practice in treating patients with ovarian cancer. In the study, 361 women with epithelial ovarian, fallopian tube or primary peritoneal cancers that had not responded to platinumbased chemotherapy were randomized to receive standard chemotherapy or bevacizumab plus chemotherapy (with one of three standard chemotherapy agents topotecan, liposomal pegylated doxorubicin or weekly
paclitaxel). Secondary endpoints were objective response rate, overall survival, safety, and quality of life. After a median follow-up of 13.5 months, 91 percent of patients in the chemotherapyalone group had progressed compared with 75 percent in the combination therapy group. The difference translated into a 0.48 hazard ratio of progression (P<0.001). Data on overall survival is expected next year. Rates of hypertension and proteinuria were higher among the bevacizumab group than with the chemotherapy-only group but bleeding events, febrile neutropenia and congestive heart failure were the same. These adverse effects were consistent with the known effects of bevacizumab and the different chemotherapeutic agents used in the study. These results are very significant. The addition of bevacizumab offers a new treatment option for 20 percent of women who have primary platinum-resistant disease as well as those whose disease later becomes platinum-resistant, Lauraine concluded. Bevacizumab is a humanized anti- human vascular endothelial growth factor A (VEGFA) monoclonal antibody (mAb) indicated for metastatic colon cancer, renal cancer, certain lung cancers and glioblastoma multiforme of the brain typically in combination with standard chemotherapy.
*AURELIA: A Study of Avastin (Bevacizumab) Added to Chemotherapy in Patients With Platinum-resistant Ovarian Cancer
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Continue annual breast screening from age 40

Rajesh Kumar
esearchers are reminding women in their 40s that no family history of breast cancer is no reason to miss their yearly mammograms. This follows a study which showed that more than half of women aged 40-49 diagnosed with breast cancer on screening mammography had no family history of the disease. The reminder seeks to address the confusion created by an earlier meta-analysis which questioned the benefit of regular screening for preventing cancers in this age group, compared with screening of older women; and the subsequent advice from the US task force on preventive services. Clinical radiologists analyzed all breast cancers diagnosed between 2000 and 2010 at the Elizabeth Wende Breast Care in Rochester, New York, US, and found that 228 out of 373 cancers (61 percent) were found in women aged 40-49 with no family history. Seventeen of the 228 patients did have a prior personal history of breast cancer or abnormal cells at a prior biopsy, and were not included in this analysis. Out of 211 women who remained in the study, 135 (64 percent) had invasive disease, although they did not have either the family history or a prior personal history of breast cancer or abnormal cells, said lead author Dr. Stamatia Destounis. The findings were presented at the American Roentgen Ray Society annual meeting held recently in Vancouver, Canada.
Invasive disease includes invasive ductal, invasive lobular, mucinous, tubular and papillary cancers. Ninety-two of the patients with invasive disease were treated with lumpectomy, eight going on to mastectomy after close or positive margins; 42 had a mastectomy and 1 patient did not have surgery due to metastatic disease, said Destounis. We have follow-up imaging available for 149 of the 211 patients, and 144 are doing well; 5 have been diagnosed with new or recurrent cancer, she said. Destounis and colleagues decided to look at the clinics register of patients diagnosed with breast cancer in the 40-49 age group following intense debate on the issue. In 2009, the US Preventive Services Taskforce left the decision to screen up to women in their 40s and their doctors, rather than explicitly recommending it, after finding little evidence of benefit in that group. The taskforce quoted evidence that showed one cancer death was prevented for every 1,904 women aged 40-49 screened for 10 years, compared with one death for every 1,339 women aged 50-59, and one death for every 377 women aged 60-69. The revised recommendation did not apply to women with risk factors for breast cancer. Although the benefit of screening a woman in her 40s may be slightly less than a 60 year old, there is good reason to identify these tumors small where treatment is minimal and prognosis the best, said Destounis.
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good outcome, she said. Singapore breast surgeon Dr. Georgette Chan agreed with the findings and said more and more women in their 40s are realizing this and coming forward for screening in her practice, but she added no statistics were available to see the wider trend. Singapores Health Promotion Board has local statistics on the percentage of women aged 50 to 69 years who participated in BreastScreen Singapore national breast screening programme during 2004-2010, but not for the younger women, Chan said, adding the recommendation remained for younger women to get yearly scans.
Pre-cancerous lesions may have been ignored or not taken into account... different regions of the breast were compared that may have had different rates of cancer, and women were not followed long enough in time to evaluate for survival differences, she said of the studies the US task force relied upon. With the advent of digital mammography, improved ultrasound techniques and breast MRI, Destounis said radiologists are now identifying small treatable cancers and pre-cancerous lesions. As a radiologist specializing in breast cancer detection, my role is to identify tiny cancers that can be treated and the patient will have a

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July 2012
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Google algorithm useful in cancer study

Malvinderjit Kaur Dhillon
dopting Googles strategy in deciding which pages are relevant to a search query, proteins in a cancer patient that are relevant to disease progression can be narrowed down, a group of researchers from Germany have found. Researchers at Dresden University of Technology adapted Googles PageRank algorithm to list approximately 20,000 proteins by their genetic relevance to pancreatic cancer. The ranking allowed them to zoom in on seven proteins that can help assess how aggressive a patients tumor is and assist the clinician to decide if that patient will benefit from chemotherapy. [PLoS Comput Biol 2012; doi:10.1371/ journal.pcbi.1002511] The researchers used the modified version of the Google algorithm to find new cancer biomarkers, molecules emitted by cancer cells. Biomarkers can help detect cancer in body fluids or directly in the cancer tissue obtained by surgery or a biopsy. Finding these biomarkers have often proved difficult and time consuming. Another problem is that markers found in different studies for the same type of cancer almost never overlap. The basis behind Googles algorithm is that it takes into account the content of a web page and how these pages are connected via hyperlinks. A web page with no other pages linking to it and no social media interaction has
Researchers are using Googles PageRank algorithm to sift through proteins related to cancer.
a lower search engine placement and seems less important to Google. Using this as a model, the researchers took advantage of the fact that proteins in a cell are connected through a network of physical and regulatory interactions; the protein Facebook. Once we added the network information in our analysis, our biomarkers became more reproducible, said Dr. Christof Winter, of the universitys department of bioinformatics and the papers first author. Using this network information and the Google Algorithm, a significant overlap was found with an earlier study from the University of North Carolina, US. There, a connection was made with a protein which can assess aggressiveness in pancreatic cancer, he said. Although the new biomarkers are an improvement over currently available diagnostic tools, there is room for improvement and [these biomarkers] still need validation in a larger follow-up study before they can be used in clinical practice.
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Common childhood viral infection linked to epilepsy

Saras Ramiya
third of infants with prolonged seizures and fever suffer from either a new or reactivated roseola virus infection, shows a 10year US study. While febrile or fever-related seizures occur in 2 to 5 percent of infants, most of whom recover with no adverse consequences, less is known about the outcome in children who suffer from the prolonged febrile seizures associated with human herpesvirus-6B (HHV6B) or HHV-7. These children are still being followed and investigators expect that 30 to 40 percent of them will develop epilepsy within 5 years. Roseola viruses are among the common causes of childhood rash, but can also result in limbic encephalitis, a condition that frequently progresses to epilepsy. Investigators discovered one of the roseola viruses, HHV-6B, in the blood of 32 percent of 169 infants with prolonged seizures, a condition known as status epilepticus. They also found HHV-7 (another roseola virus) in 7.1 percent of the patients, usually as a coinfection with HHV-6B. It is possible that these patients harbor latent virus in the brain tissue that reactivates later in response to unknown triggers, said Dr. Leon Epstein, lead author and a pediatric neurologist at the Northwestern University Feinberg School of Medicine and Ann and Robert H. Lurie Childrens Hospital of Chicago. The study strengthens the link between
HHV-6B and mesial temporal lobe epilepsy. The study findings were published online in Epilepsia on 14 June. Antiviral therapy HHV-6B is the primary cause of limbic encephalitis in transplant patients and half of those cases go on to develop epilepsy within 3 to 5 years. Furthermore, several studies have found HHV-6B DNA at high levels in the brain tissue of patients with refractory epilepsy. A clinical trial is urgently needed to determine if repeat seizures and some cases of temporal lobe epilepsy might be prevented using existing antiviral therapy, said Kristin Loomis, executive director of the HHV-6 Foundation. HHV-6 and HHV-7 persist in the brain cells and can be activated during periods of immunosuppression or stress. These viruses are spread via the saliva and everyone in the population would have been infected by early adulthood. Currently, infants with seizures are not tested for HHV-6B or HHV-7 and treatment consists of anti-seizure drugs. However, the authors expect clinical trials to be established as soon as more evidence is gathered. Transplant patients suffering from seizures due to HHV-6 reactivation are routinely treated with antivirals. Antiviral treatment is also now common practice for symptomatic infants infected with a closely related virus
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cytomegalovirus or CMV (HHV-5). Infants who contract CMV from their mothers during pregnancy or shortly following birth can develop seizures and mental retardation as well as permanent losses in both hearing and vision. Antiviral therapy can reduce neurological complications and seizures in these infants. However, the neurologists who conducted the study remain cautious about antiviral therapy. They noted that the oral antiviral drug used to treat CMV infections, valganciclovir, can cause reversible neutropenia, a form of anemia. Less toxic antivirals such as CMX001 are in the pipeline. HHV-6B can cause a strong cytokine response, and there is emerging data that inflammatory mechanisms may be involved in developing epilepsy after an insult such as a prolonged seizure, explained Dr. Shlomo Shinnar, of Montefiore Medical Center and Albert Einstein College of Medicine, and principal investigator of the study. So it is possible that anti-inflammatory treatment could benefit these patients whether or not HHV-6B is the cause of the prolonged seizure. This is another area that needs further research. [Epilepsia 2008;49:1828-37] Cognitive impairment Investigators will also be studying the roseola virus infected subset of patients to determine if they develop cognitive problems in the years following the seizures. We know that children and adults with temporal lobe epilepsy have cognitive problems. It will be interesting to see whether those who started out with an HHV-6B infection have more cognitive im-
Some children do not recover from roseola virus related febrile seizures.
pairment down the road, said Shinnar. A study by Danielle Zerr, an infectious disease specialist at Seattle Childrens Hospital and the University of Washington, suggested that Shinnar may be on the right track. Zerr reported last year that patients who reactivate with HHV-6B during a transplant procedure are far more likely to develop cognitive dysfunction or delirium. The declines were especially significant in areas of attention, processing speed, and concentration, as well as cognitive flexibility or the ability to operate with divided attention. [Blood 2011;117:5243-9] Children who develop seizures in response to these common viruses may harbor genes that cause them to be susceptible. A mutation in the SCN1A gene has been linked to several epilepsy conditions. Variants of another gene, IRF5, have also been associated with active HHV-6A infections in multiple sclerosis patients.
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Antibiotic use raises risk of antifungalresistant Candida infection

Rajesh Kumar
xposure to certain antibiotics could increase the risk of infection with drugresistant strains of a severe fungal infection, according to Israeli research. Candida fungal species are frequent causes of hospital-acquired infection and those with prolonged hospitalization, abdominal surgery, antibiotic treatment, neutropenia, and central venous catheterization are at greatest risk, said the researchers. [Antimicrob Agents Chemother 2012;56:2518-2523] They identified 444 patients who had Candida growing in their blood, 8.5 percent of them infected with strains that were resistant to fluconazole. They obtained detailed histories of antibiotic exposure in all patients during the month prior to onset of candidemia and found that previous exposure to four antibiotic drugs or drug classes increased the risk of infection with fluconazole-resistant Candida nearly three-fold. C. glabrata bloodstream infection was strongly associated with recent metronidazole exposure (odds ratio [OR] 3.2; P<0.001). Infection with a fluconazole-resistant isolate was associated with exposure to carbapenems, trimethoprim-sulfamethoxazole, clindamycin, and colistin (OR 2.8; P=0.01). A striking feature of the current cohort of patients with candidemia is the almost universal exposure to antibacterial drugs in the preceding month, said the researchers. Moreover, the majority of patients received multiple classes of antibacterials, either con-
All patients with Candidemia had taken an antibiotic in the preceding month.
comitantly or sequentially. The findings underscore the importance of limiting the use of antibiotics to those situations where these drugs are strictly indicated, said researcher Dr. Ronen Ben-Ami of Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. He added that clinicians treating patients with candidemia should take the patients recent antibiotic exposure history into account when selecting the antifungal treatment. The findings may be relevant to the selection of empirical antifungal treatment and broaden the scope of antibiotic-associated collateral damage. But the study had limitations due to its inherently observational nature. Exposure to antibacterial drugs may reflect several confounding covariates, such as severity of illness, length of hospitalization, and comorbid conditions (confounding by indication), researchers said, adding in the study cohort there was no significant association between the occurrence of fluconazole-resistant candida blood stream infection or exposure to the antibacterials of interest and severity of illness.
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Tenofovir a reasonable choice in HIV-positive pregnancies

Yen Yen Yip
nti-HIV drug tenofovir (Viread, Gilead Sciences), recommended by the World Health Organisation as first-line anti-retroviral therapy (ART), has been found to be safe for use in pregnant women with HIV. The Development of Anti-Retroviral Therapy in Africa (DART) trial compared monitoring methodologies for ART, and collected information on the pregnancies, births and infants of HIV-positive women taking tenofovir-containing regimens in Uganda and Zimbabwe. The children were followed for a period of up to 4 years. We observed no evidence that tenofovir versus non-tenofovir ART had any adverse effects on pregnancy outcomes or on congenital, renal, bone or growth abnormalities up to age 4 years among children born to women with severe HIV immunodeficiency at ART initiation and exposed throughout the intrauterine period, the investigators reported. [PLoS Med 2012;9. Epub ahead of print] Prior to the trial results, concerns on the safety of tenofovir arose from animal studies, where tenofovir use in pregnant Rhesus macaques was associated with bone demineralization, impaired growth, and renal abnormalities in their offspring. The findings from DART did not support such concerns. The 1-year infant mortality rate among the 226 live births recorded in the study group (5 percent) was similar to the rates observed in the general population of the African region (2 to 4 percent), said the
investigators, and much lower than among babies born to untreated HIV-positive women. The babies in DART did not experience any bone fractures or kidney problems associated with tenofovir during the 4-year followup period. There was no effect on growth at 2 years of age. Rates of congenital abnormalities were also similar between tenofovir and non-tenofovir-exposed infants. None of the infants who were tested for HIV were positive, although testing was not 100 percent, the researchers reported. These findings are significant as the chances of HIV-positive women taking tenofovir while conceiving or going through pregnancy is likely to increase. New recommendations to start ART earlier and evidence of reduced onward HIV transmission with earlier ART initiation are some reasons behind this trend, according to the researchers. Furthermore, a recent study has shown that tenofovir-containing regimens can prevent HIV acquisition in HIV-uninfected women having sex with men. The study was limited by its relatively small sample size, the investigators acknowledged. Detailed safety of tenofovir for preexposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children. However, given the scarcity of available data in such resource-limited settings in Africa, tenofovir-containing ART is a reasonable choice in pregnancy and tenofovir pre-exposure prophylaxis is also reasonable for women who are at high risk of seroconverting during pregnancy, they stated.
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IUDs, implants significantly more reliable for contraception

Radha Chitale
nplanned pregnancy is 20 times more likely for women on the pill or other forms of short term birth control than if she were using an intrauterine device (IUD) or contraceptive implant, report researchers from Washington University in St. Louis in Missouri, US. Oral contraceptive pills are the most common form of birth control by far among women in the US, the researchers reported, but their efficacy hinges on proper use. The same is true for vaginal rings and trans-dermal contraceptive patches. Annual failure rates of oral contraceptives are 9 percent in the general US population and 13 percent among teenagers. IUDs and sub-dermal implants have failure rates less than 1 percent. About half of the 3 million pregnancies that occur in the US each year are a result of contraceptive failure, the researchers said. If there were a drug for cancer, heart disease or diabetes that was 20 times more effective, we would recommend it first, said study author Dr. Jeffrey Peipert, of the Washington University School of Medicine, St. Louis, Missouri, US. Unintended pregnancies can have negative effects on womens health and education and the health of newborns. The trial included 7,486 participants between ages 14-45 who were not using contraception or looking to switch contraceptive methods, who did not plan to become
pregnant in the coming 12 months, and who were sexually active or were planning to be within 6 months. [N Engl J Med 2012;366:19982007] Patients were counselled on the types and efficacy of short and long term birth control methods and their choice was provided free of charge. During the trial, 334 women became pregnant and the researchers determined that 156 of these were due to contraceptive failure. Twenty-one of the pregnant women had been using an IUD or an implant while 133 were on the pill, patch or ring. Pregnancy was also twice as likely among women under age 21 who used short-term contraception compared with older women using similar forms of birth control. The failure rate for women using the pill, patch or ring was 4.55 per 100 participant years and 0.27 for women using IUDs and implants. Over 80 percent of women using longterm contraception demonstrated continued use at 12 months compared with 49 to 57 percent among women on short-term contraception. The data matches previous work on unplanned pregnancy rates but the researchers emphasized the magnitude of discrepancy between short and long term contraception. They also reported unexpected demographic data in preferred contraceptive choice.
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If more women used the highly effective, long acting reversible methods, we would expect a decrease in the number of unintended pregnancies, because there would be more women continuing to use contraception, the researchers said, adding that lowering the cost of IUDs and implants might make it a more viable option for more women.
Short-term contraception was more prevalent among younger, educated women with private insurance who had no children. Long-term contraception was favored by older, less educated women on public health insurance who already had children, characteristics that the researchers said are typically associated with higher rates of unplanned pregnancy.
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Low-fiber diet linked to more visceral fat in teenagers

Alexandra Kirsten
dolescents who eat less fiber tend to have more visceral fat and higher levels of inflammatory biomarkers. This was the main finding of a recent US study. [J Clin Endocrinol Metab 2012 May 16. Epub ahead of print. DOI:10.1210/jc.20121784] Dr. Samip Parikh and colleagues from the Georgia Health Sciences University in Augusta, Georgia, US, investigated associations of dietary fiber intake with inflammatory-related biomarkers and total and central adiposity. The 559 participants were American students, aged 14 to 18, recruited from local high schools in the city area of Augusta. It is estimated that American adolescents consume less than one-half of the recommended intake of dietary fiber (14g/1,000 kcal). The researchers measured inflammatoryrelated biomarkers in fasting blood samples of the participants. Up to seven 24-hour recalls were used to evaluate their diet. X-ray absorptiometry and magnetic resonance imaging were employed to measure visceral adipose tissue and fat-free soft tissue of the teens. After adjusting for age, race, physical activity and fat-free soft tissue mass, they observed that higher fiber intake was associated with lower visceral fat mass found
in and around organs in the abdominal cavity (P<0.05). A higher total fat mass was only found in boys (P<0.03). Teens consuming a low-fiber diet tended to have higher levels of the so-called acutephase proteins plasma C-reactive protein and plasma fibrinogen. Generally plasma concentrations of these proteins increase in response to inflammation in the body. Low-fiber consumers also showed lower levels of adiponectin, a protective protein exclusively secreted from fat cells which helps the body to use glucose, break down fatty acid and fight inflammation. A recent development in obesity research is the concept that increased adiposity is characterized by greater systemic inflammation, the authors explained. Different studies in the past showed that adipocytes and macrophages within the fat mass can secrete cytokines and acute-phase proteins. Consequently more visceral fat leads to a greater production of inflammatory-related factors. This chronic low-grade systemic inflammation is a well-known risk factor for cardiovascular disease and diabetes, they added. The researchers concluded that, while the mechanism remains unclear, dietary fiber intake may play a protective role against disorders associated with obesity-related inflammation.
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Drinking alcohol may trigger AF

Alexandra Kirsten
lcohol consumption may be an important trigger for paroxysmal atrial fibrillation (AF), the results of a recent study suggest. Patients suffering from recurrent episodes of AF experience palpitations, fainting, chest pain, and have a higher risk of stroke and congestive heart failure. Alcohol has been recognized as a possible clinical trigger for AF since the 1970s, said senior study author Dr. Gregory Marcus, assistant professor of medicine in the division of cardiology, UCSF, San Francisco, California, US. But it remains unknown if these associations occur more often than would be expected by chance alone because of the lack of a comparator group in previous studies, he added. Marcus and colleagues interviewed 223 patients with documented cardiac arrhythmia associated with alcohol consumption, of whom 133 had PAF and 90 had other supraventricular tachycardias (SVTs). [Am J Cardiol 2012; Epub ahead of print. DOI:10.1016/j.amjcard.2012.03.033] After adjusting for multiple confounding variables, the researchers found that patients with paroxysmal AF were 4.42 times more likely to report alcohol as an arrhythmia trigger compared with patients with
SVTs (P=0.014). Additionally, patients with paroxysmal AF had a 2.02 greater chance of reporting vagal activity as an arrhythmia trigger than those with SVTs (P=0.044). Patients with a history of paroxysmal AF triggered by alcohol consumption were also more likely to have episodes provoked by vagal activity (P=0.045). Vagal triggers can include sleep, as well as digestive precipitants such as spicy foods, cold bolus of food or liquid and large meals with resultant gastric distension. Alcohol consumption and vagal activity elicit PAF significantly more often than SVT, concluded the authors. Alcohol and vagal triggers often were found in the same patients with paroxysmal AF, raising the possibility that alcohol may precipitate AF by vagal mechanisms. It is important that we do not recommend alcohol because it is heart healthy, Marcus explained. However it is probably too strong and too early to recommend against alcohol. Nevertheless, cardiologists should advise patients not to drink if they have episodes of palpitations, especially after drinking alcohol, or if they suffer from high blood pressure and heart failure.
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Can yoga reduce CVD risk in postmenopausal women?

Saras Ramiya
team of researchers plans to conduct a pilot study later this year on the effects of yoga on cardiovascular disease (CVD) risk profiles among postmenopausal, sedentary South Asian women in Canada. Postmenopausal women are more at risk of developing CVD, regardless of ethnicity and background, but [South Asian women, in particular, are more at risk because of their genetic predisposition,] lead researcher Dr. Amandah Hoogbruin, of the Kwantlen Polytechnic University in Surrey, British Columbia, Canada, told Medical Tribune. In Canada, South Asians suffer disproportionate rates of cardiovascular-related morbidity and mortality. Postmenopausal South Asian women are at even greater risk due to a higher prevalence of hypertension, physical inactivity and obesity. Given that yoga, an ancient mind-body practice, is a long-standing feature of East Indian culture, and may reduce psychological and physiological CVD risk factors, it represents a potential and suitable intervention for this target population, Hoogbruin wrote in her poster. Yoga works by relaxing the autonomic nervous system, so youre less likely to get excited. It also increases your capacity to be more relaxed as it increases [the activity of] the parasympathetic nervous system, she said. A systematic review of published literature on the effects of yoga on CVD or indices
Yoga has been linked to positive effects on physiological CVD risk factors.
of CVD risk associated with insulin resistance syndrome by Dr. Innes K.E. and colleagues showed that doing yoga for about 30 minutes, ideally every day or at least three times a week, reduced participants blood pressure. Other beneficial changes were also noted in terms of glucose tolerance and insulin sensitivity, lipid profiles, anthropometric characteristics, blood pressure, oxidative stress and coagulation profiles. [J Am Board Fam Pract 2005;18(6):491-519] The pilot study will investigate the effects of a 12-week Iyengar yoga program on primary change in fasting lipid profiles and blood pressure at 12 weeks, and secondary change in glycemia, blood pressure levels and body mass index (BMI). For this pilot study, Iyengar yoga has been chosen as it can be easily replicated by using props and carefully scripted yoga positions, or asanas. It can also be readily performed by individuals who are elderly, overweight, unfit, or who suffer from chronic illnesses, Hoogbruin said.
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Palpitations may predict future AF

Rajesh Kumar
istory of palpitations and hypertension are the strongest risk factors for atrial fibrillation (AF) in both men and women, according to a large Norwegian study. While hypertension is already well-known as a risk factor for AF, the impact of self-reported palpitations on later occurrence of AF has not been documented earlier, the researchers noted. [Eur J Prev Cardiol 2012. DOI:101177/2047487312446562] Patients with recurrent episodes of palpitations should [therefore] undergo prolonged ambulatory ECG monitoring to ascertain the cause, especially if they have predisposing factors such as hypertension, diabetes mellitus and obesity, said Dr. Ching Chi Keong, director of cardiac electrophysiology and pacing at the National Heart Centre Singapore, while commenting on the findings. The researchers followed up 22,815 men and women aged 25 to 96 (mean age 46 years at baseline) in Troms, Norway for about 11 years. Information on palpitations was included at baseline along with measurements of height, weight, blood pressure, heart rate, total cholesterol and high-density lipoprotein (HDL) cholesterol. All subjects were cross-linked to the local diagnostic registry and to the national death register for information on AF documented by electrocardiogram (ECG). Hospital records were searched for subjects with diagnoses of cerebrovascular or cardiovascular events but without a recorded diagnosis of arrhythmia. AF was recorded in 361 women (3.0 percent) and 461 men (4.2 percent) during the 11.1
years of follow-up, an incidence rate of 2.71 per thousand per year for women and 3.87 for men. Age, self-reported palpitations and hypertension were the strongest risk factors for AF. Palpitations increased the risk of AF in women by 62 percent (HR 1.62) and in men by 91 percent (HR 1.91). Though height, antihypertensive treatment and coronary heart disease were also found to be risk factors for both palpitations and AF, the investigators concluded that palpitations are probably causally associated with AF. Although the occurrence of palpitations was assessed before a diagnosis of AF and the association remained significant even after adjustment for other AF risk factors, we cannot conclude with certainty that the association is causal, said lead author Dr. Audhild Nyrnes from the department of community medicine in University of Troms, Norway. However, in this case it is not unreasonable to propose a causal relationship. Palpitations are used subjectively to describe irregular heartbeats or accelerated heart rate, and it is likely that a proportion of palpitations also represent cases of irregular heart rhythm, which is a main characteristic of AF. Nyrnes reminded that palpitations per se are not harmful. Instead, the challenge is to detect those which might signify an underlying condition and future AF. Thus, while palpitations might be reduced by modifying lifestyle factors, such as alcohol consumption and smoking, both of which increase heart rate, it is still unclear if this will reduce the risk of AF. It was interesting that
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stringent BP control to modify the AF risk in hypertensive patients. In conclusion, the study highlights the difficulty in making a diagnosis of AF in the general population, Ching commented, adding that physicians need to remember AF is common and often under-diagnosed and they need to have a high index of suspicion.
our study found no significant association between lifestyle factors and future AF - and only with palpitations. The study did confirm that hypertension is a significant risk factor for AF. Raised blood pressure at baseline (defined as above 140/90 mmHg) almost doubled the risk of AF in women (HR 1.98) and increased by 40 percent (HR 1.40) in men. This suggested a
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Exercise stress test still a gold standard for diagnosing, predicting CAD
Saras Ramiya
xercise stress testing is effective and the most commonly used noninvasive method to diagnose and predict coronary artery disease (CAD) in both men and women, says a US cardiologist. Dr. Martha Gulati, of Ohio State Universitys Wexner Medical Center, co-authored a paper in the Current Problems in Cardiology touting the benefits of exercise stress tests, especially in this age of nuclear heart scans, magnetic resonance imaging (MRI) and computed tomography (CT) imaging. [www. cpcardiology.com/article/S0146-2806(11)002581/abstract Accessed on 15 June] Although emphasis has been placed on the diagnostic value of ST-segment depression, the exercise stress test provides other valuable diagnostic and prognostic data beyond ST-segment depression. Even though [exercise stress test] has been around for nearly a century, it can not only tell us if you currently have heart disease, but can also predict your risk for it in the future, said Gulati. By todays standards this test may seem low-tech, but it can be highly effective and very efficient in diagnosing heart problems. In her practice, Gulati uses advanced imaging when appropriate. But I think we need to get away from just doing the most
Patients who can exercise should be evaluated with the exercise stress test.
expensive test because we can. While advanced imaging can be effective, it is expensive and often involves radiation, which, in some cases, can lead to other health complications, she said. We need to be doing the right test for our patients, and when the guidelines are strictly followed, for almost all patients who can exercise, the right test, initially, will be the exercise stress test. During a stress test, doctors simply attach small electrodes to the patients body to monitor the heart during exercise, charting everything from beats per minute to blood pressure, and even measuring things like capacity, blood flow and recovery times. The test can be administered in clinics. We sometimes get caught up in the latest technology in our society, and often what gets ignored is the simple stuff, said Gulati.
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New ESC guidelines for heart failure

Rajesh Kumar
ew European Society of Cardiology (ESC) guidelines for heart failure (HF) diagnosis and treatment recommend that all patients with an ejection fraction of 40 percent or less receive a beta-blocker in addition to an ACE inhibitor (or an angiotensin receptor blocker [ARB] if an ACE inhibitor is not tolerated). In addition to the treatment for HF with reduced ejection fraction (HF-REF), the 2012 guidelines also include new algorithms for diagnosis of the patient with suspected HF and the management of acute HF. The new therapeutic recommendations, revised from the 2008 document, more specifically relate the treatment to effects with a focus on important clinical outcomes. [Eur Heart J 2012; DOI:10.1093/eurheartj/ehs104] Dr. John McMurray of the University of Glasgow, Scotland and chairperson of the new guidelines, said the diagnosis section recognizes the increasingly important role of cardiac MRI in evaluation of patients with HF and includes mid-regional proANP (pro-atrial natriuretic peptide) as a rule-out blood test in patients with suspected acute HF. The pharmacological therapy part has a new indication for the mineralocorticoid antagonist (MRA) eplerenone in patients with HF-REF and mild symptoms. This broadens the indication for an MRA to essentially all HF-REF patients remaining symptomatic despite adequate treatment with a beta-blocker and ACE inhibitor/ARB. The addition of ivabradine to an ACE inhibitor, beta-blocker and MRA is also
recommended in HF-REF patients in sinus rhythm with a persistently high heart rate despite optimized beta-blocker dosing, said McMurray. In the non-surgical devices section, the wider use of cardiac resynchronization therapy (CRT) in HF-REF patients with milder symptoms and in sinus rhythm is recommended. The new guidelines, however, acknowledge the uncertain role of CRT in patients in atrial fibrillation and in patients with non-left bundle branch QRS morphology. Transcatheter aortic valve replacement is recommended as a completely new treatment option in patients with severe aortic stenosis unsuitable for conventional surgical valve replacement, said McMurray. Key new developments in surgery are new evidence on the role of coronary revascularization from the STICH* trial and the growing evidence that ventricular assist devices (VADs) have an important role in the management of patients with end-stage heart failure. The guidelines address the use of VADs both as a bridge to transplantation and, in highly selected patients, as destination therapy, he said. The new guidelines also recognize that the presence of HF and left ventricular systolic dysfunction may alter therapeutic options for co-morbidities and that co-morbidities may also influence the use of HF therapies. No substantive new evidence has emerged in the area of acute heart failure and this section of the guidelines has been shortened and extensively revised with some
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mendation or evidence grading in the new guidelines due to uncertainty about the value of some (eg, sodium restriction) and the lack of robust outcome data for others.
*STICH: Surgical Treatment for Ischemic Heart Failure
regarding of recommendations in keeping with the guidelines focus of improved clinical outcomes, said McMurray. Non-pharmacological/device/surgical treatments other than exercise and multi-disciplinary intervention are not given a recom-
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Blood donation can reduce cardiovascular risk

Rajesh Kumar
lood donation can help overweight people with metabolic syndrome reduce their risk of cardiovascular disease, according to a small German study. In the study, just two sessions of bloodletting, 4 weeks apart, were enough to improve subjects blood pressure and markers of cardiovascular disease such as heart rate, blood glucose and HDL/LDL ratio, the researchers said. Accumulation of iron in the body is associated with hypertension and diabetes and bloodletting seems to reduce the iron load, thereby reducing the risk. To confirm this, researchers from University DuisburgEssen in Berlin randomized 64 patients with metabolic syndrome to iron reduction by phlebotomy (N=33) or a control group (N=31). The iron-reduction patients had 300ml of blood removed at the start of the trial and between 250 and 500ml removed 4 weeks later. Six weeks later, allowing plenty of time for blood volume to be replaced, the patients who gave blood had a significant reduction in systolic blood pressure compared with controls (from 148.5 mmHg to 130.5 mmHg in the phlebotomy group versus 144.7 mmHg to 143.8 mmHg in controls [95% CI -20.7 to -12.5; P=0.001]). The phlebotomy group also experienced significant reduction in blood glucose levels and heart rate, and an improvement in their LDL/HDL ratio. Consecutive reduction in iron stores
was able to improve markers of cardiovascular risk and glycemic control, said lead researcher Professor Andreas Michalsen from the Charit-University Medical Centre, Berlin, Germany. Consequently blood donation may prevent not just diabetes but also cardiovascular disease for the obese. Obviously this treatment will not be suitable for people with anemia. However for those eligible for treatment, blood donation may prevent escalation of their condition. There was no change in the BMI or waist circumference, but the researchers could not be sure if the participants had made any lifestyle changes that might have also contributed to the improvement in their cardiovascular disease markers. Larger trials with much longer observation period are, therefore, required to further evaluate the long-term effects and potential rebound effects of phlebotomy therapy, the researchers said. [Meanwhile], adequately controlled phlebotomy could be considered as a cost-effective additional treatment option in metabolic syndromea beneficial health-related effect for blood donation might be a motivating factor to encourage more people to donate more blood, providing public healthcare benefits as well, the researchers said. While the idea is appealing, Singapores Health Sciences Authority, which manages the countrys blood services, is not convinced yet. A spokesperson said global scientific
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Critics said while iron load in blood is indeed detrimental to cardiovascular health, there were better ways to reduce the risk than bloodletting.
evidence on the issue is still insufficient, due to which people with chronic diseases will continue to be advised against blood donations for their own safety.
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Heart Friends takes its mission to Africa

Saras Ramiya
eart Friends Around the World (HFATW) is setting up facilities for cardiac disease prevention and rehabilitation in African countries, says its founder and executive director Dr. Flavio Burgarella. I started in 1994 a worldwide organization called Heart Friends Around the World. The main [goal] in the beginning was to set up cardiac rehabilitation facilities around the world and to take care of prevention and rehabilitation in developing countries. We are now under the umbrella of the World Heart Federation and work together with the WHO, Burgarella, a cardiologist from Bergamo, Italy, told Medical Tribune. Among other activities that the HFATW has organized include a scholarship program for young cardiologists in Africa in 2011. Currently, eight cardiologists are training in Italy on cardiac disease prevention and rehabilitation. Plans are also underway to establish a heart hospital in Tanzania. In addition, the organization has produced educational materials on health that primary school teachers can download and distribute to students. Burgarella has also started a new platform in Africa (www.healthafrica.info) to disseminate health information to the people. Since its formation, the HFATW has set up cardiac facilities in Eastern Europe, South America and Asia. Its mission to promote good health encompasses all aspects of body, mind and spirit. I think this is the new mission of the cardiologist that Id like to call integrated cardiology, where the relationship between
doctor and patient should be at the top of the list of the cardiologist. The best way to improve health is to re-establish the equilibrium of patients after myocardial infarction, for instance, or any illness that has broken the integrity between body, mind and spirit, Burgarella said. This may be difficult, but we need to work in this way if we love our patients. And that is exactly what patients need after a heart attack, bypass surgery or angioplasty they need to re-integrate their whole body. He said cardiologists presently take care of their patients body, but not their mind and spirit. This has to change because the mind is related to behavioral changes, which are crucial to reduce health risk factors. This connection between body, mind and spirit is the basis of a new branch of medicine called psychoneuroendocrinology, which takes care of the relationship between the mind and the endocrinology and immunological systems, and could give rise to new theories on the development of cardiovascular diseases. Studying this new subject may help cardiologists gain an integrated vision, besides preparing them to help patients in the best way possible with secondary prevention, ultimately leading to a modification of patients risk factors. On spirituality, Burgarella said doctors need to learn more about prayer and meditation. All people have their own spirituality, but the relationship between a patient and doctor could be improved if the doctor has compassion.
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more confident and enthusiastic in helping their patients get better, he said. Towards this end, Burgarella has started a program to teach meditation to doctors in Italy. He believes that meditation will have a collateral effect in improving the compassion of doctors. In future, I hope doctors will not only be good specialists, but also good people. For further information on HFATW, go to: www.hfatw.org
Being compassionate is one way doctors can forge a good relationship with patients. I think compassion is a good way to help people because they understand that their doctors support them. But improving the compassion of doctors is a difficult task. I may not be able to teach the doctor to improve his compassion, but I can teach the doctor to meditate, for instance, because meditation is one way where you can change your soul. Doctors can then become

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Singapore rugby tournament: Eye infections raise ire of visiting teams

Greg Town
ingapores Ministry of Health (MOH) says it is investigating cases of keratoconjunctivitis in young rugby players aged 5 to 17 who played in a tournament held at Singapores Turf City from 20-22 April. This is in response to information provided by the Centre for Health Protection (CHP) in Hong Kong. Immediately after the tournament, 33 individuals associated with two of the touring Hong Kong teams developed symptoms compatible with keratoconjunctivitis, such as red and itchy eyes, and were subsequently confirmed to have the condition, which is reportedly rare in Hong Kong. Many of the boys were incorrectly diagnosed and treated with steroids on their return, resulting in the apparent exacerbation of symptoms, and had to miss school and be confined to darkened rooms for weeks afterwards, leading to an outcry from parents. As of 24 May, surveys by clubs ascertained a further 80 to 90 keratoconjunctivitis cases amongst the Singapore teams, 14 in the Malaysia teams and 13 cases from the Australia teams. There was a total of 1,600 players at the tournament. Keratoconjunctivitis is a well known condition in Singapore, especially with ophthalmologists. Keratoconjunctivitis caused by microsporidial infection can be fairly severe and lasts for several weeks to more than a month, especially if the diagnosis has been missed earlier and topical steroids have been given,
Young rugby players contest the ball in muddy conditions during the Singapore tournament held in April.
One of the affected Hong Kong players whose eye was still red and painful weeks later.
said Dr. Au Eong Kah Guan, medical director and senior consultant at the Singapore International Eye Cataract Retina Centre, Mount Elizabeth Medical Centre. The condition occurs sporadically in Singapore during rainy seasons but can also occur in a small outbreak such as when a group of rugby
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We experienced heavy rain on the first morning of the tournament and the pitches became very muddy, said Spooner. I recall constantly hearing parents giving general advice to visiting and local players to wash mud from their hands and faces, especially from around the eyes. We also increased the number of medics on site, and these guys were irrigating dirty eyes throughout the event. While investigations are ongoing, the MOH has issued some advisories that members of the public should avoid using the Turf City fields for rugby when it is rainy or muddy and that those engaged in sports involving contact with soil or mud should maintain good personal hygiene. People are advised to wash their faces if they come into contact with mud, and use different towels for the face and body after engaging in such sports. MOH would [also] like to advise members of the public to seek early medical consultation should they experience similar symptoms such as itchy or painful red eyes with discharge occurring from two days up to three weeks after engaging in sports that involve contact with soil or mud.
players play on a wet field. Infection occurs when mud enters the eye. Common symptoms include redness of the eye, pain, foreign body sensation, photophobia, and reduced vision and tearing, added Au Eong.
Keratoconjunctivitis
caused by microsporidial
infection can be fairly severe and lasts for several weeks to more than a month
Mr. Derek Finch, a coach of the Hong Kong DB Pirates Under 10s team that played at the tournament in April, complained that the host club Tanglin Rugby Club (TRC) did not warn the touring teams about the general risks of playing rugby in Singapore. If only a warning had been made in writing by TRC to all from the outset and before the boys were playing, it would have allowed us, as parents and coaches, to have made informed decisions and managed our own charges effectively, said Finch. As a coach I feel a great responsibility for the safety of the boys and yet, five out of 11 from my age group have been laid low. As a father, it breaks my heart to see my son sitting in a darkened room, eye reddened and missing school. Sadly, other boys are in far worse condition than Jack. Tanglin Rugby Club vice-president and chairman of the Singapore Youth Rugby Union Club Leagues, Mr. Andrew Spooner, suggested however that warnings about the risks of eye infection at Turf City were adequately given before the games at the tournament.
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Molecular switch boosts immune response

Rajesh Kumar
ingapore scientists have identified a molecular switch that triggers the bodys innate immune response against viral infections. When turned on, the switch (called Brutons tyrosine kinase [BTK]) activates the production of interferons - a potent class of virus killers that enable the body to fight harmful pathogens such as dengue and influenza viruses. [PNAS 2012.DOI: 10.1073/ pnas.1119238109] This finding could pave the way for more effective therapies for humans that strengthen the bodys own immune response against viral infections, said the researchers from the Agency for Science, Technology and Research (A*STAR) Bioprocessing Technology Institute (BTI). They extracted a class of immune cells known as macrophages from both normal mice and from mice deficient in BTK and exposed them to dengue virus. The BTKdeficient immune cells were unable to produce interferons, and hence had much higher viral counts compared to the healthy immune cells that had high-levels of interferons to fight the virus effectively. To further demonstrate the critical role of BTK in anti-viral response, the team focused on BTKs role in Toll-like Receptor 3 (TLR3) signaling. TLR3 is needed for cells to activate the interferon response when cells are infected by viruses. They examined the effect of having a perpetually on or off BTK switch in
Singapore scientists have identified a molecular switch which can activate antiviral interferon production.
TLR3 signaling and found that a perpetually active or on BTK switch enhanced the production of interferon, resulting in a stronger and more lasting anti-viral response with significant reduction in dengue viral counts. An always off BTK switch led to a poor anti-viral response with very low levels of interferons produced, and little protection against the infection.
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July 2012
News
Skin immune cell origins found

Radha Chitale
ertain immune cells located in the skin that are important in initiating immune responses against pathogens were found to derive from embryonic yolk sac and fetal liver cells, according to Singaporean researchers. [J Exp Med 2012;209:1167-1181] The origin of these Langerhans cells, a type of dendritic cell, may help identify new vaccination strategies and treatments for autoimmune diseases and inflammatory skin disorders. Langerhans cells are the vanguard of protective immune responses to foreign bodies and pathogens as they are the first to see these invaders and signal other immune cells to act.
Normal dendritic cells are derived from bone marrow progenitors and are replaced constantly. Langerhans cells can last throughout life, derived first from early yolk sac cells and later replaced by cells recruited from the fetal liver once it develops, according to research from scientists at the Singapore Immunology Network at the Agency for Science Technology and Research. The researchers determined the lineage of these cells via fate-mapping. Although it is unclear whether the properties of Langerhans cells are a function of their origin, they do provide new pathways for treating diseases like psoriasis, the researchers said.
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July 2012
News
American workers benefit from occupational health insurance

Pank Jit Sin
study by the University of California Davis, US, has revealed that the bulk of the payment for workplace injuries and illnesses is paid by employer-provided health insurance and other private payers. The study found that workers compensation insurance in 2007 was only used about 20 percent of the time, with the other 80 percent of payment being forked out by the likes of Medicare, Medicaid, Social Security and other disability funds, as well as by employees. The authors of the study, which appeared in the April issue of Journal of Occupational and Environmental Medicine, said the situation led to artificially low workers compensation premiums that should be used to cover wage replacement and medical care for employees injured on the job instead. [2012 54(4):445-50 doi: 10.1097/ JOM.0b013e3182451e54] Based on 2007 data gathered from several government and non-profit organizations, the researchers found that workers compensation insurance only paid US$29.86 billion for medical cost claims for occupational injuries and illnesses. In comparison, the other payees were responsible for covering the remaining US$160.68 billion occupational injury health costs for that year. Dr. Paul Leigh, lead author and professor of public health sciences, UC Davis Center for Healthcare Policy, said the situation is a classic example of negative externality in economics as prices are not truly reflective of the costs that spill over to others, thus resulting in negative social outcomes. Leighs argument is that the workers
Increasing the premiums for workplace insurance may spur companies to provide better and safer working environments for their staff.
injuries and illnesses actually cost more than current compensation payments suggest. The corresponding low premiums (associated with such low claims) provide little incentive for companies to promote workplace safety. He suggested three changes in workers compensation and employee health practices eliminating the stigma associated with filing workers compensation claims by openly acknowledging the legitimacy of using workers compensation insurance for occupational injuries; encouraging more states to adopt single-payer governmentmanaged workers compensation systems to reduce administrative costs; and linking premiums with company-specific injury experience instead of industry-wide estimates (as this would encourage companies to lower premiums by reducing workplace hazards). These three changes would contribute to overcoming cost shifting and help ensure workplace safety. Leigh added that the ultimate goals (of the changes) would be to comprehensively address the way occupational health is managed and to establish cultures of safety for workers.
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July 2012
News
Cleaner air in Beijing reduced CVD biomarkers during 2008 Olympics

Radha Chitale
ecreasing pollution significantly impacted biomarkers associated with pathways for cardiovascular disease (CVD), according to a study conducted during the 2008 Olympic Games in Beijing, China. Air pollution is a risk factor for cardiovascular diseases, but the mechanisms by which air pollution leads to CVD is not well understood, said researchers from the University of Southern California in the US and Peking University in China. The Chinese government went to great lengths to decrease pollution and improve air quality between July and September of 2008 in preparation for the games, particularly sulfur dioxide, carbon monoxide and nitrogen dioxide. Measures included reducing vehicular traffic emissions, closing factories, halting construction projects, keeping roads damp to reduce dust and seeding clouds to induce rain. Particulate and gaseous pollutants decreased up to 60 percent during the Olympic Games. In a group of 125 healthy young adults, concentrations of soluble P-selectin and von Willebrand factor, markers for thrombotic and endothelial dysfunction, decreased significantly during the games compared to preOlympic Games concentrations. Subjects began the study in June 2008 and were followed up through October. Concentrations of soluble P-selectin and von Willebrand factor fell 34 percent and
31.1 percent, respectively (P<0.001 for both). [JAMA 2012;307:2068-2078] Biomarkers for inflammation, including C-reactive protein, fibrinogen and white blood cell count, heart rate and blood pressure were unaffected. Post-Olympics, environmental regulations were loosened and air quality returned to pre-Olympic pollution levels. All outcomes reverted to pre-Olympic levels except for soluble P-selectin and systolic blood pressure, which worsened. The researchers reported that previous cases of large-scale pollution reduction efforts resulted in significant health benefits including lower rates of cardiorespiratory mortality, bronchitis and hospital admissions for respiratory diseases but did not explore the potential underlying mechanistic pathways. The findings from our quasi-experimental design may reflect the effects of air pollution as a whole mixture rather than as the action of one or more specific pollutants, the researchers said. They also noted that the effects on older or more vulnerable populations could be more exaggerated than in their young, healthy cohort. Although these findings are of uncertain clinical significance, this study provides quasi-experimental mechanistic data to support the argument that air pollution may be a global risk factor for CVD.
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July 2012
In Practice
Therapeutics in osteoporosis: What every GP should know

Associate Professor Leong Keng Hong
Consultant Rheumatologist, Gleneagles Medical Centre, Singapore Adjunct Associate Professor, Yong Loo Lin School of Medicine, National University of Singapore
wrist. Of these, hip fracture is the most severe as it is associated with poor or slow healing after a surgical repair. Pathogenesis of osteoporosis Inadequate peak bone mass and imbalances in bone resorption and bone formation lead to structural deterioration and eventually, osteoporosis. Lack of estrogen as a consequence of menopause increases bone resorption and decreases bone deposition. Calcium metabolism may play an important role in bone turnover, as well as deficiency in calcium and vitamin D. Diagnosing osteoporosis As in any asymptomatic disease, a high index of suspicion is needed to diagnose osteoporosis. Fracture history at any site, fall history, height reduction and reduced body mass index (BMI) are important indicators, but the most significant clinical risk factors for validating osteoporotic fractures are age and weight, which have become the basis of the Osteoporosis Self-assessment Tool for Asians (OSTA) test. The OSTA test determines a patients risk of developing osteoporosis (high, moderate or low) and helps a physician decide who to send for a bone mineral density (BMD) test. A score of >20 in the OSTA test means the patient is at high risk, 0-20 equals moderate risk and <0 means low risk. Patients at high risk, or at moderate risk with other risk factors, should take a BMD test using a dual-energy x-ray absorptiometry (DEXA) scan. DEXA gives both the T score (deviation from the mean of the peak bone-
Osteoporosis: A silent epidemic Osteoporosis often called a silent disease is characterized by a low bone mass and deterioration of the bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. The condition primarily affects post-menopausal women, but may also affect elderly men. Bones undergo continuous remodelling through repeated cycles of destruction and rebuilding to prevent accumulation of bone microdamage. Osteoclasts and osteoblasts sequentially carry out resorption of old bone and formation of new bone. In the elderly and in post-menopausal women, the extent of bone resorption far exceeds bone formation, resulting in bone loss. If this continues over the years, the result is osteoporosis. Approximately 200 million women worldwide suffer from osteoporosis. It is estimated that by 2050, half of all fractures in the world will occur in Asia. In Singapore, the incidence of hip fractures rose five-fold to 403 cases per 100,000 in women >50, or eight times more than the breast cancer cases. Aside from hip fractures, the most common clinical outcomes of osteoporosis are fractures of the spine, pelvis, upper arm and
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July 2012
In Practice
mass) and the Z score (identifies secondary osteoporosis). Negative T and Z scores indicate weaker and thinner bones than normal bones. The more negative the number, the higher the risk of a bone fracture. A T score between -1 and -2.5 indicates osteopenia, the beginning of bone loss. A T score below -2.5 indicates osteoporosis. Aside from abnormal BMD, diagnosis requires investigation of underlying causes. While BMD testing does not diagnose fractures, it helps predict the risk of bone fracture in the future and can be used to track bone density changes over time. The FRAX algorithm calculates both the 10-year major osteoporotic and hip fracture risks of an individual and helps physicians to identify patients requiring immediate treatment. Women with osteopenia, for example, may need urgent intervention if their FRAX score is high. Traditional x-rays are good at picking up fractures, but may not detect osteoporosis until it has become advanced, or 30 percent of bone mass is already lost. Thus, early and accurate diagnosis is the key to preventing irreversible damage and disability that may arise from fractures. Signs and symptoms Osteoporosis has no signs or symptoms and patients may not be aware they have it until they suffer a painful fracture. Only one third of vertebral fractures come to medical attention, where patients typically present with acute back pain, reduction in height and curving of the spine or kyphosis (hunch back appearance or dowagers hump) due to vertebral collapse which is often seen in older women.
Osteoporosis, as is widely known, affects predominantly women, but may affect elderly men as well.
Clinical Guidelines GPs can refer to various guidelines on osteoporosis available at the International Osteoporosis Foundation website. Each country China, Malaysia, Philippines and Thailand has its own guidelines as the prevalence of osteoporosis, diagnosis and treatment of fractures may differ for each country. In Singapore, we have the Osteoporosis Clinical Practice Guidelines which we released in 2009, an updated version of which will be available in 2014. The Singapore guidelines recommend lifestyle measures such as increase intake of calcium, vitamin D and exercise 2-3 times a week particularly resistance and weight-bearing types to increase bone strength and posture stability. Treatment options The goal of treatment in osteoporosis is to improve bone health and prevent fractures. Aside from lifestyle changes, it also helps to reduce falls as it means fewer fractures.
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In Practice
When to refer Very often, the condition is not thought of. Patients who seek consultation for chest symptoms may have compression fractures, but very often, no further action is taken. The vast majority of osteoporosis patients should be managed by GPs, just like hypertension. In case of doubt, use the OSTA test. Then, decide which patient should undergo BMD testing. If the BMD result is abnormal, use the FRAX test. Young patients with fractures who may have endocrine problems and those who do not respond well to treatment should be referred to specialists. Osteopenic patients may also need referral if GPs are unsure whether treatment should be started. Conclusion Osteoporosis is a common, devastating condition that can be treated and prevented. Patients at risk of a first fracture and those with previous fractures need more than lifestyle changes. They need evaluation and specific medication. Once therapy has started, compliance is the key to preventing fractures. Osteoporotic fractures can lead to posture changes, muscle weakness, loss of height; and deformity of the spine. They can also cause chronic pain, disability, loss of independence and premature death. The earlier we treat, the more patients are saved from this debilitating disease.
There is no single drug for all patients. Estrogen replacement can slow bone loss in newly menopausal women. For younger patients (early 60s), there is a wide choice of treatment regimen. Selective estrogen receptor modulators (SERMs), raloxifene, for example, may prevent spine fractures. Biphosphonates (alendronate, risedronate, zoledronate) may be good at preventing both spine and hip fractures in the elderly; however caution is needed in patients with gastroesophageal reflux and kidney problems. Injection with prolia (a RANK ligand inhibitor) may reduce osteoporotic spine and hip fractures and is safe in patients with renal impairment. Some drugs such as teriparetide are bone-forming agents and strontium ranelate has a dual mode of action. Aside from proof of efficacy, the ideal drug should suit a patients fracture type, is convenient to take, is not costly and with fewer side effects. BMD testing can be done every year to monitor treatment response. I would only use bone turnover markers, for example urinary or serum collagen type 1 cross-linked C-telopeptide (CTX), to predict the degree of bone loss without therapeutic intervention and identify which patients to treat, particularly those with osteopenia. One in five patients with an incident vertebral fracture will have another fracture within a year. Thus it is important that vertebral fractures are detected early and treatment is started.
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July 2012
Calendar
European Society of Cardiology Congress 2012
25/8/2012 to 29/8/2012 Location: Munich, Germany Info: European Society of Cardiology Tel: (33) 4 9294 7600 Fax : (33) 4 9294 7601 E-Mail: ascoregistration@jspargo.com Website: www.escardio.org/congresses/esc-2012
38th Annual Meeting of Society of Pediatric Dermatology

11/7/2012 to 14/7/2012 Location: California, US Info: Society for Pediatric Dermatology Tel: (317) 202-0224 Fax: (317) 205-9481 Email: spd@hp-assoc.com Website: www.pedsderm.net
Upcoming
European Respiratory Society Annual Congress
1/9/2012 to 5/9/2012 Location: Vienna, Austria Info: European Respiratory Society Tel: (41) 21 213 01 01 Fax: (41) 21 213 01 00 E-Mail: ers2012groups@kit-group.org Website: www.erscongress2012.org/
30th International Congress of Psychology

22/7/2012 to 27/7/2012 Location: Cape Town, South Africa Tel: (27) 11 486 3322 Fax : (27) 11 486 3266 E-Mail: info@icp2012.com Website: www.icp2012.com
Healthcare in China 2012

24/7/2012 Location: Beijing, China Info: Economist Conferences Tel: (852) 2585 3312 Email: conferencesasia@economist.com Website: http://www.economistconferences.asia/event/HCCN
14th Congress of the International Society for Peritoneal Dialysis

9/9/2012 to 12/9/2012 Location: Kuala Lumpur, Malaysia Info: International Society for Peritoneal Dialysis Tel: (603) 2162 0566 Fax : (603) 2161 6560 E-Mail: ispd2012@console.com.my Website: www.ispd2012.org.my
17th World Congress on Heart Disease 2012

27/7/2012 to 30/7/2012 Location: Toronto, Ontario, Canada Info: International Academy of Cardiology Tel: (1) 310 657 8777 Fax: (1) 310 659 4781 E-Mail: Klimedco@ucla.edu Website: www.cardiologyonline.com
Hospital Management Asia 2012

13/9/2012 to 14/9/2012 Location: Hanoi, Vietnam Info: Ms. Sheila Pepito Tel: (632) 846 8339 Email: sheilapepito@exedraevents.com Website: hospitalmanagementasia.com
August
11th Asian Congress of Urology of The Urological Association of Asia
22/8/2012 to 26/8/2012 Location: Pattaya, Thailand Info: 11th ACU Local Organiser Tel: (662) 287 3942 to 3 Fax: (662) 677 5868 Email: secretariat@11thacu2012.org Website: http://www.11thacu2012.org/
15th Biennial Meeting of the European Society for Immunodeficiencies (ESID 2012)
3/10/2012 to 6/10/2012 Location: Florence, Italy Tel: (41) 22 908 0488 Fax: (41) 22 732 2850 Email: esid@kenes.com Website: www.kenes.com/esid
82
July 2012
Calendar
42nd Annual Meeting of the International Continence Society

15/10/2012 to 19/10/2012 Location: Beijing, China Tel: (41) 22 908 0488 Fax: (41) 22 906 9140 Email: ics@kenes.com Website: www.kenes.com/ics
National Diagnostic Imaging Symposium

2/12/2012 to 6/12/2012 Location: Orlando, Florida, US Info: World Class CME Tel: (980) 819 5095 Email: office@worldclaswscme.com Website: www.cvent.com/events/national-diagnostic-imaging-symposium-2012/event-summary-d9ca77152935404ebf0404a0898e13e9. aspx
Asian Pacific Digestive Week 2012

5/12/2012 to 8/12/2012 Location: Bangkok, Thailand Tel: (66) 2 748 7881 ext. 111 Fax: (66) 2 748 7880 E-mail: secretariat@apdw2012.org Website: www.apdw2012.org
World Allergy Organization International Scientific Conference (WISC 2012)

6/12/2012 to 9/12/2012 Location: Hyderabad, India Info: World Allergy Organization Tel: (1) 414 276 1791 Fax: (1) 414 276 3349 E-mail: WISC@worldallergy.org Website: www.worldallergy.org
83
July 2012
After Hours
Chengdu Land of Tea

,
hengdu is truly a place of stark contrasts and contradictions. At one end of the spectrum are large modern buildings and tall elevated highways looming over the city; at the other, you have the old weathered historical buildings dating back centuries and narrow pedestrian walkways. You have Starbucks outlets at every corner and quaint little tea houses dotting the sidewalks. There is a big tea-drinking culture in Chengdu, with many types of green teas grown locally. People sip tea on the sidewalks, people-watching and whiling away the time. There is an unusual level of coziness among the people at the teahouses, which is in sharp contrast to the hustle and bustle around them. The tea culture dates back to the Western Han period from 206 BC and 220 AD, when both the tea trade and tea culture were thriving in Sichuan province, with Chengdu as the starting point of the Southern Silk Road.
Tao& Pandas
Chengdu epitomizes todays China modern, yet historical and quaint. Leonard Yap writes.
About an hours drive (without trafc) and 70 km out of Chengdu lies Mount Qingcheng. Among the most important centers of Taoism in China, it is situated on the outskirts of Dujiangyan City and connected to downtown Chengdu by a modern expressway.
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July 2012
After Hours
boo groves that mimic the animals native habitat. It is very entertaining to watch pandas going through their daily routine, which includes eating bamboo, taking a nap and playing (for the young ones). One can only feel a hint of envy at the life of the panda, devoid of the complications of human life. Chengdu is certainly a place of surprises and contrasts, where one can get away and yet not be too far away from the conveniences of modern life.
With its peak 1,260 m above sea level, Mount Qingcheng is cool and green all year round, and surrounded by hills and waterways. Laojun Temple and Qingcheng Celestial Hall top its peak and is made easily accessible via cable car. Cable cars glide up through the green forest, providing a breathtaking view of the surrounding mountains. For the adventurous, the climb to the summit is a spirited trek sprinkled with spectacular views and little temples dotting the path. Taoism is a fundamentally Chinese philosophy and religious tradition that emphasizes living in harmony with the Tao, which can be translated as the way or path. Its sacred text, the Tao Te Ching, opens with this poetic line, The Tao that can be named is not the absolute Tao, pointing to a spiritual force that is ultimately beyond our grasp. Taoism emphasizes wu wei (action through inaction), simplicity, spontaneity and harmony between the individual and the cosmos. No trip to Chengdu is complete without a visit to the Giant Panda Research Base. It has a huge breeding and research base for giant and red pandas, and attracts scores of visitors from all over the world. Covering an area of 106 hectares, the research base is filled with bam-
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July 2012
Humor
Take it easy!
What a pleasant surprise for a change. With all the hypochondriacs coming here, its nice to see someone whos actually sick!
Remember the pills you prescribed to boost my self-confidence? Well, they worked, I just robbed the bank across the street!
We are gonna have to open you up again. My colleague cant find his wedding ring!
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July 2012

OSA can be successfully managed in primary care

FORUM Surviving the approaching tsunami of diabetes

IN PRACTICE Therapeutics in osteoporosis

CONFERENCE Promising drug combination for breast cancer

AFTER HOURS Chengdu Land of Tea, Tao and Pandas

OSA can be successfully managed in primary care

International diabetes research prize announced

A biennial prize of US$250,000 is being offered to recongnize breakthroughs in diabetes research.

Surviving the approaching tsunami of diabetes

Hong Kong Focus

Anabolic therapy improves functioning in osteoporosis

Hong Kong Focus

The Complete Solution

DRUG INTERACTION CHECKER MEDICAL NEWS

MEDICAL EVENTS PUBMED

Hong Kong Focus

Call for more aggressive therapy in RA

Hong Kong Focus

Tighter checks on adverts for oral products

Hong Kong Focus

Experts advocate home-based NIV for respiratory failure

Hong Kong Focus

Tocilizumab monotherapy in rheumatoid arthritis

Hong Kong Focus

Hong Kong Focus

Adopting a proactive approach in atopic dermatitis

Hong Kong Focus

JPOG is NOW CME-Accredited...

Hong Kong Focus

Advances in Medicine (AIM)*, 2-3 June 2012 Naomi Rodrig reports

Chronic chest pain evaluation: High-tech or low-tech?

Hong Kong Focus

Hong Kong Focus

Advances in Medicine (AIM)*, 2-3 June 2012 Naomi Rodrig reports

New hope for Parkinsons patients

Hong Kong Focus

Hong Kong Focus

Survey: High burnout rates among HA doctors

22 HKMF Meeting Higlights

DPP-4 inhibitors: Looking beyond glycemic control

23 HKMF Meeting Higlights

Sitagliptin (n=210) Glipizide (n=212)

0.5 0.9 Vomiting

Symptomatic Severe Required hypoglycemia hypoglycemia non-medical 6.2 assistance

Required medical assistance

0.5 0.9 Vomiting

Required medical assistance

T2DM = type 2 diabetes mellitus

Adapted from Proc EASD 2011.

Figure 2. Add-on sitagliptin vs increasing insulin dose in insulin-treated patients

Event / person-year Event / person-year

Event / person-year Event / person-year

Sitagliptin HbA Insulin

*p<0.05 vs insulin titration; * p<0.05 vs baseline * 8

*p<0.05 vs insulin titration; p<0.05 vs baseline

24 HKMF Meeting Higlights

Adapted from Circ Cardiovasc Imaging 2010;3:195-201.

25 HKMF Meeting Higlights

Evolving concepts in hepatitis C therapy

26 HKMF Meeting Higlights

39 20 77 51 142 113 32 27 34 16 29 24 118 47 59 40 50 54 36 8 22 99 52

27 HKMF Meeting Higlights

Figure 1. Adding boceprevir to pegIFN alfa-2b+RBV: Treatment-experienced genotype-1 patients

p<0.05 vs insulin titration; p<0.05 vs baseline * 8