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2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Nonvoting panel:
Philippine Health Insurance Corporation
Past Presidents and the Directors of the PHA and the offices of the
PHA President, the PHA Vice President and the PHA Treasurer
iii
iv
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Voting Panelists
Paul Ferdinand M. Reganit, MD
PHA Council on Preventive Cardiology
Victor L. Lazaro, MD
Jane Villaseor-Andaman, MD
PHA Council on Coronary Artery Disease
Federick C. Cheng, MD
Bernadette S. Halasan, MD
Raymund Paul C. Baello, MD
PHA Council on Hypertension
Romeo U. Merino, MD
Camilo G. Te, Jr, MD
Manila Doctors Hospital
Rosa Allyn-Sy, MD
Philippine Lipid and Atherosclerosis Society
Frederick Philip B. Gloria, MD
Philippine College of Physicians
Elmer M. Angus, MD
Philippine Academy of Family Physicians
Cecilia Cristina Santos-Acuin, MD
Charmaine A. Duante, RMT, MSc
Food and Nutrition Research Institute
Department of Science and Technology
Carmela N. Granada, MD
Department of Health
Adela Jamorabo-Ruiz, RND, MSN, DPA, PhD
Ms. Elisa D. Toledo
Nutritionists-Dietitians Association of the
Philippines
Ma. Janetth B. Serrano, MD
Philippine Medical Association
Ignacia G. Fajardo, MD
Las Pias General Hospital
Bien J. Matawaran, MD
Philippine Society of Endocrinology, Diabetes
and Metabolism
Non Voting Panelists
Leisa Jeanne Rave C. Gobenciong, MD
Philippine Health Insurance Corporation
Nannette R. Rey, MD
Aurelia G. Leus, MD
Orlando R. Bugarin, MD
Directors, Philippine Heart Association
Jorge A. Sison, MD
Secretary, Philippine Heart Association
Helen Ong-Garcia, MD
Treasurer, Philippine Heart Association
Raul L. Lapitan, MD
Vice President, Philippine Heart Association
Alex T. Junia, MD
President, Philippine Heart Association
Eugenio B. Reyes, MD
Joel M. Abanilla, MD
Past Presidents, Philippine Heart Association
Adriel E. Guerrero, MD
Chairman, Philippine Heart Association
Council on Preventive Cardiology
Technical Research Committee
Lourdes Ella Gonzalez-Santos, MD
Chair
Members
Imelda V. Caole-Ang, MD
Jude Erric L. Cinco, MD
Cecilia A. Jimeno, MD
Elmer Jasper B. Llanes, MD
Raymond V. Oliva, MD
Deborah Ignacia D. Ona, MD
Noemi S. Pestao, MD
Felix Eduardo R. Punzalan, MD
Facilitator to the Technical Research
Committee
Steering committee
Leandro C. Bongosia, MD
Chair
Adriel E. Guerrero, MD
Co-chair
Members
Bien J. Matawaran, MD (PSEMD)
Albert Atilano, MD (PLAS)
Joel M. Abanilla, MD (PHA)
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
CLINICAL QUESTIONS
CQ1 Among patients diagnosed to have dyslipidemia, regardless
of their present morbid condition or risk profile, should
lifestyle modifications (i.e., smoking cessation, weight
management, regular physical activity and adequate blood
pressure monitoring and control) be advised to reduce
overall CV risk?
CQ2 Among non-diabetics without ASCVD but with multiple risk
factors, should statin therapy be given?
CQ3 Among diabetic individuals without ASCVD, should statins
be recommended?
CQ4 Among diabetic individuals without ASCVD, should fibrates
be recommended as an alternative to statin therapy?
CQ5 Among patients with established ASCVD, should statins be
given?
CQ6 Among individuals with ASCVD, should fibrates be given as
an alternative to statins?
CQ7 Among patients with acute coronary syndrome (ACS),
should statin therapy be given?
CQ8 Among patients with established ASCVD or diabetes,
should lipid profile determination be done?
Among patients without ASCVD but with multiple risk
factors, should lipid profile determination be done?
CQ9 Among patients with ASCVD, should omega-fatty acids be
given as an alternative to statin treatment?
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
CONTENTS
Background................................................................................. 5
Scope of the guidelines............................................................. 5
Methods....................................................................................... 6
Literature Search.......................................................................... 6
Clinical Questions......................................................................... 6
Clinical Outcomes........................................................................ 7
Data Analysis................................................................................ 8
Formulation of Recommendations............................................... 9
Consensus Building...................................................................... 9
Epidemiology of Dyslipidemia in the Philippines.................. 10
CPG CQs and Recommendations............................................. 13
Clinical Question 1................................................................... 13
Statement 1.1 Diet.................................................................... 14
Summary of Evidence................................................................ 14
Addressing Malnutrition.............................................................. 18
Statement 1.2 Smoking Cessation........................................... 19
Summary of Evidence................................................................ 19
Use of Electronic Cigarrettes as Alternative to Cigarrette
Smoking and as a smoking cessation aid............................ 20
Statement 1.3 Exercise............................................................ 20
Summary of Evidence................................................................ 21
Exercise Prescription.................................................................. 21
Clinical Question 2................................................................... 22
Statement 2............................................................................... 22
Summary of Evidence................................................................ 23
Comparison with Other Guidelines............................................. 24
Clinical Question 3................................................................... 25
Statement 3............................................................................... 25
Summary of Evidence................................................................ 25
Recommendation from Other Guidelines................................... 26
Clinical Question 4................................................................... 27
Statement 4............................................................................... 27
Clinical Question 5................................................................... 27
Statement 5............................................................................... 27
Summary of Evidence................................................................ 27
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
BACKGROUND
The Philippine Heart Association, the Philippine Lipid and
Atherosclerosis Society, and the Philippine Society of Endocrinology,
Diabetes, and Metabolism, collaborated to develop the 2015 Clinical
Practice Guidelines for the Management of Dyslipidemia in the
Philippines (2015 CPG). These guidelines are meant to update the 2005
Clinical Practice Guidelines on the Management of Dyslipidemia in the
Philippines (2005 CPG). A panel of experts in the fields of dyslipidemia,
cardiology, endocrinology and clinical epidemiology were assembled
to comprise the technical research committee (TRC) tasked to review
available clinical evidence on dyslipidemia management. Together
with a panel of experts, the TRC developed specific recommendations
regarding the treatment of dyslipidemia among various risk groups.
The main objective for this document is to develop clinical guidelines in
the management of Filipino patients who are diagnosed with elevated
cholesterol. This may influence standards and national policies for
optimal patient care and cardiovascular health.
The physician may use the recommendations confidently in caring
for most patients, and is meant to guide practices that meet the needs
of patients in most but not all circumstances. The ultimate decision must
be made by the Filipino physician and patient together, and should not
be a replacement for clinical judgment.
SCOPE OF THE GUIDELINES
The scope of this CPG includes current statistics on the prevalence
of dyslipidemia in our setting, recommendations on screening and
monitoring using lipid profile determination, identification of groups at
risk for cardiovascular (CV) events which will be targeted for prevention
and treatment, and recommendations for the treatment of dyslipidemia
for the prevention of CV events and mortality in Filipinos.
Primary prevention refers to interventions in patients without
prior coronary heart disease (CHD) or other clinical atherosclerotic
cardiovascular disease (ASCVD). Primary prevention of CV events
targets individuals who are considered to be at-risk including those
with diabetes mellitus (DM) or multiple risk factors (i.e., advanced age,
male gender, smoking, hypertension, body mass index [BMI]> 25 kg/m2,
family history of premature CHD[first-degree relatives with fatal or nonfatal myocardial infarction, coronary angioplasty, coronary artery bypass
surgery or stroke before the age of 55 years in male relatives or before
65 years of age in female relatives]1, familial hypercholesterolemia [an
elevated cholesterol level > 190 mg/dL, the presence of xanthomas and
a family history of premature cardiovascular disease]2, and laboratory
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
CQ2
CQ3
CQ4
CQ5
CQ6
CQ7
CQ8
CQ9
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Outcome
NNT
Recommendation
High
Critical
Low
Strongly Recommend
Moderate
Critical
Low
Recommend
Moderate
Important
Low
May Recommend
Low
Critical or
important
High or not
significant
Do not recommend
10
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Prevalence, %
2003
2008
2013
33.5%
31.4%
46.9%
43.2%
31.4%
47.2%
54.2%
64.1%
71.3%
30%
30.1%
38.6%
Reconstructed from the 2003, 2008 and 2013 FNRI NNHES data
* Based on ATP-III cut off values
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
11
12
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Figure 3. Prevalence of low HDL-C (<40 for males and <50 mg/dL
for females) among adult Filipinos by age group
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
13
14
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
15
16
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Evidence Relative
Overall
Overall
Quality Importance Control Rate Treatment
Rate
Relative
Risk
NNT
Total Mortality
High
2404/40957 1888/30833
0.98
(0.93,1.04)
NS
Cardiovascular
Deaths
High
774/37840
633/28138
0.94
(0.85,1.04)
NS
High
1174/37280
894/27611
0.9
(0.72,1.11)
NS
Strokes (Fatal
and nonfatal)
High
683/34790
NS
Cardiovascular
events
Moderate
209
Coronary
intervention
Moderate
NS
NS
NS
NS
cholesterol.
Reduction or modification of dietary fat may be protective of
cardiovascular events, with a decrease in levels of total and LDL
cholesterol, and triglycerides. However, the trials showed no clear benefit
on overall mortality and cardiovascular mortality. Table 4 summarizes
the results of the review and the relevant outcomes.
The latest guidelines from the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines9
emphasized that lifestyle modification, particularly heart healthy diets,
remains a critical component of health promotion atherosclerotic
cardiovascular disease, both prior to and in concert with the use of
cholesterol-lowering therapy. The International Atherosclerotic Society10
released a position paper recommending a reduction of saturated fat
in the diet to <7%, decreasing trans fat by 1%, and dietary cholesterol
to < 200 mg/day of the daily total calorie intake. This is similar to
the recommendations of the National Institute for Health and Care
Excellence of the United Kingdom 2014.11
Simple Dietary Plan for Fat Modification
In the Philippines, the Food and Nutrition Research Institute (FNRI)
has developed a food pyramid, which is a simple and easy to follow
daily eating guide and is based on the daily food intake of Filipinos. A
comprehensive list of food menu was published in the 2005 Philippine
Practice Guidelines. Based on the food pyramid, the total fat intake is
only 15% of the total caloric intake, accounting for the low calorie intake.
It was advised in the FNRI food pyramid to increase fat intake by adding
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
17
margarine or butter in the diet, and some of the invisible oils found in
fruits and nuts.
In 2014, the FNRI released a simpler version of the food pyramid,
which they termed as Pinggang Pinoyor Pinoy Plate (Figure 5 and
Table 5). It used a science-based approach with the best scientific
evidence and compliments and supplements the food pyramid of the
FNRI. It serves as a reminder to Filipinos on how to fill up their plates
properly. A nine-inch plate is advised, and distributing foods proportionally
among the food groups provides approximately 1,200 to 1,500 calories
per day. It is advised that half of the plate is composed of green leafy
vegetables and one serving of fruit per meal. For fruits, 4 to 6 servings
are encouraged per day.
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2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Vegetables
Fruits
Addressing Malnutrition
Malnutrition due to low caloric and low protein intake is an important
public health problem in the Philippines, even among adults. Data from
the Food and Agriculture Organization reported that 17% of Filipino
adults are underweight for age.12 Malnutrition is also a major problem
among certain patient subgroups, such a chronically ill patients, where
the prevalence can exceed 70%.13 Malnutrition in these patients
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
19
adversely diminish outcomes. Data from NNHeS showed that one out
of ten (10.0%) adults have chronic energy deficiency (CED, BMI <18.5),
while three out of ten (31.1%) are overweight or obese.
Therefore, it is important to perform an overall assessment of
nutritional status in patients when advising about dietary changes.
Dietary advice should ensure that patients, even those with evidence
of cardiovascular disease, do not predispose the patient to caloric and
protein malnutrition. In underweight patients, majority of the caloric
intake comes from carbohydrates and proteins to ensure low fat intake.
A referral to a nutritionist or dietitian is recommended in all patients,
regardless of nutritional status, when accurate dietary advice is sought.
Statement 1.2 Smoking Cessation
For individuals at any level of cardiovascular risk, cigarette smoking
cessation is STRONGLY RECOMMENDED.
Summary of Evidence
Randomized controlled trials on smoking cessation and their effect
on cardiovascular morbidity and mortality were included in the review
for this recommendation. There are 1,355 clinical trials on smoking
cessation but, only three (3) trials had relevant outcomes and were thus
included. All three trials looked at primary prevention outcomes. Two
of the studies looked at multiple risk factors, such as diet and smoking
cessation, while the last one also included respiratory and cancer
outcomes.
The clinical trials included in the CPG are seen in the appendix.
Two clinical trials, MRFIT and OSLO study included men with multiple
risk factors, while the Lung Health Research Study Group had both men
and women in the study.14-16 The interventional group had an intensive
treatment program for smoking cessation, which include behavior
modification and may use devices such as nicotine gum or patches.
Table 6 summarizes the review and relevant outcomes. Statistically
significant results are seen in the total mortality (N=18,023; RR 0.90
[95% CI 0.82, 0.99)], and acute major CV events (N=18,023; RR 0.85
[95% CI 0.76, 0.95). There was a trend towards benefit of cigarette
cessation in CV mortality. Only one trial looked at secondary outcomes
such as MI and stroke, and the former outcome showed a trend in favor
of cigarette cessation.
The GRADE balance sheet seen in the appendix combines the
appraisal of the studies included in the guideline recommendation with
the outcomes. Generally, the quality of the evidence is moderate with
the downgrade due to the question of directness. The studies were all
20
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Studies
Participants
Effect Estimate
(RR, 95% CI)
Total Mortality
18,023
Cardiovascular
deaths
16,791
2 fewer per
1000 (500)
Fatal and
nonfatal
myocardial
infarction
12,866
Cardiovascular
events
18,023
12,866
Stroke
NNT
NS
10 fewer than
1000 (100)
NS
21
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Studies
Participants
6,027
Cardiovascular
mortality
5,305
Cardiovascular events
5,305
48
Non-fatal myocardial
infarction
160
Stroke
5,305
Coronary intervention
5,312
Summary of Evidence
Literature review revealed 48 articles that evaluated the benefit
of exercise on the risk of cardiovascular outcomes. Mostly were
observational and cohort studies. The lack of randomized controlled
trials was mostly attributed to poor long-term adherence to exercise
programs. Furthermore, only a few studies evaluated hard cardiovascular
outcomes. Thus, only four studies were included in the analysis: the
LOOK Ahead trial, the STENO2 trial, the Chengdu trial, and the study by
Fowler and colleagues (2002).18-22
In general, these studies recommended approximately 150 minutes
of moderate- to high-intensity exercise per week. Pooled analysis
revealed that such an exercise regimen reduced major acute coronary
events by 25%, and non-fatal myocardial infarction by 71% (Table 7).
Quality of evidence for the important outcome of major adverse
cardiovascular events was moderate, with an NNT of 48. Additionally,
exercise was found to marginally reduce LDL-C by 17.4 mg/dL (0.45
mmol/L), triglycerides by 20.37 mg/dL (0.23 mmol/L), and increase
HDL-C by 0.7 mg/dL (0.02 mmol/L).
Thus, exercise of approximately 150 minutes of moderate- to highintensity exercise per week is recommended in individuals to improve
patients outcomes.
Exercise prescription
Compliance is one of the major difficulties when prescribing exercise
to patients. It is important to highlight that consistency and regularity are
important so that exercise becomes an integral part of a patients lifestyle.
One way to achieve this is to explain that the time allotted per week
should be split into several exercise sessions. In this case, 150 minutes
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2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
per week should be cumulated from around five sessions per week with
a duration of 30 minutes. This will also ensure that the exercise sessions
do not interfere with a persons daily routines. Furthermore, physical
activity may be integrated into their daily routine, such as climbing of
stairs or brisk walking.
It is important to specify that the patient should exert moderate to
intense activity during exercise. A general rule is that they should have
difficulty speaking during the exercise. However, at the same time, they
should not be experiencing symptoms such as chest pain, difficulty of
breathing, or dizziness/syncope. Examples of exercises may include
swimming, jogging, brisk walking, stair-climbing, cycling, dancing, sports
activities, and supervised aerobic exercise programs. Slow exercises
such as yoga or tai chi may improve strength and flexibility, but may be
inadequate in intensity as the patient becomes physically stronger.
The physician should assess the functional capacity and overall
risk of patients before prescribing exercise. If assessment reveals that a
patient is physically incapable of safely performing moderate to intense
exercise, refer the patient for physical rehabilitation and strengthening
to a qualified physiatrist.
Clinical Question 2
CQ 2. Among non-diabetics without ASCVD but with multiple risk
factors, should statin therapy be given?
This clinical question aims to give guidance to the use of cholesterollowering treatment for primary prevention in patients with several
cardiovascular risk factors. These risk factors were identified based on
the clinical trials reviewed for the CPG.
Statement 2
For non-diabetic individuals aged 45 years with LDL-C 130 mg/
dL AND 2 risk factors*, without atherosclerotic cardiovascular disease,
statins are RECOMMENDED for the prevention of cardiovascular
events.
*Risk factors are: male sex, postmenopausal women, smoker,
hypertension, BMI > 25 kg/m2, family history of premature CHD,
microalbuminuria, proteinuria, and left ventricular hypertrophy.
*Patients who fulfill the criteria for the diagnosis of familial
hypercholesterolemia (see statement 6 on screening and lipid
monitoring for familial hypercholesterolemia) should be initiated therapy
for aggressive LDL-C lowering
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
23
Summary of evidence
Randomized controlled trials (RCT) evaluating statins in individuals
without atherosclerotic cardiovascular disease (ASCVD) with at least a
minimum duration of one-year follow-up were reviewed for this clinical
question. A total of 7 RCTs were included, with a minimal number of
diabetics evenly distributed in both arms (with the exception of the MEGA
and ASCOT-LLT which have 21% and 24% diabetics, respectively)
(Appendix 1, Table 1.4).23-29 Trials whose entry criteria included the
presence of diabetes mellitus were evaluated in a different subgroup.
All of these trials either used total cholesterol (TC) and/or LDL-C as part
of their inclusion criteria, with the lowest levels seen in the JUPITER
trial, which were 168 mg/dl for TC and 94 mg/dL for LDL-C. Lipid profile
determination was repeated after 3 months and was done yearly until
the end of these studies. The average reductions in TC and LDL- C in
the clinical trials were 20% and 29%, respectively. The average age of
the trial participants was 58 years old with a range of 44 -71 years of
age.
As for the desired outcomes, statins in individuals without
ASCVD showed a significant reduction in all-cause mortality by 19%,
cardiovascular death by 33%, myocardial infarction (MI) by 39%, stroke
by 26%, cardiovascular (CV) events by 27% and coronary intervention
by 29% (Table 8). Even if MEGA and ASCOT-LLT, which have a modest
number of diabetics, were excluded from the analysis, all of these
outcomes remained significant.
These trials enrolled mostly men with at least 1 other risk factor.
Based on the INTERHEART study, as the number of risk factor increases
in an individual, the incidence of a myocardial infarction increased as
well.30 Therefore, the TRC agreed that if an individual has 2 or more risk
factors, statin is recommended due to the fact that there were significant
reductions in the pre-specified outcomes.
The quality of evidence was mostly moderate owing to indirectness
in the enrolled population which mostly included Caucasians, with
the exception of the MEGA study, which enrolled Japanese patients
(Appendix 1 Table 1.4). The evidence on cardiovascular events as an
outcome was graded as low due to its issue of inconsistency with a large
I2 of 59% (this could be due to CV events being a secondary outcome in
all the trials with the exception of AFCAPS/TexCAPS). All the outcomes
were deemed critically important except for coronary revascularization,
which was important since it is an outcome least likely to happen if these
24
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Studies
Total
Participants
Effect Estimate
(RR, 95% CI)
NNT
Total Mortality
42,534
0.81 (0.72-0.90)
167
CV death
50,450
250
MI
50,450
111
Stroke
43,845
250
Cardiovascular
events
42,544
56
Coronary
intervention
49,586
100
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
25
26
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Studies
Participants
Effect Estimate
(RR, 95% CI)
NNT
Total Mortality
2,837
0.73 (0.53,1.010)
NS
7,544
NS
27,810
100
Stroke
27,810
200
Cardiovascular
events
16,095
45
Coronary
intervention
25,783
200
dL. The studies included both genders, and the age range for most of the
studies is from 45 to late 70s, with the PROSPER study being specific
for elderly 70-82 years.
Table 9 summarizes the results of the review and the relevant
outcomes. Statistically significant results are seen from the outcomes
of fatal and nonfatal MI (N=27,810, RR 0.73 [0.64, 0.83]), stroke
(N=27,810, RR 0.75 [0.63, 0.89]), acute major CV events (MACE) (N=
16,095, RR=0.78 [0.70, 0.86]) and coronary interventions (N=25,783,
RR= 0.84 [0.73, 0.97]). A trend to benefit is seen for the outcomes of
total mortality, and CV death. Significant impact on clinical outcomes
was achieved using even low to moderate intensity statins.
The GRADE balance sheet combines the appraisal of the studies
included in the guideline recommendation with the outcomes. Generally,
the quality of the evidence is moderate with the downgrade due to
the question of directness. The studies were all done in Caucasian
populations and Asians, and in particular Filipinos were not included in
the samples that were included in these trials. Likewise, 5 out of the
8 studies were subgroup analysis of diabetic individuals from a larger
group of individuals with no previous cardiovascular events.
Thus, the recommendation is only moderate for the use of statins for
primary prevention in diabetic individuals without ASCVD.
Recommendation from other guidelines
Other guidelines have similar recommendations but add on a layer
of risk on top of diabetes mellitus. For example, the Canadian Diabetes
Association guidelines recommend statin therapy for diabetic individuals
with an indication for lipid-lowering therapy.38 The American Diabetes
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
27
28
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Studies
Total
Participants
Effect Estimate
(RR, 95% CI)
NNT
General population
All cause
Mortality
15
60,166
67
CV death
14
59,949
62
Myocardial
infarction
13
54,018
45
Stroke
11
52,426
83
4,351
16
Myocardial
infarction
1,091
NS
Stroke
2,370
37
All-cause
mortality
707
NS
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
29
% LDL-C reduction
Drug regimen
Low intensity
< 30%
Fluvastatin 20-40 mg
Pravastatin 10-20 mg
Simvastatin 10 mg
Moderate intensity
30% - 50%
Atorvastatin 10-20 mg
Fluvastatin 80 mg
Rosuvastatin 5-10 mg
Simvastatin 20-40 mg
Pravastatin 40-80 mg
High intensity
> 50%
Atorvastatin 40-80 mg
Rosuvastatin 20-40 mg
The GRADE balance sheet for the appraisal of evidence on the use
of statins in secondary prevention among patients with ASCVD and DM
showed that the quality of evidence is moderate for both subgroups,
with the quality downgrade resulting from questions of directness.
The studies included were all performed on Caucasian populations.
Asians, particularly Filipinos, were not well-represented in these trials.
Heterogeneity of pooled studies also resulted in serious inconsistencies
and a further downgrade of the evidence.
Evidence on the appropriate statin intensity for secondary prevention
in individuals with ASCVD were obtained from 4 trials (Appendix 2 Table
2.8) that compared varying statin regimens: Armitage et al (2010), Phase
Z of the A-Z trial(2004), TNT (2005) and IDEAL (2005) clinical trials.63-66
These abovementioned studies compared high intensity (atorvastatin
80 mg or simvastatin 80 mg) to medium intensity (atorvastatin 10 mg
or simvastatin 20 mg) statins. High intensity statins reduce LDL-C by
>40%, compared to low intensity statins which reduces LDL-C by 2030%.
Analysis of the evidence on high-intensity vs moderate intensity
statin therapy using GRADE Pro showed that the quality of evidence
is moderate, with quality downgrade due to the question of directness.
Filipinos where not well represented in the clinical trials, and were mostly
done in Caucasians. The evidence was able to show a net benefit
favoring high-intensity statin therapy in reducing the critical outcome
of myocardial infarction (RR 0.85; 95% CI 0.78-0.92).
This updated guideline recommends that high-intensity statin
therapy be used in secondary prevention of patients diagnosed with
ASCVD. It should be emphasized that the definition of statin treatment
intensity rests on the degree of LDL-C reduction, and less on the drug
dose used. There are some evidences that Asians may require a lesser
30
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
dose to achieve target LDL-C goals, and using high dose statins may
lead to higher risk of developing adverse drug reactions. One trial
looking at the efficacy of simvastatin and atorvastatin 20 mg once daily,
which included Filipinos, reduced LDL-C levels by 34.8% and 42.5%
respectively; however, the sample size is small.67 Thus, there is a need
to conduct a bigger clinical trial for Filipino patients. The TRC decided
to retain the table on statin intensity to be used for Filipino patients for
secondary prevention (Table 11) and LDL-C reduction as applicable to
our population. Needless to say, we also recommend to individualize
treatment in patients who may develop intolerance to high dose statins,
that physicians use appropriate statin dose that will achieve the needed
treatment reduction goal but will also minimize the risk of adverse events.
Statin Treatment Goal
In general, the 2015 CPG recommends a 30% or greater reduction
in LDL-C for appropriate treatment goal with statin therapy, as trials
on moderate- vs high-intensity statin therapy have shown a dosedependent response in terms of benefit in the reduction of adverse
outcomes. However, for purposes in clinical practice, a treatment goal
LDL-C level of < 70 mg/dL may be recommended, as adapted by some
international guidelines.
Comparison with other guidelines
Several international guidelines have their own recommendations for
managing patients with established ASCVD. The 2011 European Society
of Cardiology (ESC) guidelines on dyslipidemia recommend statins at the
highest tolerable dose as part of the interventions for patients with very
high cardiovascular risk, including those with established cardiovascular
disease.31 The 2012 Canadian Cardiovascular Society guidelines
likewise recommend statins for those with high risk (e.g., those with
clinical vascular disease or those with Framingham Heart Risk score
>20%).68 Treatment is focused on achieving target serum lipid levels,
and dose is adjusted accordingly to this end. On the other hand, the
2013 American Heart Association/American College of Cardiology (AHA/
ACC) guidelines recommend that high-intensity statin therapy should be
initiated or continued as first-line therapy in those 75 years of age or
younger who have clinical ASCVD, unless contraindicated.9 Moderateintensity statin therapy is indicated only in those who cannot tolerate
high-intensity statin therapy. Judicious use of statins after consideration
of benefits and risks is recommended for those with clinical ASCVD
aged over 75 years.
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
31
Clinical Question 6
CQ 6. Among patients with ASCVD, should fibrates be given as an
alternative to statins?
Statement 6
See section on Non-statin therapies.
Clinical Question 7
CQ7. Among patients with acute coronary syndrome (ACS), should
statin therapy be given?
Statement 7
For individuals with acute coronary syndrome, early high-intensity
statin therapy is RECOMMENDED and should be continued when
already on statin therapy.
Summary of Evidence
Timing of therapy is critical among patients with acute coronary
syndrome. Early intervention is advocated to optimize recovery and
minimize complications. The adage time is muscle is based on the
principle of the necessity for immediate action during the golden period
in which myocardial ischemic damage is still potentially reversible or
myocyte necrosis can still be contained and much of the myocardium
in the ischemic penumbra can still be salvaged. This new guideline
statement focuses on the timing of initiation (or continuation) of statin
therapy among patients diagnosed with acute coronary syndrome
(ACS).
Among randomized controlled trials on early statin therapy for acute
coronary syndrome, ten trials were adjudicated to be included in the
analysis of initiation of statins falling within the first 5 days after an acute
coronary event and that total mortality, cardiovascular death, myocardial
infarction, major cardiovascular events, revascularization, and stroke
are reported. These ten trials are A to Z, PACT, MIRACL, Musashi-AMI,
LAMIL, PTT, ESTABLISH, LIPS, PAIS, and FACS.64,69-77
Table 12 summarizes the results of the review and the relevant
outcomes. Statistically significant results are seen from the outcomes
of total mortality, CV death, stroke and major cardiovascular events.
A trend to benefit was seen for the outcomes of non-fatal myocardial
infarction and revascularization. This pooled analysis shows that statins,
when initiated early within 5 days of ACS, results in fewer total deaths,
cardiovascular deaths, stroke and major cardiovascular events, with a
32
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Studies
Participants
Effect Estimate
(95% CI)
NNT
10
13,707
0.80 (0.67-0.94)
110
CV death
10,465
0.74 (0.58-0.94)
125
Non Fatal Mi
10
13,707
0.93 (0.81-1.08
NS
Stroke
10
13,707
0.70 (0.50-0.99)
227
Cardiovascular
event
10
13,707
0.88 (0.82-0.94)
43
Coronary
Revascularization
10
13,707
0.95 (0.86-1.06)
NS
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
33
34
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
35
36
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
POINTS
Family history
First-degree relative with known premature* coronary and
vascular disease, OR
First-degree relative with known LDL-C level above the 95th
percentile
Clinical history
Patient with premature* coronary artery disease
Physical examination
Tendinous xanthomata
DNA analysis
Functional mutation in the LDLR, apo B or PCSK9 gene
>8
6-8
3-5
<3
per 1,000 individuals for the significant beneficial outcomes were six
for all-cause mortality, 5 for cardiovascular death, 9 for myocardial
infarction, 4 for stroke, 18 for cardiovascular events, and 11 for coronary
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
37
38
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
39
Myopathy
Focal or
diffuse muscle
Any disease of
aches or
muscle
weakness with
normal CK
NLA
US FDA
Myalgia with
CK > 10x ULN
Myositis
Rhabdomyolysis
Muscle
pain
with CK
elevation
Severe muscle
damage with
damage to
another organ
(i.e., kidney) and
CK > 10 x ULN
CK >50x ULN +
organ damage
Legend
ALT alanine aminotransferase; AST aspartate aminotransferase; ULN upper limit of
normal
40
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
*If symptoms recur after multiple statin use at multiple dosing, may use non-statin therapy
(fibrates or ezetimibe)
41
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Studies Participants
Effect Estimate
(RR, 95% CI)
Total Mortality
2926
Fatal CHD/CV
death
4662
Nonfatal MI
2531
CHD death
2531
Stroke
2531
Coronary
revascularization
2531
NNT
34
Non-statin Therapy
Use of Fibrates in non-diabetic individuals with established ASCVD
Among patients with established ASCVD, fibrates are NOT
RECOMMENDED as an alternative to statins.
Summary of Evidence
The evidence on fibrates was taken mainly from the Veterans Affairs
High-density lipoprotein Intervention Trial (VA-HIT) and a subgroup of
patients with pre-existing ASCVD in the Effects of long-term fenofibrate
therapy on cardiovascular events in 9795 people with type 2 diabetes
mellitus (FIELD) study.86,87 The LOCAT study also contributed a small
number of patients.88 In the 2006 guidelines, the study on bezafibrate
was included in the analysis. In this update, bezafibrate study was
not included because it is not locally available. In VA-HIT, gemfibrozil
reduced nonfatal myocardial infarction (OR 0.77 [95% CI 0.61, 0.97])
and cardiovascular events (OR 0.73 [95% CI 0.6, 0.88]) among 2,531
men with coronary heart disease, a HDL-C of 40 mg/dL or less, and
an LDL-C level of 140 mg/dL or less. There was no effect on all-cause
mortality, stroke, CHD death and revascularization. In the FIELD study,
22% of both fenofibrate and placebo arms have prior cardiovascular
diseases. Among these patients, the authors reported cardiovascular
event rates of 25.5% in the fenofibrate group and 25.1% in the placebo
group. This is the only outcome reported under the specific subgroup of
patients with ASCVD (Table 15). In the LOCAT study, no mortality was
noted during the study for either arm.
42
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
The GRADE Pro balance sheet (Appendix 2 Table 2.10) shows the
quality assessment of the evidence on the use of fibrates in secondary
prevention. Generally, the quality of the evidence is low with the
downgrade due to the question of directness. The studies were all done
in Caucasian populations and Asians, and in particular Filipinos were
not included in the samples that were included in these trials. A second
downgrade was given for indirectness since the populations included
were not statin-intolerant patients. Thus, given the very low quality of
evidence, fibrates are not recommended as an alternative to statin
therapy in patients with established ASCVD.
Use of Fibrates on diabetic individuals without established ASCVD
For diabetic individuals without evidence of ASCVD, fibrates are
NOT RECOMMENDED as an alternative to statin for the primary
prevention of cardiovascular events.
Summary of the evidence
Evidence on the use of fibrates for primary prevention of
cardiovascular outcomes were derived from 4 different clinical trials: the
SENDCAP (1998), DAIS (2001), FIELD (2005) and HHS (1987).87,89-92 In
the original guideline published in 2006, only 2 studies were included;
this statement updates the previous recommendations. Two of the
four trials (FIELD and DAIS) are combined primary and secondary
prevention studies on diabetic individuals. For FIELD, 22% of the trial
subjects had a history of previous cardiovascular disease. Data from
the primary prevention aspect of the trial could not be separated from
the rest of the subjects and hence, was reported as a combined total of
all patients with and without history of CV disease.For DAIS, 48% of the
study subjects also had a history of CV disease whose data could not be
extracted apart from the main trial results.2Hence, the full data set was
also reported.
In the review of literature, there were two other trials on the use
of fibrates among diabetic individuals: the BIP (2000) and VA-HIT
(2002).86,93 However, since these were purely secondary prevention
trials, they were not included in the meta-analysis nor the GRADE PRO
review.
In the end, only three trials were included in the analysis: SENDCAP
(1998), DAIS (2001), and FIELD (2005). HHS study was excluded not
only because it had a very small subgroup of patients with diabetes (N=
135, representing 3% of the total number of volunteers) but also because
it reported a composite outcome of myocardial infarction and CV death,
which was not one of the outcomes that were included in this guideline.
43
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Studies
Participants
Effect Estimate
(RR, 95% CI)
NNT
Total Mortality
10,377
NS
Cardiac mortality
10,377
NS
Stroke
9,795
NS
Major Adverse
Cardiovascular
Events
10,377
100
Data from the HHS revealed that the incidence of the combined outcome
of MI and cardiac death is 2/59 (3.4%) for the treatment (gemfibrozil)
group and 8/76 (10.5%) for the placebo group for a RR of 0.32.
Of the six outcomes that were considered (total mortality, CV deaths,
fatal and non-fatal MI, stroke or CVD, coronary revascularization and
major adverse cardiovascular events), only four were investigated as
outcomes by the clinical trials on fibrates. The outcomes of fatal and
non-fatal MI, as well as coronary revascularization were not investigated
by the fibrate trials.
The pooled data for each of 3 of the single outcomes (total mortality,
CV deaths and Stroke) did not show any statistically significant results
in favor of fibrates (Table 16). It was only for the composite outcome of
MACE where there was a small, statistically significant result in favor of
fibrates with an RR 0.85 (0.73,0.98) and NNT of 100.
GRADE PRO evaluation of evidence quality for each outcome
(Appendix 2 Table 2.9) showed that the quality of evidence for the
significant outcome was low, based on the lack of a Filipino population
(applicability) and the inclusion of small studies (DAIS and SENDCAP)
that contributed to imprecision. None of the trials involved Asians
specifically Filipinos.
Thus, for primary prevention in diabetic individuals without ASCVD,
fibrates are not recommended.
Until more data are available, there appears to be no evidence to
recommend routinely adding fibrates to statins once LDL-cholesterol
goals have been reached. It may be considered among men with high
baseline TG and low HDL-C once LDL-C has been reached.
Comparison with other guidelines
The recommendations for the use of fibrates in this guideline are
similar to other guidelines, in that the principal drug for the primary
44
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Studies
Participants
Effect Estimate
(RR, 95% CI)
NNT
Total Mortality
15,371
62
Fatal CHD/CV
death
12,710
Stroke
15,211
Major
8,388
Coronary
revascularization
2,501
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
45
46
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
% Change in
Triglycerides
% Change in
LDL-C
% Change in
HDL-C
Fibrates
20%-50% decrease
5%-20% decrease
10%-20% decrease
Omega-3
fatty acids
20%-50% decrease
5%-10% increase
1%-23% increase
Ezetimibe
0-7%% decrease
18% decrease
0%-1% increase
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
47
48
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
4.
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18;372(25):2387-97.
100. The AIM-HIGH Investigators. Niacin in Patients with Low HDL Cholesterol Levels
Receiving Intensive Statin Therapy. N Engl J Med 2011; 365:2255-2267.
101. The HPS2-THRIVE Collaborative Group. Effects of Extended-Release Niacin with
Laropiprant in High-Risk Patients. N Engl J Med 2014; 371:203-212.
102. Gordts SC, Singh N, Muthuramu I, De Geest B. Pleiotropic effects of HDL: towards
new therapeutic areas of HDL-targeted interventions. Curr Mol Med. 2014 May; 14
(4): 481-503.
103. Verma DR, Brinton EA. Management of hypercholesterolemia for prevention of
atherosclerotic cardiovascular disease: focus on the potential role of recombinant
anti-PCSK9 monoclonal antibodies. Rev Cardiovasc Med. 2014;15:86101.
104. Toth LL. Emerging LDL Therapies: mipomersen antisense oligonucleotide therapy in
the management of hypercholesterolemia. J. of Clin. Lipidology 2013; 7 (3 Suppl):
S16-S10.
55
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Methods
Participants
Interventions
Outcomes
Anderson
1990
Reduced fat
diet vs usual
diet
Total mortality,
cardiovascular
mortality, total
and non-fatal
MI, stroke, total,
LDL and HDL
cholesterol
Azadbakht
2007
Reduced fat
Weight,
diet vs modified metabolic risk,
fat diet
total mortality,
CV mortality.
total MI,
stroke, cancer
diagnoses,
cancer deaths
Ball 1965
Reinfarction,
death, MACE,
CV deaths,
non-fatal MI,
total MI
BDIT Pilot
Studies 1996
Reduced fat
intake vs usual
diet
Dietary
fat, serum
cholesterol,
total mortality,
weight, BMI,
total and HDL
cholesterol
beFIT 1997
Reduced and
modified fat vs
usual diet
Lipids, total
mortalit
Black 1994
Reduced fat
intake vs usual
diet
Incidence of
actinic keratosis
and nonmelanoma skin
cancer, total
mortality, CV
mortality
56
Study/Year
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Methods
Participants
Interventions
Outcomes
Boyd 1988
Reduced fat vs
usual diet
Mastopathy
symptoms,
plasma
hormone and
lipids, total
mortality, CV
deaths
BRIDGES
2001
Reduced fat vs
usual diet
CARMEN
2000
Reduced fat vs
usual diet
Weight, body
composition,
lipids, total
mortality, CV
mortality,
cancer deaths
and diagnoses
CARMEN MS
sub-study
2002
Reduced fat vs
usual diet
Weight, body
composition,
lipids, total
mortality, CV
mortality,
cancer deaths
and diagnoses,
non-fatal MI,
stroke, heart
failure, PVD
Curzio 1989
Unclear
Blood pressure,
weight, lipids,
total mortality,
CV mortality,
cancer deaths
DART 1989
Reduced and
modified fat vs
usual diet
Mortality,
reinfarction,
CV mortality,
MACE, cancer
deaths, total MI,
non-fatal MI
DO IT 2006
Reduced fat vs
usual diet
CVD, total
mortality
57
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Study/Year
Methods
Participants
Interventions
Outcomes
CVD risk,
diabetes risk,
weight, total
mortality, CV
mortality, total
MI, stroke,
cancer deaths
and diagnoses,
total and nonfatal MI
Due Low vs
Mod 2008
CVD risk,
diabetes risk,
weight, total
mortality, CV
mortality, total
MI, stroke,
cancer deaths
and diagnoses,
total and nonfatal MI
CVD risk,
diabetes risk,
weight, total
mortality, CV
mortality, total
MI, stroke,
cancer deaths
and diagnoses,
total and nonfatal MI
Dullaart 1992
Modified fat vs
usual fat
Albuminuria
and serum
lipoproteins,
total mortality,
CV mortality,
non-fatal MI,
stroke, cancer
deaths
Frenkiel 1986
Modified fat vs
average diet
Bile acid
kinetics, total
mortality
Houtsmuller
1979
Modified fat vs
usual diet
Progression
of diabetic
retinopathy,
total MI and
angina
58
Study/Year
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Methods
Participants
Interventions
Outcomes
Lean 1997
Reduced fat vs
usual diet
Weight loss,
CV risk factors,
total mortality,
CV mortality,
total and nonfatal MI, stroke,
cancer deaths
Ley 2004
Reduced fat vs
usual diet
Lipids, glucose,
blood pressure,
total mortality,
CV death,
total MI,
stroke, cancer
diagnoses,
cancer deaths
Weight loss,
lipids, total
mortality, CV
mortality,
non-fatal and
total MI, stroke,
cancer deaths
and diagnoses
McKeownEyssen 1994
Recurrence
of neoplastic
polyps, total
mortality, CV
mortality,
cancer
diagnoses,
cancer deaths
MeDiet 2002
Reduced and
modified fat vs
usual diet
Breast cancer,
weight, lipids,
wellbeing,
total mortality,
CV mortality,
cardiovascular
deaths, non
fatal MI, stroke,
ventricular
fibrillation,
ventricular
overload
59
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Study/Year
Methods
Participants
Interventions
Outcomes
Minnesota
Coron men
1989
Modified fat
diet vs. usual
diet
MI, total
mortality,
sudden deaths,
CV mortality,
stroke, cancer
deaths, total MI
Minnesota
Coron women
1989
Modified fat
diet vs. usual
diet
MI, total
mortality,
sudden deaths,
CV mortality,
stroke, cancer
deaths, total MI
Moy 2001
MRC 1968
Modified fat vs
usual diet
MI or sudden
death, total
mortality, CV
mortality, total
and non-fatal
MI
MSFAT 1997
Reduced fat vs
usual diet
Weight, vitamin
and fatty
acid intake,
anti-oxidative
capacity, total
mortality, CV
mortality,
stroke, MI,
cancer
diagnoses and
deaths
Modified fat vs
usual diet
Lipid levels
and dietary
assessment,
total mortality
NDHS
Randomized 224 men living in a
Faribault 1968 controlled trial mental health institute
60
Study/Year
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Methods
Participants
Interventions
Outcomes
NDHS Open
1st L&M 1968
Reduced and
modified fat
diet vs. usual
diet
Lipid levels
and dietary
assessment,
total mortality,
CV mortality,
total or non-fatal
MI, peripheral
vascular events
NDHS Open
1st mod 1968
Modified fat
diet vs. usual
diet
Lipid levels
and dietary
assessment,
CV mortality,
cancer
diagnoses, total
and non-fatal
MI
NDHS Open
Randomized 489 men
2nd L&M 1968 controlled trial
Reduced and
modified fat vs
usual diet
Lipid levels
and dietary
assessment,
CV mortality,
cancer
diagnoses, total
and non-fatal
MI
NDHS Open
Randomized 431 men
2nd Mod 1968 controlled trial
Modified fat vs
usual diet
Lipid levels
and dietary
assessment,
total mortality,
CV mortality,
total or non-fatal
MI, peripheral
vascular events
Nutrition &
Breast Health
Reduced fat vs
usual diet
Body weight,
dietary
compliance,
total mortality,
CV mortality,
non-fatal
and total MI,
stroke, cancer
diagnoses and
deaths
61
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Study/Year
Methods
Participants
Interventions
Outcomes
Ole Study
2002
Reduced fat vs
usual diet
Body weight,
body fat,
lipids, glucose,
insulin, total
mortality, CV
mortality,
non-fatal
and total MI,
stroke, cancer
diagnoses and
deaths
Modified fat
diet vs control
Coronary
heart disease
morbidity and
mortality, total
mortality, nonfatal and total
MI, stroke
Oxford
Retinopathy
1978
Reduced
and modified
dietary fat vs
average diet
Retinopathy,
total mortality
Polyp
Prevention
1996
PREMIER
2003
Reduced fat vs
usual diet
Blood pressure,
total mortality,
cardiovascular
mortality,
cancer
deaths, cancer
diagnoses,
diabetes,
stroke, total and
non-fatal MI
Reduced fat
vs Modified fat
diet
Metabolic
effects, total
mortality, CV
mortality,
stroke, total and
non-fatal MI
Recurrence
of polyps,
prostate cancer,
total mortality,
cancer
diagnoses
62
Study/Year
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Methods
Participants
Interventions
Outcomes
Rose 1965
Cardiac events,
total mortality,
CV mortality,
cardiovascular
deaths, nonfatal MI, angina,
stroke
Sacks high
protein 2009
Reduced fat
vs Modified fat
diet
Weight, total
mortality, CV
mortality,
cancer deaths
and cancer
diagnoses
Sacks low
protein 2009
Reduced fat
vs Modified fat
diet
Weight, total
mortality, CV
mortality,
cancer deaths
and cancer
diagnoses
Sarkkinen Fat
Mod 1995
Modified fat vs
usual diet
Lipids and
blood pressure,
total mortality
Reduced and
modified fat vs
usual diet
Lipids and
blood pressure,
total mortality
Reduced fat vs
usual diet
Lipids and
blood pressure,
total mortality
Sarkkinen Red Randomized 81 people aged 30vs Mod 1995 controlled trial 60 with serum total
cholesterol levels
6.5-8.0mmol/L
Reduced fat vs
modified fat
Lipids and
blood pressure,
total mortality
Seppelt 1996
Reduced fat vs
usual diet
Weight, total
mortality, CV
mortality, total
and non-fatal
MI, stroke,
cancer deaths
Simon 1997
Reduced fat vs
usual diet
Total mortality,
cancer
diagnosis
63
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Study/Year
Methods
Participants
Interventions
Outcomes
Sondergaard
2003
Reduced and
modified fat
intake vs. usual
diet
Endothelial
function,
total mortality,
CV mortality,
cancer
diagnoses and
deaths, stroke,
total MI
STARS 1992
Reduced and
modified fat
diet vs usual
diet
Angiography,
total mortality,
CV mortality,
cancer deaths,
stroke, total MI
Strychar 2009
Reduced fat
vs Modified fat
diet
Triglycerides
and other CVD
risk factors,
total mortality,
CV mortality,
cancer deaths
and diagnoses
Modified fat
diet vs usual
diet
Cardiovascular
mortality and
morbidity, total
mortality
THIS DIET
2008
Low fat vs
modified fat
Mortality and
morbidity,
CV mortality,
cancer deaths,
stroke, total and
non-fatal MI
Veterans
Admin 1969
WHEL 2007
Reduced fat
intake vs usual
diet
Total mortality,
heart disease,
CV mortality,
cancer deaths,
cancer
diagnoses,
stroke, non-fatal
MI, total MI
Total mortality,
invasive breast
cancer, CV
mortality
64
Study/Year
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Methods
Participants
Interventions
Outcomes
WHI with CVD Randomized 2,277 post-menopausal Reduced fat vs. Breast cancer,
2006
controlled trial women aged 50-79 with usual diet
total mortality,
CVD at baseline
other cancers,
cardiovascular
events,
diabetes,
CV mortality,
cancer deaths,
cancer
diagnoses,
stroke, non-fatal
MI
WHI without
CVD 2006
WINS 2006
Breast cancer,
total mortality,
other cancers,
cardiovascular
events,
diabetes,
CV mortality,
cancer deaths,
cancer
diagnoses,
stroke, non-fatal
MI
Reduced fat
Dietary fat
intake vs. usual intake, total
diet
cholesterol,
weight and
waist, total
mortality,
cancer
diagnoses
65
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Methods
Participants
Intervention
Outcomes
Lung Health
Study Program
Randomized
controlled trial
5,887 patients
Intensive
smoking
cessation
program versus
usual care
Total mortality,
COPD, lung
cancer, CV Death
MRFIT
Randomized
controlled trial
12,866 men
In-depth
multifactor
intervention
program
aimed at
lowering serum
cholesterol, BP
and smoking
cessation
CV mortality,
Fatal and nonfatal
MI, stroke,
revascularization
and total mortality
OSLO Study
Randomized
controlled trial
diet and
smoking
cessation
Total mortality, CV
Events, CV deaths
Methods
Participants
Intervention
Outcomes
LOOK Ahead
Randomized
controlled
trial
5,145 overweight
or obese
patients with
type2diabetes
to participate
Intensive lifestyle
intervention that
promoted weight
loss through
decreased
caloric intake and
increased physical
activity
Death from
cardiovascular
causes, nonfatal
myocardial
infarction,
nonfatal stroke, or
hospitalization for
angina (composite)
STENO2
Randomized
controlled
trial
160 diabetic
Stepwise
patients with
implementation of
microalbuminuria exercise program
Composite of
death from
cardiovascular
causes, nonfatal
myocardial
infarction,
nonfatal stroke,
revascularization,
and amputation.
Chengdu trial
Randomized
controlled
trial
Total mortality, CV
Events, CV deaths
Fowler et
al/2002
Randomized
controlled
trial
A stop smoking
and keep
walking regime
- a combined
community-based
intervention of
cessation of
smoking and
increased physical
activity.
Maximum
walking distance,
myocardial
infarction, stroke
Method
Randomized
controlled Trial
Randomized
controlled Trials
Randomized
controlled Trials
Study/Year
WOSCOPS
1995
KAPS 1995
AFCAPS/
TexCAPS 1998
Participants
6595 men, aged 45-64 years old, fasting LDL
cholesterol level of at least 4 mmol/L during the
second and third visits, with at least one value
of 4.5 mmol/L and one value of 6.0 mmol/L;
no serious ECG abnormalities according
to Minnesota code 1 (pathologic Q waves),
arrhythmia such as atrial fibrillation; and no
history of myocardial infarction or other serious
illness, although men with stable angina who
had not been hospitalized within the previous 12
months
447 men, LDL-C > 4.25 mmol/L, total cholesterol
< 8.0 mmol/L, body mass index < 32 kg/m2,
and liver enzymes (alanine aminotransferase
[ALT] and aspartate aminotransferase [AST]) not
exceeding 1.5-fold the laboratory upper normal
limit
Intervention: 20-40
mg of lovastatin
Control: placebo
Follow up: 5 years
Intervention: 40 mg
of pravastatin
Control: placebo
Follow-up: 3 years
Intervention
Intervention: 40 mg
of pravastatin
Control: placebo
Follow-up:
5 years
After 1 year
TC 184 (17%)
LDL-C 115 (24%)
TG 143
HDL-C 39
Outcomes
Non-fatal MI
CHD death
Coronary
revascularization
Any death
TC 200.8 (22%)
LDL-C 131.3 (31%)
HDL-C 42.5
TG 132.7
TC - 20%
LDL-C 26%
HDL-C 5%
TG - 12%
Table 1.4. Summary of Clinical Trials in the Use of Statins in Primary Prevention
66
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Method
Randomized
controlled Trials
Randomized
controlled Trial
Randomized
controlled Trial
Randomized
controlled Trial
Study/Year
ASCOT-LLT
2003
PREVEND IT
2004
MEGA 2006
JUPITER 2008
Participants
10, 305 participants, aged 40-79 years old, with
either untreated HPN (SBP 160 mmHg or DBP
100 mmHg or both), or treated HPN (SBP
140 mmHg or DBP 90mmHg or both), total
cholesterol of 6.5 mmol/L or lower, not currently
taking statin or fibrate, at least 3 CV risk factors
(LVH, other specified abnormalities on ECG,
type 2 DM, PAD, previous stroke or TIA, male
sex, 55 years or older, microalbuminuria or
proteinuria, smoking, ratio of TC/ HDL 6,
premature family history of CHD
864 participants, aged 28-75 years old,
persistent microalbuminuria (a urinary albumin
concentration 10 mg/L in 1 early morning spot
urine sample and a concentration of 15 to 300
mg/24 hours in 2 24-hour urine samples at least
once), blood pressure 160/100 mm Hg and no
use of antihypertensive medication, and a total
cholesterol level 8.0 mmol/L, or 5.0 mmol/L in
case of previous myocardial infarction, and no
use of lipid-lowering medication.
7832 Japanese men and post-menopausal
women (3966 control, 3866 intervention), aged
40-70 years old, total cholesterol concentration
5.69-6.98 mmol/L
Intervention: 20 mg
of rosuvastatin
Control: placebo
Follow-up: 1.9 years
Intervention: NCEP
step I diet plus 20
mg of pravastatin
Control: NCEP step
I diet
Follow-up: 5 years
Follow-up: 4 years
Intervention: 40 mg
of pravastatin
Control: placebo
Intervention
Intervention: 10 mg
of atorvastatin
Control: placebo
After 4 years
LDL-C 55 (49%)
HDL-C 50
TG- 99
After 9 years
TC 208.9 (14%)
LDL-C 122.4 (23%)
HDL-C 62.2
TG 107
Cardiovascular
mortality
Myocardial infarction
and/ or myocardial
ischemia
Heart failure
Peripheral vascular
disease
Stroke
Outcomes
Primary:
Non-fatal MI and fatal
CHD
After 4 years
TC 185.3 (17%)
LDL-C 119.7 (24%)
After 3 years
TC 161.4 (24%)
LDL-C 88 (34%)
HDL-C 50.2
TG 116.8
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
67
Method
800
75
1,217
844
10,269
206
187
2,081
2,891
75
4,512
2,138
2,365
Medium-intensity
statin
High-intensity statin
Low-intensity statin
Low-intensity statin
Low-intensity statin
Medium-intensity
statin
Medium-intensity
statin
Low-intensity statin
High-intensity statin
Low-intensity statin
High-intensity statin
Medium-intensity
statin
Low-intensity statin
Low-intensity statin
High-intensity statin
2,221
Intervention
Intervention details
Intervention
group (N)
LIPID, 199856
GISSI, 200057
Amarenco et al, 2006
(SPARCL)58
Athyros et al, 2002
(GREACE)59
Byington et al, 1995
(PLAC II)60
Koren et al, 2004
(ALLIANCE)61
Lemos et al, 2003
(LIPS)62
Meade et al, 1999
(HPS)63
Pitt et al, 1995 (PLAC
I)64
Rieggeret al, 199965
Sacks et al, 1996
(CARE)66
Shepherd et al, 2002
(PROSPER)67
Shukla et al, 200568
Study Name
Atorvastatin 20 mg
Atorvastatin 10 mg
Pravastatin 40 mg
Fluvastatin 40 mg
Pravastatin 40 mg
Pravastatin 40 mg
Simvastatin 40 mg
Fluvastatin 80 mg
Atorvastatin 80 mg
Pravastatin 40 mg
Atorvastatin 20 mg
Pravastatin 40 mg
Pravastatin 20 mg
Atorvastatin 80 mg
Simvastatin 20 mg
54
75
2,913
178
2,078
202
10,267
833
1,225
76
800
4,502
2,133
2,366
2,223
Table 1.5 Summary of Clinical Trials in the Use of Statins in Secondary Prevention.
1 year
1 years
1 year
5 years
3 years
5 years
3-4 years
3 years
Mean 3 years
6.1 years
Mean 23 months
Median 4.9 years
5.4 years
Follow-up
68
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Medium-intensity
statin
Medium-intensity
statin
Low-intensity statin
Medium-intensity
statin
Low-intensity statin
105
252
282
972
542
186
Intervention
Intervention details
Low-intensity statin
Medium-intensity
statin
Low-intensity statin
Intervention
group (N)
230
19
Pravastatin 40 mg
Simvastatin 40 mg
Pravastatin 40 mg
Atorvastatin 10 mg
Simvastatin 20 mg
Pravastatin 20 mg
Simvastatin 10 mg
Atorvastatin 10 mg
535
1009
304
253
97
187
230
19
6.0 years
5.0 years
5.0 years
4.0 years
5.4 years
3 years
3 - 5 years
3 years
Follow-up
T1=Type 1 diabetes; T2=Type 2 diabetes; MI=myocardial infarction; AP=angina pectoris; IP=interventional procedure; UAP=unstable angina
pectoris.
Method
Study Name
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
69
FIELD (2005)
HHS (1987)
VA-HIT (2002)
BIP (2000)
Population
DAIS (2001)
SENDCAP
(1998)
INCLUDED
Study/year
TC mg/dL
LDL mg/dL
HDL mg/dL
TG mg/dL
TC 213.2 mg/dL
LDL 147.5 mg/dL
HDL 34.5 mg/dL
TG 156.1 mg/dL
TC 213.2 mg/dL
LDL 147.5 mg/dL
HDL 34.5 mg/dL
TG 156.1 mg/dL
TC 194 mg/dL
LDL 118 mg/dL
HDL 42.5 mg/dL
TG 154 mg/dL
TC 3301. mg/dL
LDL 130.5 mg/dL
HDL 39.0 mg/dL
TG 229.5 mg/dL
TC 223.3 mg/dL
LDL 141.3 mg/dL
HDL 39.5 mg/dL
TG 198.5 mg/dL
Gemfibrozil 600
mg/day
Gemfibrozil 1,200
mg/day
Bezafibrate
400 mg/day
Fenofibrate 200
mg per day
Micronized
fenofibrate 200
mg/day for 3
years
Bezafibrate 400
mg OD for 3
years
Intervention
Table 1.6. Summary of Clinical Trials Using Fibrates in Individuals with Diabetes
5 years
5.1 years
6.2 years
5 years
3.3 years
3 years
Duration of
follow up
MI (fatal and
nonfatal),
cardiac death
Combined incidence
of nonfatal MI &
death from CAD
CHD death,
non-fatal MI
Outcome Measures
70
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
71
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Population
Intervention
Outcomes
Frick/1997
(LOCAT)
Three hundred
ninety-five men
70 years old
post CABG
with lipid (197
intervention vs
198)
slowreleasegemfibrozil
(Lopid SR)
1200 mg/d or a
matching placebo.
Rubins/1999
(VA-HIT)
gemfibrozil (1200
mg per day) vs
placebo
Combined
incidence of
nonfatal myocardial
infarction or death
from coronary heart
disease; stroke;
death from any
cause, transient
ischemic attack,
revascularization
procedures, carotid
endarterectomy,
and hospitalization
for unstable angina
or congestive heart
failure.
FIELD/2005
9,795
participants
aged 5075
years, with
type 2 diabetes
mellitus, and
not taking statin
therapy at study
entry
micronised
fenofibrate 200
mg daily (n=4895)
or matching
placebo (n=4900)
Primary outcome
was coronary events
(coronary heart
disease death or
non-fatal myocardial
infarction); the
outcome for
prespecified
subgroup
analyses was total
cardiovascular
events (the
composite of
cardiovascular
death, myocardial
infarction, stroke,and
coronary and carotid
revascularisation
Remarks
no mortality
2131 with
previous
cardiovascular
disease and
7664 without
Within 96 hours
Within 48 hours
Within 48 hours
Within 24 hours
Within 48 hours
Within 24 hours
Within 24 hours
Musashi-AMI
LAMIL, 1997
PAIS 2001
PTT, 2002
LIPS, 2002
ESTABLISH,
2004
FACS, 2010
24-96 hours
Schwartz, 2004
MIRACL
Fluvastatin 80 mg
Atorvastatin 20 mg
Fluvastatin 80 mg
Pravastatin 40 mg
Pravastatin 40 mg
Pravastatin 10-20 mg
Any Statin
Atorvastatin 80 mg
Pravastatin 20-40 mg
Within 24 hours
Thompson,
2004
PACT
Intervention 1:
details
Simvastatin 40 mg for
1 month then 80 mg
Intervention: 1:
timing
Study Name
78
35
844
79
50
36
241
1538
1710
2265
Number
randomised
intervention
group
Placebo
Usual Care
Placebo
Usual Care
Placebo
Placebo
No statin
Placebo
Placebo
Comparison
Table 1.8 Summary of Clinical Trials in the Use of Statins in Patients with ACS
78
35
833
85
49
33
245
1548
1698
2232
Number
randomized
comparison
group
1 year
6 months
45 months
4 months
3 months
3 months
Up to 24 months
First 16 weeks
30 days
2 years
Follow-up
72
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
CHF II-IV
GISSI HF/2008
GISSI
PREVENZIONE/1999
SCIMO/1999
Population
Galan/2011
Study/Year
79 PUFA vs 81 control
Intervention
Cardiovascular mortality,
cardiovascular mortality or admission
for any reason, sudden cardiac
death, admission for any reason,
admission for cardio vascular
reasons, admission for heart failure,
myocardial infarction, and stroke
Outcomes
Table 1.9. Summary of Clinical Trials using Omega 3 Fatty Acids in Patients with Dyslipidemia
Open label
Cause of HF is
ischemic in 50%
Remarks
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
73
Overall
quality of
evidence
With Control
Serious
no serious Undetected
imprecision
MODERATE
due to
indirectness
no
no serious
71790
(21 studies) serious inconsistency
11 years
risk of
bias
Serious1
no serious Undetected
imprecision
MODERATE1
due to
indirectness
Total mortality (CRITICAL OUTCOME; assessed with: reduction of dietary fat vs control diet)
no
no serious
65508
(31 studies) serious inconsistency
8 years
risk of
bias
2404/40957
(5.9%)
2867/37402
(7.7%)
1888/30833 RR 0.98
(6.1%)
(0.93 to
1.04)
2020/28106 RR 0.86
(7.2%)
(0.79 to
0.96)
With
Reduced
dietary fat
11 fewer
per 1000
(3 fewer to
16 fewer)
1 fewer
per 1000
(4 fewer to
2 more)
Moderate
59 per
1000
Study population
Moderate
77 per
1000
Study population
Risk
Risk
with difference
Control (95%CI)
Summary of Findings
Study event rates (%)
Major Acute Coronary Event(MACE) (CRITICAL OUTCOME; assessed with: reduction of fat vs control diet)
Quality assessment
Serious1
no serious Undetected
imprecision
MODERATE1
due to
indirectness
Serious1
Serious1
no
no serious
59853
(11 studies) serious inconsistency
8 years
risk of
bias
774/37840
(2%)
no serious Undetected
894/27611 1174/37280
imprecision
MODERATE1 (3.2%)
(3.1%)
due to
indirectness
457/25063 683/34790
no serious Undetected
MODERATE1 (1.8%)
imprecision
(2%)
due to
indirectness
no
no serious
64891
(19 studies) serious inconsistency
8 years
risk of
bias
Fatal and Nonfatal MI (CRITICAL OUTCOME; assessed with: reduction of fat in diet)
no
no serious
65978
(16 studies) serious inconsistency
11 years
risk of
bias
Cardiovascular mortality (CRITICAL OUTCOME; assessed with: reduced/modified fat vs usual diet)
RR 0.99
(0.89 to
1.11)
RR 0.90
(0.72 to
1.11)
633/28138
(2.2%)
1 fewer
per 1000
(3 fewer to
1 more)
Moderate
20 per
1000
Study population
Moderate
-
18 per
1000
Moderate
-
Study population
32 per
1000
Study population
RR 0.94
(0.84 to
1.04)
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
75
Risk of
bias
Inconsistency
no
serious
risk of
bias
no serious
inconsistency
serious1
Indirectness
18023
(2 studies)
7 years
no
serious
risk of
bias
no serious
inconsistency
serious1
18023
(3 studies)
7 years
Participants
(studies)
Follow up
Overall
quality of
evidence
no serious Undetected
MODERATE1
imprecision
due to
indirectness
no serious Undetected
MODERATE1
imprecision
due to
indirectness
Imprecision Publication
bias
Quality assessment
219/9030
(2.4%)
918/9030
(10.2%)
With Control
200/8993
(2.2%)
826/8993
(9.2%)
With
Smoking
cessation
RR 0.92
(0.76 to
1.11)
RR 0.90
(0.82 to
0.99)
Relative
effect
(95%CI)
Risk
difference
with
Smoking
cessation
(95%CI)
10 fewer
per 1000
(from 1
fewer to 18
fewer)
Study population
102 per
1000
Study population
Risk with
Control
Anticipated absolute
effects
Summary of Findings
Table 2.2 GRADE PRO summary of evidence on the benefit of smoking cessation
76
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Risk of
bias
Inconsistency
no
serious
risk of
bias
no serious
inconsistency
18023
(3 studies)
7 years
Participants
(studies)
Follow up
serious1
Indirectness
Overall
quality of
evidence
no serious undetected
MODERATE1
imprecision
due to
indirectness
Imprecision Publication
bias
Quality assessment
599/9030
(6.6%)
With Control
506/8993
(5.6%)
With
Smoking
cessation
RR 0.85
(0.76 to
0.95)
Relative
effect
(95%CI)
Risk
difference
with
Smoking
cessation
(95%CI)
66 per 1000
10 fewer
per 1000
(from 3 to
16 fewer)
Study population
Risk with
Control
Anticipated absolute
effects
Summary of Findings
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
77
425/2655 410/2650
(16%)
(15.5%)
594/3011
(19.7%)
Major Acute Coronary Event (CRITICAL OUTCOME; assessed with: Moderate exercise versus usual care)
5305
226/2655 170/2650
no
no serious
serious2
no serious undetected
MODERATE1,2 (8.5%)
(2 studies)
serious inconsistency
imprecision
(6.4%)
due to
9 years
risk of
indirectness
bias1
CV Mortality (CRITICAL OUTCOME; assessed with: Moderate exercise versus usual care)
5305
serious1 no serious
serious2
no serious undetected
LOW1,2
(2 studies)
inconsistency
imprecision
due to risk
9 years
of bias,
indirectness
All cause mortality (CRITICAL OUTCOME; assessed with: Moderate exercise vs usual care)
6027
624/3016
no
no serious
serious2
no serious undetected
MODERATE1,2 (20.7%)
(2 studies)
serious inconsistency
imprecision
due to
9 years
risk of
indirectness
bias1
RR 0.75
(0.62 to
0.91)
RR 0.97
(0.85 to
1.09)
RR 0.95
(0.86 to
1.05)
Relative
effect
(95%CI)
Risk diff with
Exercise
(95%CI)
10 fewer per
1000
(from 29 fewer
to 10 more)
5 fewer per
1000
(from 24 fewer
to 14 more)
21 fewer per
1000
(from 8 fewer
to 32 fewer)
Moderate
85 per
1000
Study population
160 per
1000
Study population
207 per
1000
Study population
Risk with
Control
Anticipated absolute
effects
Summary of Findings
Participants Risk of Inconsistency Indirectness Imprecision Publication Overall quality Study event rates (%)
(studies)
bias
bias
of evidence
Follow up
With
With
Control Exercise
Quality assessment
Quality assessment
LOW1,2
due to risk
of bias,
indirectness
5312
serious1 no serious
no serious no serious undetected
MODERATE1
(2 studies)
inconsistency indirectness imprecision
due to risk of
9 months
bias
Non-fatal MI (CRITICAL OUTCOME; assessed with: Moderate exercise versus usual advice)
160
serious1 no serious
serious2
no serious undetected
(1 study)
inconsistency
imprecision
LOW1,2
due to risk
of bias,
indirectness
88/2650
(3.3%)
5/80
(6.3%)
289/2659 284/2653
(10.9%)
(10.7%)
100/2655
(3.8%)
17/80
(21.3%)
RR 0.99
(0.84 to
1.15)
RR 0.88
(0.67 to
1.17)
RR 0.29
(0.11 to
0.76)
Relative
effect
(95%CI)
5 fewer per
1000
(from 12 fewer
to 6 more)
109 per
1000
1 fewer per
1000
(from 17 fewer
to 16 more)
Study population
38 per
1000
Study population
212 per
1000
Study population
Risk with
Control
Anticipated absolute
effects
Summary of Findings
Participants Risk of Inconsistency Indirectness Imprecision Publication Overall quality Study event rates (%)
(studies)
bias
bias
of evidence
Follow up
With
With
Control Exercise
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
79
not serious
not serious
Cardiovascular death
7
randomised not
trials
serious
Myocardial infarction
7
randomised not
trials
serious
serious 1
serious 1
serious 1
not serious
not serious
not serious
none
none
none
not serious
Study
design
Total mortality
4
randomised not
trials
serious
of
studies
Quality assessment
placebo
Effect
Relative Absolute
(95%
(95% CI)
CI)
Quality
Statins
of patients
Table 2.4. GRADE PRO Summary of Evidence on the benefit of statins for primary prevention
CRITICAL
CRITICAL
CRITICAL
Importance
80
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
serious 2
not serious
Coronary revascularization
6
randomised not
trials
serious
not serious
serious 1
serious 1
serious 1
not serious
not serious
not serious
none
none
none
randomised not
trials
serious
Study
design
Cardiovascular events
4
randomised not
trials
serious
Stroke
6
of
studies
Quality assessment
placebo
Effect
Relative Absolute
(95%
(95% CI)
CI)
Quality
2.3%
3.6%
LOW
CRITICAL
CRITICAL
Importance
11 fewer
IMPORTANT
per 1000 MODERATE
(from 8
fewer to 13
fewer)
7 fewer per
1000 (from
5 fewer to 8
fewer)
18 fewer
per 1000
(from 14
fewer to 22
fewer)
10 fewer
per 1000
(from 8
fewer to 12
fewer)
Statins
of patients
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
81
Study
design
randomised not
trials
serious
randomised not
trials
serious
randomised not
trials
serious
not serious
not serious
not serious
serious3
serious2
serious1
not serious
not serious
not serious
none
none
none
Other
Risk of
Inconsistency Indirectness Imprecision
considerations
bias
Total Mortality
of
studies
Quality assessment
58/3629
(1.6%)
82/1409
(5.8%)
Placebo
Quality
RR 0.98 0 fewer
(0.68 to per 1000 MODERATE
1.41) (from 5
fewer to 7
more)
RR 0.73 16 fewer
(0.53 to per 1000 MODERATE
1.01) (from 1
more to
27 fewer)
Relative
Absolute
(95%
(95% CI)
CI)
Effect
60/3645
(1.6%)
61/1428
(4.3%)
Statins
of patients
Table 2.5. GRADE PRO Summary of Evidence in the use of Statin in Diabetes without ASCVD.
CRITICAL
CRITICAL
CRITICAL
Importance
82
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Study
design
randomised not
trials
serious
not serious
randomised not
trials
serious
not serious
serious5
randomised not
trials
serious
not serious
serious5
not serious
not serious
not serious
none
strong
association
none
Placebo
Relative
Absolute
(95%
(95% CI)
CI)
Effect
Quality
CRITICAL
(7)
CRITICAL
Importance
Statins
of patients
RR=relative risk
1. No explanation was provided
2. All the studies are on DM but none were done locally or included Filipinos
3. All the studies except for HPS, were done on DM patients. However, NONE of these studies were done locally or included Filipinos
4. All the studies except for ASCOT were done on DM but none were done locally or included Filipinos
5. None of the studies included Filipinos or were done locally
serious5
Other
Risk of
Inconsistency Indirectness Imprecision
considerations
bias
CVD/Stroke
of
studies
Quality assessment
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
83
Quality assessment
of patients
Effect
Quality Importance
of
Study
Risk of
Other
Relative Absolute
studies
design
bias Inconsistency Indirectness Imprecision considerations Fibrates Placebo (95% CI) (95% CI)
Total mortality
3
randomised not
not serious
serious 1
serious 2
strong
362/5183 333/5194 RR 1.09 6 more
CRITICAL
trials
serious
association
(7.0%)
(6.4%)
(0.94 to per 1000 MODERATE
1.26) (from 4
fewer to
17 more)
Cardiac Mortality
3
randomised not
not serious
CRITICAL
serious 1
serious 2
strong
143/5183 132/5194 RR 1.09 2 more
trials
serious
association
(2.8%)
(2.5%)
(0.86 to per 1000 MODERATE
1.37) (from 4
fewer to
9 more)
Stroke
1
randomised not
not serious
CRITICAL
serious 1
not serious
none
158/4895 175/4900 RR 1.1 4 more
trials
serious
(3.2%)
(3.6%)
(0.87 to per 1000 MODERATE
1.4)
(from 5
fewer to
14 more)
Major adverse CV events
3
randomised not
not serious
CRITICAL
serious 1
serious 2
none
300/5183 355/5194 RR 0.85 10 fewer
LOW
trials
serious
(5.8%)
(6.8%)
(0.73 per 1000
-0.98) (from 1
fewer
to 18
fewer)
Table 2.6 GRADE PRO Summary table for the Use of Fibrates for the Primary Prevention of Cardiovascular
Events Among Diabetic Individuals.
84
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
serious 1
randomized
trials
not
serious
not serious
serious 2
serious 1
not serious
not serious
not serious
not serious
Imprecision
none
none
none
none
Other
considerations
placebo
1060/26221 1356/26205
(4.0%)
(5.2%)
1377/27009 1960/27009
(5.1%)
(7.3%)
1812/29980 2287/29969
(6.0%)
(7.6%)
2978/30085 3436/30081
(9.9%)
(11.4%)
statins
of patients
RR 0.78
(0.72 to
0.84)
RR 0.70
(0.66 to
0.75)
RR 0.79
(0.75 to
0.84)
RR 0.87
(0.83 to
0.91)
Quality
LOW
MODERATE
11 fewer
per 1000 MODERATE
(from 8
fewer to
14 fewer)
22 fewer
per 1000
(from 18
fewer to
25 fewer)
16 fewer
per 1000
(from 12
fewer
to 19
fewer) 1
15 fewer
per 1000 MODERATE
(from 10
fewer to
19 fewer)
Effect
Relative Absolute
(95% CI) (95% CI)
Stroke
11
not
serious
serious 1
not serious
Indirectness
Myocardial infarction
13
randomized
trials
not
serious
Inconsistency
serious 1
randomized
trials
Risk of
bias
15
Total mortality
Quality assessment
of
Study design
studies
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Table 2.7 GRADE PRO Summary of evidence on the use of statins for secondary prevention in individuals with
ASCVD.
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
85
Study
design
randomized
not
trials
serious
randomized
not
trials
serious
randomized
not
trials
serious
not serious
not serious
not serious
serious 1
serious 1
serious 1
serious 1
not serious
not serious
not serious
not serious
Stroke
Myocardial infarction
not serious
none
none
none
none
Relative Absolute
(95% CI) (95% CI)
Effect
Quality
388/12735 439/12714
(3.0%)
(3.5%)
RR 0.88 4 fewer
(0.77 to per 1000 MODERATE
(from 0
1.01)
fewer to
8 fewer)
medium
intensity
statin
of patients
high
Risk of Inconsistency Indirectness Imprecision
Other
bias
considerations intensity
statin
randomized
not
trials
serious
Cardiovascular mortality
Total mortality
of
studies
Quality assessment
CRITICAL
CRITICAL
CRITICAL
CRITICAL
Importance
Table 2.8 GRADE Pro summary of evidence on the use of high-intensity (atorvastatin 80 or simvastatin 80 mg) vs
medium-intensity (atorvastatin 10 mg or simvastatin 20 mg) statin therapy for secondary prevention in ASCVD
86
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
randomised not
trials
serious
not serious
serious 1
serious 1
serious 2
not serious
Stroke
1
none
none
strong
association
300/5183
(5.8%)
158/4895
(3.2%)
355/5194
(6.8%)
175/4900
(3.6%)
132/5194
(2.5%)
143/5183
(2.8%)
serious 2
Cardiac Mortality
3
randomised not
trials
serious
serious 1
333/5194
(6.4%)
362/5183
(7.0%)
not serious
Placebo
Fibrates
of patients
Quality assessment
of
Study
Risk of Inconsistency Indirectness Imprecision
Other
studies
design
bias
considerations
Total mortality
3
randomised not
not serious
serious 1
serious 2
strong
trials
serious
association
RR 0.85
(0.73
-0.98)
RR 1.1
(0.87 to
1.4)
RR 1.09
(0.86 to
1.37)
RR 1.09
(0.94 to
1.26)
Quality
Importance
10 fewer
per 1000
(from 1
fewer to
18 fewer)
LOW
CRITICAL
CRITICAL
4 more
per 1000 MODERATE
(from 5
fewer to
14 more)
CRITICAL
2 more
per 1000 MODERATE
(from 4
fewer to 9
more)
CRITICAL
6 more
per 1000 MODERATE
(from 4
fewer to
17 more)
Effect
Relative Absolute
(95% CI) (95% CI)
Table 2.9. GRADE PRO Summary table for the Use of Fibrates for the Primary Prevention of Cardiovascular
Events Among Diabetic Individuals.
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
87
Study
design
CVE
randomised not
trials
serious
not serious
not serious
serious 1
serious 1
not serious
not serious
none
none
randomised not
trials
serious
of
studies
Quality assessment
placebo
Relative
(95% CI)
25.6%
8.9%
Quality
28 fewer
per 1000
(from 38
more to 79
fewer)
28 fewer
per 1000 MODERATE
(from 38
more to 79
fewer)
9 fewer per
1000 (from
7 more to
21 fewer)
15 fewer
per 1000 MODERATE
(from 12
more to 36
fewer)
Absolute
(95% CI)
Effect
Fibrates
of patients
Table 2.10. Grade PRO Summary of Evidence in the Use of Fibrates as Alternative Treatment to Statin
CRITICAL
CRITICAL
Importance
88
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
Stroke
Study
design
randomised not
trials
serious
not serious
not serious
serious 1
serious 1
not serious
not serious
none
none
randomised not
trials
serious
Nonfatal MI
of
studies
Quality assessment
placebo
Relative
(95% CI)
58/1264
(4.6%)
6.0%
76/1267
(6.0%)
14.5%
RR 0.76
(0.55 to
1.07)
Quality
14 fewer
per 1000
(from 4
more to 27
fewer)
14 fewer
per 1000 MODERATE
(from 4
more to 27
fewer)
29 fewer
per 1000
(from 4
fewer to 51
fewer)
29 fewer
Absolute
(95% CI)
Effect
Fibrates
of patients
CRITICAL
CRITICAL
Importance
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
89
randomised not
trials
serious
not serious
serious 1
serious 1
not serious
not serious
none
none
9.3%
118/1267 RR 0.79
(9.3%)
(0.61 to
1.02)
placebo
22.6%
Quality
CRITICAL
Importance
16 fewer
per 1000
(from 18
more to 45
fewer)
16 fewer
IMPORTANT
per 1000 MODERATE
(from 18
more to 45
fewer)
20 fewer
per 1000
(from 2
more to 36
fewer)
20 fewer
per 1000 MODERATE
(from 2
more to 36
fewer)
Absolute
(95% CI)
Effect
Relative
(95% CI)
93/1264
(7.4%)
Fibrates
of patients
1. Serious indirectness in two levels: lack of Filipino population, and intervention not tested in statin-intolerant patients.
not serious
Risk of
Other
bias Inconsistency Indirectness Imprecision considerations
randomised not
trials
serious
Study
design
Revascularization
CHD death
of
studies
Quality assessment
90
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
not serious
not serious
Cardiovascular death
8
randomised
not
trials
serious
Non-fatal MI
10
randomised
not
trials
serious
serious2
serious2
serious3
not serious
none
none
344/6872
(5.0%)
114/5256
(2.2%)
4.0%
365/6835
(5.3%)
2.9%
154/5209
(3.0%)
3.8%
Quality assessment
of patients
of
Study
Risk of Inconsistency Indirectness Imprecision
Other
Placebo
studies design
bias
considerations Statins
Total Mortality
10
randomised
not
not serious
serious1
not serious
none
236/6872 295/6835
trials
serious
(3.4%)
(4.3%)
RR 0.93
(0.81 to
1.08)
RR 0.74
(0.58 to
0.94)
RR 0.80
(0.67 to
0.94)
Quality
4 fewer
per 1000
(from 4
more to
10 fewer)
3 fewer
per 1000
(from 3
more to 8
fewer)
LOW
8 fewer
9 fewer
per 1000 MODERATE
(from 3
fewer to
14 fewer)
8 fewer
per 1000
(from 2
fewer to
13 fewer)
Effect
Relative Absolute
(95% CI) (95% CI)
CRITICAL
CRITICAL
CRITICAL
Importance
Table 2.11. GRADE Pro Summary of Evidence for trials in the use of Statins in Patients with Acute Coronary
Syndrome
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
91
serious4
serious7
none
582/4925
(11.8%)
not serious
Revascularization
8
randomised
not
trials
serious
none
1165/6872 1317/6835
(17.0%)
(19.3%)
not serious
serious6
Major CV events
10
randomised
not
trials
serious
serious4
78/6835
(1.1%)
54/6872
(0.8%)
23.0%
609/4893
(12.4%)
25.1%
1.0%
Placebo
Statins
of patients
Quality assessment
of
Study
Risk of Inconsistency Indirectness Imprecision
Other
studies design
bias
considerations
Stroke
10
randomised
not
not serious
serious4
not serious5
none
trials
serious
RR 0.95
(0.86 to
1.06)
RR 0.88
(0.82 to
0.94)
RR 0.70
(0.50 to
0.99)
Quality
6 fewer
per 1000
(from 7
more to
17 fewer)
12 fewer
per 1000
(from 14
more to
32 fewer)
23 fewer
per 1000
(from 12
fewer to
35 fewer)
30 fewer
per 1000
(from 15
fewer to
45 fewer)
LOW
LOW
3 fewer
Effect
Relative Absolute
(95% CI) (95% CI)
IMPORTANT
CRITICAL
CRITICAL
Importance
92
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
of patients
not serious
not serious
CV death
2
randomised not
trials
serious
Nonfatal MI
1
randomised not
trials
serious
serious 1
serious 1
not serious
not serious
none
none
102/4894
(2.5%)
848/6365
(13.3%)
14.5%
135/4876
(2.8%)
14.3%
958/6345
(15.1%)
15.7%
of
Study
Risk of Inconsistency Indirectness Imprecision
Other
studies design
bias
considerations Fibrates placebo
All cause mortality
2
randomised not
not serious
serious 1
not serious
none
1250/7697 1368/7674
trials
serious
(16.2%)
(17.8%)
Quality assessment
RR 0.89
(0.70 to
1.13)
3 fewer per
1000 (from
4 fewer to 8
fewer)
3 fewer per
1000 (from
4 fewer to 8
fewer)
27 fewer per
1000 (from
12 more to
56 fewer)
26 fewer per
1000 (from
11 more to 53
fewer)
16 fewer per
1000 (from
2 more to 29
fewer)
14 fewer per
1000 (from
2 more to 25
fewer)
RR 0.91
(0.84 to
0.99)
RR 0.82
(0.63 to
1.08)
Absolute
(95% CI)
Relative
(95% CI)
Effect
LOW
LOW
LOW
Quality
CRITICAL
CRITICAL
CRITICAL
Importance
Table 2.12. GRADEPRO Summary of Evidence in the Use of Omega 3 Fatty Acids as Alternative to Statin
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
93
randomised not
trials
serious
not serious
not serious
serious 1
serious 1
not serious
not serious
none
none
RR 0.97
(0.79,
1.20)
RR 1.19
(0.97,
1.45)
RR 0.76
(0.55 to
1.07)
Relative
(95% CI)
13 fewer per
1000 (from
16 more to
34 fewer)
8 fewer per
1000 (from
4 more to 27
fewer)
Absolute
(95% CI)
Effect
1. Serious indirectness in two levels: lack of Filipino population, and intervention not tested in statin-intolerant patients.
Revascularization
1
randomised not
trials
serious
Stroke
1
6.1%
405/4188
(9.7%)
placebo
of patients
of
Study
Risk of Inconsistency Indirectness Imprecision
Other
studies design
bias
considerations Fibrates
MACE
1
randomised not
not serious
serious 1
not serious
none
345/4200
trials
serious
(4.6%)
Quality assessment
LOW
LOW
LOW
Quality
IMPORTANT
CRITICAL
CRITICAL
Importance
94
2015 Updated Clinical Practice Guidelines for the Management of Dyslipidemia in the Philippines
DISCLOSURES
Ms. Duante and Toledo, and Drs. Angus, Baello, Caole-Ang, Gobenchiong, Gloria, Jamorabo-Ruiz, Lazaro,
Merino, Olegario, Ona, Reganit, Santiago-Halasan, Serrano, Te, and Villasenor-Andaman declared no
potential conflicts of interest. Dr. Pestano has received non-financial support from industry. Dr. Jimeno is a
consultant or advisory board member of a pharmaceutical company. Drs. Bongosia, Gonzales-Santos and
Guerrero are members of the speakers bureau of various pharmaceutical companies. Dr. Sy is a consultant
or advisory board member and has received honorarium from industry. Dr. Acuin is a consultant or advisory
board member and has received honorarium from a non-industry organization. Dr. Cheng is a member of
the speakers bureau and has received honorarium from industry. Dr. Llanes is a member of the speakers
bureau and has received honorarium and other forms of support from industry. Dr. Matawaran is a consultant
or advisory board member, and speakers bureau member, from a pharmaceutical company. Dr. Cinco is a
consultant or advisory board member, a speakers bureau member, and has received honorarium and other
financial support from industry.