The Early Prevention of Stroke and Heart Attack: Recent Evidence

Asia Pacific Cohort Studies Collaboration

Objectives: to estimate age, sex and region-specific associations of blood pressure with cardiovascular diseases Setting studies: Australia, China, Hongkong, Japan, New Zealand, Singapore, South Korea, and Taiwan Participants: a total of 425.325
Journal of Hypertension 2003, 21:707-716

Asia Pacific Cohort Studies Collaboration

Main outcomes measures:
Stroke Ischaemic heart disease Total cardiovascular death Conclusions: about half of the worlds cardiovascular burden is predicted to occur in the Asia Pacific region. Blood pressure is an important determinant of this burden, with considerable potential benefit of blood pressure lowering down to levels of at least 115 mmHg systolic pressure
Journal of Hypertension 2003, 21:707-716

Journal of Hypertension 2003, 21:707-716

Vascular beds linked in terms of prognosis & risk factors

Pts w/ a 1st time stroke have a 1,7x higher risk of death within 5 yrs if they have a history of intermittent claudications Pts w/ TIA are not only at higher risk of a subsequent stroke, but also of MI PAD confers a 2,3x excess hazard of stroke,MI or vascular death within 5 yrs of TIA
Stroke 2000, 31: 2080-2086

Hypertension Increases the Risk of Mortality and Morbidity

High blood pressure significantly increases the risk of Death Stroke Myocardial infarction Atrial fibrillation Heart failure Peripheral vascular disease Renal impairment
Adapted from Brown MJ, Haydock S. Drugs. 2000;59(suppl 2):1-12; Wright JM. Can Med Assoc J. 2000;163:188-192.

Elevated SBP Alone Is Associated With Increased Risk of Cardiovascular and Renal Disease
Disease Kidney failure (ESRD) Stroke Heart failure Peripheral vascular disease Myocardial infarction* Coronary artery disease
ESRD = end-stage renal disease; SBP 165 mm Hg. *Men only. Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S; Perry HM Jr et al. Hypertension. 1995;25(part 1):587-594; Klag MJ et al. N Engl J Med. 1996;334:13-18; Nielsen WB et al. Ugeskr Laeger. 1996;158:3779-3783; Neaton JD et al. Arch Intern Med. 1992;152:56-64.

Relative Risk 2.8 2.7 1.5 1.8 =1.6 1.5

Risk of Cardiovascular Events With Elevated SBP*

Disease Coronary disease Stroke Cardiac failure Peripheral vascular disease Men Women 1.5 2.6 2.0 1.8 1.6 1.8 1.5 2.1

*36-year follow-up for subjects 65 to 94 years old. Age-adjusted risk ratios. Adapted from Kannel WB. Am J Hypertens. 2000;13:3S-10S; Kannel WB. J Am Coll Cardiol. 1990;15:206-211.

Lowering SBP Benefits Older Patients

Clinical trials document importance of controlling elevated SBP to prevent cardiovascular disease
SHEP (Systolic Hypertension in the Elderly Program) Syst-Eur (Systolic Hypertension in Europe)

Adapted from SHEP Cooperative Research Group. JAMA. 1991;265:3255-3264; Staessen JA et al. Lancet. 1997;350:757-764.

Effect of Antihypertensive Therapy

0 10 % Reduction 20 30 40 50 60
MacMahon SW et al. Prog Cardiovasc Dis. 1986;29(suppl 1):99118.

Cerebrovascular Disease

Coronary Heart Disease

16%

48%

Event Reduction in Patients on Active Antihypertensive Treatment versus Placebo or No Treatment

Systolic-diastolic hypertension
Fatal and non-fatal events Stroke CHD Mortality All cause CV Non CV
NS

Isolated systolic hypertension

Fatal and non-fatal events Stroke CHD Mortality All cause CV Non CV
NS

0 10
(%)

0 10

<0.001

(%)

20 30 40

<0.01

<0.01

20
<0.001

0.02 0.01

30 40

<0.001

<0.001

50
ESH-ESC Hypertension Guidelines. J Hypertens. 2003.

50

Morning Surge
Sudden activation of sympathetic nervous system is the primary mediator Recognition of MS by Ambulatory Blood Pressure Monitoring(ABPM) In older hypertensives, a higher morning BP surge is associated w/ stroke risk independently of ambulatory BP, nocturnal BP falls and silent infarct

Morning Surge

(contd)

Reduction of MS could thus be a new therapeutic target for preventing target organ damage and subsequent cardiovascular events The choice of antihypertensive agents should be include formulations that provide 24-hour or longer efficacy for maximal protection

50 45 40 Elimination half-lives (hours) 35 30 25 20 15 10 5 Verapamil Nifedipine Amlodipine Felodipine Nisodipine Isradipine

Elimination half-lives of a range of calcium antagonists in volunteer subjects (Nayler, 1993)

Drug Holiday Protection

Amlodipine provides greater protection than nifedipine GITS againts loss of BP control following missed doses (Ongtengco et al., 2002)
Nifedipine short acting doesnt recommended for essential hypertension (The pharmacologic management of hypertension 2000)

VALUE
Valsartan Antihypertensive Long-Term Use Evaluation

VALUE: Design
Elective titration to target BP (<140/90 mm Hg)
Valsartanbased regimen
V 160 mg V 160 mg + HCTZ 25 mg V 160 mg + HCTZ 25 mg + "Free" add-on V 160 mg + HCTZ 12.5 mg

Rollover from previous therapy (92%)

V 80 mg

A 5 mg A 10 mg A 10 mg + HCTZ 12.5 mg

Amlodipine besylate-based regimen

Month 0.5 0 1

A 10 mg + HCTZ 25 mg

A 10 mg + HCTZ 25 mg + "Free" add-on 4 6 * 72

Screening End of treatment adjustment period Randomisation *Patient visits every 6 months for months 6-72. Reproduced from Julius et al. Lancet. 2004;363:2022-2031.

VALUE: Primary Hypothesis

In hypertensive patients at high cardiovascular risk, for the same level of blood pressure reduction, valsartan will be more effective than amlodipine besylate in reducing cardiac morbidity and mortality

Julius et al. Lancet. 2004;363:2022-2031.

VALUE: Primary End Point

Time to First Cardiac Morbidity or Mortality Event
Cardiac morbidity = CHF requiring hospital management, nonfatal MI, or emergency procedures to prevent MI Cardiac mortality = fatal MI, death during or after interventions, death due to CHF, death associated with recent MI on autopsy
Mann et al. Blood Press. 1998;7:176-183.

VALUE: Prespecified Secondary End Points

MI

Heart failure All-cause mortality Stroke Worsening of chronic stable or unstable angina Routine interventional procedures Potentially lethal arrhythmias Syncope or near syncope Silent MI End-stage renal failure

Mann et al. Blood Press. 1998;7:176-183.

VALUE: Antihypertensive Treatment and Blood Pressure Results

VALUE: BP Changes From Baseline to the End of the Study (72 mo) or Final Visit
0 -5 mm Hg -10 -15 -20 P<0.0001 P<0.0001
Valsartan arm Amlodipine besylate arm

Systolic BP

Diastolic BP

BP, mm Hg -15.2/-8.2 -17.3/-9.9

Overall BP difference= 2.2/1.6 mm Hg

Julius et al. Lancet. 2004;363:2022-2031.

VALUE: Systolic BP in Study

Sitting SBP by Time and Treatment Group 155

mm Hg

150 145 140

Valsartan arm (n=7649)

Amlodipine besylate arm (n=7596)

135 Baseline 1

6 12 18 24 30 36 42 48 54 60 66 (or final visit) Months Difference in SBP Between Valsartan and Amlodipine Besylate Arms 5.0 4.0 3.0 2.0 1.0 0 1.0 1 2 3 4 6 12 18 24 30 36 42 48 54 60 66 (or final visit) Months

Adapted from Julius et al. Lancet. 2004;363:2022-2031.

mm Hg

VALUE: Diastolic BP in Study

Sitting DBP by Time and Treatment Group 90

mm Hg

85 80 75

Valsartan arm (n=7649)

Amlodipine besylate arm (n=7596)

Baseline 1

6 12 18 24 30 36 42 48 54 60 66 Months (or final visit) Difference in DBP Between Valsartan and Amlodipine Besylate Arms

5.0 4.0 3.0 2.0 1.0 0 1.0

mm Hg

6 12 18 24 30 36 42 48 54 60 66 Months (or final visit)

Adapted from Julius et al. Lancet. 2004;363:2022-2031.

VALUE: Primary End Point Results

VALUE: Primary Composite Cardiac End Point

14 Proportion of Patients With First Event (%) 12 10 8 6 4 2 0 0 Number at risk
Valsartan Amlodipine besylate

Valsartan-based therapy Amlodipine besylate-based therapy

HR=1.03; 95% CI, 0.94-1.14, P=0.49 6 12 18 24 30 36 42 48 54 60 66 Time (months)

7649 7459 7407 7250 7085 6906 6732 6536 6349 5911 3764 1474 7596 7469 7424 7267 7117 6955 6772 6576 6391 5959 3725 1474

NORVASC is indicated for the treatment of hypertension and angina.

Reproduced from Julius et al. Lancet. 2004;363:2022-2031.

VALUE: End Points*

Valsartan (n=7649) n (%) Primary composite Cardiac mortality 810 (10.6%) 304 (4.0%) Amlodipine Besylate (n=7596) n (%) Hazard ratio 789 (10.4%) 304 (4.0%) 578 (7.6%) 313 (4.1%) 400 (5.3%) 281 (3.7%) 1.04 (0.94-1.15) 1.01 (0.86-1.18) 1.02 (0.91-1.15) 1.19 (1.02-1.38) 0.89 (0.77-1.03) 1.15 (0.98-1.35) P 0.49 0.90 0.71 0.02 0.12 0.08

Cardiac morbidity 586 (7.7%)

Myocardial infarction
Heart failure Stroke

369 (4.8%) 354 (4.6%) 322 (4.2%)

All-cause death

841 (11.0%)

818 (10.8%)

1.04 (0.94-1.14)

0.45

Amlodipine besylate is indicated for the treatment of hypertension and angina.

*Proportion of patients with first event. Fatal and nonfatal. Adapted from Julius et al. Lancet. 2004;363:2022-2031.

VALUE: Fatal and Nonfatal MI

7 6 5 4 3 Proportion of Patients With First Event (%)

Valsartan-based therapy Amlodipine besylate-based therapy

2
1 HR=1.19; 95% CI, 1.02-1.38; P=0.02

0
0
Number at risk Valsartan Amlodipine besylate

12

18

24 30 36 42 48 Time (months)

54

60

66

7649 7499 7458 7319 7177 7016 6853 6680 6504 6078 3864 1520 7596 7497 7458 7332 7205 7065 6905 6727 6562 6141 3840 1532

Reproduced from Julius et al. Lancet. 2004;363:2022-2031.

VALUE: Fatal and Nonfatal Stroke

6 Proportion of Patients With First Event (%) 5 4 3 2 1 HR=1.15; 95% CI, 0.98-1.35; P=0.08 0 0 6 12 18 24 30 36 42 48 54 60 66 Valsartan-based therapy Amlodipine besylate-based therapy

Time (months) Number at risk Valsartan 7649 7494 7448 7312 7170 7022 6877 6692 6515 6093 3859 1516 Amlodipine besylate 7596 7499 7455 7334 7195 7055 6918 6744 6587 6163 3846 1532
Reproduced from Julius et al. Lancet. 2004;363:2022-2031.

VALUE: Fatal and Nonfatal Heart Failure

9 8 Proportion of Patients With First Event (%) 7 6 Valsartan-based therapy Amlodipine besylate-based therapy

5 4
3 2 1 0 0 6 12 18 24 30 36 42 48 54 60 66 Time (months)
7649 7485 7444 7312 7169 7012 6852 6671 6498 6072 3860 1513 7596 7486 7444 7312 7176 7033 6874 6702 6534 6100 3823 1511

HR=0.89; 95% CI, 0.77-1.03; P=0.12

Number at risk Valsartan Amlodipine besylate

Reproduced from Julius et al. Lancet. 2004;363:2022-2031.

VALUE: All-Cause Death

16

14
Proportion of Patients With First Event (%) 12 10 8 6 4 2

Valsartan-based therapy Amlodipine besylate-based therapy

HR=1.04; 95% CI, 0.94-1.14; P=0.45

0
0
Number at risk Valsartan Amlodipine besylate

12

18

24 30 36 42 48 Time (months)

54

60

66

7649 7527 7496 7383 7267 7136 6994 6843 6682 7596 7520 7484 7385 7276 7155 7025 6874 6729

6273 3981 1563 6312 3961 1582

Reproduced from Julius et al. Lancet. 2004;363:2022-2031.

Other Prespecified Secondary End Points

Valsartan (n=7622) 708 (9.3%) 335 (4.4%) 182 (2.4%) 129 (1.7%)

Angina pectoris*
Angina pectoris Atrial fibrillation Syncope

Amlodipine besylate (n=7576) 485 (6.4%)

234 (3.1%) 151 (2.0%) 75 (1.0%)

P <0.0001 <0.0001 0.1197 <0.0001

*With an incidence >3% and a difference between treatment groups >1%. Reported as serious. Mann et al. Blood Press. 1998;7:176-183; Adapted from Julius et al. Lancet. 2004;363: 2022-2031.

BP-Lowering Treatment Trialists Meta-analysis:

Comparisons of Active Treatments and Control
BP Difference (mm Hg)
Stroke ACEI vs placebo CA vs placebo Coronary heart disease ACEI vs placebo CA vs placebo Heart failure ACEI vs placebo CA vs placebo Major CV events ACEI vs placebo CA vs placebo CV mortality ACEI vs placebo CA vs placebo Total mortality ACEI vs placebo CA vs placebo -5/-2 -8/-4 -5/-2 -8/-4 -5/-2 -8/-4 -5/-2 -8/-4 -5/-2 -8/-4 -5/-2 -8/-4

Relative Risk

RR (95% CI)
0.72 (0.64, 0.81) 0.62 (0.47, 0.82) 0.80 (0.73, 0.88) 0.78 (0.62, 0.99) 0.82 (0.69, 0.98) 1.21 (0.93, 1.58) 0.78 (0.73, 0.83) 0.82 (0.71, 0.95) 0.80 (0.71, 0.89) 0.78 (0.61, 1.00) 0.88 (0.81, 0.96) 0.89 (0.75, 1.05)

0.5

Favors 1.0 Active

Favors 2.0 Control

Blood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2003;362:1527-1535.

BP-Lowering Treatment Trialists Meta-analysis: More Intensive vs Less Intensive

Difference in BP Mean (mm Hg) Relative Risk Relative Risk (95% CI)

Stroke CHD Heart failure Major CV events CV death Total mortality

-4/-3 -4/-3 -4/-3 -4/-3 -4/-3 -4/-3 0.5

Favors More Intensive

0.77 (0.630.95) 0.95 (0.811.11) 0.84 (0.591.18) 0.85 (0.760.95) 0.93 (0.771.11) 0.96 (0.841.09) 1.0
Favors 2.0 Less intensive

Blood Pressure Lowering Treatment Trialists Collaboration. Lancet. 2003;362:1527-1535.

VALUE Secondary End Points

Outcome Favors valsartan Favors amlodipine besylate RR (95% CI)

Stroke

1.15 (0.98-1.35) 1.19 (1.02-1.38) 0.89 (0.77-1.03)

MI Heart failure Total mortality

0.5 1 1.5

1.04 (0.94-1.14)

Relative Risk

us et al. Lancet. 2004;363:2022-2031.

CONCLUSION
Morning BP surge is a predictor of silent & clinical cerebrovascular disease The findings emphasize the importance of prompt BP control in hypertensive patients at high CV risk The choice of Anti-hypertensive should be include formulations that provide 24 hours or longer efficacy for maximal protection Blood pressure was aggressively controlled in VALUE as compared with usual community practice Confirms amlodipine besylate-based therapy is significantly more efficacious in reducing BP than valsartan-based therapy Confirms the proven safety and tolerability of amlodipine besylate therapy