The Early Prevention of Stroke Heart Attack Perki Smg 05.ppt

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The Early Prevention of Stroke andHeart Attack: Recent Evidence


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Asia Pacific Cohort Studies

Collaboration

Objectives: to estimate age, sex and

region-specific associations of bloodpressure with cardiovascular diseases

Setting studies: Australia, China,

Hongkong, Japan, New Zealand,Singapore, South Korea, and Taiwan

Participants: a total of 425.325Journal of Hypertension 2003, 21:707-716


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Asia Pacific Cohort Studies

Collaboration Main outcomes measures:

Stroke

Ischaemic heart disease Total cardiovascular death

Conclusions: about half of the worldscardiovascular burden is predicted to occur in theAsia Pacific region. Blood pressure is an importantdeterminant of this burden, with considerablepotential benefit of blood pressure lowering downto levels of at least 115 mmHg systolic pressure

Journal of Hypertension 2003, 21:707-716


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Vascular beds linked in terms ofprognosis & risk factors

Pts w/ a 1st time stroke have a 1,7xhigher risk of death within 5 yrs if theyhave a history of intermittentclaudications

Pts w/ TIA are not only at higher risk ofa subsequent stroke, but also of MI

PAD confers a 2,3x excess hazard ofstroke,MI or vascular death within 5 yrsof TIA

Stroke 2000, 31: 2080-2086


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Hypertension Increases the Riskof Mortality and Morbidity

High blood pressure significantly increases the risk of

Death

StrokeMyocardial infarction

Atrial fibrillation

Heart failure

Peripheral vascular disease

Renal impairmentAdapted from Brown MJ, Haydock S. Drugs. 2000;59(suppl 2):1-12; Wright JM. Can Med Assoc J.

2000;163:188-192.


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Disease Relative Risk

Kidney failure (ESRD) 2.8

Stroke 2.7Heart failure 1.5Peripheral vascular disease 1.8Myocardial infarction* =1.6

Coronary artery disease

1.5

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.

Elevated SBP Alone Is Associated WithIncreased Risk of Cardiovascular and

Renal Disease


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Disease Men Women

Coronary disease 1.5 1.6

Stroke 2.6 1.8

Cardiac failure 2.0 1.5

Peripheral vascular disease 1.8 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.

Risk of Cardiovascular Events

With Elevated SBP*


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Lowering SBP Benefits Older

Patients

Clinical trials document importance of

controlling elevated SBP to prevent

cardiovascular diseaseSHEP (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.


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Effect of Antihypertensive Therapy

%

Reduction

MacMahon SW et al. Prog Cardiovasc Dis.1986;29(suppl 1):99118.

60

50

40

30

20

10

0

48%

16%

Cerebrovascular

Disease

Coronary Heart

Disease


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Isolated systolic hypertension

(%)

0

10

20

30

40

50

0

10

20

30

40

50

(%)

Stroke CHDAll

cause CVNonCV

Fatal andnon-fatal events Mortality

Systolic-diastolic hypertension

Stroke CHDAll

cause CVNonCV

Fatal andnon-fatal events Mortality

Event Reduction in Patients on Active Antihypertensive

Treatment versus Placebo or No Treatment

ESH-ESC Hypertension Guidelines. J Hypertens.2003.


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Morning Surge Sudden activation of sympatheticnervous system is the primary mediator

Recognition of MS by Ambulatory BloodPressure Monitoring(ABPM)

In older hypertensives, a highermorning BP surge is associated w/stroke risk independently of ambulatoryBP, nocturnal BP falls and silent infarct


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Verapamil Nifedipine Amlodipine Felodipine Nisodipine Isradipine

5

10

15

20

25

30

35

40

45

50

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

Eliminationhalf-lives(hours)


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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)


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VALUE

ValsartanAntihypertensive

Long-Term Use

Evaluation


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Elective titration to target BP (


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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, valsartanwill be more effective than amlodipine

besylate in reducing cardiac morbidity

and mortality


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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


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VALUE: Antihypertensive

Treatment and Blood Pressure

Results


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

VALUE: BP Changes From Baseline to the

End of the Study (72 mo)

or Final Visit

Systolic BP Diastolic BP

Valsartan arm

Amlodipine

besylate arm-20

-15

-10

-5

0

mmHg

P


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

VALUE: Systolic BP in Study

Valsartan arm

(n=7649)Amlodipine

besylate arm

(n=7596)

135

140

145

150

155

mmHg

Months

Sitting SBP by Time and Treatment Group

Baseline 1 24 482 3 4 6 12 18 30 36 42 54 60 66(or final visit)

01.02.03.0

4.0

mmH

g

1 24 482 3 4 6 12 18 30 36 42 54 60 66

Months

5.0Difference in SBP Between Valsartan and Amlodipine Besylate Arms

1.0

(or final visit)


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VALUE: Primary End Point

Results

VALUE P i C i


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NORVASC is indicated for the treatment of hypertension and angina.

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

Valsartan-based therapy

Amlodipine besylate-based therapy

Proportio

nofPatients

WithFirstEvent(%)

HR=1.03; 95% CI, 0.94-1.14, P=0.49

14

12

10

8

6

4

2

0

0 6 12 18 24 30 36 42 48 54 60 66Time (months)

Number at risk

Valsartan 7649 7459 7407 7250 7085 6906 6732 6536 6349 5911 3764 1474

Amlodipine besylate 7596 7469 7424 7267 7117 6955 6772 6576 6391 5959 3725 1474

VALUE: Primary Composite

Cardiac End Point


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VALUE: End Points*Valsartan

(n=7649)

n (%)

Amlodipine Besylate

(n=7596)

n (%) Hazard ratio P

Primary composite 810 (10.6%) 789 (10.4%) 1.04 (0.94-1.15) 0.49

Cardiac mortality 304 (4.0%) 304 (4.0%) 1.01 (0.86-1.18) 0.90

Cardiac morbidity 586 (7.7%) 578 (7.6%) 1.02 (0.91-1.15) 0.71Myocardial

infarction369 (4.8%) 313 (4.1%) 1.19 (1.02-1.38) 0.02

Heart failure 354 (4.6%) 400 (5.3%) 0.89 (0.77-1.03) 0.12

Stroke 322 (4.2%) 281 (3.7%) 1.15 (0.98-1.35) 0.08

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.


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Number at risk

Valsartan 7649 7499 7458 7319 7177 7016 6853 6680 6504 6078 3864 1520


VALUE: Fatal and Nonfatal MI

Propo

rtionofPatients

With

FirstEvent(%)

6

5

4

3

2

1

0

0 6 12 18 24 30 36 42 48 54 60 66

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

Time (months)



7


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VALUE: Fatal and Nonfatal Heart Failure

ProportionofPatients

With

FirstEvent(%)

76

5

4

32

1

0

0 6 12 18 24 30 36 42 48 54 60 66

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

Time (months)

8

9

Number at risk

Valsartan 7649 7485 7444 7312 7169 7012 6852 6671 6498 6072 3860 1513




VALUE All C D th


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VALUE: All-Cause Death

Number at risk

Valsartan 7649 7527 7496 7383 7267 7136 6994 6843 6682 6273 3981 1563


16

14

12

10

8

4

2

0

0 6 12 18 24 30 36 42 48 54 60 66

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

Time (months)

6

ProportionofPatients

With

FirstEvent(%)





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Other Prespecified Secondary

End Points

Valsartan

(n=7622)

Amlodipine

besylate

(n=7576) P

Angina pectoris* 708 (9.3%) 485 (6.4%)


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BP-Lowering Treatment Trialists Meta-analysis:Comparisons of Active Treatments and Control

FavorsActive

FavorsControl

0.5 1.0 2.0

Relative Risk RR (95% CI)

Stroke

Coronary heart disease

Heart failure

BP Difference(mm Hg)

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

Major CV events

CV mortality

Total mortality

-5/-2

-5/-2

-5/-2

-5/-2

0.72 (0.64, 0.81)ACEI vs placebo -5/-2

0.80 (0.73, 0.88)-5/-2ACEI vs placebo

0.82 (0.69, 0.98)ACEI vs placebo

ACEI vs placebo 0.88 (0.81, 0.96)

ACEI vs placebo 0.78 (0.73, 0.83)

ACEI vs placebo 0.80 (0.71, 0.89)

0.62 (0.47, 0.82)CA vs placebo -8/-4

0.78 (0.62, 0.99)-8/-4CA vs placebo

CA vs placebo 0.82 (0.71, 0.95)-8/-4

1.21 (0.93, 1.58)CA vs placebo -8/-4

CA vs placebo 0.78 (0.61, 1.00)-8/-4

CA vs placebo 0.89 (0.75, 1.05)-8/-4

BP L i T t t T i li t M t l i


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BP-Lowering Treatment Trialists Meta-analysis:

More Intensive vs Less Intensive

FavorsMore Intensive

FavorsLess intensive

0.5 1.0 2.0

Difference in BPMean (mm Hg)

Stroke

CHD

Heart failure

Major CV events

CV death

Total mortality

-4/-3

-4/-3

-4/-3

-4/-3

-4/-3

-4/-3

0.77 (0.630.95)

0.95 (0.811.11)

0.85 (0.760.95)

0.84 (0.591.18)

0.93 (0.771.11)

0.96 (0.841.09)

Relative Risk(95% CI)Relative Risk

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

VALUE Secondar End Points


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VALUE Secondary End Points

Relative Risk

RR (95% CI)

Favors

valsartan

Favors

amlodipine besylateOutcome

Stroke

MI

Heart failure

Total mortality

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

0.5 1 1.5

1.15 (0.98-1.35)

1.19 (1.02-1.38)

0.89 (0.77-1.03)

1.04 (0.94-1.14)


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CONCLUSION

Morning BP surge is a predictor of silent & clinical cerebrovasculardisease

The findings emphasize the importance of prompt BP control inhypertensive 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 moreefficacious in reducing BP than valsartan-based therapy

Confirms the proven safety and tolerability of amlodipine besylatetherapy


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The Early Prevention of Stroke Heart Attack Perki Smg 05.ppt

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