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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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Reproduced from Julius et al. Lancet. 2004;363:2022-2031.
Number at risk
Valsartan 7649 7499 7458 7319 7177 7016 6853 6680 6504 6078 3864 1520
Amlodipine besylate 7596 7497 7458 7332 7205 7065 6905 6727 6562 6141 3840 1532
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)
Valsartan-based therapy
Amlodipine besylate-based therapy
7
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Reproduced from Julius et al. Lancet. 2004;363:2022-2031.
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
Amlodipine besylate 7596 7486 7444 7312 7176 7033 6874 6702 6534 6100 3823 1511
Valsartan-based therapy
Amlodipine besylate-based therapy
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
Amlodipine besylate 7596 7520 7484 7385 7276 7155 7025 6874 6729 6312 3961 1582
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(%)
Valsartan-based therapy
Amlodipine besylate-based therapy
Reproduced from Julius et al. Lancet. 2004;363:2022-2031.
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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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