Beruflich Dokumente
Kultur Dokumente
Cardiology
Ramesh Singh Veriah
Cardiology Unit
University Malaya Medical Centre
CLINICAL TRIALS IN
DYSLIPIDEMIA
Primary Prevention Trials
• Pre‐ HMG CoA Reductase Inhibitor era
‐ Lipid Research Clinics Coronary Primary
Prevention Trial
‐ Helsinki Heart Study (HHS)
• Post Statin era
‐ WOSCOPS
‐ AFCAPS/TexCAPS
‐ Heart Protection Study (HPS)
‐ Collaborative Atorvastatin Diabetes Study (CARDS)
‐ Anglo‐Scandinavian Cardiac Outcomes Trial LLA
Early Primary-Prevention Trials: Overview
Oslo: Diet/smoking
TC * CHD events * cessation N=1,232,
0 P=0.02
-5 WHO: Clofibrate
-10 -9 -9 -8.5 N=15,745, P<0.05
-11
-15 -14 Upjohn: Colestipol
-20 -19
-20 N=2,278, P≤0.02
%+ -25 -23 LRC-CPPT:
-30 Cholestyramine
-35 -34 N=3,806, P<0.05
-40
HHS: Gemfibrozil
-45 N=4,081, P<0.02
-50 -47
N=number enrolled.
25 Placebo 9%
22.3 21.7***
17.3
20 15.0
66% 13.6 13.0
15
34%
8.0
10
4.1***
2.7 2.7
5
0
HHS HHS BIP BIP VA-HIT
(Post Hoc)* (Post Hoc)**
Deaths 2.2 2.1 10.4 9.9 15.7 17.4
PRIMARY PREVENTION SECONDARY PREVENTION
* Post hoc analysis of subgroup with TG >200 mg/dL and HDL-C <42 mg/dL.
** Post hoc analysis of subgroup with TG ≥200 mg/dL and HDL-C <35 mg/dL.
*** Difference between placebo and Rx for primary endpoint was statistically significant (p < 0.05).
Frick MH et al. N Engl J Med 1987;317:1237-1245. | Manninen V et al. Circulation Slide Source
1992;85:37-45. | BIP Study Group. Circulation 2000;102:21-27. | Rubins HB et al. Lipids Online Slide Library
www.lipidsonline.org
N Engl J Med 1999;341:410-418.
WOSCOPS: Effects of Lipid Lowering on Coronary
Events in Primary Prevention Trial in Men
10 Nonfatal
5 MI/CHD CHD All-cause
5
TC LDL-C death death mortality
0
HDL-C
-5 N= 6595 men
-10 45 – 64 yrs
%+ Mean Baseline TC
-15 = 272 mg/dL
-20 Mean Baseline LDL
-20 ‡ = 192 mg/dL
-25
-22 5 yr duration
-30 -26 Intervention:
-35 † Pravastatin 40mg dly
-31*
-33
* P<0.0005.
† P=0.042.
‡ P=0.051.
12
Placebo (n=3293)
10
Percent With Event
1 2 3 4 5 6
Years
0.07
0.06
37% risk reduction
Cumulative incidence
0.04
0.03
Lovastatin
0.02
0.01
N=6605
0.00 45-73 yrs
Healthy subjects with
0 1 2 3 4 5 5+ low HDL
Years of follow-up
Lovastatin 20-40 mg
vs placebo
Downs JR et al. JAMA 1998;279:1615–1622
Copyright ©1998, American Medical Association.
Air Force/Texas Coronary Atherosclerosis Prevention
Study (AFCAPS/TexCAPS)
Event Rates by Baseline HDL-C Tertile
-45%
16
risk reduction -44%
14 risk reduction
Lovastatin
Event rate per 1,000
patient-years at risk
12
-15% Placebo
10 risk reduction
8
6
4
2
0
≤ 34 35–39 ≥ 40
HDL-C (mg/dL)
11
Eligibility: MRC/BHF Heart
Protection Study
Role of lipid lowering in individuals with diabetes
or at high risk for vascular events
Age 40–80 years
Slide Source
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Lipids Online Slide Library
www.lipidsonline.org
Factorial Treatment Comparisons
Simvastatin Placebo
VS
(40 mg daily) tablets
Vitamins
Placebo
(600 mg E, 250 mg C, VS
capsules
and 20 mg β-carotene)
Slide Source
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Lipids Online Slide Library
www.lipidsonline.org
Simvastatin: Major Vascular Events
Risk ratio and 95% CI
Vascular Simvastatin Placebo STATIN PLACEBO
Event (10,269) (10,267) Better Better
24% SE 3
2033 2585
ANY OF ABOVE reduction
(19.8%) (25.2%) (2P<0.00001)
Slide Source
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Lipids Online Slide Library
Reprinted with permission from Elsevier Science. www.lipidsonline.org
Simvastatin: Coronary Events and
Revascularization
Risk ratio and 95% CI
Major Coronary Simvastatin Placebo STATIN PLACEBO
Event (10,269) (10,267) Better Better
27% SE 4
CORONARY EVENTS 898 (8.7%) 1212 (11.8%) reduction
(2P<0.00001)
Revascularization
Coronary 513 725
Noncoronary 450 532
24% SE 4
reduction
REVASCULARIZATIONS 939 (9.1%) 1205 (11.7%) (2P<0.00001)
Severity
Fatal 96 119
Severe 42 51
Moderate 107 155
Mild 138 189
Unknown 61 71
25% SE 5
reduction
ALL STROKES 444 (4.3%) 585 (5.7%) (2P<0.00001)
30
25
Placebo
20
15 Simvastatin
10
0
0 1 2 3 4 5 6
Years of Follow-up
Benefit/1000 (SE): 5 (3) 20 (4) 35 (5) 46 (5) 54 (7) 60 (18)
Slide Source
Heart Protection Study Collaborative Group. Lancet 2002;360:7–22. Lipids Online Slide Library
www.lipidsonline.org
Reprinted with permission from Elsevier Science.
HPS: Conclusions
Slide Source
Lipids Online Slide Library
www.lipidsonline.org
The Collaborative
AtoRvastatin
Diabetes Study
Whether Diabetics with normal to mildly elevated
cholesterol levels and no history of CVD
would benefit from further lipid reduction.
Geiss LS, et al. In: National Diabetes Data Group. Diabetes in America. 2nd ed. Bethesda, Md: National Institutes of Health,
National Institute of Diabetes and Digestive and Kidney Diseases, 1995:233-257. Haffner SM, Lehto S, Rönnemaa T, et al.
N Engl J Med. 1998;339:229-234
Colhoun HM, Thomason MJ, Mackness MI, et al. Diabet Med. 2002;19:201-211.
20
Colhoun HM, Thomason MJ, Mackness MI, et al. Diabet Med. 2002;19:201-211.
Design
Atorvastatin 10 mg/day N=
1428
Placebo 2838
patients
N=
Placebo 1410
6-week placebo lead-in
prerandomization 304 primary end points
Patient population:
Type 2 diabetes with no previous MI or CHD
Mean follow-up of 3.7 years
≥1 other CHD risk factor plus LDL-C ≤4.14 mmol/L
65% on OHA
and TG ≤6.78 mmol/L
83% Hypertensive
Aged 40-75 years
0
0 1 2 3 4 4.75 Years
Placebo 1410 1351 1306 1022 651 305
Atorva 1428 1392 1361 1074 694 328
Hypertension 100
Age ≥ 55 years 84
Male
77
Microalbuminuria/proteinuria
61
Smoker
30
Family history of CHD
27
Plasma TC:HDL-C ≥ 6 24
Type 2 diabetes 24
Certain ECG abnormalities
14
LVH 13
Previous cerebrovascular events
11
Peripheral vascular disease
6
0 10 20 30 40 50 60 70 80 90 100
Patients with risk factor (%)
The Anglo -Scandinavian Cardiac Outcomes Trial (ASCOT): A
Anglo-Scandinavian
Study in Hypertensive Patients at Low to Moderate CV Risk
Hypertensive patients with additional risk factors
Randomised
N=19,257
BPLA
Amlodipine ± perindopril ± Atenolol ± bendroflumethiazide-K+
doxazosin GITS ± doxazosin GITS
3.0
2.0
1.0
HR=0.90 (0.79-1.02)
0.0
0.0 1.0 2.0 3.0 4.0 5.0 6.0
Years
Dahlöf B et al, for the ASCOT Investigators. Lancet. 2005;366:895-906.
VBWG
ASCOT -BPLA:
ASCOT-BPLA:
Reduction
Reduction in
in fatal
fatal and
and nonfatal
nonfatal stroke
stroke
10
Placebo (n=5137)
3
Trial stopped early
P=.0005
2
1
Significant
benefits HR=0.64 (0.50-0.83)
observed in
90 days 0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.3 5.0
Years
RRR=relative risk reduction.
Sever PS et al for the ASCOT Investigators. Lancet. 2003;361:1149-1158. Sever PS et al, for the
ASCOT Investigators. Am J Cardiol. 2005;96:39F-44F.
ASCOT -LLA: 27% RRR in Fatal and Nonfatal
ASCOT-LLA:
Stroke When Atorvastatin Added to
BP Treatment
Atorvastatin 10 mg (n=5168)
3 Placebo (n=5137)
Proportion of Events (%)
HR=0.73 (0.56-0.96)
0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 5.0
Years
• Study design
− Double-blind, placebo-controlled trial
− 2531 men with CHD, HDL-C ≤ 40,
LDL-C ≤ 140, and TG ≤ 300
• Study intervention
− Gemfibrozil 1200 mg/day or placebo
• Primary endpoint
− Nonfatal MI or death from coronary causes
Results
• Median follow-up, 5.1 years
• Primary endpoint reached in 21.7% of placebo
group and 17.3% of gemfibrozil group
– 22% relative risk reduction in CHD death (P =
0.07) and 23% reduction in nonfatal MI (P =
0.02)
– 24% relative risk reduction in combined
outcome
of CHD death, nonfatal MI, or confirmed stroke
(P ≤ 0.001)
• ↑ HDL-C 6%
• ↓ TG 31%
• No change in LDL-C
Rubins HB et al. N Engl J Med. 1999;341:410-418.
VA-HIT: Relation of 5-Year CHD Rates to On-Treatment Lipid Values
25 HDL-C LDL-C
5-Year CHD Event Rate, %
22
19
16
13
10
24 28 32 36 40 44 80 95 110 125 140 155
• 4695 patients over age 59 with a mean initial sitting blood pressure of
174/86 randomnized to therapy with placebo or nitrendipine plus, if
necessary, enalapril and hydrochlorothiazide
• The fall in blood pressure was greater with active therapy, 23/7 versus
13/2 mmHg
• At four years, significant reductions were noted in stroke (7.9 versus
13.7 total endpoints per 1000 patient years), and fatal and non-fatal
cardiac endpoints
The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997; 350:757.
Syst-Eur trial - cont
Syst-Eur
The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997; 350:757.
Prevention of Dementia in ISH:
Syst-Eur Trial
Syst-Eur
Cohort
• 42,418 patients (≥55 years old) from 623 sites in North America
− Stage 1 or 2 hypertension
− 1 additional risk factor for CHD
• Comparisons between chlorthalidone and amlodipine and
chlorthalidone and lisinopril have been reported together,
excluding the doxazosin arm (n=9,062), which was terminated
early
Intent-to-
n=15,255 n=9,048 n=9,054
Treat 339 (2.2%) lost to follow-up 200 (2.2%) lost to follow-up 218 (2.4%) lost to follow-up
Analysis 80 (0.5%) refused follow-up 58 (0.6%) refused follow-up 58 (0.6%) refused follow-up
Primary endpoint
• Composite of fatal coronary heart disease (CHD) or nonfatal
myocardial infarction (MI)
Other predefined endpoints
− all-cause mortality
− stroke
− combined CHD – nonfatal MI, CHD death, coronary
revascularization, hospitalized angina
− combined cardiovascular disease – combined CHD, stroke,
lower extremity revascularization, treated angina, fatal/
hospitalized/treated congestive heart failure, hospitalized or
outpatient peripheral arterial disease
− other – renal
New-onset 8
diabetes
(% HOPE-TOO 6 Placebo
patients)
4
RRR 31%
P = 0.0006
2
Ramipril
0
n 1 2 3 4 5 6 7 Years
Placebo 2883 2803 2704 2600 2392 1813 1269 1021
Ramipril 2837 2763 2672 2587 2431 1853 1324 1092
treatment group)
(% of patients in
12
10
16.4%
8
13.1%
6
4
2
0
Valsartan-based Amlodipine-based
Regimen Regimen
(n = 5254) (n = 5168)
0.09
Atenolol
0.08 Atenolol (N=3979)
Losartan (N=4019)
0.07
Endpoint Rate
0.06
0.05 Losartan
0.04
0.03
0.02
25% lower incidence in losartan group
0.01 P<0.001
0.00
Study Month 0 6 12 18 24 30 36 42 48 54 60 66
B. Dahlöf at the American College of Cardiology, Atlanta, GA, March 17-20, 2002.
European trial on Reduction Of cardiac events with
Perindopril in stable coronary Artery disease
Stable CAD, age 18 and above with no clinical heart failure or LV systolic
dysfunction with one of the below:
Randomisation
14
12 Placebo
10
Perindopril
8
4 RRR: 20%
2 p = 0.0003
0
0 1 2 3 4 5 Years
Perindopril
1.0
0.5
0.0
0 1 2 3 4 5 Years
Stroke Prevention
• PROGRESS Study
• HOPE Study
• ASCOT Study
• JIKEI HEART Study
• LIFE Study
• To determine the effects • History of
of an ACEI-based blood cerebrovascular
pressure lowering
disease within the
regimen on the risk of
recurrent stroke among previous 5 years
patients with a history of • No definite indication
stroke or TIA.
for treatment with an
ACE inhibitor (e.g.
heart failure)
0.20
28% risk reduction
P<0.0001
Proportion with event
0.15
Placebo
Active*
0.10
0.05
0.00
0 1 2 3 4
*Active: Coversyl 4 mg ± Natrilix Follow-up time (years)
Reference: Lancet 2001; 358: 1033-41
3/2mmHg
Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm
Reduction in fatal and nonfatal stroke
6 RRR = 23%
Proportion P = 0.0003
of events 4
(%)
Atenolol ±
2 bendroflumethiazide
Amlodipine ± perindopril
0
0 1 2 3 4 5 6
Time (years)
Number at risk
Amlodipine-based regimen 9639 9483 9331 9156 8972 7863
(327 events)
Atenolol-based regimen 9618 9461 9274 9059 8843 7720
(422 events)
Valsartan
Non-ARB arm
arm
Medical history (n=1,540)
(n=1,541)
Hypertension 1,358 (88%) 1,341 (87%)
Coronary heart
514 (33%) 522 (34%)
disease
Heart failure 176 (11%) 174 (11%)
Hyperlipidaemia 812 (53%) 813 (53%)
Diabetes mellitus 315 (20%) 314 (20%)
Primary endpoint
Combined endpoint of CV morbidity and
mortality
15
Valsartan arm 92 events
Non-ARB arm 149 events
10
Event rate (%)
5 39%
p=0.00021
95% CI 0.47–0.79
0
0 6 12 18 24 30 36 42 48
Time
Stroke/TIA
3.5
Valsartan arm 29 events
3.0 Non-ARB arm 48 events
2.5
Event rate (%)
2.0
40%
1.5
1.0
p=0.028
0.5 95% CI 0.38–0.95
0.0
0 6 12 18 24 30 36 42 48
Time
Losartan IIntervention
Losartan ntervention For E
For ndpoint
Endpoint
Reduction in Hypertension Study
• 9193 hypertensive patients with left ventricular
hypertrophy (LVH)
• Compared to atenolol.
• The primary endpoint was a composite of:
− Cardiovascular mortality
− Stroke
− Myocardial infarction
Secondary Endpoint:
Fatal and Non-Fatal Stroke
Non-Fatal
8
Losartan
Atenolol
Percent of Patients
6
with First Event
2
Adjusted risk reduction 24.8%, p=0.001
0
0 6 12 18 24 30 36 42 48 54 60 66
n at risk Study Month
Losartan (n) 4605 4469 4332 4224 4117 1928
Atenolol (n) 4588 4424 4317 4180 4055 1901
Prevention of New Onset AF
• LIFE Study
• Val-Heft Study
New Onset Atrial Fibrillation
Post-Hoc Analysis
No. of Events
Endpoints Los Atl Hazard Ratio (95% CI)
0.5 1 1.5 2
Favors Favors
← Losartan Atenolol →
Addition of DIOVAN to Standard HF Therapy
Significantly Reduces Incidence of AF
Occurrence by 37%
0.15
Estimated probability of AF
0.05
0
0 2 4 6 8 10 12 14 16 18 20 22 24
Time post-randomisation (months)
AF = atrial fibrillation
Val-HeFT: Valsartan in Heart Failure Trial
Maggioni et al. Am Heart J 2005;149:548–57