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RAAS Modulation
in High-Risk Patients
ACEIs: Evolution of benefits
BP reduction
Cardioprotection
Vascular protection
Renal protection
Improved glycemic control (?)
Lonn E et al. Eur Heart J Suppl. 2003;5(suppl A):A43-8.
DREAM Trial Investigators. N Engl J Med. 2006;355:1551-62.
Effect of ACEIs and ARBs on new-onset diabetes
Meta-analysis of 12 randomized controlled trials
Less likely to develop T2DM
CAPPP
STOP-2
HOPE
LIFE
ALLHAT
ANBP2
SCOPE
ALPINE
CHARM
SOLVD
VALUE
PEACE
More likely to develop T2DM
0.79 (0.67–0.94)
0.96 (0.72–1.27)
0.66 (0.51–0.85)
0.75 (0.63–0.88)
0.70 (0.56–0.86)
0.66 (0.54–0.85)
0.81 (0.61–1.02)
0.13 (0.03–0.99)
0.78 (0.64–0.96)
0.26 (0.13–0.53)
0.77 (0.69–0.86)
0.83 (0.72–0.96)
All pooled
ACEI pooled
ARB pooled
0.75 (0.69–0.82)
0.73 (0.63–0.84)
0.77 (0.71–0.83)
0.125
0.25
0.5
1
2
Relative risk (95% CI)
4
8
Abuissa H et al. J Am Coll Cardiol. 2005;46:821-6.
HOPE, EUROPA, PEACE: Reduction in new-onset
diabetes (placebo-controlled trials)
n = 23,340 free from diabetes* at baseline
Overall
14% RRR
RR 0.86 (0.78–0.95)
P = 0.0023
14
12
10
New-onset
diabetes
(%)
8
6
4
2
0
HOPE
Ramipril
10 mg
Placebo
*Not a prespecified end point
EUROPA
Perindopril
8 mg
PEACE
Trandolapril
4 mg
Pooled data
(all trials)
ACEI
Dagenais GR et al. Lancet. 2006;368:581-8.
TZDs blunt diabetes progression
Diabetes Prevention Program (DPP)
15
Cumulative
incidence
of diabetes
(%)
Placebo
Metformin
850 mg bid
10
Lifestyle
Troglitazone
400 mg/d*
5
0
0
0.5
1.0
1.5
Follow-up (years)
n=
2343
*Withdrawn from study after 1.5 yr
1568
739
237
DPP Research Group. Diabetes. 2005;54:1150-6.
DPP: Long-term benefit of lifestyle intervention
or metformin on diabetes prevention
N = 3234 with IFG and IGT, without diabetes
40
Placebo
P*
30
Cumulative
incidence
of diabetes 20
(%)
Metformin
31%
<0.001
Lifestyle
58%
<0.001
10
0
0
1.0
*vs placebo
IFG = impaired fasting glucose
IGT = impaired glucose tolerance
2.0
3.0
4.0
Years
DPP Research Group.
N Engl J Med. 2002;346:393-403.
DREAM: Background
Diabetes REduction Assessment with ramipril and rosiglitazone Medication
• Prevalence of T2DM continues to rise
• Persons with diabetes are at risk for macro- and
microvascular complications
• Current options for diabetes prevention include:
– Lifestyle intervention: ≥50%
– Acarbose, metformin: 25%–30%
• New approaches are needed
DREAM Trial Investigators. Lancet. 2006;368:1096-105.
N Engl J Med. 2006;355:1551-62.
DREAM: Study design
Randomized, double-blind 2 × 2 factorial design
N = 5269 with IFG and/or IGT, free from CV disease
Ramipril 15 mg/d vs placebo
AND
Rosiglitazone 8 mg/d vs placebo
Primary outcome:
Diabetes or death from any cause
Secondary outcomes I: CV
events
Combined MI, stroke, CV
death, revascularization,
HF, angina,
ventricular arrhythmia
Secondary outcomes II:
Renal events
Progression to micro- or
macroalbuminuria,
or 30% CrCl
Secondary outcomes III:
Glycemic status
Glucose levels,
conversion to
normoglycemia
Follow-up: 3–5 years
DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.
DREAM: 2 × 2 factorial design
N = 5269 with IFG and/or IGT
Rosiglitazone
Placebo
Ramipril
Ramipril +
Rosiglitazone
Ramipril +
Placebo
Placebo
Rosiglitazone +
Placebo
Placebo +
Placebo
Ramipril: 5 mg × 2 months; 10 mg × 10 months; 15 mg thereafter
Rosiglitazone: 4 mg × 2 months; 8 mg thereafter
DREAM Trial Investigators.
Diabetologia. 2004;47:1519-27.
DREAM: Adjudicated HF
Overnight (2 calendar days) hospitalization or ER
attendance for 2 of the following criteria:
• Signs/symptoms of HF
• Radiologic evidence of HF
• Need for IV/oral diuretic, vasodilator, and/or inotrope
DREAM Trial Investigators. N Engl J Med. 2006;355:suppl appendix (epub).
DREAM: Ramipril effect on new-onset diabetes
or death
0.6
9% RRR
HR 0.91 (0.81–1.03)
P = 0.15
0.5
Placebo
0.4
Cumulative
hazard rate
0.3
0.2
Ramipril
0.1
0.0
No. at risk
Placebo
Ramipril
0
1
2646
2623
2510
2498
2
3
Follow-up (years)
2277
2287
1240
1218
4
200
194
DREAM Trial Investigators. N Engl J Med. 2006;355:1551-62.
DREAM: Ramipril effect on glycemia
1.60
16% increase
HR 1.16 (1.07–1.27)
P = 0.001
1.20
Ramipril
Cumulative
hazard rate of
0.80
conversion to
normoglycemia
0.40
Placebo
0.0
No. at risk
Placebo
Ramipril
0
1
2646
2623
2494
2487
FPG < 110 mg/dL and 2-h glucose < 140 mg/dL
2
3
Follow-up (years)
2090
2060
876
791
4
145
127
DREAM Trial Investigators. N Engl J Med. 2006;355:1551-62.
DREAM: Rosiglitazone effect on primary
end point
0.6
0.5
0.4
Cumulative
hazard rate
Placebo
60% RRR
HR 0.40 (0.35–0.46)
P < 0.0001
0.3
0.2
Rosiglitazone
0.1
0.0
0
No. at risk
Placebo
Rosiglitazone
1
2
3
4
Follow-up (years)
2634
2635
2470
2538
2150
2414
1148
1310
177
217
DREAM Trial Investigators. Lancet. 2006;368:1096-105.
DREAM: Conversion to normoglycemia with
rosiglitazone
N = 5269
71% increase
HR 1.71 (1.571.87)
P < 0.0001
60
50
40
Participants
(%)
30
20
10
0
Diabetes
Placebo
IFG and/or IGT
Normoglycemia*
Rosiglitazone
*FPG < 110 mg/dL and 2-h glucose < 140 mg/dL
DREAM Trial Investigators. Lancet. 2006;368:1096-105.
DREAM: Safety
Ramipril vs placebo
• No adverse hepatic effects
– Alanine aminotransferase (ALT) levels 1.1 U/L at 1 year (P = 0.004)
Rosiglitazone vs placebo
• Increased incidence of HF* (0.5% vs 0.1%, P = 0.01)
– No cases of fatal HF
– No difference for other CV events
• Increased incidence of peripheral edema
(6.8% vs 4.9%, P = 0.003)
• 4.9-lb weight gain (P < 0.0001)
– Increased hip circumference (0.71 in, P < 0.0001)
– No difference in waist circumference
– Decreased waist-hip ratio (P < 0.0001)
• No adverse hepatic effects
– ALT levels 4.2 U/L at 1 year (P < 0.0001)
*Adjudicated
DREAM Trial Investigators.
N Engl J Med. 2006;355:1551-62; Lancet. 2006;368:1096-105.
DREAM: Clinical implications
Ramipril
• No significant effect on new-onset diabetes
– Improved glucose metabolism; further research is needed
– Routine use for diabetes prevention cannot be recommended
• When ACEIs are indicated, improved glucose metabolism
may be additional benefit
Rosiglitazone
• Provides evidence that pharmacologic intervention is an option
for treatment of prediabetes
• Benefit/risk: Of 1000 individuals treated for 3 years,
~144 cases of new-onset diabetes could be prevented with excess
of 4–5 HF cases
DREAM Trial Investigators.
N Engl J Med. 2006;355:1551-62; Lancet. 2006;368:1096-105.
Evolution of ACE inhibition for treating patients
with CHD
Severe HF
CONSENSUS
Low LVEF
SOLVD-Prevent
SOLVD-Treat
SAVE
AIRE
1987
*Chinese Captopril Trial
1991–1993
Acute MI
GISSI-3
ISIS-4
CCT*
CONSENSUS II
1992–1995
CHD without HF or
LV dysfunction
QUIET
HOPE
EUROPA
PEACE
1999–2004
Adapted from Yusuf S, Lonn E. Eur Heart J. 1998;19(suppl J):J36-44.
Lonn EM et al. Circulation. 1994;90:2056-69.
Meta-analyses show consistency of ACEI benefit
in preventing CV events
Randomized, placebo-controlled trials in patients with CAD without
HF or LV dysfunction
Relative risk reduction (%)
No. of trials
N
CV death
MI
Danchin, 2006
7
33,960
19
18
Al-Mallah, 2006
6
33,500
17
16
Dagenais, 2006
3
29,805
18
18
Danchin N et al. Arch Intern Med. 2006.
Al-Mallah MH et al. J Am Coll Cardiol. 2006.
Dagenais GR et al. Lancet. 2006.
EUROPA, HOPE, PEACE, QUIET: Treatment
effect on CV end points
EUROPA
HOPE
15
CV death/MI/cardiac arrest*
20
10
20% RRR
HR 0.80 (0.71–0.91)
P = 0.0003
15
Placebo
Perindopril
8 mg
5
0
30
20
22% RRR
HR 0.78 (0.70–0.86)
P < 0.001
10
Ramipril
10 mg
5
0
0
Patients
(%)
Placebo
CV death/MI/stroke*
1
2
3
4
5
PEACE
0
Placebo
CV death/MI/CABG/PCI*
Trandolapril
4 mg
10
2
3
4
QUIET
8
CV death/MI/cardiac arrest†
5
4% RRR
HR 0.96 (0.88–1.06)
P = 0.43
1
Placebo
13% RRR
HR 0.87 (0.59–1.29)
3
Quinapril 20 mg
1
0
0
1
2
3
4
5
0
6
1
2
3
Time (years)
*Primary end point
†Secondary end point
EUROPA Investigators. Lancet. 2003; HOPE Study Investigators. N Engl J Med. 2000;
PEACE Trial Investigators. N Engl J Med. 2004; Pitt B et al. Am J Cardiol. 2001.
HOPE, EUROPA, PEACE: Overview
Study
ACE inhibitor
Key inclusion criteria
Primary end point
HOPE
N = 9297
(4.5 years)
Ramipril 10 mg
Vascular disease*
(80% had CAD)
LVEF ≥40%
No HF
Age ≥55 years
CV death,
MI, stroke
EUROPA
N = 12,218
(4.2 years)
Perindopril 8 mg
CAD
No HF
Age ≥18 years
CV death, MI,
cardiac arrest
PEACE
N = 8290
(4.8 years)
Trandolapril 4 mg
CAD
LVEF >40%
Age ≥50 years
CV death, MI,
coronary
revascularization
*or diabetes + ≥1 CV risk factor
HOPE Study Investigators. N Engl J Med. 2000.
EUROPA Investigators. Lancet. 2003.
PEACE Trial Investigators. N Engl J Med. 2004.
HOPE, EUROPA, PEACE: Reduction in all-cause
mortality
Events (%)
ACEI
Placebo
HOPE
10.4
12.2
EUROPA
6.1
6.9
PEACE
7.2
8.1
Total
7.8
8.9
Favors
ACEI
0.6
Favors
placebo
1.0
Odds ratio (95% CI)
1.4
Dagenais GR et al. Lancet. 2006;368:581-8.
HOPE, EUROPA: Benefit consistent across
ancillary therapy
Subgroup
Antiplatelets
4-year
rates in
Patients placebo
(n)
groups
18,331
13.2
No antiplatelets
3184
17.9
Lipid-lowering agents
9489
10.6
No lipid-lowering agents 12,026
16.4
-blockers
11,323
13.4
No -blockers
10,192
14.3
Revascularization
10,394
11.5
No revascularization
11,123
16.0
ACEI
better
ACEI
worse
P*
0.003
0.651
0.139
0.078
0.5
0.6
0.7
0.8
0.9
1.0
1.1
Odds ratio (95% CI)
*For interaction
CV death, nonfatal MI, or stroke
Adapted from: Dagenais GR et al. Lancet. 2006;368:581-8.
HOPE, EUROPA: Benefit of ACEIs consistent
across baseline combinations
Subgroup
Patients
(n)
4-year rate in
placebo groups
ACEI
better
ACEI
worse
P*
Antiplatelets (ASA)
No antiplatelets
18,331
3184
13.2
17.9
0.003
Lipid-lowering agents (LL)
No lipid-lowering agents
9489
12,026
10.6
16.4
0.651
β-blockers (BB)
No β-blockers
11,323
10,192
13.4
14.3
0.139
All of the above
One of the above
Two of the above
None of the above
5103
15,314
13,093
1701
10.4
12.6
12.0
17.4
0.357
Revascularization
No revascularization
10,394
11,123
11.5
16.0
0.078
2945
7447
9.8
12.3
0.470
Revasc + ASA + LL + BB
Revasc but no ASA, LL, or BB
0.5
*For interaction
CV death, nonfatal MI, or stroke
0.6
0.7
0.8
0.9
Odds ratio (95% CI)
1.0
1.1
Dagenais GR et al. Lancet. 2006;368:581-8.
Benefit of ACEIs in patients with/without
LVD or HF
Events (%)
ACEI
Placebo
Preserved LV function*
7.8
8.9
LV dysfunction or HF†
12.3
14.3
Preserved LV function*
5.3
6.4
LV dysfunction or HF†
6.3
8.1
Preserved LV function*
2.2
2.8
LV dysfunction or HF†
3.7
3.9
Favors
ACEI
All-cause mortality
Favors
placebo
Nonfatal MI
Stroke
0.6
*HOPE, EUROPA, PEACE
†SAVE, AIRE, TRACE, SOLVD
1.0
Odds ratio (95% CI)
1.4
Dagenais GR et al. Lancet. 2006;368:581-8.
EUROPA: Consistent risk reduction regardless
of baseline risk
Relative risk reduction
12%
20
15.4
15
Event
rate*
(%)
13.5
32%
17%
9.0
10
6.1
5.3
4.4
5
0
Low
Medium
High
Relative baseline risk
Placebo
*CV death and nonfatal MI
Perindopril
Deckers JW et al. Eur Heart J. 2006;27:796-801.
HOPE, EUROPA, PEACE: Benefit of ACEIs across
broad spectrum of risk
CV death,* nonfatal MI or stroke
Trial
Patients
(n)
Annual rates in
placebo groups
OR
(95% CI)
P
PEACE
8290
2.13
7 (-8 to 19)
0.328
HOPE total
HOPE lower risk
HOPE med risk
HOPE high risk
9297
3083
3100
3114
3.95
2.17
3.58
5.98
25 (16 to 32)
18 (-4 to 35)
20 (3 to 33)
24 (12 to 34)
0.0001
12,218
3976
3975
3975
2.60
1.40
2.41
4.00
19 (8 to 28)
19 (-5 to 38)
28 (11 to 41)
10 (-4 to 22)
0.0007
AIRE
1986
22.6
24 (7 to 38)
0.0068
TRACE
SOLVD-P
SOLVD-T
SAVE
1749
4228
2569
2231
17.0
7.4
13.1
9.8
25 (9 to 33)
15 (2 to 27)
23 (10 to 33)
20 (4 to 33)
0.0028
0.0252
0.0009
0.0168
EUROPA total
EUROPA lower risk
EUROPA med risk
EUROPA high risk
ACEI ACEI
worse better
-5
*Or total mortality in AIRE,
TRACE, SOLVD, SAVE trials
0
5 10 15 20 25 30 35
Odds reduction (%)
40
Dagenais GR et al. Lancet. 2006;368:581-8.
ACEIs in vascular disease: Conclusions
• ACEIs reduce mortality, MI, HF, and stroke in patients with vascular
disease with/without LVSD or HF
• Benefit in addition to antiplatelet agents, β-blockers, and lipidlowering agents
– Combining ACEIs with these agents provides greatest benefit
• Benefit in patients across a broad range of risk for CV events
– Annual rate in placebo groups of 1.4%–22.6%
Consider ACEIs in all patients with vascular disease
– Assess risk/benefits and tolerability
– Use doses proven in clinical trials
Dagenais GR et al. Lancet. 2006;368:581-8.
Fox K et al. Eur Heart J. 2006;27:2154-7.
ACEIs and elevated serum creatinine in renal
insufficiency
• Creatinine elevations are modest and self-limiting
– ≤30% above baseline
– Stabilize within 2 to 4 weeks
– If BP is controlled, elevation after 4 weeks is unlikely
• Causes
– Effective circulating volume (most common)
– Bilateral renal stenosis
• Withdraw ACEI only if creatinine is >30% above baseline
or K ≥21.9 mg/dL (5.6 mmol/L)
Bakris GL, Weir MR. Arch Intern Med. 2000;160:685-93.
HOPE: CV end point by baseline creatinine
Primary end point*
80
60
Events
per 1000
personyears (n)
40
20
0
<1.4
≥1.4
Creatinine concentration
(mg/dL)
All patients
*CV death, MI, stroke
Placebo
Myocardial infarction
60
50
40
30
20
10
0
<1.4
≥1.4
Creatinine concentration
(mg/dL)
Ramipril 10 mg
Mann JFE et al. Ann Intern Med. 2001:134:629-36.
Meta-analysis of trials comparing ARB vs
placebo, non-ACEI comparators, or ACEI
9 of 11 trials show excess MI for ARB
Trial
ARB
n/N (MI)
Control
n/N (MI)
ELITE
DETAIL
ELITE II
IDNT
CHARM-Alt
SCOPE
RENAAL
LIFE
VALUE
OPTIMAAL
VALIANT
3/352
9/120
31/1578
39/579
75/1013
70/2477
50/751
198/4605
369/7649
384/2744
587/4909
4/370
6/130
28/1574
66/1136
48/1015
63/2460
68/762
188/4588
313/7596
379/2733
559/4909
26,777
27,273
Total
Favors
ARB
Favors
control
1.08 (1.01–1.16)
0.5
1.0
1.5
Odds ratio (95% Cl)
2.0
Strauss MH, Hall AS. Circulation. 2006;114:838-54.
Meta-analyses of ACEI and ARB trials
Relative risk
Strauss
N
MI
CV death
ACEI
150,943
ARB
55,050
Tsuyuki
Volpe
Verdecchia
ARB
68,711
ARB
56,254
ARB
64,381
14%
8%
3%
4%
2%
(P < 0.00001)
Event Rate 5.8%
(P = 0.03)
Event Rate 6.3%
(P = ns)
(P = ns)
(P = ns)
12%
1%
NA
NA
1%
(P < 0.0005)
Event Rate 8.4%
(P = ns)
Event Rate 9.2%
Strauss MH, Hall AS. Circulation. 2006.
Tsuyuki RT, McDonald MA. Circulation. 2006.
Volpe M et al. J Hypertension. 2005.
Verdecchia P et al. Eur Heart J. 2005.
ACEIs vs ARBs: Comparative effect on stroke,
HF, and CHD
Blood Pressure Lowering Treatment Trialists’ Collaboration meta-analysis
N = 137,356; 21 randomized clinical trials
ACEI
RRR (95%)
Stroke
-1% (9% to -10%)
HF
10% (10% to 0%)
CHD
9% (14% to 3%)
Stroke
P = 0.6
HF
P = 0.4
ARB
Stroke
2% (33% to -3%)
HF
16% (36% to -5%)
CHD
-7% (7% to -24%)
CHD
P = 0.001
30%
0
30%
Decrease Increase
Risk
CHD = MI and CV death
Turnbull F. 15th European Meeting on Hypertension. 2005.
Adapted by Strauss MH, Hall AS. Circulation. 2006;114:838-54.
EPHESUS: New subgroup analysis
N = 6632 with post-MI LVSD, mean follow-up 16 months
History of hypertension
All-cause mortality
CV mortality/hospitalization
Sudden cardiac death
Eplerenone better
Placebo better
P
0.001
0.002
0.022
History of diabetes
All-cause mortality
CV mortality/hospitalization
Sudden cardiac death
0.127
0.03
0.641
LVEF ≤30%
All-cause mortality
CV mortality/hospitalization
Sudden cardiac death
0.012
0.001
0.01
0.2
0.4
Eplerenone Post-Acute Myocardial Infarction
Heart Failure Efficacy and Survival Study
0.6 0.8 1.0 1.2 1.4
Odds ratio (95% Cl)
1.6
1.8
Pitt B et al. Am J Cardiol. 2006;97(suppl):26F-33F.
Role of RAAS modulation continues to evolve
IFG/IGT
Vascular disease
Diabetes
IGT
Heart failure
DREAM
ONTARGET
TRANSCEND
NAVIGATOR
EMPHASIZE-HF
TOPCAT
2006
2007
2008
2011
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004.
Skyler JS. Clin Diabetes. 2004.
Greenberg B et al. Am J Cardiol. 2006.
ONTARGET: Study design
ONgoing Telmisartan Alone and in combination with Ramipril Global
Endpoint Trial
N = 25,620
≥55 years with coronary, cerebrovascular, or peripheral vascular disease,
or diabetes + end-organ damage
Ramipril 10 mg
Telmisartan 80 mg
Ramipril 10 mg +
telmisartan 80 mg
Primary end point:
CV death, MI, stroke, hosp for HF
Secondary end point:
Newly diagnosed diabetes
Results anticipated in 2007
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
TRANSCEND: Study design
Telmisartan Randomized AssessmeNt Study in aCE iNtolerant
subjects with cardiovascular Disease
N = 5776 ACEI-intolerant
≥55 years with coronary, cerebrovascular, or peripheral vascular disease,
or diabetes + end-organ damage
Placebo
Telmisartan 80 mg
Primary end point:
CV death, MI, stroke, hosp for HF
Secondary end point:
Newly diagnosed diabetes
Results anticipated in 2007
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
ONTARGET/TRANSCEND: Baseline medical
conditions vs HOPE
ONTARGET
TRANSCEND
HOPE
Current (%)
Hypertension
Diabetes
68.3
37.3
75.9
35.4
46.5
38.3
History (%)
MI
Stable angina
Unstable angina
CABG
PCI
Stroke/TIA
Intermittent claudication
Peripheral artery surgery
Carotid endarterectomy
48.7
34.8
14.8
22.1
28.9
20.7
11.8
5.8
2.8
46.2
36.9
14.9
18.9
26.0
22.1
10.1
4.2
1.8
52.8
55.8
25.7
26.0
18.0
10.8
15.9
6.2
2.7
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
ONTARGET/TRANSCEND: Baseline medications
vs HOPE
ONTARGET
TRANSCEND
HOPE
ACEIs
57.5
58.1
11.6
ARBS
8.6
29.9
–
β-blockers
56.9
57.9
39.5
Statins
60.7
54.5
28.9
Aspirin
75.6
74.7
73.6
CCBs
33.5
41.1
47.6
Nitrates
29.2
33.9
31.1
Oral hypoglycemics
25.0
23.8
21.8
Insulin
10.4
7.2
11.7
Medications (%)
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
NAVIGATOR: Study design
Nateglinide and Valsartan in Impaired Glucose Tolerance
Outcomes Research
N = 9150 with IGT
≥50 years with prior CV disease or
≥55 years with CV risk factors
Randomized, double-blind 2 × 2 factorial design
Valsartan vs placebo
AND
Nateglinide* vs placebo
Primary end points:
CV events, new-onset diabetes
*Insulin secretagogue
NAVIGATOR Trial Steering Committee. Diabetes. 2003;52(suppl 1):A505.
Skyler JS. Clin Diabetes. 2004;22:162-6.
EMPHASIZE-HF: Study design
Effect of Eplerenone in Chronic Systolic Heart Failure
N = 2584 with NYHA class II chronic systolic HF
Eplerenone
+ standard therapy
Placebo
+ standard therapy
Primary end point:
CV death, hosp for HF
Follow-up: 4 years
Results anticipated 2010
Greenberg B et al. Am J Cardiol. 2006;97(suppl):34F-40F.
TOPCAT: Study design
Treatment of Preserved Cardiac Function Heart Failure with an
Aldosterone Antagonist
N  4500 with HF and LVEF >45%
Spironolactone
Placebo
Primary end point:
CV death, hosp for HF
Follow-up: ≥2 years
Results anticipated 2011
Greenberg B et al. Am J Cardiol. 2006;97(suppl):34F-40F.
RAAS modulation in high-risk patients: Summary
• Opportunity for greater use of RAAS modulation in
patients at high risk for CV events
• ACEIs reduce CV death, MI, HF, and stroke across a
broad range of patients with vascular disease
– With/without LVSD or HF
– With/without other proven CV therapies
– Annual event rates of 1.4%–22.6% in untreated groups
• ARBs reduce HF and stroke
• ACEIs may be considered in all patients with vascular
disease
– ARBs are an alternative in ACEI-intolerant patients
Dagenais GR et al. Lancet. 2006.
Strauss MH, Hall AS. Circulation. 2006.
Smith SC et al. Circulation. 2006.