raas modulation in high-risk patients
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
RAAS Modulationin High-Risk Patients
ACEIs: Evolution of benefits
BP reduction
Cardioprotection
Improved glycemic control (?)
Vascular protection
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.
Renal protection
Effect of ACEIs and ARBs on new-onset diabetes
Abuissa H et al. J Am Coll Cardiol. 2005;46:821-6.
Meta-analysis of 12 randomized controlled trials
CAPPPSTOP-2
HOPELIFE
ALLHATANBP2SCOPEALPINECHARMSOLVDVALUEPEACE
All pooledACEI pooledARB pooled
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)
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 4 8
Less likely to develop T2DM
Relative risk (95% CI)
More likely to develop T2DM
HOPE, EUROPA, PEACE: Reduction in new-onset diabetes (placebo-controlled trials)
0
2
4
6
8
10
12
14
HOPE EUROPA PEACE Pooled data
New-onset diabetes
(%)
Placebo ACEI
Dagenais GR et al. Lancet. 2006;368:581-8.
n = 23,340 free from diabetes* at baseline
Ramipril 10 mg
Perindopril 8 mg
Trandolapril 4 mg
Overall14% RRRRR 0.86 (0.78–0.95)P = 0.0023
(all trials)
*Not a prespecified end point
0
TZDs blunt diabetes progression
DPP Research Group. Diabetes. 2005;54:1150-6.*Withdrawn from study after 1.5 yr
10
15
5
1.5
Cumulativeincidence
of diabetes(%)
Follow-up (years)
0.50
Placebo
Metformin850 mg bid
Lifestyle
Troglitazone400 mg/d*
23715682343n =
Diabetes Prevention Program (DPP)
1.0
739
DPP: Long-term benefit of lifestyle intervention or metformin on diabetes prevention
DPP Research Group. N Engl J Med. 2002;346:393-403.
Years
N = 3234 with IFG and IGT, without diabetes
0
0
10
20
30
40
1.0 2.0 3.0 4.0
Placebo
Metformin
Lifestyle
Cumulativeincidence
of diabetes(%)
31%
58%
P*
<0.001
<0.001
*vs placeboIFG = impaired fasting glucoseIGT = impaired glucose tolerance
DREAM: Background
• 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.
Diabetes REduction Assessment with ramipril and rosiglitazone Medication
DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.
DREAM: Study design
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
Ramipril 15 mg/d vs placeboAND
Rosiglitazone 8 mg/d vs placebo
Randomized, double-blind 2 × 2 factorial designN = 5269 with IFG and/or IGT, free from CV disease
Follow-up: 3–5 years
Secondary outcomes III: Glycemic statusGlucose levels,conversion to
normoglycemia
Ramipril + Rosiglitazone
Ramipril
Rosiglitazone Placebo
Ramipril + Placebo
PlaceboRosiglitazone +
PlaceboPlacebo +Placebo
DREAM: 2 × 2 factorial design
DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.
N = 5269 with IFG and/or IGT
Ramipril: 5 mg × 2 months; 10 mg × 10 months; 15 mg thereafterRosiglitazone: 4 mg × 2 months; 8 mg thereafter
DREAM: Adjudicated HF
Overnight (2 calendar days) hospitalization or ERattendance 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
DREAM Trial Investigators. N Engl J Med. 2006;355:1551-62.
Placebo
Ramipril
No. at riskPlaceboRamipril
Follow-up (years)
0.6
0.5
0.4
0.3
0.2
0.1
0.00 1 2 3 4
26462623
25102498
22772287
12401218
200194
9% RRRHR 0.91 (0.81–1.03)
P = 0.15
Cumulative hazard rate
DREAM: Ramipril effect on glycemia
DREAM Trial Investigators. N Engl J Med. 2006;355:1551-62.
Cumulative hazard rate of conversion to
normoglycemia Placebo
Ramipril
No. at riskPlaceboRamipril
1 2 3 4
Follow-up (years)0
1.60
1.20
0.40
0.0
26462623
24942487
20902060
876791
145127
16% increaseHR 1.16 (1.07–1.27)
P = 0.001
FPG < 110 mg/dL and 2-h glucose < 140 mg/dL
0.80
DREAM: Rosiglitazone effect on primary end point
No. at riskPlaceboRosiglitazone
DREAM Trial Investigators. Lancet. 2006;368:1096-105.
26342635
24702538
21502414
11481310
177217
0.6
0.5
0 1 2 3 4
Follow-up (years)
0.4
0.3
0.2
0.1
0.0
Rosiglitazone
Placebo60% RRR HR 0.40 (0.35–0.46) P < 0.0001
Cumulative hazard rate
DREAM: Conversion to normoglycemia with rosiglitazone
0
10
20
30
40
50
60
Diabetes IFG and/or IGT Normoglycemia*
Participants (%)
Placebo Rosiglitazone
*FPG < 110 mg/dL and 2-h glucose < 140 mg/dL DREAM Trial Investigators. Lancet. 2006;368:1096-105.
71% increaseHR 1.71 (1.571.87)P < 0.0001
N = 5269
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)
DREAM Trial Investigators.N Engl J Med. 2006;355:1551-62; Lancet. 2006;368:1096-105.*Adjudicated
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
CONSENSUS
QUIETHOPE EUROPAPEACE
SOLVD-PreventSOLVD-Treat SAVE AIRE
Low LVEF
GISSI-3ISIS-4CCT*CONSENSUS II
Severe HF Acute MICHD without HF or LV dysfunction
1987 1991–1993 1992–1995 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.*Chinese Captopril Trial
Meta-analyses show consistency of ACEI benefit in preventing CV events
No. of trials N
Relative risk reduction (%)
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.
Randomized, placebo-controlled trials in patients with CAD without HF or LV dysfunction
EUROPA, HOPE, PEACE, QUIET: Treatment effect on CV end points
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.
*Primary end point†Secondary end point
EUROPACV death/MI/cardiac arrest*
PEACECV death/MI/CABG/PCI*
HOPECV death/MI/stroke*
15
5
10
0
20
0
Placebo
Ramipril 10 mg
2 41
22% RRRHR 0.78 (0.70–0.86)P < 0.001
3
5
10
0
15Placebo
Perindopril 8 mg
20% RRRHR 0.80 (0.71–0.91)P = 0.0003
5
0
8
0
Placebo
Quinapril 20 mg
1
13% RRRHR 0.87 (0.59–1.29)
1
2 3
QUIETCV death/MI/cardiac arrest†
Time (years)
Trandolapril4 mg
Placebo30
20
10
1 2 3 4 50
6
4% RRRHR 0.96 (0.88–1.06)P = 0.43
Patients(%)
1 3 40 52
3
HOPE Study Investigators. N Engl J Med. 2000.EUROPA Investigators. Lancet. 2003.
PEACE Trial Investigators. N Engl J Med. 2004.
HOPE, EUROPA, PEACE: Overview
Study ACE inhibitor Key inclusion criteria Primary end point
HOPEN = 9297(4.5 years)
Ramipril 10 mg Vascular disease*(80% had CAD)LVEF ≥40%No HFAge ≥55 years
CV death, MI, stroke
EUROPAN = 12,218(4.2 years)
Perindopril 8 mg CADNo HF Age ≥18 years
CV death, MI, cardiac arrest
PEACEN = 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, 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
Favors placebo
Odds ratio (95% CI)
Dagenais GR et al. Lancet. 2006;368:581-8.
0.6 1.0 1.4
HOPE, EUROPA: Benefit consistent across ancillary therapy
Adapted from: Dagenais GR et al. Lancet. 2006;368:581-8.
1.11.00.5 0.9
Odds ratio (95% CI)
Antiplatelets
No antiplatelets
Lipid-lowering agents
No lipid-lowering agents
-blockers
No -blockers
Revascularization
No revascularization
SubgroupPatients
(n)
4-year rates in placebo groups
0.003
0.651
0.139
0.078
P*
0.6 0.7 0.8
18,331
3184
9489
12,026
11,323
10,192
10,394
11,123
13.2
17.9
10.6
16.4
13.4
14.3
11.5
16.0
*For interactionCV death, nonfatal MI, or stroke
ACEI better
ACEI worse
HOPE, EUROPA: Benefit of ACEIs consistent across baseline combinations
SubgroupPatients
(n)4-year rate in
placebo groups
0.5 0.8 1.10.6 0.90.7 1.0
P*
0.003
*For interactionCV death, nonfatal MI, or stroke
Odds ratio (95% CI)
ACEI better
ACEI worse
0.651
0.139
0.357
0.078
0.470
Antiplatelets (ASA) 18,331 13.2No antiplatelets 3184 17.9
Lipid-lowering agents (LL) 9489 10.6No lipid-lowering agents 12,026 16.4
β-blockers (BB) 11,323 13.4No β-blockers 10,192 14.3
All of the above 5103 10.4One of the above 15,314 12.6Two of the above 13,093 12.0None of the above 1701 17.4
Revascularization 10,394 11.5No revascularization 11,123 16.0
Revasc + ASA + LL + BB 2945 9.8Revasc but no ASA, LL, or BB 7447 12.3
Dagenais GR et al. Lancet. 2006;368:581-8.
Benefit of ACEIs in patients with/withoutLVD or HF
Events (%)
ACEI Placebo
All-cause mortality
Preserved LV function* 7.8 8.9
LV dysfunction or HF† 12.3 14.3
Nonfatal MI
Preserved LV function* 5.3 6.4
LV dysfunction or HF† 6.3 8.1
Stroke
Preserved LV function* 2.2 2.8
LV dysfunction or HF† 3.7 3.9
Favors ACEI
Favors placebo
1.0Odds ratio (95% CI)
0.6 1.4
*HOPE, EUROPA, PEACE†SAVE, AIRE, TRACE, SOLVD Dagenais GR et al. Lancet. 2006;368:581-8.
EUROPA: Consistent risk reduction regardless of baseline risk
Deckers JW et al. Eur Heart J. 2006;27:796-801.
5.3
9.0
15.4
4.46.1
13.5
0
5
10
15
20
Low Medium High
Event rate* (%)
Placebo Perindopril
Relative baseline risk
*CV death and nonfatal MI
Relative risk reduction
17%
32%
12%
HOPE, EUROPA, PEACE: Benefit of ACEIs across broad spectrum of risk
Dagenais GR et al. Lancet. 2006;368:581-8.
TrialPatients
(n)Annual rates in placebo groups
OR(95% CI) P
-5 20 405 3015 35Odds reduction (%)
25100
PEACE 8290 2.13 7 (-8 to 19) 0.328
HOPE total 9297 3.95 25 (16 to 32) 0.0001
HOPE lower risk 3083 2.17 18 (-4 to 35)
HOPE med risk 3100 3.58 20 (3 to 33)
HOPE high risk 3114 5.98 24 (12 to 34)EUROPA total 12,218 2.60 19 (8 to 28) 0.0007
EUROPA lower risk 3976 1.40 19 (-5 to 38)
EUROPA med risk 3975 2.41 28 (11 to 41)
EUROPA high risk 3975 4.00 10 (-4 to 22)
AIRE 1986 22.6 24 (7 to 38) 0.0068
TRACE 1749 17.0 25 (9 to 33) 0.0028SOLVD-P 4228 7.4 15 (2 to 27) 0.0252SOLVD-T 2569 13.1 23 (10 to 33) 0.0009SAVE 2231 9.8 20 (4 to 33) 0.0168
CV death,* nonfatal MI or strokeACEI worse
ACEI better
*Or total mortality in AIRE, TRACE, SOLVD, SAVE trials
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 lipid-lowering 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%
Dagenais GR et al. Lancet. 2006;368:581-8.Fox K et al. Eur Heart J. 2006;27:2154-7.
Consider ACEIs in all patients with vascular disease– Assess risk/benefits and tolerability– Use doses proven in clinical trials
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
Eventsper 1000person-years (n)
All patients Placebo Ramipril 10 mg
Primary end point*
<1.4 <1.4
Myocardial infarction
Creatinine concentration(mg/dL)
Creatinine concentration(mg/dL)
80
60
40
20
0
405060
3020100
≥1.4 ≥1.4
Mann JFE et al. Ann Intern Med. 2001:134:629-36.*CV death, MI, stroke
Meta-analysis of trials comparing ARB vs placebo, non-ACEI comparators, or ACEI
Strauss MH, Hall AS. Circulation. 2006;114:838-54.
9 of 11 trials show excess MI for ARB
TrialARB
n/N (MI)Controln/N (MI)
ELITE 3/352 4/370
DETAIL 9/120 6/130
ELITE II 31/1578 28/1574
IDNT 39/579 66/1136
CHARM-Alt 75/1013 48/1015
SCOPE 70/2477 63/2460
RENAAL 50/751 68/762
LIFE 198/4605 188/4588
VALUE 369/7649 313/7596
OPTIMAAL 384/2744 379/2733
VALIANT 587/4909 559/4909
Total 26,777 27,273
0.5 1.0 1.5 2.0Odds ratio (95% Cl)
Favors ARB
Favors control
1.08 (1.01–1.16)
Meta-analyses of ACEI and ARB trials
StraussStrauss TsuyukiTsuyuki VolpeVolpe VerdecchiaVerdecchia
NACEIACEI
150,943150,943ARBARB
55,05055,050ARBARB
68,71168,711ARBARB
56,25456,254ARBARB
64,38164,381
MIMI 14%14%(P < 0.00001)(P < 0.00001)
Event Rate 5.8%Event Rate 5.8%
8%(P = 0.03)(P = 0.03)
Event Rate 6.3%Event Rate 6.3%
3%(P = ns)
4%(P = ns)
2% (P = ns)
CV deathCV death 12%12%(P < 0.0005)(P < 0.0005)
Event Rate 8.4%Event Rate 8.4%
1%(P = ns)
Event Rate 9.2%Event Rate 9.2%
NA NA 1%
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.
Relative risk
ACEIs vs ARBs: Comparative effect on stroke, HF, and CHD
Turnbull F. 15th European Meeting on Hypertension. 2005.Adapted by Strauss MH, Hall AS. Circulation. 2006;114:838-54.CHD = MI and CV death
Blood Pressure Lowering Treatment Trialists’ Collaboration meta-analysisN = 137,356; 21 randomized clinical trials
ACEI
ARB
Stroke -1% (9% to -10%)
HF 10% (10% to 0%)
CHD 9% (14% to 3%)
Stroke 2% (33% to -3%)
HF 16% (36% to -5%)
CHD -7% (7% to -24%)
30% 0 30%Decrease Increase
StrokeP = 0.6
HFP = 0.4
CHDP = 0.001
Risk
RRR (95%)
EPHESUS: New subgroup analysis
Pitt B et al. Am J Cardiol. 2006;97(suppl):26F-33F.
N = 6632 with post-MI LVSD, mean follow-up 16 months
Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study
History of hypertensionAll-cause mortalityCV mortality/hospitalizationSudden cardiac death
History of diabetesAll-cause mortalityCV mortality/hospitalizationSudden cardiac death
LVEF ≤30%All-cause mortalityCV mortality/hospitalizationSudden cardiac death
P
0.0010.0020.022
0.1270.03
0.641
0.0120.001
0.010.2 1.0 1.2 1.8
Eplerenone better Placebo better
1.4 1.60.4 0.6 0.8Odds ratio (95% Cl)
Role of RAAS modulation continues to evolve
DREAMEMPHASIZE-HFTOPCAT
ONTARGETTRANSCEND
Vascular diseaseDiabetes
NAVIGATOR
IFG/IGT IGT Heart failure
2006 2007
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004.Skyler JS. Clin Diabetes. 2004.
Greenberg B et al. Am J Cardiol. 2006.
20112008
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
ONTARGET: Study design
Ramipril 10 mg Telmisartan 80 mg
N = 25,620≥55 years with coronary, cerebrovascular, or peripheral vascular disease,
or diabetes + end-organ damage
Results anticipated in 2007
Ramipril 10 mg + telmisartan 80 mg
Primary end point:CV death, MI, stroke, hosp for HF
Secondary end point:Newly diagnosed diabetes
ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
TRANSCEND: Study design
Telmisartan 80 mg
N = 5776 ACEI-intolerant≥55 years with coronary, cerebrovascular, or peripheral vascular disease,
or diabetes + end-organ damage
Results anticipated in 2007
Placebo
Primary end point:CV death, MI, stroke, hosp for HF
Secondary end point:Newly diagnosed diabetes
Telmisartan Randomized AssessmeNt Study in aCE iNtolerant subjects with cardiovascular Disease
ONTARGET/TRANSCEND: Baseline medical conditions vs HOPE
ONTARGET TRANSCEND HOPE
Current (%)
Hypertension 68.3 75.9 46.5
Diabetes 37.3 35.4 38.3
History (%)
MI 48.7 46.2 52.8
Stable angina 34.8 36.9 55.8
Unstable angina 14.8 14.9 25.7
CABG 22.1 18.9 26.0
PCI 28.9 26.0 18.0
Stroke/TIA 20.7 22.1 10.8
Intermittent claudication 11.8 10.1 15.9
Peripheral artery surgery 5.8 4.2 6.2
Carotid endarterectomy 2.8 1.8 2.7
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
ONTARGET/TRANSCEND: Baseline medications vs HOPE
ONTARGET TRANSCEND HOPE
Medications (%)
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
ONTARGET/TRANSCEND Investigators. Am Heart J. 2004;148:52-61.
Primary end points:CV events, new-onset diabetes
NAVIGATOR Trial Steering Committee. Diabetes. 2003;52(suppl 1):A505.Skyler JS. Clin Diabetes. 2004;22:162-6.
NAVIGATOR: Study design
Valsartan vs placeboAND
Nateglinide* vs placebo
N = 9150 with IGT≥50 years with prior CV disease or
≥55 years with CV risk factorsRandomized, double-blind 2 × 2 factorial design
Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research
*Insulin secretagogue
Greenberg B et al. Am J Cardiol. 2006;97(suppl):34F-40F.
EMPHASIZE-HF: Study design
Eplerenone+ standard therapy
N = 2584 with NYHA class II chronic systolic HF
Results anticipated 2010
Placebo+ standard therapy
Primary end point:CV death, hosp for HF
Follow-up: 4 years
Effect of Eplerenone in Chronic Systolic Heart Failure
Greenberg B et al. Am J Cardiol. 2006;97(suppl):34F-40F.
TOPCAT: Study design
Spironolactone
N 4500 with HF and LVEF >45%
Results anticipated 2011
Placebo
Primary end point:CV death, hosp for HF
Follow-up: ≥2 years
Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist
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.