raas modulation in high-risk patients

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 Diabetes. 2005;54:1150-6.*Withdrawn from study after 1.5 yr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)


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


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



Stroke



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


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)


3%(P = ns)

4%(P = ns)

2% (P = ns)

CV deathCV death 12%12%(P < 0.0005)(P < 0.0005)


1%(P = ns)


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


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: 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


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.

raas modulation in high-risk patients

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