HOPE

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Yusuf S, et al. "Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients". The New England Journal of Medicine. 2000. 342(3):145-153.
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Clinical Question

In patients with multiple CV risk factors, does ramipril reduce cardiovascular morbidity and mortality?

Bottom Line

Ramipril reduces rates of death, MI, and stroke among patients with multiple CV risk factors and without heart failure.

Major Points

CONSENSUS (1987), SOLVD (1991), and SAVE (1992) demonstrated the benefit of enalapril and captopril in reducing mortality and hospitalizations among patients with reduced systolic function. However, the role of ACE inhibitors was unclear among patients with multiple CV risk factors and preserved systolic function.

The Heart Outcomes Prevention Evaluation (HOPE) trial randomized 9,297 patients with multiple risk factors for CV events but without heart failure to either ramipril or placebo. The trial was stopped early when the ramipril arm demonstrated a significant reduction in the primary endpoint of MI, stroke, and CV death compared to placebo (14.0% vs. 17.8%; NNT 27); the Kaplan-Meier survival curves separated at approximately 200 days and continued to diverge. Ramipril was associated with prevention of heart failure, need for revascularization, diabetic complications, and development of diabetes. In addition, all-cause mortality was significantly reduced (10.4% vs. 12.2%). The benefits of ramipril were seen in all subgroups including those with and without hypertension, diabetes, CAD, and irrespective of baseline therapy with beta-blockers and statins. The most common adverse effect of ramipril was cough.

The HOPE authors initially reported a modest 3.3 mmHg average SBP reduction with ramipril suggesting that the benefits of ACE inhibitors may stem from RAAS inhibition in addition to BP modification.[1] Although a later substudy monitoring ambulatory BP suggests that the actual BP reduction may have been greater,[2] therapy with ACE inhibitors were not titrated to BP goals as was performed with lisinopril in ALLHAT (2002).[3] Of note, the 2006 DREAM trial[4] did not demonstrate the same prevention of diabetes with administration of ramipril in a non-diabetic population though it was associated with improved fasting glucose.

Guidelines

ACC/AHA Hypertension in ischemic heart disease (2007)[5]

  • Suggest ACE inhibitors in stable coronary disease with diabetes and/or LV systolic dysfunction (class IIa, level B)

Design

  • Multicenter, double-blind, 2x2 factorial, randomized, placebo-controlled trial
  • N=9,297
    • Ramipril (n=4,645)
    • Placebo (n=4,652)
  • Setting: 267 centers in US, Canada, Europe, South America
  • Enrollment: 1993-1995
  • Follow-up: Up to 5-years but terminated early in March 1999
  • Analysis: Intention-to-treat
  • Primary outcome: Composite of MI, CVA, or CV death

Population

Inclusion Criteria

  • Age ≥55 years at high risk for CV events because of:
    • History of CAD, CVA, PAD
    • DM plus one other CV risk factor (HTN, HL, smoking, microalbuminuria)

Exclusion Criteria

  • Heart failure or LVEF <40%
  • Already taking ACE inhibitor or vitamin E
  • Uncontrolled HTN or overt nephropathy
  • MI or CVA within previous four weeks

Baseline Characteristics

  • Age: 66 years
  • Female: 26.7%
  • BP: 139/79; HR: 69 BPM
  • BMI: 28 kg/m2
  • CAD: 80.5%
  • MI: 52.7% (9.6% within 1 year)
  • CABG: 25.8%
  • PTCA: 17.9%
  • CVA or TIA: 10.9%
  • PVD: 43.6%
  • DM: 38.4%
  • HTN: 46.8% (8.5% LVH on EKG)
  • HL: 65.9%
  • Current smoker: 14.2%
  • Microalbuminuria: 21.1%

Baseline Medications

  • Beta-blocker: 39.5%
  • Anti-platelet (including ASA): 76.1%
  • Lipid-lowering agent: 28.6%
  • Diuretic: 15.2%
  • CCB: 47.1%

Interventions

  • Run-in phase with low-dose ramipril excluded patients due to non-compliance, side effects, or abnormal serum creatinine or potassium.
  • Patients subsequently randomized to ramipril 10 mg daily or placebo for 5 years.
  • Patients were also randomized to vitamin E 400 IU daily or placebo. [6]
  • Follow-up at one month and every six months thereafter

Outcomes

Comparisons are ramipril vs. placebo.

Primary Outcome

Composite of MI, CVA, CV death
14.0% vs. 17.8% (HR 0.78; 95% CI 0.70-0.86; P<0.001; NNT=27)

Secondary Outcomes

MI
9.9% vs. 12.3% (RR 0.80; 95% CI 0.70-0.90; P<0.001)
CVA
3.4% vs. 4.9% (RR 0.68; 95% CI 0.56-0.84: P<0.001)
CV death
6.1% vs. 8.1% (RR 0.74; 95% CI 0.64-0.87; P<0.001)
All-cause mortality
10.4% vs. 12.2% (RR 0.84; 95% CI 0.75-0.95; P=0.005)
Worsening angina
23.8% vs. 26.2% (RR 0.89; 95% CI 0.82-0.96; P=0.004)
Cardiac arrest
0.8% vs. 1.3% (RR 0.62; 95% CI 0.41-0.94; P=0.02)
Revascularization
16.0% vs. 18.3% (RR 0.85; 95% CI 0.77-0.94; P=0.002)
Heart failure
9.0% vs. 11.5% (RR 0.77; 95% CI 0.67-0.87; P<0.001)
Hospitalizations for heart failure
3.0% vs. 3.4% (RR 0.88; 95% CI 0.70-1.10; P=0.25)
New diagnosis of DM
3.6% vs. 5.4% (RR 0.66; 95% CI 0.51-0.85; P<0.001)
Complications related to diabetes
6.4% vs. 7.6% (RR 0.84; 95% CI 0.72-0.98; P=0.03)

Subgroup Analysis

The benefits of ramipril were seen in virtually all pre-specified subgroups: patients with or without coronary artery disease, diabetics and nondiabetics, young and old patients, hypertensives and nonhypertensives, and in those with and without cerebrovascular disease, peripheral vascular disease, or microalbuminuria.

Adverse Events

Discontinuation secondary to
Cough: 7.3% vs. 1.8%
Hypotension or dizziness: 1.9% vs. 1.5%
Angioedema: 0.4% vs. 0.2%

Criticisms

  • Patients with reduced LVEF were not entirely excluded.
  • Many patients were not receiving OMT for comorbidities, such as CAD[7]

Funding

Medical Research Council of Canada, Hoechst-Marion Roussel, AstraZeneca, King Pharmaceuticals, Natural Source Vitamin E Association, Negma, Heart and Stroke Foundation of Ontario

Further Reading

  1. Concurrent editorial
  2. Svensson P, et al. "Comparative Effects of Ramipril on Ambulatory and Office Blood Pressures A HOPE Substudy." Hypertension 38.6 (2001): e28-e32.
  3. Sica, Domenic A. "Is there HOPE for ALLHAT: similarities and differences." Expert Review of Cardiovascular Therapy 1.1 (2003): 1-2.
  4. Mohan V, et al. "Effect of ramipril on the incidence of diabetes." The New England Journal of Medicine. 2006(355.15):1551-1562.
  5. Rosendorff C, et al. "Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease." Hypertension. 2007; 50: e28-e55
  6. The Heart Outcomes Prevention Evaluation Study Investigators. "Vitamin E supplementation and cardiovascular events in high-risk patients." The New England Journal of Medicine. 2000;342:154-160.
  7. NEJM Letters to the editor