EUROPA

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Fox KM, et al. "Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease". The Lancet. 2003. 362(9386):782–788.
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Clinical Question

In patients with stable CAD without heart failure, does perindopril reduce CV mortality, MI, or cardiac arrest, as compared to placebo?

Bottom Line

In patients with stable CAD without heart failure, perindopril reduces CV mortality, MI, or cardiac arrest, as compared to placebo.

Major Points

ACE inhibitors are a mainstay of therapy in patients with a variety of CV disease subtypes and CV risk factors. In 1992, SAVE showed that captopril significantly reduced the risk of all-cause mortality, fatal and nonfatal CV events, and heart failure in patients with LV dysfunction following MI.[1] In 2000, HOPE demonstrated that ramipril decreased the risk of MI, stroke, and CV mortality in patients at high risk of CV disease.[2] Others including CONSENSUS and SOLVD established the role of ACE inhibitors in symptomatic HFrEF. The role of ACE inhibition in patients with stable CAD had not yet been well established.

The European Trial on Reduction of Cardiac Events with Perindopril in Patients with Stable Coronary Artery Disease (EUROPA) aimed to determine the effect of the ACE inhibitor perindopril in patients with stable CAD without clinical evidence of heart failure. Approximately 12,000 patients were randomized to either perindopril or placebo and followed for the primary composite outcome of CV mortality, non-fatal MI, or cardiac arrest. The composite outcome was observed in 8% of patients assigned to perindopril and 10% of patients assigned to placebo (relative risk reduction 20%; 95% CI 9-29%, P=0.0003; NNT=50). The main adverse effects causing cessation of perindopril were cough (2.7%), intolerance (2.4%), and hypotension (1%).

ACE inhibitors have been evaluated in other studies of patients with stable CAD with normal LV systolic function with contrasting results. For example, PEACE evaluated trandolapril in individuals with stable CAD and predominantly normal LV function, yet found no improvement in CV outcomes when compared to placebo.[3] Nevertheless a 2006 meta-analysis of 29,805 patients including those from the HOPE, EUROPA, and PEACE trials demonstrated that ACE inhibitors significantly reduce all-cause mortality, CV mortality, stroke, incident heart failure, and rates of CABG.[4] Consequently, ACE inhibitors have joined the fray of beta-blockers and thiazides in the treatment of patients with hypertension and chronic CAD.

Guidelines

ACC/AHA Treatment of Hypertension in patients with coronary artery disease (2015)[5]

  • Patients with hypertension and chronic stable angina should be treated with a regimen which includes:
    • β-blocker if there is prior MI;
    • ACE inhibitor or ARB in patients with prior MI, LV systolic dysfunction, DM, or CKD; and
    • Thiazide or thiazide-like diuretic (Class I; Level of Evidence A)

Design

  • Multicenter, double-blind, randomized, placebo-controlled trial
  • N=12,218 patients with stable CAD without clinical HF
    • Perindopril (n=6,110)
    • Placebo (n=6,108)
  • Setting: 424 centers in 24 European countries
  • Enrollment: 1997-2000
  • Follow-up: 4.2 years
  • Analysis: Intention-to-treat
  • Primary outcome: Composite of CV mortality, non-fatal MI, and cardiac arrest

Population

Inclusion Criteria

  • Age ≥18 years
  • Coronary artery disease, as documented by:
    • Prior MI (>3 months prior to enrollment), revascularization (>6 months prior to enrollment)
    • Coronary artery stenosis (≥70%) on angiography
  • In males, a history of chest pain and positive ECG, echo, or nuclear stress test

Exclusion Criteria

  • Clinical evidence of heart failure
  • Planned revascularization
  • Hypotension (sitting systolic BP <110 mm Hg)
  • Uncontrolled hypertension (systolic BP >180 mm Hg, diastolic BP >100 mm Hg, or both)
  • ACE inhibitor or ARB use <1 month prior to enrollment
  • Chronic kidney disease (creatinine >150 μmol/L)
  • Hyperkalemia (>5.5 mmol/L)

Baseline Characteristics

From the perindopril group.

  • Demographics: age 60±9 years, females 14.5%
  • History of coronary artery disease:
    • MI 64.9%, PCI 29.0%, CABG, 29.3%;
    • significant coronary artery stenosis 60.4%;
    • positive stress test (in males) 22.6%
  • Medical history: hypertension 27%, DM 11.8%, hypercholesterolemia 63.3%, PAD 7.1%, stroke or TIA 3.4%
  • Clinical measurements: systolic BP 137±16 mm Hg, diastolic BP 82±8 mm Hg; heart rate 68±10 beats/min
  • Medications: antiplatelet agents 91.9%, lipid-lowering therapy 57.8%, beta-blocker 62%, calcium-channel blocker 31.7%, nitrates 42.8%, diuretics 9.1%

Interventions

  • Run-in period where patients received perindopril PO 4mg daily, for 2 weeks, and increased to PO 8 mg daily for 2 weeks. The dose was halved in patients ≥70 years. During this period, BP of patients in the perindopril group decreased from 137/82 to 128/78 mm Hg.
  • Patients subsequently randomized to perindopril PO 8 mg or placebo for at least 3 years.
  • The dose was reduced to PO 4 mg daily or patients were switched to a matching placebo if the medication was not well tolerated.
  • After randomization, the BP of the treatment group was 5/2±15/9 mm Hg higher than the placebo group.
  • Follow-up at 3, 6, 12 months and every 6 months thereafter.

Outcomes

Comparisons are perindopril vs. placebo.

Primary Outcome

CV mortality, non-fatal MI, and cardiac arrest
8.0% vs. 9.9% (RRR 20%; 95% CI 9-29, P=0.0003; NNT=50)

Secondary Outcomes

Total mortality, non-fatal MI, unstable angina, and cardiac arrest
14.8% vs. 17.1% (RRR 14%, 95% CI 6-21; P=0.0009; NNT=43)
CV mortality
3.5% vs. 4.1% (RRR 14%; 95% CI -3 to 28: P=0.107)
Non-fatal MI
4.8% vs. 6.2% (RRR 22%; 95% CI 10-33; P=0.001; NNT=71)
Cardiac arrest
0.1% vs. 0.2% (RRR 46%; 95% CI -47 to 80; P=0.22)
Total mortality
6.1% vs. 6.9% (RRR 11%; 95% CI -2 to 23; P=0.1)
Hospitalization for heart failure
1.0% vs. 1.7% (RRR 39%; 95% CI 17-56; P=0.002; NNT=143)
Unstable angina
5.6% vs. 6.4% (P-value not significant)
Stroke
1.6% vs. 1.7% (P-value not significant)
Revascularization
9.4% vs. 9.8% (P-value not significant)

Subgroup Analysis

The benefit of perindopril was observed in all pre-defined subgroups: age, gender, history of MI, revascularization, hypertension, DM, use of beta-blocker, lipid-lowering drug, or calcium-channel blocker.

Adverse Events

Withdrawal from treatment due to
Cough: 2.7% vs. 0.5%
Hypotension: 1% vs. 0.3%
Kidney injury: 0.3% vs. 0.3%
Intolerance: 2.4% vs. 1.3%
Hypertension: 0.4% vs. 0.8%

Total percentage of patients who withdrew from treatment: 22.8% vs. 20.7%

Criticisms

  • Patients who received perindopril had a 5/2 mm Hg reduction in BP. Although ACE inhibitors have been reported to have direct cardioprotective effects independent of their antihypertensive mechanism, it has been argued that even a 2 mm Hg diastolic BP reduction can confer significant CV benefits.[6] An analysis adjusted for antihypertensive effect would have been able to clarify this.[7]
  • LV function assessment in trial patients was not discussed in the paper.[8] However, the authors reported that most patients were likely to have had preserved systolic function.[9]
  • It is unclear how many cases of MI were diagnosed based on troponin or creatine kinase-MB concentration.[7]
  • The effect of perindopril could have been underestimated due to patients withdrawing from treatment.[7]

Funding

  • Servier, France

Further Reading

  1. Pfeffer MA et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N. Engl. J. Med. 1992. 327:669-77.
  2. Yusuf S et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N. Engl. J. Med. 2000. 342:145-53.
  3. Braunwald E et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N. Engl. J. Med. 2004. 351:2058-68.
  4. Dagenais GR et al. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet 2006. 368:581-8.
  5. Rosendorff C, Lackland DT, Allison M, et al. Treatment of Hypertension in Patients With Coronary Artery Disease: A Scientific Statement from the American Heart Association, American College of Cardiology, and American Society of Hypertension. J Am Coll Cardiol. 2015;65(18):1998-2038. doi:10.1016/j.jacc.2015.02.038.
  6. Kwaku, Maxwell et al. The EUROPA trial. Lancet. 2003 Dec 6;362(9399):1935; author reply 1936-7.
  7. 7.0 7.1 7.2 White HD. Should all patients with coronary disease receive angiotensin-converting-enzyme inhibitors? Lancet. 2003 Sep 6;362(9386):755-7.
  8. Boos C. The EUROPA trial. Lancet. 2003 Dec 6;362(9399):1935; author reply 1936-7.
  9. Fox, K. The EUROPA trialLancet. 2003 Dec 6;362(9399):1935; author reply 1936-7.