Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events - ACTIVE I

Mar 09, 2011
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Bristol-Myers Squibb and Sanofi-Aventis
Date Presented:
01/01/2009
Date Published:
01/01/2011
Date Updated:
03/09/2011
Original Posted Date:
03/09/2011
References

Description:

Since hypertension is one of the most prevalent risk factors for the development of atrial fibrillation (AF), the current trial sought to study the safety and efficacy of irbesartan, an angiotensin-receptor blocker (ARB), on the development of cardiovascular events and maintenance of sinus rhythm in patients with AF.

Hypothesis:

Irbesartan would be superior to placebo in reducing cardiovascular events in patients with AF.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized

Patient Populations:

  • Permanent AF or at least two episodes of intermittent AF in the previous 6 months
  • Not receiving ARB
  • Systolic BP ≥110 mm Hg
  • At least one of the following:
    Age of 75 years or older
    Treatment for hypertension
    History of stroke, TIA, or non-CNS systemic embolism
    Left ventricular ejection fraction <45%
    Peripheral vascular disease
    Age 55-74 years plus either diabetes mellitus or coronary artery disease

    Number of enrollees: 9,016
    Duration of follow-up: 4.1 years (mean)
    Mean patient age: 69.6 years
    Percentage female: 39%
    Ejection fraction: 55%

Exclusions:

  • Diagnosis of peptic ulcer disease within the previous 6 months
  • History of intracerebral hemorrhage
  • Thrombocytopenia
  • Mitral stenosis

Primary Endpoints:

  • Composite of stroke, MI, and vascular death
  • Composite of stroke, MI, vascular death, and CHF hospitalization

Secondary Endpoints:

  • Recurrence of AF on electrocardiogram at 2 years, and at the end of the study
  • Rehospitalization for AF
  • Recurrence of AF using transtelephonic monitoring

Drug/Procedures Used:

Patients were randomized to receive either 150 mg of irbesartan once daily or placebo for 2 weeks. The dose of irbesartan was then increased to 300 mg daily.

Concomitant Medications:

Aspirin (59%), oral anticoagulant (38%), angiotensin-converting enzyme inhibitor (60.4%), beta-blockers (54.5%), digoxin (35%), lipid-lowering drug (31.7%), anti-arrhythmic drug (23%)

Principal Findings:

A total of 9,016 patients were randomized, 4,518 to irbesartan and 4,498 to placebo. Baseline characteristics were fairly similar between the two arms. The mean CHADS2 score at baseline was 2.0. About 76% of patients had evidence of AF (65% with permanent AF, 20% with paroxysmal AF), 1% had atrial flutter, and about 19% of patients were in normal sinus rhythm (NSR) at baseline. About 35% of patients were ≥75 years of age, and 13.5% had evidence of prior cerebrovascular accident. Previous cardioversion had been attempted in about 37.5% of the patients. Mean baseline blood pressure (BP) was about 132/82 mm Hg.

The mean reduction in BP was 6.8 mm Hg systolic and 4.5 mm Hg diastolic in patients who received irbesartan, as compared with 3.9 mm Hg systolic and 2.6 mm Hg diastolic in patients who received placebo (mean difference, 2.9 mm Hg systolic and 1.9 mm Hg diastolic). The coprimary endpoint of stroke, myocardial infarction (MI), or vascular death was similar between the irbesartan and placebo arms (5.4%/100 patient-years in both arms, hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91-1.08, p = 0.85), as was the coprimary endpoint of stroke, MI, vascular death, congestive heart failure (CHF) hospitalization (7.3% vs. 7.7%/100 patient-years, HR 0.94, 95% CI 0.87-1.02, p = 0.12). All-cause (5.1% vs. 5.0%, p = 0.75) and vascular (3.6% vs. 3.5%, p = 0.67) mortality were similar, whereas there was a reduction in CHF hospitalization with irbesartan (2.7% vs. 3.2%, p = 0.02). The combination of stroke, transient ischemic attack (TIA), and non-central nervous system (CNS) embolization was also lower with irbesartan (2.9% vs. 3.3%, p = 0.02).

In patients who were in AF at baseline, there was no reduction in the incidence of NSR at follow-up (10.6% vs. 9.7%, p = 0.26). Similarly, in patients who were in NSR at baseline, AF was noted on follow-up in 36.8% of patients in the irbesartan arm compared with 38.1% in the placebo arm (p = 0.61). Overall rates of AF hospitalization were also similar (p = 0.41).

About 30.3% of patients in both arms prematurely stopped the study medication at 4 years. Drug discontinuation due to hypotension (2.8% vs. 1.4%, p < 0.0001) and renal dysfunction (1.0% vs. 0.5%, p = 0.02) were more prevalent in the irbesartan arm.

Interpretation:

The results of the ACTIVE I trial indicate that irbesartan, an ARB, is not associated with a reduction in major cardiovascular events or recurrent AF in patients with AF. Secondary endpoints including CHF hospitalization and stroke, TIA, or non-CNS embolization were lower in the irbesartan arm, although this could be due to chance due to multiple testing.

The authors had hypothesized that irbesartan, by lowering BP, and by effectively blocking the renin-angiotensin system, would demonstrate improved outcomes, as compared with placebo. However, many patients in this trial had only modest elevation in their baseline BP (mean baseline BP was 132/82 mm Hg), the mean difference in BP between the arms over the duration of follow-up was 2.9 mm Hg, and more than 60% of patients were also on an angiotensin-converting enzyme inhibitor. These effects probably biased the results of the trial towards the null. These results indicate that there is no role for routine or preferential ARB use in patients with AF.

References:

The ACTIVE I Investigators. Irbesartan in patients with atrial fibrillation. N Engl J Med 2011;364:928-38.

Presented by Dr. Salim Yusuf at the European Society of Cardiology Congress, Barcelona, Spain, September 2009.

Keywords: Coronary Artery Disease, Myocardial Infarction, Stroke, Ischemic Attack, Transient, Electric Countershock, Renin-Angiotensin System, Hypotension, Risk Factors, Blood Pressure, Tetrazoles, Peripheral Vascular Diseases, Biphenyl Compounds, Angiotensin II Type 1 Receptor Blockers, Heart Failure, Stroke Volume, Embolism, Hospitalization, Hypertension, Diabetes Mellitus, Atrial Flutter


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