Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico–Atrial Fibrillation - GISSI-AF

Jun 03, 2009
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Trial Sponsor:
Associazione Nazionale Medici Cardiologi Ospedalieri and by Istituto di Ricerche Farmacologiche Mario Negri
Date Published:
01/01/2009
Date Updated:
06/03/2009
Original Posted Date:
06/03/2009
References

Description:

Given that several studies have shown a role of the angiotensin-renin system in atrial remodeling in patients with atrial fibrillation (AF), the GISSI-AF trial sought to evaluate the safety and efficacy of adding valsartan to established therapies in patients with recurrent AF.

Hypothesis:

Valsartan would reduce the rate of recurrence of AF.

Study Design

Study Design:

Patients Enrolled: 1,442
Mean Follow Up: 1 year
Mean Patient Age: 68.0 years
Female: 38
Mean Ejection Fraction: Heart failure or ejection fraction ≤40%: 8%

Patient Populations:

  • Age >40 years
  • Two or more episodes of symptomatic AF in the past 6 months, or successful cardioversion (electric or pharmacologic) for AF between 14 days to 48 hours before randomization
  • At least one of the following conditions:
    • Heart failure or a documented history of left ventricular dysfunction (defined as an ejection fraction of less than 40%),
    • History of hypertension for 6 months or more, with or without left ventricular hypertrophy,
    • Type 2 diabetes,
    • History of stroke or peripheral artery disease,
    • History of coronary artery disease,
    • AF without coexisting cardiovascular conditions but with left atrial dilatation

Exclusions:

  • Treatment with ARBs for another indication
  • Contraindications to ARBs
  • Recently (within the previous 6 weeks) had an acute myocardial infarction, coronary bypass operation, or percutaneous coronary intervention
  • Clinically significant valvular disease; had thyroid dysfunction
  • Scheduled to undergo catheter ablation or implantation of a pacemaker or defibrillator

Primary Endpoints:

  • Time to recurrence of AF
  • Proportion of patients with >1 episode of AF over 1 year

Secondary Endpoints:

  • Total number of hospitalizations for AF
  • Hospitalization for any cause
  • Hospitalization for cardiovascular cause
  • Death and thromboembolic events
  • Number of patients in normal sinus rhythm at each study visit
  • Duration of and ventricular rate at first recurrence of AF
  • Safety endpoints

    Drug/Procedures Used:

    Patients received either valsartan or matching placebo. The drug was initiated at 80 mg daily for the first 2 weeks, then titrated up to 160 mg daily for the next 2 weeks. Following this, the dose was force titrated to 320 mg daily for the remainder of the follow-up, unless patients developed hypotension.

    Concomitant Medications:

    Amiodarone (35%), sotalol (7%), class I AAD (32%), beta-blockers (30%), digoxin (4%), aldosterone antagonists (6%), statins (25%), and oral anticoagulants (56%)

Principal Findings:

A total of 1,442 patients were randomized, 722 to the valsartan arm, and 720 to the placebo arm. Baseline characteristics were similar between the two arms. Only about 12% of the patients had AF alone (without any other comorbidities), about 40% had ≥2 episodes of AF in the preceding 6 months, and about 88.5% of the patients had undergone a cardioversion in the preceding 2 weeks. AF was well rate controlled, with a mean heart rate of 63.6 bpm.

By the end of the study period, the least mean systolic blood pressure was reduced by 4.1 ± 0.6 mm Hg and 2.0 ± 0.6 mm Hg in the valsartan and placebo arms, respectively. The mean heart rate was unchanged from baseline in both groups. At the end of 1 year, the incidence of recurrent AF was similar between the valsartan and placebo arms (51.4% vs. 52.1%, hazard ratio 0.98, 95% confidence interval 0.85-1.14, p = 0.83). The median times to recurrence of AF were also similar (295 days vs. 271 days). Other endpoints such as death (1.1% vs. 1.0%, p = 0.78) and hospitalization for cardiovascular reason (15.8% vs. 16.9%, p = 0.59) were similar between the two arms; thromboembolic episodes such as ischemic stroke or transient ischemic attack seemed to be higher in the valsartan arm (1.4% vs. 0.3%, p = 0.04).

Permanent discontinuation of study drug was more common in the valsartan arm (14.8% vs. 10.6%, p = 0.02). Serious side effects such as hyperkalemia and severe hypotension were infrequent, but more common in the valsartan arm compared with placebo.

Interpretation:

The results of this large multicenter clinical trial indicate that the use of valsartan is not associated with a clinical benefit in patients with AF associated with cardiovascular disease, diabetes, or left atrial enlargement, who are already on established therapies. The results of this trial are contrary to those reported by earlier smaller studies, which studied other angiotensin-receptor blockers (ARBs) along with amiodarone for the recurrence of AF. Although only 35% of the patients in this trial were on concomitant amiodarone, no difference was noted in that subgroup either.

GISSI-AF was also a secondary prevention study. It is thus unknown if valsartan or other renin-angiotensin system inhibitors would be associated with a lower incidence of AF in patients at high risk for developing AF.

References:

The GISSI-AF Investigators. Valsartan for prevention of recurrent atrial fibrillation. N Engl J Med 2009;360:1606-17.

Keywords: Hypertrophy, Left Ventricular, Coronary Artery Disease, Stroke, Ischemic Attack, Transient, Electric Countershock, Diabetes Mellitus, Type 2, Renin-Angiotensin System, Hypotension, Dilatation, Peripheral Arterial Disease, Blood Pressure, Hyperkalemia, Valine, Tetrazoles, Heart Rate, Heart Failure, Atrial Remodeling, Ventricular Dysfunction, Left, Hypertension


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