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ACTIVE-I - ACTIVE-I — Presented at ESC 2009
Description:
The goal of the trial was to evaluate the efficacy and safety of the angiotensin receptor-blocker (ARB) irbesartan compared with placebo among patients with atrial fibrillation.
Hypothesis:
The ARB irbesartan would be associated with a reduction in vascular death, stroke, MI, or hospitalization for heart failure compared with placebo among patients with atrial fibrillation.
Study Design
Patients Enrolled: 9016
Mean Follow Up: Mean 4.2 years
Mean Patient Age: Mean age 69 years
Female: 39
Patient Populations:
Enrollment in the ACTIVE-A or ACTIVE-W trial
Permanent AF or ≥2 episodes of intermittent AF in the past 6 months
≥ 1 risk factor, including age ≥75 years, treatment of systemic hypertension, prior stroke, TIA, or non-CNS systemic embolus, left ventricular dysfunction with LV ejection fraction ≤45%, documented peripheral vascular disease, and age 55 to 74 years with either diabetes requiring drug therapy or previous MI or documented coronary artery disease
Systolic BP ≥110 mm Hg but <160 mm="">
Not receiving an ARB, unless they are willing and able to be changed to another antihypertensive agent
No previous intolerance to ARBs
No proven indication for ARB, unless an ACE inhibitor can be substituted
Exclusions:
Need for clopidogrel or oral anticoagulant, documented peptic ulcer disease in prior 6 months, prior intracerebral hemorrhage, significant thrombocytopenia, and mitral stenosis
Primary Endpoints:
Co-primary endpoints:
Vascular death, stroke, or MI;
Secondary Endpoints:
Total mortality and stroke
Drug/Procedures Used:
Patients were randomized in a double-blind manner to irbesartan (n = 4,518; 150 mg starting dose titrated up to 300 mg as needed) or placebo (n = 4,498).
Concomitant Medications:
ACE-inhibitor (60%), beta-blocker (55%), diuretic (54%), calcium channel blocker (27%), digoxin (35%), vitamin K antagonist (38%)
Principal Findings:
Type of atrial fibrillation was permanent in 65% of patients, paroxysmal in 20% and persistent in 14%. Sinus rhythm was present in 19% of patients at baseline. One-third of patients had a history of heart failure. There was no difference in the frequency of discontinuation of study medication. Mean blood pressure at baseline was 138/82 mm Hg. SBP was reduced by 6.84 mm Hg in the irbesartan group and 3.93 mm Hg in the placebo group by 2 years, a reduction of 2.91 mm Hg. Likewise, DPB was reduced by 4.51 mm Hg in the irbesartan group and 2.63 mm Hg in the placebo group.
There was no difference between treatment groups in the primary endpoint of vascular death, stroke, or MI, which occurred in 5.4% of each group (hazard ratio [HR] 0.99, 95% CI 0.89-1.07, p=0.846). There was also no difference in the co-primary endpoint of vascular death, stroke, MI, or hospitalization for heart failure (7.3% vs 7.7%, HR 0.94, 95% CI 0.87-1.02, p=0.12). Heart failure hospitalization occurred less frequently in the irbesartan group (HR 0.86, 95% CI 0.76-0.98, p=0.018). Hospitalization for cardiovascular events were less common with irbesartan (p=0.003), as was total number of days hospitalized (p<0.001). there="" was="" no="" difference="" in="" stroke="" (2.1%="" vs="" 2.3%,="" p="0.21)" but="" in="" a="" post-hoc="" analysis="" the="" composite="" of="" stroke,="" tia="" or="" non-cns="" embolism="" was="" lower="" with="" irbesartan="" (2.9%="" vs="" 3.4%,="" hr="" 0.87,="" 95%="" ci="" 0.78-0.98,="" p="0.024)." in="" another="" post-hoc="" analysis="" that="" looked="" at="" total="" primary="" endpoint="" events="" rather="" than="" first="" primary="" endpoint="" event,="" there="" was="" no="" difference="" in="" vascular="" death,="" stroke,="" or="" mi="" (hr="" 0.97,="" p="0.579)" but="" vascular="" death,="" stroke,="" mi,="" or="" hospitalization="" for="" heart="" failure="" occurred="" less="" frequently="" in="" the="" irbesartan="" group="" (hr="" 0.89,="" p="0.016)." there="" was="" no="" difference="" in="" stroke="" (2.1%="" vs="" 2.3%,="" p="0.21)" but="" in="" a="" post-hoc="" analysis="" the="" composite="" of="" stroke,="" tia="" or="" non-cns="" embolism="" was="" lower="" with="" irbesartan="" (2.9%="" vs="" 3.4%,="" hr="" 0.87,="" 95%="" ci="" 0.78-0.98,="" p="0.024)." in="" another="" post-hoc="" analysis="" that="" looked="" at="" total="" primary="" endpoint="" events="" rather="" than="" first="" primary="" endpoint="" event,="" there="" was="" no="" difference="" in="" vascular="" death,="" stroke,="" or="" mi="" (hr="" 0.97,="" p="0.579)" but="" vascular="" death,="" stroke,="" mi,="" or="" hospitalization="" for="" heart="" failure="" occurred="" less="" frequently="" in="" the="" irbesartan="" group="" (hr="" 0.89,="" p="">
Interpretation:
Among patients with atrial fibrillation, treatment with the ARB irbesartan was not associated with a reduction in the composite endpoint of vascular death, stroke, or MI, or in the composite plus hospitalization for heart failure at a mean follow-up of 4 years compared with placebo.
Stroke and heart failure are frequent complications of atrial fibrillation, and both are impacted by elevated blood pressure. The trial was designed to determine if irbesartan, an ARB that reduces blood pressure, could reduce cardiovascular and heart failure events. Despite a nearly 3 mm Hg decline in SBP with irbesartan, the primary endpoints of the trial were not met. However, heart failure hospitalization and CV hospitalization were reduced with irbesartan. It should be noted that blood pressure at entry to the ACTIVE-I trial was generally well controlled (mean 138/82 mm Hg) and patients were on an average of 2 other blood pressure lowering agents, thus possibly limiting the impact of adding an ARB on clinical outcomes.
References:
Presented by Dr. Salim Yusuf at the European Society of Cardiology Congress, Barcelona, Spain, September 2009.
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