BACKGROUND It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm. METHODS We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause. RESULTS The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P = 0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P = 0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P = 0.82). CONCLUSIONS Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized.

Hypertrophic cardiomyopathy is caused by mutations in the genes that encode sarcomeric proteins and is primarily characterized by unexplained left ventricular hypertrophy, impaired cardiac function, reduced exercise tolerance, and a relatively high incidence of sudden cardiac death, especially in the young. The extent of left ventricular hypertrophy is one of the major determinants of disease prognosis. Angiotensin II has trophic effects on the heart and plays an important role in the development of myocardial hypertrophy. Here in a double-blind, placebo-controlled, randomized study, we show that the long-term administration of the angiotensin II type 1 receptor antagonist candesartan in patients with hypertrophic cardiomyopathy was associated with the significant regression of left ventricular hypertrophy, improvement of left ventricular function, and exercise tolerance. The magnitude of the treatment effect was dependent on specific sarcomeric protein gene mutations that had the greatest responses on the carriers of ß-myosin heavy chain and cardiac myosin binding protein C gene mutations. These data indicate that modulating the role of angiotensin II in the development of hypertrophy is specific with respect to both the affected sarcomeric protein gene and the affected codon within that gene. Thus, angiotensin II type 1 receptor blockade has the potential to attenuate myocardial hypertrophy and may, therefore, provide a new treatment option to prevent sudden cardiac death in patients with hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy (HCM) is a primary cardiac disease characterized by unexplained cardiac hypertrophy and a relatively high incidence of sudden cardiac death, especially in young people.1,2 The extent of left ventricular hypertrophy is one of the major determinants of symptoms and prognosis. 3,4 Angiotensin II has trophic effects on the heart and plays an important role in the development of myocardial hypertrophy. 5,6 Inhibition of angiotensin-converting enzyme (ACE) or the angiotensin II type 1 receptor (AT1-R) induced regression of myocardial hypertrophy in patients with hypertension or after myocardial infarction. [7][8][9] In HCM, ACE and AT1-R gene polymorphisms have been shown to be associated with severity of hypertrophy, a high incidence of atrial fibrillation and the risk of sudden cardiac death. -17Therefore, we designed a double-blind, placebo-controlled, randomized, multicenter study to test the safety and effects of AT1-R antagonist candesartan in patients with nonobstructive HCM. We hypothesized that long-term use of candesartan would be associated with regression of left ventricular (LV) hypertrophy and improvement of LV function. Materials and Methods PatientsThis was a double-blind, placebo-controlled, randomized multicenter study. The study population consisted of 24 consecutive, genetically independent, adult (Ն18 years) patients (age 43 Ϯ 13 yrs; 46% males) with nonobstructive HCM, and normal ejection fraction (Ն60%) and sinus rhythm, who visited the participating in...

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