The New England Journal of Medicine

BackgroundThe optimal combination drug therapy for hypertension is not established, although current U.S. guidelines recommend inclusion of a diuretic. We hypothesized that treatment with the combination of an angiotensin-converting–enzyme (ACE) inhibitor and a dihydropyridine calcium-channel blocker would be more effective in reducing the rate of cardiovascular events than treatment with an ACE inhibitor plus a thiazide diuretic.MethodsIn a randomized, double-blind trial, we assigned 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The primary end point was the composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization.ResultsThe baseline characteristics of the two groups were similar. The trial was terminated early after a mean follow-up of 36 months, when the boundary of the prespecified stopping rule was exceeded. Mean blood pressures after dose adjustment were 131.6/73.3 mm Hg in the benazepril–amlodipine group and 132.5/74.4 mm Hg in the benazepril–hydrochlorothiazide group. There were 552 primary-outcome events in the benazepril–amlodipine group (9.6%) and 679 in the benazepril–hydrochlorothiazide group (11.8%), representing an absolute risk reduction with benazepril–amlodipine therapy of 2.2% and a relative risk reduction of 19.6% (hazard ratio, 0.80, 95% confidence interval [CI], 0.72 to 0.90; P<0.001). For the secondary end point of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke, the hazard ratio was 0.79 (95% CI, 0.67 to 0.92; P=0.002). Rates of adverse events were consistent with those observed from clinical experience with the study drugs.ConclusionsThe benazepril–amlodipine combination was superior to the benazepril–hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension who were at high risk for such events. (ClinicalTrials.gov number, NCT00170950.)

doi: 10.1056/NEJMoa0707615pmid: 19052125

BackgroundIn patients with chronic hepatitis C who do not have a response to antiviral treatment, the disease may progress to cirrhosis, liver failure, hepatocellular carcinoma, and death. Whether long-term antiviral therapy can prevent progressive liver disease in such patients remains uncertain.MethodsWe conducted a randomized, controlled trial of peginterferon alfa-2a at a dosage of 90 μg per week for 3.5 years, as compared with no treatment, in 1050 patients with chronic hepatitis C and advanced fibrosis who had not had a response to previous therapy with peginterferon and ribavirin. The patients, who were stratified according to stage of fibrosis (622 with noncirrhotic fibrosis and 428 with cirrhosis), were seen at 3-month intervals and underwent liver biopsy at 1.5 and 3.5 years after randomization. The primary end point was progression of liver disease, as indicated by death, hepatocellular carcinoma, hepatic decompensation, or, for those with bridging fibrosis at baseline, an increase in the Ishak fibrosis score of 2 or more points.ResultsWe randomly assigned the patients to receive peginterferon (517 patients) or no therapy (533 patients) for 3.5 years. The level of serum aminotransferases, the level of serum hepatitis C virus RNA, and histologic necroinflammatory scores all decreased significantly (P<0.001) with treatment, but there was no significant difference between the groups in the rate of any primary outcome (34.1% in the treatment group and 33.8% in the control group; hazard ratio, 1.01; 95% confidence interval, 0.81 to 1.27; P=0.90). The percentage of patients with at least one serious adverse event was 38.6% in the treatment group and 31.8% in the control group (P=0.07).ConclusionsLong-term therapy with peginterferon did not reduce the rate of disease progression in patients with chronic hepatitis C and advanced fibrosis, with or without cirrhosis, who had not had a response to initial treatment with peginterferon and ribavirin. (ClinicalTrials.gov number, NCT00006164.)

doi: 10.1056/NEJMoa0802878pmid: 19052126

BackgroundTenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase.MethodsIn two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)–negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations.ResultsAt week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies.ConclusionsAmong patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)

BackgroundApproximately 50% of patients with heart failure have a left ventricular ejection fraction of at least 45%, but no therapies have been shown to improve the outcome of these patients. Therefore, we studied the effects of irbesartan in patients with this syndrome.MethodsWe enrolled 4128 patients who were at least 60 years of age and had New York Heart Association class II, III, or IV heart failure and an ejection fraction of at least 45% and randomly assigned them to receive 300 mg of irbesartan or placebo per day. The primary composite outcome was death from any cause or hospitalization for a cardiovascular cause (heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). Secondary outcomes included death from heart failure or hospitalization for heart failure, death from any cause and from cardiovascular causes, and quality of life.ResultsDuring a mean follow-up of 49.5 months, the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group. Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% confidence interval [CI], 0.86 to 1.05; P=0.35). Overall rates of death were 52.6 and 52.3 per 1000 patient-years, respectively (hazard ratio, 1.00; 95% CI, 0.88 to 1.14; P=0.98). Rates of hospitalization for cardiovascular causes that contributed to the primary outcome were 70.6 and 74.3 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% CI, 0.85 to 1.08; P=0.44). There were no significant differences in the other prespecified outcomes.ConclusionsIrbesartan did not improve the outcomes of patients with heart failure and a preserved left ventricular ejection fraction. (ClinicalTrials.gov number, NCT00095238.)