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Background. The therapeutic efficacy of the cardiac glycoside digitoxin in patients with heart failure and reduced ejection fraction is not established.
Methods. In this international, double-blind, placebo-controlled trial, we randomly assigned patients with chronic heart failure who had a left ventricular ejection fraction of 40% or less and a New York Heart Association (NYHA) functional class of III or IV or a left ventricular ejection fraction of 30% or less and an NYHA functional class of II in a 1:1 ratio to receive digitoxin (at a starting dose of 0.07 mg once daily) or matching placebo in addition to guideline-directed medical therapy. The primary outcome was a composite of death from any cause or hospital admission for worsening heart failure, whichever occurred first.
Results. Among 1240 patients who underwent randomization, 1212 fulfilled the criteria for inclusion in the modified intention-to-treat population: 613 patients in the digitoxin group and 599 in the placebo group. Over a median follow-up of 36 months, a primary-outcome event occurred in 242 patients (39.5%) in the digitoxin group and 264 (44.1%) in the placebo group (hazard ratio for death or first hospital admission for worsening heart failure, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03). Death from any cause occurred in 167 patients (27.2%) in the digitoxin group and 177 (29.5%) in the placebo group (hazard ratio, 0.86; 95% CI, 0.69 to 1.07). A first hospital admission for worsening heart failure occurred in 172 patients (28.1%) in the digitoxin group and 182 (30.4%) in the placebo group (hazard ratio, 0.85; 95% CI, 0.69 to 1.05). At least one serious adverse event occurred in 29 patients (4.7%) in the digitoxin group and 17 (2.8%) in the placebo group.
Conclusions. Treatment with digitoxin led to a lower combined risk of death from any cause or hospital admission for worsening heart failure than placebo among patients with heart failure and reduced ejection fraction who received guideline-directed medical therapy. (Funded by the German Federal Ministry of Research, Technology, and Space and others; DIGIT-HF EudraCT number, 2013-005326-38.).
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Background. The appropriate duration of anticoagulation for venous thromboembolism (VTE) in patients who have a transient provoking factor (e.g., surgery, trauma, or immobility) and concomitant enduring risk factors is uncertain.
Methods. In this single-center, double-blind, randomized trial, adults with VTE after the occurrence of a transient provoking factor who had at least one enduring risk factor and had completed at least 3 months of anticoagulation were assigned to receive oral apixaban (at a dose of 2.5 mg twice daily) or placebo for 12 months. The primary efficacy outcome was the first symptomatic recurrent VTE. The primary safety outcome was the first episode of major bleeding according to the criteria of the International Society on Thrombosis and Hemostasis.
Results. A total of 600 patients underwent randomization (mean age, 59.5 years; female sex, 57.0%; non-White race, 19.2%). The trial population had a broad range of provoking factors and enduring risk factors. Symptomatic recurrent VTE occurred in 4 of the 300 patients (1.3%) in the apixaban group and in 30 of the 300 patients (10.0%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.04 to 0.36; P<0.001). Major bleeding occurred in 1 patient in the apixaban group and none in the placebo group. Clinically relevant nonmajor bleeding was observed in 14 of 294 patients (4.8%) in the apixaban group and in 5 of 294 patients (1.7%) in the placebo group (hazard ratio, 2.68; 95% CI, 0.96 to 7.43; P = 0.06). One patient in the apixaban group and 3 patients in the placebo group died, with no deaths attributed to cardiovascular or hemorrhagic causes. Nonhemorrhagic, nonfatal adverse events occurred in 6 patients (2.0%) in each group.
Conclusions. Among patients with provoked VTE and enduring risk factors, low-intensity therapy with apixaban for 12 months resulted in a lower risk of symptomatic recurrent VTE than placebo, with a low risk of major bleeding. (Funded by Bristol-Myers Squibb-Pfizer Alliance; HI-PRO ClinicalTrials.gov number, NCT04168203.).
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Background. An interim analysis of progression-free survival in this trial showed that ibrutinib-venetoclax was superior to fludarabine-cyclophosphamide-rituximab (FCR) among patients with chronic lymphocytic leukemia (CLL). Whether ibrutinib-venetoclax is more effective than ibrutinib alone is unclear.
Methods. In this phase 3, multicenter, open-label trial, we randomly assigned patients with CLL to receive ibrutinib-venetoclax, ibrutinib alone, or FCR. The primary end points were undetectable measurable residual disease (MRD) in bone marrow within 2 years in the ibrutinib-venetoclax group as compared with the ibrutinib-alone group and progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group. A powered secondary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the ibrutinib-alone group. Other secondary end points included overall survival.
Results. A total of 172 of the 260 participants (66.2%) in the ibrutinib-venetoclax group had undetectable MRD in bone marrow within 2 years, as compared with none of the 263 participants in the ibrutinib-alone group (P<0.001) and 127 of the 263 participants (48.3%) in the FCR group. With a median follow-up of 62.2 months, disease progression or death occurred in 18 participants (6.9%) in the ibrutinib-venetoclax group, as compared with 59 (22.4%) in the ibrutinib-alone group (hazard ratio, 0.29; 95% confidence interval [CI], 0.17 to 0.49; P<0.001) and 112 (42.6%) in the FCR group (hazard ratio, 0.13; 95% CI, 0.08 to 0.21; P<0.001). Progression-free survival at 5 years was 93.9% with ibrutinib-venetoclax, 79.0% with ibrutinib alone, and 58.1% with FCR. Death occurred in 11 participants (4.2%) in the ibrutinib-venetoclax group, as compared with 26 (9.9%) in the ibrutinib-alone group (hazard ratio, 0.41; 95% CI, 0.20 to 0.83) and 39 (14.8%) in the FCR group (hazard ratio, 0.26; 95% CI, 0.13 to 0.50). Sudden death occurred in 3, 8, and 4 participants in the ibrutinib-venetoclax, ibrutinib-alone, and FCR groups, respectively.
Conclusions. With extended follow-up and increased enrollment, our trial showed that undetectable MRD and extended progression-free survival were more common with ibrutinib-venetoclax than with ibrutinib alone or FCR. The results for overall survival were also consistent with a benefit of ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).
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Background. Intravenous thrombolysis remains a standard treatment for acute ischemic stroke within 4.5 hours after onset. Vascular reocclusion may occur after intravenous thrombolysis and may be preventable with an antiplatelet agent within the first 24 hours after thrombolysis. Tirofiban, a platelet glycoprotein IIb-IIIa receptor antagonist, has reduced macrovascular reocclusion in experimental models.
Methods. In this phase 3, multicenter, double-blind, randomized, placebo-controlled trial conducted at 38 centers in China, we assigned patients with acute ischemic noncardioembolic stroke who presented within 4.5 hours after stroke onset and who were not eligible for thrombectomy to receive a 24-hour intravenous infusion of tirofiban or placebo within 60 minutes after intravenous thrombolysis. The primary efficacy outcome was an excellent functional outcome, defined as a score of 0 to 1 on the modified Rankin scale, at 90 days. The safety outcomes were symptomatic intracranial hemorrhage within 36 hours and death at 90 days.
Results. A total of 414 patients were assigned to receive tirofiban and 418 to receive placebo. Thrombolytic agents included alteplase (in 75% of the patients) and tenecteplase (in 25%). At 90 days, a score of 0 to 1 on the modified Rankin scale was reported in a higher percentage of patients in the tirofiban group than in the placebo group (65.9% vs. 54.9%; risk ratio, 1.20; 95% confidence interval, 1.07 to 1.34; P = 0.001). Symptomatic intracranial hemorrhage occurred in 1.7% of the patients in the tirofiban group and none in the placebo group. Mortality at 90 days was 4.1% in the tirofiban group and 3.8% in the placebo group.
Conclusions. In patients with acute ischemic noncardioembolic stroke who underwent thrombolysis within 4.5 hours after onset, early tirofiban increased the likelihood of an excellent functional outcome. The incidence of intracranial hemorrhage was low but higher with tirofiban than placebo. (Funded by the Fundamental Research Funds for Central Universities; ASSET-IT ClinicalTrials.gov number, NCT06134622.).
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