Article

Ivabradine in heart failure: what about digoxin?

Poole Hospital, Poole BH15 2JB, UK.
The Lancet (Impact Factor: 39.21). 01/2010; 372(9656):2113; author reply 2113-4. DOI: 10.1016/S0140-6736(08)61923-6
Source: PubMed
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    ABSTRACT: To determine the effects of digoxin on all-cause mortality and heart failure (HF) hospitalizations, regardless of ejection fraction, accounting for serum digoxin concentration (SDC). This comprehensive post-hoc analysis of the randomized controlled Digitalis Investigation Group trial (n=7788) focuses on 5548 patients: 1687 with SDC, drawn randomly at 1 month, and 3861 placebo patients, alive at 1 month. Overall, 33% died and 31% had HF hospitalizations during a 40-month median follow-up. Compared with placebo, SDC 0.5-0.9 ng/mL was associated with lower mortality [29 vs. 33% placebo; adjusted hazard ratio (AHR), 0.77; 95% confidence interval (CI), 0.67-0.89], all-cause hospitalizations (64 vs. 67% placebo; AHR, 0.85; 95% CI, 0.78-0.92) and HF hospitalizations (23 vs. 33% placebo; AHR, 0.62; 95% CI, 0.54-0.72). SDC> or =1.0 ng/mL was associated with lower HF hospitalizations (29 vs. 33% placebo; AHR, 0.68; 95% CI, 0.59-0.79), without any effect on mortality. SDC 0.5-0.9 reduced mortality in a wide spectrum of HF patients and had no interaction with ejection fraction >45% (P=0.834) or sex (P=0.917). Digoxin at SDC 0.5-0.9 ng/mL reduces mortality and hospitalizations in all HF patients, including those with preserved systolic function. At higher SDC, digoxin reduces HF hospitalization but has no effect on mortality or all-cause hospitalizations.
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    ABSTRACT: Ivabradine specifically inhibits the I(f) current in the sinoatrial node to lower heart rate, without affecting other aspects of cardiac function. We aimed to test whether lowering the heart rate with ivabradine reduces cardiovascular death and morbidity in patients with coronary artery disease and left-ventricular systolic dysfunction. Between December, 2004, and December, 2006, we screened 12 473 patients at 781 centres in 33 countries. We enrolled 10 917 eligible patients who had coronary artery disease and a left-ventricular ejection fraction of less than 40% in a randomised, double-blind, placebo-controlled, parallel-group trial. 5479 patients received 5 mg ivabradine, with the intention of increasing to the target dose of 7.5 mg twice a day, and 5438 received matched placebo in addition to appropriate cardiovascular medication. The primary endpoint was a composite of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening heart failure. We analysed patients by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00143507. Mean heart rate at baseline was 71.6 (SD 9.9) beats per minute (bpm). Median follow-up was 19 months (IQR 16-24). Ivabradine reduced heart rate by 6 bpm (SE 0.2) at 12 months, corrected for placebo. Most (87%) patients were receiving beta blockers in addition to study drugs, and no safety concerns were identified. Ivabradine did not affect the primary composite endpoint (hazard ratio 1.00, 95% CI 0.91-1.1, p=0.94). 1233 (22.5%) patients in the ivabradine group had serious adverse events, compared with 1239 (22.8%) controls (p=0.70). In a prespecified subgroup of patients with heart rate of 70 bpm or greater, ivabradine treatment did not affect the primary composite outcome (hazard ratio 0.91, 95% CI 0.81-1.04, p=0.17), cardiovascular death, or admission to hospital for new-onset or worsening heart failure. However, it did reduce secondary endpoints: admission to hospital for fatal and non-fatal myocardial infarction (0.64, 95% CI 0.49-0.84, p=0.001) and coronary revascularisation (0.70, 95% CI 0.52-0.93, p=0.016). Reduction in heart rate with ivabradine does not improve cardiac outcomes in all patients with stable coronary artery disease and left-ventricular systolic dysfunction, but could be used to reduce the incidence of coronary artery disease outcomes in a subgroup of patients who have heart rates of 70 bpm or greater.
    The Lancet 10/2008; 372(9641):807-16. DOI:10.1016/S0140-6736(08)61170-8 · 39.21 Impact Factor
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    ABSTRACT: BACKGROUND: This review summarizes the current status of randomized trials of digitalis in treating patients with congestive heart failure who are in sinus rhythm. Methods and results Randomized double-blind placebo-controlled trials of 20 or more adult patients followed for 7 weeks or more were selected. We identified 13 trials that met the inclusion criteria, comprising a total of 7896 patients. Of this number, 7755 patients contributed to information on mortality, 7262 to information on hospitalization for worsening heart failure, and 1096 to information on clinical status. Patients treated with digitalis compared with placebo had an odds ratio and confidence intervals for mortality of 0.98 (0.89, 1.09), for hospitalization of 0.68 (0.61, 0.75), and for a lesser degree of deterioration in clinical status of 0.31 (0.21, 0.43). CONCLUSIONS: The literature indicates that the drug has no effect on long-term mortality, but reduces the incidence of hospitalization, and has a positive effect on the clinical status of symptomatic patients. The drug has beneficial effects in patients who remain symptomatic despite being appropriately treated with diuretics and angiotensin-converting enzyme inhibitors. However the effects of coadministration with beta-blockers, spironolactone, and valsartan remain uncertain.
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