Search

Aims Heart failure with reduced ejection fraction (HFrEF) and chronic obstructive pulmonary disease (COPD) individually cause significant morbidity and mortality. Their coexistence is associated with even worse outcomes, partly due to suboptimal heart failure therapy, especially underutilisation of beta-blockers. Our aim was to investigate outcomes in HFrEF patients with and without COPD, and the effects of mineralocorticoid receptor antagonists (MRAs) on outcomes. Methods and results We studied the effect of MRA therapy in a post-hoc pooled analysis of 4397 HFrEF patients in the RALES and EMPHASIS-HF trials. The primary endpoint was the composite of heart failure hospitalisation or cardiovascular death. A total of 625 (14.2%) of the 4397 patients had COPD. Patients with COPD were older, more often male, and smokers, but less frequently treated with a beta-blocker. In patients with COPD, event rates (per 100 person-years) for the primary endpoint and for all-cause mortality were 25.2 (95% confidence interval 22.1-28.7) and 17.2 (14.9-19.9), respectively, compared with 19.9 (18.8-21.1) and 12.8 (12.0-13.7) in participants without COPD. The risks of all-cause hospitalisation and sudden death were also higher in patients with COPD. The benefit of MRA, compared with placebo, was consistent in patients with or without COPD for all outcomes, e.g. hazard ratio for the primary outcome 0.66 (0.50-0.85) for COPD and 0.65 (0.58-0.73) for no COPD (interaction p = 0.93). MRA-induced hyperkalaemia was less frequent in patients with COPD. Conclusions In RALES and EMPHASIS-HF, one-in-seven patients with HFrEF had coexisting COPD. HFrEF patients with COPD had worse outcomes than those without. The benefits of MRAs were consistent, regardless of COPD status. [ABSTRACT FROM AUTHOR]

Aims To investigate the safety and potential efficacy of the novel non-steroidal mineralocorticoid receptor antagonist finerenone in patients with worsening chronic heart failure and reduced left ventricular ejection fraction ( HFrEF) and at high risk of hyperkalaemia and worsening renal dysfunction. Methods and results The MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure ( ARTS-HF; NCT01807221) is a multicentre, randomized, double-blind, active-comparator-controlled, six-parallel-group, phase 2b dose-finding study. In total, 1060 patients with HFrEF and concomitant type 2 diabetes mellitus and/or chronic kidney disease ( CKD) will be randomized within 7 days of emergency presentation to hospital for worsening chronic HF to receive finerenone (one of five doses in the range 2.5-20.0 mg once daily) or eplerenone (25 mg every second day to 50 mg once daily for 90 days). The primary objective is to investigate the safety and potential efficacy (measured as the percentage of individuals with a decrease in plasma N-terminal pro-B-type natriuretic peptide [ NT-proBNP] of more than 30% relative to baseline at day 90 ± 2) of different oral doses of finerenone compared with eplerenone. Other objectives are to assess the effects of finerenone on a composite clinical endpoint (death from any cause, cardiovascular hospitalizations, or emergency presentations for worsening chronic HF), and on changes in health-related quality of life from baseline. Conclusions ARTS-HF is the first phase 2b clinical trial to investigate the effects of finerenone on plasma NT-proBNP in a high-risk population of patients who have worsening chronic HF with type 2 diabetes mellitus and/or CKD presenting at the emergency department. [ABSTRACT FROM AUTHOR]

Patients with acute coronary syndrome are recommended for early aggressive low-density lipoprotein (LDL) cholesterol–lowering therapy. The LUNAR study compared the efficacy of rosuvastatin with that of atorvastatin in decreasing LDL cholesterol in patients with acute coronary syndrome. Adult patients with coronary artery disease who were hospitalized for an acute coronary syndrome within 48 hours of first symptoms were randomized (n = 825) to an open-label, once-daily treatment with rosuvastatin 20 mg (RSV20), rosuvastatin 40 mg (RSV40), or atorvastatin 80 mg (ATV80) for 12 weeks. Patients were evaluated at weeks 2, 6, and 12. The primary end point was treatment efficacy in lowering LDL cholesterol averaged over 6 to 12 weeks. Changes in other lipoproteins, including high-density lipoprotein (HDL) cholesterol, and safety were evaluated. Analysis of covariance was used to compare least squares mean differences between each rosuvastatin treatment arm and the atorvastatin arm. The efficacy of RSV40 in lowering LDL cholesterol was significantly greater than that of ATV80 (46.8% vs 42.7% decrease, p = 0.02). LDL cholesterol lowering by RSV20 was similar to that by ATV80. Increases in HDL cholesterol were significantly greater with RSV40 (11.9%, p <0.001) and RSV20 (9.7%, p <0.01) than with ATV80 (5.6%). RSV40 was also significantly more effective than ATV80 in improving most other secondary efficacy variables, whereas the effects of RSV20 on these parameters were generally similar to those of ATV80. All 3 treatments were generally well tolerated over 12 weeks. In conclusion, results from the LUNAR study show that RSV40 more effectively decreased LDL cholesterol, increased HDL cholesterol, and improved other blood lipid parameters than ATV80 in patients with acute coronary syndrome. [ABSTRACT FROM AUTHOR]

Abstract: Combination therapy may reduce racial/ethnic differences in response to antihypertensives. In this post-hoc analysis, we evaluated treatment response by race/ethnicity among hypertensive adults enrolled in a 12-week, double-blind study in which patients previously uncontrolled (mean sitting systolic blood pressure [MSSBP] ≥150 and <200 mm Hg) on angiotensin receptor blocker (ARB) monotherapy (other than valsartan) for 28 days or more (n = 728) were randomized to amlodipine/valsartan 10/320 mg (intensive) or 5/160 mg (moderate). Treatment-naïve patients (in previous 28 days) or those who failed on a non-ARB first underwent a 28-day run-in period with olmesartan 20 mg or 40 mg, respectively. Hydrochlorothiazide (HCTZ) 12.5 mg was added to both arms at week 4; optional up-titration to 25 mg at week 8 (if MSSBP >140 mm Hg). Intensive treatment provided greater BP lowering versus moderate treatment throughout the study, regardless of race/ethnicity (474 white, 198 African American, 165 Hispanic individuals). Least-square mean reductions from baseline to week 4 in MSSBP (primary outcome) ranged from 20.4 to 23.5 mm Hg (intensive) versus 17.5 to 19.0 mm Hg (moderate), across racial/ethnic subgroups. Both regimens were well tolerated. Amlodipine/valsartan/HCTZ combination therapy was efficacious across racial/ethnic subgroups. Maximal efficacy was obtained with intensive treatment. [Copyright &y& Elsevier]

Background: Percutaneous coronary revascularization is widely used in improving symptoms and exercise performance in patients with ischemic heart disease and stable angina pectoris. In this study, we compared percutaneous coronary revascularization with lipid-lowering treatment for reducing the incidence of ischemic events. Methods: We studied 341 patients with stable coronary artery disease, relatively normal left ventricular function, asymptomatic or mild-to-moderate angina, and a serum level of low-density lipoprotein (LDL) cholesterol of at least 115 mg per deciliter (3.0 mmol per liter) who were referred for percutaneous revascularization. We randomly assigned the patients either to receive medical treatment with atorvastatin, at 80 mg per day (164 patients), or to undergo the recommended percutaneous revascularization procedure (angioplasty) followed by usual care, which could include lipid-lowering treatment (177 patients). The follow-up period was 18 months. Results: Twenty-two (13 percent) of the patients who received aggressive lipid-lowering treatment with atorvastatin (resulting in a 46 percent reduction in the mean serum LDL cholesterol level, to 77 mg per deciliter [2.0 mmol per liter]) had ischemic events, as compared with 37 (21 percent) of the patients who underwent angioplasty (who had an 18 percent reduction in the mean serum LDL cholesterol level, to 119 mg per deciliter [3.0 mmol per liter]). The incidence of ischemic events was thus 36 percent lower in the atorvastatin group over an 18-month period (P=0.048, which was not statistically significant after adjustment for interim analyses). This reduction in events was due to a smaller number of angioplasty procedures, coronary-artery bypass operations, and hospitalizations for worsening angina. As compared with the patients who were treated with angioplasty and usual care, the patients who received atorvastatin had a significantly longer time to the first ischemic event (P=0.03). Conclusions: In low-risk patients with stable coronary artery disease, aggressive lipid-lowering therapy is at least as effective as angioplasty and usual care in reducing the incidence of ischemic events. (N Engl J Med 1999;341:70-6.) [ABSTRACT FROM AUTHOR]

Post hoc analyses of the Digitalis Investigation Group (DIG) trial indicate that digoxin at low (0.5 to 0.9 ng/ml) serum digoxin concentration (SDC) reduces mortality, which is eliminated at higher (≥1 ng/ml) SDC, and that low-dose digoxin (≤0.125 mg/day) predicts low SDC. In the DIG trial, patients with ambulatory chronic systolic and diastolic heart failure (HF) (n = 7,788) in normal sinus rhythm receiving angiotensin-converting enzyme inhibitors and diuretics were randomized to receive placebo (n = 3,899) or digoxin (n = 3,889). The median dose of digoxin (0.25 mg/day) and the target SDC (0.8 to 2.5 ng/ml) were higher than what are currently recommended, which in part may explain the lack of long-term mortality benefit of digoxin in the DIG trial. To test this hypothesis, we examined the effect of digoxin on short-term outcomes; 1-year all-cause mortality occurred in 392 and 448 patients respectively in the digoxin and placebo groups (hazard ratio for digoxin 0.87, 95% confidence interval [CI] 0.76 to 0.995, p = 0.043). Respective hazard ratios for cardiovascular and HF deaths were 0.87 (95% CI 0.76 to 1.01, p = 0.072) and 0.66 (95% CI 0.52 to 0.85, p = 0.001). All-cause hospitalization occurred in 1,411 and 1,529 patients receiving digoxin and placebo respectively (hazard ratio 0.89, 95% CI 0.83 to 0.96, p = 0.002). Respective hazard ratios for cardiovascular and HF hospitalizations were 0.82 (95% CI 0.75 to 0.89, p <0.0001) and 0.59 (95% CI 0.52 to 0.66, p <0.0001). In conclusion, digoxin reduced 1-year mortality and hospitalization in patients with chronic HF receiving angiotensin-converting enzyme inhibitors and diuretics. Randomized clinical trials are needed to determine the effect of low-dose digoxin in contemporary patients with chronic HF. [Copyright &y& Elsevier]

Background: In the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial, similar clinical benefits were observed between starting doses of enalapril and the target dose achieved by postrandomization up-titration. In our current analysis, protecting the randomization, we examined the early effects of starting doses of enalapril.Methods: There were 2569 patients with mild-to-moderate chronic heart failure with reduced ejection fraction (ejection fraction ≤35%) randomized to receive starting doses (5-10 mg/day) of placebo (n = 1284) or enalapril (n = 1285). At day 14, both study drugs were blindly up-titrated to the target dose (20 mg/day). Overall, 96% (2458/2569) of the patients returned for dose up-titration, which was achieved in 59% (1444/2458), 48% (696/1444) of whom were in the enalapril group. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes in the enalapril group were estimated.Results: HRs (95% CIs) for all-cause mortality, heart failure hospitalization, and the combined endpoint of heart failure hospitalization or all-cause mortality at 14 days after randomization were 0.80 (0.32-2.03), 0.63 (0.35-1.12), and 0.65 (0.39-1.06), respectively. Corresponding HRs (95% CIs) at 30 days were 0.82 (0.41-1.67), 0.43 (0.27-0.68), and 0.43 (0.27-0.68), respectively. The magnitude of these early effects of starting doses of enalapril is similar to its previously reported long-term effects at the target dose.Conclusion: These data suggest that in stable ambulatory patients with heart failure with reduced ejection fraction, the magnitude of the early effect of starting doses of enalapril is similar to that observed during longer-term therapy with the target doses of the drug. [ABSTRACT FROM AUTHOR]

Objectives: The study sought to investigate the safety and efficacy of eplerenone in patients at high risk for hyperkalemia or worsening renal function (WRF) in EMPHASIS-HF, a trial that enrolled patients at least 55 years old with heart failure and reduced ejection fraction (HF-REF), in New York Heart Association (NYHA) functional class II and with an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m2 and serum potassium <5.0 mmol/l. Patients were receiving optimal therapy and most had been hospitalized for a cardiovascular reason within 180 days of inclusion. Background: Underuse of eplerenone in patients with HF-REF may be due to fear of inducing hyperkalemia or WRF in high-risk patients. Methods: This was a pre-specified analysis of subgroups of patients at high risk of hyperkalemia or WRF (patients ≥75 years of age, with diabetes, with eGFR <60 ml/min/1.73 m2, and with systolic blood pressure < median of 123 mm Hg), examining the major safety measures (potassium >5.5, >6.0, and <3.5 mmol/l; hyperkalemia leading to study-drug discontinuation or hospitalization; and hospitalization for WRF) as well as the primary outcome (hospitalization for HF or cardiovascular mortality). Results: In all high-risk subgroups, patients treated with eplerenone had an increased risk of potassium >5.5 mmol/l but not of potassium >6.0 mmol/l, and of hospitalization for hyperkalemia or discontinuation of study medication due to adverse events. Eplerenone was effective in reducing the primary composite endpoint in all subgroups. Conclusions: In patients with chronic HF-REF, in NYHA functional class II, and meeting specific inclusion and exclusion criteria, including an eGFR >30 ml/min/1.73 m2 and potassium <5.0 mmol/l, eplerenone was both efficacious and safe when carefully monitored, even in subgroups at high risk of developing hyperkalemia or WRF. (A Comparison Of Outcomes In Patients In New York Heart Association [NYHA] Class II Heart Failure When Treated With Eplerenone Or Placebo In Addition To Standard Heart Failure Medicines [EMPHASIS-HF Study]; NCT00232180) [Copyright &y& Elsevier]

Objectives: This study investigated the influence of baseline and worsening renal function (WRF) on the efficacy of spironolactone in patients with severe heart failure (HF). Background: Renal dysfunction or decline in renal function is a known predictor of adverse outcome in patients with HF, and treatment decisions are often on the basis of measures of renal function. Methods: We used data from the RALES (Randomized Aldactone Evaluation Study) in 1,658 patients with New York Heart Association functional class III or IV HF and an ejection fraction <35%. Participants were randomized to spironolactone 25 mg, which could be titrated to 50 mg, or placebo daily. Renal function (estimated glomerular filtration rate [eGFR]) was estimated by the Modification of Diet in Renal Disease equation. Worsening renal function was defined as a 30% reduction in eGFR from baseline to 12 weeks post-randomization. Results: Individuals with reduced baseline eGFR exhibited similar relative risk reductions in all-cause death and the combined endpoint of death or hospital stays for HF as those with a baseline eGFR >60 ml/min/1.73 m2 and greater absolute risk reduction compared with those with a higher baseline eGFR (10.3% vs. 6.4%). Moreover, WRF (17% vs. 7% for spironolactone and placebo groups, p < 0.001) was associated with an increased adjusted risk of death in the placebo group (hazard ratio: 1.9, 95% confidence interval: 1.3 to 2.6) but not in those randomized to spironolactone (hazard ratio: 1.1, 95% confidence interval: 0.79 to 1.5, p interaction = 0.009). The risk of hyperkalemia and renal failure was higher in those with worse baseline renal function and those with WRF, particularly in the spironolactone arm, but the substantial net benefit of spironolactone therapy remained. Conclusions: The absolute benefit of spironolactone was greatest in patients with reduced eGFR. Worsening renal function was associated with a negative prognosis, yet the mortality benefit of spironolactone was maintained. [Copyright &y& Elsevier]

Background: Older people are predisposed to hyperkalemia because of impaired renal function, comorbid conditions, and polypharmacy. Renin-angiotensin-aldosterone system inhibitors (RAASi), which are recommended to treat chronic kidney disease and heart failure augment the risk. Patiromer, a nonabsorbed potassium binder, was shown in the phase 3 OPAL-HK study to decrease serum potassium in patients with chronic kidney disease taking RAASi. We studied the efficacy and safety of patiromer in a prespecified subgroup of patients aged ≥65 years from OPAL-HK.Methods: Chronic kidney disease patients with mild or moderate-to-severe hyperkalemia received patiromer, initially 8.4 g/d or 16.8 g/d, respectively, for 4 weeks (treatment phase, part A). Eligible patients entered an 8-week randomized withdrawal phase (part B) and continued patiromer or switched to placebo.Results: Mean ± standard error change in serum potassium from baseline to week 4 of part A (primary endpoint) in patients aged ≥65 years was -1.01 ± 0.05 mEq/L (P < .001); 97% achieved serum potassium 3.8-<5.1 mEq/L. The serum potassium increase during the first 4 weeks of part B was greater in patients taking placebo than in those taking patiromer (P < .001). Fewer patients taking patiromer (30%) than placebo (92%) developed recurrent hyperkalemia (serum potassium ≥5.1 mEq/L). Mild-to-moderate constipation occurred in 15% (part A) and 7% (part B) of patients aged ≥65 years. Serum potassium <3.5 mEq/L and serum magnesium <1.4 mg/dL were infrequent (4% each in patients aged ≥65 years in part A).Conclusions: Patiromer reduced recurrent hyperkalemia and was well tolerated in older chronic kidney disease patients taking RAASi. [ABSTRACT FROM AUTHOR]