Anaemia is defined by WHO as Hb < 13.0 g/dL in male adults and <12.0 g/dL in female adults. It is a common comorbidity in patients of heart failure with both HFrEF and HFpEF. The incidence ranges ...between 30% and 50%, though in certain communities, it is likely to be higher still. Elderly age, severe heart failure, poor nutrition, and elevation of inflammatory markers are associated with a higher incidence of anaemia. However, the commonest contributing factor to anaemia in HF is iron deficiency. In a Canadian study of 12 065 patients, the incidence of absolute ID was 21% in anaemic patients. Many other western studies have also quoted incidences varying between 35% and 43%.
The earlier attempts to improve outcomes by supplementation with Erythropoietic‐stimulating factors were unsuccessful and resulted in a higher incidence of thrombotic events. Iron deficiency (ID) has emerged as an important factor in patients of HF, even in those without anaemia and worsens outcomes. It is defined as Ferritin levels below 100 mcg/L or 100–299 μg/L with transferrin saturation of <20%. Attempts to correct ID by oral supplementation have been unsuccessful as seen in IRON‐HF and IRONOUT‐HF trials. FAIR‐HF and CONFIRM‐HF conclusively established the role of IV Iron in improving exercise capacity and quality of life in patients with HFrEF. ESC guidelines have given a class IC indication for testing all heart failure patients for ID, and an IIaA recommendation for its correction by IV ferric carboxymaltose was found to be deficient. Ongoing trials will establish the role of IV iron in improving mortality and in HFpEF patients and in patients with acute heart failure.
Patients with heart failure with preserved ejection fraction have significant impairment in health-related quality of life. In the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients ...With Chronic Heart Failure With Preserved Ejection Fraction), we evaluated the efficacy of empagliflozin on health-related quality of life in patients with heart failure with preserved ejection fraction and whether the clinical benefit observed with empagliflozin varies according to baseline health status.
Health-related quality of life was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12, 32, and 52 weeks. Patients were divided by baseline KCCQ Clinical Summary Score (CSS) tertiles, and the effect of empagliflozin on outcomes was examined. The effect of empagliflozin on KCCQ-CSS, Total Symptom Score, and Overall Summary Score was evaluated. Responder analyses were performed to compare the odds of improvement and deterioration in KCCQ related to treatment with empagliflozin.
The effect of empagliflozin on reducing the risk of time to cardiovascular death or heart failure hospitalization was consistent across baseline KCCQ-CSS tertiles (hazard ratio, 0.83 95% CI, 0.69-1.00, 0.70 95% CI, 0.55-0.88, and 0.82 95% CI, 0.62-1.08 for scores <62.5, 62.5-83.3, and ≥83.3, respectively;
trend=0.77). Similar results were seen for total heart failure hospitalizations. Patients treated with empagliflozin had significant improvement in KCCQ-CSS versus placebo (+1.03, +1.24, and +1.50 at 12, 32, and 52 weeks, respectively;
<0.01); similar results were seen for Total Symptom Score and Overall Summary Score. At 12 weeks, patients on empagliflozin had higher odds of improvement ≥5 points (odds ratio, 1.23 95% CI, 1.10-1.37), ≥10 points (odds ratio, 1.15 95% CI, 1.03-1.27), and ≥15 points (odds ratio, 1.13 95% CI, 1.02-1.26) and lower odds of deterioration ≥5 points in KCCQ-CSS (odds ratio, 0.85 95% CI, 0.75-0.97). A similar pattern was seen at 32 and 52 weeks, and results were consistent for Total Symptom Score and Overall Summary Score.
In patients with heart failure with preserved ejection fraction, empagliflozin reduced the risk for major heart failure outcomes across the range of baseline KCCQ scores. Empagliflozin improved health-related quality of life, an effect that appeared early and was sustained for at least 1 year. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03057951.
IMPORTANCE: Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients ...with HFrEF, even those without diabetes. OBJECTIVE: To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes. DESIGN, SETTING, AND PARTICIPANTS: Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. INTERVENTIONS: Addition of once-daily 10 mg of dapagliflozin or placebo to recommended therapy. MAIN OUTCOMES AND MEASURES: The primary outcome was the composite of an episode of worsening heart failure or cardiovascular death. This outcome was analyzed by baseline diabetes status and, in patients without diabetes, by glycated hemoglobin level less than 5.7% vs greater than or equal to 5.7%. RESULTS: Among 4744 patients randomized (mean age, 66 years; 1109 23% women; 2605 55% without diabetes), 4742 completed the trial. Among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and 231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 95% CI, 0.60-0.88). In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio, 0.75 95% CI, 0.63-0.90) (P value for interaction = .80). Among patients without diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in the placebo group (hazard ratio, 0.67 95% CI, 0.47-0.96). In patients with a glycated hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%) in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio, 0.74 95% CI, 0.59-0.94) (P value for interaction = .72). Volume depletion was reported as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin group and 7.8% in the placebo group among patients with diabetes. A kidney adverse event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin group and 8.7% in the placebo group among patients with diabetes. CONCLUSIONS AND RELEVANCE: In this exploratory analysis of a randomized trial of patients with HFrEF, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03036124
Abstract
Aims
Concern about hypotension often leads to withholding of beneficial therapy in patients with heart failure and reduced ejection fraction (HFrEF). We evaluated the efficacy and safety of ...dapagliflozin, which lowers systolic blood pressure (SBP),according to baseline SBP in Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF).
Methods and results
Key inclusion criteria were: New York Heart Association Class II−IV, left ventricular ejection fraction ≤ 40%, elevated N-terminal pro-B-type natriuretic peptide level, and SBP ≥95 mmHg. The primary outcome was a composite of worsening heart failure or cardiovascular death. The efficacy and safety of dapagliflozin were examined using SBP as both a categorical and continuous variable. A total of 1205 patients had a baseline SBP <110 mmHg; 981 ≥ 110 < 120; 1149 ≥ 120 < 130; and 1409 ≥ 130 mmHg. The placebo-corrected reduction in SBP from baseline to 2 weeks with dapagliflozin was −2.54 (−3.33 to −1.76) mmHg (P < 0.001), with a smaller between-treatment difference in patients in the lowest compared to highest SBP category. Patients in the lowest SBP category had a much higher rate (per 100 person-years) of the primary outcome 20.6, 95% confidence interval (95% CI) 17.6–24.2 than those in the highest SBP category (13.8, 11.7–16.4). The benefit and safety of dapagliflozin was consistent across the range of SBP; hazard ratio (95% CI) in each SBP group, lowest to highest: 0.76 (0.60–0.97), 0.76 (0.57–1.02), 0.81 (0.61–1.08), and 0.67 (0.51–0.87), P interaction = 0.78. Study drug discontinuation did not differ between dapagliflozin and placebo across the SBP categories examined.
Conclusion
Dapagliflozin had a small effect on SBP in patients with HFrEF and was superior to placebo in improving outcomes, and well tolerated, across the range of SBP included in DAPA-HF.
Clinical Trial Registration:
ClinicalTrials.gov NCT03036124.
Graphical Abstract
BACKGROUND:In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), the sodium-glucose cotransporter 2 inhibitor dapagliflozin reduced the risk of worsening heart ...failure and death in patients with heart failure and reduced ejection fraction. We examined the efficacy and tolerability of dapagliflozin in relation to background diuretic treatment and change in diuretic therapy after randomization to dapagliflozin or placebo.
METHODS:We examined the effects of study treatment in the following subgroupsno diuretic and diuretic dose equivalent to furosemide <40, 40, and >40 mg daily at baseline. We examined the primary composite end point of cardiovascular death or a worsening heart failure event and its components, all-cause death and symptoms.
RESULTS:Of 4616 analyzable patients, 736 (15.9%) were on no diuretic, 1311 (28.4%) were on <40 mg, 1365 (29.6%) were on 40 mg, and 1204 (26.1%) were taking >40 mg. Compared with placebo, dapagliflozin reduced the risk of the primary end point across each of these subgroupshazard ratios were 0.57 (95% CI, 0.36–0.92), 0.83 (95% CI, 0.63–1.10), 0.77 (95% CI, 0.60–0.99), and 0.78 (95% CI, 0.63–0.97), respectively (P for interaction=0.61). The hazard ratio in patients taking any diuretic was 0.78 (95% CI, 0.68–0.90). Improvements in symptoms and treatment toleration were consistent across the diuretic subgroups. Diuretic dose did not change in most patients during follow-up, and mean diuretic dose did not differ between the dapagliflozin and placebo groups after randomization.
CONCLUSIONS:The efficacy and safety of dapagliflozin were consistent across the diuretic subgroups examined in DAPA-HF.
REGISTRATION:URLhttps://www.clinicaltrials.gov; Unique identifierNCT03036124.
Background:There are concerns that Asian patients respond differently to some medications. This study evaluated the efficacy and safety of evolocumab among Asian vs. other subjects in the FOURIER ...trial, which randomized stable atherosclerosis patients to receive either evolocumab or placebo.Methods and Results:Effects of adding evolocumab vs. placebo to background statin therapy on low-density lipoprotein cholesterol (LDL-C) reductions, cardiovascular outcomes, and adverse events were compared among 27,564 participants with atherosclerotic disease, according to self-reported Asian (n=2,723) vs. other (n=24,841) races followed for a median of 2.2 years in the FOURIER trial. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. At randomization, Asians had slightly lower LDL-C (median 89 IQR 78–104 mg/dL vs. 92 80–109 mg/dL; P<0.001) and were much less likely to be on a high-intensity statin (33.3% vs. 73.3%; P<0.001). Evolocumab lowered LDL-C more in Asians than in others (66% vs. 58%; P<0.001). The effect of evolocumab on the primary endpoint was similar in Asians (HR, 0.79; 95% CI, 0.61–1.03) and others (HR, 0.86; 95% CI, 0.79–0.93; P interaction=0.55). There was no excess of serious adverse events with evolocumab among Asians over others.Conclusions:Use of evolocumab robustly lowers LDL-C and is equally efficacious in lowering the risk of cardiovascular events and safe in Asians as it is in others.
India has one of the largest population of heart failure (HF) patients in the world; yet only limited information is available about HF in India.
This observational study was performed at Medanta- ...The Medicity, a large, tertiary-care institute in the National Capital Region of India. Records of HF patients with reduced left ventricular ejection fraction (LVEF) registered at Medanta HF clinic during the period early 2014 to mid-2017 were reviewed. Disease characteristics and one-year mortality details were collected.
Mean age of the subjects (n = 5590) was 59.1 ± 11.8 years with 83.0% males. Mean LVEF was 30.0 ± 6.6%. Coronary artery disease (CAD) was the dominant cause of HF, accounting for 77.8% of the total population. Most patients received guideline-directed medical therapy with a beta blocker being prescribed to 81.8% subjects. The one-year all-cause mortality was 17.6%. On multivariate analysis, age, usage of loop diuretics and ivabradine, and serum creatinine were independently associated with one-year mortality, whereas rheumatic etiology had an inverse association.
This represents the largest single-center data of HF patients reported so far and the largest study describing clinical outcomes from HF patients in India. Our patients were younger, had high proportion of CAD, and there was higher usage of beta-blockers. Despite this, the one-year mortality was substantial. Given the enormous magnitude of HF burden in India and the paucity of information on this subject, these findings should be of help in identifying key problem areas and potential solutions for management of HF in India.
Importance
Coronavirus disease (COVID‐19) causes an immunosuppressed state and increases risk of secondary infections like mucormycosis. We evaluated clinical features, predisposing factors, ...diagnosis and outcomes for mucormycosis among patients with COVID‐19 infection.
Methods
This prospective, observational, multi‐centre study included 47 consecutive patients with mucormycosis, diagnosed during their course of COVID‐19 illness, between January 3 and March 27, 2021. Data regarding demography, underlying medical conditions, COVID‐19 illness and treatment were collected. Clinical presentations of mucormycosis, imaging and biochemical characteristics and outcome were recorded.
Results
Of the 2567 COVID‐19 patients admitted to 3 tertiary centres, 47 (1.8%) were diagnosed with mucormycosis. Mean age was 55 ± 12.8years, and majority suffered from diabetes mellitus (n = 36, 76.6%). Most were not COVID‐19 vaccinated (n = 31, 66.0%) and majority (n = 43, 91.5%) had developed moderate‐to‐severe pneumonia, while 20 (42.6%) required invasive ventilation. All patients had received corticosteroids and broad‐spectrum antibiotics while most (n = 37, 78.7%) received at least one anti‐viral medication. Mean time elapsed from COVID‐19 diagnosis to mucormycosis was 12.1 ± 4.6days. Eleven (23.4%) subjects succumbed to their disease, mostly (n = 8, 72.7%) within 7 days of diagnosis. Among the patients who died, 10 (90.9%) had pre‐existing diabetes mellitus, only 2 (18.2%) had received just one vaccine dose and all developed moderate‐to‐severe pneumonia, requiring oxygen supplementation and mechanical ventilation.
Conclusions
Mucormycosis can occur among COVID‐19 patients, especially with poor glycaemic control, widespread and injudicious use of corticosteroids and broad‐spectrum antibiotics, and invasive ventilation. Owing to the high mortality, high index of suspicion is required to ensure timely diagnosis and appropriate treatment in high‐risk populations.
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in ...clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas.
Women and men with heart failure (HF) and preserved ejection fraction may differ in their clinical characteristics and their response to therapy. The aim of this study was to evaluate the influence ...of sex on the effects of empagliflozin in patients with HF and preserved ejection fraction enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction).
The effects of empagliflozin on the primary outcome of cardiovascular death or hospitalization for HF and on secondary outcomes (including total HF hospitalization, cardiovascular and all-cause mortality, and Kansas City Cardiomyopathy Questionnaire scores) were compared in women and men in the overall cohort and in subgroups defined by left ventricular ejection fraction (41%-49%, 50%-59%, and ≥60%). The effects of empagliflozin on physiological measures, including changes in systolic blood pressure, uric acid, hemoglobin, body weight, and natriuretic peptide levels, were also assessed.
Of the 5988 patients randomized, 2676 (44.7%) were women. In the placebo arm, women tended to have lower risk for adverse outcomes, including a lower risk of all-cause mortality (hazard ratio, 0.69 95% CI, 0.56, 0.84). Compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF to a similar degree in both sexes (hazard ratio, 0.81 95% CI, 0.69, 0.96 for men; and hazard ratio, 0.75 95% CI, 0.61, 0.92 for women;
=0.54). Sex did not modify the relationship between empagliflozin and outcomes across ejection fraction groups. Similar results were seen for secondary outcomes and physiological measures. Compared with placebo, empagliflozin improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score to a similar extent in both sexes (1.38 for men versus 1.63 for women at 52 weeks;
=0.77); the results were similar for Kansas City Cardiomyopathy Questionnaire overall summary score and total summary score.
Empagliflozin produced similar benefits on outcomes and health status in women and men with HF and preserved ejection fraction.
URL: https://www.
gov; Unique identifier: NCT03057951.
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