Renin–Angiotensin–Aldosterone System inhibitors in patients with Covid-19

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Prevention of heart failure events with sodium-glucose co-transporter 2 inhibitors across a spectrum of cardio-renal-metabolic risk

Aims Trials have tested the safety and efficacy of sodium-glucose co-transporter 2 inhibitors (SGLT2i) across various disease states. We performed a meta-analysis of randomized controlled trials (RCTs) to estimate the relative and absolute effects of SGLT2i in the prevention of heart failure (HF) events across different risk groups. Methods and results We conducted a systematic review and meta-analysis of large, placebo-controlled RCTs with >1000 participants evaluating HF hospitalization and the composite of cardiovascular (CV) death or HF hospitalization. Due to varying durations of therapeutic exposure and follow-up, absolute risk reductions and number needed to treat were calculated based on incidence rates (per 100 patient-years). Across 71 553 patients enrolled in 10 late-phase RCTs, SGLT2i reduced the risk of HF hospitalization by 31% [hazard ratio (HR) 0.69, 95% confidence interval (CI) 0.64-0.74; I-2 = 0%] and the composite outcome of CV death or HF hospitalization by 24% (HR 0.76, 95% CI 0.72-0.80; I-2 = 1.4%) compared with placebo. The number of patient-years of treatment exposure needed to prevent one CV death or HF hospitalization ranged from 19-26 (established HF) to 72-125 (chronic kidney disease) to 96-400 (high-risk type 2 diabetes). In mixed-effects meta-regression analyses, the benefits of SGLT2i on HF hospitalizations or the composite outcome (CV death or HF hospitalization) were not influenced by age, sex, or change in intermediate markers (glycated haemoglobin, systolic blood pressure, and body weight) (all P >= 0.10). Conclusion Despite wide variation in baseline risks and disease states evaluated, SGLT2i demonstrated comparable relative risk reductions in preventing HF events. Patients at highest baseline risk derived the greatest absolute benefits in preventing HF events. These composite estimates may help guide targeted implementation of SGLT2i for the prevention of HF events in type 2 diabetes and chronic kidney disease and in the treatment of HF

Perioperative statin therapy reduces mortality in normolipidemic patients undergoing cardiac surgery

ObjectiveStatins might have pleiotropic effects, independent of their ability to reduce lipid levels. Recent data have suggested that statins improve early survival and cardiovascular outcomes after coronary artery bypass graft surgery. The effectiveness of statin therapy in normolipidemic cardiac surgery patients is as yet unclear.MethodsWe evaluated 3056 consecutive patients who had undergone cardiac surgery between April 2004 and April 2009. Perioperative statin therapy was defined as continued treatment both before (≥ 6 months) and after the index surgery (included as a discharge medication). Hyperlipidemia (HL) was defined as a total cholesterol level greater than 200 mg/dL within 6 months before surgery. Four groups were analyzed: (1) statin-untreated normolipidemic (NL−, n = 1052); (2) statin-treated normolipidemic (NL+, n = 206); (3) statin-untreated hyperlipidemic (HL−, n = 638); and (4) statin-treated hyperlipidemic (HL+, n = 1160) patients. Adjusted hazard ratios accounted for the known preoperative cardiac risk factors. Mortality was ascertained by retrospective database review and the Social Security Death Index.ResultsThe mean follow-up was 2.2 years. The crude rate of 30-day mortality was 3.0% (32/1052), 0% (0/206), 8.0% (51/638), and 0.7% (8/1160) for the NL−, NL+, HL−, and HL+ groups, respectively. The overall all-cause crude mortality rate was 9.6% (101/1052), 3.9% (8/206), 17.2% (110/638), and 6.5% (75/1160) for the NL−, NL+, HL−, and HL+ groups, respectively. Statin therapy for NL patients undergoing cardiac surgery independently reduced the overall all-cause mortality (adjusted hazard ratio, 0.34; 95% confidence interval, 0.16–0.71; P = .004).ConclusionsPerioperative statin therapy was associated with reduced mid-term mortality for patients undergoing cardiac surgery, irrespective of their baseline lipid status. This clinical evidence suggests that the beneficial effects of statins might extend beyond their lipid-lowering ability

Estimated Lifetime Benefit of Combined RAAS and SGLT2 Inhibitor Therapy in Patients with Albuminuric CKD without Diabetes

Background and objectives: Despite high rates of complications in patients with CKD without diabetes, the implementation of proven therapies in this group remains low. Expressing the clinical benefitofatherapyin terms of extra years free from the disease or death may facilitate implementation. We estimated lifetime survival free of kidney failure for patients with albuminuric CKD without diabetes treated with the combination therapy of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and sodium-glucose cotransporter-2 (SGLT2) inhibitors relative to patients not treated. Design, setting, participants, & measurements: We used trial-level estimates of the effect of treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ramipril/benazepril; n=690) and SGLT2 inhibitors (dapagliflozin; n=1398) compared with placebo to derive the effect of combination therapy versus no treatment. Using this effect, we estimated treatment effect of combination therapy to the active treatment group of patients with albuminuric CKD without diabetes participating in the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial (n=697) and projected eventfree and overall survival for those treated and not treated with combination therapy. We also performed our calculations anticipating lower adherence and less pronounced benefits than were observed in the clinical trials. The primary outcome was a composite of doubling of serum creatinine, kidney failure, or death. Results: The aggregate estimated hazard ratio comparing combination therapy with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and SGLT2 inhibitor versus no treatment for the primary end point was 0.35 (95% confidence interval, 0.30 to 0.41). For a 50-year-old patient until the age of 75 years, the estimated survival free from the primary composite end point was 17.0 (95% confidence interval, 12.4 to 19.6) years with the combination therapy and 9.6 years (95% confidence interval, 8.4 to 10.7) with no treatment with any of these agents, corresponding to a gain in eventfree survival of 7.4 (95% confidence interval, 6.4 to 8.7) years. When assuming lower adherence and less pronounced efficacy of combination therapy, the gain in eventfree survival ranged from 5.3 years (95% confidence interval, 4.4 to 6.1) to 5.8 years (95% confidence interval, 4.8 to 6.8). Conclusions: Treatment with the combination of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and SGLT2 inhibitor in patients with albuminuric CKD without diabetes is expected to substantially increase kidney failure–free survival. Clinical Trial registry name and registration number: Benazepril for Advanced Chronic Renal Insufficiency, NCT00270426, and a Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (Dapa-CKD), NCT03036150

The rise and fall of aspirin in the primary prevention of cardiovascular disease

Aspirin is one of the most frequently used drugs worldwide and is generally considered effective for the secondary prevention of cardiovascular disease. By contrast, the role of aspirin in primary prevention of cardiovascular disease is controversial. Early trials evaluating aspirin for primary prevention, done before the turn of the millennium, suggested reductions in myocardial infarction and stroke (although not mortality), and an increased risk of bleeding. In an effort to balance the risks and benefits of aspirin, international guidelines on primary prevention of cardiovascular disease have typically recommended aspirin only when a substantial 10-year risk of cardiovascular events exists. However, in 2018, three large randomised clinical trials of aspirin for the primary prevention of cardiovascular disease showed little or no benefit and have even suggested net harm. In this narrative Review, we reappraise the role of aspirin in primary prevention of cardiovascular disease, contextualising data from historical and contemporary trials

Contemporary economic burden in a real-world heart failure population with Commercial and Medicare supplemental plans

Background Limited real-world data exist on healthcare resource utilization (HCRU) and associated costs of patients with heart failure (HF) with reduced ejection fraction (HFrEF) and preserved EF (HFpEF), including urgent HF visits, which are assumed to be less burdensome than HF hospitalizations (hHFs) Hypothesis This study aimed to quantify the economic burden of HFrEF and HFpEF, via a retrospective, longitudinal cohort study, using IBM(R) linked claims/electronic health records (Commercial and Medicare Supplemental data only). Methods Adult patients, indexed on HF diagnosis (ICD-10-CM: I50.x) from July 2012 through June 2018, with 6-month minimum baseline period and varying follow-up, were classified as HFrEF (I50.2x) or HFpEF (I50.3x) according to last-observed EF-specific diagnosis. HCRU/costs were assessed during follow-up. Results About 109 721 HF patients (22% HFrEF, 31% HFpEF, 47% unclassified EF; median 18 months' follow-up) were identified. There were 3.2 all-cause outpatient visits per patient-month (HFrEF, 3.3; HFpEF, 3.6); 69% of patients required inpatient stays (HFrEF, 80%; HFpEF, 78%). Overall, 11% of patients experienced hHFs (HFrEF, 23%; HFpEF, 16%), 9% experienced urgent HF visits (HFrEF, 15%; HFpEF, 12%); 26% were hospitalized less than 30 days after first urgent HF visit versus 11% after first hHF. Mean monthly total direct healthcare cost per patient was $9290 (HFrEF,$11 053; HFpEF, $7482). Conclusions HF-related HCRU is substantial among contemporary real-world HF patients in US Commercial or Medicare supplemental health plans. Patients managed in urgent HF settings were over twice as likely to be hospitalized within 30 days versus those initially hospitalized, suggesting urgent HF visits are important clinical events and quality improvement targets

A putative placebo analysis of the effects of sacubitril/valsartan in heart failure across the full range of ejection fraction

Abstract Aims The PARADIGM-HF and PARAGON-HF trials tested sacubitril/valsartan against active controls given renin–angiotensin system inhibitors (RASi) are ethically mandated in heart failure (HF) with reduced ejection fraction and are used in the vast majority of patients with HF with preserved ejection fraction. To estimate the effects of sacubitril/valsartan had it been tested against a placebo control, we made indirect comparisons of the effects of sacubitril/valsartan with putative placebos in HF across the full range of left ventricular ejection fraction (LVEF). Methods and results We analysed patient-level data from the PARADIGM-HF and PARAGON-HF trials (n = 13 194) and the CHARM-Alternative and CHARM-Preserved trials (n = 5050, candesartan vs. placebo). The rate ratio (RR) of sacubitril/valsartan vs. putative placebo was estimated by the product of the RR for sacubitril/valsartan vs. RASi and the RR for RASi vs. placebo. Total HF hospitalizations and cardiovascular death were analysed using the negative binomial method. Treatment effects were estimated using cubic spline methods by ejection fraction as a continuous measure. Across the range of LVEF, sacubitril/valsartan was associated with a RR 0.54 [95% confidence interval (CI) 0.45–0.65] for the recurrent primary endpoint compared with putative placebo (P < 0.001). Treatment benefits of sacubitril/valsartan vs. putative placebo varied non-linearly with LVEF with attenuation of effects observed at LVEF above 60%. When analyzing data from PARADIGM-HF and CHARM-Alternative, the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 48% (95% CI 35–58%); P < 0.001. When analyzing data from PARAGON-HF and CHARM-Preserved (with LVEF ≥ 45%), the estimated risk reduction of sacubitril/valsartan vs. putative placebo was 29% (95% CI 7–46%); P = 0.013. Across the full range of LVEF, consistent effects were observed for time-to-first endpoints: first primary endpoint (RR 0.72, 95% CI 0.64–0.82), first HF hospitalization (RR 0.67, 95% CI 0.58–0.78), cardiovascular death (RR 0.76, 95% CI 0.64–0.89), and all-cause death (RR 0.83, 95% CI 0.71–0.96); all P < 0.02. Conclusion This putative placebo analysis reinforces the treatment benefits of sacubitril/valsartan on risk of adverse cardiovascular events across the full range of LVEF, with most pronounced effects observed at a LVEF up to 60%