Neuromodulation interventions in the management of heart failure.

Despite remarkable improvements in the management of heart failure (HF), HF remains one of the most rapidly growing cardiovascular condition resulting in a substantial burden on healthcare systems worldwide. In clinical practice, however, a relevant proportion of patients are treated with suboptimal combinations and doses lower than those recommended in the current guidelines. Against this background, it remains important to identify new targets and investigate additional therapeutic options to alleviate symptoms and potentially improve prognosis in HF. Therefore, non-pharmacological interventions targeting autonomic imbalance in HF have been evaluated. This paper aims to review the physiology, available clinical data, and potential therapeutic role of device-based neuromodulation in HF.

[Therapy of heart failure with reduced pump function]. / Therapie der Herzinsuffizienz mit reduzierter Pumpfunktion.

HFrEF causes significant morbidity and mortality and represents a major public health burden. Recently, there have been significant scientific advances in the treatment of HFrEF, with ARNI, BB, MRA, and SGLT-2i forming the GDMT for HFrEF. Basic quadruple therapy has been shown to significantly reduce of HF hospitalizations, all-cause mortality, and cardiovascular mortality. In addition, new initiation and titration procedures have recently been introduced that may progressively improve the management and prognosis of HFrEF. Further efforts are also needed to improve the use of GDMT, which is currently underutilized.

Chronic renal failure as predictive factor for acute elevation of systolic blood pressure after fluorescein angiography in patients with retinal diseases.

Purpose: To investigate the influence of fluorescein angiography (FA) on blood pressure (BP) in patients with retinal diseases, and analyze the predictive factors for acute elevation of systolic BP after FA. Design: and Methods: A prospective study was conducted with 636 patients undergoing FA between April 2021 and October 2021. BP and pulse were measured in each patient before and 20 min after FA. The baseline characteristics of patients who developed an acute elevation in systolic BP (>10 mmHg) were compared with those of the remaining patients to detect factors that may predict this acute elevation. Results: Overall, mean systolic BP changed from 142 ± 17 mmHg to 140 ± 20 mmHg after 20 min (p = 0.1). Mean diastolic BP changed from 79 ± 15 mmHg to 78 ± 13 mmHg after 20 min (p = 0.45). Mean pulse rate changed from 73 ± 14 bpm to 70 ± 12 bpm after 20 min (p = 0.001). 103 patients (16 %) had acute elevation of systolic BP (>10 mmHg). Mean systolic BP changed from 143 ± 17 mmHg to 162 ± 19 mmHg after 20 min in this group (p = 0.001). Patients in this group were significantly older compared to the rest (73 ± 12 vs 67 ± 15, p = 0.001). The rate of chronic renal failure was significantly higher in this group compared to the rest of the patients (42/7.8 % vs 15/14.6 %, p = 0.01). Conclusions: This study demonstrated that fluorescein angiography is a relatively safe procedure with regards to blood pressure changes. However, chronic renal failure could be considered as predictive factor for acute elevation of systolic blood pressure after this procedure.

Impact of the COVID-19 pandemic on implementation of novel guideline-directed medical therapies for heart failure in Germany: a nationwide retrospective analysis.

Background: Guideline-directed medical therapy (GDMT) is the cornerstone in the treatment of patients with heart failure and reduced ejection fraction (HFrEF) and novel substances such as sacubitril/valsartan (S/V) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) have demonstrated marked clinical benefits. We investigated their implementation into real-world HF care in Germany before, during, and after the COVID-19 pandemic period. Methods: The IQVIA LRx data set is based on ∼80% of 73 million people covered by the German statutory health insurance. Prescriptions of S/V were used as a proxy for HFrEF. Time trends were analysed between Q1/2016 and Q2/2023 for prescriptions for S/V alone and in combination therapy with SGLT2i. Findings: The number of patients treated with S/V increased from 5260 in Q1/2016 to 351,262 in Q2/2023. The share of patients with combination therapy grew from 0.6% (29 of 5260) to 14.2% (31,128 of 219,762) in Q2/2021, and then showed a steep surge up to 54.8% (192,429 of 351,262) in Q2/2023, coinciding with the release of the European Society of Cardiology (ESC) guidelines for HF in Q3/2021. Women and patients aged >80 years were treated less often with combined therapy than men and younger patients. With the start of the COVID-19 pandemic, the number of patients with new S/V prescriptions dropped by 17.5% within one quarter, i.e., from 26,855 in Q1/2020 to 22,145 in Q2/2020, and returned to pre-pandemic levels only in Q1/2021. Interpretation: The COVID-19 pandemic was associated with a 12-month deceleration of S/V uptake in Germany. Following the release of the ESC HF guidelines, the combined prescription of S/V and SGLT2i was readily adopted. Further efforts are needed to fully implement GDMT and strengthen the resilience of healthcare systems during public health crises. Funding: Supported by Novartis Pharma GmbH, Nuremberg, Germany.

Outcomes of left bundle branch area pacing compared to His bundle pacing as a primary pacing strategy: Systematic review and meta-analysis.

BACKGROUND: Novel pacing technologies, such as His bundle pacing (HBP) and left bundle branch area pacing (LBBaP), have emerged to maintain physiological ventricular activation. We investigated the outcomes of LBBP with HBP for patients requiring a de novo permanent pacing. METHODS AND RESULTS: Systematic review of randomized clinical trials and observational studies comparing LBBaP with HBP until March 01, 2023 was performed. Random and fixed effects meta-analyses of the effect of pacing technology on outcomes were performed. Study outcomes included pacing metrics, QRS duration, lead revision, procedure parameters, all-cause mortality and heart failure hospitalization (HFH). Overall, 10 studies with 1596 patients were included. Implant success rate was higher in LBBaP compared with HBP (RR 1.24, 95% CI: 1.08 to 1.42, p = .002). LBBaP was associated with lower capture threshold at implantation (mean difference (MD) -0.62 V, 95% CI: -0.74 to -0.51 V, p < .0001) and at follow-up (MD -0.74 V, 95% CI: -0.96 to -0.53, p < .0001), shorter procedure duration (MD -14.66 min, 95% CI: -23.54 to -5.78, p = .001) and shorter fluoroscopy time (MD -4.2 min, 95% CI: -8.4 to -0.0, p = .05). Compared with HBP, LBBaP was associated with a decreased risk of all-cause mortality (RR: 0.50, 95% CI: 0.33 to 0.77, p = .002) and HFH (RR: 0.57, 95% CI: 0.33 to 1.00, p = .05). No statistical differences were found in lead revisions and QRS duration before and after pacing. CONCLUSION: This meta-analysis found that LBBaP was superior to HBP regarding pacing metrics and implant success rate as an initial pacing strategy, although absence of head-to-head randomized comparison warrants caution in interpretation of the results.

Associations between baseline heart rate and blood pressure and time to events in heart failure with reduced ejection fraction patients: Data from the QUALIFY international registry.

AIMS: A high resting heart rate (RHR) and low systolic blood pressure (SBP) are a risk factor and a risk indicator, respectively, for poor heart failure (HF) outcomes. This analysis evaluated the associations between baseline RHR and SBP with outcomes and treatment patterns in patients with HF and reduced ejection fraction (HFrEF) in the QUALIFY (QUality of Adherence to guideline recommendations for LIFe-saving treatment in heart failure surveY) international registry. METHODS AND RESULTS: Between September 2013 and December 2014, 7317 HFrEF patients with a previous HF hospitalization within 1-15 months were enrolled in the QUALIFY registry. Complete follow-up data were available for 5138 patients. The relationships between RHR and SBP and outcomes were assessed using a Cox proportional hazards model and were analysed according to baseline values as high RHR (H-RHR) ≥75 bpm versus low RHR (L-RHR) <75 bpm and high SBP (H-SBP) ≥110 mmHg versus low SBP (L-SBP) <110 mmHg and analysed according to each of the following four phenotypes: H-RHR/L-SBP, L-RHR/L-SBP, H-RHR/H-SBP and L-RHR/H-SBP (reference group). Compared to the reference group, H-RHR/L-SBP was associated with the worst outcomes for the combined primary endpoint of cardiovascular death and HF hospitalization (hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.51-2.21, p < 0.001), cardiovascular death (HR 2.70, 95% CI 1.69-4.33, p < 0.001), and HF hospitalization (HR 1.62, 95% CI 1.30-2.01, p < 0.001). Low-risk patients with L-RHR/H-SBP achieved more frequently ≥50% of target doses of angiotensin-converting enzyme inhibitors (ACEIs) and beta-blockers (BBs) than the other groups. However, 48% and 46% of low-risk patients were not well treated with ACEIs and BBs, respectively (≤50% of target dose or no treatment). CONCLUSION: In patients with HFrEF and recent hospitalization, elevated RHR and lower SBP identify patients at increased risk for cardiovascular endpoints. While SBP and RHR are often recognized as barriers that deter physicians from treating with high doses of recommended drugs, they are not the only reason leaving many patients suboptimally treated.

The burden of ischemic heart disease and the epidemiologic transition in the Eastern Mediterranean Region: 1990-2019.

It has been estimated that in the next decade, IHD prevalence, DALYs and deaths will increase more significantly in EMR than in any other region of the world. This study aims to provide a comprehensive description of the trends in the burden of ischemic heart disease (IHD) across the countries of the Eastern Mediterranean Region (EMR) from 1990 to 2019. Data on IHD prevalence, disability-adjusted life years (DALYs), mortality, DALYs attributable to risk factors, healthcare access and quality index (HAQ), and universal health coverage (UHC) were extracted from the Global Burden of Disease (GBD) database for EMR countries. The data were stratified based on the social demographic index (SDI). Information on cardiac rehabilitation was obtained from publications by the International Council of Cardiovascular Prevention and Rehabilitation (ICCPR), and additional country-specific data were obtained through advanced search methods. Age standardization was performed using the direct method, applying the estimated age structure of the global population from 2019. Uncertainty intervals were calculated through 1000 iterations, and the 2.5th and 97.5th percentiles were derived from these calculations. The age-standardized prevalence of IHD in the EMR increased from 5.0% to 5.5% between 1990 and 2019, while it decreased at the global level. In the EMR, the age-standardized rates of IHD mortality and DALYs decreased by 11.4% and 15.4%, respectively, during the study period, although both rates remained higher than the global rates. The burden of IHD was found to be higher in males compared to females. Bahrain exhibited the highest decrease in age-standardized prevalence (-3.7%), mortality (-65.0%), and DALYs (-69.1%) rates among the EMR countries. Conversely, Oman experienced the highest increase in prevalence (14.5%), while Pakistan had the greatest increase in mortality (30.0%) and DALYs (32.0%) rates. The top three risk factors contributing to IHD DALYs in the EMR in 2019 were high systolic blood pressure, high low-density lipoprotein cholesterol, and particulate matter pollution. The trend analysis over the 29-year period (1990-2019) revealed that high fasting plasma glucose (64.0%) and high body mass index (23.4%) exhibited increasing trends as attributed risk factors for IHD DALYs in the EMR. Our findings indicate an increasing trend in the prevalence of IHD and a decrease in mortality and DALYs in the EMR. These results emphasize the need for well-planned prevention and treatment strategies to address the risk factors associated with IHD. It is crucial for the countries in this region to prioritize the development and implementation of programs focused on health promotion, education, prevention, and medical care.

Trends in the burden and determinants of hypertensive heart disease in the Eastern Mediterranean region, 1990-2019: an analysis of the Global Burden of Disease Study 2019.

Background: Hypertensive heart disease (HHD), one of the end-organ damage consequences of hypertension, is an important public health issue worldwide. Data on the HHD burden in the Eastern Mediterranean region (EMR) are scarce. We aimed to investigate the burden of HHD in the EMR, its member countries, and globally from 1990 to 2019. Methods: We used 2019 Global Burden of Disease (GBD) data to report the HHD age-standardised prevalence, disability adjusted life years (DALYs), years of life lost (YLLs), and mortality, as well as HHD risk factors attribution percent with their 95% uncertainty interval (UI). Global data are reported alongside EMR data, and its 22 respective countries. We compared the burden of HHD by socio-demographic index (SDI), sex, age groups, and countries. Findings: The age-standardised prevalence rate (per 100,000 population) of HHD was higher in the EMR (281.7; 95% UI: 204.5-383.4) in 2019, compared with the global prevalence (233.8; 95% UI: 170.5-312.9). The EMR age-standardised DALYs (per 100,000 population) for HHD in 2019 was 561.9 (361.0-704.1), compared with 268.2 (204.6-298.1) at the global level. There was an increase in HHD prevalence, reduction in mortality, and DALYs between 1990 and 2019 (4.01%, -7.6%, and -6.5%, respectively) in EMR. Among EMR countries, the highest versus lowest rates of age-standardised prevalence, mortality, and DALYs in 2019 [estimate (95% UI)] were in Jordan [561.62 (417.9-747.6)] versus Saudi Arabia [94.9 (69.5-129.0)]; Afghanistan [74.5 (23.7-112.3)] versus Saudi Arabia [4.3 (3.3-5.9)]; and Afghanistan [1374.1 (467.2-2020.7)] versus Qatar [87.11 (64.40-114.29)], respectively. Interpretation: HHD remains a significant problem in the EMR, with a higher burden than global levels. Serious efforts toward high-quality management and prevention are strongly recommended. Based on this study, our recommendation for the EMR is to adopt effective preventive strategies. For example, promoting healthy dietary patterns and prompt screening for undiagnosed HTN in public places, promoting regular blood pressure measurements at home, and creating community awareness about early detection of HTN. Funding: None.

Efficacy of ivabradine in heart failure patients with a high-risk profile (analysis from the SHIFT trial).

AIMS: Early start and patient profile-oriented heart failure (HF) management has been recommended. In this post hoc analysis from the SHIFT trial, we analysed the treatment effects of ivabradine in HF patients with systolic blood pressure (SBP) < 110 mmHg, resting heart rate (RHR) ≥ 75 b.p.m., left ventricular ejection fraction (LVEF) ≤ 25%, New York Heart Association (NYHA) Class III/IV, and their combination. METHODS AND RESULTS: The SHIFT trial enrolled 6505 patients (LVEF ≤ 35% and RHR ≥ 70 b.p.m.), randomized to ivabradine or placebo on the background of guideline-defined standard care. Compared with placebo, ivabradine was associated with a similar relative risk reduction of the primary endpoint (cardiovascular death or HF hospitalization) in patients with SBP < 110 and ≥110 mmHg [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.74-1.08 vs. HR 0.80, 95% CI 0.72-0.89, P interaction = 0.34], LVEF ≤ 25% and >25% (HR 0.85, 95% CI 0.72-1.01 vs. HR 0.80, 95% CI 0.71-0.90, P interaction = 0.53), and NYHA III-IV and II (HR 0.83, 95% CI 0.74-0.94 vs. HR 0.81, 95% CI 0.69-0.94, P interaction = 0.79). The effect was more pronounced in patients with RHR ≥ 75 compared with <75 (HR 0.76, 95% CI 0.68-0.85 vs. HR 0.97, 95% CI 0.81-0.1.16, P interaction = 0.02). When combining these profiling parameters, treatment with ivabradine was also associated with risk reductions comparable with patients with low-risk profiles for the primary endpoint (relative risk reduction 29%), cardiovascular death (11%), HF death (49%), and HF hospitalization (38%; all P values for interaction: 0.40). No safety concerns were observed between study groups. CONCLUSIONS: Our analysis shows that RHR reduction with ivabradine is effective and improves clinical outcomes in HF patients across various risk indicators such as low SBP, high RHR, low LVEF, and high NYHA class to a similar extent and without safety concern.

Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction.

AIMS: In the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with HF and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of HR reduction and the significant treatment effect on outcomes among patients with HFrEF. METHODS AND RESULTS: The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days. CONCLUSION: Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta-blockers at maximally tolerated doses.

Efficacy and safety of intravenous iron repletion in patients with heart failure: a systematic review and meta-analysis.

INTRODUCTION: AFFIRM-AHF and IRONMAN demonstrated lower rates of the combined endpoint recurrent heart failure (HF) hospitalizations and cardiovascular death (CVD) using intravenous (IV) ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), respectively in patients with HF and iron deficiency (ID) utilizing prespecified COVID-19 analyses. MATERIAL AND METHODS: We meta-analyzed efficacy, between trial heterogeneity and data robustness for the primary endpoint and CVD in AFFIRM-AHF and IRONMAN. As sensitivity analysis, we analyzed data from all eligible exploratory trials investigating FCM/FDI in HF. RESULTS: FCM/FDI reduced the primary endpoint (RR = 0.81, 95% CI 0.69-0.95, p = 0.01, I2 = 0%), with the number needed to treat (NNT) being 7. Power was 73% and findings were robust with fragility index (FI) of 94 and fragility quotient (FQ) of 0.041. Effects of FCM/FDI were neutral concerning CVD (OR = 0.88, 95% CI 0.71-1.09, p = 0.24, I2 = 0%). Power was 21% while findings were fragile with reverse FI of 14 and reversed FQ of 0.006. The sensitivity analysis from all eligible trials (n = 3258) confirmed positive effects of FCM/FDI on the primary endpoint (RR = 0.77, 95% CI 0.66-0.90, p = 0.0008, I2 = 0%), with NNT being 6. Power was 91% while findings were robust (FI of 147 and FQ of 0.045). Effect on CVD was neutral (RR = 0.87, 95% CI 0.71-1.07, p = 0.18, I2 = 0%). Power was 10% while findings were fragile (reverse FI of 7 and reverse FQ of 0.002). Rate of infections (OR = 0.85, 95% CI 0.71-1.02, p = 0.09, I2 = 0%), vascular disorder (OR = 0.84, 95% CI 0.57-1.25, p = 0.34, I2 = 0%) and general or injection-site related disorders (OR = 1.39, 95% CI 0.88-1.29, p = 0.16, I2 = 30%) were comparable between groups. There was no relevant heterogeneity (I2 > 50%) between the trials for any of the analyzed outcomes. CONCLUSIONS: Use of FCM/FDI is safe and reduces the composite of recurrent HF hospitalizations and CVD, while effects on CVD alone are based on available level of data indeterminate. Findings concerning composite outcomes exhibit a high level of robustness without heterogeneity between trials with FCM and FDI.

A practical approach to the guideline-directed pharmacological treatment of heart failure with reduced ejection fraction.

Over the last 15-20 years, remarkable developments of heart failure (HF) pharmacotherapies have been achieved. However, HF remains a global healthcare challenge with more than 64 million patients worldwide. Optimization of guideline-directed chronic HF medical therapy is highly recommended with every patient visit to improve outcomes in patients with HF with reduced ejection fraction. However, the majority of patients in real-world settings are treated with doses that are lower than those with proven efficacy in clinical trials, which might be due to concerns of adverse effects and inertia of physicians. Likewise, a significant proportion of patients still do not receive all drug classes that could improve their prognosis. The recent European Society of Cardiology guidelines do not provide detailed recommendations on how these drug classes should be implemented in the treatment of inpatients to allow for both safety and a high likelihood of efficacy. We therefore propose a practical approach algorithm to support physicians to treat HF patients in their daily practice.

Application of recommended therapies among patients with heart failure during the Syrian conflict: reality and barriers.

AIMS: Lower socio-economic status may delay and even prevent the application of guideline-directed heart failure (HF) therapy for most patients. This study aims to evaluate the feasibility and possible difficulties facing the application of this treatment during the current Syrian conflict. METHODS AND RESULTS: A questionnaire on HF management and feasibility of recommended HF therapy was addressed to physicians practising cardiology in Syria. The questionnaire consisted of 30 questions and focused on the quality of HF management and awareness of recommended drug and device therapy for HF among physicians practising cardiology in Syria. A total of 228 physicians participated in the survey. Awareness of recommended medical and device therapy of HF was very high among participants (98% and 95%, respectively). The majority of participants (>75%) believe that more than half of HF patients do not receive optimal medical HF therapy. Ninety per cent of participants believe that <10% of patients with an appropriate indication for device therapy receive it. More than 75% of participants believe that the cost of medications, alone or in combination with other medical causes, represents the major problem facing the application of optimal HF medical therapy. More than 95% of participants reported that cost alone, or in combination with unavailability, is the primary reason why patients with appropriate indications are not offered device therapy. CONCLUSIONS: Despite the high level of awareness of recommended HF therapies among Syrian cardiologists, the majority of HF patients are still undertreated. Financial difficulties and lack of resources are the main causes of this problem.

Sacubitril/valsartan in heart failure: efficacy and safety in and outside clinical trials.

Heart failure (HF) treatment has changed substantially over the last 30 years, leading to significant reductions in mortality and hospital admissions in patients with HF with reduced ejection fraction (HFrEF). Currently, the optimization of guideline-directed chronic HF therapy remains the mainstay to further improve quality of life, mortality, and HF hospitalizations for patients with HFrEF. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (S/V) has an important role in the treatment of patients with HFrEF. The PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) randomized controlled trial has established solid evidence for the treatment of HFrEF in various subgroups. Apart from HFrEF, several studies have been conducted using S/V in various indications: patients hospitalized with acute decompensated HF, HF with preserved ejection fraction, acute myocardial infarction with reduced ejection fraction, uncontrolled and resistant hypertension, and chronic kidney disease. Data from the German Institute for Drug Use Evaluation reveal that implementation of S/V has increased steadily over time and, by the end of 2021, an estimated 266 000 patients were treated with S/V in Germany. The estimated cumulative real-world patient exposure is >5.5 million patient-treatment years worldwide. The number of patients treated with S/V largely exceeds the number of patients treated in clinical trials, and the current indication for S/V is larger than the strict inclusion/exclusion criteria of the randomized trials. Especially elderly patients, women, and patients with more and more severe comorbidities are underrepresented in the clinical trials. We therefore aimed to summarize the importance of S/V in HF in terms of efficacy and safety in clinical trials and daily clinical practice.

[A practical approach to guideline-directed pharmacological treatment for heart failure with reduced ejection fraction]. / Frühe Implementierung der "Fantastic four" bei Herzinsuffizienz mit reduzierter Ejektionsfraktion.

The 2021 guidelines of the European Society of Cardiology for the diagnosis and treatment of heart failure recommend the early implementation of all four mortality-lowering drug classes for heart failure with reduced ejection fraction (HFrEF), i. e. angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor II blocker-neprilysin inhibitor (ARNI), betablocker (BB), mineralocorticoid receptor-antagonists (MRA), and sodium-glucose linked transporter-2 inhibitors (SGLT2i). This article aims to give a practical compendium supporting physicians to enable safe and efficacious treatment for patients with HFrEF.

Side effects and treatment initiation barriers of sodium-glucose cotransporter 2 inhibitors in heart failure: a systematic review and meta-analysis.

AIMS: Physicians are sometimes reluctant to initiate guideline-directed therapy in patients with heart failure and reduced ejection fraction (HFrEF) due to concerns of adverse events. We explored the risk of hypotension, volume depletion, and acute kidney injury (AKI) on sodium-glucose cotransporter 2 (SGLT2) inhibitors in HFrEF populations. METHODS AND RESULTS: We determined summary risk ratios (RRs) by conducting a meta-analysis on reported aforementioned adverse events on SGLT2 inhibitors from randomized controlled trials. We explored robustness of meta-analyses by computing fragility and/or reverse fragility index (FI or RFI) and its corresponding fragility quotient (FQ or RFQ) for each outcome. A total of 10 050 patients with HFrEF entered the final meta-analysis. Hypotension was reported in 4.5% (219/4836) on SGLT2 inhibitors and in 4.1% (202/4846) on placebo (RR 1.09, 95% confidence interval [CI] 0.91-1.31, p = 0.36). An RFI of 21 and RFQ of 0.002 suggest robust findings for hypotension. Volume depletion occurred in 9.4% (473/5019) on SGLT2 inhibitors and in 8.7% (438/5031) on placebo (RR 1.07, 95% CI 0.95-1.21, p = 0.25), respectively. RFI of 19 and RFQ of 0.001 suggest moderately robust findings for volume depletion. AKI was reported in fewer patients (1.9% [95/4888]) on SGLT2 inhibitors than on placebo (2.8% [140/4899]) providing lower incidence of AKI (RR 0.69, 95% CI 0.51-0.93, p = 0.02). FI of 14 and RFQ of 0.001 suggest moderately robust findings for AKI. CONCLUSION: Sodium-glucose cotransporter 2 inhibitor therapy is not associated with a clinically relevant risk of hypotension and volume depletion. Its use reduces the risk of AKI. This analysis supports current guideline recommendations on early use of SGLT2 inhibitors.

Empagliflozin Improves Outcomes in Patients With Heart Failure and Preserved Ejection Fraction Irrespective of Age.

BACKGROUND: Empagliflozin reduces cardiovascular death (CVD) or heart failure (HF) hospitalization (HFH) in patients with HF and preserved ejection fraction. Treatment effects and safety in relation to age have not been studied. OBJECTIVES: The purpose of this study was to evaluate the interplay of age and empagliflozin effects in EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction). METHODS: We grouped patients (n = 5,988) according to their baseline age (<65 years [n = 1,199], 65-74 years [n = 2,214], 75-79 years [n = 1,276], ≥80 years [n = 1,299]). We explored the influence of age on empagliflozin effects on CVD or HFH (primary outcome), total HFH, rate of decline in estimated glomerular filtration rate, health-related quality of life with the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score, and frequency of adverse events. RESULTS: Considering only patients on placebo, the incidence of primary outcomes (P trend = 0.02) and CVD (P trend = 0.003) increased with age. Empagliflozin reduced primary outcomes (P trend = 0.33), first HFH (P trend = 0.22), and first and recurrent HFH (P trend = 0.11) across all age groups with an effect being similar at ≥75 years (P interaction = 0.22) or >80 years (P interaction = 0.51). Empagliflozin improved Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score at week 52 and attenuated the decline of estimated glomerular filtration rate without age interaction (P = 0.48 and P = 0.32, respectively). There were no clinically relevant differences in adverse events between empagliflozin and placebo across the age groups. CONCLUSIONS: Empagliflozin reduced primary outcomes and first and recurrent HFH and improved symptoms across a broad age spectrum. High age was not associated with reduced efficacy or meaningful intolerability. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction [EMPEROR-Preserved]; NCT0305951).