Desai, Nihar R.

Abstract Aims Heart failure (HF) continues to portend significant morbidity and mortality within the USA. Data regarding the efficacy of mineralocorticoid receptor antagonists (MRAs) in HF with preserved ejection fraction (HFpEF) remains unclear. Finerenone, a non-steroidal MRA, has demonstrated reduction in hospitalizations in this population. However, the comparative efficacy of different MRA classes in these patients remains elusive. Methods and results We conducted a retrospective observational cohort study using the TriNetX research network. We applied 1:1 propensity score matching (PSM) to compare patients with HFpEF initiated on finerenone vs. spironolactone. We examined 1-year risks of HF exacerbation, acute kidney injury (AKI), electrolyte derangements, and cardiovascular outcomes. We identified 254,417 patients with HFpEF and MRA use. After PSM, each cohort contained 491 patients. Analysis revealed that finerenone use was associated with a significantly lower risk of HF exacerbation (hazard ratio [HR] = 0.63 [95% confidence interval [CI]: 0.54, 0.74], P < 0.001), all-cause mortality (HR = 0.38 [95% CI: 0.23, 0.64], P < 0.001), and hypokalaemia (HR = 0.58 [95% CI: 0.40, 0.85], P = 0.001). The aforementioned results, along with a reduction in AKI risk, were statistically significant after stratified subgroup analysis by diabetes mellitus and chronic kidney disease. Conclusion In this large real-world HFpEF cohort, finerenone use was associated with lower risks of HF exacerbation and all-cause mortality compared with spironolactone. These observational findings are hypothesis-generating and warrant confirmation in randomized trials.

Abstract Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is a heterogeneous clinical syndrome associated with substantial morbidity and mortality. We developed a machine learning-based mortality model to identify features and patient subgroups associated with the largest change in mortality risk when evaluating treatment with Impella devices or intra-aortic Balloon Pump (IABP). Our cohort comprised 369 sites and 15,796 patient visits to the cardiac catheterization laboratory from the National Cardiovascular Data Registry. The estimated population mean excess mortality effect of treatment with Impella devices vs IABP was 10.4 ± 0.8%. However, we identified clinical subgroups of 282 patients for whom a decreased risk of mortality was associated with use of Impella as compared with IABP. Those patients were on average younger, presented with higher systolic blood pressure, higher rate of salvage percutaneous coronary intervention, higher initial creatinine, and lower hemoglobin. While Impella devices were associated with higher mortality risk overall, certain clinical profiles were associated with lower risk, illustrating heterogeneity of treatment effects.

Background: VICTORION-INITIATE (NCT04929249) showed significantly greater LDL-C lowering in patients (pts) with ASCVD with an inclisiran first (IF) strategy (adding inclisiran immediately on failure to achieve LDL-C <70 mg/dL on maximally tolerated statin therapy) vs usual care (UC). Tokenization can be leveraged to link clinical trial data to pt-level real-world data (RWD) to provide a comprehensive overview of the pt journey pre- and post-trial and enhance understanding of clinical trial and long-term pt outcomes. Aim: To utilize tokenization and linked RWD to characterize the pt journey pre-VICTORION-INITIATE enrollment. Methods: Eligible pts from VICTORION-INITIATE were deidentified and tokenized with unique IDs, allowing linking to RWD (EMR, claims, hospital, and lab records) to follow the pt journey in the 3-year pre-trial and 2-year post-trial periods. Here we present demographics, clinical characteristics, and lipid-lowering therapy (LLT) use of pts with linked pre-trial RWD. Results: Of 450 pts randomized, 383 (85.1%) were linked with pre-trial RWD (IF arm, n=193; UC arm, n=190); 26.9% were female, first available recorded mean (SD) age was 64 (9.36) years. Among the 74.2% (n=284) of pts with linked, pre-trial, lipid test RWD, mean (SD) earliest and latest LDL-C values were 100.1 mg/dL (35.70) and 99.3 mg/dL (30.06), respectively, for pts in the IF arm vs 97.3 mg/dL (40.43) and 97.8 mg/dL (27.60) for pts in the UC arm ( Table ). Overall, in the pre-trial period, LLT was dispensed/prescribed to 66.1% of pts, statins to 64.5%, ezetimibe to 4.4%, and PCSK9i to 4.4%. Of pts with ≥1 recorded ASCVD events in the pre-trial period (n=141), 53.2% and 68.8% had available LLT dispensing/prescription records pre- and post-event, respectively. Conclusions: In the 3 years pre-VICTORION-INITIATE, mean LDL-C levels were above recommended goals, non-statin LLT prescription was infrequent, and ~31% of pts with ≥1 recorded ASCVD event had no evidence of post-event LLT use, highlighting a need for more aggressive LDL-C management. Full data visibility for each pt is a limitation of this approach. Tokenization post-trial will allow for long-term evaluation of LLT practices.

Background: Etripamil nasal spray (NS) is a fast acting, self-administered calcium channel blocker in development for the termination of AV-nodal-dependent supraventricular tachycardia (SVT). Prior randomized, placebo-controlled and open-label studies have demonstrated favorable safety and efficacy of etripamil in converting paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm (SR) self-administered without direct medical supervision. Research Question/Hypothesis: To assess patterns and annualized PSVT episode frequency among patients opting to self-administer acute treatment with etripamil. Methods: NODE-303 was an event-driven, multi-center, open-label Phase 3 study, conducted in North and South America to evaluate the safety and efficacy of etripamil in patients with documented PSVT over multiple episodes. Test dosing was not performed prior to at-home use. Enrolled patients, upon perceiving symptoms of PSVT: applied an ambulatory ECG monitor, performed a previously trained vagal maneuver and, if symptoms persisted, self-administered etripamil NS 70 mg. During the study, the protocol was amended to allow a repeat dose (70 mg) if symptoms persisted 10 min after the first dose. Each patient could self-treat up to 4 episodes. Results: Of 1,116 enrolled patients, 503 (45.1%) treated ≥1 perceived PSVT episode (safety population). Etripamil achieved conversion to SR in 60% of patients by 30 minutes and 70% by 60 minutes. A total of 220, 118, 62, and 103 patients completed the study with 1, 2, 3, and 4 etripamil-treated perceived episodes of PSVT, respectively, with an average time on study of 440 days. Among these patients, the average number of annualized etripamil-treated PSVT episodes was 3.2 (standard deviation 3.8). Annualized use: etripamil was self-administered for 0-2 PSVT episodes per year, 2-6 episodes, 6-12 episodes, and >12 episodes, in 54%, 32%, 10%, and 4% of patients, respectively (Figure). Conclusions: This analysis aimed to assess the annualized use of etripamil NS in a real-world setting, by analyzing how often patients would self-administer the drug for PSVT episodes. Of patients that self-administered etripamil (n=503), the majority treated >1 episode and the annualized frequency of episodes treated with etripamil was 3.2 episodes/yr.

BACKGROUND: Following regulatory approval, medical devices may be used “off-label.” Patent foramen ovale (PFO) closure is indicated to reduce recurrent stroke but has been proposed for other indications, including migraine, transient ischemic attack, and diving decompression illness. We sought to evaluate PFO closure rates and indications relative to the timing of regulatory approval and publication of key randomized trials. METHODS: We performed a retrospective cohort study using the OptumLabs Data Warehouse of US commercial insurance enrollees from 2006 to 2019. We quantified PFO closure among individuals with ≥2 years of preprocedure coverage to establish indications, classified hierarchically as stroke/systemic embolism, migraine, transient ischemia attack, or other. RESULTS: We identified 5315 patients undergoing PFO closure (51.8% female, 29.2%≥60 years old), which increased from 4.75 per 100 000 person-years in 2006 to 6.60 per 100 000 person-years in 2019. Patients aged ≥60 years accounted for 29.2% of closures. Procedure volumes corresponded weakly with supportive clinical publications and device approval. Among patients with PFO closure, 58.6% underwent closure for stroke/systemic embolism, 10.2% for transient ischemia attack, 8.8% for migraine, and 22.4% for other indications; 17.6% of patients had atrial fibrillation at baseline; and 11.9% developed atrial fibrillation postprocedure. Those aged ≥60 years and male were less likely to undergo closure for migraine than stroke/systemic embolism. CONCLUSIONS: From 2006 to 2019, PFO closure use was consistently low and corresponded weakly with clinical trial publications and regulatory status. Nearly half of patients underwent PFO closure for indications unapproved by the Food and Drug Administration. Regulators and payers should coordinate mechanisms to promote utilization for approved indications to ensure patient safety and should facilitate clinical trials for other possible indications.

Observational medical data present unique opportunities for analysis of medical outcomes and treatment decision making. However, because these datasets do not contain the strict pairing of randomized control trials, matching techniques are to draw comparisons among patients. A key limitation to such techniques is verification that the variables used to model treatment decision making are also relevant in identifying the risk of major adverse events. This article explores a deep mixture of experts approach to jointly learn how to match patients and model the risk of major adverse events in patients. Although trained with information regarding treatment and outcomes, after training, the proposed model is decomposable into a network that clusters patients into phenotypes from information available before treatment. This model is validated on a dataset of patients with acute myocardial infarction complicated by cardiogenic shock. The mixture of experts approach can predict the outcome of mortality with an area under the receiver operating characteristic curve of 0.85 ± 0.01 while jointly discovering five potential phenotypes of interest. The technique and interpretation allow for identifying clinically relevant phenotypes that may be used both for outcomes modeling as well as potentially evaluating individualized treatment effects.

Various pharmacotherapies exist for heart failure with preserved ejection fraction (HFpEF), but with unclear comparative efficacy. We searched EMBASE, Medline, and Cochrane Library from inception through August 2021 for all randomized clinical trials in HFpEF (EF >40%) that evaluated beta-blockers, mineralocorticoid receptor antagonist (MRA), angiotensin-converting enzyme inhibitors (ACE), angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin inhibitor (ARNI), and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Outcomes assessed were cardiovascular mortality, all-cause mortality, and HF hospitalization. A frequentist network meta-analysis was performed with a random-effects model. We included 22 randomized clinical trials (30,673 participants; mean age = 71.7 ± 4.2 years; females = 49.3 ± 7.7%; median follow-up = 24.4 ± 11.1 months). Compared with placebo, there was no statistically significant difference in cardiovascular mortality [beta-blockers; odds ratio (OR) 0.79 (0.46–1.34), MRA; OR 0.90 (0.70–1.14), ACE OR 0.95 (0.59–1.53), ARB; OR 1.02 (0.87–1.19), ARNI; OR 0.97 (0.74–1.26) and SGLT2i; OR 1.00 (0.84–1.18)] or all-cause mortality [beta blockers; OR 0.75 (0.54–1.04), MRA; OR 0.90 (0.75–1.08) ACE; OR 1.05 (0.71–1.54), ARB; OR 1.03 (0.91–1.15), ARNI; OR 0.99 (0.82–1.20) and SGLT2i; OR 1.00 (0.89–1.13)]. The certainty in these estimates was low or very low. There was a significantly reduction in HF hospitalization with the use of SGLT2i [OR 0.71 (0.62–0.82), moderate certainty], ARNI [OR 0.77 (0.63–0.94), low certainty], and MRA [OR 0.81 (0.66–0.98), moderate certainty]; with corresponding P scores of 0.84, 0.68, and 0.58, respectively. In HFpEF, the use of beta-blockers, MRA, ACE/ARB/ARNI, or SGLT2i was not associated with improved cardiovascular or all-cause mortality. SGLT2i, ARNI, and MRA reduced the risk of HF hospitalizations.

Background: Physicians’ professional networks are an important source of new medical information and have been shown to influence the adoption of new treatments, but it is unknown how physician networks impact the de-adoption of harmful practices. Methods: We analyzed changes in physicians’ use of dronedarone after the PALLAS trial (Palbociclib Collaborative Adjuvant Study; November 2011) showed that dronedarone increased the risk of death from cardiovascular events among patients with permanent atrial fibrillation. Deidentified administrative claims from the OptumLabs Data Warehouse were combined with physicians’ demographic information from the Doximity database and publicly available data on physicians’ patient-sharing relationships compiled by the Centers for Medicare and Medicaid Services. We used a linear probability model with an interrupted linear time trend specification to model the impact of the PALLAS trial on physicians’ dronedarone usage between 2009 and 2014. Results: Before the PALLAS trial, the use of dronedarone was increasing by 0.22 percentage points per quarter (95% CI, 0.19–0.25) in our Medicare Advantage sample (N=343 429 patient-quarter observations) and 0.63 percentage points per quarter (95% CI, 0.52–0.75) in our commercially insured sample (N=44 402 patient-quarter observations). After the PALLAS trial and subsequent United States Food and Drug Administration black box warning, physicians in the Medicare Advantage sample with an above-median number of network connections to other physicians decreased their quarterly usage of dronedarone by 0.12 percentage points more per quarter (95% CI, −0.20 to −0.04; P =0.031) than physicians with equal to or below the median number of network connections. Similar patterns existed in the commercially insured sample ( P =0.0318). Conclusions: After controlling for a wide range of patient, physician, and geographic characteristics, physicians with a greater number of network connections were faster de-adopters of dronedarone for patients with permanent atrial fibrillation after the PALLAS trial and subsequent United States Food and Drug Administration black box warning detailed the harmfulness of dronedarone for these patients. Policies for improving physicians’ responsiveness to new medical information should consider utilizing the influence of these important professional network relationships.

Objective: To characterize changes in rates of hospitalization for digoxin toxicity and trends in the associated mortality and readmission among older adults over a 12-year period in the United States. Methods: We studied 33,952,331 Medicare fee-for-service beneficiaries 65 years or older with a hospital discharge diagnosis of digoxin toxicity in the United States from 1999 to 2011. Outcome measures were rates of hospitalization for digoxin toxicity; in-hospital mortality; 30-day mortality; and 30-day readmission. Results: There were 20,957 hospitalizations for a principal or secondary diagnosis of digoxin toxicity between 1999 and 2011. The rate declined significantly from 15.2 per 100,000 person-years (95% confidence interval [CI]: 14.7-15.7) in 1999 to 2.1 per 100,000 person-years (95% CI: 1.9-2.3) in 2011 (p<0.001), representing an adjusted annual decline of 17.0% (95% CI: 16.2-17.0) (Figure 1). Between 1999 and 2011, the observed in-hospital and 30-day mortality rates associated with hospitalization for digoxin toxicity declined significantly, from 6.0% (95% CI: 5.2-6.8) to 3.3% (95% CI: 2.0-5.1) (p<0.01) and 14.0% (95% CI: 13.0-15.2) to 10.6% (95% CI: 8.2-13.4) (p<0.05), respectively, representing an annual decline for in-hospital mortality of 5.0% (95% CI: 3.7-7.2) and for 30-day mortality of 4.0% (95% CI: 3.1-5.7). The overall observed 30-day readmission rate declined significantly from 23.5% (95% CI: 22.1-24.9) in 1999 to 18.9% (95% CI: 15.6-22.3) in 2011 (p<0.05), but there was no significant decline in the adjusted annual change in 30-day readmission (1.0%, 95% CI: 0.0-1.7). Conclusions: In a national sample of Medicare beneficiaries, the rate of hospitalization for digoxin toxicity and subsequent mortality declined significantly between 1999 and 2011.

Abstract Variation in de-adoption of ineffective or unsafe treatments is not well-understood. We examined de-adoption of erythropoiesis-stimulating agents (ESA) in anemia treatment among patients with chronic kidney diseases (CKD) following new clinical evidence of harm and ineffectiveness (the TREAT trial) and the FDA's revision of its safety warning. We used an interrupted time series approach to estimate changes in use of epoetin alfa (EPO) and darbepoetin alfa (DPO) in the commercial and Medicare Advantage (MA) and Medicare fee-for-service (FFS) populations. We also examined how changes in both trends and levels of use were associated with physicians’ characteristics. Study cohort included patients with CKD stages 3 to 5 during 2007-2015. Use of DPO and EPO declined over the study period. There were no consistent changes in DPO trend across insurance groups, but the level of DPO use decreased right after the FDA revision in all groups. The decline in EPO use trend was faster after the TREAT trial for all groups. Nephrologists were largely more responsive to evidence than primary care physicians. Differences by physician's gender, and age were not consistent across insurance populations and types of ESA.