Cardiology

Packer, M. and McMurray, J.J.V. (2021). “Rapid Evidence-Based Sequencing of Foundational Drugs for Heart Failure and a Reduced Ejection Fraction.” Eur J Heart Fail Mar 11. [Epub ahead of print].

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Foundational therapy for heart failure and a reduced ejection fraction consists of a combination of an angiotensin receptor neprilysin inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor. However, the conventional approach to the implementation is based on a historically-driven sequence that is not strongly evidence-based, typically requires ≥6 months, and frequently lead to major gaps in treatment. We propose a rapid sequencing strategy that is based on four principles. First, since drugs act rapidly to reduce morbidity and mortality, patients should be started on all four foundational treatments within 2-4 weeks. Second, since the efficacy of each foundational therapy is independent of treatment with the other drugs, priority can be determined by considerations of relative efficacy, safety and ease-of-use. Third, low starting doses of foundational drugs have substantial therapeutic benefits, and achievement of low doses of all four classes of drugs should take precedence over uptitration to target doses. Fourth, since drugs can influence the tolerability of other foundational agents, sequencing can be based on whether agents started earlier can enhance the safety of agents started simultaneously or later in the sequence. We propose an accelerated 3-step approach, which consists of the simultaneous initiation of a beta-blocker and an SGLT2 inhibitor, followed 1-2 weeks later by the initiation of sacubitril/valsartan, and 1-2 weeks later by a mineralocorticoid receptor antagonist. The latter two steps can be reordered or compressed depending on patient circumstances. Rapid sequencing is a novel evidence-based strategy that has the potential to dramatically improve the implementation of treatments that reduce the morbidity and mortality of patients with heart failure and a reduced ejection fraction.

Packer, M., Anker, S.D., Butler, J., Filippatos, G., Ferreira, J.P., Pocock, S.J., Sattar, N., Brueckmann, M., Jamal, W., Cotton, D., Iwata, T. and Zannad, F. (2021). “Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial.” J Am Coll Cardiol 77(11): 1381-1392.

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BACKGROUND: Investigators have hypothesized that sodium-glucose cotransporter 2 (SGLT2) inhibitors exert diuretic effects that contribute to their ability to reduce serious heart failure events, and this action is particularly important in patients with fluid retention. OBJECTIVES: This study sought to evaluate the effects of the SGLT2 inhibitor empagliflozin on symptoms, health status, and major heart failure outcomes in patients with and without recent volume overload. METHODS: This double-blind randomized trial compared the effects of empagliflozin and placebo in 3,730 patients with heart failure and a reduced ejection fraction, with or without diabetes. Approximately 40% of the patients had volume overload in the 4 weeks before study enrollment. RESULTS: Patients with recent volume overload were more likely to have been hospitalized for heart failure and to have received an intravenous diuretic agent in an outpatient setting in the previous 12 months, and to experience a heart failure event following randomization, even though they were more likely to be treated with high doses of a loop diuretic agent as an outpatient (all p < 0.001). When compared with placebo, empagliflozin reduced the composite risk of cardiovascular death or hospitalization for heart failure, decreased total hospitalizations for heart failure, and improved health status and functional class. Yet despite the predisposition of patients with recent volume overload to fluid retention, the magnitude of these benefits (even after 1 month of treatment) was not more marked in patients with recent volume overload (interaction p values > 0.05). Changes in body weight, hematocrit, and natriuretic peptides (each potentially indicative of a diuretic action of SGLT2 inhibitors) did not track each other closely in their time course or in individual patients. CONCLUSIONS: Taken together, study findings do not support a dominant role of diuresis in mediating the physiological changes or clinical benefits of SGLT2 inhibitors on the course of heart failure in patients with a reduced ejection fraction. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977).

Packer, M. (2021). “What causes exertional dyspnoea in patients with atrial fibrillation? Implications for catheter ablation in patients with heart failure.” Eur J Heart Fail Mar 26. [Epub ahead of print].

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Patients with atrial fibrillation (AF) often complain of exertional dyspnoea, and many physicians believe that the atrial tachyarrhythmia is the cause of the impairment in functional capacity. The assumption of a causal relationship has led electrophysiologists to propose that suppression of AF (either pharmacologically or by catheter ablation) can improve exercise tolerance and yield important clinical benefits, both with respect to quality of life and major outcomes. [No abstract; excerpt from article].

Nazif, T.M., Moses, J., Sharma, R., Dhoble, A., Rovin, J., Brown, D., Horwitz, P., Makkar, R., Stoler, R., Forrest, J., Messé, S., Dickerman, S., Brennan, J., Zivadinov, R., Dwyer, M.G. and Lansky, A.J. (2021). “Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Replacement: REFLECT II.” JACC Cardiovasc Interv 14(5): 515-527.

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OBJECTIVES: The REFLECT II (Randomized Evaluation of TriGuard 3 Cerebral Embolic Protection After Transcatheter Aortic Valve Implantation) trial was designed to investigate the safety and efficacy of the TriGUARD 3 (TG3) cerebral embolic protection in patients undergoing transcatheter aortic valve replacement. BACKGROUND: Cerebral embolization occurs frequently following transcatheter aortic valve replacement and procedure-related ischemic stroke occurs in 2% to 6% of patients at 30 days. Whether cerebral protection with TriGuard 3 is safe and effective in reducing procedure-related cerebral injury is not known. METHODS: This prospective, multicenter, single-blind, 2:1 randomized (TG3 vs. no TG3) study was designed to enroll up to 345 patients. The primary 30-day safety endpoint (Valve Academic Research Consortium-2 defined) was compared with a performance goal (PG). The primary hierarchical composite efficacy endpoint (including death or stroke at 30 days, National Institutes of Health Stroke Scale score worsening in hospital, and cerebral ischemic lesions on diffusion-weighted magnetic resonance imaging at 2 to 5 days) was compared using the Finkelstein-Schoenfeld method. RESULTS: REFLECT II enrolled 220 of the planned 345 patients (63.8%), including 41 roll-in and 179 randomized patients (121 TG3 and 58 control subjects) at 18 US sites. The sponsor closed the study early after the U.S. Food and Drug Administration recommended enrollment suspension for unblinded safety data review. The trial met its primary safety endpoint compared with the PG (15.9% vs. 34.4% (p < 0.0001). The primary hierarchal efficacy endpoint at 30 days was not met (mean scores [higher is better]: -8.58 TG3 vs. 8.08 control; p = 0.857). A post hoc diffusion-weighted magnetic resonance imaging analysis of per-patient total lesion volume above incremental thresholds showed numeric reductions in total lesion volume >500 mm(3) (-9.7%) and >1,000 mm(3) (-44.5%) in the TG3 group, which were more pronounced among patients with full TG3 coverage: -51.1% (>500 mm(3)) and -82.9% (>1,000 mm(3)). CONCLUSIONS: The REFLECT II trial demonstrated that the TG3 was safe compared with a historical PG but did not meet its pre-specified primary superiority efficacy endpoint.

McCullough, P.A., Rahimi, G. and Tecson, K.M. (2021). “Ambulatory Worsening of Renal Function in Heart Failure With Preserved Ejection Fraction.” J Am Coll Cardiol 77(9): 1222-1224.

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The emergence of new pharmacological therapies for heart failure (HF) patients, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and angiotensin receptor–neprilysin inhibitors, has improved the life expectancy of those living with this disease markedly. [No abstract; excerpt from article].