Research Spotlight

Packer, M. and P. A. Grayburn (2019). “Contrasting Effects of Pharmacological, Procedural, and Surgical Interventions on Proportionate and Disproportionate Functional Mitral Regurgitation in Chronic Heart Failure.” Circulation 140(9): 779-789.

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Two distinct pathways can lead to functional mitral regurgitation (MR) in patients with chronic heart failure and a reduced ejection fraction. When remodeling and enlargement of the left ventricle (LV) cause annular dilatation and tethering of the mitral valve leaflets, there is a linear relationship between LV end-diastolic volume and the effective regurgitant orifice area of the mitral valve. These patients, designated as having proportionate MR, respond favorably to treatments that lead to reversal of LV remodeling and a decrease in LV volumes (eg, neurohormonal antagonists and LV assist devices), but they may not benefit from interventions that are directed only at the mitral valve leaflets (eg, transcatheter mitral valve repair). In contrast, when ventricular dyssynchrony causes functional MR attributable to unequal contraction of the papillary muscles, the magnitude of regurgitation is greater than that predicted by LV volumes. These patients, designated as having severe but disproportionate MR, respond favorably to treatments that are directed to the mitral valve leaflets or their supporting structures (eg, cardiac resynchronization or transcatheter mitral valve repair), but they may derive little benefit from interventions that act only to reduce LV cavity size (eg, pharmacological treatments). This novel conceptual framework reflects the important interplay between LV geometry and mitral valve function in determining the clinical presentation of patients, and it allows characterization of the determinants of functional MR to guide the most appropriate therapy in the clinical setting.

Packer, M. (2019). “Reconceptualization of the Molecular Mechanism by Which Sodium-Glucose Cotransporter 2 Inhibitors Reduce the Risk of Heart Failure Events.” Circulation 140(6): 443-445.

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Two sodium-glucose cotransporter 2 (SGLT2) inhibitors (ie, empagliflozin and canagliflozin) are currently approved by the Food and Drug Administration to reduce cardiovascular death or major adverse thromboembolic events in patients with type 2 diabetes mellitus. Yet, the current labeling for this class of drugs is misleading. The Food and Drug Administration indication reflects certain design features of the major cardiovascular outcome safety trials with these drugs, but it does not accurately describe the most important efficacy findings of these studies. In none of the 3 major cardiovascular trials did SGLT2 inhibitors reduce the risk of myocardial infarction and stroke.1 Instead, the primary benefit of SGLT2 inhibitors was a 25% to 35% decrease in the risk of heart failure hospitalizations, which was seen consistently across the trials. The additional benefit of empagliflozin to decrease the risk of cardiovascular death is primarily driven by an effect on pump failure deaths and sudden deaths: the 2 most common modes of death in patients with heart failure. How can inhibition of glucose transport in the proximal renal tubule lead to such a striking decrease in the risk of heart failure events? The effect of these drugs to block glucose reabsorption is accompanied by a lowering of hemoglobin A1c, body weight, and blood pressure. However, the magnitude of these effects is modest, and these changes are not well correlated with the observed decrease in the risk of heart failure deaths or hospitalizations. Furthermore, most drugs that lower blood glucose, body weight, and blood pressure do not have beneficial effects on, and they often adversely influence, the course of heart failure. (Excerpt from text, p. 443; no abstract available.)

Packer, M. (2019). “The Parable of Schrodinger’s Cat and the Illusion of Statistical Significance in Clinical Trials.” Circulation 140(10): 799-800.

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The field of quantum physics offers important lessons for those involved in the interpretation of clinical trials. A key distinction between quantum physics and classical Newtonian physics is that the latter is deterministic; it describes the future state of a system with definitiveness, and it is useful for understanding the behavior of large objects (ie, those encountered on a human scale). However, at a subatomic level, the utility of Newtonian physics breaks down; it is superseded by quantum physics, in which the future state of a system is defined in a probabilistic rather than deterministic manner. The quantification of uncertainty allows quantum physics to resolve issues that classical physics cannot address. In many ways, the evolution of thinking about clinical evidence parallels the evolution of thinking in physics. When the effect size of a drug or device is large, descriptive studies generally suffice in establishing the efficacy of an intervention. If the mortality rate of pneumococcal pneumonia is uniformly 90% and declines to 10% with the advent of penicillin, there is no need for a randomized controlled trial. The response to imatinib in leukemia was so dramatic that the Food and Drug Administration approved the drug based on an open-label uncontrolled trial of <50 patients.1 If the clinical course of a serious event is highly predictable, a substantial benefit after an intervention represents compelling evidence for efficacy. However, just as classical physics loses its applicability when one shifts to very small effects, the usefulness of descriptive studies evaporates when physicians move from drugs with a 90% benefit to agents that reduce risk by only 10% to 20%. Cardiovascular drugs typically exert small treatment effects and are studied in a setting where outcomes cannot be predicted with precision. (Excerpt from text, p. 799.)

Packer, M. (2019). “A Compelling Case for Less Aggressive Arrhythmia Management in Patients With Chronic Heart Failure and Long-Standing Atrial Fibrillation.” J Card Fail Aug 26. [Epub ahead of print].

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BACKGROUND AND METHODS: Atrial fibrillation (AF) is common in chronic heart failure, and some have advocated intensive rate and/or rhythm control strategies for these patients. However, the loss of atrial systole and irregularity of the ventricular response has not been shown to contribute to the progression of heart failure, and the presence or rate of long-standing AF in patients with chronic heart failure does not have prognostic significance. RESULTS: In randomized clinical trials, pharmacological rhythm control has not been shown to be superior to rate-control in influencing long-term outcomes, but the use of membrane-active antiarrhythmic drugs can increase the risk of both pump failure and arrhythmic deaths in patients with heart failure. Additionally, intensive efforts to slow the ventricular rate in AF can potentially cause clinically inapparent bradyarrhythmias, which can trigger rate-dependent lethal rhythm disturbances or hemodynamic abnormalities. In patients with AF, a more stringent approach to rate control (target rate <80/min) is not superior to a more lenient strategy (target rate <110/min) on the risk of major events. Little is known about the effects of catheter ablation of long-standing AF in established heart failure, particularly in patients with a preserved or a meaningfully reduced ejection fraction, but ablation can add to the fibrotic burden of the left atrium and impair its capacitance functions. CONCLUSIONS: For all of these reasons, the management of heart failure and long-standing AF should be primarily directed to slowing of the progression of their underlying cardiomyopathic process rather than the treatment of the arrhythmia. In addition, patients should receive long-term oral anticoagulation with non-vitamin K-antagonist oral anticoagulants to reduce the risk of thromboembolic events. The utility of intensive rate and rhythm control interventions for long-standing AF in patients with established heart failure requires further study.

Morand, O., J. Johnson, J. Walter, L. Atkinson, G. Kline, A. Frey, J. Politei and R. Schiffmann (2019). “Symptoms and Quality of Life in Patients with Fabry Disease: Results from an International Patient Survey.” Adv Ther Aug 21. [Epub ahead of print].

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INTRODUCTION: Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of alpha-galactosidase A. Symptoms include neuropathic pain and gastrointestinal problems, such as diarrhoea. To inform and support the design of a Phase III clinical trial for a new oral treatment for Fabry disease, this study evaluated patients’ experiences of Fabry disease symptoms, the impact of symptoms on their quality of life, and their views on participating in clinical trials. METHODS: An online survey questionnaire was distributed to patients with Fabry disease, through relevant patient organisations. The questionnaire consisted mainly of quantitative, closed questions with pre-defined response options. Fabry-specific pain intensity and its impact on quality of life were rated on a scale from 0 to 10. RESULTS: In total, 367 patients completed the survey, of whom half reported frequent pain, moderate to severe pain, and pain in their hands and feet. Pain frequency, intensity and location were similar for males and females. There was no clear association between Fabry-specific pain and the use of enzyme replacement therapy (ERT), with moderate to severe pain reported by 80.4% of participants receiving ERT and by 75.0% of participants not receiving ERT. Of participants who were receiving ERT, 35.7% said they were willing to discontinue it to take part in a clinical trial testing a new oral drug for treating Fabry disease. Gastrointestinal symptoms were more heterogeneous in nature and frequency than Fabry-specific pain, but still affected a significant proportion of participants. CONCLUSIONS: Both male and female patients with Fabry disease experience significant Fabry-specific pain, which affects their quality of life. Furthermore, frequent diarrhoea affects many patients. The symptoms occur independently of the use of ERT. This suggests the healthcare needs of patients with Fabry disease are not being fully met, and additional treatments are required to improve symptoms and quality of life. FUNDING: This study was sponsored by Actelion Pharmaceuticals Ltd. Study sponsorship was transferred to Idorsia Pharmaceuticals Ltd in July 2018.