Cardiology

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.)

Malik, A., R. Masson, S. Singh, W. C. Wu, M. Packer, B. Pitt, F. Waagstein, C. J. Morgan, R. M. Allman, G. C. Fonarow and A. Ahmed (2019). “Digoxin Discontinuation and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction.” J Am Coll Cardiol 74(5): 617-627.

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BACKGROUND: The deleterious effects of discontinuation of digoxin on outcomes in ambulatory patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) receiving angiotensin-converting enzyme inhibitors are well-documented. OBJECTIVES: The authors sought to determine the relationship between digoxin discontinuation and outcomes in hospitalized patients with HFrEF receiving more contemporary guideline-directed medical therapies including beta-blockers and mineralocorticoid receptor antagonists. METHODS: Of the 11,900 hospitalized patients with HFrEF (EF less-than-or-equal-to 45%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 3,499 received pre-admission digoxin, which was discontinued in 721 patients. Using propensity scores for digoxin discontinuation, estimated for each of the 3,499 patients, a matched cohort of 698 pairs of patients, balanced on 50 baseline characteristics (mean age 76 years; mean EF 28%; 41% women; 13% African American; 65% on beta-blockers) was assembled. RESULTS: Four-year post-discharge, digoxin discontinuation was associated with significantly higher risks of HF readmission (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05 to 1.39; p = 0.007), all-cause readmission (HR: 1.16; 95% CI: 1.04 to 1.31; p = 0.010), and the combined endpoint of HF readmission or all-cause mortality (HR: 1.20; 95% CI: 1.07 to 1.34; p = 0.002), but not all-cause mortality (HR: 1.09; 95% CI: 0.97 to 1.24; p = 0.163). Discontinuation of digoxin was associated with a significantly higher risk of all 4 outcomes at 6 months and 1 year post-discharge. At 30 days, digoxin discontinuation was associated with higher risks of all-cause mortality (HR: 1.80; 95% CI: 1.26 to 2.57; p = 0.001) and the combined endpoint (HR: 1.36; 95% CI: 1.09 to 1.71; p = 0.007), but not of HF readmission (HR: 1.19; 95% CI: 0.90 to 1.59; p = 0.226) or all-cause readmission (HR: 1.03; 95% CI: 0.84 to 1.26; p = 0.778). CONCLUSIONS: Among hospitalized older patients with HFrEF on more contemporary guideline-directed medical therapies, discontinuation of pre-admission digoxin therapy was associated with poor outcomes.

Lam, P. H., M. Packer, G. C. Fonarow, C. Faselis, R. M. Allman, C. J. Morgan, S. Singh, B. Pitt and A. Ahmed (2019). “Early Effects of Starting Doses of Enalapril in Patients with Chronic Heart Failure in the SOLVD Treatment Trial.” Am J Med Aug 8. [Epub ahead of print].

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BACKGROUND: In the Studies of Left Ventricular Dysfunction (SOLVD) Treatment trial, similar clinical benefits were observed between starting doses of enalapril and the target dose achieved by post-randomization up-titration. In our current analysis, protecting the randomization, we examined the early effects of starting doses of enalapril. METHODS: 2569 patients with mild-to-moderate chronic heart failure with reduced ejection fraction (HFrEF; ejection fraction less-than-or-equal-to 35%) were randomized to receive starting doses (5-10mg/day) of placebo (n=1284) or enalapril (n=1285). At day 14, both study drugs were blindly up-titrated to the target dose (20mg/day). Overall, 89% (2284/2569) of the patients returned for dose up-titration, which was achieved in 56% (1444/2248), 48% (696/1444) of whom were in the enalapril group. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes in the enalapril group were estimated. RESULTS: HRs (95% CIs) for all-cause mortality, heart failure hospitalization, and the combined endpoint of heart failure hospitalization or all-cause mortality at 14days after randomization were 0.80 (0.32-2.03), 0.63 (0.35-1.12), and 0.65 (0.39-1.06) 0.82, respectively. Corresponding HRs (95% CIs) at 30days were (0.41-1.67), 0.43 (0.27-0.68), and 0.43 (0.27-0.68). The magnitude of these early effects of starting doses of enalapril is similar to its previously reported long-term effects at the target dose. CONCLUSION: These data suggest that in stable ambulatory patients with heart failure with reduced ejection fraction, the magnitude of the early effect of starting doses of enalapril is similar to that observed during longer-term therapy with the target doses of the drug.

Kaneko, T., V. H. Thourani, G. Ailawadi, M. B. Leon, M. J. Mack and G. H. L. Tang (2019). “Transseptal Access-Gateway to Transcatheter Mitral Interventions.” Ann Thorac Surg 108(3): 654-656.

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Over the past 8 years, we have witnessed a significant growth of transcatheter aortic valve replacement (TAVR) replacing 1 of our most commonly performed surgeries, the surgical aortic valve replacement for severe aortic stenosis. In 2017, for the first time, the number of TAVRs performed exceeded surgical aortic valve replacements with or without coronary revascularization. Recently, 2 randomized studies comparing surgical aortic valve replacement with TAVR in low-risk patients with severe aortic stenosis revealed superiority on mortality and disabling stroke with a balloon-expandable valve, and non-inferiority with a self-expanding valve will most definitely favor an increase in transcatheter aortic valve procedures. With the success in TAVR, industry is searching for the next frontier. In 2015, Edwards Lifesciences (Irvine, CA) bought a start-up company, CardiAQ for $200 million, and Medtronic (Minneapolis, MN) bought another start-up company, Twelve, for $458 million. These start-up companies have one thing in common—they both created new technology for transcatheter mitral valve replacement. Investment in these start-up companies clearly shows the direction of the next chapter in the treatment of structural heart disease. (Excerpt from text, p. 654; no abstract available.)