Research Spotlight

Baron, S. J., K. Wang, S. V. Arnold, E. A. Magnuson, B. Whisenant, A. Brieke, M. Rinaldi, A. W. Asgar, J. Lindenfeld, W. T. Abraham, M. J. Mack, G. W. Stone and D. J. Cohen (2019). “Cost-Effectiveness of Transcatheter Mitral Valve Repair versus Medical Therapy in Patients with Heart Failure and Secondary Mitral Regurgitation: Results from the COAPT Trial.” Circulation Sep 29. [Epub ahead of print].

Full text of this article.

Background: The COAPT trial demonstrated that edge-to-edge transcatheter mitral valve repair (TMVr) using the MitraClip resulted in reduced mortality and heart-failure hospitalizations and improved quality of life when compared with maximally-tolerated guideline-directed medical therapy (GDMT) in heart-failure patients with 3-4+ secondary mitral regurgitation (SMR). Whether TMVr is cost-effective compared with GDMT in this population is unknown. Methods: We used data from the COAPT trial to perform a formal, patient-level economic analysis of TMVr + GDMT vs. GDMT alone for patients with heart failure and 3-4+ SMR from the perspective of the US health care system. Costs for the index TMVr hospitalization were assessed using a combination of resource-based accounting and hospital billing data (when available). Follow-up medical care costs were estimated based on medical resource use collected during the COAPT trial. Health utilities were estimated for all patients at baseline, 1, 6, 12 and 24 months using the SF-6D. Results: Initial costs for the TMVr procedure and index hospitalization were $35,755 and $48,198, respectively. Although follow-up costs were significantly lower with TMVr compared with GDMT ($26,654 vs. $38,345; p=0.018), cumulative 2-year costs remained higher with TMVr due to the up-front cost of the index procedure ($73,416 vs. $38,345; p<0.001). When intrial survival, health utilities, and costs were modeled over a lifetime horizon, TMVr was projected to increase life-expectancy by 1.13 years and quality-adjusted life-years (QALYs) by 0.82 years at a cost of $45,648, yielding a lifetime incremental cost-effectiveness ratio of $40,361/life-year gained and $55,600/QALY gained. Conclusions: For symptomatic heart-failure patients with 3-4+ SMR, TMVr increases lifeexpectancy and quality-adjusted life-expectancy compared with GDMT at an incremental cost per QALY gained that represents acceptable economic value based on current U.S. thresholds. Clinical Trial Registration: NCT01626079.

Selvaraj, S., B. Claggett, A. Pozzi, J. J. V. McMurray, P. S. Jhund, M. Packer, A. S. Desai, E. F. Lewis, M. Vaduganathan, M. P. Lefkowitz, J. L. Rouleau, V. C. Shi, M. R. Zile, K. Swedberg and S. D. Solomon (2019). “Prognostic Implications of Congestion on Physical Examination Among Contemporary Patients with Heart Failure and Reduced Ejection Fraction:PARADIGM-HF.” Circulation Sep 12. [Epub ahead of print].

Full text of this article.

Background: The contemporary prognostic value of the physical examination, beyond traditional risk factors including natriuretic peptides (NPs), risk scores, and symptoms, in heart failure with reduced ejection fraction (HFrEF) is unknown. We sought to determine the association between physical signs of congestion at baseline and during study follow up with quality of life (QoL) and clinical outcomes and to assess the treatment effects of sacubitril/valsartan on congestion. Methods: We analyzed participants from PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF) with an available physical examination at baseline. We examined the association of the number of signs of congestion (jugular venous distention, edema, rales, and S3) with the primary outcome (cardiovascular death or HF hospitalization), its individual components, and all-cause mortality using time-updated, multivariable-adjusted Cox regression. We further evaluated whether sacubitril/valsartan reduced congestion during follow-up, and whether improvement in congestion is related to changes in clinical outcomes and QoL, assessed by Kansas City Cardiomyopathy Questionnaire clinical summary scores (KCCQ-OSS). Results: Among 8380 participants, 0, 1, 2, and 3+ signs of congestion were present in 70%, 21%, 7%, and 2%. Patients with baseline congestion were older, more often female, had higher Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk scores and lower KCCQ-OSS (p<0.05). After adjusting for baseline NPs, time-updated MAGGIC score, and time-updated New York Heart Association class, increasing time-updated congestion was associated with all outcomes (p<0.001). Sacubitril/valsartan reduced the risk of the primary outcome irrespective of clinical signs of congestion at baseline (p=0.16 for interaction), and treatment with the drug improved congestion to a greater extent than enalapril (p=0.011). Each 1-sign reduction was independently associated with a 5.1 (95%CI: 4.7-5.5) point improvement in KCCQ-OSS. Change in congestion strongly predicted outcomes even after adjusting for baseline congestion (p<0.001). Conclusions: In HFrEF, the physical exam continues to provide significant, independent prognostic value even beyond symptoms, NPs, and MAGGIC risk score. Sacubitril/valsartan improved congestion to a greater extent than enalapril. Reducing congestion in the outpatient setting is independently associated with improved QoL and reduced cardiovascular events, including mortality. Clinical Trial Registration: NCT01035255.

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

Full text of this article.

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.)

Asch, F. M., P. A. Grayburn, R. J. Siegel, S. Kar, D. S. Lim, J. G. Zaroff, J. M. Mishell, B. Whisenant, M. J. Mack, J. Lindenfeld, W. T. Abraham, G. W. Stone and N. J. Weissman (2019). “Transcatheter Mitral Valve Replacement in Patients with Heart Failure and Secondary Mitral Regurgitation: From COAPT Trial.” Journal of the American College of Cardiology Sep 19. [Epub ahead of print].

Full text of this article.

BACKGROUND: In the COAPT trial among patients with heart failure (HF) and moderate-to-severe (3+) or severe (4+) secondary mitral regurgitation (SMR), patients treated with the transcatheter mitral valve replacement (TMVR) had reduced rates of HF hospitalization and mortality compared with guideline-directed medical therapy (GDMT) alone. OBJECTIVES: To describe the echocardiographic patient qualification process for COAPT, baseline echocardiographic characteristics, changes over time, and the interaction between treatment group and echocardiographic parameters on clinical outcomes. METHODS: A novel echocardiographic algorithm was implemented for grading MR severity during the screening process. Standardized echocardiograms were obtained at baseline and during regular follow-up intervals through 2 years, and analyzed by a core laboratory. RESULTS: A total of 614 patients were randomized to TMVR plus maximally- tolerated GDMT or GDMT alone. Mean baseline left ventricular ejection fraction (LVEF) was 31.3+/-9.3%, LV end-diastolic volume was 192.7+/-71 ml, and effective regurgitant orifice area was 0.41+/-0.15 cm(2). The beneficial effect of TMVR compared with GDMT alone was consistent in all echocardiographic subgroups, independent of the severity of LV dysfunction, LV dilatation, pulmonary hypertension, severity of tricuspid regurgitation or individual MR characteristics. The LVEF decreased and the LV volumes progressively increased in both groups during follow-up, although less after TMVR (P<0.05). CONCLUSIONS: HF patients in the COAPT trial with 3+ or 4+ SMR, selected using strict echocardiographic criteria, benefitted from TMVR with reduced 2-year rates of death and HF hospitalization. Strict application of these echocardiographic criteria should enable the COAPT results to be translated to clinical practice.

Baron, S. J., E. A. Magnuson, M. Lu, K. Wang, K. Chinnakondepalli, M. Mack, V. H. Thourani, S. Kodali, R. Makkar, H. C. Herrmann, S. Kapadia, V. Babaliaros, M. R. Williams, D. Kereiakes, A. Zajarias, M. C. Alu, J. G. Webb, C. R. Smith, M. B. Leon and D. J. Cohen (2019). “Health Status after Transcatheter vs. Surgical Aortic Valve Replacement in Low-Risk Patients with Aortic Stenosis.” Journal of the American College of Cardiology Sep 18. [Epub ahead of print].

Full text of this article.

BACKGROUND: In patients with severe aortic stenosis (AS) at low surgical risk, treatment with transcatheter aortic valve replacement (TAVR) results in lower rates of death, stroke, and re-hospitalization at 1 year compared with surgical aortic valve replacement; however, the effect of treatment strategy on health status is unknown. OBJECTIVES: This study sought to compare health status outcomes of TAVR vs. surgery in low-risk patients with severe AS. METHODS: Between 3/2016 and 10/2017, 1000 low-risk AS patients were randomized to transfemoral TAVR using a balloon-expandable valve or surgery in the PARTNER 3 Trial. Health status was assessed at baseline, 1, 6 and 12 months using the Kansas City Cardiomyopathy Questionnaire (KCCQ), SF-36 and EQ-5D. The primary endpoint was change in KCCQ-Overall Summary (KCCQ-OS) score over time. Longitudinal growth curve modeling was used to compare changes in health status between treatment groups over time. RESULTS: At 1 month, TAVR was associated with better health status than surgery (mean difference in KCCQ-OS 16.0 points; p<0.001). At 6 and 12 months, health status remained better with TAVR, although the effect was reduced (mean difference in KCCQ-OS 2.6 and 1.8 points respectively; p<0.04 for both). The proportion of patients with an excellent outcome (alive with KCCQ-OS >/= 75 and no significant decline from baseline) was greater with TAVR than surgery at 6 months (90.3% vs. 85.3%; p=0.03) and 12 months (87.3% vs. 82.8%; p=0.07). CONCLUSIONS: Among low-risk patients with severe AS, TAVR was associated with meaningful early and late health status benefits compared with surgery.