Milton Packer M.D.

McMurray, J. J. V., A. M. Jackson, C. S. P. Lam, M. M. Redfield, I. S. Anand, J. Ge, M. P. Lefkowitz, A. P. Maggioni, F. Martinez, M. Packer, M. A. Pfeffer, B. Pieske, A. R. Rizkala, S. V. Sabarwal, A. M. Shah, S. J. Shah, V. C. Shi, D. J. van Veldhuisen, F. Zannad, M. R. Zile, M. Cikes, E. Goncalvesova, T. Katova, A. Kosztin, M. Lelonek, N. K. Sweitzer, O. Vardeny, B. Claggett, P. S. Jhund and S. D. Solomon (2019). “Effects of Sacubitril-Valsartan, versus Valsartan, in Women Compared to Men with Heart Failure and Preserved Ejection Fraction: Insights from PARAGON-HF.” Circulation Nov 17. [Epub ahead of print].

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Background: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction (HFpEF), the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women, compared with men. Methods: In a pre-specified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial which compared sacubitril-valsartan and valsartan in patients with HFpEF. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. Results: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older, had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI 0.59-0.90) in women and 1.03 (0.84-1.25) in men; P interaction=0.017. The benefit from sacubitril-valsartan was due to reduction in heart failure hospitalization. The improvement in NYHA class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in KCCQ-CSS was less in women than in men. The difference in adverse events, between sacubitril-valsartan and valsartan, was similar in women and men. Conclusions: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. While the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding (Clinicaltrials.gov unique identifier: NCT01920711).

Solomon, S. D., J. J. V. McMurray, I. S. Anand, J. Ge, C. S. P. Lam, A. P. Maggioni, F. Martinez, M. Packer, M. A. Pfeffer, B. Pieske, M. M. Redfield, J. L. Rouleau, D. J. van Veldhuisen, F. Zannad, M. R. Zile, A. S. Desai, B. Claggett, P. S. Jhund, S. A. Boytsov, J. Comin-Colet, J. Cleland, H. D. Dungen, E. Goncalvesova, T. Katova, J. F. Kerr Saraiva, M. Lelonek, B. Merkely, M. Senni, S. J. Shah, J. Zhou, A. R. Rizkala, J. Gong, V. C. Shi and M. P. Lefkowitz (2019). “Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.” New England Journal of Medicine 381(17): 1609-1620.

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BACKGROUND: The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS: We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS: There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS: Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.).

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 140(17): 1369-1379.

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BACKGROUND: The contemporary prognostic value of the physical examination- beyond traditional risk factors including natriuretic peptides, risk scores, and symptoms-in heart failure (HF) with reduced ejection fraction is unknown. We aimed to determine the association between physical signs of congestion at baseline and during study follow-up with quality of life 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 third heart sound) 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 quality of life, assessed by Kansas City Cardiomyopathy Questionnaire overall summary scores. RESULTS: Among 8380 participants, 0, 1, 2, and 3+ signs of congestion were present in 70%, 21%, 7%, and 2% of patients, respectively. Patients with baseline congestion were older, more often female, had higher MAGGIC risk scores (Meta-Analysis Global Group in Chronic Heart Failure) and lower Kansas City Cardiomyopathy Questionnaire overall summary scores (P<0.05). After adjusting for baseline natriuretic peptides, time-updated Meta-Analysis Global Group in Chronic Heart Failure 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 did enalapril (P=0.011). Each 1-sign reduction was independently associated with a 5.1 (95% CI, 4.7-5.5) point improvement in Kansas City Cardiomyopathy Questionnaire overall summary scores. Change in congestion strongly predicted outcomes even after adjusting for baseline congestion (P<0.001). CONCLUSIONS: In HF with reduced ejection fraction, the physical exam continues to provide significant independent prognostic value even beyond symptoms, natriuretic peptides, and Meta-Analysis Global Group in Chronic Heart Failure risk score. Sacubitril/valsartan improved congestion to a greater extent than did enalapril. Reducing congestion in the outpatient setting is independently associated with improved quality of life and reduced cardiovascular events, including mortality. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01035255.

Packer, M. (2019). “Methodological and Clinical Heterogeneity and Extraction Errors in Meta-Analyses of Catheter Ablation for Atrial Fibrillation in Heart Failure.” J Am Heart Assoc Nov 5: 8(21). [Epub 2019 Oct 18].

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Background Meta-analyses are expected to follow a standardized process, and thus, they have become highly formulaic, although there is little evidence that such regimentation yields high-quality results. Methods and Results This article describes the results of a critical examination of 14 published meta-analyses of catheter ablation for atrial fibrillation in heart failure that were based on a nearly identical core set of 4 to 6 primary trials. Methodological issues included (1) the neglect of primary data or the failure to report any primary data; (2) the inaccurate recording of the number of randomized patients; (3) the lack of attention to data missingness or baseline imbalances; (4) the failure to contact investigators of primary trials for additional data; (5) the incorrect extraction of data, the misidentification of events, and the assignment of events to the wrong treatment groups; (6) the calculation of summary estimates based on demonstrably heterogenous data, methods of differing reliability, or unrelated end points; and (7) the development of conclusions based on sparse numbers of events or overly reliant on the results of 1 dominant trial. Conclusions These findings reinforce existing concerns about the methodological validity of meta-analyses and their current status in the hierarchy of medical evidence, and they raise new questions about the process by which meta-analyses undergo peer review by medical journals.

Packer, M. (2019). “Methodological and Clinical Heterogeneity and Extraction Errors in Meta-Analyses of Catheter Ablation for Atrial Fibrillation in Heart Failure.” J Am Heart Assoc Nov 5: 8(21). [Epub 2019 Oct 18].

Full text of this article.

Background Meta-analyses are expected to follow a standardized process, and thus, they have become highly formulaic, although there is little evidence that such regimentation yields high-quality results. Methods and Results This article describes the results of a critical examination of 14 published meta-analyses of catheter ablation for atrial fibrillation in heart failure that were based on a nearly identical core set of 4 to 6 primary trials. Methodological issues included (1) the neglect of primary data or the failure to report any primary data; (2) the inaccurate recording of the number of randomized patients; (3) the lack of attention to data missingness or baseline imbalances; (4) the failure to contact investigators of primary trials for additional data; (5) the incorrect extraction of data, the misidentification of events, and the assignment of events to the wrong treatment groups; (6) the calculation of summary estimates based on demonstrably heterogenous data, methods of differing reliability, or unrelated end points; and (7) the development of conclusions based on sparse numbers of events or overly reliant on the results of 1 dominant trial. Conclusions These findings reinforce existing concerns about the methodological validity of meta-analyses and their current status in the hierarchy of medical evidence, and they raise new questions about the process by which meta-analyses undergo peer review by medical journals.