Milton Packer M.D.

Dewan, P., R. Rorth, P. S. Jhund, J. P. Ferreira, F. Zannad, L. Shen, L. Kober, W. T. Abraham, A. S. Desai, K. Dickstein, M. Packer, J. L. Rouleau, S. D. Solomon, K. Swedberg, M. R. Zile and J. J. V. McMurray (2019). “Income Inequality and Outcomes in Heart Failure: A Global Between-Country Analysis.” JACC Heart Fail 7(4): 336-346.

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OBJECTIVES: This study examined the relationship between income inequality and heart failure outcomes. BACKGROUND: The income inequality hypothesis postulates that population health is influenced by income distribution within a society, with greater inequality associated with worse outcomes. METHODS: This study analyzed heart failure outcomes in 2 large trials conducted in 54 countries. Countries were divided by tertiles of Gini coefficients (where 0% represented absolute income equality and 100% represented absolute income inequality), and heart failure outcomes were adjusted for standard prognostic variables, country per capita income, education index, hospital bed density, and health worker density. RESULTS: Of the 15,126 patients studied, 5,320 patients lived in Gini coefficient tertile 1 countries (coefficient: <33%), 6,124 patients lived in tertile 2 countries (33% to 41%), and 3,772 patients lived in tertile 3 countries (>41%). Patients in tertile 3 were younger than tertile 1 patients, were more often women, and had less comorbidity and several indicators of less severe heart failure, yet the tertile 3-to-1 hazard ratios (HRs) for the primary composite outcome of cardiovascular death or heart failure hospitalization were 1.57 (95% confidence interval [CI]: 1.38 to 1.79) and 1.48 for all-cause death (95% CI: 1.29 to 1.71) after adjustment for recognized prognostic variables. After additional adjustments were made for per capita income, education index, hospital bed density, and health worker density, these HRs were 1.46 (95% CI: 1.25 to 1.70) and 1.30 (95% CI: 1.10 to 1.53), respectively. CONCLUSIONS: Greater income inequality was associated with worse heart failure outcomes, with an impact similar to those of major comorbidities. Better understanding of the societal and personal bases of these findings may suggest approaches to improve heart failure outcomes.

Zile, M. R., E. O’Meara, B. Claggett, M. F. Prescott, S. D. Solomon, K. Swedberg, M. Packer, J. J. V. McMurray, V. Shi, M. Lefkowitz and J. Rouleau (2019). “Effects of Sacubitril/Valsartan on Biomarkers of Extracellular Matrix Regulation in Patients With HFrEF.” J Am Coll Cardiol 73(7): 795-806.

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BACKGROUND: Myocardial fibrosis is an important pathophysiological mechanism underlying the development of heart failure (HF). Given the biochemical targets of sacubitril/valsartan, we hypothesized that circulating biomarkers reflecting the mechanisms that determine extracellular matrix (ECM) homeostasis, including collagen synthesis, processing, and degradation, are altered by sacubitril/valsartan in comparison to enalapril. OBJECTIVES: The purpose of this study was to examine the effects of sacubitril/valsartan on biomarkers of ECM homeostasis and the association between the rate of primary composite outcome (cardiovascular death or HF hospitalization) and these biomarkers. METHODS: Biomarkers at baseline (n = 2,067) and both baseline and 8 months after randomization (n = 1,776) included aldosterone, soluble ST2 (sST2), tissue inhibitor of matrix metalloproteinase (TIMP)-1, matrix metalloproteinase (MMP)-2, MMP-9, Galectin-3 (Gal-3), N-terminal propeptide of collagen I (PINP), and N-terminal propeptide of collagen III (PIIINP). The effects of sacubitril/valsartan on biomarkers were compared with enalapril. Baseline biomarker values and changes from baseline to 8 months were related to primary outcome. RESULTS: At baseline, the profibrotic biomarkers aldosterone, sST2, TIMP-1, Gal-3, PINP, and PIIINP were higher, and biomarkers associated with collagen degradation, MMP-2 and -9, were lower than published referent control values. Eight months after randomization, aldosterone, sST2, TIMP-1, MMP-9, PINP, and PIIINP had decreased more in the sacubitril/valsartan than enalapril group. At baseline, higher values of sST-2, TIMP-1, and PIIINP were associated with higher primary outcome rates. Changes from baseline to 8 months in sST-2 and TIMP-1 were associated with change in outcomes. CONCLUSIONS: Biomarkers associated with profibrotic signaling are altered in HF with reduced ejection fraction, sacubitril/valsartan significantly decreased many of these biomarkers, and these biomarkers have important prognostic value. These findings suggest that sacubitril/valsartan may reduce profibrotic signaling, which may contribute to the improved outcomes. (This Study Will Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure [PARADIGM-HF]; NCT01035255).

Vardeny, O., B. Claggett, J. Kachadourian, A. S. Desai, M. Packer, J. Rouleau, M. R. Zile, K. Swedberg, M. Lefkowitz, V. Shi, J. J. V. McMurray and S. D. Solomon (2019). “Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial.” Eur J Heart Fail.

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AIMS: To assess differences in diuretic dose requirements in patients treated with sacubitril/valsartan compared with enalapril in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) trial. METHODS AND RESULTS: Overall, 8399 patients with New York Heart Association class II-IV heart failure and reduced LVEF were randomized to sacubitril/valsartan 200 mg bid or enalapril 10 mg twice daily. Loop diuretic doses were assessed at baseline, 6, 12, and 24 months, and furosemide dose equivalents were calculated via multiplication factors (2x for torsemide and 40x for bumetanide). Percentages of participants with reductions or increases in loop diuretic dose were determined. At baseline, 80.8% of participants were taking any diuretics (n = 6290 for loop diuretics, n = 496 for other diuretics); of those, recorded dosage data for loop diuretics were available on 5487 participants. Mean baseline furosemide equivalent doses were 48.2 mg for sacubitril/valsartan and 49.6 mg for enalapril (P = 0.25). Patients treated with sacubitril/valsartan were more likely to reduce diuretic dose and less likely to increase diuretic dose relative to those randomized to enalapril at 6, 12, 24 months post-randomization, with an overall decreased diuretic use of 2.0% (P = 0.02), 4.1% (P < 0.001), and 6.1% (P < 0.001) at 6, 12, and 24 months, respectively, with similar findings in an on-treatment analysis. CONCLUSION: Treatment with sacubitril/valsartan was associated with more loop diuretic dose reductions and fewer dose increases compared with enalapril, suggesting that treatment with sacubitril/valsartan may reduce the requirement for loop diuretics relative to enalapril in patients with heart failure with reduced ejection fraction.

Packer, M. (2019). “When Cardiovascular Trials Collide.” Eur Heart J 40(6): 501-504.

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In the modern era of clinical trials, we do not expect large-scale, definitively designed and executed studies to yield misleading results if they are meticulously analysed in an unbiased manner. Fortunately, the discordant results of the MITRA-FR and COAPT trials do not undermine this conventional wisdom. Instead, the reporting of discordant results from the two studies has led us to rediscover a conceptual framework in which the results of both trials are valid. With respect to MITRA-FR and COAPT, the combined results of the trials tell us that patients with functional MR do not have a homogenous disorder. By providing complementary information, the trials (when considered together) indicate that we must now make a clear distinction between MR that is proportionate or disproportionate to the degree of LV enlargement. Optimal medical therapy seems to be the best choice for patients with proportionate MR, whereas mitral valve repair is highly desirable in those with disproportionate MR. Such a coherent understanding could not have been achieved if the MITRA-FR and COAPT trials had studied the same patients and yielded the same results. Integration of the results of MITRA-FR and COAPT allows us to optimally individualize the management of the heterogeneous group of patients who present with functional MR, heart failure, and LV dysfunction. (Excerpt from text, p. 503; no abstract available.)

Dewan, P., R. Rorth, P. S. Jhund, L. Shen, V. Raparelli, M. C. Petrie, W. T. Abraham, A. S. Desai, K. Dickstein, L. Kober, U. M. Mogensen, M. Packer, J. L. Rouleau, S. D. Solomon, K. Swedberg, M. R. Zile and J. J. V. McMurray (2019). “Differential Impact of Heart Failure With Reduced Ejection Fraction on Men and Women.” J Am Coll Cardiol 73(1): 29-40.

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BACKGROUND: Heart failure (HF) trials initiated in the last century highlighted many differences between men and women. Of particular concern was undertreatment of women compared with men, but much has changed during the past 20 years. OBJECTIVES: This study sought to identify these changes, which may give a new perspective on the management of, and outcomes in, women with HF. METHODS: The study analyzed 12,058 men and 3,357 women enrolled in 2 large HF with reduced ejection fraction (HFrEF) trials with near identical inclusion and exclusion criteria and the same principal outcomes. Outcomes were adjusted for other prognostic variables including N-terminal pro-B-type natriuretic peptide. RESULTS: Women were older and more often obese than men were, had slightly higher systolic blood pressure and heart rate, and were less likely to have most comorbidities, except hypertension. Women had more symptoms and signs (e.g., pedal edema 23.4% vs 19.9%; p < 0.0001) and worse quality of life-median Kansas City Cardiomyopathy Questionnaire Clinical Summary Score 71.3 (interquartile range: 53.4 to 86.5) versus 81.3 (interquartile range: 65.1 to 92.7; p < 0.0001)-despite similar left ventricular ejection fraction and N-terminal pro-B-type natriuretic peptide. However, women had lower mortality (adjusted hazard ratio: 0.68; 95% confidence interval: 0.62 to 0.74; p < 0.001) and risk of HF hospitalization (hazard ratio: 0.80; 95% confidence interval: 0.72 to 0.89; p < 0.001). Diuretics and anticoagulants were underutilized in women. Device therapy was underused in both men and women, but more so in women (e.g., defibrillator 8.6% vs. 16.6%; p < 0.0001). CONCLUSIONS: Although women with HFrEF live longer than men, their additional years of life are of poorer quality, with greater self-reported psychological and physical disability. The explanation for this different sex-related experience of HFrEF is unknown as is whether physicians recognize it. Women continue to receive suboptimal treatment, compared with men, with no obvious explanation for this shortfall.