Milton Packer M.D.

Kotecha, D., S. K. Gill, M. D. Flather, J. Holmes, M. Packer, G. Rosano, M. Bohm, J. J. V. McMurray, J. Wikstrand, S. D. Anker, D. J. van Veldhuisen, L. Manzano, T. G. von Lueder, A. S. Rigby, B. Andersson, J. Kjekshus, H. Wedel, F. Ruschitzka, J. G. F. Cleland, K. Damman, J. Redon and A. J. S. Coats (2019). “Impact of Renal Impairment on Beta-Blocker Efficacy in Patients With Heart Failure.” J Am Coll Cardiol 74(23): 2893-2904.

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BACKGROUND: Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy. OBJECTIVES: This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR). METHODS: Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and stratified by heart rhythm. RESULTS: Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m(2); 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m(2), and 2,286 (13.7%) 30 to 44 ml/min/1.73 m(2). Over a median follow-up of 1.3 years, eGFR was independently associated with mortality, with a 12% higher risk of death for every 10 ml/min/1.73 m(2) lower eGFR (95% confidence interval [CI]: 10% to 15%; p < 0.001). In 13,861 patients in sinus rhythm, beta-blockers reduced mortality versus placebo; adjusted hazard ratio (HR): 0.73 for eGFR 45 to 59 ml/min/1.73 m(2) (95% CI: 0.62 to 0.86; p < 0.001) and 0.71 for eGFR 30 to 44 ml/min/1.73 m(2) (95% CI: 0.58 to 0.87; p = 0.001). The authors observed no deterioration in renal function over time in patients with moderate or moderately severe renal impairment, no difference in adverse events comparing beta-blockers with placebo, and higher mortality in patients with worsening renal function on follow-up. Due to exclusion criteria, there were insufficient patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m(2)) to draw conclusions. In 2,879 patients with atrial fibrillation, there was no reduction in mortality with beta-blockers at any level of eGFR. CONCLUSIONS: Patients with heart failure, left ventricular ejection fraction <50% and sinus rhythm should receive beta-blocker therapy even with moderate or moderately severe renal dysfunction.

Docherty, K. F., L. Shen, D. Castagno, M. C. Petrie, W. T. Abraham, M. Bohm, A. S. Desai, K. Dickstein, L. V. Kober, M. Packer, J. L. Rouleau, S. D. Solomon, K. Swedberg, A. Vazir, M. R. Zile, P. S. Jhund and J. J. V. McMurray (2019). “Relationship between heart rate and outcomes in patients in sinus rhythm or atrial fibrillation with heart failure and reduced ejection fraction.” Eur J Heart Fail Dec 17. [Epub ahead of print].

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AIMS: To investigate the relationship between heart rate and outcomes in heart failure and reduced ejection fraction (HFrEF) patients in sinus rhythm (SR) and atrial fibrillation (AF) adjusting for natriuretic peptide concentration, a powerful prognosticator. METHODS AND RESULTS: Of 13 562 patients from two large HFrEF trials, 10 113 (74.6%) were in SR and 3449 (25.4%) in AF. The primary endpoint was the composite of cardiovascular death or heart failure hospitalization. Heart rate was analysed as a categorical (tertiles, T1-3) and continuous variable (per 10 bpm), separately in patients in SR and AF. Outcomes were adjusted for prognostic variables, including N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and also examined using change from baseline heart rate to 1 year (/= +10 bpm, < +/-10 bpm). SR patients with a higher heart rate had worse symptoms and quality of life, more often had diabetes and higher NT-proBNP concentrations. They had higher risk of the primary endpoint [T3 vs. T1 adjusted hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.35-1.66; P < 0.001; per 10 bpm: 1.12, 95% CI 1.09-1.16; P < 0.001]. In SR, heart rate was associated with a relatively higher risk of pump failure than sudden death (adjusted HR per 10 bpm 1.17, 95% CI 1.09-1.26; P < 0.001 vs. 1.07, 95% CI 1.02-1.13; P = 0.011). Heart rate was not predictive of any outcome in AF. CONCLUSIONS: In HFrEF, an elevated heart rate was an independent predictor of adverse cardiovascular outcomes in patients in SR, even after adjustment for NT-proBNP. There was no relationship between heart rate and outcomes in AF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers NCT01035255 and NCT00853658.

Butler, J., M. Packer, S. J. Greene, M. Fiuzat, S. D. Anker, K. J. Anstrom, P. E. Carson, L. B. Cooper, G. C. Fonarow, A. F. Hernandez, J. L. Januzzi, Jr., M. Jessup, R. R. Kalyani, S. Kaul, M. Kosiborod, J. Lindenfeld, D. K. McGuire, M. S. Sabatine, S. D. Solomon, J. R. Teerlink, M. Vaduganathan, C. W. Yancy, N. Stockbridge and C. M. O’Connor (2019). “Heart Failure End Points in Cardiovascular Outcome Trials of Sodium Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Critical Evaluation of Clinical and Regulatory Issues.” Circulation 140(25): 2108-2118.

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Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.

Vaduganathan, M., B. L. Claggett, A. S. Desai, S. D. Anker, S. V. Perrone, S. Janssens, D. Milicic, J. L. Arango, M. Packer, V. C. Shi, M. P. Lefkowitz, J. J. V. McMurray and S. D. Solomon (2019). “Prior Heart Failure Hospitalization, Clinical Outcomes, and Response to Sacubitril/Valsartan Compared with Valsartan in HFpEF.” J Am Coll Cardiol Nov 6. [Epub ahead of print].

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BACKGROUND: The period shortly after hospitalization for heart failure (HF) represents a high-risk window for recurrent clinical events, including rehospitalization or death. OBJECTIVES: To determine whether the efficacy and safety of sacubitril/valsartan varies in relation to the proximity to HF hospitalization among patients with HF and preserved ejection fraction (HFpEF). METHODS: In this post hoc analysis of PARAGON-HF, we assessed risk of clinical events and response to sacubitril/valsartan in relation to time from last HF hospitalization among patients with HFpEF (>/=45%). Primary outcome was composite total HF hospitalizations and cardiovascular death, analyzed using a semiparametric proportional rates method, stratified by geographic region. RESULTS: Of 4,796 validly randomized patients in PARAGON-HF, 622 (13%) were screened during hospitalization or within 30 days of prior hospitalization, 555 (12%) within 31-90 days, 435 (9%) within 91-180 days, 694 (14%) after 180 days, and 2,490 (52%) were never previously hospitalized. Over median 35 months follow-up, risk of total HF hospitalizations and cardiovascular death was inversely and non-linearly associated with timing from prior HF hospitalization (P<0.001). There was a gradient in relative risk reduction in primary events with sacubitril/valsartan from patients hospitalized within 30 days (rate ratio 0.73; 95% confidence interval 0.53-0.99) to patients never hospitalized (rate ratio 1.00; 95% confidence interval 0.80-1.24); trend in relative risk reduction Pinteraction=0.15. With valsartan alone, rate of total primary events was 26.7 (180 days), and 7.9 (not previously hospitalized) per 100 patient-years. Compared with valsartan, absolute risk reductions with sacubitril/valsartan were more prominent in patients enrolled early after hospitalization: 6.4% (180 days or who were never hospitalized; trend in absolute risk reduction Pinteraction=0.050. CONCLUSIONS: Recent hospitalization for HFpEF identifies patients at high-risk for near-term clinical progression. In the PARAGON-HF trial, relative and absolute benefits of sacubitril/valsartan compared with valsartan in HFpEF appear to be amplified when initiated in the high-risk window after hospitalization and warrants prospective validation.

Solomon, S. D., M. Vaduganathan, B. L. Claggett, M. Packer, M. Zile, K. Swedberg, J. Rouleau, M. A. Pfeffer, A. Desai, L. H. Lund, L. Koeber, I. Anand, N. K. Sweitzer, G. Linssen, B. Merkely, J. L. Arango, D. Vinereanu, C. H. Chen, M. Senni, A. Sibulo, S. Boytsov, V. Shi, A. Rizkala, M. Lefkowitz and J. J. V. McMurray (2019). “Sacubitril/Valsartan Across the Spectrum of Ejection Fraction in Heart Failure.” Circulation Nov 17. [Epub ahead of print].

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Background: While disease modifying therapies exist for heart failure (HF) with reduced left ventricular ejection fraction (LVEF), few options are available for patients in the higher range of LVEF (>40%). Sacubitril/valsartan has been compared with a renin-angiotensin- system (RAS) inhibitor alone in two similarly designed clinical trials of patients with reduced and preserved LVEF, permitting examination of its effects across the full spectrum of LVEF. Methods: We combined data from PARADIGM-HF (LVEF eligibility/=45%; n=4,796) in a prespecified pooled analysis. We divided randomized patients into LVEF categories:22.5% to 32.5% (n=3987), >32.5% to 42.5% (n=3143), > 42.5% to 52.5% (n=1427), > 52.5% to 62.5% (n=2166), >62.5% (n=1202). We assessed time to first cardiovascular death and HF hospitalization, its components, and total heart failure hospitlizations, all-cause mortality and non-cardiovascular mortality. Incidence rates and treatment effects were examined across categories of LVEF. Results: Among 13,195 randomized patients, we observed lower rates of cardiovascular death and HF hospitalization, but similar rates of non-cardiovascular death, among patients in the highest vs. lowest groups. Overall sacubitril/valsartan was superior to RAS inhibition for first cardiovascular death or heart failure hospitalization (HR 0.84, 95% CI 0.78, 0.90), cardiovascular death (HR 0.84, 95% CI 0.76, 0.92), heart failure hospitalization (HR 0.84, 95% CI 0.77, 0.91), and all-cause mortality (HR 0.88, 95% CI 0.81, 0.96). The effect of sacubitril/valsartan was modified by LVEF (treatment-by-continuous LVEF interaction p=0.02), and benefit appeared to be present for individuals with EF primarily below the normal range, although the treatment benefit for cardiovascular death diminished at a lower ejection fraction. We observed effect modification by LVEF on the efficacy of sacubitril/valsartan in both men and women with respect to composite total HF hospitalizations and cardiovascular death, although women derived benefit to higher ejection fractions. Conclusions:The therapeutic effects of sacubitril/valsartan, compared with a RAS inhibitor alone, vary by LVEF, with treatment benefits, particularly for heart failure hospitalization, that appear to extend to patients with heart failure and mildly reduced ejection fraction. These therapeutic benefits appeared to extend to a higher LVEF range in women compared with men. Clinical Trial Registration: NCT01920711. PARADIGM-HF Unique Identifier: NCT01035255.