Milton Packer M.D.

Solomon, S. D., A. R. Rizkala, J. Gong, W. Wang, 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, V. C. Shi, M. P. Lefkowitz and J. J. V. McMurray (2017). “Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: Rationale and design of the paragon-hf trial.” JACC Heart Fail 5(7): 471-482.

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OBJECTIVES: The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial is designed to determine the efficacy and safety of the angiotensin receptor neprilysin inhibitor sacubitril/valsartan compared with valsartan in patients with chronic heart failure and preserved ejection fraction (HFpEF). BACKGROUND: HFpEF is highly prevalent, associated with substantial morbidity and mortality, and in need of effective therapies that improve outcomes. The angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan, which has been shown to benefit patients with heart failure (HF) and reduced ejection fraction, demonstrated favorable physiologic effects in a phase II HFpEF trial. METHODS: The PARAGON-HF trial is a randomized, double-blind, parallel group, active-controlled, event-driven trial comparing the long-term efficacy and safety of valsartan and sacubitril/valsartan in patients with chronic HFpEF (left ventricular ejection fraction >/=45%), New York Heart Association functional class II to IV symptoms, elevated natriuretic peptides, and evidence of structural heart disease. Before randomization, all patients entered sequential single-blind run-in periods to ensure tolerability of both drugs at half the target doses (i.e., valsartan titrated to 80 mg bid followed by sacubitril/valsartan 49/51 mg [100 mg] bid). The primary outcome is the composite of cardiovascular death and total (first and recurrent) HF hospitalizations. CONCLUSIONS: PARAGON-HF will determine whether sacubitril/valsartan is superior to angiotensin receptor blockade alone in patients with chronic symptomatic HFpEF. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF].

Packer, M. and J. J. V. McMurray (2017). “Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin-angiotensin system for the treatment of heart failure.” Lancet 389(10081): 1831-1840.

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The magnitude of the clinical benefits produced by inhibitors of the renin-angiotensin system in heart failure has been modest, possibly because of the ability of renin-angiotensin activity to escape from suppression during long-term treatment. Efforts to intensify pharmacological blockade by use of dual inhibitors that interfere with the renin-angiotensin system at multiple sites have not yielded consistent incremental clinical benefits, but have been associated with serious adverse reactions. By contrast, potentiation of endogenous compensatory vasoactive peptides can act to enhance the survival effects of inhibitors of the renin-angiotensin system, as evidenced by trials that have compared angiotensin-converting enzyme inhibitors with drugs that inhibit both the renin-angiotensin system and neprilysin. Several endogenous vasoactive peptides act as adaptive mechanisms, and their augmentation could help to broaden the benefits of renin-angiotensin system inhibitors for patients with heart failure.

Packer, M., C. O’Connor, J. J. V. McMurray, J. Wittes, W. T. Abraham, S. D. Anker, K. Dickstein, G. Filippatos, R. Holcomb, H. Krum, A. P. Maggioni, A. Mebazaa, W. F. Peacock, M. C. Petrie, P. Ponikowski, F. Ruschitzka, D. J. van Veldhuisen, L. S. Kowarski, M. Schactman and J. Holzmeister (2017). “Effect of ularitide on cardiovascular mortality in acute heart failure.” N Engl J Med 376(20): 1956-1964.

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BACKGROUND: In patients with acute heart failure, early intervention with an intravenous vasodilator has been proposed as a therapeutic goal to reduce cardiac-wall stress and, potentially, myocardial injury, thereby favorably affecting patients’ long-term prognosis. METHODS: In this double-blind trial, we randomly assigned 2157 patients with acute heart failure to receive a continuous intravenous infusion of either ularitide at a dose of 15 ng per kilogram of body weight per minute or matching placebo for 48 hours, in addition to accepted therapy. Treatment was initiated a median of 6 hours after the initial clinical evaluation. The coprimary outcomes were death from cardiovascular causes during a median follow-up of 15 months and a hierarchical composite end point that evaluated the initial 48-hour clinical course. RESULTS: Death from cardiovascular causes occurred in 236 patients in the ularitide group and 225 patients in the placebo group (21.7% vs. 21.0%; hazard ratio, 1.03; 96% confidence interval, 0.85 to 1.25; P=0.75). In the intention-to-treat analysis, there was no significant between-group difference with respect to the hierarchical composite outcome. The ularitide group had greater reductions in systolic blood pressure and in levels of N-terminal pro-brain natriuretic peptide than the placebo group. However, changes in cardiac troponin T levels during the infusion did not differ between the two groups in the 55% of patients with paired data. CONCLUSIONS: In patients with acute heart failure, ularitide exerted favorable physiological effects (without affecting cardiac troponin levels), but short-term treatment did not affect a clinical composite end point or reduce long-term cardiovascular mortality.

Packer, M. (2017). “Tetralogy of fallow: Four trials and tribulations.” JACC Heart Fail 5(6): 408-410.

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When Chris O’Connor became the Founding Editor of JACC: Heart Failure, he opened a dead letter office (1) to welcome old trials that had been completed and reported years before but had never been published. Their results had been fully analyzed and presented at scientific meetings, and often drafts of the primary papers had been written…Once the papers were sidelined, it was easy to fantasize that they would eventually be published. Yet, despite the overwhelming ethical mandate to place the results in print, there was always a reason to pursue different priorities and to follow other paths of immediate interest. The papers were left fallow; they were plots of land that had been plowed and harrowed but remained unsown, presumably under the premise that doing so would restore their fertility. It was this false premise that allowed time to pass…

Packer, M., B. Pitt, J. L. Rouleau, K. Swedberg, D. L. DeMets and L. Fisher (2017). “Long-term effects of flosequinan on the morbidity and mortality of patients with severe chronic heart failure: Primary results of the profile trial after 24 years.” JACC Heart Fail 5(6): 399-407.

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OBJECTIVES: The purpose of this clinical trial was to evaluate the long-term effects of flosequinan on the morbidity and mortality of patients with severe chronic heart failure. BACKGROUND: Flosequinan was the first oral vasodilator to be used in the clinic to augment the effects of digitalis, diuretics, and angiotensin-converting enzyme inhibitors in heart failure. However, the drug activated neurohormonal systems and exerted both positive inotropic and chronotropic effects, raising concerns about its safety during long-term use. METHODS: Following a run-in period designed to minimize the risk of tachycardia, we randomly assigned 2,354 patients in New York Heart Association functional class III to IV heart failure and with an ejection fraction