Milton Packer M.D.

Packer, M., R. Holcomb, W. T. Abraham, S. Anker, K. Dickstein, G. Filippatos, H. Krum, A. P. Maggioni, J. J. McMurray, A. Mebazaa, C. O’Connor, F. Peacock, P. Ponikowski, F. Ruschitzka, D. J. van Veldhuisen and J. Holzmeister (2016). “Rationale for and design of the true-ahf trial: The effects of ularitide on the short-term clinical course and long-term mortality of patients with acute heart failure.” Eur J Heart Fail: 2016 Nov [Epub ahead of print].

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The TRUE-AHF is a randomized, double-blind, parallel-group, placebo-controlled trial which is evaluating the effects of a 48-h infusion of ularitide (15 ng/kg/min) on the short- and long-term clinical course of patients with acute heart failure. Noteworthy features of the study include the early enrolment of patients following their initial clinical presentation (within 12 h), and entry blood pressure criteria and thresholds for the adjustment of drug infusion rates, which aim to minimize the risk of hypotension. The trial has two primary endpoints: (i) cardiovascular mortality during long-term follow-up; and (ii) the clinical course of patients during their index hospitalization. Cardiovascular mortality is evaluated in this event-driven trial by following all randomized patients for the occurrence of death until the end of the entire study without truncation at an arbitrarily determined early time point. The clinical course during the index hospitalization is evaluated using the hierarchical clinical composite endpoint, which combines information regarding changes in symptoms and the occurrence of in-hospital worsening heart failure events and death into a single ranked metric that captures interval clinical events and minimizes the likelihood of missing data and confounding due to intensification of background therapy. The design of the TRUE-AHF trial capitalizes on lessons learned from earlier trials and aims to evaluate definitively the potential benefit of ularitide in patients with acute heart failure.

Cannon, J. A., L. Shen, P. S. Jhund, S. L. Kristensen, L. Kober, F. Chen, J. Gong, M. P. Lefkowitz, J. L. Rouleau, V. C. Shi, K. Swedberg, M. R. Zile, S. D. Solomon, M. Packer and J. J. McMurray (2016). “Dementia-related adverse events in paradigm-hf and other trials in heart failure with reduced ejection fraction.” Eur J Heart Fail: 2016 Nov [Epub ahead of print].

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AIMS: Inhibition of neprilysin, an enzyme degrading natriuretic and other vasoactive peptides, is beneficial in heart failure with reduced ejection fraction (HFrEF), as shown in PARADIGM-HF which compared the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan with enalapril. As neprilysin is also one of many enzymes clearing amyloid-beta peptides from the brain, there is a theoretical concern about the long-term effects of sacubitril/valsartan on cognition. Therefore, we have examined dementia-related adverse effects (AEs) in PARADIGM-HF and placed these findings in the context of other recently conducted HFrEF trials. METHODS AND RESULTS: In PARADIGM-HF, patients with symptomatic HFrEF were randomized to sacubitril/valsartan 97/103 mg b.i.d. or enalapril 10 mg b.i.d. in a 1:1 ratio. We systematically searched AE reports, coded using the Medical Dictionary for Regulatory Activities (MedDRA), using Standardized MedDRA Queries (SMQs) with ‘broad’ and ‘narrow’ preferred terms related to dementia. In PARADIGM-HF, 8399 patients aged 18-96 years were randomized and followed for a median of 2.25 years (up to 4.3 years). The narrow SMQ search identified 27 dementia-related AEs: 15 (0.36%) on enalapril and 12 (0.29%) on sacubitril/valsartan [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.33-1.59]. The broad search identified 97 (2.30%) and 104 (2.48%) AEs (HR 1.01, 95% CI 0.75-1.37), respectively. The rates of dementia-related AEs in both treatment groups in PARADIGM-HF were similar to those in three other recent trials in HFrEF. CONCLUSION: We found no evidence that sacubitril/valsartan, compared with enalapril, increased dementia-related AEs, although longer follow-up may be necessary to detect such a signal and more sensitive tools are needed to detect lesser degrees of cognitive impairment. Further studies to address this question are warranted.

Packer, M. (2016). “Cobalt cardiomyopathy: A critical reappraisal in light of a recent resurgence.” Circ Heart Fail 9(12).

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Cobalt can cause a distinctive, rapidly progressive and reversible depression of cardiac systolic function, which is readily distinguished from other causes of cardiomyopathy. Patients present with the subacute onset of severe heart failure, which is accompanied by hypotension and cyanosis, pericardial effusion, low voltage on the electrocardiogram, marked elevation of serum enzymes, and lactic acidosis. They typically have a history of lethargy, anorexia, and weight loss in the months preceding the illness and exhibit other evidence of cobalt’s effects on the body (eg, polycythemia and goiter). The course of cobalt-related cardiomyopathy may be progressive and fatal, but those who survive and cease exposure generally demonstrate complete resolution of symptoms and recovery of cardiac function. Patients presenting with rapid onset of cardiomyopathy, who also exhibit polycythemia, pericardial effusion, or goiter should be evaluated for cobalt exposure. Exposure can be confirmed by the measurement of cobalt in the serum, but serum levels of the ion are not reliably predictive of clinical cardiotoxicity. The clinical emergence of cobalt cardiomyopathy seems to require the coexistence of one or more cofactors, particularly a low-protein diet, thiamine deficiency, alcoholism, and hypothyroidism. As the medicinal use of cobalt has waned and measures to reduce industrial exposure have been implemented, subacute cobalt-related cardiomyopathy had become rare. However, reports describing classical features of the disease have recently surged among patients with a malfunctioning cobalt-alloy hip prosthesis.

Desai, A. S., O. Vardeny, B. Claggett, J. J. McMurray, M. Packer, K. Swedberg, J. L. Rouleau, M. R. Zile, M. Lefkowitz, V. Shi and S. D. Solomon (2016). “Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril: A secondary analysis of the paradigm-hf trial.” JAMA Cardiol: 2016 Nov [Epub ahead of print].

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Importance: Consensus guidelines recommend the use of mineralocorticoid receptor antagonists (MRAs) for selected patients with symptomatic heart failure and reduced ejection fraction (HFrEF) to reduce morbidity and mortality; however, the use of MRAs in combination with other inhibitors of the renin-angiotensin-aldosterone system increases the risk of hyperkalemia. Objective: To determine whether the risk of hyperkalemia associated with use of MRAs for patients with HFrEF is reduced by sacubitril/valsartan in comparison with enalapril. Design, Setting, and Participants: The PARADIGM-HF (Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial randomly assigned 8399 patients with chronic HF, New York Heart Association class II to IV symptoms, and a left ventricular EF of 40% or less to treatment with enalapril 10 mg twice daily or sacubitril/valsartan 97/103 mg twice daily (previously known as LCZ696 [200 mg twice daily]) in addition to guideline-directed medical therapy. Use of MRAs was encouraged but left to the discretion of study investigators. Serum potassium level was measured at every study visit. The incidence of hyperkalemia (potassium level >5.5 mEq/L) and severe hyperkalemia (potassium level >6.0 mEq/L) among patients treated or not treated with an MRA at baseline and the risk of subsequent hyperkalemia for those newly treated with an MRA during study follow-up were defined in time-updated Cox proportional hazards models. Analyses were conducted between August 1 and October 15, 2016. Main Outcomes and Measures: Incident hyperkalemia and severe hyperkalemia. Results: In comparison with the 3728 patients (44.4% of enrolled participants [21.6% female]) not taking an MRA at baseline, the 4671 patients (55.6% [22.0% female]) taking an MRA tended to be younger, with a lower EF, lower systolic blood pressure, and more advanced HF symptoms. Among those taking an MRA at baseline, the overall rates of hyperkalemia were similar between treatment groups, but severe hyperkalemia was more common in patients randomly assigned to enalapril than to sacubitril/valsartan (3.1 vs 2.2 per 100 patient-years; HR, 1.37 [95% CI, 1.06-1.76]; P = .02). In analyses including patients who newly started taking MRAs during the PARADIGM-HF trial, severe hyperkalemia remained more common in those randomly assigned to enalapril than to those randomly assigned to sacubitril/valsartan (3.3 vs 2.3 per 100 patient-years; HR, 1.43 [95% CI, 1.13-1.81]; P = .003). Conclusions and Relevance: Among MRA-treated patients with symptomatic HFrEF, severe hyperkalemia is more likely during treatment with enalapril than with sacubitril/valsartan. These data suggest that neprilysin inhibition attenuates the risk of hyperkalemia when MRAs are combined with other inhibitors of the renin-angiotensin-aldosterone system in patients with HF.

Packer, M. (2016). “Angiotensin neprilysin inhibition for patients with heart failure: What if sacubitril/valsartan were a treatment for cancer?” JAMA Cardiol.

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Oncologists would adopt the new drug as the standard of care in a heartbeat, but US physicians who treat patients with heart failure often do little. Heart failure is a fatal disorder, and current drugs achieve only a brief clinical remission. Twoyears ago, sacubitril/valsartanwas shown to be superior to a conventional inhibitor of the renin-angiotensin system in reducing the risk of cardiovascular death,1 and it received expedited US Food and Drug Administration approval for treatment of chronic heart failure. Owing to cost, third-party payors discouraged the use of the drug by requiring high patient copays and administrative preapprovals. Oncologists are accustomed to overcoming these distractions, but other physicians are not. Consequently, uptake of sacubitril/ valsartan by US practitioners has been slow.