Milton Packer M.D.

Packer, M. (2016). “Data sharing: Lessons from copernicus and kepler.” Bmj 354: i4911.

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To understand the workings of science, pick up a copy of De Revolutionibus Orbium Coelestium. Published with great reluctance by the astronomer Nicolaus Copernicus in 1543, the book puts forth a compelling argument for a heliocentric universe. Turn the pages and you will see the book is filled with data. Whose data? Copernicus relied on the data collected by others in addition to his own to formulate his revolutionary theory. Publication of these data subsequently allowed Johannes Kepler to identify discrepancies, which led to his innovative proposal in 1605 that the planets moved in an ellipse (rather than in a circle), an idea that he had previously assumed to be too simple for earlier astronomers to have overlooked. Of course, Kepler presented his data at the same time that he published his conclusions. In contrast, Tycho Brahe (who opposed Copernicus) famously withheld his astronomical data from Kepler because he knew they could be used to confirm Copernicus’s heliocentric model.

Solomon, S. D., B. Claggett, M. Packer, A. Desai, M. R. Zile, K. Swedberg, J. Rouleau, V. Shi, M. Lefkowitz and J. J. McMurray (2016). “Efficacy of sacubitril/valsartan relative to a prior decompensation: The paradigm-hf trial.” JACC Heart Fail 4(10): 816-822.

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OBJECTIVES: This study assessed whether the benefit of sacubtril/valsartan therapy varied with clinical stability. BACKGROUND: Despite the benefit of sacubitril/valsartan therapy shown in the PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, it has been suggested that switching from an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker should be delayed until occurrence of clinical decompensation. METHODS: Outcomes were compared among patients who had prior hospitalization within 3 months of screening (n = 1,611 [19%]), between 3 and 6 months (n = 1,009 [12%]), between 6 and 12 months (n = 886 [11%]), >12 months (n = 1,746 [21%]), or who had never been hospitalized (n = 3,125 [37%]). RESULTS: Twenty percent of patients without prior HF hospitalization experienced a primary endpoint of cardiovascular death or heart failure (HF) hospitalization during the course of the trial. Despite the increased risk associated with more recent hospitalization, the efficacy of sacubitril/valsartan therapy did not differ from that of enalapril according to the occurrence of or time from hospitalization for HF before screening, with respect to the primary endpoint or with respect to cardiovascular or all-cause mortality. CONCLUSIONS: Patients with recent HF decompensation requiring hospitalization were more likely to experience cardiovascular death or HF hospitalization than those who had never been hospitalized. Patients who were clinically stable, as shown by a remote HF hospitalization (>3 months prior to screening) or by lack of any prior HF hospitalization, were as likely to benefit from sacubitril/valsartan therapy as more recently hospitalized patients.

Packer, M. (2016). “The room where it happens: A skeptic’s analysis of the new heart failure guidelines.” J Card Fail 22(9): 726-730.

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New heart failure guidelines have been issued during the past several months, both in the United States and in Europe, in response to recent advances in and the approval of new drugs for the treatment of heart failure. Although guidelines documents are often viewed as authoritative and purely evidence-based, there are replete with meaningful (and inexplicable) inconsistencies, which derive from a review of the same body of scientific data by different groups. This satirical review highlights several examples of the entertaining foolishness of recent guideline documents in the good-natured hope that physicians will understand what the guidelines are, and more importantly, what they are not. Specifically, this paper describes the emergence of a new nonexistent disease; the strange battle between 2 bradycardic drugs (digoxin and ivabradine); the confusion that reigns over the positioning and dosing of inhibitors of the renin-angiotensin system; and the special recommendations that have been issued for certain special populations. As Otto von Bismarck remarked, guideline deliberations are like sausages; it is better not to see them being made. Yet, even after they are ready for public view, we should be cautious. Practitioners who rely on them for clinical decision-making engage in an unnecessary form of self-deception; those who read them literally and adhere to them strictly do not practice evidence-based medicine; and those who delve into them in a search for the truth are destined to be disappointed.

Packer, M. (2016). “Kicking the tyres of a heart failure trial: Physician response to the approval of sacubitril/valsartan in the USA.” Eur J Heart Fail: 2016 Aug [Epub ahead of print].

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Angiotensin receptor-neprilysin inhibition has been shown to be superior to target doses of an ACE inhibitor in reducing the risk of cardiovascular death and clinical disease progression in patients with chronic heart failure and a reduced EF. Nevertheless, although sacubitril/valsartan has been available in the USA for a year, uptake of the drug by practitioners has been slow, in part because of misconceptions about the pivotal trial that demonstrated its efficacy in heart failure (PARADIGM-HF). This review addresses questions that have been raised in the USA about the design of the trial as well as the patients who were studied, the replicability and applicability of the results, and the safety of neprilysin inhibition. The totality of evidence indicates that the PARADIGM-HF trial used an appropriate comparator; enrolled patients typical of those seen in the community with mild to moderate symptoms; yielded highly persuasive and replicable results; and demonstrated benefits that are applicable to patients taking subtarget doses of ACE inhibitors and ARBs. Regulatory review in the USA concluded that the established advantages of sacubitril/valsartan on cardiovascular death and disease progression outweighed hypothetical uncertainties about the long-term effects of neprilysin inhibition in patients who might not have survived without the drug. Accordingly, both the new US and European Society of Cardiology heart failure guidelines recommend sacubitril/valsartan as the preferred approach to inhibiting the renin-angiotensin system in patients with chronic heart failure who are currently receiving an ACE inhibitor or ARB.

Packer, M. (2016). “Heart failure’s dark secret: Does anyone really care about optimal medical therapy?” Circulation 134(9): 629-631.

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Today, most heart failure physicians focus on devices and transplantation; hospital-based management teams devoted only to achieving optimal medical therapy are scarce. The financial demands on heart failure specialists are enormous. A viable business plan can no longer be based on the misguided hope that payers will reimburse generously for prescriptions of digitalis and diuretics; in contrast, cardiac procedures generate meaningful revenues. A growing advocacy now encourages the use of ventricular assist devices in ambulatory patients on the basis of the dual misconceptions that the hazards are readily managed and that the clinical responses to medical therapy are poor. The biases in favor of performing procedures are so great that a National Institutes of Health–sponsored randomized trial comparing left ventricular assistance and optimal medical therapy in ambulatory patients was closed because of slow recruitment.