Milton Packer M.D.

Packer, M. (2017). “Response by packer to letter regarding article, “development and evolution of a hierarchical clinical composite end point for the evaluation of drugs and devices for acute and chronic heart failure: A 20-year perspective”.” Circulation 135(15): e892-e893.

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The hierarchical clinical composite end point (HCCE) was developed to address 2 important goals in the analysis of clinical trial data: (1) to minimize the bias inherent in the censoring of important adverse events when the primary end point was focused entirely on a patient benefit, and (2) to expand the range of responses when the primary end point was focused entirely on the risk of an adverse event. Over the past 20 years, the hierarchical clinical composite has succeeded with respect to both goals, and yet, as I described in my article,1 the HCCE still has important limitations and remains a work in progress.

Packer, M. (2017). “Let Us Not Forget the Long-term Safety Concerns of Sacubitril/Valsartan-Reply.” JAMA Cardiol: 2017 Mar [Epub ahead of print].

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The letter by McCarthy and McEvoy illustrates the distinctive process that permeates the thinking of physicians who treat heart failure in contrast to those who treat cancer. Oncologists enthusiastically use drugs in high doses in the hope that they might prolong life, knowing with certainty that the drugs cause serious adverse effects. In contrast, cardiologists hesitate to use a drug that has been demonstrated (beyond a reasonable doubt) to prolong life simply because someone raises the hypothetical concern about an unobserved adverse effect that might occur 10 to 20 years later. McCarthy and McEvoy make reference to the concerns of the US Food and Drug Administration about the risk of dementia with sacubitril/valsartan; fortunately, their position is far more reassuring than the authors of the letter have conveyed. A comprehensive summary of the regulatory position on the safety of the drug has recently been published.

Seferovic, J. P., B. Claggett, S. B. Seidelmann, E. W. Seely, M. Packer, M. R. Zile, J. L. Rouleau, K. Swedberg, M. Lefkowitz, V. C. Shi, A. S. Desai, J. J. McMurray and S. D. Solomon (2017). “Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial.” Lancet Diabetes Endocrinol: 2017 Mar [Epub ahead of print].

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BACKGROUND: Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA1c and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF. METHODS: In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA1c >/=6.5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA1c, triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Time to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups. FINDINGS: There were no significant differences in HbA1c concentrations between randomised groups at screening. During the first year of follow-up, HbA1c concentrations decreased by 0.16% (SD 1.40) in the enalapril group and 0.26% (SD 1.25) in the sacubitril/valsartan group (between-group reduction 0.13%, 95% CI 0.05-0.22, p=0.0023). HbA1c concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0.14%, 95% CI 0.06-0.23, p=0.0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 [7%] patients) compared with patients receiving enalapril (153 [10%]; hazard ratio 0.71, 95% CI 0.56-0.90, p=0.0052). Similarly, fewer patients were started on oral antihyperglycaemic therapy (0.77, 0.58-1.02, p=0.073) in the sacubitril/valsartan group. INTERPRETATION: Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA1c than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF.

Packer, M. (2017). “Double vision: Replicating a trial showing a survival benefit.” JACC Heart Fail 5(3): 232-235.

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Many physicians boast that there is no reason to read or keep up with the medical literature. Why? If it is true that 1 trial is never enough to change clinical practice, clinicians can always claim that they are waiting for confirmatory evidence and for critical review by regulatory authorities and peer groups. Such thinking greatly simplifies the challenge of maintaining medical knowledge. Practitioners need not become familiar with any scientific study; they need only to wait for guideline statements, which will determine when a critical mass of evidence has been compiled. Sadly, some clinicians will also wait to see what practices and procedures are reimbursed, because this—not scientific evidence—has become a major factor influencing medical care.

Bohm, M., R. Young, P. S. Jhund, S. D. Solomon, J. Gong, M. P. Lefkowitz, A. R. Rizkala, J. L. Rouleau, V. C. Shi, K. Swedberg, M. R. Zile, M. Packer and J. J. McMurray (2017). “Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (lcz696) in patients with chronic heart failure and reduced ejection fraction: Results from paradigm-hf.” Eur Heart J: 2017 Feb [Epub ahead of print].

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Background: Compared to heart failure patients with higher systolic blood pressure (SBP), those with lower SBP have a worse prognosis. To make matters worse, the latter patients often do not receive treatment with life-saving therapies that might lower blood pressure further. We examined the association between SBP and outcomes in the Prospective Comparison of angiotensin receptor-neprilysin inhibitor (ARNI) with an angiotensin-converting enzyme (ACE) inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF), as well as the effect of sacubitril/valsartan, compared with enalapril, according to baseline SBP. Methods: We analysed the effect of treatment on SBP and on the primary composite outcome (cardiovascular death or heart failure hospitalization), its components and all-cause death. We examined baseline SBP as a categorical (<110, 110 to < 120, 120 to < 130, 130 to < 140 and ≥140 mmHg) and continuous variable, as well as average in-trial SBP and time-updated SBP. Findings: All-cause and cardiovascular mortality rates were highest in patients with the lowest SBP whereas there was a U-shaped relationship between SBP and the rate of heart failure hospitalization. The benefit of sacubitril/valsartan over enalapril was consistent across all baseline SBP categories for all outcomes. For example, the sacubitril/valsartan versus enalapril hazard ratio for the primary endpoint was 0.88 (95%CI 0.74–1.06) in patients with a baseline SBP <110 mmHg and 0.81 (0.65–1.02) for those with a SBP ≥140 mmHg (P for interaction = 0.55). Symptomatic hypotension, study drug dose-reduction and discontinuation were more frequent in patients with a lower SBP. Interpretation: In PARADIGM-HF, patients with lower SBP at randomization, notably after tolerating full doses of both study drugs during a run-in period, were at higher risk but generally tolerated sacubitril/valsartan and had the same relative benefit over enalapril as patients with higher baseline SBP.