Cardiology

Packer, M., C. O’Connor, J. J. 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: Apr [Epub ahead of print].

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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.

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. V. 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 5(5): 333-340.

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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.

Velasco, C. E. and C. Howard (2017). “Trouble on both sides: Pulmonary embolism with pneumothorax.” Am J Med 130(5): 530-533.

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Potential causes of syncope range from fairly trifling to life threatening. For a 49-year-old, previously healthy, African American man, the trigger proved dangerous. While unloading cargo from a truck, he fainted and fell approximately 3 feet to the ground. When emergency medical services arrived, his manager reported that the patient lost consciousness but was unable to quantify the period of time. The patient, upon awakening, experienced shortness of breath with severe right-sided chest and back pain. He attributed his accident to fatigue, stating that he had worked as a security guard the previous night, was tired, and simply fell asleep while emptying the vehicle. He denied seizure-like activity, prodrome, drug use, a family history of syncope, and loss of bowel or bladder function.

Edgerton, J. R. (2017). “Tick tock. Tick tock. Tic-tic-tic-tic: If you watch the pot long enough, it boils.” J Thorac Cardiovasc Surg 153(5): 1095-1096.

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In this issue of the Journal, Damiano and colleagues1 provide 5-year results of surgical ablation (SA) concomitant to coronary artery bypass grafting (CABG). Given the problems associated with following referral patients over 5 years, this is a laudable effort. In surgical and catheter ablation literature filled with glowing 1-year results, this type of long-term follow-up, reported according to the 2012 Consensus Statement,2 is sorely needed. And the results are sobering: 70% of patients were free of atrial tachyarrhythmias and off antiarrhythmic drugs at 5 years. These results are similar to a previously reported larger group of 512 patients who had a 66% similar outcome.3 These papers, in the modern reporting era of continuous rhythm monitoring, contrast with their 2003 report of 98% freedom from AF at 5 years in patients undergoing CABG/maze.4…Despite these things, we need to be aggressively treating our operative patients who have AF.

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. V. 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 38(15): 1132-1143.

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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.