Research Spotlight

Brennan, J. M., L. Thomas, D. J. Cohen, D. Shahian, A. Wang, M. J. Mack, D. R. Holmes, F. H. Edwards, N. Z. Frankel, S. J. Baron, J. Carroll, V. Thourani, E. M. Tuzcu, S. V. Arnold, R. Cohn, T. Maser, B. Schawe, S. Strong, A. Stickfort, E. Patrick-Lake, F. L. Graham, D. Dai, F. Li, R. A. Matsouaka, S. O’Brien, F. Li, M. J. Pencina and E. D. Peterson (2017). “Transcatheter versus surgical aortic valve replacement: Propensity-matched comparison.” J Am Coll Cardiol 70(4): 439-450.

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BACKGROUND: Randomized trials support the use of transcatheter aortic valve replacement (TAVR) for the treatment of aortic stenosis in high- and intermediate-risk patients, but the generalizability of those results in clinical practice has been challenged. OBJECTIVES: The aim of this study was to determine the safety and effectiveness of TAVR versus surgical aortic valve replacement (SAVR), particularly in intermediate- and high-risk patients, in a nationally representative real-world cohort. METHODS: Using data from the Transcatheter Valve Therapy Registry and Society of Thoracic Surgeons National Database linked to Medicare administrative claims for follow-up, 9,464 propensity-matched intermediate- and high-risk (Society of Thoracic Surgeons Predicted Risk of Mortality score >/=3%) U.S. patients who underwent commercial TAVR or SAVR were examined. Death, stroke, and days alive and out of the hospital to 1 year were compared, as well as discharge home, with subgroup analyses by surgical risk, demographics, and comorbidities. RESULTS: In a propensity-matched cohort (median age 82 years, 48% women, median Society of Thoracic Surgeons Predicted Risk of Mortality score 5.6%), TAVR and SAVR patients experienced no difference in 1-year rates of death (17.3% vs. 17.9%; hazard ratio: 0.93; 95% confidence interval [CI]: 0.83 to 1.04) and stroke (4.2% vs. 3.3%; hazard ratio: 1.18; 95% CI: 0.95 to 1.47), and no difference was observed in the proportion of days alive and out of the hospital to 1 year (rate ratio: 1.00; 95% CI: 0.98 to 1.02). However, TAVR patients were more likely to be discharged home after treatment (69.9% vs. 41.2%; odds ratio: 3.19; 95% CI: 2.84 to 3.58). Results were consistent across most subgroups, including among intermediate- and high-risk patients. CONCLUSIONS: Among unselected intermediate- and high-risk patients, TAVR and SAVR resulted in similar rates of death, stroke, and DAOH to 1 year, but TAVR patients were more likely to be discharged home.

Kivelevitch, D., J. M. Schussler and A. Menter (2017). “Coronary plaque characterization in psoriasis.” Circulation 136(3): 277-280.

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Psoriasis is strongly associated with multiple comorbidities, including obesity, tobacco smoking, diabetes mellitus, dyslipidemia, hypertension, and psychiatric, autoimmune, renal, and cardiovascular diseases, among others.5 Multiple publications have confirmed the association between psoriasis and vascular disease.5–8 Patients with psoriasis, especially those <50 years old and with more severe disease, are at higher risk of developing coronary artery disease (CAD).9 Furthermore, patients with moderate to severe psoriasis have a reduced life expectancy of ≈4 to 5 years relating to cardiovascular disease (CVD). Traditional risk assessment tools such as the Framingham risk score do not appropriately estimate this CAD risk. Recent studies that used both noninvasive and invasive coronary artery studies of patients with psoriasis and have shown a higher prevalence of CAD in patients with psoriasis compared with healthy individuals.10–13 Our recent coronary artery calcium score study of 129 patients with psoriasis with moderate to severe disease revealed a risk similar to that of patients with type II diabetes mellitus and significantly higher than that of healthy patients.10 One of the major areas of research and interest in the therapy of moderate to severe psoriasis is the potential benefit of systemic therapies such as methotrexate and biological therapies, especially tumor necrosis factor-α antagonist agents, on CAD.14

Shen, L., P. S. Jhund, M. C. Petrie, B. L. Claggett, S. Barlera, J. G. F. Cleland, H. J. Dargie, C. B. Granger, J. Kjekshus, L. Kober, R. Latini, A. P. Maggioni, M. Packer, B. Pitt, S. D. Solomon, K. Swedberg, L. Tavazzi, J. Wikstrand, F. Zannad, M. R. Zile and J. J. V. McMurray (2017). “Declining risk of sudden death in heart failure.” N Engl J Med 377(1): 41-51.

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BACKGROUND: The risk of sudden death has changed over time among patients with symptomatic heart failure and reduced ejection fraction with the sequential introduction of medications including angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, and mineralocorticoid-receptor antagonists. We sought to examine this trend in detail. METHODS: We analyzed data from 40,195 patients who had heart failure with reduced ejection fraction and were enrolled in any of 12 clinical trials spanning the period from 1995 through 2014. Patients who had an implantable cardioverter-defibrillator at the time of trial enrollment were excluded. Weighted multivariable regression was used to examine trends in rates of sudden death over time. Adjusted hazard ratios for sudden death in each trial group were calculated with the use of Cox regression models. The cumulative incidence rates of sudden death were assessed at different time points after randomization and according to the length of time between the diagnosis of heart failure and randomization. RESULTS: Sudden death was reported in 3583 patients. Such patients were older and were more often male, with an ischemic cause of heart failure and worse cardiac function, than those in whom sudden death did not occur. There was a 44% decline in the rate of sudden death across the trials (P=0.03). The cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial and 1.0% in the most recent trial. The rate of sudden death was not higher among patients with a recent diagnosis of heart failure than among those with a longer-standing diagnosis. CONCLUSIONS: Rates of sudden death declined substantially over time among ambulatory patients with heart failure with reduced ejection fraction who were enrolled in clinical trials, a finding that is consistent with a cumulative benefit of evidence-based medications on this cause of death.

Busse, L. W., X. S. Wang, D. M. Chalikonda, K. W. Finkel, A. K. Khanna, H. M. Szerlip, D. Yoo, S. L. Dana and L. S. Chawla (2017). “Clinical experience with iv angiotensin ii administration: A systematic review of safety.” Crit Care Med 45(8): 1285-1294.

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OBJECTIVE: Angiotensin II is an endogenous hormone with vasopressor and endocrine activities. This is a systematic review of the safety of IV angiotensin II. DATA SOURCES: PubMed, Medline, Scopus, and Cochrane. STUDY SELECTION: Studies in which human subjects received IV angiotensin II were selected whether or not safety was discussed. DATA EXTRACTION: In total, 18,468 studies were screened by two reviewers and one arbiter. One thousand one hundred twenty-four studies, in which 31,281 participants received angiotensin II (0.5-3,780 ng/kg/min), were selected. Data recorded included number of subjects, comorbidities, angiotensin II dose and duration, pressor effects, other physiologic and side effects, and adverse events. DATA SYNTHESIS: The most common nonpressor effects included changes in plasma aldosterone, renal function, cardiac variables, and electrolytes. Adverse events were infrequent and included headache, chest pressure, and orthostatic symptoms. The most serious side effects were exacerbation of left ventricular failure in patients with congestive heart failure and bronchoconstriction. One patient with congestive heart failure died from refractory left ventricular failure. Refractory hypotensive shock was fatal in 55 of 115 patients treated with angiotensin II in case studies, cohort studies, and one placebo-controlled study. One healthy subject died after a pressor dose of angiotensin II was infused continuously for 6 days. No other serious adverse events attributable to angiotensin II were reported. Heterogeneity in study design prevented meta-analysis. CONCLUSION: Adverse events associated with angiotensin II were infrequent; however, exacerbation of asthma and congestive heart failure and one fatal cerebral hemorrhage were reported. This systematic review supports the notion that angiotensin II has an acceptable safety profile for use in humans.

Fernandez, O., G. Giovannoni, R. J. Fox, R. Gold, J. T. Phillips, J. Potts, M. Okwuokenye and J. L. Marantz (2017). “Efficacy and safety of delayed-release dimethyl fumarate for relapsing-remitting multiple sclerosis in prior interferon users: An integrated analysis of define and confirm.” Clin Ther: 2017 Jul [Epub ahead of print].

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PURPOSE: In Phase III studies (DEFINE [Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS]/CONFIRM [Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis]), delayed-release dimethyl fumarate (DMF) demonstrated significant efficacy and a favorable benefit-risk profile in patients with relapsing-remitting multiple sclerosis (RRMS). Post hoc analyses of integrated data from DEFINE/CONFIRM were conducted to evaluate the effect of DMF in patients previously treated with interferon (IFN) beta. METHODS: Patients (age 18-55 years; Expanded Disability Status Scale score, 0-5.0) were randomized to receive DMF 240 mg BID or TID, placebo, or glatiramer acetate (CONFIRM only) for up to 2 years. Previous IFN users received at least 1 IFN treatment >3 months before randomization. Data for DMF 240 mg BID (approved dosing regimen) are reported. FINDINGS: In the integrated intention-to-treat population, 172 and 169 patients receiving DMF or placebo, respectively, had received >/=1 prior IFN. In this subgroup, significant reductions with DMF versus placebo were observed for the annualized relapse rate (rate ratio, 0.55 [95% CI, 0.40-0.77]), new/newly enlarging T2-hyperintense lesions (lesion mean ratio, 0.16 [95% CI, 0.09-0.29]), odds of having more gadolinium-enhancing lesions (odds ratio, 0.17 [95% CI, 0.07-0.44]), and new T1-hypointense lesions (lesion mean ratio, 0.25 [95% CI, 0.14-0.45]). Median Expanded Disability Status Scale scores remained stable during the study period. Adverse events associated with DMF included flushing and gastrointestinal events. IMPLICATIONS: In this post hoc analysis in patients with previous IFN treatment, DMF demonstrated significant efficacy over 2 years versus placebo and an adverse event profile consistent with the overall population of DEFINE/CONFIRM.