Five Years of Sacubitril/Valsartan-a Safety Analysis of Randomized Clinical Trials and Real-World Pharmacovigilance.

PURPOSE: In PARADIGM-HF, sacubitril/valsartan showed a significant reduction in mortality and hospitalization for patients with heart failure with reduced ejection fraction. Despite proven efficacy, sacubitril/valsartan has moderate uptake in clinical practice. This study explores the safety profile of sacubitril/valsartan by comparing adverse events in RCT and real-world use. METHODS: We studied hypotension, renal dysfunction, hyperkalemia, and angioedema associated with sacubitril/valsartan in RCTs and pharmacovigilance databases. A random-effects meta-analysis was performed with six RCTs investigating sacubitril/valsartan vs. control/comparators in heart failure patients. WHO's VigiBase, FAERS, and EMA's EudraVigilance were mined to obtain spontaneously reported real-world adverse events. Disproportionality analysis was performed with the FDA's OpenVigil 2.0. RESULTS: Six RCTs enrolled 15,538 patients with heart failure with reduced and preserved ejection fractions. There was no statistical difference for the composite of hypotension, renal dysfunction, hyperkalemia, and angioedema between sacubitril/valsartan and its comparators viz. ACEi or ARBs (OR 1.23, CI 0.98-1.56; p = 0.08). A total of 103,038 adverse events were registered in the spontaneous reporting systems. Hypotension was the most reported adverse event. Proportions of composite adverse events were 20% in VigiBase, 17% in FAERS, and 39% with EudraVigilance. Disproportionality analysis showed a lower risk of adverse events with sacubitril/valsartan than other guideline-directed heart failure medications used in clinical practice. CONCLUSION: With increased uptake of sacubitril/valsartan, risks of hypotension, renal dysfunction, hyperkalemia, and angioedema appear low and acceptable in RCTs and global clinical practice.

The effect of an end-of-clerkship review session on NBME psychiatry subject exam scores.

OBJECTIVE: The NBME Psychiatry Subject Examination (PSE) is used throughout North America to test MS-III end-of-clerkship knowledge; yet, literature on PSE preparatory methods remains sparse. This study assesses the effect of a curriculum intervention on NBME PSE scores. METHOD: An optional 1.5-hour review session and accompanying fill-in-the-blank handout was offered to 62 MS-III students 3 days before their exam. Students who did not attend the session were e-mailed the handout with completed answers. The primary outcome measure was a change in scores, with students in the previous year serving as the control group. RESULTS: The average raw PSE score of students offered the review session was 84.53, versus 77.15 for matched controls (p <0.0001). The effect size for the intervention was 0.89. CONCLUSION: This study may suggest that offering a comprehensive review session to third-year medical students 3 days before their NBME PSE significantly improves their scores.

Bifurcation stenting with drug-eluting stents: a systematic review and meta-analysis of randomised trials.

AIMS: We sought to determine if outcomes differ between provisional (elective side branch stenting) compared to a routine two-stent strategy (mandatory side branch stenting) for the treatment of bifurcation stenoses of the coronary arteries using drug-eluting stents. METHODS AND RESULTS: We searched Medline, EMBASE, and the Cochrane library from January 2000 to February 2009 for studies comparing the provisional and two-stent strategies. Six randomised controlled trials, including 1,641 patients, were identified. The relative risk (95% confidence interval) for death, MI, target lesion revascularisation, and stent thrombosis within 1-year of the index procedure for a provisional vs. two-stent strategy were 1.12 (0.42-3.02), 0.57 (0.37-0.87), 0.91 (0.61-1.35), and 0.56 (0.23-1.35), respectively. By quantitative coronary angiography, there was no difference in the difference in means (95% CI) between the provisional and two-stent strategies for percent diameter stenosis (95% CI) in the main vessel or side branch, -1.08 (-2.91 to 0.74) and 1.30 (-3.35 to 5.96), respectively. CONCLUSION: While death, stent thrombosis, and restenosis were similar between the treatment groups, MI was more common with the two-stent strategy. Thus, compared to a routine two-stent strategy, provisional stenting yields similar efficacy with superior safety and lower costs.

Sodium bicarbonate for the prevention of contrast induced-acute kidney injury: a systematic review and meta-analysis.

BACKGROUND AND OBJECTIVES: Infusion of sodium bicarbonate has been suggested as a preventative strategy but reports are conflicting on its efficacy. The aim of this study was to assess the effectiveness of hydration with sodium bicarbonate for the prevention of contrast-induced acute kidney injury (CI-AKI). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Medline, EMBASE, Cochrane library, and the Internet were searched for randomized controlled trials comparing hydration between sodium bicarbonate and chloride for the prevention of CI-AKI between 1966 and November 2008. Fourteen trials that included 2290 patients were identified. There was significant heterogeneity between studies (P heterogeneity = 0.02; I(2) = 47.8%), which was largely accounted for by trial size (P = 0.016). Trials were therefore classified by size. RESULTS: Three trials were categorized as large (n = 1145) and 12 as small (n = 1145). Among the large trials, the incidence of CI-AKI for sodium bicarbonate and sodium chloride was 10.7 and 12.5%, respectively; the relative risk (RR) [95% confidence interval (CI)] was 0.85 (0.63 to 1.16) without evidence of heterogeneity (P = 0.89, I(2) = 0%). The pooled RR (95% CI) among the 12 small trials was 0.50 (0.27 to 0.93) with significant between-trial heterogeneity (P = 0.01; I(2) = 56%). The small trials were more likely to be of lower methodological quality. CONCLUSIONS: A significant clinical and statistical heterogeneity was observed that was largely explained by trial size and published status. Among the large randomized trials there was no evidence of benefit for hydration with sodium bicarbonate compared with sodium chloride for the prevention of CI-AKI. The benefit of sodium bicarbonate was limited to small trials of lower methodological quality.

Use of drug-eluting stents in acute myocardial infarction: a systematic review and meta-analysis.

OBJECTIVES: The primary aim of the analysis was to compare outcomes by stent type for death, myocardial infarction (MI), target vessel revascularization (TVR), and stent thrombosis in randomized trials of ST-segment elevation myocardial infarction (STEMI). A secondary analysis was performed among registry studies. BACKGROUND: It is not known whether there are differences in outcomes between drug-eluting stents (DES) and bare-metal stents (BMS) for STEMI. METHODS: We searched MEDLINE, EMBASE, the Cochrane Library, and Internet sources for articles comparing outcomes between DES and BMS among patients with STEMI between January 2000 and October 2008. Randomized controlled trials and registries including patients 18 years of age and older receiving a DES or BMS were included. We extracted variables related to the study design, setting, participants, and clinical end points. RESULTS: Thirteen randomized trials were identified (N = 7,352). Compared with BMS, DES significantly reduced TVR (relative risk [RR]: 0.44; 95% confidence interval [CI]: 0.35 to 0.55), without increasing death (RR: 0.89; 95% CI: 0.70 to 1.14), MI (RR: 0.82; 95% CI: 0.64 to 1.05), or stent thrombosis (RR: 0.97; 95% CI: 0.73 to 1.28). These observations were durable over 2 years. Among 18 registries (N = 26,521), DES significantly reduced TVR (RR: 0.54; 95% CI: 0.40 to 0.74) without an increase in MI (RR: 0.87, 95% CI: 0.62 to 1.23). Death was significantly lower in the DES group within 1 year of the index percutaneous coronary intervention, but there were no differences within 2 years (p = 0.45). CONCLUSIONS: The use of DES appears safe and efficacious in randomized trials and registries of patients with STEMI. The DES significantly reduce TVR compared with BMS, without an increase in death, MI, or stent thrombosis within 2 years of the index procedure.

Long-term outcomes by clopidogrel duration and stent type in a diabetic population with de novo coronary artery lesions.

OBJECTIVES: The purpose of this study was to determine whether long-term clinical outcomes differed between bare-metal stents (BMS) and drug-eluting stents (DES) by duration of clopidogrel use among diabetic patients. BACKGROUND: There is concern that DES are associated with late adverse events such as death and myocardial infarction (MI) secondary to stent thrombosis. However, data on outcomes in diabetic patients remain limited. METHODS: We identified 749 patients with diabetes mellitus who underwent stent implantation with either BMS (n = 251) or DES (n = 498) from October 2002 to December 2004. We performed survival analysis on the full cohort and on those event-free from death, MI, or repeat revascularization at 6 months (n = 671). RESULTS: By clopidogrel duration, the event rate for death or MI was 3.2% in the >9-month group, 9.4% in the 6- to 9-month group, and 16.5% in the <6-month group, p < 0.001. For death alone, the event rate was 0.5% in the >9-month group, 4.3% in the 6- to 9-month group, and 10.0% in the <6-month group, p < 0.001. When taking BMS clopidogrel non-users as a referent in the multivariate analysis, the hazard ratio (95% confidence interval [CI]) for death and nonfatal MI for DES clopidogrel users, DES clopidogrel nonusers, and BMS clopidogrel users were: HR 0.22 (95% CI 0.08 to 0.62, p = 0.005), HR 0.39 (95% CI 0.13 to 1.13, p = 0.08), and HR 0.25 (95% CI 0.08 to 0.81, p = 0.02), respectively. CONCLUSIONS: Longer duration of clopidogrel use was associated with a lower incidence of death or MI in both the BMS and DES groups. Among clopidogrel nonusers, the incidence of death/MI or death did not differ by stent type.