Baseline Predictors of Low-Density Lipoprotein Cholesterol and Systolic Blood Pressure Goal Attainment After 1 Year in the ISCHEMIA Trial.

BACKGROUND: Risk factor control is the cornerstone of managing stable ischemic heart disease but is often not achieved. Predictors of risk factor control in a randomized clinical trial have not been described. METHODS AND RESULTS: The ISCHEMIA trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) randomized individuals with at least moderate inducible ischemia and obstructive coronary artery disease to an initial invasive or conservative strategy in addition to optimal medical therapy. The primary aim of this analysis was to determine predictors of meeting trial goals for LDL-C (low-density lipoprotein cholesterol, goal <70 mg/dL) or systolic blood pressure (SBP, goal <140 mm Hg) at 1 year post-randomization. We included all randomized participants in the ISCHEMIA trial with baseline and 1-year LDL-C and SBP values by January 28, 2019. Among the 3984 ISCHEMIA participants (78% of 5179 randomized) with available data, 35% were at goal for LDL-C, and 65% were at goal for SBP at baseline. At 1 year, the percent at goal increased to 52% for LDL-C and 75% for SBP. Adjusted odds of 1-year LDL-C goal attainment were greater with older age (odds ratio [OR], 1.11 [95% CI, 1.03-1.20] per 10 years), lower baseline LDL-C (OR, 1.19 [95% CI, 1.17-1.22] per 10 mg/dL), high-intensity statin use (OR, 1.30 [95% CI, 1.12-1.51]), nonwhite race (OR, 1.32 [95% CI, 1.07-1.63]), and North American enrollment compared with other regions (OR, 1.32 [95% CI, 1.06-1.66]). Women were less likely than men to achieve 1-year LDL-C goal (OR, 0.68 [95% CI, 0.58-0.80]). Adjusted odds of 1-year SBP goal attainment were greater with lower baseline SBP (OR, 1.27 [95% CI, 1.22-1.33] per 10 mm Hg) and with North American enrollment (OR, 1.35 [95% CI, 1.04-1.76]). CONCLUSIONS: In ISCHEMIA, older age, male sex, high-intensity statin use, lower baseline LDL-C, and North American location predicted 1-year LDL-C goal attainment, whereas lower baseline SBP and North American location predicted 1-year SBP goal attainment. Future studies should examine the effects of sex disparities, international practice patterns, and provider behavior on risk factor control.

Determination of fasiglifam-induced liver toxicity: Insights from the data monitoring committee of the fasiglifam clinical trials program.

BACKGROUND: Different approaches to safety event collection influence the determination of liver toxicity within drug development programs. Herein, a description of how fasiglifam-induced liver injury was detected is provided. METHODS: This eight-trial drug development program was intended to evaluate fasiglifam (25 mg, 50 mg) against placebo or active comparators (glimepiride, sitagliptin) in approximately 11,000 suboptimally controlled patients with type 2 diabetes (terminated Dec 2013 due to liver toxicity). Liver safety had been pre-identified as a concern, and within the phase 3 trials, was measured through (1) adverse event reporting, (2) central predefined liver monitoring schedule with various thresholds for potential drug-induced liver injury, and (3) blinded adjudication of serious liver toxicity by a panel of experts in drug-induced liver injury. A single data monitoring committee provided safety oversight across all trials within the program. FINDINGS: Prior to program termination, 7595 of 7602 (99.9%) randomized participants across the eight trials received at least one dose of the study drug (fasiglifam, placebo, or active control). No concerning trends were noted in adverse or serious adverse event frequency, suspected unexpected serious adverse reaction, alanine or aspartate transaminase elevations, or hepatobiliary or gastrointestinal adverse events as reported by local site investigators. However, the predefined central liver safety measurements revealed a greater frequency of possible Hy's Law cases (5 vs 2) and a 3- to 7-fold greater relative risk in alanine or aspartate transaminase elevation (with respect to upper limit of normal) within fasiglifam recipients compared with placebo/active control: alanine or aspartate transaminase > 3×: relative risk 3.34 (95% confidence interval 2.29-4.90), alanine or aspartate transaminase > 5×: relative risk 6.60 (95% confidence interval 3.03-14.38), alanine or aspartate transaminase > 8×: relative risk 6.14 (95% confidence interval 2.18-17.27), and alanine or aspartate transaminase > 10×: relative risk 6.74 (95% confidence interval 2.05, 22.14). All elevations resolved on study drug discontinuation. Drug-induced liver injury was adjudicated as highly likely or probably related in 0.64% of fasiglifam-treated versus 0.06% placebo or active control-treated patients. CONCLUSION: In spite of clear liver toxicity detected with a systematic surveillance program, liver safety signals were not identified from investigator adverse event reporting alone. By integrating key safety monitoring processes within the randomized design of adequately sized clinical trials, the rare but serious liver toxicity signal became clear, leading to timely program termination.

Impact of Regional Systems of Care on Disparities in Care Among Female and Black Patients Presenting With ST-Segment-Elevation Myocardial Infarction.

BACKGROUND: The American Heart Association Mission: Lifeline STEMI (ST-segment-elevation myocardial infarction) Systems Accelerator program, conducted in 16 regions across the United States to improve key care processes, resulted in more patients being treated within national guideline goals (time from first medical contact to device: <90 minutes for direct presenters to hospitals capable of performing percutaneous coronary intervention; <120 minutes for transfers). We examined whether the effort reduced reperfusion disparities in the proportions of female versus male and black versus white patients. METHODS AND RESULTS: In total, 23 809 patients (29.3% female, 82.3% white, and 10.7% black) presented with acute STEMI between July 2012 and March 2014. Change in the proportion of patients treated within guideline goals was compared between sex and race subgroups for patients presenting directly to hospitals capable of performing percutaneous coronary intervention (n=18 267) and patients requiring transfer (n=5542). The intervention was associated with an increase in the proportion of men treated within guideline goals that presented directly (58.7-62.1%, P=0.01) or were transferred (43.3-50.7%, P<0.01). An increase was also seen among white patients who presented directly (57.7-59.9%, P=0.02) or were transferred (43.9-48.8%, P<0.01). There was no change in the proportion of female or black patients treated within guideline goals, including both those presenting directly and transferred. CONCLUSION: The STEMI Systems Accelerator project was associated with an increase in the proportion of patients meeting guideline reperfusion targets for male and white patients but not for female or black patients. Efforts to organize systems of STEMI care should implement additional processes targeting barriers to timely reperfusion among female and black patients.