Publications

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Agboola, McKenna, and Pearson are employed by ICER. Lin and Kazi received funding from ICER for work on this report.

BACKGROUND: Statistical testing in phase III clinical trials is subject to chance errors, which can lead to false conclusions with substantial clinical and economic consequences for patients and society.

METHODS: We collected summary data for the primary endpoints of overall survival (OS) and progression-related survival (PRS) (eg, time to other type of event) for industry-sponsored, randomized, phase III superiority oncology trials from 2008 through 2017. Using an empirical Bayes methodology, we estimated the number of false-positive and false-negative errors in these trials and the errors under alternative P value thresholds and/or sample sizes.

RESULTS: We analyzed 187 OS and 216 PRS endpoints from 362 trials. Among 56 OS endpoints that achieved statistical significance, the true efficacy of experimental therapies failed to reach the projected effect size in 33 cases (58.4% false-positives). Among 131 OS endpoints that did not achieve statistical significance, the true efficacy of experimental therapies reached the projected effect size in 1 case (0.9% false-negatives). For PRS endpoints, there were 34 (24.5%) false-positives and 3 (4.2%) false-negatives. Applying an alternative P value threshold and/or sample size could reduce false-positive errors and slightly increase false-negative errors.

CONCLUSIONS: Current statistical approaches detect almost all truly effective oncologic therapies studied in phase III trials, but they generate many false-positives. Adjusting testing procedures in phase III trials is numerically favorable but practically infeasible. The root of the problem is the large number of ineffective therapies being studied in phase III trials. Innovative strategies are needed to efficiently identify which new therapies merit phase III testing.

BACKGROUND: In 2007, the American Heart Association published updated evidence-based guidelines on the recommended use of antibiotic prophylaxis to prevent viridans group streptococcal (VGS) infective endocarditis (IE) in cardiac patients undergoing invasive procedures. The 2007 guidelines significantly scaled back the underlying conditions for which antibiotic prophylaxis was recommended, leaving only 4 categories thought to confer the highest risk of adverse outcome. The purpose of this update is to examine interval evidence of the acceptance and impact of the 2007 recommendations on VGS IE and, if needed, to make revisions based on this evidence.

METHODS AND RESULTS: A writing group was formed consisting of experts in prevention and treatment of infective endocarditis including members of the American Dental Association, the Infectious Diseases Society of America, and the American Academy of Pediatrics, in addition to the American Heart Association. MEDLINE database searches were done for English language articles on compliance with the recommendations in the 2007 guidelines and the frequency of and morbidity or mortality from VGS IE after publication of the 2007 guidelines. Overall, there was good general awareness of the 2007 guidelines but variable compliance with recommendations. There was no convincing evidence that VGS IE frequency, morbidity, or mortality has increased since 2007.

CONCLUSIONS: On the basis of a review of the available evidence, there are no recommended changes to the 2007 VGS IE prevention guidelines. We continue to recommend VGS IE prophylaxis only for categories of patients at highest risk for adverse outcome while emphasizing the critical role of good oral health and regular access to dental care for all. Randomized controlled studies to determine whether antibiotic prophylaxis is effective against VGS IE are needed to further refine recommendations.

IMPORTANCE: Low-density lipoprotein cholesterol (LDL-C) is a major risk factor for cardiovascular disease (CVD). Most observational studies on the association between LDL-C and CVD have focused on LDL-C level at a single time point (usually in middle or older age), and few studies have characterized long-term exposures to LDL-C and their role in CVD risk.

OBJECTIVE: To evaluate the associations of cumulative exposure to LDL-C, time-weighted average (TWA) LDL-C, and the LDL-C slope change during young adulthood and middle age with incident CVD later in life.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed pooled data from 4 prospective cohort studies in the US (Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Framingham Heart Study Offspring Cohort, and Multi-Ethnic Study of Atherosclerosis). Participants were included if they had 2 or more LDL-C measures that were at least 2 years apart between ages 18 and 60 years, with at least 1 of the LDL-C measures occurring during middle age at 40 to 60 years. Data from 1971 to 2017 were collected and analyzed from September 25, 2020, to January 10, 2021.

EXPOSURES: Cumulative exposure to LDL-C, TWA LDL-C, and LDL-C slope from age 18 to 60 years.

MAIN OUTCOMES AND MEASURES: Incident coronary heart disease (CHD), ischemic stroke, and heart failure (HF).

RESULTS: A total of 18 288 participants were included in this study. These participants had a mean (SD) age of 56.4 (3.7) years and consisted of 10 309 women (56.4%). During a median follow-up of 16 years, 1165 CHD, 599 ischemic stroke, and 1145 HF events occurred. In multivariable Cox proportional hazards regression models that adjusted for the most recent LDL-C level measured during middle age and for other CVD risk factors, the hazard ratios for CHD were as follows: 1.57 (95% CI, 1.10-2.23; P for trend = .01) for cumulative LDL-C level, 1.69 (95% CI, 1.23-2.31; P for trend <.001) for TWA LDL-C level, and 0.88 (95% CI, 0.69-1.12; P for trend = .28) for LDL-C slope. No association was found between any of the LDL-C variables and ischemic stroke or HF.

CONCLUSIONS AND RELEVANCE: This cohort study showed that cumulative LDL-C and TWA LDL-C during young adulthood and middle age were associated with the risk of incident CHD, independent of midlife LDL-C level. These findings suggest that past levels of LDL-C may inform strategies for primary prevention of CHD and that maintaining optimal LDL-C levels at an earlier age may reduce the lifetime risk of developing atherosclerotic CVD.

[Figure: see text].

BACKGROUND: Warfarin is one of the most commonly prescribed medications in the United States, and it causes a significant proportion of adverse drug events. Patients taking warfarin fall outside of the recommended therapeutic range 30% of the time, largely because of inadequate laboratory monitoring and dose adjustment. This leads to an increased risk of blood clots or bleeding events. We propose a comparative effectiveness study to examine whether a technology-enabled anticoagulation management program can improve long-term clinical outcomes compared with usual care.

OBJECTIVE: Our proposed intervention is the implementation of an electronic dashboard (integrated into a preexisting electronic health record) and standardized workflow to track patients' laboratory results, identify patients requiring follow-up, and facilitate the use of a validated nomogram for dose adjustment. The primary outcome of this study is the time in therapeutic range (TTR) at 6 months post intervention (a validated metric of anticoagulation quality among patients receiving warfarin).

METHODS: We will employ a pre-post quasi-experimental design with a nonequivalent usual-care comparison site and a difference-in-differences approach to compare the effectiveness of a technology-enabled anticoagulation management program compared with usual care at a large university-affiliated safety-net clinic.

RESULTS: We used a commercially available health information technology (HIT) platform to host a registry of patients on warfarin therapy and create the electronic dashboard for panel management. We developed the intervention with, and for, frontline clinician users, using principles of human-centered design. This study is funded until September 2020 and is approved by the University of California, San Francisco Institutional Review Board until June 22, 2020. We completed data collection in September 2019 and expect to complete our proposed analyses by February 2020.

CONCLUSIONS: We anticipate that the intervention will increase TTR among patients taking warfarin and that the use of this HIT platform will facilitate tracking and monitoring of patients on warfarin, which could enable outreach to those overdue for visits or laboratory monitoring. We will use these findings to iteratively improve the platform in preparation for a larger, multiple-site, pragmatic clinical trial. If successful, our study will demonstrate the integration of HIT platforms into existing electronic health records to improve patient care in real-world clinical settings.

INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/13835.