Julie C. Lauffenburger

Effectiveness and Safety of Dabigatran and Warfarin in Real‐World US Patients With Non‐Valvular Atrial Fibrillation: A Retrospective Cohort Study

Background The recent availability of dabigatran, a novel oral anticoagulant, provided a new treatment option for stroke prevention in atrial fibrillation beyond warfarin, the main therapy for years. Little is known about their real‐world comparative effectiveness and safety, even less among patient demographic and clinical subgroups. Methods and Results Using a cohort of non‐valvular AF patients initiating anticoagulation from October 2010 to December 2012 drawn from a large US database of commercial and Medicare supplement claims, we applied propensity score weights to Cox proportional hazards regression to assess the comparative effectiveness and safety of dabigatran versus warfarin. Analyses were repeated among clinical and demographic subgroups using stratum‐specific propensity scores as an exploratory analysis. Of the 64 935 patients initiating anticoagulation, 32.5% used dabigatran. Compared with warfarin, dabigatran was associated with a lower risk of ischemic stroke or systemic embolism (composite adjusted Hazard Ratio [aHR], 95% CI: 0.86, 95% CI: 0.79 to 0.93), hemorrhagic stroke (aHR: 0.51, 0.40 to 0.65), and acute myocardial infarction (aHR: 0.88, 95% CI: 0.77 to 0.99), and no relation was seen between dabigatran and the composite harm outcome (aHR: 0.94, 95% CI: 0.87 to 1.01). However, dabigatran was associated with a higher risk of gastrointestinal bleeding (aHR: 1.11, 95% CI: 1.02 to 1.22). Estimates of effectiveness and safety appeared to be mostly similar across subgroups. Conclusions Dabigatran could be a safe and potentially more effective alternative to warfarin in patients with atrial fibrillation managed in routine practice settings.

Racial/Ethnic and Gender Gaps in the Use of and Adherence to Evidence-Based Preventive Therapies Among Elderly Medicare Part D Beneficiaries After Acute Myocardial Infarction

Background— It is unclear whether gender and racial/ethnic gaps in the use of and patient adherence to &bgr;-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and statins after acute myocardial infarction have persisted after establishment of the Medicare Part D prescription program. Methods and Results— This retrospective cohort study used 2007 to 2009 Medicare service claims among Medicare beneficiaries ≥65 years of age who were alive 30 days after an index acute myocardial infarction hospitalization in 2008. Multivariable logistic regression models examined racial/ethnic (white, black, Hispanic, Asian, and other) and gender differences in the use of these therapies in the 30 days after discharge and patient adherence at 12 months after discharge, adjusting for patient baseline sociodemographic and clinical characteristics. Of 85 017 individuals, 55%, 76%, and 61% used angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, &bgr;-blockers, and statins, respectively, within 30 days after discharge. No marked differences in use were found by race/ethnicity, but women were less likely to use angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and &bgr;-blockers compared with men. However, at 12 months after discharge, compared with white men, black and Hispanic women had the lowest likelihood (≈30%–36% lower; P<0.05) of being adherent, followed by white, Asian, and other women and black and Hispanic men (≈9%–27% lower; P<0.05). No significant difference was shown between Asian/other men and white men. Conclusions— Although minorities were initially no less likely to use the therapies after acute myocardial infarction discharge compared with white patients, black and Hispanic patients had significantly lower adherence over 12 months. Strategies to address gender and racial/ethnic gaps in the elderly are needed.

Completeness of prescription information in US commercial claims databases

Pharmacy commercial claims databases are widely used for pharmacoepidemiologic research. However, concerns have been raised that these databases may not fully capture claims for generic medications as a result of patients filling outside the context of their insurance. This has implications for many research activities and quality improvement programs. We sought to estimate the percentage of missing prescriptions in US commercial claims data using a novel design.

Failure of Investigational Drugs in Late-Stage Clinical Development and Publication of Trial Results.

Importance Many investigational drugs fail in late-stage clinical development. A better understanding of why investigational drugs fail can inform clinical practice, regulatory decisions, and future research. Objective To assess factors associated with regulatory approval or reasons for failure of investigational therapeutics in phase 3 or pivotal trials and rates of publication of trial results. Design, Setting, and Participants Using public sources and commercial databases, we identified investigational therapeutics that entered pivotal trials between 1998 and 2008, with follow-up through 2015. Agents were classified by therapeutic area, orphan designation status, fast track designation, novelty of biological pathway, company size, and as a pharmacologic or biologic product. Main Outcomes and Measures For each product, we identified reasons for failure (efficacy, safety, commercial) and assessed the rates of publication of trial results. We used multivariable logistic regression models to evaluate factors associated with regulatory approval. Results Among 640 novel therapeutics, 344 (54%) failed in clinical development, 230 (36%) were approved by the US Food and Drug Administration (FDA), and 66 (10%) were approved in other countries but not by the FDA. Most products failed due to inadequate efficacy (n = 195; 57%), while 59 (17%) failed because of safety concerns and 74 (22%) failed due to commercial reasons. The pivotal trial results were published in peer-reviewed journals for 138 of the 344 (40%) failed agents. Of 74 trials for agents that failed for commercial reasons, only 6 (8.1%) were published. In analyses adjusted for therapeutic area, agent type, firm size, orphan designation, fast-track status, trial year, and novelty of biological pathway, orphan-designated drugs were significantly more likely than nonorphan drugs to be approved (46% vs 34%; adjusted odds ratio [aOR], 2.3; 95% CI, 1.4-3.7). Cancer drugs (27% vs 39%; aOR, 0.5; 95% CI, 0.3-0.9) and agents sponsored by small and medium-size companies (28% vs 42%; aOR, 0.4; 95% CI, 0.3-0.7) were significantly less likely to be approved. Conclusions and Relevance Roughly half of investigational drugs entering late-stage clinical development fail during or after pivotal clinical trials, primarily because of concerns about safety, efficacy, or both. Results for the majority of studies of investigational drugs that fail are not published in peer-reviewed journals.

The Effect of Community Pharmacy–Based Interventions on Patient Health Outcomes A Systematic Review

Many studies have demonstrated the beneficial effects that pharmacist-provided patient care services can have on patient health outcomes. However, the effectiveness of patient care services delivered by pharmacists in community pharmacy settings, where organizational barriers may affect service implementation or limit effectiveness, remains unclear. The authors systematically reviewed the literature on the effectiveness of pharmacist-delivered patient care services in community pharmacy settings in the United States. Of the 749 articles retrieved, 21 were eligible for inclusion in the review. Information concerning 134 outcomes was extracted from the included articles. Of these, 50 (37.3%) demonstrated statistically significant, beneficial intervention effects. The percentage of studies reporting favorable findings ranged from 50% for blood pressure to 0% for lipids, safety outcomes, and quality of life. Our findings suggest that evidence supporting the effectiveness of pharmacist-provided direct patient care services delivered in the community pharmacy setting is more limited than in other settings.

Medication use and medical comorbidity in patients with chronic hepatitis C from a US commercial claims database: high utilization of drugs with interaction potential.

Background With the advent of the direct-acting antiviral agents, significant drug–drug interaction (DDI) potential now exists for patients treated for chronic hepatitis C virus (HCV) infection. However, little is known about how often patients with HCV infection use medications that may interact with newer HCV treatments, especially those with cytochrome P450 3A (CYP3A) DDI potential. Methods Using a large US commercial insurance database, medication use and comorbidity burden were examined among adult patients with a chronic HCV diagnosis from 2006 to 2010. Medications were examined in terms of total number of prescription claims, proportion of patients exposed, and DDI potential with the prototypical CYP3A direct-acting antiviral agents boceprevir and telaprevir, for which data were available. Results Patient comorbidity burden was high and increased over the study period. Medication use was investigated in 53 461 patients with chronic HCV. Twenty-one (53%) of the top 40 most utilized medications were classified as having interaction potential, with 62% of patients receiving at least one of the top 22 interacting medications by exposure. Of these, 59 and 41% were listed in a common DDI resource but not in medication-prescribing information, 77 and 77% had not been investigated in DDI studies, 41 and 36% did not have clear recommendations for DDI management, and only 14 and 23% carried a recommendation to avoid coadministration for boceprevir and telaprevir, respectively. Conclusion Practitioners may expect a medication with CYP3A DDI potential in two-thirds of patients with HCV and may expect almost one-half of the most frequently used medications to have CYP3A DDI potential. However, DDI potential may not be reflected in prescribing information.

Temporal Trends and Factors Associated With Cardiovascular Drug Development, 1990 to 2012

Summary Cardiovascular disease remains a leading cause of death, but stakeholders have recently raised concerns about the pace of innovation and investment in developing new therapeutics. Here, the authors characterized temporal trends in cardiovascular research and development over the past 2 decades and the likelihood of successful completion of pre-approval clinical trials. The authors also evaluated the reasons for discontinuation, novelty, and rates of trial results publication for cardiovascular therapies in late-stage development. Between 1990 and 2012, the number of new cardiovascular drugs entering clinical trials declined across all stages of development (p < 0.001 for linear trends). There was no evidence for a difference in probability of successful progression to the next stage of development between cardiovascular and noncardiovascular drugs. Small and medium-sized companies sponsored 43%, 38%, and 31% of new Phase 1, Phase 2, and Phase 3 trials, respectively. Roughly one-half of the drugs in Phase 3 trials were categorized as targeting a novel biological pathway. The number of cardiovascular trials sponsored by small and medium-sized companies and the number of novel drugs entering Phase 3 trials increased over time. Most drugs were discontinued in Phase 3 due to inadequate efficacy (44%) or safety issues (24%), but the Phase 3 trial results for only one-half of the discontinued drugs were published in peer-reviewed journals. These results shed light on important shifts in research and development activity and confirm the perceived challenges in cardiovascular translational research.

Prevalent but moderate variation across small geographic regions in patient nonadherence to evidence-based preventive therapies in older adults after acute myocardial infarction

Background:Patient long-term adherence to &bgr;-blockers, HMG-CoA reductase inhibitors (statins), and angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) after acute myocardial infarction (AMI) is alarmingly low. It is unclear how prevalent patient adherence may be across small geographic areas and whether this geographic prevalence may vary. Methods:This is a retrospective cohort study using Medicare service claims files from 2007 to 2009 with Medicare beneficiaries 65 years and above who were alive 30 days after the index AMI hospitalization between January 1, 2008 and December 31, 2008 (N=85,017). The adjusted proportions of patients adherent to &bgr;-blockers, statins, and ACEIs/ARBs, respectively, in the 12 months after discharge across the 306 Hospital Referral Regions (HRRs) were measured and compared by control chart. The intracluster correlation coefficient (ICC) and the additional prediction power from this small-area variation on individual patient adherence were assessed. Results:The adjusted proportion of patients adherent across HRRs ranged from 58% to 74% (median, 66%) for &bgr;-blockers, from 57% to 67% (median, 63%) for ACEIs/ARBs, and from 58% to 73% (median, 66%) for statins. The ICC was 0.053 (95% CI, 0.043–0.064) for &bgr;-blockers, 0.050 (95% CI, 0.039–0.061) for ACEIs/ARBs, and 0.041 (95% CI, 0.031–0.052) for statins. The adjusted proportion of patients adherent across HRRs increased the c-statistic by 0.01–0.02 (P < 0.0001). Conclusions:Nonadherence to evidence-based preventive therapies post-AMI among older adults was prevalent across small geographic regions. Moderate small-area variation in patient adherence exists.

Association of a Smartphone Application With Medication Adherence and Blood Pressure Control: The MedISAFE-BP Randomized Clinical Trial

Importance Medication nonadherence accounts for up to half of uncontrolled hypertension. Smartphone applications (apps) that aim to improve adherence are widely available but have not been rigorously evaluated. Objective To determine if the Medisafe smartphone app improves self-reported medication adherence and blood pressure control. Design, Setting, and Participants This was a 2-arm, randomized clinical trial (Medication Adherence Improvement Support App For Engagement—Blood Pressure [MedISAFE-BP]). Participants were recruited through an online platform and were mailed a home blood pressure cuff to confirm eligibility and to provide follow-up measurements. Of 5577 participants who were screened, 412 completed consent, met inclusion criteria (confirmed uncontrolled hypertension, taking 1 to 3 antihypertensive medications), and were randomized in a ratio of 1:1 to intervention or control. Interventions Intervention arm participants were instructed to download and use the Medisafe app, which includes reminder alerts, adherence reports, and optional peer support. Main Outcomes and Measures Co–primary outcomes were change from baseline to 12 weeks in self-reported medication adherence, measured by the Morisky medication adherence scale (MMAS) (range, 0-8, with lower scores indicating lower adherence), and change in systolic blood pressure. Results Participants (n = 411; 209 in the intervention group and 202 controls) had a mean age of 52.0 years and mean body mass index, calculated as weight in kilograms divided by height in meters squared, of 35.5; 247 (60%) were female, and 103 (25%) were black. After 12 weeks, the mean (SD) score on the MMAS improved by 0.4 (1.5) among intervention participants and remained unchanged among controls (between-group difference: 0.4; 95% CI, 0.1-0.7; P = .01). The mean (SD) systolic blood pressure at baseline was 151.4 (9.0) mm Hg and 151.3 (9.4) mm Hg, among intervention and control participants, respectively. After 12 weeks, the mean (SD) systolic blood pressure decreased by 10.6 (16.0) mm Hg among intervention participants and 10.1 (15.4) mm Hg among controls (between-group difference: −0.5; 95% CI, −3.7 to 2.7; P = .78). Conclusions and Relevance Among individuals with poorly controlled hypertension, patients randomized to use a smartphone app had a small improvement in self-reported medication adherence but no change in systolic blood pressure compared with controls. Trial Registration clinicaltrials.gov Identifier: NCT02727543

Predictors of Gastrointestinal Bleeding Among Patients with Atrial Fibrillation After Initiating Dabigatran Therapy

To identify demographic and clinical risk factors associated with gastrointestinal (GI) bleeding among a large cohort of patients with atrial fibrillation (AF) who initiated dabigatran therapy for stroke prevention, and to describe patterns of subsequent anticoagulant use after occurrence of the GI bleeding event.