Personalized benefit-risk assessments combining clinical trial and real-world data provide further insights into which patients may benefit most from therapy: Demonstration for a new oral antiplatelet therapy.

PURPOSE: Quantitative benefit-risk (B-R) assessments are used to characterize treatment by combining key benefits and risks into a single metric but have historically been done for the "average" patient. Our aim was to conduct an individualized assessment for the oral antiplatelet vorapaxar by combining trial and real-world data to further personalize the treatment profiles. METHODS: Using linked UK health care databases, we developed risk prediction equations for key ischemic and bleeding events using Cox proportional hazards models. Trial hazard ratios, relative to placebo, were applied to baseline risk estimates to compute expected attributable risks, summed to derive a per-patient net clinical benefit (NCB). High risk subgroups were defined a priori, and Gaussian mixture models (GMM) were fit to characterize the NCB distribution and identify subgroups with similar NCBs. RESULTS: NCB was consistently positive for all subgroups, likely due to the outcome correlation, and would remain positive with a 12-fold increase in bleeding risk. GMMs identified three distinct NCB subgroups. Compared with the middle/lower NCB subgroups, those with a higher NCB tended to be older, female, and have higher CV disease burden. CONCLUSIONS: Personalized B-R assessments are feasible and clinically valuable and can be used to better predict who would benefit most from therapy.

Net clinical benefit of antiplatelet therapy was affected by patient preferences: A personalized benefit-risk assessment.

OBJECTIVES: To assess the effect of patient preferences on the net clinical benefit (NCB) of an antiplatelet therapy for the secondary prevention of cardiovascular complications. STUDY DESIGN AND SETTING: Risk equations were developed to estimate the individual predicted risk of key outcomes of antiplatelet treatment in patients with a prior myocardial infarction using the Clinical Practice Research Datalink linked to the Hospital Episode Statistics and UK Office of National Statistics databases. Patient preferences for outcomes of antiplatelet therapies were elicited in a separate discrete choice experiment survey. Trial hazard ratios, relative to placebo, were used to calculate the per-patient NCB using equal or preference weighting of outcomes. RESULTS: Risk equations were estimated using 31,941 adults in the Clinical Practice Research Datalink population, of which 22,125 were included in the benefit-risk assessment. The mean NCB was lower in the preference-weighted than in the equal-weighted analysis (0.040 vs. 0.057; P < 0.0001), but the direction of effect was unchanged by the weighting. In analyses stratified by the presence of bleeding risk factors, including preference weighting altered the ranking of subgroups by NCB. CONCLUSION: Patient preference weighting may have a significant effect on NCB and should be included in personalized benefit-risk assessments.

Comparing Patient Preferences for Antithrombotic Treatment During the Acute and Chronic Phases of Myocardial Infarction: A Discrete-Choice Experiment.

BACKGROUND: Antithrombotic drugs are used as preventive treatment in patients with a prior myocardial infarction (MI) in both the acute and chronic phases of the disease. To support patient-centered benefit-risk assessment, it is important to understand the influence of disease stage on patient preferences. OBJECTIVE: The aim of this study was to examine patient preferences for antithrombotic treatments and whether they differ by MI disease phase. METHODS: A discrete-choice experiment was used to elicit preferences of adults in the acute (≤ 365 days before enrolment) or chronic phase (> 365 days before enrolment) of MI for key ischemic events (risk of cardiovascular [CV] death, non-fatal MI, and non-fatal ischemic stroke) and bleeding events (risk of non-fatal intracranial hemorrhage and non-fatal other severe bleeding). Preference data were analyzed using the multinomial logit model. Trade-offs between attributes were calculated as the maximum acceptable increase in the risk of CV death for a decrease in the risk of the other outcomes. To assess the potential effect of sociodemographic and clinical characteristics on patient preferences, subgroups were introduced as interaction terms in logit models. RESULTS: The evaluable population included 155 patients with MI in the acute phase of disease and 180 in the chronic phase. The overall population was 82% male, mean age was 64.2 ± 9.6 years, and 93% had not experienced bleeding events or key ischemic events other than MI. Patients valued reduction in the risk of non-fatal intracranial hemorrhage more than CV death (p < 0.01) and CV death more than non-fatal ischemic events (p < 0.01). Preferences were similar in the acute and chronic populations (p = 0.17). However, older patients valued reduction in risk of MI more than younger patients (p = 0.04), and patients with bleeding risk factors valued reduction in the risk of CV death (p = 0.01) and MI (p = 0.01) less than patients without bleeding risk factors. Also, patients who were at high risk of future ischemic events valued reduction of the risk of CV death less than those at low risk (p = 0.01). CONCLUSION: Patient preferences for antithrombotic treatments were unaffected by disease stage but varied by bleeding risk and other factors. This heterogeneity in preferences is an important consideration because it can affect the benefit-risk balance and the acceptability of antithrombotic treatments to patients.

Social Support, Help-Seeking, and Mental Health Outcomes Among Veterans in Non-VA Facilities: Results from the Veterans' Health Study.

Using a stress process model, the authors examined social and psychological resources to better understand mental health outcomes among veterans. For this study, we surveyed 700 U.S. veterans who were outpatients in the Geisinger Health System. Independent variables included demographic factors, stressful and traumatic events, social support measures, and psychosocial factors. Using logistic regression, the authors examined 4 types of social connections: social support, help-seeking support, social capital, and other mental health support to predict mental health outcomes, including posttraumatic stress disorder, depression, suicide ideation, alcohol misuse, mental health service use, and Veterans Affairs service use. Results suggested that help-seeking support since deployment was a risk factor for 5 adverse outcomes, whereas social support was protective for 1 outcome. We concluded that high levels of help-seeking support since deployment among veterans was associated with a higher prevalence of mental health problems. These findings were unexpected and suggest the need for additional social support-related research among veterans.

Yohimbine reinstates extinguished 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) seeking in rats with prior exposure to chronic yohimbine.

Although exposure to acute stress has been shown to reinstate extinguished responding for a wide variety of drugs, no studies have investigated stress-induced reinstatement in animals with a history of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) self-administration. Thus, rats were trained to press a lever for MDMA (0.50 mg/kg/infusion) in daily sessions, and lever pressing was subsequently extinguished in the absence of MDMA and conditioned cues (light and tone). We then tested the ability of acute yohimbine (2.0 mg/kg), a pharmacological stressor, to reinstate lever-pressing under extinction conditions. Additionally, to model chronic stress, some rats were injected daily with yohimbine (5.0 mg/kg × 10 days) prior to reinstatement tests. To assess dopaminergic involvement, chronic yohimbine injections were combined with injections of SCH-23390 (0.0 or 10.0 µg/kg), a dopamine D1-like receptor antagonist. In a separate experiment, rats with a history of food self-administration were treated and tested in the same way. Results showed that acute yohimbine injections reinstated extinguished MDMA and food seeking, but only in rats with a history of chronic yohimbine exposure. Co-administration of SCH-23390 with chronic yohimbine injections prevented the potentiation of subsequent food seeking, but not MDMA seeking. These results suggest that abstinent MDMA users who also are exposed to chronic stress may be at increased risk for future relapse, and also that the effects of chronic stress on relapse may be mediated by different mechanisms depending on one's drug use history.