Clinicians’ Contributions to the Development of Coronary Artery Stents: A Qualitative Study of Transformative Device Innovation

Background: Medical device innovation remains poorly understood, and policymakers disagree over how to incentivize early development. We sought to elucidate the components of transformative health care innovation by conducting an in-depth case study of development of a key medical device: coronary artery stents. Methods and Findings: We conducted semi-structured interviews with the innovators whose work contributed to the development of coronary artery stents who we identified based on a review of the regulatory, patent, and medical literature. Semi-structured interviews with each participant covered the interviewee’s personal involvement in coronary artery stent development, the roles of institutions and other individuals in the development process, the interplay of funding and intellectual property in the interviewee’s contribution, and finally reflections on lessons arising from the experience. Transcripts were analyzed using standard coding techniques and the constant comparative method of qualitative data analysis. Conclusions: We found that the first coronary artery stents emerged from three teams: Julio Palmaz and Richard Schatz, Cesare Gianturco and Gary Roubin, and Ulrich Sigwart. First, these individual physician-inventors saw the need for coronary artery stents in their clinical practice. In response, they developed prototypes with the support of academic medical centers leading to early validation studies. Larger companies entered afterwards with engineering support. Patents became paramount once the technology diffused. The case of coronary stents suggests that innovation policy should focus on supporting early physician-inventors at academic centers

Preterm Birth and Antidepressant Medication Use during Pregnancy: A Systematic Review and Meta-Analysis

Introduction: Preterm birth is a major contributor to neonatal morbidity and mortality and its rate has been increasing over the past two decades. Antidepressant medication use during pregnancy has also been rising, with rates up to 7.5% in the US. The objective was to systematically review the literature to determine the strength of the available evidence relating to a possible association between antidepressant use during pregnancy and preterm birth. Methods: We conducted a computerized search in PUBMED, MEDLINE and PsycINFO through September 2012, supplemented with a manual search of reference lists, to identify original published research on preterm birth rates in women taking antidepressants during pregnancy. Data were independently extracted by two reviewers, and absolute and relative risks abstracted or calculated. Our a priori design was to group studies by level of confounding adjustment and by timing of antidepressant use during pregnancy; we used random-effects models to calculate summary measures of effect. Results: Forty-one studies met inclusion criteria. Pooled adjusted odds ratios (95% CI) were 1.53 (1.40–1.66) for antidepressant use at any time and 1.96 (1.62–2.38) for 3rd trimester use. Controlling for a diagnosis of depression did not eliminate the effect. There was no increased risk [1.16 (0.92–1.45)] in studies that identified patients based on 1st trimester exposure. Sensitivity analyses demonstrated unmeasured confounding would have to be strong to account for the observed association. Discussion Published evidence is consistent with an increased risk of preterm birth in women taking antidepressants during the 2nd and 3rd trimesters, although the possibility of residual confounding cannot be completely ruled out

Principles of Educational Outreach ('Academic Detailing') to Improve Clinical Decision Making

With the efficacy and costs of medications rising rapidly, it is increasingly important to ensure that drugs be prescribed as rationally as possible. Yet, physicians' choices of drugs frequently fall short of the ideal of precise and cost-effective decision making. Evidence indicates that such decisions can be improved in a variety of ways. A number of theories and principles of communication and behavior change can be found that underlie the success of pharmaceutical manufacturers in influencing prescribing practices. Based on this behavioral science and several field trials, it is possible to define the theory and practice of methods to improve physicians' clinical decision making to enhance the quality and cost-effectiveness of care. Some of the most important techniques of such "academic detailing" include (1) conducting interviews to investigate baseline knowledge and motivations for current prescribing patterns, (2) focusing programs on specific categories of physicians as well as on their opinion leaders, (3) defining clear educational and behavioral objectives, (4) establishing credibility through a respected organizational identity, referencing authoritative and unbiased sources of information, and presenting both sides of controversial issues, (5) stimulating active physician participation in educational interactions, (6) using concise graphic educational materials, (7) highlighting and repeating the essential messages, and (8) providing positive reinforcement of improved practices in follow-up visits. Used by the nonprofit sector, the above techniques have been shown to reduce inappropriate prescribing as well as unnecessary health care expenditures

Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison

Objective: To evaluate whether smoking status is associated with the efficacy of antiplatelet treatment in the prevention of cardiovascular events. Design: Systematic review, meta-analysis, and indirect comparisons. Data sources Medline (1966 to present) and Embase (1974 to present), with supplementary searches in databases of abstracts from major cardiology conferences, the Cumulative Index to Nursing and Allied Health (CINAHL) and the CAB Abstracts databases, and Google Scholar. Study selection Randomized trials of clopidogrel, prasugrel, or ticagrelor that examined clinical outcomes among subgroups of smokers and nonsmokers. Data extraction Two authors independently extracted all data, including information on the patient populations included in the trials, treatment types and doses, definitions of clinical outcomes and duration of follow-up, definitions of smoking subgroups and number of patients in each group, and effect estimates and 95% confidence intervals for each smoking status subgroup. Results: Of nine eligible randomized trials, one investigated clopidogrel compared with aspirin, four investigated clopidogrel plus aspirin compared with aspirin alone, and one investigated double dose compared with standard dose clopidogrel; these trials include 74 489 patients, of whom 21 717 (29%) were smokers. Among smokers, patients randomized to clopidogrel experienced a 25% reduction in the primary composite clinical outcome of cardiovascular death, myocardial infarction, and stroke compared with patients in the control groups (relative risk 0.75, 95% confidence interval 0.67 to 0.83). In nonsmokers, however, clopidogrel produced just an 8% reduction in the composite outcome (0.92, 0.87 to 0.98). Two studies investigated prasugrel plus aspirin compared with clopidogrel plus aspirin, and one study investigated ticagrelor plus aspirin compared with clopidogrel plus aspirin. In smokers, the relative risk was 0.71 (0.61 to 0.82) for prasugrel compared with clopidogrel and 0.83 (0.68 to 1.00) for ticagrelor compared with clopidogrel. Corresponding relative risks were 0.92 (0.83 to 1.01) and 0.89 (0.79 to 1.00) among nonsmokers. Conclusions: In randomized clinical trials of antiplatelet drugs, the reported clinical benefit of clopidogrel in reducing cardiovascular death, myocardial infarction, and stroke was seen primarily in smokers, with little benefit in nonsmokers

Treatment Effects in the Presence of Unmeasured Confounding: Dealing With Observations in the Tails of the Propensity Score Distribution--A Simulation Study

Frailty, a poorly measured confounder in older patients, can promote treatment in some situations and discourage it in others. This can create unmeasured confounding and lead to nonuniform treatment effects over the propensity score (PS). The authors compared bias and mean squared error for various PS implementations under PS trimming, thereby excluding persons treated contrary to prediction. Cohort studies were simulated with a binary treatment T as a function of 8 covariates X. Two of the covariates were assumed to be unmeasured strong risk factors for the outcome and present in persons treated contrary to prediction. The outcome Y was simulated as a Poisson function of T and all X’s. In analyses based on measured covariates only, the range of PS's was trimmed asymmetrically according to the percentile of PS in treated patients at the lower end and in untreated patients at the upper end. PS trimming reduced bias due to unmeasured confounders and mean squared error in most scenarios assessed. Treatment effect estimates based on PS range restrictions do not correspond to a causal parameter but may be less biased by such unmeasured confounding. Increasing validity based on PS trimming may be a unique advantage of PS's over conventional outcome models

Association of Medical Students' Reports of Interactions with the Pharmaceutical and Medical Device Industries and Medical School Policies and Characteristics: A Cross-Sectional Study

Background: Professional societies use metrics to evaluate medical schools' policies regarding interactions of students and faculty with the pharmaceutical and medical device industries. We compared these metrics and determined which US medical schools' industry interaction policies were associated with student behaviors. Methods and Findings: Using survey responses from a national sample of 1,610 US medical students, we compared their reported industry interactions with their schools' American Medical Student Association (AMSA) PharmFree Scorecard and average Institute on Medicine as a Profession (IMAP) Conflicts of Interest Policy Database score. We used hierarchical logistic regression models to determine the association between policies and students' gift acceptance, interactions with marketing representatives, and perceived adequacy of faculty–industry separation. We adjusted for year in training, medical school size, and level of US National Institutes of Health (NIH) funding. We used LASSO regression models to identify specific policies associated with the outcomes. We found that IMAP and AMSA scores had similar median values (1.75 [interquartile range 1.50–2.00] versus 1.77 [1.50–2.18], adjusted to compare scores on the same scale). Scores on AMSA and IMAP shared policy dimensions were not closely correlated (gift policies, r = 0.28, 95% CI 0.11–0.44; marketing representative access policies, r = 0.51, 95% CI 0.36–0.63). Students from schools with the most stringent industry interaction policies were less likely to report receiving gifts (AMSA score, odds ratio [OR]: 0.37, 95% CI 0.19–0.72; IMAP score, OR 0.45, 95% CI 0.19–1.04) and less likely to interact with marketing representatives (AMSA score, OR 0.33, 95% CI 0.15–0.69; IMAP score, OR 0.37, 95% CI 0.14–0.95) than students from schools with the lowest ranked policy scores. The association became nonsignificant when fully adjusted for NIH funding level, whereas adjusting for year of education, size of school, and publicly versus privately funded school did not alter the association. Policies limiting gifts, meals, and speaking bureaus were associated with students reporting having not received gifts and having not interacted with marketing representatives. Policy dimensions reflecting the regulation of industry involvement in educational activities (e.g., continuing medical education, travel compensation, and scholarships) were associated with perceived separation between faculty and industry. The study is limited by potential for recall bias and the cross-sectional nature of the survey, as school curricula and industry interaction policies may have changed since the time of the survey administration and study analysis. Conclusions: As medical schools review policies regulating medical students' industry interactions, limitations on receipt of gifts and meals and participation of faculty in speaking bureaus should be emphasized, and policy makers should pay greater attention to less research-intensive institutions. Please see later in the article for the Editors' Summar

Propensity Score Calibration in the Absence of Surrogacy

Propensity score calibration (PSC) can be used to adjust for unmeasured confounders using a cross-sectional validation study that lacks information on the disease outcome (Y), under a strong surrogacy assumption. Using directed acyclic graphs and path analysis, the authors developed a formula to predict the presence and magnitude of the bias of PSC in the simplest setting of a binary exposure (T) and 1 confounder (X) that are observed in the main study and 1 confounder (C) that is observed in the validation study only. PSC bias is predicted on the basis of parameters that can be estimated from the data and a single unidentifiable parameter, the relative risk (RR) associated with C (RRCY). The authors simulated 1,000 cohort studies each with a Poisson-distributed outcome Y, varying parameter values over a wide range. When using the true parameter for RRCY, the formula predicts PSC bias almost perfectly in this simple setting (correlation with observed bias over 24 scenarios assessed: r = 0.998). The authors conclude that the bias from PSC observed in certain scenarios can be estimated from the imbalance in C between treated and untreated persons, after adjustment for X, in the validation study and assuming a range of plausible values for the unidentifiable RRCY

Risk of Ischemic Cerebrovascular and Coronary Events in Adult Users of Anticonvulsant Medications in Routine Care Settings

Background: Older‐generation anticonvulsants that highly induce cytochrome P450 enzyme system activity produce metabolic abnormalities that may increase cardiovascular risk. The objective of this study was to evaluate the risk of ischemic cerebrovascular and coronary events in adult new users of anticonvulsants that highly induce cytochrome P450 activity compared with other anticonvulsant agents, as observed in a routine care setting. Methods and Results: This was a cohort study of patients 40 to 64 years old from the HealthCore Integrated Research Database who had initiated an anticonvulsant medication between 2001 and 2006 and had no recorded major coronary or cerebrovascular condition in the 6 months before treatment initiation. Propensity score (PS) matching was used to evaluate ischemic cerebrovascular and coronary risk among anticonvulsant new users. High‐dimensional propensity score (hdPS)–matched analyses were used to confirm adjusted findings. The study identified 913 events in 166 031 unmatched new treatment episodes with anticonvulsant drugs. In a PS‐matched population of 22 864 treatment episodes, the rate ratio (RR) for ischemic coronary or cerebrovascular events associated with highly inducing agents versus other agents was 1.22 (95% CI, 0.90‐1.65). The RR moved to 0.99 (95% CI, 0.73‐1.33) with adjustment for hdPS matching (RR, 1.47; 95% CI, 0.95‐2.28 for cerebrovascular events; RR, 0.70; 95% CI, 0.47‐1.05 for coronary events). Conclusions: In this exploratory analysis, there was no evidence of a consistent and statistically significant effect of initiating anticonvulsants that highly induce cytochrome P450 activity on ischemic coronary or cerebrovascular outcomes compared with other agents, given routine care utilization patterns

The Effect of Altitude Change on Anemia Treatment Response in Hemodialysis Patients

Hemodialysis patients who live at high altitude use less exogenous erythropoietin but achieve higher hematocrit levels than those living at a lower altitude. The authors hypothesized that the effect of altitude would be strongest in hemodialysis patients with poor anemia treatment response. To explore this hypothesis, they studied anemia-related outcomes in US hemodialysis patients who move to higher altitudes. Using Medicare and US Geological Survey data, in 1992–2004 they identified instances in which a patient moved from a dialysis center at an altitude of <2,000 feet (600 m) to one at a higher elevation. Of these moves, 5,274 were ≥3,000 feet (900 m; the altitude group) and 25,345 were 250–500 feet (75–150 m; the control group). Among patients with poor treatment response at baseline, large increases in hematocrit and decreases in erythropoietin dosing were observed in the altitude relative to the control group. At 6 months, hematocrit had increased more in the altitude group (5.1%, 95% confidence interval (CI): 4.1, 6.2 vs. 3.7%, 95% CI: 3.5, 3.9), and erythropoietin dosing decreased more (4,600 units/week, 95% CI: 500, 8,700 vs. 1,700 units/week, 95% CI: 1,000, 2,400). No effect of altitude was observed in patients with better treatment response at baseline. These results support the hypothesis that altitude-induced hypoxia reduces erythropoietin requirements in hemodialysis patients with treatment-refractory anemia