Early technology review: towards an expedited pathway.

OBJECTIVES: Evidence development for medical devices is often focused on satisfying regulatory requirements with the result that health professional and payer expectations may not be met, despite considerable investment in clinical trials. Early engagement with payers and health professionals could allow companies to understand these expectations and reflect them in clinical study design, increasing chances of positive coverage determination and adoption into clinical practice. METHODS: An example of early engagement through the EXCITE International model using an early technology review (ETR) is described which includes engagement with payers and health professionals to better inform companies to develop data that meet their expectations. ETR is based on an early evidence review, a framework of expectations that guides the process and identified gaps in evidence. The first fourteen ETRs were reviewed for examples of advice to companies that provided additional information from payers and health professionals that was thought likely to impact on downstream outcomes or strategic direction. Given that limitations were imposed by confidentiality, examples were genericized. RESULTS: Advice through early engagement can inform evidence development that coincides with expectations of payers and health professionals through a structured, objective, evidence-based approach. This could reduce the risk of business-related adverse outcomes such as failure to secure a positive coverage determination and/or acceptance by expert health professionals. CONCLUSIONS: Early engagement with key stakeholders exemplified by the ETR approach offers an alternative to the current approach of focusing on regulatory expectations. This could reduce the time to reimbursement and clinical adoption and benefit patient outcomes and/or health system efficiencies.

Attribution of Adverse Events Following Coronary Stent Placement Identified Using Administrative Claims Data.

Background More than 600 000 coronary stents are implanted during percutaneous coronary interventions (PCIs) annually in the United States. Because no real-world surveillance system exists to monitor their long-term safety, claims data are often used for this purpose. The extent to which adverse events identified with claims data can be reasonably attributed to a specific medical device is uncertain. Methods and Results We used deterministic matching to link the NCDR (National Cardiovascular Data Registry) CathPCI Registry to Medicare fee-for-service claims for patients aged ≥65 years who underwent PCI with drug-eluting stents (DESs) between July 1, 2009 and December 31, 2013. We identified subsequent PCIs within 1 year of the index procedure in Medicare claims as potential safety events. We linked these subsequent PCIs back to the NCDR CathPCI Registry to ascertain how often the revascularization could be reasonably attributed to the same coronary artery as the index PCI (ie, target vessel revascularization). Of 415 306 DES placements in 368 194 patients, 33 174 repeat PCIs were identified in Medicare claims within 1 year. Of these, 28 632 (86.3%) could be linked back to the NCDR CathPCI Registry; 16 942 (51.1% of repeat PCIs) were target vessel revascularizations. Of these, 8544 (50.4%) were within a previously placed DES: 7652 for in-stent restenosis and 1341 for stent thrombosis. Of 16 176 patients with a claim for acute myocardial infarction in the follow-up period, 4446 (27.5%) were attributed to the same coronary artery in which the DES was implanted during the index PCI (ie, target vessel myocardial infarction). Of 24 288 patients whose death was identified in claims data, 278 (1.1%) were attributed to the same coronary artery in which the DES was implanted during the index PCI. Conclusions Most repeat PCIs following DES stent implantation identified in longitudinal claims data could be linked to real-world registry data, but only half could be reasonably attributed to the same coronary artery as the index procedure. Attribution among those with acute myocardial infarction or who died was even less frequent. Safety signals identified using claims data alone will require more in-depth examination to accurately assess stent safety.

Overview and experience of the YODA Project with clinical trial data sharing after 5 years.

The Yale University Open Data Access (YODA) Project has facilitated access to clinical trial data since 2013. The purpose of this article is to provide an overview of the Project, describe key decisions that were made when establishing data sharing policies, and suggest how our experience and the experiences of our first two data generator partners, Medtronic, Inc. and Johnson & Johnson, can be used to enhance other ongoing or future initiatives.

Advancing the Science of Healthcare Service Delivery: The NHLBI Corporate Healthcare Leaders' Panel.

There is a growing gap between available science and evidence and the ability of service providers to deliver high-quality care in a cost-effective way to the entire population. We believe that the chasm between knowledge and action is due to a lack of concerted effort among all organizations that deliver health care services across the life span of patients. Broad participation is needed and necessitates a far more explicit and concerted public-private partnership focused on large-scale transformation. In this context, the National Heart, Lung, and Blood Institute convened a panel made up of leaders of corporate health care entities, including academic health centers, and government agency representatives to inform contemporary strategic partnerships with health care companies. This article provides insights from the meeting on how to execute a transformative innovation research agenda that will foster improvements in health care service delivery by leveraging the translation of biomedical research evidence in real-world settings.

Quantifying the utilization of medical devices necessary to detect postmarket safety differences: A case study of implantable cardioverter defibrillators.

PURPOSE: To estimate medical device utilization needed to detect safety differences among implantable cardioverter defibrillators (ICDs) generator models and compare these estimates to utilization in practice. METHODS: We conducted repeated sample size estimates to calculate the medical device utilization needed, systematically varying device-specific safety event rate ratios and significance levels while maintaining 80% power, testing 3 average adverse event rates (3.9, 6.1, and 12.6 events per 100 person-years) estimated from the American College of Cardiology's 2006 to 2010 National Cardiovascular Data Registry of ICDs. We then compared with actual medical device utilization. RESULTS: At significance level 0.05 and 80% power, 34% or fewer ICD models accrued sufficient utilization in practice to detect safety differences for rate ratios <1.15 and an average event rate of 12.6 events per 100 person-years. For average event rates of 3.9 and 12.6 events per 100 person-years, 30% and 50% of ICD models, respectively, accrued sufficient utilization for a rate ratio of 1.25, whereas 52% and 67% for a rate ratio of 1.50. Because actual ICD utilization was not uniformly distributed across ICD models, the proportion of individuals receiving any ICD that accrued sufficient utilization in practice was 0% to 21%, 32% to 70%, and 67% to 84% for rate ratios of 1.05, 1.15, and 1.25, respectively, for the range of 3 average adverse event rates. CONCLUSIONS: Small safety differences among ICD generator models are unlikely to be detected through routine surveillance given current ICD utilization in practice, but large safety differences can be detected for most patients at anticipated average adverse event rates.

Can machine learning complement traditional medical device surveillance? A case study of dual-chamber implantable cardioverter-defibrillators.

BACKGROUND: Machine learning methods may complement traditional analytic methods for medical device surveillance. METHODS AND RESULTS: Using data from the National Cardiovascular Data Registry for implantable cardioverter-defibrillators (ICDs) linked to Medicare administrative claims for longitudinal follow-up, we applied three statistical approaches to safety-signal detection for commonly used dual-chamber ICDs that used two propensity score (PS) models: one specified by subject-matter experts (PS-SME), and the other one by machine learning-based selection (PS-ML). The first approach used PS-SME and cumulative incidence (time-to-event), the second approach used PS-SME and cumulative risk (Data Extraction and Longitudinal Trend Analysis [DELTA]), and the third approach used PS-ML and cumulative risk (embedded feature selection). Safety-signal surveillance was conducted for eleven dual-chamber ICD models implanted at least 2,000 times over 3 years. Between 2006 and 2010, there were 71,948 Medicare fee-for-service beneficiaries who received dual-chamber ICDs. Cumulative device-specific unadjusted 3-year event rates varied for three surveyed safety signals: death from any cause, 12.8%-20.9%; nonfatal ICD-related adverse events, 19.3%-26.3%; and death from any cause or nonfatal ICD-related adverse event, 27.1%-37.6%. Agreement among safety signals detected/not detected between the time-to-event and DELTA approaches was 90.9% (360 of 396, k=0.068), between the time-to-event and embedded feature-selection approaches was 91.7% (363 of 396, k=-0.028), and between the DELTA and embedded feature selection approaches was 88.1% (349 of 396, k=-0.042). CONCLUSION: Three statistical approaches, including one machine learning method, identified important safety signals, but without exact agreement. Ensemble methods may be needed to detect all safety signals for further evaluation during medical device surveillance.

Transcatheter valve therapy registry is a model for medical device innovation and surveillance.

Heart valve diseases are increasingly prevalent, especially in people older than age seventy. Many of these elderly people have other comorbid conditions, making them poor candidates for surgical treatment of heart valve diseases. Since 2011 such patients have been eligible to receive new nonsurgical heart valve treatments approved by the Food and Drug Administration (FDA) and covered by Medicare. This article examines the Transcatheter Valve Therapy Registry, which captures clinical information on all US patients undergoing new nonsurgical heart valve treatments. The registry has patient-level data from more than 27,000 patients treated with the novel devices. Patient- and procedure-related data are gathered from hospitals, patient-reported outcomes are assessed pre- and postprocedure, and longer-term data on mortality and repeat hospitalization are provided by linking the registry's data to Medicare patient data. The registry is a model of collaboration among professional societies, the FDA, the Centers for Medicare and Medicaid Services, hospitals, patients, and the medical device industry. It has been used to support Medicare coverage decisions, expand device indications, provide comprehensive device surveillance, and establish national quality benchmarks. Beyond having it serve as a collaborative model, future goals for the registry include shortening the FDA-approval timeline for devices, providing data for decision-making tools for patients, and public reporting of hospital performance.

The reporting of blinding in physical medicine and rehabilitation randomized controlled trials: a systematic review.

OBJECTIVE: To conduct a systematic review evaluating the reporting of blinding in randomized controlled trials published in the field of Physical Medicine and Rehabilitation over two time periods. DATA SOURCES: We searched MEDLINE via PubMed for all randomized controlled trials published in American Journal of Physical Medicine and Rehabilitation, Archives of Physical Medicine and Rehabilitation, Clinical Rehabilitation, Disability and Rehabilitation and (Scandinavian) Journal of Rehabilitation Medicine in the years 2000 and 2010. STUDY SELECTION: We initially identified 222 articles, and 139 (62.6%) met our selection criteria. DATA EXTRACTION: Two independent investigators collected data regarding study characteristics and blinding from each article. Consistency of data extraction was evaluated. DATA SYNTHESIS: When comparing articles from 2010 and 2000, the former showed significantly higher rates for reporting of blinding, explicitly describing key persons' blinding status, and discussing the absence of blinding as a study limitation. There was a trend for lower reporting among trials with positive outcomes. No improvement was observed in other CONSORT-enforced parameters. CONCLUSIONS: Although the reporting of blinding in Physical Medicine and Rehabilitation randomized controlled trials shows some improvement over the past decade, it still does not fulfill current recommendations. Given its critical role in determining internal validity, stricter enforcement of CONSORT guidelines is needed.

Rationale and design of the MASS COMM trial: A randomized trial to compare percutaneous coronary intervention between MASSachusetts hospitals with cardiac surgery on-site and COMMunity hospitals without cardiac surgery on-site.

BACKGROUND: Emergency surgery has become an increasingly rare event after percutaneous coronary intervention (PCI). There have been no randomized trials evaluating whether cardiac surgery services on-site are essential for patient safety and optimal outcomes during and after PCI. STUDY DESIGN: The MASS COMM trial (ClinicalTrials.gov no. NCT01116882) is a randomized trial comparing the safety and effectiveness of nonemergency PCI at hospitals without surgery on-site (SOS) (non-SOS hospitals) and hospitals with SOS (SOS hospitals). A total of 3,690 subjects will be randomized in a 3:1 fashion to undergo PCI at non-SOS and SOS hospitals, with follow-up at hospital discharge, 30 days, and 12 months after PCI. The rate of major adverse cardiac events (all-cause mortality, myocardial infarction, repeat revascularization, and stroke) will serve as the primary safety end point at 30 days and the primary effectiveness end point at 12 months. The design is a 1-way randomized trial with a statistical hypothesis of noninferiority of nonemergency PCI at non-SOS hospitals for both safety and effectiveness end points. CONCLUSIONS: This multicenter, randomized trial will compare the relative safety and effectiveness of nonemergency PCI at sites with and without cardiac SOS.

Relative spatial distributions of coronary artery bypass graft insertion and acute thrombosis: a model for protection from acute myocardial infarction.

BACKGROUND: Randomized trials have demonstrated coronary artery bypass surgery (CABG) to be superior to percutaneous coronary intervention with respect to long-term mortality and morbidity from myocardial infarction within specific high-risk cohorts. The purpose of this study was to analyze the spatial distribution of coronary artery bypass graft anastomoses relative to acute thromboses in native coronary arteries. We hypothesized that insertion sites of bypass grafts are located distal to sites of acute thrombosis and consequently decrease cardiac morbidity and mortality associated with plaque rupture. METHODS: We analyzed 168 patients with prior CABG and 208 patients with ST-segment elevation myocardial infarctions (STEMI) presenting to the Brigham and Women's Hospital who underwent coronary angiography. We constructed a spatial map of the coronary arterial bypass graft insertion sites and compared these locations to sites of acute thrombosis leading to STEMI. RESULTS: Graft insertion sites were consistently located distal to acute thrombosis sites (left anterior descending artery median graft insertion versus median thrombosis site = 72 versus 34 mm, right coronary artery 91 versus 42 mm, left circumflex artery 44 versus 37 mm). Greater than 97% of thrombosis sites were located proximal to 75% of graft insertion sites. CONCLUSIONS: Coronary arterial bypass grafts provide the coverage of anatomic zones at risk for STEMI. The superior performance of CABG in high risk patients may be attributed to targeting of proximal coronary locations where thrombosis risk is clustered.

Lack of association between migraine headache and patent foramen ovale: results of a case-control study.

BACKGROUND: Clinical observations of migraine headache symptoms in patients with a patent foramen ovale (PFO), both of which conditions are highly prevalent, have raised the question of a possible pathophysiological relationship. We sought to evaluate the assumption of an association between migraine headaches and the presence of PFO by use of a large case-control study. METHODS AND RESULTS: We conducted a case-control study to assess the prevalence of PFO in subjects with and without migraine. Case subjects were those with a history of migraine (diagnosed by neurologists at a specialty academic headache clinic). Control subjects were healthy volunteers without migraine 1:1 matched on the basis of age and sex with case subjects. Presence of PFO was determined by transthoracic echocardiogram with second harmonic imaging and transcranial Doppler ultrasonography during a standardized procedure of infused agitated saline contrast with or without Valsalva maneuver and a review of the results by experts blinded to case-control status. PFO was considered present if both studies were positive. Odds ratios were calculated with conditional logistic regression in the matched cohort (n=288). In the matched analysis, the prevalence of PFO was similar in case and control subjects (26.4% versus 25.7%; odds ratio 1.04, 95% confidence interval 0.62 to 1.74, P=0.90). There was no difference in PFO prevalence in those with migraine with aura and those without (26.8% versus 26.1%; odds ratio 1.03, 95% confidence interval 0.48 to 2.21, P=0.93). CONCLUSIONS: We found no association between migraine headaches and the presence of PFO in this large case-control study.

Location of acute coronary artery thromboses in patients with and without chronic kidney disease.

Patients with chronic kidney disease have high rates of myocardial infarction and death following an initial attack. Proximal location of coronary atherosclerotic lesions has been linked to the risk of acute myocardial infarction and to infarction-associated mortality. To examine if the spatial distribution of lesions differs in patients with and without chronic kidney disease, we used quantitative coronary angiography to measure this in patients with acute coronary thromboses who were having angiography following acute myocardial infarction. Multivariable linear regression was used to adjust for differences in baseline characteristics. Among 82 patients with stage 3 or higher chronic kidney disease, 55.6% of lesions were located within 30 mm and 87.7% were within 50 mm of the coronary ostia. This compared to 34.7 and 71.8%, respectively, among 299 patients without significant kidney disease. Chronic kidney disease was independently and significantly associated with a 7.0 mm decrease in the distance from the coronary ostia to the problem lesion. Our study suggests that a causal link between a more proximal culprit lesion location in patients with chronic kidney disease and their high mortality rates after myocardial infarct is possible and may have important implications for interventions to prevent infarction.

Saphenous vein graft stenting and major adverse cardiac events: a predictive model derived from a pooled analysis of 3958 patients.

BACKGROUND: Treatment of saphenous vein graft (SVG) stenosis with percutaneous coronary intervention has a 15% to 20% incidence of major adverse cardiac events (MACE) within 30 days. Although MACE rates are reduced significantly by the use of embolic protection devices (EPDs), neither the level of baseline risk nor the benefit provided by EPDs has been well characterized. METHODS AND RESULTS: Data from 5 randomized controlled trials and 1 registry evaluating EPDs in SVG percutaneous coronary intervention (n=3958 patients) were pooled for analysis. MACE was defined as a composite of death, myocardial infarction, and target vessel revascularization. Baseline variables and 2 summary angiographic variables (an SVG degeneration score and an estimate of lesion plaque volume) were included in a multivariable logistic regression model to predict 30-day MACE, with adjustment for the type of device used and inter-study variation. The angiographic variables were potent predictors of MACE (increasing SVG degeneration score, P<0.0001; larger estimated plaque volume, P<0.0001), with significant contributions from the presence of thrombus (P<0.01), increasing patient age (P<0.01), glycoprotein IIb/IIIa inhibitor use (P=0.02), and current tobacco abuse (P=0.03). The treatment benefit of EPDs was preserved across all categories of risk as categorized by SVG degeneration or plaque volume. CONCLUSIONS: The strongest predictors of 30-day MACE in SVG percutaneous coronary intervention are angiographic estimates of plaque volume and SVG degeneration. Identification of these predictors of 30-day MACE allows reliable prediction of patient outcomes and confirms consistent treatment benefit with the use of EPDs across the range of patients tested in randomized trials.

Zotarolimus-eluting stents in patients with native coronary artery disease: clinical and angiographic outcomes in 1,317 patients.

Early studies of a cobalt-based alloy stent coated with the novel antiproliferative agent zotarolimus and a phosphorylcholine polymer have demonstrated significant reductions in angiographic restenosis and target vessel revascularization compared with bare metal stents. However, the generalizability of the angiographic outcomes and clinical benefit of zotarolimus-eluting stents (ZESs) to a more real-world patient population is undetermined. Clinical and angiographic outcomes in 1,317 patients treated with the ZES in the first 4 trials of the Endeavor ZES (Medtronic Vascular, Santa Rosa, CA) clinical trials program were pooled for systematic analysis. Protocol-specified follow-up angiography was performed at 8 or 12 months for a subset of 750 of these patients, and clinical follow-up was performed at 9 months after the index procedures in all patients. Diabetes mellitus was present in 22.5% of patients, the mean reference vessel diameter was 2.73 mm, and the mean lesion length was 14.59 mm. At 8 months (12 months for ENDEAVOR I), mean +/- SD in-stent late luminal loss was 0.61 +/- 0.49 mm. In-stent late luminal loss was greatest in larger caliber (>2.9 mm) vessels (0.65 +/- 0.49 mm) and longer (>16.3 mm) lesions (0.70 +/- 0.52 mm) but did not statistically vary according to diabetic status. At 9 months, overall rates of target lesion revascularization (TLR) and major adverse cardiac events (MACE) were 4.9% and 7.7%, respectively. The rate of TLR at 12 months was not significantly different relative to diabetes and lesion length >16.3 mm (7.2% and 7.7%, respectively), although TLR was significantly more common when reference vessel diameter was <2.5 mm (8.5%; p = 0.013). At 24 months, overall rates of TLR and MACE were 6.5% and 9.9%, respectively. The overall 24-month rate of stent thrombosis was 0.3%, with no events occurring >14 days after the procedure. Despite varied clinical and angiographic characteristics, treatment with the ZES is associated with consistently low rates of TLR and overall major adverse events, including stent thrombosis. Although these findings indicate the efficacy and safety of the ZES over the time course of the first 4 ENDEAVOR clinical trials, additional ongoing study with more open patient inclusion criteria (including long lesions, small vessels, bifurcations, etc) will be important for discerning whether comparable clinical outcomes can be extended to lesion subsets of higher complexity.