Testing a Cloud-Based Model for Active Surveillance of Medical Devices with Analyses of Coronary Stent Safety Using the Data Extraction and Longitudinal Trend Analysis (DELTA) System.

Objective: To demonstrate the use of the Data Extraction and Longitudinal Trend Analysis (DELTA) system in the National Evaluation System for health Technology's (NEST) medical device surveillance cloud environment by analyzing coronary stent safety using real world clinical data and comparing results to clinical trial findings. Design and Setting: Electronic health record (EHR) data from two health systems, the Social Security Death Master File, and device databases were ingested into the NEST cloud, and safety analyses of two stents were performed using DELTA. Participants and Interventions: This is an observational study of patients receiving zotarolimus drug-eluting coronary stents (ZES) or everolimus eluting coronary stents (EES) between July 1, 2015 and December 31, 2017. Results: After exclusions, 3334 patients receiving EES and 1002 receiving ZES were available for study. Analysis using inverse probability weighting showed no significant difference in one-year mortality or major adverse cardiac events (MACE) for EES compared to ZES [Mortality Odds Ratio 0.94 (95% CI 0.81-1.175); p = 0.780] [MACE Odds Ratio 1.04 (95% CI 0.92-1.16; p = 0.551]). Analysis using propensity matching showed no significant difference in EES one-year mortality (547 of 992 alive and available after censoring) compared to ZES (546 of 992) [Log-Rank statistic 0.3348 (p = 0.563)]. Conclusion: Automated cloud-based medical device safety surveillance using EHR data is feasible and was efficiently performed using DELTA. No statistically significant differences in 1-year safety outcomes between ZES and EES were identified using two statistical approaches, consistent with randomized trial findings.

Simulating complex patient populations with hierarchical learning effects to support methods development for post-market surveillance.

BACKGROUND: Validating new algorithms, such as methods to disentangle intrinsic treatment risk from risk associated with experiential learning of novel treatments, often requires knowing the ground truth for data characteristics under investigation. Since the ground truth is inaccessible in real world data, simulation studies using synthetic datasets that mimic complex clinical environments are essential. We describe and evaluate a generalizable framework for injecting hierarchical learning effects within a robust data generation process that incorporates the magnitude of intrinsic risk and accounts for known critical elements in clinical data relationships. METHODS: We present a multi-step data generating process with customizable options and flexible modules to support a variety of simulation requirements. Synthetic patients with nonlinear and correlated features are assigned to provider and institution case series. The probability of treatment and outcome assignment are associated with patient features based on user definitions. Risk due to experiential learning by providers and/or institutions when novel treatments are introduced is injected at various speeds and magnitudes. To further reflect real-world complexity, users can request missing values and omitted variables. We illustrate an implementation of our method in a case study using MIMIC-III data for reference patient feature distributions. RESULTS: Realized data characteristics in the simulated data reflected specified values. Apparent deviations in treatment effects and feature distributions, though not statistically significant, were most common in small datasets (n < 3000) and attributable to random noise and variability in estimating realized values in small samples. When learning effects were specified, synthetic datasets exhibited changes in the probability of an adverse outcomes as cases accrued for the treatment group impacted by learning and stable probabilities as cases accrued for the treatment group not affected by learning. CONCLUSIONS: Our framework extends clinical data simulation techniques beyond generation of patient features to incorporate hierarchical learning effects. This enables the complex simulation studies required to develop and rigorously test algorithms developed to disentangle treatment safety signals from the effects of experiential learning. By supporting such efforts, this work can help identify training opportunities, avoid unwarranted restriction of access to medical advances, and hasten treatment improvements.

Real-World Safety Analysis of Paclitaxel Devices Used for the Treatment of Peripheral Artery Disease.

PURPOSE: To investigate the real-world safety of paclitaxel (PTX)-coated devices for treating lower extremity peripheral artery disease using a commercial claims database. MATERIALS AND METHODS: Data from FAIR Health, the largest commercial claims data warehouse in the United States, were used for this study. The study consisted of patients who underwent femoropopliteal revascularization procedures between January 1, 2015, and December 31, 2019, with PTX and non-PTX devices. The primary outcome was 4-year survival following treatment. The secondary outcomes included 2-year survival, 2- and 4-year freedom from amputation, and repeat revascularization. Propensity score matching was used to minimize confounding, and the Kaplan-Meier methods were used to estimate survival. RESULTS: A total of 10,832 procedures were included in the analysis, including 4,962 involving PTX devices and 5,870 involving non-PTX devices. PTX devices were associated with a reduced hazard of death following treatment at 2 and 4 years (hazard ratio [HR], 0.74 [95% confidence interval {CI}, 0.69-0.79]; P <.05, and HR, 0.89 [95% CI, 0.77-1.02]; log-rank P =.018, respectively). The risk of amputation was also lower following treatment with PTX devices than with non-PTX devices at 2 and 4 years (HR, 0.82 [95% CI, 0.76-0.87]; P =.02, and HR, 0.77 [95% CI, 0.67-0.89]; log-rank P =.01, respectively). In addition, the odds of repeat revascularization were similar with PTX and non-PTX devices at 2 and 4 years. CONCLUSIONS: In the real-world commercial claims database, no short- or long-term signal for increased mortality or amputations was observed following treatment with PTX devices.

Evaluation of intervertebral body implant performance using active surveillance of electronic health records.

Objectives: To assess the feasibility of using electronic health record (EHR) derived clinical data within an active surveillance setting to evaluate the safety of a novel intervertebral body implant (IVBI) stabilization device. Design: Retrospective, longitudinal observational cohort study comparing clinical outcomes for patients seen through 1 year following spinal fusion surgery. Setting: Lahey Health network, which includes academic tertiary hospitals, outpatient clinics, and independent provider offices in the New England region of the USA. Participants: All spine surgery patients aged 18 or older who underwent thoracic or lumbar spinal arthrodesis surgeries were included. Main outcome measures: The clinical outcomes of patients treated with the CONCORDE Bullet (CB) interbody spine system (DePuy) between April 2015 and December 2018 were compared with those patients receiving alternative spine stabilization interbody device implants. The primary endpoint was reoperation rate at 1 year, with secondary endpoints including the requirement for blood transfusion during index hospitalization, 1 year rate of any cause hospitalization, 1 year rate of surgical site infection, and mortality at 1 year. Results: Among the 606 patients undergoing thoracic or lumbar spinal fusion surgery during the study period, 136 received only the CB. In comparison with patients who did not receive the CB, no significant differences were found in the rate of reoperation at 1 year or the rates of secondary safety outcomes. Conclusions: Data derived from the EHR can be successfully leveraged to assess the safety of IVBI devices, in this case demonstrating no significant differences in the rates of risk-adjusted safety endpoints between patients undergoing spinal surgery with the CB as compared with alternative spinal implants.

Vascular Quality Initiative Surveillance of Femoropopliteal Artery Paclitaxel Devices.

OBJECTIVES: This study sought to determine the safety and efficacy of paclitaxel (PTX) devices in the treatment of peripheral artery disease involving the femoropopliteal artery. BACKGROUND: A meta-analysis of PTX devices for the treatment of femoropopliteal artery disease reported a mortality signal. METHODS: This was a multicenter cohort study using an integrated clinical data surveillance system to conduct a prospective, propensity score-matched survival analysis of 2,456 patients in the Society for Vascular Surgery Vascular Quality Initiative from January 2017 to May 2020. The study compared PTX drug-coated balloon angioplasty versus percutaneous transluminal balloon angioplasty, PTX drug-eluting stents versus bare-metal stents, and any PTX device versus any non-PTX device. The primary outcome was 2-year survival. Secondary endpoints were successful ambulation and interventional success. RESULTS: Treatment with any PTX device versus any non-PTX device was associated with increased 2-year survival (89.5% vs 86.7%; HR: 0.79; 95% CI: 0.72-0.87; P = 0.004), improved interventional success (81.6% vs 77.6%; HR: 0.82; 95% CI: 0.74-0.91; P < 0.001), and higher rates of independent ambulation at 1 year (86.0% vs 83.4%; HR: 0.85; 95% CI: 0.79-0.91; P = 0.008). Treatment with PTX drug-coated balloon angioplasty was associated with improved survival at 2 years (88.9% vs 85.7%; HR: 0.77; 95% CI: 0.70-0.86; P = 0.005), while PTX drug-eluting stent therapy was associated with similar survival compared with bare-metal stent therapy (91.3% vs 89.6%; HR: 0.84; 95% CI: 0.70-1.01; P = 0.36). CONCLUSIONS: In this prospective, active surveillance of a national clinical registry, PTX-containing devices were associated with increased survival at 2 years and improved clinical outcomes at 1 year. (VQI DELTA Paclitaxel Device Safety Analysis [VQI-PTX]; NCT04110288).

Active Surveillance of the Implantable Cardioverter-Defibrillator Registry for Defibrillator Lead Failures.

BACKGROUND: Several defibrillator leads have been recalled due to early lead failure leading to significant patient harm. Confirming the safety of contemporary defibrillator leads is essential to optimizing treatment for patients receiving implantable cardioverter-defibrillators (ICDs). We therefore sought to assess the comparative long-term safety of the 4 most commonly implanted ICD leads within the National Cardiovascular Data Registry ICD Registry. METHODS AND RESULTS: A propensity-matched survival analysis of the ICD Registry was performed evaluating 4 contemporary ICD leads in patients receiving an ICD system for the first time. All patients in the ICD Registry aged ≥18 years who underwent an implant of an ICD between April 1, 2011 and March 31, 2016 were included. Monitoring of safety began with ICD implant and continued up to 5 years. A meaningful difference in ICD failure rate was defined as twice (or more) the lead failure rate observed in the propensity-matched comparator patients. Among the 374 132 patients who received a new ICD implant, no safety alerts were triggered for the primary safety end point of lead failure for any of the high energy leads studied. Estimated rates of freedom from lead failure at 5 years ranged from 97.7% to 98.9% for the 4 high-energy leads of interest. CONCLUSIONS: Though limited by incomplete long-term outcomes ascertainment, active surveillance of the ICD Registry suggests that there were no meaningful differences in the rate of ICD high-energy lead survival for the 4 most commonly used high-energy ICD leads.

Impact of early surveillance on safety signal identification in the CathPCI DELTA study.

OBJECTIVES: The CathPCI Data Extraction and Longitudinal Trend Analysis study was designed to determine the feasibility of conducting prospective surveillance of a large national registry to perform comparative safety analyses of medical devices. We sought to determine whether the complementary use of retrospective case data could improve safety signal detection time. DESIGN: We performed a simulated surveillance study of the comparative safety of the Mynx vascular closure device (VCD) with propensity score matched alternate VCD recipients, using both retrospective and prospective cohort data. SETTING: Centers within the USA using the National Cardiovascular Data Registry (NCDR) CathPCI Registry. PARTICIPANTS: Percutaneous coronary intervention cases captured within the NCDR CathPCI Registry from July 1, 2009 to September 30, 2013 were included in the analysis. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Absolute and relative risk (RR) of any vascular complication (a composite of bleeding at access site, hematoma at access site, retroperitoneal bleeding, and other vascular complications requiring treatment); time to signal detection. RESULTS: A safety alert was detected for the primary outcome of "any vascular complication" after 15 months of surveillance and was sustained for the study duration (absolute risk of any vascular complication, 1.20% vs 0.73%, RR, 1.63; 95% CI 1.50 to 1.79; p<0.001). The safety signal was identified 12 months earlier with the use of retrospective case data than during the initial study. CONCLUSIONS: Prospective, active surveillance of cardiovascular registries is feasible to perform comparative analyses of medical devices. Retrospective data may complement prospective surveillance to improve time to signal detection, indicating the need for earlier prospective application of safety surveillance for devices new to the market.

Comparative Safety of Aspiration Thrombectomy Catheters Utilizing Prospective, Active Surveillance of the NCDR CathPCI Registry.

Background Current strategies for ensuring the postmarket safety of medical devices are limited by small sample size and reliance on voluntary reporting of adverse events. Prospective, active surveillance of clinical registries may provide early warnings in the postmarket evaluation of medical device safety but has not been demonstrated in national clinical data registries. Methods and Results The CathPCI DELTA (Data Extraction and Longitudinal Trend Analysis) study was designed to assess the feasibility of prospective, active safety surveillance of medical devices within a national cardiovascular registry. We sought to assess the ability of our surveillance strategy to avoid false safety alerts by conducting an active safety surveillance study of aspiration thrombectomy catheters using data within the National Cardiovascular Data Registry CathPCI registry, where no difference in safety outcomes were anticipated for the primary in-hospital safety outcome of death and major adverse cardiovascular events (MACE). We performed a propensity-matched analysis of 5 aspiration thrombectomy catheter devices used during percutaneous coronary intervention among 95 925 patients presenting with ST-segment-elevation myocardial infarction between January 1, 2011 and September 30, 2013. After 33 months of surveillance, no safety alerts were triggered for the primary safety endpoints of death or MACE, with no between-catheter differences observed. The absolute risk of death during acute hospitalization ranged from 5.11% to 5.32% among the most commonly used aspiration thrombectomy catheter devices, with relative risks for death ranging from 0.96 to 1.03. The absolute risk of MACE ranged from 9.78% to 10.18%, with relative risks for MACE ranging from 0.99 to 1.02. There were no statistically significant differences in the rates of death or MACE between any of the aspiration thrombectomy catheter devices analyzed. Conclusions The CathPCI DELTA study demonstrates that prospective, active safety surveillance of national clinical registries is feasible to provide near-real-time safety assessments of new medical devices.

Registry-Based Prospective, Active Surveillance of Medical-Device Safety.

BACKGROUND: The process of assuring the safety of medical devices is constrained by reliance on voluntary reporting of adverse events. We evaluated a strategy of prospective, active surveillance of a national clinical registry to monitor the safety of an implantable vascular-closure device that had a suspected association with increased adverse events after percutaneous coronary intervention (PCI). METHODS: We used an integrated clinical-data surveillance system to conduct a prospective, propensity-matched analysis of the safety of the Mynx vascular-closure device, as compared with alternative approved vascular-closure devices, with data from the CathPCI Registry of the National Cardiovascular Data Registry. The primary outcome was any vascular complication, which was a composite of access-site bleeding, access-site hematoma, retroperitoneal bleeding, or any vascular complication requiring intervention. Secondary safety end points were access-site bleeding requiring treatment and postprocedural blood transfusion. RESULTS: We analyzed data from 73,124 patients who had received Mynx devices after PCI procedures with femoral access from January 1, 2011, to September 30, 2013. The Mynx device was associated with a significantly greater risk of any vascular complication than were alternative vascular-closure devices (absolute risk, 1.2% vs. 0.8%; relative risk, 1.59; 95% confidence interval [CI], 1.42 to 1.78; P<0.001); there was also a significantly greater risk of access-site bleeding (absolute risk, 0.4% vs. 0.3%; relative risk, 1.34; 95% CI, 1.10 to 1.62; P=0.001) and transfusion (absolute risk, 1.8% vs. 1.5%; relative risk, 1.23; 95% CI, 1.13 to 1.34; P<0.001). The initial alerts occurred within the first 12 months of monitoring. Relative risks were greater in three prespecified high-risk subgroups: patients with diabetes, those 70 years of age or older, and women. All safety alerts were confirmed in an independent sample of 48,992 patients from April 1, 2014, to September 30, 2015. CONCLUSIONS: A strategy of prospective, active surveillance of a clinical registry rapidly identified potential safety signals among recipients of an implantable vascular-closure device, with initial alerts occurring within the first 12 months of monitoring. (Funded by the Food and Drug Administration and others.).

Assessing the cost burden of United States FDA-mandated post-approval studies for medical devices.

Approved medical devices frequently undergo FDA mandated post-approval studies (PAS). However, there is uncertainty as to the value of PAS in assessing the safety of medical devices and the cost of these studies to the healthcare system is unknown. Since PAS costs are funded through device manufacturers who do not share the costs with regulators, we sought to estimate the total PAS costs through interviews with a panel of experts in medical device clinical trial design in order to design a general cost model for PAS which was then applied to the FDA PAS. A total of 277 PAS were initiated between 3/1/05 through 6/30/13 and demonstrated a median cost of $2.16 million per study and an overall cost of $1.22 billion over the 8.25 years of study. While these costs are funded through manufacturers, the ultimate cost is borne by the healthcare system through the medical device costs. Given concerns regarding the informational value of PAS, the resources used to support mandated PAS may be better allocated to other approaches to assure safety.