Art Sedrakyan

Conducting quantitative synthesis when comparing medical interventions: AHRQ and the Effective Health Care Program

OBJECTIVE This article is to establish recommendations for conducting quantitative synthesis, or meta-analysis, using study-level data in comparative effectiveness reviews (CERs) for the Evidence-based Practice Center (EPC) program of the Agency for Healthcare Research and Quality. STUDY DESIGN AND SETTING We focused on recurrent issues in the EPC program and the recommendations were developed using group discussion and consensus based on current knowledge in the literature. RESULTS We first discussed considerations for deciding whether to combine studies, followed by discussions on indirect comparison and incorporation of indirect evidence. Then, we described our recommendations on choosing effect measures and statistical models, giving special attention to combining studies with rare events; and on testing and exploring heterogeneity. Finally, we briefly presented recommendations on combining studies of mixed design and on sensitivity analysis. CONCLUSION Quantitative synthesis should be conducted in a transparent and consistent way. Inclusion of multiple alternative interventions in CERs increases the complexity of quantitative synthesis, whereas the basic issues in quantitative synthesis remain crucial considerations in quantitative synthesis for a CER. We will cover more issues in future versions and update and improve recommendations with the accumulation of new research to advance the goal for transparency and consistency.

Clinical Effectiveness of Coronary Stents in Elderly Persons: Results From 262,700 Medicare Patients in the American College of Cardiology―National Cardiovascular Data Registry

OBJECTIVES The aim of this study was to compare outcomes in older individuals receiving drug-eluting stents (DES) and bare-metal stents (BMS). BACKGROUND Comparative effectiveness of DES relative to BMS remains unclear. METHODS Outcomes were evaluated in 262,700 patients from 650 National Cardiovascular Data Registry sites during 2004 to 2006 with procedural registry data linked to Medicare claims for follow-up. Outcomes including death, myocardial infarction (MI), revascularization, major bleeding, stroke, death or MI, death or MI or revascularization, and death or MI or stroke were compared with estimated cumulative incidence rates with inverse probability weighted estimators and Cox proportional hazards ratios. RESULTS The DES were implanted in 217,675 patients and BMS were implanted in 45,025. At 30 months, DES patients had lower unadjusted rates of death (12.9% vs. 17.9%), MI (7.3 of 100 patients vs. 10.0 of 100 patients), and revascularization (23.0 of 100 patients vs. 24.5 of 100 patients) with no difference in stroke or bleeding. After adjustment, DES patients had lower rates of death (13.5% vs. 16.5%, hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.72 to 0.79, p < 0.001) and MI (7.5 of 100 patients vs. 8.9 of 100 patients, HR: 0.77, 95% CI: 0.72 to 0.81, p < 0.001), with minimal difference in revascularization (23.5 of 100 patients vs. 23.4 of 100 patients; HR: 0.91, 95% CI: 0.87 to 0.96), stroke (3.1 of 100 patients vs. 2.7 of 100 patients, HR: 0.97, 95% CI: 0.88 to 1.07), or bleeding (3.4 of 100 patients vs. 3.6 of 100 patients, HR: 0.91, 95% CI: 0.84 to 1.00). The DES survival benefit was observed in all subgroups analyzed and persisted throughout 30 months of follow-up. CONCLUSIONS In this largest ever real-world study, patients receiving DES had significantly better clinical outcomes than their BMS counterparts, without an associated increase in bleeding or stroke, throughout 30 months of follow-up and across all pre-specified subgroups.

The International Consortium of Orthopaedic Registries: Overview and Summary

FDA Post-Market Efforts and Interest in Orthopaedics The United States Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH) monitors both mandatory and voluntary post-market reporting to identify adverse events and problems associated with medical devices. Although the manufacturers of medical devices are required to report deaths, injuries, and malfunctions directly to the FDA, the device users are required to report these events to the manufacturer and are required to report only deaths to the FDA. Voluntary reporting systems such as the MedWatch program, the MAUDE (Manufacturer and User Facility Device Experience) database, and the MedSun (Medical Product Safety Network) enhanced surveillance network provide nationwide medical device surveillance in the U.S. However, these reporting systems have important weaknesses, such as incomplete, inaccurate, or nonvalidated data, reporting biases related to event severity, concerns that reporting may result in adverse publicity or litigation, and general underreporting of events. Most importantly, denominator data are missing, which makes evaluation of the incidence or prevalence of a safety-related event impossible. The FDA’s interest in orthopaedic device safety and in the development of infrastructure for enhanced safety monitoring is natural and timely; the lack of such safety evidence is particularly troubling for the most commonly used implants. Over 700,000 joint replacements involving implantable devices are conducted annually in the U.S. alone, and the annual volume is projected to increase twofold for hip joint replacements and sevenfold for knee joint replacements, to a total of more than 3 million annually, in just the next twenty years. Moreover, these surgical procedures are expected to become more expensive, with costs tripling in just the next five years. Despite remarkable advancements in orthopaedics, including new devices and improved surgical techniques, the value of many therapeutic devices has not been established in clinical trials or in real-world settings. Several factors contribute to this shortcoming: (1) rapidly changing device technology coupled with an enormous number of devices on the market; (2) the need for large numbers of patients and long-term follow-up to adequately evaluate the primary safety end point, which is longterm device failure or need for revision; and (3) the need for prospective data collection, planning, and substantial funding to evaluate short and long-term patient-reported outcomes, which are the primary effectiveness end points. The poor state of research and the resulting inability to learn about a device’s benefits, its potential harms, and the balance between them hinder decision-making by the FDA and other stakeholders such as the Centers for Medicare & Medicaid Services (CMS) and commercial insurers.

Clinical Effectiveness of Coronary Stents in the Elderly: Results from 262,700 Medicare Patients in ACC-NCDR®

OBJECTIVES The aim of this study was to compare outcomes in older individuals receiving drug-eluting stents (DES) and bare-metal stents (BMS). BACKGROUND Comparative effectiveness of DES relative to BMS remains unclear. METHODS Outcomes were evaluated in 262,700 patients from 650 National Cardiovascular Data Registry sites during 2004 to 2006 with procedural registry data linked to Medicare claims for follow-up. Outcomes including death, myocardial infarction (MI), revascularization, major bleeding, stroke, death or MI, death or MI or revascularization, and death or MI or stroke were compared with estimated cumulative incidence rates with inverse probability weighted estimators and Cox proportional hazards ratios. RESULTS The DES were implanted in 217,675 patients and BMS were implanted in 45,025. At 30 months, DES patients had lower unadjusted rates of death (12.9% vs. 17.9%), MI (7.3 of 100 patients vs. 10.0 of 100 patients), and revascularization (23.0 of 100 patients vs. 24.5 of 100 patients) with no difference in stroke or bleeding. After adjustment, DES patients had lower rates of death (13.5% vs. 16.5%, hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.72 to 0.79, p < 0.001) and MI (7.5 of 100 patients vs. 8.9 of 100 patients, HR: 0.77, 95% CI: 0.72 to 0.81, p < 0.001), with minimal difference in revascularization (23.5 of 100 patients vs. 23.4 of 100 patients; HR: 0.91, 95% CI: 0.87 to 0.96), stroke (3.1 of 100 patients vs. 2.7 of 100 patients, HR: 0.97, 95% CI: 0.88 to 1.07), or bleeding (3.4 of 100 patients vs. 3.6 of 100 patients, HR: 0.91, 95% CI: 0.84 to 1.00). The DES survival benefit was observed in all subgroups analyzed and persisted throughout 30 months of follow-up. CONCLUSIONS In this largest ever real-world study, patients receiving DES had significantly better clinical outcomes than their BMS counterparts, without an associated increase in bleeding or stroke, throughout 30 months of follow-up and across all pre-specified subgroups.

IDEAL framework for surgical innovation 3: randomised controlled trials in the assessment stage and evaluations in the long term study stage

The complexity of surgical procedures often poses challenges for conducting a rigorous and comprehensive evaluation. This paper considers the final two IDEAL stages of surgical innovation. Surgical randomised controlled trials are often challenging to undertake and require careful consideration of the intervention definition, who should deliver it, and the impact of surgeon and patient preferences. In the long term study stage, better monitoring of surgical procedures is needed, along with improved surveillance of devices.

Outcomes after lobectomy using thoracoscopy vs thoracotomy: a comparative effectiveness analysis utilizing the Nationwide Inpatient Sample database

OBJECTIVES We examined the Nationwide Inpatient Sample (NIS) database to compare short-term postoperative outcomes following open and thoracoscopic lobectomy. Thoracoscopic (video-assisted thoracic surgery) lobectomy has been demonstrated to be associated with fewer postoperative complications compared with open thoracotomy lobectomy in several large case series. However, as no randomized trial has been performed, there are many who question this. METHODS We examined the NIS database for all patients undergoing lobectomy as their principal procedure either via thoracoscopic or open thoracotomy from 2007 to 08. We compared the postoperative outcomes of these two groups of patients after propensity matching these groups based on several preoperative variables. RESULTS Over a 2-year-period, 68 350 patients underwent a lobectomy by either thoracoscopy [n = 10 554 (15%)] or thoracotomy [n = 57 796(85%)]. Thirty-two percent of thoracoscopic lobectomies (n = 3421) were performed in either rural or non-teaching urban centres. Although in propensity-matched cohorts there was no difference in operative mortality, thoracoscopic lobectomy was associated with a lower incidence of postoperative complications [n = 4146 (40.8%) vs n = 13 913 (45.1%), P < 0.001] and shorter length of stay (5.0 vs 7.0 days; P < 0.001) compared with open lobectomy. Specifically, the incidences of supraventricular arrhythmias, myocardial infarction, pulmonary embolism and empyema were lower. CONCLUSIONS This large national database study demonstrates that thoracoscopic lobectomy is associated with fewer in-hospital postoperative complications compared with open lobectomy. Thoracoscopic lobectomy appears to be applicable to the wider general thoracic surgical community.

A Multinational Assessment of Metal-on-Metal Bearings in Hip Replacement

There is emerging evidence that many metal-on-metal (MoM) bearings, when used with large femoral heads in conventional hip replacement and some resurfacing prostheses, are associated with increased rates of revision arthroplasty. Registries are the main sources of data on MoM prostheses. At the recent International Consortium of Orthopaedic Registries (ICOR) meeting, data were presented from the Australian, England and Wales, and New Zealand registries. All registries reported an increased rate of revision for large femoral head MoM prostheses when prostheses were aggregated compared with the aggregated data of hip prostheses with other bearing surfaces. There was also evidence, however, that the outcome varied, depending on the type of prostheses used, in both large femoral head MoM conventional hip replacement as well as resurfacing hip replacement.The relevance of the recent isolated case reports on systemic metal toxicity was also discussed at the ICOR meeting. Although systemic metal toxicity appears to be a rare occurrence, there is a need to undertake appropriately designed studies to define the true prevalence of this phenomenon. There may be advantages in nesting these studies within registries. The ICOR meeting highlighted the implications of the MoM experience for the orthopaedic industry, regulators, and surgeons.

Association Between Endoscopic vs Open Vein-Graft Harvesting and Mortality, Wound Complications, and Cardiovascular Events in Patients Undergoing CABG Surgery

CONTEXT The safety and durability of endoscopic vein graft harvest in coronary artery bypass graft (CABG) surgery has recently been called into question. OBJECTIVE To compare the long-term outcomes of endoscopic vs open vein-graft harvesting for Medicare patients undergoing CABG surgery in the United States. DESIGN, SETTING, AND PATIENTS An observational study of 235,394 Medicare patients undergoing isolated CABG surgery between 2003 and 2008 at 934 surgical centers participating in the Society of Thoracic Surgeons (STS) national database. The STS records were linked to Medicare files to allow longitudinal assessment (median 3-year follow-up) through December 31, 2008. MAIN OUTCOME MEASURES All-cause mortality. Secondary outcome measures included wound complications and the composite of death, myocardial infarction, and revascularization. RESULTS Based on Medicare Part B coding, 52% of patients received endoscopic vein-graft harvesting during CABG surgery. After propensity score adjustment for clinical characteristics, there were no significant differences between long-term mortality rates (13.2% [12,429 events] vs 13.4% [13,096 events]) and the composite of death, myocardial infarction, and revascularization (19.5% [18,419 events] vs 19.7% [19,232 events]). Time-to-event analysis for those patients receiving endoscopic vs open vein-graft harvesting revealed adjusted hazard ratios [HRs] of 1.00 (95% CI, 0.97-1.04) for mortality and 1.00 (95% CI, 0.98-1.05) for the composite outcome. Endoscopic vein-graft harvesting was associated with lower harvest site wound complications relative to open vein-graft harvesting (3.0% [3654/122,899 events] vs 3.6% [4047/112,495 events]; adjusted HR, 0.83; 95% CI, 0.77-0.89; P < .001). CONCLUSION Among patients undergoing CABG surgery, the use of endoscopic vein-graft harvesting compared with open vein-graft harvesting was not associated with increased mortality.

Use of patient-reported outcomes in the context of different levels of data.

There is increasing interest in measuring patient-reported outcomes as part of routine medical practice, particularly in fields like total joint replacement surgery, where pain relief, satisfaction, function, and health-related quality of life, as perceived by the patient, are primary outcomes. We review some well-known outcome instruments, measurement issues, and early experiences with large-scale collection of patient-reported outcome measures in joint registries. The patient-reported outcome measures are reviewed in the context of multidimensional outcome assessment that includes the traditional clinical outcome parameters as well as disease-specific and general patient-reported outcome measures.

Adverse Events After Stopping Clopidogrel in Post–Acute Coronary Syndrome Patients Insights From a Large Integrated Healthcare Delivery System

Background—A prior study from the Veterans Health Administration found a clustering of cardiovascular events after clopidogrel cessation. We sought to confirm and expand these findings. Methods and Results—This was a retrospective cohort study of 2017 patients with acute coronary syndrome discharged on clopidogrel from an integrated health care delivery system. Rates of all-cause mortality or acute myocardial infarction (MI) within 1 year after stopping clopidogrel were assessed among patients who did not have an event before stopping clopidogrel. Death/MI occurred in 4.3% (n=71) of patients. The rates of death/MI were 3.07, 1.62, 0.70, and 0.95 per 10 000 patient-days for the time intervals of 0 to 90, 91 to 180, 181 to 270, and 271 to 360 days after stopping clopidogrel. In multivariable analysis, the 0- to 90-day interval after stopping clopidogrel was associated with higher risk of death/MI (incidence rate ratio, 2.74; 95% confidence interval, 1.69 to 4.44) compared with 91- to 360-day interval. There was a similar trend of increased events after stopping clopidogrel for various subgroups (women versus men, medical therapy versus percutaneous coronary intervention, stent type, and ≥6 months or <6 months of clopidogrel treatment). Among patients taking clopidogrel but stopping ACE inhibitor medications, the event rates were similar in the 0- to 90-day versus the 91- to 360-day interval (2.67 versus 2.91 per 10 000 patient-days; P=0.91). Conclusions—We observed a clustering of adverse events in the 0 to 90 days after stopping clopidogrel. This clustering of events was not present among patients stopping ACE inhibitors. These findings are consistent with a possible rebound platelet hyper-reactivity after stopping clopidogrel and additional platelet studies are needed to confirm this effect.