Publications

BACKGROUND: Peripheral vascular devices (stents and balloons) coated with paclitaxel were developed to address suboptimal outcomes associated with percutaneous revascularization procedures of the femoral-popliteal arteries. In randomized controlled trials (RCT), paclitaxel-coated devices (PCD) provided increased long-term patency and a decreased need for repeat revascularization procedures compared with uncoated devices. This finding resulted in the adoption of their use for endovascular lower extremity revascularization procedures. However, in late 2018 a study-level meta-analysis showed increased all-cause mortality at 2 years or more after the procedure in patients treated with PCDs. This review examines the subsequent data evaluation following the publication of the meta-analysis.

METHODS: We review the published responses of physicians, regulatory agencies, and patient advocates during 15-month period after the meta-analysis. We present the additional data gathered from RCTs that comprised the meta-analysis and safety outcomes from large insurance databases in both the United States and Europe.

RESULTS: Immediately after the publication of the meta-analysis, concern for patient safety resulted in less PCD use, the suspension of large RCTs evaluating their use, and the publication of a letter from the U.S. Food and Drug Administration informing physicians that there was uncertainty in the benefit-risk profile of these devices for indicated patients and that the potential risk should be assessed before the use of PCDs. Review of the meta-analysis found that a mortality signal was present, but criticisms included that the evaluation was performed on study-level, not patient-level data, and the studies in the analysis were heterogenous in device type, paclitaxel doses, and patient characteristics. Further, the studies were not designed to be pooled nor were they powered for evaluating long-term safety. Clinical characteristics associated with a drug effect or causal relationship were also absent. Specifically, there was no dose response, no clustering of causes of death, and a lack of signal consistency across geographic regions. As more long-term data became available in the RCTs the strength of the mortality signal diminished and analysis of real-world use in large insurance databases, showed that there was no significant increase in all-cause mortality associated with PCD use.

CONCLUSIONS: The available data do not provide definitive proof for increased mortality with PCD use. A key observation is that trial design improvements will be necessary to better evaluate the risk-benefit profile of PCDs.

BACKGROUND: Multiple studies have demonstrated the high economic burden related to the management of lower extremity peripheral artery disease (PAD). This is the first study to examine long-term PAD-related costs among unselected patients undergoing endovascular intervention, and to investigate how clinical and anatomic factors impact cost outcomes over time.

METHODS AND RESULTS: We performed a prospective health economic study alongside the LIBERTY 360° trial (ClinicalTrials.gov; identifier NCT01855412) - a prospective, multi-center study evaluating the long-term outcomes of endovascular revascularization to treat claudication or critical limb ischemia. Costs (2018) were calculated using a combination of standard "bottom-up" cost accounting methods (for index procedures), itemized hospital charges and department level cost-to-charge ratios (for non-procedural hospital resources), national Medicare Severity-Diagnosis Related Group-specific average reimbursements (for follow-up hospitalizations) and Medicare payments (for outpatient/chronic care). Methods for the analysis of censored cost data were used to adjust cost estimates for patients with incomplete follow-up. Independent predictors of cumulative 2-year costs were explored using generalized linear models. A total of 1,189 patients were included (500 Rutherford 2-3, 589 Rutherford 4-5, 100 Rutherford 6). Mean total costs associated with the index procedure hospitalization increased with Rutherford classification ($10,304, $11,418, and $19,403 for Rutherford 2-3, 4-5, and 6, respectively; p < 0.01 in all pairwise comparisons). Mean total 2-year follow-up costs were $11,416, $24,846, and $25,720 for Rutherford 2-3, 4-5, and 6, respectively (p < 0.001 comparing Rutherford 2-3 to the other 2 groups; p = 0.09 comparing Rutherford 4-5 and Rutherford 6). Key predictors of higher cumulative 2-year costs included female sex, pedal lesion location, severe lesion calcification, the presence of one or more chronic total occlusions, the number of wounds present on the target limb at baseline, and Rutherford classification.

CONCLUSIONS: Among patients with symptomatic lower extremity PAD undergoing endovascular revascularization, initial treatment costs and total 2-year costs vary significantly according to clinical and lesion-level characteristics, as well as symptom burden.

BACKGROUND: Recent evidence from randomized controlled trials has raised concerns about the long-term safety of paclitaxel-coated peripheral devices used for femoropopliteal artery revascularization. In response to a call for more real-world data on the safety of these devices, the SAFE-PAD study (Safety Assessment of Femoropopliteal Endovascular treatment with Paclitaxel-coated Devices) was designed with input from the Food and Drug Administration to provide a long-term, comprehensive evaluation of the mortality risk associated with paclitaxel-coated devices among Medicare beneficiaries.

METHODS AND RESULTS: SAFE-PAD is an observational cohort study of fee-for-service Medicare beneficiaries that underwent femoropopliteal artery revascularization with either a drug-coated device or nondrug-coated device from 2015 through 2018. All patients age 66 years or older who underwent revascularization will be identified using a combination of International Classification of Diseases, Tenth Revision procedural codes, Current Procedural Terminology codes, and Healthcare Common Procedure Coding System C-codes. The safety end point of all-cause death will be updated semiannually and continued until the median duration of follow-up surpasses 5 years. Sub-group analyses will be conducted by device type, patient characteristics, and procedural setting. Registration: The SAFE-PAD study has been registered on URL: https://www.clinicaltrials.gov; Unique identifier: NCT04496544.

CONCLUSIONS: The SAFE-PAD study will evaluate the long-term safety of drug-coated devices compared with nondrug-coated devices for femoropopliteal artery revascularization among a broad, real-world population of patients with peripheral artery disease.

BACKGROUND: Data from administrative claims may provide an efficient alternative for end point ascertainment in clinical trials. However, it is uncertain how well claims data compare to adjudication by a clinical events committee in trials of patients with cardiovascular disease.

METHODS: We matched 1336 patients ≥65 years old who received percutaneous coronary intervention in the DAPT (Dual Antiplatelet Therapy) Study with the National Cardiovascular Data Registry CathPCI Registry linked to Medicare claims as part of the EXTEND (Extending Trial-Based Evaluations of Medical Therapies Using Novel Sources of Data) Study. Adjudicated trial end points were compared with Medicare claims data with International Classification of Diseases, Ninth Revision codes from inpatient hospitalizations using time-to-event analyses, sensitivity, specificity, positive predictive value, negative predictive value, and kappa statistics.

RESULTS: At 21-month follow-up, the cumulative incidence of major adverse cardiovascular and cerebrovascular events (combined mortality, myocardial infarction, and stroke) was similar between trial-adjudicated events and claims data (7.9% versus 7.2%, respectively; P=0.50). Bleeding rates were lower using adjudicated events compared with claims (5.0% versus 8.6%, respectively; P<0.001). The sensitivity and positive predictive value of comprehensive billing codes for identifying adjudicated events were 65.6% and 85.7% for myocardial infarction, 61.5% and 47.1% for stroke, and 76.8% and 39.3% for bleeding, respectively. Specificity and negative predictive value for all outcomes ranged from 93.7% to 99.5%. All 39 adjudicated deaths were identified using Medicare data. Kappa statistics assessing agreement between events for myocardial infarction, stroke, and bleeding were 0.73, 0.52, and 0.49, respectively.

CONCLUSIONS: Claims data had moderate agreement with adjudication for myocardial infarction and poor agreement but high specificity for bleeding and stroke in the DAPT Study. Deaths were identified equivalently. Using claims data in clinical trials could be an efficient way to assess mortality among Medicare patients and may help detect other outcomes, although additional monitoring is likely needed to ensure accurate assessment of events.

PURPOSE: Patients with diabetes mellitus (DM) are known to be at higher risk for peripheral artery disease (PAD), amputations, and major adverse cardiovascular events, though it is unclear whether they are at any higher risk for repeat intervention. LIBERTY 360 offered an opportunity to study a real-world cohort of patients who underwent distal superficial femoral artery endovascular revascularizations. We aimed to describe patients with DM, their outcomes following peripheral vascular intervention, and the effect of DM on outcomes in the LIBERTY 360 cohort.

METHODS: LIBERTY 360 is a prospective, multi-center, non-randomized, mono-industry funded observational study of patients undergoing endovascular revascularization. Outcomes included 30-day and 1-year all-cause mortality, major amputation, target vessel/lesion revascularization, and a composite of those events. A multivariable regression model including DM was constructed to examine the effect of DM on outcomes. Multivariable survival estimates were made using Cox proportional hazards models.

RESULTS: A total of 1,204 patients were enrolled, of whom 727 had DM (60.4%). Patients with DM had significantly more comorbidities and a third required insulin for DM management. Patients with DM had more severe disease based on Rutherford classification at baseline. After adjusting for comorbidities and disease severity, DM patients had more frequent major amputations at 1 year (5.2% versus 1.2%; HR 2.71, 95%CI 1.05-6.98, p = 0.040). The 1-year rates of all-cause mortality and target vessel/lesion revascularization were not significantly higher for patients with DM.

CONCLUSIONS: Diabetes mellitus was associated with increased major amputations at 1 year following endovascular revascularization after accounting for demographics, comorbidities, and PAD-related characteristics. Further research is needed to determine which aspects of PAD and DM are most strongly associated with poor outcomes following lower extremity revascularization.

OBJECTIVES: The authors analyzed data from the NCDR (National Cardiovascular Data Registry) PVI Registry and defined acute kidney injury (AKI) as increased creatinine of ≥0.3 mg/dl or 50%, or a new requirement for dialysis after PVI.

BACKGROUND: AKI is an important and potentially modifiable complication of peripheral vascular intervention (PVI). The incidence, predictors, and outcomes of AKI after PVI are incompletely characterized.

METHODS: A hierarchical logistic regression risk model using pre-procedural characteristics associated with AKI was developed, followed by bootstrap validation. The model was validated with data submitted after model creation. An integer scoring system was developed to predict AKI after PVI.

RESULTS: Among 10,006 procedures, the average age of patients was 69 years, 58% were male, and 52% had diabetes. AKI occurred in 737 (7.4%) and was associated with increased in-hospital mortality (7.1% vs. 0.7%). Reduced glomerular filtration rate, hypertension, diabetes, prior heart failure, critical or acute limb ischemia, and pre-procedural hemoglobin were independently associated with AKI. The model to predict AKI showed good discrimination (optimism corrected c-statistic = 0.68) and calibration (corrected slope = 0.97, intercept of -0.07). The integer point system could be incorporated into a useful clinical tool because it discriminates risk for AKI with scores ≤4 and ≥12 corresponding to the lower and upper 20% of risk, respectively.

CONCLUSIONS: AKI is not rare after PVI and is associated with in-hospital mortality. The NCDR PVI AKI risk model, including the integer scoring system, may prospectively estimate AKI risk and aid in deployment of strategies designed to reduce risk of AKI after PVI.