Drug-coated balloons to improve femoropopliteal artery patency: rationale and design of the LEVANT 2 trial

Background Atherosclerotic peripheral artery disease (PAD) is common and results in limitations in quality of life and potential progression to limb loss. Options for therapy include medical therapy, supervised exercise, surgical revascularization, and, more recently, endovascular therapies to restore arterial perfusion to the limb. Endovascular revascularization has evolved over the past 2 decades, from percutaneous transluminal angioplasty (PTA) to self-expanding stents, atherectomy, laser angioplasty, and drug-eluting stents. Despite impressive technologic advances, PTA remains the standard of care at many institutions and is the recommended primary treatment modality for femoral-popliteal PAD according to current American College of Cardiology Foundation/American Heart Association guidelines. However, restenosis after PTA is common. Therefore, a significant clinical need remains for a device that is able to achieve more durable patency than PTA but does not require a permanent implant. Drug-coated balloons (DCBs) have the potential to address this need. Several randomized controlled clinical trials of PTA balloons coated with different formulations of paclitaxel have been conducted in Europe (N Engl J Med 2008;358:689-699) (Circulation 2008;118:1358-1365) (Circ Cardiovasc Interv 2012;5:831-840) (JACC Cardiovas Interv 2014;7:10-19) and demonstrated more durable efficacy than PTA with comparable safety. These studies were limited by small sample sizes and powered solely for an angiographic primary end point. The pivotal LEVANT 2 trial was designed in collaboration with the US Food and Drug Administration to demonstrate safety and efficacy in a large population and to obtain US Food and Drug Administration approval. Methods A prospective, multicenter, single-blind trial comparing the Lutonix DCB (Bard Lutonix; New Hope, MN) versus PTA for treatment of femoropopliteal PAD (LEVANT 2) is the first US-based 2:1 randomized controlled trial of 476 patients with femoral-popliteal PAD designed to demonstrate superior efficacy and noninferior safety of a novel paclitaxel DCB compared with PTA. The primary efficacy end point is primary patency at 12 months. The primary safety end point is composite freedom at 12 months from perioperative death, index limb amputation, reintervention, and limb-related mortality. A series of important secondary end points include physical functioning, quality of life, revascularizations, and alternative measures of patency. To minimize bias potential for confounding variables, LEVANT 2 (1) excluded patients stented after predilation before randomization, (2) incorporated very stringent criteria for bailout stenting, (3) did not count bailout stenting as a target lesion revascularization or failure of any end point, (4) required a blinded clinician to perform clinical evaluations at follow-up, and (5) required clinical assessment before review of duplex ultrasound results. Conclusions LEVANT 2 represents the first US-inclusive multicenter, randomized controlled trial to assess the safety and efficacy of a novel DCB compared with PTA as primary therapy for symptomatic PAD on the background of standard medical therapy

Effects of canagliflozin on amputation risk in type 2 diabetes:the CANVAS Program

Aims/hypothesis The primary analysis of the Canagliflozin cardioVascular Assessment Study (CANVAS) Program showed canagliflozin to have a beneficial effect on cardiovascular and renal outcomes in people with type 2 diabetes at high cardiovascular risk, but also an unexpected increased risk of major or minor lower extremity amputation. These secondary analyses explore this finding in more detail.Methods The effect of canagliflozin on amputation risk in the CANVAS Program was calculated for amputations of different types and proximate aetiologies and different canagliflozin doses. Univariate and multivariate associations of baseline characteristics with amputation risk were determined and proportional and absolute effects of canagliflozin were compared across subgroups.Results There were 187 (1.8%) participants with atraumatic lower extremity amputations (minor 71%, major 29%); as previously published, rates were 6.30 vs 3.37 per 1000 participant-years with canagliflozin vs placebo (HR 1.97 [95% CI 1.41, 2.75]). Risk was similar for ischaemic and infective aetiologies and for 100mg and 300mg doses. Overall amputation risk was strongly associated with baseline history of prior amputation (major or minor) (HR 21.31 [95% CI 15.40, 29.49]) and other established risk factors. No interactions between randomised treatment and participant characteristics explained the effect of canagliflozin on amputation risk. For every clinical subgroup studied, numbers of amputation events projected were smaller than numbers of major adverse cardiovascular events averted.Conclusions/interpretation The CANVAS Program demonstrated that canagliflozin increased the risk of amputation (mainly minor) in this study population. Anticipated risk factors for amputation were identified, such as prior history of amputation, peripheral vascular disease and neuropathy, but no specific aetiological mechanism or at-risk subgroup for canagliflozin was identified.</p

Sex-Based Differences in Outcomes Following Peripheral Artery Revascularization: Insights From VOYAGER PAD.

Background Despite high female prevalence of peripheral artery disease (PAD), little is known about sex-based outcomes after lower extremity revascularization (LER) for symptomatic PAD. The effects of rivaroxaban according to sex following LER have not been fully reported. Methods and Results In VOYAGER PAD (Vascular Outcomes Study of ASA [acetylsalicylic acid] Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease), low-dose rivaroxaban versus placebo on a background of aspirin reduced the composite primary efficacy outcome of cardiovascular and limb events in patients with PAD undergoing LER. Unplanned index limb revascularization was prespecified and prospectively ascertained. The primary safety outcome was Thrombolysis in Myocardial Infarction major bleeding. Analyses of outcomes and treatment effects by sex were performed using Cox proportional hazards models. Among 6564 randomly assigned patients followed for a median of 28 months, 1704 (26.0%) were women. Among patients administered placebo, women were at similar risk for the primary efficacy outcome (hazard ratio [HR], 0.90; [95% CI, 0.74-1.09]; P=0.29) as men, while female sex was associated with a trend toward higher risk of unplanned index limb revascularization (HR, 1.18; [95% CI, 1.00-1.40]; P=0.0499). Irrespective of sex, effects of rivaroxaban were consistent for the primary efficacy outcome (P-interaction=0.22), unplanned index limb revascularization (P-interaction=0.64), and bleeding (P-interaction=0.61). Women were more likely than men to discontinue study treatment (HR, 1.13; [95% CI, 1.03-1.25]; P=0.0099). Conclusions Among >1700 women with PAD undergoing LER, women and men were at similar risk for the primary outcome, but a trend for greater risk of unplanned index limb revascularization among women was observed. Effects of rivaroxaban were consistent by sex, though women more often discontinued treatment. Better understanding of sex-based outcomes and treatment adherence following LER is needed. Registration URL: http://clinicaltrials.gov; Unique identifier: NCT02504216

Major Cardiovascular Events After COVID-19, Event Rates Post-vaccination, Antiviral or Anti-inflammatory Therapy, and Temporal Trends: Rationale and Methodology of the Corona-VTE-Network Study

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with excess risk of cardiovascular and thrombotic events in the early post-infection period and during convalescence. Despite the progress in our understanding of cardiovascular complications, uncertainty persists with respect to more recent event rates, temporal trends, association between vaccination status and outcomes, and findings within vulnerable subgroups such as older adults (aged 65 years or older), or those undergoing hemodialysis. Sex-informed findings, including results among pregnant and breastfeeding women, as well as adjusted comparisons between male and female adults are similarly understudied. METHODS: Adult patients, aged ≥18 years, with polymerase chain reaction-confirmed COVID-19 who received inpatient or outpatient care at the participating centers of the registry are eligible for inclusion. A total of 10,000 patients have been included in this multicenter study, with Brigham and Women\u27s Hospital (Boston, MA) serving as the coordinating center. Other sites include Beth Israel Deaconess Medical Center, Anne Arundel Medical Center, University of Virginia Medical Center, University of Colorado Health System, and Thomas Jefferson University Health System. Data elements will be ascertained manually for accuracy. The two main outcomes are 1) a composite of venous or arterial thrombotic events, and 2) a composite of major cardiovascular events, defined as venous or arterial thrombosis, myocarditis or heart failure with inpatient treatment, new atrial fibrillation/flutter, or cardiovascular death. Clinical outcomes are adjudicated by independent physicians. Vaccination status and time of inclusion in the study will be ascertained for subgroup-specific analyses. Outcomes are pre-specified to be reported separately for hospitalized patients versus those who were initially receiving outpatient care. Outcomes will be reported at 30-day and 90-day follow-up. Data cleaning at the sites and the data coordinating center and outcomes adjudication process are in-progress. CONCLUSIONS: The CORONA-VTE-Network study will share contemporary information related to rates of cardiovascular and thrombotic events in patients with COVID-19 overall, as well as within key subgroups, including by time of inclusion, vaccination status, patients undergoing hemodialysis, the elderly, and sex-informed analyses such as comparison of women and men, or among pregnant and breastfeeding women

Epidemiology of peripheral arterial disease and critical limb ischemia in an insured national population

BackgroundCritical limb ischemia (CLI) represents the most severe clinical manifestation of peripheral arterial disease (PAD) and is the major cause of ischemic amputation in the United States. Risk factors and the associated incidence and prevalence of CLI have not been well described in the general population. This study describes the risk factors for PAD progression to CLI and estimates the annual incidence and prevalence of CLI in a representative United States patient cohort.MethodsThis was a retrospective cohort analysis of adults with commercial, Medicare supplemental, or Medicaid health insurance who had at least one PAD or CLI health care claim from January 1, 2003, through December 31, 2008, and 12 months of continuous coverage. Two subgroups of CLI presentation were identified: primary CLI (patients without any prior PAD or subsequent PAD diagnostic code >30 days after CLI diagnostic code) and secondary CLI (patients with prior PAD or subsequent PAD diagnostic codes ≤30 days of a CLI diagnostic code). Patterns of presentation, annual incidence, and prevalence of CLI were stratified by health care plan. Risk factors for progression to CLI were compared by presentation type.ResultsFrom 2003 to 2008, the mean annual incidence of PAD was 2.35% (95% confidence interval [CI], 2.34%-2.36%) and the incidence of CLI was 0.35% (95% CI, 0.34%-0.35%) of the eligible study population, with primary and secondary presentations occurring at similar rates. The mean annualized prevalence of PAD was 10.69% (95% CI, 10.67%10.70%) and the mean annualized prevalence of CLI was 1.33% (95% CI, 1.32%-1.34%) of the eligible study population, and two-thirds of the cases presented as secondary CLI. CLI developed in 11.08% (95% CI, 11.30%-11.13%) of patients with PAD. A multivariable model demonstrated that diabetes, heart failure, stroke, and renal failure were stronger predictors of primary rather than secondary CLI presentation.ConclusionsThese data establish new national estimates of the incidence and prevalence of CLI and define key risk factors that contribute to primary or secondary presentations of CLI within a very large contemporary insured population cohort in the United States

Assessment of functional status and quality of life in claudication

BackgroundTreadmill walking is commonly used to evaluate walking impairment and efficacy of treatment for intermittent claudication (IC) in clinical and research settings. Although this is an important measure, it does not provide information about how patients perceive the effects of their treatments on more global measures of health-related quality of life (HRQOL).MethodsPubMed/Medline was searched to find publications about the most commonly used questionnaires to assess functional status and/or general and disease-specific HRQOL in patients with peripheral artery disease (PAD) who experience IC. Inclusion criteria for questionnaires were based on existence of a body of literature in symptomatic PAD.ResultsSix general questionnaires and seven disease-specific questionnaires are included, with details about the number of domains covered and how each tool is scored. The Medical Outcomes Study Short Form 36-item questionnaire and Walking Impairment Questionnaire are currently the most used general and disease-specific questionnaires at baseline and after treatment for IC, respectively.ConclusionsThe use of tools that assess functional status and HRQOL has importance in both the clinical and research areas to assess treatment efficacy from the patient's perspective. Therefore, assessing HRQOL in addition to treadmill-measured walking ability provides insight as to the effects of treatments on patient outcomes and may help guide therapy

Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia

Objective: To develop a set of suggested objective performance goals (OPG) for evaluating new catheter-based treatments in critical limb ischemia (CLI), based on evidence from historical controls. Methods: Randomized, controlled trials of surgical, endovascular, and pharmacologic/biologic treatments for CLI were reviewed according to specified criteria regarding study population and data quality. Line-item data were obtained for selected studies from the sponsor/funding agency. A set of specific outcome measures was defined in accordance with the treatment goals for the CLI population. Risk factors were examined for their influence on key endpoints, and models of stratification based on specific clinical and anatomic variables developed. Sample size estimates were made for single-arm trial designs based on comparison to the suggested OPG. Results: Bypass with autogenous vein was considered the established standard, and data compiled from three individual randomized, controlled trials (N = 838) was analyzed. The primary efficacy endpoint was defined as perioperative (30-day) death or any major adverse limb event (amputation or major reintervention) occurring within one year. Results of open surgery controls demonstrated freedom from the primary endpoint in 76.9% (95% confidence interval [CI] 74.0%-79.9%) of patients at one year, with amputation-free survival (AFS) of 76.5% (95% CI 73.7%-79.5). An additional 3% non-inferiority margin was suggested in generating OPG for catheter-based therapies. Defined clinical (age \u3e 80 years and tissue loss) and anatomic (infra-popliteal anatomy or lack of good quality saphenous vein) risk subgroups provided significantly different point estimates and OPG threshold values. Conclusions: For new catheter-based therapies in CLI, OPGs offer a feasible approach for pre-market evaluation using non-randomized trial designs. Such studies should incorporate risk stratification in design and reporting as the CLI population is heterogeneous with respect to baseline variables and expected outcomes. Guidelines for CLI trial design to address consistency in study cohorts, methods of assessment, and endpoint definitions are provided. © 2009 Society for Vascular Surgery