How can patient preferences be used and communicated in the regulatory evaluation of medicinal products? Findings and recommendations from IMI PREFER and call to action.

Objective: Patients have unique insights and are (in-)directly affected by each decision taken throughout the life cycle of medicinal products. Patient preference studies (PPS) assess what matters most to patients, how much, and what trade-offs patients are willing to make. IMI PREFER was a six-year European public-private partnership under the Innovative Medicines Initiative that developed recommendations on how to assess and use PPS in medical product decision-making, including in the regulatory evaluation of medicinal products. This paper aims to summarize findings and recommendations from IMI PREFER regarding i) PPS applications in regulatory evaluation, ii) when and how to consult with regulators on PPS, iii) how to reflect PPS in regulatory communication and iv) barriers and open questions for PPS in regulatory decision-making. Methods: PREFER performed six literature reviews, 143 interviews and eight focus group discussions with regulators, patient representatives, industry representatives, Health Technology Assessment bodies, payers, academics, and clincians between October 2016 and May 2022. Results: i) With respect to PPS applications, prior to the conduct of clinical trials of medicinal products, PPS could inform regulators' understanding of patients' unmet needs and relevant endpoints during horizon scanning activities and scientific advice. During the evaluation of a marketing authorization application, PPS could inform: a) the assessment of whether a product meets an unmet need, b) whether patient-relevant clinical trial endpoints and outcomes were studied, c) the understanding of patient-relevant effect sizes and acceptable trade-offs, and d) the identification of key (un-)favorable effects and uncertainties. ii) With respect to consulting with regulators on PPS, PPS researchers should ideally have early discussions with regulators (e.g., during scientific advice) on the PPS design and research questions. iii) Regarding external PPS communication, PPS could be reflected in the assessment report and product information (e.g., the European Public Assessment Report and the Summary of Product Characteristics). iv) Barriers relevant to the use of PPS in regulatory evaluation include a lack of PPS use cases and demonstrated impact on regulatory decision-making, and need for (financial) incentives, guidance and quality criteria for implementing PPS results in regulatory decision-making. Open questions concerning regulatory PPS use include: a) should a product independent broad approach to the design of PPS be taken and/or a product-specific one, b) who should optimally be financing, designing, conducting, and coordinating PPS, c) when (within and/or outside clinical trials) to perform PPS, and d) how can PPS use best be operationalized in regulatory decisions. Conclusion: PPS have high potential to inform regulators on key unmet needs, endpoints, benefits, and risks that matter most to patients and their acceptable trade-offs. Regulatory guidelines, templates and checklists, together with incentives are needed to foster structural and transparent PPS submission and evaluation in regulatory decision-making. More PPS case studies should be conducted and submitted for regulatory assessment to enable regulatory discussion and increase regulators' experience with PPS implementation and communication in regulatory evaluations.

Immunologic profiles in patients with chronic limb-threatening ischemia undergoing endovascular revascularization.

BACKGROUND: Inflammation and immune dysregulation have been associated with adverse outcomes in cardiovascular disease. There is limited understanding of the association of different profiles of white blood cell (WBC) subsets and red cell distribution width (RDW) in patients with chronic limb-threatening ischemia (CLTI). METHODS: Patients with CLTI undergoing endovascular revascularization in our single-center, tertiary care hospital from 2017 to 2019, who had a preceding complete blood count (CBC) with WBC differentials (n =213), were included in the analysis. Patient characteristics, laboratory values, and clinical outcomes were collected. Cox proportional hazards regression models were used to assess for associations between all-cause mortality and leukocyte subset; multivariate analysis was used to account for confounders. Kaplan-Meier curves were generated to depict survival censored at 1 year postrevascularization using baseline CBC indices. RESULTS: Adjusting for confounders, elevated RDW was associated with increased mortality (continuous per % increase, adjusted hazard ratio [HR] 1.33, p < 0.001). Baseline lymphopenia was associated with mortality in univariate analysis. Other leukocyte subtypes were not associated with mortality outcomes in our population. Exploratory analysis showed negative deflections in ∆WBC from pre- to postprocedure day 1 were affiliated with increased mortality when adjusted for age, sex, race, chronic kidney disease, and baseline hemoglobin (∆WBC HR 1.16, p = 0.004). Further exploratory analysis showed an association between RDW and all-comers readmission. CONCLUSIONS: The utilization of a periprocedural WBC subset differential can be a useful adjunct to risk-stratify patients with CLTI undergoing endovascular revascularization. Further studies are needed to understand potential ways to modulate immune dysregulation so as to improve mortality outcomes.

Novel intracardiac echocardiography-guided catheter-based removal of inoperable tricuspid valve vegetation.

With the ongoing intravenous drug abuse (IVDA) epidemic, the number of IVDA patients with infective endocarditis is increasing. These cases are often characterized by large vegetations complicated by valvular dysfunction, heart failure, and recurrent septic pulmonary emboli demanding surgical intervention. Latter cannot be offered in a good proportion of the patients due to challenging medical and social complexities. Hence, AngioVac system has been used as an alternative therapy; however, it is associated with high procedural mortality. In this document, we describe in detail the successful treatment of a case of large tricuspid valve vegetation, with prohibitive risk for surgery, using a percutaneous catheter-based system, the Triever aspiration catheter with FLEX technology, with the guidance of intracardiac echocardiogram.

The utility of geriatric nutritional risk index to predict outcomes in chronic limb-threatening ischemia.

OBJECTIVES: To assess geriatric nutritional risk index (GNRI) in patients with chronic limb-threatening ischemia (CLTI). BACKGROUND: The prevalence of CLTI continues to rise, with major amputation and mortality remaining prominent. Frailty is a vital risk factor for adverse outcomes in cardiovascular care. The GNRI is a nutrition-based surrogate for frailty that has been utilized in Southeast Asia to predict adverse events in CLTI. It has not yet been evaluated in a primarily Western population, nor in the context of wound healing. METHODS: Between 8August 2017 and April 2019, we identified patients undergoing endovascular interventions for CLTI at our institution, categorized into low GNRI (≤ 94, frail) versus normal GNRI (> 94, reference). We analyzed the risks of major adverse limb events (MALE), its individual components [mortality, major amputation, and target vessel revascularization (TVR)], amputation free survival (AFS), and wound healing using Kaplan-Meier and multivariate cox-proportional hazard regression analyses. RESULTS: A total of 255 patients were included in the analysis, with follow up of 14 ± 9.1 months. Lower GNRI was associated with higher cumulative event rates for MALE (71.0% vs. 43.3%, p < 0.001), mortality (34.3% vs. 15.2%, p < 0.001), major amputation (31.2% vs. 15.8%, p = 0.002), and freedom from AFS (56.0% vs. 28.2%, p < 0.001). There was a trend toward lower TVR and higher wound healing with higher GNRI score. CONCLUSIONS: Our single-center, retrospective evaluation of GNRI (as a surrogate for frailty) correlated with increased risks of MALE, mortality, and major amputation. Future directions should focus not only on the recognition of these patients, but risk-factor modification to optimize long-term outcomes.

Predictors and potential advantages of PERT and advanced therapy use in acute pulmonary embolism.

OBJECTIVES: We sought to examine predictors of pulmonary embolism response team (PERT) utilization and identify those who could benefit from advanced therapy. BACKGROUND: PERT and advanced therapy use remain low. Current risk stratification tools heavily weight age and comorbidities, which may not always correlate with presentation's severity. METHODS: We prospectively studied patients with CT-confirmed PE between January 2019 and December 2019 at our hospital. PERT activation was left to the treating physician. Multivariable analyses were utilized to identify predictors of PERT activation and advanced therapy. Using the log odd ratio of each significant predictor of advanced therapy, we created a scoring system and a score of 2 was associated with the highest use. Primary outcomes were 30- and 90-day all-cause mortality, readmission, and major bleed. RESULTS: Of the 307 patients, PERT was activated in 22.5%. While abnormal vital signs and right ventricular (RV) strain were associated with PERT activation, pulmonary embolism severity index (PESI) was not. Advanced therapy use was significantly higher in the PERT cohort (35% vs 2%). Predictors of advanced therapy use were composite variable (heart rate > 110 or systolic blood pressure < 100 or respiratory rate > 30 or oxygen saturation < 90%) and right-to-left ventricular ratio > 0.9. PERT patients with advanced therapy use, when compared to the no-PERT patients who could have qualified (score of 2), had significantly lower 30- and 90-day mortality and 30-day readmission without difference in major bleed. CONCLUSION: PERT has important therapeutic impact, yet no guidelines to direct activation. We recommend a multidisciplinary approach for higher acuity pulmonary embolism cases and physician education regarding PERT and the scope of advanced therapy use.

Prospective Experience of Pulmonary Embolism Management and Outcomes.

OBJECTIVE: We sought to evaluate the impact of pulmonary embolism (PE) response teams (PERTs) on all consecutive patients with PE. BACKGROUND: Multidisciplinary PERTs have been promoted for the management and treatment of (PE); however, the impact of PERTs on clinical outcomes has not been prospectively evaluated. METHODS: We prospectively studied 220 patients with computed tomography (CT)-confirmed PE between January, 2019 and August, 2019. Baseline characteristics, as well as medical, interventional, and operational care, were captured. The total population was divided into 2 groups, ie, those with PERT activation and those without PERT activation. PERT activation was left at the discretion of the primary team. Our primary outcome was 90-day composite endpoint (rate of readmission, major bleeds, and mortality). Using 2:1 propensity-matched and multivariable-adjusted Cox proportional hazard analyses, we examined the impact of PERT activation on primary outcome, treatment approach, and length of stay. RESULTS: Of the total 220 patients, PERT was activated in 47 (21.4%). The PERT cohort, as compared with the non-PERT cohort, was more likely to present with dyspnea, syncope, lower systolic blood pressure, higher heart rate, higher respiratory rate, lower oxygen saturation, higher troponin levels, and higher right ventricular to left ventricular ratio. PERT activation was associated with increased use of advanced therapies (36.2% vs 1.2%; P<.001) and catheter-directed inventions (25.5% vs 0.6%; P<.001). In multivariable-adjusted analysis of propensity-matched cohorts, PERT activation was associated with lower 90-day outcomes (hazard ratio, 0.40; 95% confidence interval, 0.21-0.75; P<.01). CONCLUSION: At our institution, PERT had a clinically significant impact on therapeutic strategies and 90-day outcomes in patients with PE.

Impact of COVID-19 pandemic on ST-elevation myocardial infarction in a non-COVID-19 epicenter.

OBJECTIVES: We sought to study the impact of COVID-19 pandemic on the presentation delay, severity, patterns of care, and reasons for delay among patients with ST-elevation myocardial infarction (STEMI) in a non-hot-spot region. BACKGROUND: COVID-19 pandemic has significantly reduced the activations for STEMI in epicenters like Spain. METHODS: From January 1, 2020, to April 15, 2020, 143 STEMIs were identified across our integrated 18-hospital system. Pre- and post-COVID-19 cohorts were based on March 23rd, 2020, whenstay-at-home orders were initiated in Ohio. We used presenting heart rate, blood pressure, troponin, new Q-wave, and left ventricle ejection fraction (LVEF) to assess severity. Duration of intensive care unit stay, total length of stay, door-to-balloon (D2B) time, and radial versus femoral access were used to assess patterns of care. RESULTS: Post-COVID-19 presentation was associated with a lower admission LVEF (45 vs. 50%, p = .015), new Q-wave, and higher initial troponin; however, these did not reach statistical significance. Among post-COVID-19 patients, those with >12-hr delay in presentation 31(%) had a longer average D2B time (88 vs. 53 min, p = .033) and higher peak troponin (58 vs. 8.5 ng/ml, p = .03). Of these, 27% avoided the hospital due to fear of COVID-19, 18% believed symptoms were COVID-19 related, and 9% did not want to burden the hospital during the pandemic. CONCLUSIONS: COVID-19 has remarkably affected STEMI presentation and care. Patients' fear and confusion about symptoms are integral parts of this emerging public health crisis.

The utility of real-world evidence for benefit-risk assessment, communication, and evaluation of pharmaceuticals: Case studies.

PURPOSE: In recent years, novel types of real-world evidence (RWE) have played a role in various decision-making processes relating to medicinal products, including regulatory approval, patient access, health technology assessment, safety monitoring, clinical use, and post-approval lifecycle management. We therefore reviewed the potential utility of RWE in the cycle of medicinal product benefit-risk (BR) assessment, communication/risk minimization and evaluation ("BRACE"). METHODS: A convenience sample of illustrative studies was drawn from the published literature and examined. Specifically, we examined the purpose for using RWE, the type of RWE used, its novelty and how it might be integrated with other data and activities of the BRACE cycle, and how it contributed to regulatory decision-making. RESULTS: Eight studies were selected with each illustrating a different activity in the BRACE cycle ranging from BR assessment in the preapproval setting, post-approval assessment of safety or effectiveness, communicating BR information to patients and healthcare professionals, and evaluating the effectiveness of risk minimization initiatives to support a positive BR balance. CONCLUSIONS: RWE has an important role in informing regulatory decision-making regarding the BR management of medicines. With increasing digitalization, facilitating data collection and stakeholder engagement in health, this role is only expected to expand in the future. To reach the full potential of RWE, both regulators and sponsors will need to be familiar with a range of existing and emerging methods for generating and analyzing such evidence appropriately and achieve convergence regarding how different types of RWE can best be used to inform BR management and decision-making.

Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients With Peripheral Artery Disease (STOP-PAD) Trial: Six-Month Results.

Purpose: To present the 6-month results of the Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Peripheral Artery Disease (STOP-PAD) trial. The trial was an attempt to alter the course of chronic limb-threatening ischemia (CLTI) with a biological agent vs placebo after successful arterial revascularization at or below the knee. Materials and Methods: The multicenter, randomized, double-blinded, placebo-controlled, phase 2B STOP-PAD trial (ClinicalTrials.gov identifier NCT02544204) randomized 109 patients (mean age 71 years; 68 men) with Rutherford category 5 or 6 CLTI and evidence of persistent impaired forefoot perfusion following recent successful revascularization to 8- (n=34) or 16-mg (n=36) intramuscular injections of a non-viral DNA plasmid-based treatment vs placebo (n=34). The primary efficacy outcome was the 6-month wound healing score evaluated by an independent wound core laboratory; the primary safety endpoint was major adverse limb events (MALE), a composite of major amputation plus clinically-driven target lesion revascularization at 6 months. Results: Only one-third of the patients had complete wound healing at 6 months in the placebo (31%), 8-mg injection (33%), and 16-mg injection (33%) groups. In addition, the observed increase in the toe-brachial index from baseline to 6 months was statistically significant in each group; however, this did not result in lower rates of MALE at 6 months (24% in the placebo, 29% in the 8-mg injection, and 11% in the 16-mg injection groups). During the 6-month period, 6 patients (6%) died, and 24 patients (23%) had an amputation [only 4 (4%) major]. Conclusion: Combining revascularization and biological therapy failed to improve outcomes in CLTI at 6 months. STOP-PAD has provided insights for future trials to evaluate biological therapy.

Personalized benefit-risk assessments combining clinical trial and real-world data provide further insights into which patients may benefit most from therapy: Demonstration for a new oral antiplatelet therapy.

PURPOSE: Quantitative benefit-risk (B-R) assessments are used to characterize treatment by combining key benefits and risks into a single metric but have historically been done for the "average" patient. Our aim was to conduct an individualized assessment for the oral antiplatelet vorapaxar by combining trial and real-world data to further personalize the treatment profiles. METHODS: Using linked UK health care databases, we developed risk prediction equations for key ischemic and bleeding events using Cox proportional hazards models. Trial hazard ratios, relative to placebo, were applied to baseline risk estimates to compute expected attributable risks, summed to derive a per-patient net clinical benefit (NCB). High risk subgroups were defined a priori, and Gaussian mixture models (GMM) were fit to characterize the NCB distribution and identify subgroups with similar NCBs. RESULTS: NCB was consistently positive for all subgroups, likely due to the outcome correlation, and would remain positive with a 12-fold increase in bleeding risk. GMMs identified three distinct NCB subgroups. Compared with the middle/lower NCB subgroups, those with a higher NCB tended to be older, female, and have higher CV disease burden. CONCLUSIONS: Personalized B-R assessments are feasible and clinically valuable and can be used to better predict who would benefit most from therapy.

SDF-1 plasmid treatment for patients with peripheral artery disease (STOP-PAD): Randomized, double-blind, placebo-controlled clinical trial.

The efficacy of biologic therapies in critical limb ischemia (CLI) remains elusive, in part, due to limitations in trial design and patient selection. Using a novel design, we examined the impact of complementing revascularization therapy with intramuscular JVS-100 - a non-viral gene therapy that activates endogenous regenerative repair pathways. In this double-blind, placebo-controlled, Phase 2B trial, we randomized 109 patients with CLI (Rutherford class V or VI) to 8 mg or 16 mg intramuscular injections of placebo versus JVS-100. Patients were eligible if they persistently had reduced forefoot perfusion, by toe-brachial index (TBI) or skin perfusion pressure (SPP), following successful revascularization with angiographic demonstration of tibial arterial flow to the ankle. The primary efficacy end point was a 3-month wound healing score assessed by an independent wound core laboratory. The primary safety end point was major adverse limb events (MALE). Patients' mean age was 71 years, 33% were women, 79% had diabetes, and 8% had end-stage renal disease. TBI after revascularization was 0.26, 0.27, and 0.26 among the three groups (placebo, 8 mg, and 16 mg injections, respectively). Only 26% of wounds completely healed at 3 months, without any differences between the three groups (26.5%, 26.5%, and 25%, respectively). Similarly, there were no significant changes in TBI at 3 months. Three (2.8%) patients died and two (1.8%) had major amputations. Rates of MALE at 3 months were 8.8%, 20%, and 8.3%, respectively. While safe, JVS-100 failed to improve wound healing or hemodynamic measures at 3 months. Only one-quarter of CLI wounds healed at 3 months despite successful revascularization, highlighting the need for additional research in therapies that can improve microcirculation in these patients. ClinicalTrials.gov Identifier: NCT02544204.

Associations of exercise ankle-brachial index, pain-free walking distance and maximum walking distance with the Peripheral Artery Questionnaire: Finding from the PORTRAIT PAD Registry.

An exercise ankle-brachial index (ABI) test can provide further insight into the functional significance of peripheral artery disease (PAD). The variability in its use, associated patient factors and its relation to patients' symptoms are unknown. From the international PORTRAIT registry, we identified 1131 patients with PAD. We fit a hierarchical logistic regression model, adjusting for patient factors, country and site, to examine predictors of and variation in ordering exercise ABI testing. We also examined the associations between test components and health status as quantified by the Peripheral Artery Questionnaire (PAQ) using semi-parametric regression methods. Testing was ordered in 22% in the United States versus 80% in the Netherlands and 90% in Australia. Testing was likely to be performed if the patient was male, younger, had typical symptoms and a higher resting ABI, with substantial variability across sites (median odds ratio=5.9, 95% CI: 3.2-19.5). Adjusting for country and site, the resting ABI and all exercise ABI metrics were associated with the PAQ Physical Limitation score. In addition, important components of the test, namely time to onset of claudication, pain-free walking distance (PFWD), and maximum walking distance (MWD), were also associated with PAQ Symptoms and Summary scores. More importantly, even after adjusting for resting ABI, a patient with a post-exercise ABI of 0.29 (25th percentile), compared to 0.61 (75th percentile), achieved 4.4 (95% CI: 0.4-8.4, p=0.031) points less on the PAQ Physical Limitation score. Exercise ABI test use is remarkably variable, and less used in the United States. Its data, specifically PFWD and MWD, might help in objectively assessing the impact of PAD on patients' functioning and quality of life.

Myocarditis Associated with Immune Checkpoint Inhibitors: An Expert Consensus on Data Gaps and a Call to Action.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for cancer. Due to the mechanism of action of ICIs, inflammatory reactions against normal tissue were an anticipated side effect of these agents; these immune-related adverse events have been documented and are typically low grade and manageable. Myocarditis has emerged as an uncommon but potentially life-threatening adverse reaction in patients treated with ICIs. Assessment and characterization of ICI-associated myocarditis is challenging because of its low incidence and protean manifestations. Nevertheless, the seriousness of ICI-associated myocarditis justifies a coordinated effort to increase awareness of this syndrome, identify patients who may be at risk, and enable early diagnosis and appropriate treatment. The "Checkpoint Inhibitor Safety Working Group," a multidisciplinary committee of academic, industry, and regulatory partners, convened at a workshop hosted by Project Data Sphere, LLC, on December 15, 2017. This meeting aimed to evaluate the current information on ICI-associated myocarditis, determine methods to collect and share data on this adverse reaction, and establish task forces to close the identified knowledge gaps. In this report, we summarize the workshop findings and proposed steps to address the impact of ICI-associated myocarditis in patients with cancer.

Renal denervation: What happened, and why?

Despite promising results in initial trials, renal denervation failed to achieve its efficacy end points as a treatment for resistant hypertension in the SYMPLICITY HTN-3 trial, the largest trial of this treatment to date (N Engl J Med 2014; 370:1393-1401). Is renal denervation dead, or will future trials and newer technology revive it?

Analysis of IN.PACT DEEP trial on the association between changes in perfusion from pre- to postrevascularization and clinical outcomes in critical limb ischemia.

OBJECTIVES: To quantify changes in ankle and toe pressure from pre- to post-endovascular revascularization for critical limb ischemia (CLI) and examine their association with major adverse limb events (MALE). BACKGROUND: Despite societal guidelines recommendation of routine hemodynamic surveillance following revascularization, little is known about hemodynamic assessment in CLI. METHODS: Among the 358 patients with CLI from the international multicenter IN.PACT DEEP trial, ankle and toe pressures measurements were available at both baseline and after intervention in 270 and 44 patients, respectively. The change in ankle and toe pressures in response to endovascular revascularization and its association with 1-year MALE (target limb revascularization, amputation, or death) were examined using Kaplan-Meier curves and multivariable Cox proportional hazard analyses. Corresponding optimal cutoff points were also identified. RESULTS: The mean increase in ankle and toe pressures following revascularization was 33 and 13 mmHg, respectively. Patients with an improvement of ankle pressure >73 mmHg or toe pressure >1 mmHg had similarly the lowest incidence of MALE (23%), while the highest rate of MALE (50%) was found in those whose toe pressure failed to improve by at least 1 mmHg following intervention. In addition, an increase in ankle pressure >73 mmHg was numerically protective against MALE, and more importantly, an increase in toe pressure of >1 mmHg provided statistically significant protection from MALE (adjusted HR = 0.15, 95% CI: 0.04-0.57, P = 0.005). CONCLUSIONS: Improvements in toe pressure post revascularization are incremental and rarely normalize. Toe pressure, compared to ankle pressure, is more useful in CLI and predicts future MALE.

The Contemporary Role of Stents and Angioplasty for the Treatment of Infrapopliteal Disease in Critical Limb Ischemia.

PURPOSE OF REVIEW: Critical limb ischemia (CLI) is associated with significant morbidity, mortality, and increased health care expenses. Revascularization has a central role in the treatment of CLI. Following publication of BASIL (bypass versus angioplasty in severe ischemia of the leg) trial a decade ago, an "endovascular first" approach had gained momentum and the technologies available for endovascular therapy have exponentially increased. Both the development of technology and technique, highlighted in this review, have allowed operators to treat complex infrapopliteal lesions which are central to CLI pathology. RECENT FINDINGS: The role of atherectomy remains controversial but for calcified lesions it has become an accepted adjunctive tool for plaque modification. The place of drug delivery technologies requires further trials. The use of a drug-coated balloon (DCB) makes intuitive sense; however, choice of excipient, lower limit of vessel size, and impact on remodeling and thrombosis remain uncertain. The optimal treatment of infrapopliteal disease remains an area of active investigation. The endpoints in CLI trials continue to be challenging and calibration of patency in relation to wound healing remains a moving target. In addition, unaccounted variables continue to confound interpretation of CLI trials-including quality and nature of wound care, status of pedal-plantar loop patency, and management of underlying diabetes and other comorbidities. In summary, these challenges will also need to be addressed as the CLI field continues to mature in the twenty-first century.

Prognostic value of an increase in post-exercise ankle-brachial index.

Prior studies have assessed the prognostic value of a decrease, not an increase, of the post-exercise ankle-brachial index (ABI) among patients with normal resting results. Thus, we sought to evaluate the prognostic significance of an increase in post-exercise ABI among these patients. From a single center vascular laboratory database between September 2005 and January 2010, we retrospectively identified 1437 consecutive patients with a normal resting ABI (1.00-1.40) and available post-exercise results. We classified them into group 1 (normal subjects; post-exercise ABI drop ⩽ 20%, 58%) and group 2 (post-exercise ABI increase, 42%) after excluding those with an ABI drop > 20% (peripheral artery disease) as they had known disease ( n=192). The primary outcome was to assess the risk of ischemic events, defined as a composite of unadjudicated death, stroke, or myocardial infraction (MACE). Associations between groups and outcomes were examined using multivariable Cox proportional hazard and propensity analyses. Both groups had similar prevalence of cardiovascular comorbidities. In unadjusted analysis, group 2 was more likely to have MACE ( p = 0.001). After adjusting for all baseline characteristics, an increase in post-exercise ABI compared to normal subjects was associated with a higher MACE (adjusted HR: 1.70, 95% CI: 1.14-2.53; p=0.009). This association stayed statistically significant after propensity matching (adjusted HR: 1.80, 95% CI: 1.17-2.76; p=0.007). This hypothesis-generating analysis showed that an increase in post-exercise ABI appears to identify a population with a higher risk for MACE. A prospective study of this association and mechanisms of risk should be conducted.