Racial Heterogeneity in Treatment Effects in Peripheral Artery Disease

HomeCirculation: Cardiovascular Quality and OutcomesVol. 11, No. 4Racial Heterogeneity in Treatment Effects in Peripheral Artery Disease Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBRacial Heterogeneity in Treatment Effects in Peripheral Artery DiseaseInsights From the CLEVER Trial (Claudication: Exercise Versus Endoluminal Revascularization) Yashashwi Pokharel, MD, MSCR, Philip G. Jones, MS, Garth Graham, MD, Tracie Collins, MD, MPH, Judith G. Regensteiner, PhD, Timothy P. Murphy, MD, David Cohen, MD, MSc, John A. Spertus, MD, MPH and Kim Smolderen, PhD Yashashwi PokharelYashashwi Pokharel Department of Medicine, University of Missouri–Kansas City (Y.P., G.G., D.C., J.A.S., K.S.). Department of Cardiovascular Research, Saint Luke's Mid America Heart Institute, Kansas City, Missouri (Y.P., P.G.J., G.G., D.C., J.A.S., K.S.). School of Medicine, University of Kansas, Wichita (T.C.). Department of Medicine, Center for Women's Health Research, University of Colorado School of Medicine, Denver (J.G.R.). Alpert Medical School of Brown University, Rhode Island Hospital, Providence (T.P.M.). , Philip G. JonesPhilip G. Jones Department of Medicine, University of Missouri–Kansas City (Y.P., G.G., D.C., J.A.S., K.S.). Department of Cardiovascular Research, Saint Luke's Mid America Heart Institute, Kansas City, Missouri (Y.P., P.G.J., G.G., D.C., J.A.S., K.S.). School of Medicine, University of Kansas, Wichita (T.C.). Department of Medicine, Center for Women's Health Research, University of Colorado School of Medicine, Denver (J.G.R.). Alpert Medical School of Brown University, Rhode Island Hospital, Providence (T.P.M.). , Garth GrahamGarth Graham Department of Medicine, University of Missouri–Kansas City (Y.P., G.G., D.C., J.A.S., K.S.). Department of Cardiovascular Research, Saint Luke's Mid America Heart Institute, Kansas City, Missouri (Y.P., P.G.J., G.G., D.C., J.A.S., K.S.). School of Medicine, University of Kansas, Wichita (T.C.). Department of Medicine, Center for Women's Health Research, University of Colorado School of Medicine, Denver (J.G.R.). Alpert Medical School of Brown University, Rhode Island Hospital, Providence (T.P.M.). , Tracie CollinsTracie Collins Department of Medicine, University of Missouri–Kansas City (Y.P., G.G., D.C., J.A.S., K.S.). Department of Cardiovascular Research, Saint Luke's Mid America Heart Institute, Kansas City, Missouri (Y.P., P.G.J., G.G., D.C., J.A.S., K.S.). School of Medicine, University of Kansas, Wichita (T.C.). Department of Medicine, Center for Women's Health Research, University of Colorado School of Medicine, Denver (J.G.R.). Alpert Medical School of Brown University, Rhode Island Hospital, Providence (T.P.M.). , Judith G. RegensteinerJudith G. Regensteiner Department of Medicine, University of Missouri–Kansas City (Y.P., G.G., D.C., J.A.S., K.S.). Department of Cardiovascular Research, Saint Luke's Mid America Heart Institute, Kansas City, Missouri (Y.P., P.G.J., G.G., D.C., J.A.S., K.S.). School of Medicine, University of Kansas, Wichita (T.C.). Department of Medicine, Center for Women's Health Research, University of Colorado School of Medicine, Denver (J.G.R.). Alpert Medical School of Brown University, Rhode Island Hospital, Providence (T.P.M.). , Timothy P. MurphyTimothy P. Murphy Department of Medicine, University of Missouri–Kansas City (Y.P., G.G., D.C., J.A.S., K.S.). Department of Cardiovascular Research, Saint Luke's Mid America Heart Institute, Kansas City, Missouri (Y.P., P.G.J., G.G., D.C., J.A.S., K.S.). School of Medicine, University of Kansas, Wichita (T.C.). Department of Medicine, Center for Women's Health Research, University of Colorado School of Medicine, Denver (J.G.R.). Alpert Medical School of Brown University, Rhode Island Hospital, Providence (T.P.M.). , David CohenDavid Cohen Department of Medicine, University of Missouri–Kansas City (Y.P., G.G., D.C., J.A.S., K.S.). Department of Cardiovascular Research, Saint Luke's Mid America Heart Institute, Kansas City, Missouri (Y.P., P.G.J., G.G., D.C., J.A.S., K.S.). School of Medicine, University of Kansas, Wichita (T.C.). Department of Medicine, Center for Women's Health Research, University of Colorado School of Medicine, Denver (J.G.R.). Alpert Medical School of Brown University, Rhode Island Hospital, Providence (T.P.M.). , John A. SpertusJohn A. Spertus Department of Medicine, University of Missouri–Kansas City (Y.P., G.G., D.C., J.A.S., K.S.). Department of Cardiovascular Research, Saint Luke's Mid America Heart Institute, Kansas City, Missouri (Y.P., P.G.J., G.G., D.C., J.A.S., K.S.). School of Medicine, University of Kansas, Wichita (T.C.). Department of Medicine, Center for Women's Health Research, University of Colorado School of Medicine, Denver (J.G.R.). Alpert Medical School of Brown University, Rhode Island Hospital, Providence (T.P.M.). and Kim SmolderenKim Smolderen Department of Medicine, University of Missouri–Kansas City (Y.P., G.G., D.C., J.A.S., K.S.). Department of Cardiovascular Research, Saint Luke's Mid America Heart Institute, Kansas City, Missouri (Y.P., P.G.J., G.G., D.C., J.A.S., K.S.). School of Medicine, University of Kansas, Wichita (T.C.). Department of Medicine, Center for Women's Health Research, University of Colorado School of Medicine, Denver (J.G.R.). Alpert Medical School of Brown University, Rhode Island Hospital, Providence (T.P.M.). Originally published11 Apr 2018https://doi.org/10.1161/CIRCOUTCOMES.117.004157Circulation: Cardiovascular Quality and Outcomes. 2018;11:e004157IntroductionImproving symptoms, functions, and quality-of-life (ie, health status) is one of the important goals in treatment of patients with peripheral artery disease (PAD).1 However, it is unknown whether health status responses differ by race (black versus white) with alternative PAD treatment modalities. Such differences may exist given the disproportionate burden of PAD in minority populations, and rapid disease progression as compared with white,2 as well as differences in psychosocial and economic factors and possibly differences in exercise level, which is known to improve outcomes in patients with PAD.3,4 Understanding whether black and white respond differently to treatments can help us better support targeted therapy to improve quality of care. This is relevant because until now, supervised exercise (SE) programs for PAD were not available in the United States, and recently, the Centers for Medicare and Medicaid Services agreed to reimburse for SE therapy.5 If there is heterogeneity in response to SE, knowing this difference is important to provide patient-centered care and to get maximum treatment benefit for each unique patient population.The CLEVER trial (Claudication: Exercise Versus Endoluminal Revascularization) randomized patients with claudication from aortoiliac disease to SE, stent therapy (ST), or optimal medical care (OMC). Short-term results indicated superior treadmill walking performance (ie, peak walking time and claudication onset time) with SE than either ST or OMC. Conversely, benefit in PAD-specific health status (Peripheral Artery Questionnaire [PAQ] summary score)6 was more favorable for ST than either SE or OMC.3 Similarly, general quality-of-life benefit as assessed with Short Form-12 Physical Component Summary (SF-12 PCS)7 was similar for ST and SE when compared with OMC.3 Long-term results, however, showed similar and sustained benefits for both ST and SE over OMC in treadmill walking performance, but PAQ summary score was more favorable for ST when compared with SE or OMC.4 Improvement in SF-12 PCS was seen only with SE.4 The purpose of this study is to understand whether there is heterogeneity in response to alternative treatment modalities, such as SE, ST, or OMC, by race (black versus white) and whether any difference in treatment varies over time, using data from the CLEVER trial.Methods and ResultsDetails about the CLEVER trial have been reported before.3,4 Briefly, it examined the benefits of ST, SE, or OMC on both walking outcomes and quality-of-life measures in 119 patients with moderate-to-severe intermittent claudication and hemodynamically significant aortoiliac arterial stenosis from 22 sites in the United States and Canada. For the current analysis, data were accessed through National Heart, Lung, and Blood Institute data repository (https://biolincc.nhlbi.nih.gov/studies/clever/?q=clever) with Institutional Review Board approval from Saint Luke's Hospital, Kansas City, MO. Our primary outcomes of interest were changes in PAQ and SF-12 PCS scores from baseline at 6 and 18 months after randomization. Higher change scores represent greater health status improvements. We also examined changes in treadmill walking performance (peak walking time and claudication onset time) and Walking Impairment Questionnaire (WIQ). We did not assess other outcomes that did not vary by treatment in the CLEVER study.3 We excluded 7 patients of races other than black or white. Change from baseline was analyzed using linear mixed-effects models, including treatment groups, race, and follow-up time in months as fixed effects. We examined all 2- and 3-way interaction terms to test for differences in treatment response over time between race groups and used an unstructured covariance matrix to account for repeated measurements. The models were adjusted for baseline health status and baseline characteristics that differed within races or by treatment within races (age, sex, hypertension, smoking status, diabetes mellitus, arthritis/musculoskeletal disorders, stroke, myocardial infarction, and percutaneous coronary intervention).Among 104 eligible patients, 41, 43, and 20 patients were randomized to SE, ST, and OMC, respectively. The mean age was 64.2 years, and 37.5% were women. Seventy-five patients were white (OMC, 14; SE, 25; ST, 36) and 29 were black (OMC, 6; SE, 16; ST, 7). Follow-up at 18 months was similar for white versus black (86.7% versus 89.7%, respectively) with no intervening death. At baseline, there were no significant racial differences in resting ankle–brachial index, use of antiplatelet, statin or cilostazol therapy, PAQ summary scores, SF-12 PCS, peak walking time, claudication onset time, or WIQ. However, compared with white participants, black participants were more likely to be women (55.2% versus 30.7%), current smokers (58.6% versus 52.0%), have diabetes mellitus (40.7% versus 18.7%), and arthritis/other musculoskeletal disorder (44.8% versus 22.5%). Within each racial group, there were no significant baseline differences by treatment groups in resting ankle–brachial index, PAQ summary scores, SF-12 PCS, peak walking time, claudication onset time, or WIQ.There was a significant race–treatment interaction for PAQ summary scores (P=0.035); in white, PAQ scores increased only with ST, whereas in black, they increased with both ST and SE, compared with OMC (Figure, top). Interestingly, in the OMC group, PAQ score decreased over time in black but not in white. Model-estimated mean changes (95% confidence interval) in PAQ summary scores in SE and ST compared with OMC were 2.9 (−10.0 to 15.8) and 26.6 (14.6 to 38.6) in white, and 28.2 (8.7 to 47.7) and 31.8 (10.4 to 53.2) in black, respectively, which was unchanged at 6 and 18 months (P=0.22 for race–month interaction and P=0.38 for race–treatment–month interaction). A significant race–treatment interaction was also found for SF-12 PCS (P=0.005), which increased only with ST in white and only with SE in black, compared with OMC (Figure, bottom). Model-estimated mean changes in SF-12 PCS scores in SE and ST compared with OMC were 3.9 (−0.6 to 8.4) and 6.7 (2.5 to 10.9) in white and 15.9 (7.0 to 24.8) and 5.8 (−2.4 to 14.1) in black, respectively, which were unchanged at 6 and 18 months (P=0.28 for race–month interaction and P=0.64 for race–treatment–month interaction). Similarly, model-estimated changes in PAQ scores were −23.7 (−34.4 to −13.0) and −3.6 (−21.2 to 14.0) in SE compared with ST in white and black, respectively, and for SF-12, the scores were −2.8 (−6.8 to 1.2) and 10.0 (3.1 to 17.0), respectively. The race–treatment, race–month, and race–treatment–month interactions were not significant for other outcomes (all P>0.05).Download figureDownload PowerPointFigure. Unadjusted Peripheral Artery Questionnaire (PAQ) summary (top) and Short Form (SF)-12 physical component (bottom) scores means by race and treatment. OMC indicates optimal medical care; SE, supervised exercise; and ST, stent therapy.CommentWe found that although PAD-specific health status scores were greater with both SE and ST compared with OMC in black, such difference was seen only with ST in white. Furthermore, compared with ST, PAQ summary scores were lower with SE in white but were not different in black. Compared with OMC, general health status scores were greater only with SE in black and only with ST in white. However, when compared with ST, SF-12 PCS scores were greater with SE in black but were not different in white. No significant differences were noted for treadmill walking performance or WIQ.Although the smaller sample size reduces statistical power, the observed significant racial differences in health status may suggest racial heterogeneity in treatment responses. Should these findings be replicated in larger studies, we need to understand why SE may be more beneficial in black as compared with white. Identifying whether these differences in treatment response are mediated by psychosocial stress, economic factors, adherence, baseline exercise level, or other unknown factors could help identify opportunities to tailor PAD treatment strategies to specific racial groups or other patient-centered factors that would benefit the most. Black may have a more compromised starting situation, such as socioeconomic, mental health, or risk factor control, as seen in this study. Engaging in exercise could provide greater overall benefit in black.A difference of 8 points in PAQ and >5 points in SF-12 is considered clinically important.3 The observed changes in health status are clinically significant. If substantiated later, additional studies should corroborate these improvements with other clinical measures to improve interpretability. Furthermore, the Centers for Medicare and Medicaid Services recently agreed to reimburse SE programs,5 and targeting such therapy to right patient population will be the most impactful.The CLEVER trial enrolled selected patients with aortoiliac disease irrespective of femoropopliteal PAD. Therefore, our findings may not extend to patients with isolated femoropopliteal lesions or patients not meeting trial eligibility criteria. Despite 3 randomization arms (SE, ST, and OMC), OMC was provided in all patients, and the primary interest of the trial was to compare the effect of SE with ST.3 So, our results require careful interpretation when considering OMC as a control.Although some overlap between PAQ and SF-12 PCS is expected, PAQ provides PAD-specific information that SF-12 does not. We did not find significant interactions for mobility-based outcomes, like WIQ and treadmill-based measures. Although WIQ provides information on PAD-specific mobility, it does not provide other quality-of-life information.8 Whether this explains the disparate findings requires further study.This hypothesis-generating post hoc analysis of the CLEVER trial demonstrates differential quality-of-life benefits by race with alternative PAD treatment modalities. These findings warrant further examination to confirm the veracity of these observations and to understand the mechanisms responsible for observed treatment responses so that treatment approaches can be optimized to fit patients' needs, preferences, and potential benefits.Sources of FundingThe CLEVER study (Claudication: Exercise Versus Endoluminal Revascularization) was sponsored mostly by the National Heart, Lung, and Blood Institute (grant numbers HL77221 and HL081656) and received financial support from Cordis/Johnson & Johnson (Warren, NJ), eV3 (Plymouth, MN), and Boston Scientific (Natick, MA). Otsuka America, Inc, (San Francisco, CA) donated cilostazol for all study participants throughout the study. Omron Healthcare, Inc, Lake Forest, IL, donated pedometers. Krames Staywell, San Bruno, CA, donated print materials for study participants on exercise and diet. Dr Pokharel is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number T32HL110837.DisclosuresDr Collins serves as a consultant for ViroMed. Dr Cohen has received research grant support from Medtronic, Abbott Vascular, and Boston Scientific and serves as a consultant for Medtronic and Cardinal Health. Dr Spertus owns the copyright to the Peripheral Artery Questionnaire. Dr Smolderen has received research grant support from Merck and Boston Scientific. The other authors report no conflicts.FootnotesThe content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.http://circoutcomes.ahajournals.orgThis article was handled by Philip Goodney, MD, as a Guest Editor. The editors had no role in the evaluation of the manuscript or in the decision about its acceptance.Yashashwi Pokharel, MD, MSCR, Department of Cardiovascular Research, Saint Luke's Mid America Heart Institute, University of Missouri–Kansas City, 4401 Wornall Rd, Cardiovascular Research, 9th Floor, Kansas City, MO 64111. E-mail [email protected]References1. Rooke TW, Hirsch AT, Misra S, Sidawy AN, Beckman JA, Findeiss LK, Golzarian J, Gornik HL, Halperin JL, Jaff MR, Moneta GL, Olin JW, Stanley JC, White CJ, White JV, Zierler RE; Society for Cardiovascular Angiography and Interventions; Society of Interventional Radiology; Society for Vascular Medicine; Society for Vascular Surgery. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.J Am Coll Cardiol. 2011; 58:2020–2045. doi: 10.1016/j.jacc.2011.08.023.MedlineGoogle Scholar2. Allison MA, Ho E, Denenberg JO, Langer RD, Newman AB, Fabsitz RR, Criqui MH. Ethnic-specific prevalence of peripheral arterial disease in the United States.Am J Prev Med. 2007; 32:328–333. doi: 10.1016/j.amepre.2006.12.010.CrossrefMedlineGoogle Scholar3. Murphy TP, Cutlip DE, Regensteiner JG, Mohler ER, Cohen DJ, Reynolds MR, Massaro JM, Lewis BA, Cerezo J, Oldenburg NC, Thum CC, Goldberg S, Jaff MR, Steffes MW, Comerota AJ, Ehrman J, Treat-Jacobson D, Walsh ME, Collins T, Badenhop DT, Bronas U, Hirsch AT; CLEVER Study Investigators. Supervised exercise versus primary stenting for claudication resulting from aortoiliac peripheral artery disease: six-month outcomes from the claudication: exercise versus endoluminal revascularization (CLEVER) study.Circulation. 2012; 125:130–139. doi: 10.1161/CIRCULATIONAHA.111.075770.LinkGoogle Scholar4. Murphy TP, Cutlip DE, Regensteiner JG, Mohler ER, Cohen DJ, Reynolds MR, Massaro JM, Lewis BA, Cerezo J, Oldenburg NC, Thum CC, Jaff MR, Comerota AJ, Steffes MW, Abrahamsen IH, Goldberg S, Hirsch AT. Supervised exercise, stent revascularization, or medical therapy for claudication due to aortoiliac peripheral artery disease: the CLEVER study.J Am Coll Cardiol. 2015; 65:999–1009. doi: 10.1016/j.jacc.2014.12.043.CrossrefMedlineGoogle Scholar5. The Centers for Medicare and Medicaid Services: Proposed Decision Memo for Supervised Exercise Therapy for Symptomatic Peripheral Artery Disease. https://www.cms.gov/medicare-coverage-database/shared/handlers/highwire.ashx?url=https://www.cms.gov/medicare-coverage-database/details/[email protected]@@NCAId$$$287&session=1cin1p45wtawuf3p0uukf4fn&kq=873007742. Accessed July 5, 2017.Google Scholar6. Spertus J, Jones P, Poler S, Rocha-Singh K. The peripheral artery questionnaire: a new disease-specific health status measure for patients with peripheral arterial disease.Am Heart J. 2004; 147:301–308. doi: 10.1016/j.ahj.2003.08.001.CrossrefMedlineGoogle Scholar7. Ware J, Kosinski M, Keller SD. A 12-item short-form health survey: construction of scales and preliminary tests of reliability and validity.Med Care. 1996; 34:220–233.CrossrefMedlineGoogle Scholar8. Poku E, Duncan R, Keetharuth A, Essat M, Phillips P, Woods HB, Palfreyman S, Jones G, Kaltenthaler E, Michaels J. Patient-reported outcome measures in patients with peripheral arterial disease: a systematic review of psychometric properties.Health Qual Life Outcomes. 2016; 14:161. doi: 10.1186/s12955-016-0563-y.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited BySmolderen K, Alabi O, Collins T, Dennis B, Goodney P, Mena-Hurtado C, Spertus J and Decker C (2022) Advancing Peripheral Artery Disease Quality of Care and Outcomes Through Patient-Reported Health Status Assessment: A Scientific Statement From the American Heart Association, Circulation, 146:20, (e286-e297), Online publication date: 15-Nov-2022. Bronas U and Regensteiner J (2022) Connecting the past to the present: A historical review of exercise training for peripheral artery disease, Vascular Medicine, 10.1177/1358863X211073620, 27:2, (174-185), Online publication date: 1-Apr-2022. Hackler E, Hamburg N and White Solaru K (2021) Racial and Ethnic Disparities in Peripheral Artery Disease, Circulation Research, 128:12, (1913-1926), Online publication date: 11-Jun-2021. April 2018Vol 11, Issue 4 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCOUTCOMES.117.004157PMID: 29643064 Manuscript receivedJuly 31, 2017Manuscript acceptedMarch 14, 2018Originally publishedApril 11, 2018 Keywordshumansgoalsexercisecontinental population groupswalkingPDF download Advertisement SubjectsHealth Services

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