Medical Therapy of Peripheral Artery Disease

Medical Therapy of Peripheral Artery Disease Alvaro Alonso, MD Assistant Professor of Medicine Associate Director, Interven4onal Cardiology Fellowship Program Tulane University Heart & Vascular Ins4tute Tulane University School of Medicine New Orleans, LA (USA)

Disclosures Grant/Research Support: Supported in part by the National Institute of General Medical Sciences of the National Institutes of Health under award number 1 U54 GM104940, which funds the Louisiana Clinical and Translational Science Center Principal Investigator: Odyssey Outcomes RCT (Sanofi-Regeneron; Alirocumab). Not-financial. Nothing to disclose regarding: Speaker s Bureau Honorarium Consultant Stockholder Medical/Scientific Boards

LE-PAD: More Prevalent and More Deadly Than Many Leading Diseases Fowkes FG. Lancet. 2013;382(9901):1329-40 Adapted, Courtesy of: Subhash Banerjee, M.D 20 17 15 10 5 0 U.S. Disease Prevalence (Millions) 12.6 12 8.9 4.8 5 4 50% 40% 30% 20% 10% 0% Five-Year Mortality Rate 39% 30% 28% 21% 14%

Natural History of Atherosclerotic LE-PAD For each of these PAD clinical syndromes Asymptomatic PAD 20%-50% Limb morbidity Claudication 10%-35% 5-year outcomes Atypical leg pain 40%-50% Cardiovascular M&M Stable claudication 70%-80% Worse claudication 10%-20% Critical limb ischemia 1%-2% Amputation (next slide) Nonfatal CV event (MI or stroke) 20% CV causes 75% Mortality 15%-30% Non-CV causes 25% Hirsch AT, et al. Circulation. 2006;113:e463-654.

Natural History of Atherosclerotic LE-PAD Cont d PAD Population Initial clinical presentation Asymptomatic PAD 20%-50% Progressive functional impairment Atypical leg pain 40%-50% 5-year outcomes Claudication 10%-35% Alive w/ 2 limbs 50% Critical limb ischemia 1%-2% 1-year outcomes Amputation 25% CV mortality 25% (previous slide) Hirsch AT, et al. Circulation. 2006;113:e463-654.

Major Goals of Treatment in LE-PAD Cardiovascular Limb outcomes á ability to walk á peak walking distance á quality-of-life (QoL) Prevention of progression to CLI and amputation morbidity and mortality outcomes â morbidity from nonfatal MI and stroke â cardiovascular mortality from fatal MI and stroke

Smoking cessation Antiplatelet therapy ASA Clopidogrel Essentials ASA + clopidogrel? Ticagrelor (ongoing EUCLID trial) Blood pressure control Glycemic control

Cilostazol and Walking Distance in Claudication Meters (mean) 260 240 220 200 180 160 140 120 100 80 60 * P < 0.05 vs. placebo * * * * * * * * 0 4 8 12 16 20 24 Weeks of Treatment * * * * * * * * * * * * Maximal Walking Distance Cilostazol 100 mg bid (n=140) Cilostazol 50 mg bid (n=139) Placebo (n=140) Pain-Free Walking Distance Beebe, et al. Arch Intern Med. 1999;159:2041-50.

Effect of Cilostazol on Quality of Life Medical Outcome Scale SF-36 RCT, N = 1751 Physical Summary Score 30 25 20 15 10 5 0 Placebo * P < 0.05 Cilostazol 100 mg bid * * * * Wk 4 Wk 8 Wk 16 Wk 20 Wk 24 Weeks of treatment * Regensteiner MG et al. J Am Geriatr Soc. 2002 Dec;50(12):1939-46

Cilostazol Restenosis and Vascular events STOP-IC RCT, N= 200 Femoropopliteal PVI Freedom from death, major amputation, clinical TLR, limb ischemia requiring surgical intervention Cilostazol Non-cilostazol 49% Cilostazol 20% 12-mo angiographic restenosis Iida O et al. Circulation. 2013;127:2307-2315

Cilostazol Improved outcomes after PVI for CLI Warner CJ, et al. J Vasc Surg 2014;59:1607-1614

Statin use Vascular Events Heart Protection Study Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22.

RCT, N= 354 Statins Pain Free Walking Time Mean change from baseline in Pain Free Walking Time (sec) 125 100 75 50 25 0 Atorvastatin 10 mg Atorvastatin 80 mg Placebo Baseline Month 3 Month 6 Month 12 * *P=0.03 No change in ABI over 12 months. Mohler ER et al. Circulation. 2003;108:1481-1486.

Ramipril use Cardiovascular risk HOPE: Benefits in CV Risk Subgroups N Engl J Med. 2000;342:145-153.

ACEI (ramipril vs. others) Δ in mean walking distance (meters) Shahin Y, et al. Atherosclerosis 2013;231:283-290

Intermittent Claudication: Supervised Exercise Therapy Warm-up Exercise Rest Exercise Rest Exercise Cool-down 3 5 supervised sessions/week 35 50 minutes of exercise/session Treadmill or track walking to nearmaximal claudication pain 6 months Gardner AW, Poehlman ET. JAMA. 1995;274:975-980. Stewart KJ et al. N Eng J Med. 2002;347:1941-1951. Change in Treadmill Walking Distance (%) 200 180 160 140 120 100 80 60 40 20 0 Meta-analysis of 21 Studies P < 0.05 Onset of Claudication Pain Exercise Training Control P < 0.05 Maximal Claudication Pain

CLEVER Combination therapy NIH-sponsored multicenter RCT, N = 111, aorto-iliac disease Randomized to OMT vs. OMT+Stent vs. OMT+Exercise, 6mo f/u 1 endpoint: Change in peak walking time 8 (p < 0.05 for all comparisons) OMT = Cilostazol 4 % 0 1.2 3.7 5.8 Optimal medical therapy ( N = 22) Stent revascularization (N = 46) Exercise program ( N = 43) Quality of Life: with stenting, supervised exercise medical therapy Circulation 2012;125(1):130-9

CLEVER mean Peak Walking Time 18 month results J Am Coll Cardiol 2015;65:999 1009

CLEVER Baseline medication use Medication use, % OMT (n = 22) Exercise + OMT (n = 43) Stenting + OMT (n = 46) Aspirin 95.5 79.1 84.8 P2Y12 inhibitor 40.9 16.3 28.3 Statin 81.8 86 82.6 No information on ACE inhibitor use No information on medication use at f/u p = NS for all groups CLEVER 6 month results. Circulation. 2012;125:130-139.

Revascularization Symptomatic patients Refractory to medical therapy; lifestyle limiting Depending on clinical presentation (ALI vs. CLI vs. Claudication) Medications Antiplatelets Cilostazol Ramipril Statin Exercise Smoking cessation Surgical Control of other CV risk factors as surgical bridge or post-surgical salvage Revascularization Endovascular Endovascular Revascularization

Conclusions Medical therapy goals Improve cardiovascular outcomes Symptom management Contemporary therapies inter-related Med Rx improves ambulation distance quality of life limb outcomes cardiovascular outcomes

cardiacandvascular.org Thank you

Medical Therapy of Peripheral Artery Disease Alvaro Alonso, MD Assistant Professor of Medicine Associate Director, Interven4onal Cardiology Fellowship Program Tulane University Heart & Vascular Ins4tute Tulane University School of Medicine New Orleans, LA (USA)

Objective Acquire/increase/affirm your knowledge about the contemporary medical management of patients with lower extremity peripheral arterial disease

Global burden of LE-PAD 220 million patients worldwide ~ 12 million patients in the United States Fowkes FG. Lancet. 2013;382(9901):1329-40

Association Between ABI and All Cause Mortality Total Mortality (%) 80 70 60 50 40 30 20 10 0 <0.61 (n=156) 0.61-0.70 (n=141) 0.71-0.80 (n=186) 0.81-0.90 (n=310) 0.91-1.00 (n=709) Risk increases with ABI values below 1.0 and above 1.3 1.01-1.10 (n=1750) 1.11-1.20 (n=1578) 1.21-1.30 (n=696) N = 5748 1.31-1.40 (n=156) >1.40 (n=66) Baseline ABI Age range mid- to late-50s Median duration of follow-up was 11 years O Hare AM et al. Circulation. 2006;113:388-393.

ABI correlates with mortality ABI collaboration meta-analysis. JAMA 2008;300(2):197

MI Risk Increases as the ABI decreases Framingham High Risk = 20% at 10 years Every patient with PAD is at very high risk Fatal and non-fatal CV events and all cause mortality Event Outcomes per Year (%) 4 3 2 1 0 N= 1500, cohort, Primary Care, Scotland 1.4% >1.1 1.1 1.01 1.0 0.91 0.9 0.71 <0.7 ABI PAD 10-year risk: 20% Annual risk 2% 10-year risk: 38% Annual risk 3.8% Leng GC, et al. Brit Med J. 1996;313:1440-44.

10-Year Natural History in Patients With Intermittent Claudication Patients (%) 100 80 60 40 20 Survival MI Intervention Amputation 6.8% annual risk of death 2.0% risk of MI 1.0% risk of intervention 0.4% risk of amputation 0 0 1 2 3 4 5 6 7 8 9 10 Time (years) Ouriel K. Lancet. 2001;358;1257-1264.

6-month outcomes in critical limb ischemia Fate of Patients With CLI After Initial Treatment Summary of 6-month outcomes from 19 studies Alive with amputation 35% Dead 20% Alive without amputation 45% Critical limb ischemia: ischemic rest pain, non-healing wounds, or gangrene Dormandy JA, Rutherford RB. J Vasc Surg. 2000;31:S1-S296.

Glycemic control and macrovascular endpoints in DM-2 and LE-PAD Study PROactive VADT Primary Macrovascular Endpoints ACS, nonfatal MI, endovascular/ surgical revascularization on leg arteries, or Amputation MI, stroke, CVD death, CHF, PVD surgery, inoperable CAD, or Amputation Intervention or goals Pioglitazone vs placebo 1.5% Reduction in HgbA1c ø ø Outcomes Non-significant 10% reduction in macrovascular Events No significant benefit in intensive glycemic control on composite Outcome UKPDS survivor cohort Death from MI, stroke, or PVD FPG <108 mg/dl w10- y Follow-up of original trial: intensive glycemic control reduced MI but not PAD UKPDS Death from MI, stroke, or PVD FPG <108 mg/dl Nonsignificant reduction in PAD RR 0.65 (95% CI, 0.36 1.18). ACCORD ADVANCE Nonfatal MI, nonfatal stroke, or CVD death Composite of macrovascular and microvascular events HgbA1c <6.0% HgbA1c <6.5% ø ø ø ø Increased mortality in intensive glycemic control Group No significant effect on macrovascular events; reduction in combined macrovascular and microvascular Events Tattersall MC, et al. Surg Clin North Am. 2013;93(4):761-78

Quitting tobacco and controlling BP and Survival in LE-PAD Smoking cessation Intensive BP management in LE-PAD patients, ABCD trial 100 Cumulative Survival (%) 80 60 40 20 0 Australian census Tobacco abstinence Continued tobacco use 0 1 2 3 4 5 Years Postoperative 133 Patients observed after bypass graft Faulkner KW, et al. Med J Aust. 1983;1:217-219. Mehler, et al. Circulation. 2003;107;753-756.

Intensive Antihypertensive Therapy in LE- PAD: The ABCD Trial Moderate treatment n = 227 Intensive treatment n = 227 *enalapril or nisoldipine Odds of MI, Stroke or Vascular Death 40 30 20 10 0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 Baseline ABI Mehler, et al. Circulation. 2003;107;753-756.

Clopidogrel vs. Aspirin in MI, Ischemic Stroke, or Vascular Death CAPRIE Cumulative Event Rate (%) 8.7%* 16 Overall Relative Risk ASA Reduction 12 8 4 5.83% 5.32% Clopidogrel 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months of Follow-Up N=19,185 CAPRIE. Lancet. 1996;348:1329-1339

Antiplatelet (Aspirin) use Risk of Vascular Events in High-Risk Patients: Antithrombotic Trialists Collaboration Risk category (N of trials) Patients with event (%) Risk vs control Antiplatelet Control Reduced Increased Claudication (n=26) Surgical bypass grafting (n=12) Peripheral Vascular intervention (n=4) 6.4 7.9 5.4 6.5 2.5 3.6 N=9706 All LE-PAD trials (n=42) 5.8 7.1 22% RRR (P<.001) 0.0 0.5 1.0 1.5 2.0 Antithrombotic Trialists Collaboration. Brit Med J. 2002;324:71-86.

Risk Reduction of Clopidogrel vs. Aspirin in Patients With PAD Aspirin favored Clopidogrel favored Stroke N=19,185 MI PAD All patients -30-20 -10 0 10 20 30 40 CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.

CHARISMA: Clopidogrel+Aspirin vs. Aspirin Alone and MI, Stroke, or CV Death Cumulative Event Rate* (%) 8 6 4 2 0 First occurrence of MI (fatal or nonfatal), stroke (fatal or nonfatal), or CV death 0 6 12 18 24 30 Months Since Randomization Placebo + ASA 7.3% Clopidogrel + ASA 6.8% RRR 7.1% (95% CI: -4.5%, 17.5%) P=0.22 Bhatt DL, Fox KA, Hacke W, et al. N Engl J Med 2006;354:1706.

CHARISMA: Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category Population RRR (95% CI) P Qualifying CAD, CVD, or PAD 0.88 (0.77, 0.998) 0.046 (n=12,153) Multiple risk factors 1.20 (0.91, 1.59) 0.20 (n=3,284) Overall population* 0.93 (0.83, 1.05) 0.22 (N=15,603) 0.4 0.6 0.8 1.2 1.4 1.6 Clopidogrel better Placebo better CAD=coronary artery disease; CI=confidence interval; CVD=cardiovascular disease; MI=myocardial infarction; RRR=relative risk ratio. *A statistical test for interaction showed marginally significant heterogeneity (P=0.045) in treatment response for these prespecified subgroups of patients. Adapted from Bhatt DL, Fox KA, Hacke W, et al. N Engl J Med 2006;354:1706..

Cilostazol dosing and Pentoxifylline and claudication walking distance % Change From Baseline MWD (mean) 50 40 30 20 10 0 Cilostazol 100 mg 2 times/day (n=227) Pentoxifylline 400 mg 3 times/day (n=232) Placebo (n=239) P<0.001 vs pentoxifylline 0 4 8 12 16 20 24 Treatment (weeks) 698 516 239 3 Randomized, Placebo Controlled Trials No. of Patients Cilostazol, 100 mg bid Pentoxifylline, 400 mg tid Cilostazol, 100 mg bid Cilostazol, 50 mg bid Cilostazol, 100 mg bid 0.8 1.0 1.2 1.4 1.6 1.8 Relative Improvement vs. Placebo Dawson DL, et al. Am J Med. 2000;109:523-530 Hiatt WR. N Engl J Med. 2001;344;1608-21

Ramipril Walking Times and QOL Multicenter RCT N= 212 Ahimastos AA.JAMA. 2013;309(5):453-460

Cilostazol mortality after PVI Fig 6 Forest plot of mortality outcomes. CI, Confidence interval; RCT, randomized controlled trial. Warner CJ, et al. J Vasc Surg 2014;59:1607-1614

ACEI (ramipril vs. others) Δ in ABI Shahin Y, et al. Atherosclerosis 2013;231:283-290

CLaudication: Exercise vs. Endoluminal Revascularization

Research Question To compare the relative effect of Optimal medical therapy vs. Optimal therapy + supervised exercise vs. Optimal therapy + Revascularization in the management of patients with claudication

Study design Multicenter (22 US sites) Randomized Open label NHLBI sponsored

Inclusion and Exclusion Inclusion à >2<11 minutes on Gardner treadmill protocol and hemodynamically significant aortoiliac disease (ABI <0.9, CFA-AT >140 ms, PSVR >2, CTA/MRA >60%, Angio >50%) Exclusion à CLI, comorbidities limiting ambulation

Treatments OPTIMAL cilostazol 100 mg bid as tolerated, written and oral advice about exercise and diet STENTING optimal plus stent revascularization of aortoiliac PAD EXERCISE optimal plus 26 weeks of supervised exercise, 3x/wk, 1 hour sessions followed by 1 year of telephone-based exercise counseling

Final: 79 pts 29% dropout

Baseline medication use No information on ACEI No information on medication use at f/u CLEVER 6 month results. Circulation. 201

Endpoints Primary: Peak walking time (PWT) on Gardner treadmill protocol Secondary: Claudication onset time (COT), QOL, CV disease biomarkers Interim f/u at 6 months Total planned f/u 18 months

Sample size Circulation. 2012;125:1

Analyses All 3 pairwise comparisons of change in PWT between baseline and 18 months among the 3 treatment groups à analysis of covariance (ANCOVA) adjusted for baseline PWT, baseline cilostazol use, and study region, Sequential testing was performed so as to allow a 2- sided 0.05 level of significance for each pairwise comparison.

CLEVER 6 moths 1 endpoint: Change in peak walking time 8 (p < 0.05 for all comparisons) 4 % 1.2 3.7 5.8 QOL: highest with stenting, intermediate with supervised exercise, and lowest with optimal medical therapy alone 0 Optimal medical therapy ( N = 22) Stent revascularization (N = 46) Exercise program ( N = 43) Circulation 2012;125(

Mean peak walking time (primary endpoint)

Mean claudication onset time

Treatment delivery 91% cilostazol compliance in all groups 71% exercise compliance 100% procedure success for stenting No crossover at 6 months; 7% crossover at 18 months

Caveats Slow enrollment (4 yrs at 29 centers) 10:1 screening to enrollment ratio Stenting plus exercise group was dropped (these 8 patients were excluded from analyses) Patient dropout rate 20% Early termination (when 51% of original sample size had enrolled; 36% of original sample size completed 18-month f/u)

Conclusions CLEVER Optimal care à little benefit. Cilostazol less than expected improvement Supervised Exercise and Stenting have benefits over optimal care Exercise: better treadmill performance Stenting: better quality of life Discordant findings limit interpretation and impact in practice Potential confounders: unblinded design, dropping of 4 th exercise +stenting group, early termination. Dropout rates could have skewed the results No other clinical outcomes known (e.g., major adverse limb events, major adverse cardiac events) CLEVER à very selected cohort