Medical Treatment for Claudication: What Works and What is on the - PDF document

Medical Treatment for Claudication: What Works and What is on the Horizon? Ehrin J. Armstrong, MD MSc MAS Director, Interventional Cardiology Director, Vascular Laboratory VA Eastern Colorado Healthcare System Associate Professor Of Medicine University of Colorado Disclosures • Advisory board member/consultant for Abbott Vascular, Boston Scientific, Cardiovascular Systems, Medtronic, Philips 1

What Are the Goals of Medical Therapy in Claudication? • Medical Treatment of Cardiovascular Risk • Medical Treatment for Symptom Relief • Medical Treatment for Prevention of Limb Events Patients with PAD Die from Cardiovascular Causes • ABI < 0.90 is associated with 2-3 fold increased risk of mortality. Criqui N Engl J Med 1992;326:381-386. 2

PAD and Survival 100 Normal subjects al (%) ival (%) 75 Asymptomatic PAD 50 Surviv Symptomatic PAD Sur 25 Severe symptomatic PAD 0 2 4 6 8 10 12 Ye Years Criqui MH et al. N Engl J Med. 1992;326:381-386. Survival with PAD and Diabetes 474 Men Age 68 Followed Prospectively for 14 Years No DM, PAD +DM, -PAD +PAD, -DM +PAD, +DM (p<0.001) Eur J Vasc Endovasc Surg 2005;29:182-9 3

Guideline-Recommended Treatment • Patients with PAD are consistently undertreated with guideline- recommended therapies.  Statins (Class I)  Smoking cessation (Class I)  Antiplatelet therapy (Class I)  ACE Inhibitors (Class IIa) Khumbani Eur Heart J 2014;35:2864-2872. Westin J Am Coll Cardiol 2014;63:682-690. Armstrong J Vasc Surg 2014;60:1565-1571. Statins in Patients with PAD • Statins are a Class I indication in patients with PAD. • No randomized trials specific to PAD, but PAD patients were part of specified subgroups. • Statins have been incorporated as a performance measure for patients with PAD. Olin, Circulation 2010 4

Statins and PAD: REACH Registry • 5,861 pts with symptomatic PAD. • Statin use 62% at baseline. • Four year adverse limb events assessed.  Defined as worsening claudication, new CLI, amputation, or revascularization. Khumbani Eur Heart J 2014 5

Statins Associated with Reduced Adverse Limb Outcomes Khumbani Eur Heart J 2014 High-Intensity Statin Therapy is Associated With Reduced Mortality Compared to Low-Intensity Therapy HR 0.50 Foley et al, JAHA 2017 6

Smoking Cessation in PAD • Smoking is a stronger risk factor for incident PAD than CAD. • Multiple studies have shown decreased surgical graft patency in patients with PAD who continue smoking. • A significant proportion of patients with PAD continue to smoke. Smoking Cessation in PAD • 124 patients with lower extremity PAD who were active smokers.  All enrolled patients were receptive to counseling. • Randomized to intensive intervention vs. standard care. • 6 month abstinence 21% vs. 7%. Hennrikus, J Am Coll Cardiol 2010 7

• 739 patients with claudication or CLI. • Assessed relationship between smoking cessation within one year and outcomes. Armstrong, J Vasc Surg 2014 Smoking Cessation after Angiography • 204 (28%) were active smokers at time of angiography. • 61/204 patients (30%) successfully quit in the next year. • Only 13% of patients utilized any pharmacologic aids. Armstrong, J Vasc Surg 2014 8

Decreased Mortality With Smoking Cessation Mortality 14% vs. 31% (HR 0.40, 95% CI 0.18-0.90) Armstrong, J Vasc Surg 2014 Improved Amputation-Free Survival 81% vs. 60% (HR 0.43, 95% CI 0.22-0.86) Armstrong, J Vasc Surg 2014 9

Adjusted Five-Year Outcomes • Significantly reduced mortality and improved amputation-free survival among successful quitters. Armstrong, J Vasc Surg 2014 Angiotensin Converting Enzyme Inhibitors In PAD • ACE Inhibitors are a Class IIa recommendation among patients with PAD.  Majority of data derived from HOPE study. 10

Decreased Rates of MACE Event rate 17.8% vs. 13.8% HOPE Investigators, NEJM 2000; 342:145-153 11

Does ASA Monotherapy Reduce CV Events in PAD? • Antiplatelet therapy associated with 23% reduction in CV events. • Analysis based on inclusion of many other agents  Picotamide (thromboxane synthesis inhibitor) Antithrombotic Trialists Collaboration, BMJ 2002 Meta-Analysis of ASA vs. Placebo Berger, JAMA 2009 12

CAPRIE Study • Randomized, blinded study of ASA 325 mg daily vs. clopidogrel 75 mg daily. • Major inclusion criteria were:  Recent ischemic stroke (1 week-6 months)  Recent MI (<35 days)  PAD (claudication, ABI <0.85, prior revasc) • 19,185 pts, mean follow up 1.91 years CAPRIE Steering Committee, Lancet 1996;348:1329-1339 CAPRIE Inclusion CAPRIE Steering Committee, Lancet 1996;348:1329-1339 13

CAPRIE Overall Outcomes 5.83% vs. 5.32% per year (p=0.043) CAPRIE Steering Committee, Lancet 1996;348:1329-1339 CAPRIE Subgroups: Benefit in PAD 3.7% vs. 4.9% per year (p=0.0028) RRR = 23.8% CAPRIE Steering Committee, Lancet 1996;348:1329-1339 14

CHARISMA Study • Low dose ASA (75-162 mg/day) vs. ASA+ clopidogrel 75 mg daily. • Either documented cardiovascular disease ( CAD, stroke or PAD) or multiple risk factors • 15,603 patients, median follow up 28 months Bhatt, NEJM 2006 CHARISMA Trial: Overall Findings • No additional benefit of DAPT among patients with stable CAD. Bhatt, NEJM 2006 15

CHARISMA Subgroups 6.9% vs. 7.9% (p=0.046) Bhatt et al, NEJM 2006 CHARISMA Trial Subgroup • Among patients with PAD, dual antiplatelet therapy possibly associated with reduced myocardial infarction. • Event rates are much lower for patients with stable PAD on optimal medical therapy. Cacoub, Eur Heart J 2008 16

Dual Antiplatelet Therapy in Patients with Symptomatic PAD • Patients with severe claudication or CLI have major adverse cardiovascular event rates much higher than populations studied in randomized trials. • DAPT may be of particular benefit in this high-risk population. Armstrong J Vasc Surg 2015;62:157-165 Major Adverse Cardiovascular Events Adjusted HR 0.65 (95% CI 0.44-0.96) Armstrong J Vasc Surg 2015;62:157-165 17

Summary of Three-Year Outcomes Armstrong J Vasc Surg 2015;62:157-165 DAPT After Lower Extremity Revascularization • VQI analysis of 57,041 patients undergoing surgical bypass or endovascular intervention. • DAPT was associated with decreased mortality among patients with CLI, but not claudication. Soden et al, J Vasc Surg 2016;64:1633-1644 18

Bypass Endovascular Intervention Soden et al, J Vasc Surg 2016;64:1633-1644 EUCLID Trial • 13,885 patients with symptomatic PAD  ABI <0.80 or prior revascularization  76.6% had claudication, 4.6% CLI • Randomized to clopidogrel or ticagrelor. • Event rate 10.8% in ticagrelor group, 10.6% in clopidogrel group. • No difference in rates of ALI. Hiatt, et al. NEJM. 2017;376:32-40. 19

PEGASUS Trial • Subgroup of 1143 patients with PAD (5% of overall cohort). • Ticagrelor reduced the rates of MACE (absolute risk reduction 4.1% over three years) and also MALE (HR 0.65). • Suggests benefit of ticagrelor among patients with polyvascular disease. Bonaca. J Am Coll Cardiol. 2016. • 739 patients with claudication or CLI referred for angiography. • Antiplatelet, ACEI, smoking cessation, statin use assessed at time of angiography. Armstrong J Am Heart Assn 2014 20

Guideline-Recommended Treatment and Outcomes Armstrong J Am Heart Assn 2014 Guideline-Recommended Treatment and Outcomes 21

What’s on the Horizon? • Vorapaxar: PAR-1 antagonist that inhibits the platelet thrombin receptor. • Rivaroxaban: Selective inhibitor of Factor Xa.  Decreases thrombin generation.  Indirectly inhibits platelet aggregation induced by thrombin. Vorapaxar in Patients With PAD Bonaca, Circulation 2013 22

Revascularization Bonaca, Circulation 2013 COMPASS PAD • 7,470 patients with symptomatic PAD (55%), prior carotid revascularization (26%), or CAD with asymptomatic PAD (20%) • Randomized to:  ASA 100 mg daily  ASA 100 mg daily + rivaroxaban 2.5 mg bid  Rivaroxaban 5 mg bid • Primary outcome was MACE; MALE key secondary outcome. Anand et al, Lancet 2018;391:219-229 23

Significant Reduction in MACE Anand et al, Lancet 2018;391:219-229 Subgroups MACE Outcomes Major Bleeding Anand et al, Lancet 2018;391:219-229 24

Reduction of Claudication Symptoms • Supervised exercise therapy remains the cornerstone of medical therapy. • Cilostazol provides symptom relief in select groups of patients. • Multiple other medical approaches have shown limited benefit.  Pentoxyfylline  Ramipril (study retracted) Cilostazol Type III Phosphodiesterase Inhibitor (↑cAMP) Cilostazol 100 mg bid (n=205) Pentoxifylline 400 mg tid (n=212) Change from Baseline Placebo (n=226) 120 ‡ * ‡ * 100 ‡ * ‡ (meters) * 80 ‡ * 60 ‡ * 40 20 0 0 4 8 12 16 20 24 Weeks on Treatment * Significantly greater than placebo, p<0.05 ‡ Significantly greater than pentoxifylline, p<0.05 Dawson DL, et al. Am J Med 2000;109:523-30. 25

Long-Term Safety of Cilostazol: CASTLE Study • 1,899 patients with PAD.  Randomized to cilostazol or placebo • Long-term adherence was poor  >60% discontinuation by 36 months • No difference in serious bleeding events (2.5% vs. 3.1%) Hiatt et al, J Vasc Surg 2008;47:330-336 No Effect of Cilostazol on Mortality Hiatt et al, J Vasc Surg 2008;47:330-336 26