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

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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

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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.

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PAD and Survival

Criqui MH et al. N Engl J Med. 1992;326:381-386.

Normal subjects Asymptomatic PAD Symptomatic PAD Severe symptomatic PAD

100 75 50 25 2 4 6 8 10 12

Sur Surviv ival (%) al (%) Ye Years

474 Men Age 68 Followed Prospectively for 14 Years

No DM, PAD +DM, -PAD +PAD, -DM +PAD, +DM (p<0.001)

Survival with PAD and Diabetes

Eur J Vasc Endovasc Surg 2005;29:182-9

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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

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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

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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

Foley et al, JAHA 2017 HR 0.50

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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

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• 739 patients with claudication or CLI.
• Assessed relationship between

smoking cessation within one year and

• utcomes.

Armstrong, J Vasc Surg 2014

Smoking Cessation after Angiography

• 204 (28%) were active smokers at time
• f angiography.
• 61/204 patients (30%) successfully quit

in the next year.

• Only 13% of patients utilized any

pharmacologic aids.

Armstrong, J Vasc Surg 2014

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Decreased Mortality With Smoking Cessation

Armstrong, J Vasc Surg 2014 Mortality 14% vs. 31% (HR 0.40, 95% CI 0.18-0.90)

Improved Amputation-Free Survival

Armstrong, J Vasc Surg 2014 81% vs. 60% (HR 0.43, 95% CI 0.22-0.86)

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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.

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Decreased Rates of MACE

Event rate 17.8% vs. 13.8% HOPE Investigators, NEJM 2000; 342:145-153

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Does ASA Monotherapy Reduce CV Events in PAD?

• Antiplatelet therapy associated with

23% reduction in CV events.

• Analysis based on inclusion of many
• ther agents

 Picotamide (thromboxane synthesis

inhibitor)

Antithrombotic Trialists Collaboration, BMJ 2002

Meta-Analysis of ASA vs. Placebo

Berger, JAMA 2009

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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

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CAPRIE Overall Outcomes

CAPRIE Steering Committee, Lancet 1996;348:1329-1339 5.83% vs. 5.32% per year (p=0.043)

CAPRIE Subgroups: Benefit in PAD

CAPRIE Steering Committee, Lancet 1996;348:1329-1339 3.7% vs. 4.9% per year (p=0.0028) RRR = 23.8%

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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

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CHARISMA Subgroups

Bhatt et al, NEJM 2006 6.9% vs. 7.9% (p=0.046)

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

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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

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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

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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.

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PEGASUS Trial

• Subgroup of 1143 patients with PAD (5% of
• verall 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

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Guideline-Recommended Treatment and Outcomes

Armstrong J Am Heart Assn 2014

Guideline-Recommended Treatment and Outcomes

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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

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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

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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

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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)

* Significantly greater than placebo, p<0.05 ‡ Significantly greater than pentoxifylline, p<0.05

20 40 60 80 100 120 4 8 12 16 20 24 Weeks on Treatment Change from Baseline (meters) Cilostazol 100 mg bid (n=205) Pentoxifylline 400 mg tid (n=212) Placebo (n=226) * * * * * *

‡ ‡ ‡ ‡ ‡ ‡ Dawson DL, et al. Am J Med 2000;109:523-30.

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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

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Limitations of Cilostazol

• Contraindicated in congestive heart

failure.

• Adverse effects including diarrhea,

headache, palpitations.

• Overall walking distance improvement

is approximately 50% greater than placebo, but absolute improvement may still be insufficient.

Statins and Claudication

Intent-to-treat population

20 40 60 80 100 120

Baseline Month 3 Month 6 Endpoint Visit

PFWT (sec)

(change from baseline) 10 mg 80 mg Placebo

P=0.02 80 mg vs placebo

Mohler, Circulation 2003

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New Drugs Being Studied

• Vorapaxar: XL-PAD TRACE Study.

 Double-blind, randomized placebo

controlled trial.

 Primary outcome is walking distance at

6 months.

• Rivaroxaban

 Study plans underway.

Medical Treatment for Prevention

• f Limb Events
• Limb-related major events are relatively

uncommon among patients with claudication.

• However, acute limb ischemia, when it occurs,

has high mortality and morbidity.

• Acute limb events are more common among

patients with prior revascularization.

• MALE endpoint has been applied to broader

population of patients with peripheral artery disease.

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One-Year Outcomes After a Major Adverse Limb Event

• Hospitalization: 95%
• Death 8.7%
• Amputation: 23%
• MACE: 3.8%

Anand et al, JACC 2018 epub ahead of print

Impact of MALE on Mortality and Major Amputation

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Voraxpaxar and Incident Acute Limb Ischemia

Bonaca, Circulation 2013

Rivaroxaban and Major Adverse Limb Events

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Additional Studies Underway

• VOYAGER-PAD: Rivaroxaban after

lower extremity revascularization.

 Primary endpoint includes MALE, repeat

revascularization.

• ASPIRE: 1 vs. 12 months of dual

antiplatelet therapy after revascularization.

Summary and Conclusions

• First goal of medical therapy is reduction of CV

risk

 Statins, smoking cessation, antiplatelet, ACE

inhibitor

 Multiple emerging antithrombotic agents

• Reduction of claudication symptoms can be

achieved with medical therapy including cilostazol.

 Limited indications and adherence

• Emerging data regarding reduction in major

adverse limb events with newer antiplatelet and antithrombotic agents.

 Vorapaxar  Rivaroxaban

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Thank You

Ehrin J. Armstrong, MD MSc MAS

Director, Interventional Cardiology Co-Director, Vascular Laboratory VA Eastern Colorado Healthcare System Associate Professor Of Medicine University of Colorado