Medical Management of PAD: What Do You Need to Know?

Matthew Menard, MD

Brigham and Women’s Hospital

DISCLOSUREMatthew Menard, MD

• Advisory Board: Janssen Pharmaceuticals

CDC Trends in 2 Major PAD Risk Factors

Trends in age-standardized rates of diabetes

mellitus–related complications, 1990 to 2010.

Beckman, JA Circ Res. 2016;118:1771-1785

Trends in Rates of Lower Extremity Amputation Among Dialysis Patients With ESRD

JAMA Intern Med. 2018;178(8):1025-1032

Retrospective study of 3 700 902 records from a US national registry of ESRD/Dialysis patients with assessed cross-sectional cohorts for each calendar year from 2000 through 2014

Trends in Rates of Lower Extremity Amputation Among Dialysis Patients With ESRD

Retrospective study of 3 700 902 records from a US national registry of ESRD/Dialysis patients with assessed cross-sectional cohorts for each calendar year from 2000 through 2014

JAMA Intern Med. 2018;178(8):1025-1032

REDUCE RISK OF

CARDIOVASCULAR EVENTS

REDUCE RISK OF

LIMB EVENTS

IMPROVE SYMPTOMS &

QUALITY OF LIFE

Medical Management of PAD

IMPROVE SYMPTOMS &

QUALITY OF LIFE

- Supervised exercise program

- Cilostazol

- Statins

REDUCE RISK OF

CARDIOVASCULAR EVENTS

REDUCE RISK OF

LIMB EVENTS

Medical Management of PAD

• The standard 12-week supervised

exercise improves exercise

performance and QOL in PAD

patients.

• Exercise training is associated

with decreased all-cause and

cardiovascular mortality.

Treat-Jacobson D et al. Circulation. 2019 Jan 22;139(4):e10-e33

Chang P. et al. Mayo Clin Proc 2015;90:339–45

Improvement in Symptoms and QOL

.Gerhard-Herman M et al. Circulation. 2017;135:e686–e725

Supervised exercise

Olin JW et al. JACC. 2016;67:1138-57

• Cilostazol - phosphodiesterase III inhibitor improves

claudication, through unknown mechanism.

• Improves walking distance approximately 50% cf placebo

• Also 1A recommendation

• May require up to 4 4

months to achieve full

clinical effect

• Troublesome side effects.cilostazol

Cilostazol

IMPROVE SYMPTOMS &

QUALITY OF LIFE

- Supervised exercise program

- Cilostazol

- Statins

REDUCE RISK OF

CARDIOVASCULAR EVENTS

REDUCE RISK OF

LIMB EVENTS

- HgA1C < 7

- Aspirin or plavix

- Statins

- Tobacco cessation

- ACE-inhibitors/ARBs

- PCSK9 inhibitor (evolocumab)

- Aspirin + rivaroxaban

Medical Management of PAD

Ratchford EV. J Vasc Surg. 2017;66:275-80

• Up to 80% of patients with PAD are current or former

smokers.

• Smoking after lower extremity bypass increases the risk

of graft failure 3X.

Smoking Cessation

Conen D et al. Ann Intern Med. 2011;154:719–726

Smoking cessation reduces the risk of incident PAD

Smoking Cessation

Barua RS et al. JACC 2018, 72 (25) 3332-3365

Smoking Cessation

Barua RS et al. JACC 2018, 72 (25) 3332-3365

Smoking Cessation

Barua RS et al. JACC 2018, 72 (25) 3332-3365

Smoking Cessation

• HOPE trial: ACE inhibition associated with significant

reduction in MACE among PAD patients.

• Ramipril’s effects were seen in both asymptomatic and

symptomatic PAD across a broad range of ABI values.

• Similar effects were seen with telmisartan in the

ONTARGET trial.

HOPE N Engl J Med 2000;342:145–53 – ONTARGET N Engl J Med 2008;358:1547–59

CV Risk Reduction: ACE-Is/ARBs

IMPROVE SYMPTOMS &

QUALITY OF LIFE

- Supervised exercise program

- Cilostazol

- Statins

REDUCE RISK OF

CARDIOVASCULAR EVENTS

REDUCE RISK OF

LIMB EVENTS

- Tobacco cessation

- Aspirin or a thienopyridine

- Statins

- ACE-inhibitors/ARBs

- PCSK9 inhibitor (evolocumab)

- Aspirin + rivaroxaban

- Statins

- PAR-1 antagonist (vorapaxar)

- PCSK9 inhibitor (evolocumab)

- Aspirin + low dose

rivaroxaban

Medical Management of PAD

Kumbhani DJ et al. Eur Heart J. 2014;35:2864–2872

Reduction of Limb Events: Statins

Days from Randomization

MA

CE

(%

)

Vorapaxar

10.7%

Placebo

12.5%

HR 0.85

(0.73-0.99)

P=0.034

3 Y

rK

M E

sti

ma

te

1.8% ARR

NNT 56

Vorapaxar and MACE in Patients with PAD

ISTH Major Bleeding HR 1.39, p<0.001GUSTO Mod/Severe 1.62 p=0.001

No significant increase in ICH or Fatal Bleeding

Vorapaxar and Limb Vascular Efficacy

Hospitalization for Acute Limb IschemiaPre-specified, adjudicated

2.3%

3.9%

Hazard Ratio 0.5895% CI 0.39 to 0.86

p = 0.006

Placebo

Vorapaxar

N = 3767

Days from randomization

Peripheral Revascularization

Prespecified, Investigator

18.4%

22.2%

Hazard Ratio 0.84;95% CI 0.73 to 0.97

p = 0.017

Bonaca et al. Circulation 2012

Summary of Effects of PCSK9i Evolocumab

• LDL-C by 59% to a median of 30 mg/dL• CV outcomes in patients on statin• Safe and well-tolerated

14.6

9.9

12.6

7.9

0

5

10

15

KM

Rat

e (

%)

at 3

Ye

ars

HR 0.85 (0.79-0.92)

P<0.0001

HR 0.80 (0.73-0.88)

P<0.0001

CVD, MI, stroke

UA, cor revasc

CVD, MI, stroke

Sabatine MS et al. NEJM 2017;376:1713-22

Evolocumab

(median 30 mg/dl, IQR 19-46 mg/dl)

Placebo

59% reduction

P<0.00001

Absolute 56 mg/dl

0%

2%

4%

6%

8%

10%

12%

0 90 180 270 360 450 540 630 720 810 900

CV

De

ath

, MI o

r St

roke

Days from Randomization

Placebo

Evolocumab

10.3%

5.5%

PAD4.8% ARRNNT2.5y 21

PAD (no MI/stroke, N=1505)

43% RRR

HR 0.57(0.38 – 0.88)

P=0.0095

CV Death, MI or Stroke in Patients with PAD and no MI or Stroke

Maj

or

Ad

vers

e Li

mb

Eve

nts

Placebo

0.45%

0.0%

0.1%

0.2%

0.3%

0.4%

0.5%

0 90 180 270 360 450 540 630 720 810 900

Days from Randomization

Major Adverse Limb Events

Placebo

Evolocumab

0.45%

0.27%

All PatientsN=27,564

42% RRR

HR 0.58(0.38 – 0.88)

P=0.0093

0.0%

0.1%

0.2%

0.3%

0.4%

0.5%

0 90 180 270 360 450 540 630 720 810 900

Days from Randomization

Bonaca et al. Circulation 2018

Maj

or

Ad

vers

e Li

mb

Eve

nts

Placebo

0.45%

0.0%

0.1%

0.2%

0.3%

0.4%

0.5%

0 90 180 270 360 450 540 630 720 810 900

Days from Randomization

Major Adverse Limb Events

Placebo

Evolocumab

0.45%

0.27%

All PatientsN=27,564

42% RRR

HR 0.58(0.38 – 0.88)

P=0.0093

0.0%

0.1%

0.2%

0.3%

0.4%

0.5%

0 90 180 270 360 450 540 630 720 810 900

Days from Randomization

Bonaca et al. Circulation 2018

Outcome HR 95% CIMALE 0.58 (0.38–0.88)

ALI or major amputation 0.52 (0.31–0.89)ALI 0.55 (0.31–0.97)

Major amputation 0.57 (0.17–1.95)Urgent revascularization 0.69 (0.38–1.26)

0%

2%

4%

6%

8%

10%

12%

14%

0 90 180 270 360 450 540 630 720 810 900

Placebo

12.8%

6.5%

PAD6.3% ARRNNT2.5y 16

Days from Randomization

MACE or MALE in Patients with Just PAD

MA

CE

or

MA

LEPAD

(no MI/stroke, N=1505)

48% RRR

HR 0.52(0.35 – 0.76)

P=0.0006

Bonaca et al. Circulation 2018

Evolocumab

Adapted from: N Engl J Med 2007;357:217-27.

COMPASS Trial PAD+CAD

>90% with CAD, large subgroup with

Concomitant PAD

28% Reduction in MACE

70% Increase in Major Bleeding

Anand SS et al. Lancet. 2018 Jan 20;391(10117):219-229

COMPASS: Reduction of Limb Events

VOYAGER PAD: Study Design

Multicenter, randomized, double-blind, placebo-controlled, event-driven phase III study

Primary efficacy outcome: CV death, MI, ischemic stroke, acute limb ischemia, and major amputation

Principal safety outcome: TIMI Major Bleeding

Event driven (~1015 PEP)

Pts age ≥ 50 yo with:• Documented moderate to severe PAD with ABI <0.90 and angiographic or imaging evidence of occlusive PAD

•Any vascular surgical

bypass to the lower

extremity including aorto-

iliac, infra-inguinal, and

extra-anatomic bypass for

symptomatic PAD

•Clinical indication to treat

symptomatic PAD with

peripheral revascularization

to restore limb perfusion

Exclusion criteria : Rutherford category 0, 1, & 6; endovascular revascularization of the aorto-iliac segment without any additional revascularization below the inguinal ligament; general criteria based on known rivaroxabancontraindication such as allergy, known bleeding diathesis, etc.

Rivaroxaban 2.5 mg bid + ASA 100 mg od

T0, Day 1

R

1 month post study

drugobservation

period

Treatment Phase

(mean treatment duration of 30 months,

maximum 42 month)

Placebo + ASA 100 mg od

post-procedural concomitant thienopyridines allowed for a maximum period of 30 days

1:1 randomization*

Revascularization procedure

(surgery or endovascular)

Screening Phase Wash-out,

Safety FU

*Onset of study drug treatment after revascularization procedure

N = 6500

Capell W, Bonaca MP, …Hiatt WR et al. AHJ in Press

BASIL 1: Mortality

Adam DJ et al. Lancet 2005; 366:1925-34.

At 5.5 years of follow up, overall mortality was 37%

Years of follow-up

Current outcomes highly significantly worse than BASIL-1 (p = 0.0001)

BASIL-1 (1999-2003)

HEFT (2009-2013)

D30

%

At 7 years of follow up, overall mortality was 67%

BASIL 1: Mortality

Yes, Real Potential to Change Outcomes

More Potent Antithrombotic Therapy:• Reduces MACE with clearest benefit in patients with polyvascular disease: PAD & CAD

• Reduces MALE and Amputation (greatest benefit after revascularization)

Achieving Very Low LDL-C (~30 mg/dL) • Reduces MACE

• Reduces MALE

• Safe

Has Medical Therapy for PAD Come of Age?

Conclusion• Most vascular surgeons have varying degrees of awareness of high impact

medical trials (CAPRIE, TIMI-50, TIMI-54, EUCLID, COMPASS, FOURIER) • From dim to less dim

• Highlights importance and value of collaboration between cardiology, vascular medicine and vascular surgery

• For patient care

• For future trials

• Diabetic patients will represent ever greater proportions of the patients with CLI

• Current PAD-associated MACE and MALE considerable

• New agents are costly, but can significantly reduce both MACE and MALE

• Better medical care, smoking cessation, and novel medical therapies will reduce adverse limb events following both endo and open revascularization