Is there enough evidence for DAPT after endovascular intervention for PAOD?

Prof. I. Baumgartner

Head Clinical & Interventional Angiology University Hospital Bern

Disclosure

Speaker name:

.........I. Baumgartner..............................................................

I have the following potential conflicts of interest to report:

Consulting

Employment in industry

Stockholder of a healthcare company

Owner of a healthcare company

X Other(s)

- Member of Executive Committee: EUCLID trial

I do not have any potential conflict of interest

X

CAPRIEEfficacy of Clopidogrel vs. Aspirin for MI,

Ischemic Stroke, or Vascular Death

ASA=aspirin. Mean follow-up=1.91 years. *ITT analysis.CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.

8.7%* P=0.043Overall relative risk reduction

Months of follow-up

Cu

mu

lati

ve e

ven

t ra

te

(%)

0

4

8

12

16

0 3 6 9 12 15 18 21 24 27 30 33 36

ASA5.83%

5.32%Clopidogrel

N=19,185

0 10 20-10-20

Aspirinfavored

-30 30 40

Clopidogrelfavored

Stroke

MI

PAD

Allpatients

ClopidogreleffectinpatientswithPADdriveresults

Clopidogrel is superior to

aspirin in PAD and indicated

Patel MR et al. Eur J Prev Cardiol 2015;22:734–742

20.6%

18.0%

HR ticagrelor vs clopidogrel:0.846 (0.644, 1.111)

Pro

bab

ility

of

CV

dea

th /

MI /

str

oke

MACE endpoint

2.65% ARR!!!

0.00

0.05

0.10

0.15

0.20

0.25

0 3 6 9 12

Time since randomization (months)

TicagrelorClopidogrel

PLATOSubgroup with PAD at baseline

RCT to determine whether BRILINTA is superior to clopidogrel forprevention of vascular events and death in ACS

Positive signal for ticagrelor

vs clopidogrel in PAD

EUCLID Study Design

Primary Endpoint: cardiovascular death, myocardial infarction, or ischemic stroke

Inclusion criteria:Symptomatic PAD AND one of the following:A. ABI ≤0.80 at Visit 1 ≤0.85 at

Visit 2 OR

B. Prior lower extremity revascularization > 30 days

Key exclusion criteria: Poor metabolizer

for CYP2C19 Patients requiring

dual anti-platelet therapy

Patients with symptomatic PAD

Ticagrelor 90 mg bid

Clopidogrel 75 mg od

N=13,885

Duration: Event Driven Trial Approximately 14-month recruitment and 26-

month follow-up

1:1

Double-blind

Double-dummy

Primary Safety Endpoint: TIMI major bleeding

Primary Efficacy Endpoint (CV Death, MI, or Ischemic Stroke)

• Caution extrapolating evidence from CAD to PAD

– individual studies in PAD patients are needed

Is more intensive antiplatelet therapy more effective and safe over time after revascularization

EUCLIDPrior Lower Limb Revascularization (> 30 d)

Subgroup Analysis

Efficacy OutcomesPatients with Prior Revascularization According to Treatment Group

Ticagrelor

(N=3923)

Clopidogrel

(N=3952)

HR

(95% CI)

P

Value

Primary outcome:

CV death, MI, or ischemic stroke, no. (%)447 (11.4) 447 (11.3) 1.01 (0.88–1.15) 0.898

CV death, no. (%) 190 (4.8) 182 (4.6) 1.05 (0.86–1.29) 0.634

MI, no. (%) 237 (6.0) 229 (5.8) 1.05 (0.87–1.25) 0.629

Ischemic stroke, no. (%) 76 (1.9) 100 (2.5) 0.76 (0.57–1.03) 0.078

Key secondary efficacy outcome:

CV death, MI, ischemic stroke plus ALI

requiring hospitalization, no. (%)

522 (13.3) 529 (13.4) 1.00 (0.88–1.12) 0.947

ALI indicates acute limb ischemia; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. Median f-u approximally 30 months

Ticagrelor

(N=3923)

Clopidogrel

(N=3952)

HR

(95% CI)

P

Value

Composite of CV death, MI, all-cause

stroke (ischemic or hemorrhagic), no. (%)456 (11.6) 461 (11.7) 1.00 (0.88–1.14) 0.970

Hospitalization for ALI, no. (%) 99 (2.5) 97 (2.5) 1.03 (0.78–1.36) 0.835

Lower extremity revascularization, no. (%) 654 (16.7) 680 (17.2) 0.97 (0.87–1.07) 0.519

Composite of all revascularizations

(coronary and peripheral [limb, mesenteric, renal,

carotid, or other]), no. (%)

906 (23.1) 914 (23.1) 1.00 (0.91–1.09) 0.929

Efficacy OutcomesPatients with Prior Revascularization According to Treatment Group

ALI indicates acute limb ischemia; CI, confidence interval; CV, cardiovascular; HR, hazard ratio; MI, myocardial infarction. Median f-u approximally 30 months

CHARISMAEffect of clopidogrel/ASA vs ASA on MI,

stroke or CV death

Bhatt DL et al. N Engl J Med 2006;354:1706

Placebo + ASA7.3%

Clopidogrel + ASA6.8%

RRR 7.1% (95% CI -4.5, 17.5)P=0.22

Months since randomization

0

2

4

6

8

0 6 12 18 24 30

Cumulative event rate* (%)

First occurrence of MI (fatal / non-fatal),stroke (fatal / non-fatal) or CV death

CHARISMAPrimary efficacy results (MI/stroke/CV death)

by category of inclusion

AT, atherothrombosis*First occurrence of MI, stroke (of any cause) or CV death

Bhatt DL. Presented at ACC 2006

Population N RR (95% CI) P value

Documented AT 12,153 0.88 (0.77, 0.998) 0.046

Coronary 5835 0.86 (0.71, 1.05) 0.13

Cerebrovascular 4320 0.84 (0.69, 1.03) 0.09

PAD 2838 0.87 (0.67, 1.13) 0.29

Multiple risk factors 3284 1.20 (0.91, 1.59) 0.20

Overall population 15,603 0.93 (0.83, 1.05) 0.22

0.6 0.8 1.41.2

Clopidogrel better Placebo better

1.60.4

Dual anti-platelet therapy with Clopidogrel/ASA not better than

Placebo/ASA

LOE Recommendation

Symptomatic patients

IAAntiplatelet therapy is recommended to reduce the risk of MI, stroke and vascular death in individuals with symptomatic atherosclerotic lower extremity PAD*

IBASA (75–325 mg) is recommended in individuals with symptomatic atherosclerotic lower extremity PAD*

IBClopidogrel (75 mg QD) is recommended in individuals with symptomatic atherosclerotic lower extremity PAD*

IIbBASA in combination with clopidogrel may be considered in patients who are not at increased risk of bleeding and who are at high perceived CV risk

Asymptomatic patients

IIaCAntiplatelet therapy can be useful to reduce the risk of MI, stroke or vascular death in asymptomatic individuals with an ABI ≤0.90

ACCF/AHA Guidelines

LOE Recommendation

Symptomatic patients

ICAntiplatelet therapy is recommended in patients with symptomatic PAD*

Antiplatelet therapy after revascularization

ICAntiplatelet therapy with aspirin is recommended in all patients with angioplasty for LEAD to reduce the risk of systemic vascular events

IADual antiplatelet therapy with aspirin and a thienopyridine for at least one month is recommended after infrainguinal bare metal-stent implantation

IIbBAntiplatelet treatment with aspirin or a combination of aspirin and dipyridamole is recommended after infrainguinal bypass surgery

IIbBDual antiplatelet therapy combining aspirin and clopidogrel may be considered in the case of below-knee bypass with a prosthetic graft

Antiplatelet therapy in PAD with CAD

IIaBIn PAD with stable CAD, clopidogrel should be considered as an alternative to aspirin for long-term antiplatelet therapy

ESC guidelines

OAP treatment variable & often associated with LER rather than CV risk

• Guidelines are not specific in recommendation for ASA v clopidogrel vs DAPT; do not reflect the evidence and are inconsistent between region

• Clopidogrel initiation is strongly correlated to endovascular intervention

Clopidogrel use in PAD patients undergoing LER (RW data)

LER

Clopidogrel Clopidogrel DAPT

LERLER

Efficacy & Safety of AP for Prevention ofMACE and Leg Amputations in PAD

Systematic Review and Network Meta- Analysis (49 RCT)

PLOS ONE 10 (8),1-19,2015

Ben

efit

(MA

CE)

-h

arm

(ble

edin

g) p

rofi

l

Surgical endovascular revascularization

• 3 RCT (of 49 RCT analysed)• 3.527 patients• > 8.000 person-years of follow up

short-term DAPT reduces majoramputations after revascularization

PLOS ONE | DOI:10.1371/journal.pone.0135692 August 14, 2015

Efficacy of Different Antiplatelet Agentsfor Prevention Leg Amputations

number of major amputations avoided greater than number of severe bleedings32% reduction of event rates compared to aspirin monotherapy; NNT = 94

3 RCTs with 3,527 patients including surgical and endovascular revascularizations

Clopidogrel should be the indicated antiplateletagent in PAD

DAPT with aspirin & clopidogrel can reduce rate of major leg amputations followingrevascularization, but carries a slightly higherrisk of severe bleeding

Conclusion

Is there enough evidence for DAPT after endovascular intervention for PAOD?

Prof. I. Baumgartner

Head Clinical & Interventional Angiology University Hospital Bern