EUCLID (Ticagrelor)

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Hiatt WR et al. "Ticagrelor versus clopidogrel in symptomatic peripheral artery disease". New Engl J Med. 2017. 376(1):32-40.
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Clinical Question

In patients with symptomatic peripheral arterial disease (PAD), is the antiplatelet ticagrelor superior to clopidogrel with regards to prevention of cardiovascular death, MI, or ischemic stroke?

Bottom Line

In patients with symptomatic PAD, ticagrelor is not superior to clopidogrel with regard to the primary outcome of cardiovascular death, MI, or ischemic stroke. The rate of the primary outcome was very similar with either agent (10.6% with ticagrelor and 10.8% with clopidogrel) at median follow-up 30 months. The rate of major bleeding was 1.6% in each group.

Major Points

PAD, or symptomatic ischemia of the extremities due to poor arterial flow secondary to atherosclerotic plaque, is considered a manifestation of systemic atherosclerosis. As a result, these patients are at high risk for other sequelae of atherosclerosis including MI, ischemic stroke, and cardiovascular death. Given this elevated risk, it stands to reason that patients with PAD (like patients with CAD or cerebral atherosclerosis) would benefit from systemic antiplatelet therapy. This benefit was suggested in the CAPRIE trial, in which the administration of clopidogrel in patients with atherosclerosis reduced cardiovascular events when compared to aspirin (particularly in the PAD subgroup). The subsequent MATCH and CHARISMA trials assessed the utility of dual antiplatelet therapy with clopidogrel and aspirin in patients with symptomatic atherosclerosis (including PAD), and demonstrated no improvement over clopidogrel alone with excess bleeding. More recently, the PLATO trial investigating the newer P2Y12 inhibitor, ticagrelor, demonstrated superior thrombotic protection (including mortality benefit) over clopidogrel in patients presenting with acute coronary syndrome (ACS). Furthermore, an analysis of the PAD subgroup in the PEGASUS-TIMI-54 trial suggested a greater benefit with ticagrelor over clopidogrel in this population given high baseline risk of CV events. Prior to EUCLID, however, a rigorous investigation of the benefit of ticagrelor in PAD patients had yet to be done.

The 2017 Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial investigated the efficacy of ticagrelor, when compared to clopidogrel, in the reduction of cardiovascular death, MI, or ischemic stroke in patients with symptomatic PAD. In EUCLID, 13,885 patients were randomized to ticagrelor or clopidogrel. At median follow-up 30 months, the rate of the primary outcome was very similar in both groups (10.6% with ticagrelor and 10.8% with clopidogrel). In secondary endpoint analyses, the only between-group difference was a 0.5% absolute risk reduction in ischemic stroke with ticagrelor. Interestingly, in subgroup analyses, patients with a history of coronary or carotid revascularization as well as patients with a history of coronary stenting appeared to derive greater benefit from ticagrelor, although this finding requires prospective validation. The rate of major bleeding was 1.6% in each group, although 5% of patients discontinued ticagrelor for the known side effect of dyspnea.

Ultimately, EUCLID provides further evidence that ticagrelor is not clearly superior to clopidogrel outside of the ACS or stable CAD populations, with similar overall efficacy with regards to CV events in patients with PAD. Nevertheless, the modest reduction in ischemic strokes with ticagrelor is similar to that observed in the SOCRATES trial and does provide further evidence that ticagrelor may provide slightly improved ischemic stroke protection than clopidogrel, although this effect requires further study.

Guidelines

As of January 2017, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, double-blind, active-comparator randomized controlled trial
  • N=13,885
    • Ticagrelor (n=6930)
    • Clopidogrel (n=6955)
  • Setting: 811 sites in 28 countries
  • Enrollment: December 2012 to March 2014
  • Median follow-up: 30 months
  • Analysis: Intention-to-treat
  • Primary outcome: MI, ischemic stroke, or cardiovascular death

Population

Inclusion Criteria

  • 50 years of age or older
  • Symptomatic peripheral arterial disease defined as one of either:
    • Previous revascularization of the lower limbs for symptomatic disease more than 30 days before randomization
    • Hemodynamic evidence of PAD (ABI 0.80 or less, TBI 0.60 or less if ABI ≥ 1.40)

Exclusion Criteria

  • Current or planned use of dual antiplatelet therapy or aspirin
  • Increased bleeding risk
  • Treatment with long-term anticoagulation
  • Poor clopidogrel metabolizer status for the CYP 2C19 allele

Baseline Characteristics

From the ticagrelor arm

  • Demographics: Age 66, female 27.5%, weight 76kg
  • PAD: Previous revascularization 56.6%, ABI 0.63, TBI 0.49, mild-moderate claudication 53.0%, severe claudication 23.4%, rest pain 2.7%, major amputation above ankle 2.3%
  • Medical: Stroke 8.3%, TIA 4.0%, CAD 29.1%, MI 17.9%, DM2 38.1%, HTN 78.5%, HLD 75.5%, Tobacco 30.7%
  • Medications: ASA 67.3%, clopidogrel 31.6%, statin 73.0%, ACEi 40.8%, ARB 25.1%

Interventions

  • 1:1 double-blind randomization to ticagrelor or clopidogrel
  • Secondary endpoints were tested in a hierarchical fashion beginning with the primary endpoint plus acute limb ischemia leading to hospitalization
  • The primary safety endpoint was major bleeding, according to TIMI criteria

Outcomes

Comparisons are ticagrelor versus clopidogrel.

Primary Outcomes

Cardiovascular death, myocardial infarction, or ischemic stroke
751/6930 (10.8%) vs. 740/6955 (10.6%) [HR 1.02; 95% CI 0.92-1.13; P=0.65]

Secondary Outcomes

Cardiovascular death
363/6930 (5.2%) vs. 343/6955 (4.9%) [HR 1.07; 95% CI 0.92-1.23; P=0.40]
Myocardial infarction
349/6930 (5.0%) vs. 334/6955 (4.8%) [HR 1.06; 95% CI 0.91-1.23; P=0.48]
Ischemic stroke
131/6930 (1.9%) vs. 169/6955 (2.4%) [HR 0.78; 95% CI 0.62-0.98; P=0.03]
All-cause mortality
628/6930 (9.1%) vs. 635/6955 (9.1%) [HR 0.99; 95% CI 0.89-1.11; P=0.91]

Subgroup Analysis

History of coronary or carotid revascularization (interaction p = 0.03)
Yes
15.5% vs. 18.3% [HR 0.88; 95% CI 0.75-1.04]
No
11.3% vs. 10.2% [HR 1.11; 95% CI 0.98-1.26]
History of coronary stent implantation (interaction p = 0.03)
Yes
15.4 vs. 20.3% [HR 0.82; 95% CI 0.65-1.03]
No
12.0% vs. 11.2% [HR 1.08; 95% CI 0.96-1.21]

Adverse Events

TIMI major bleeding
113/6930 (1.6%) vs. 109/6955 (1.6%) [HR 1.10; 95% CI 0.84-1.43; P=0.49]
Dyspnea
330/6930 (4.8%) vs. 52/6955 (0.8%) [P<0.001]

Criticisms

  • Due to a lower event rate than predicted, target sample size was increased to 13,000 and power was reduced to 85%. As a result, a smaller benefit to ticagrelor over clopidogrel cannot be fully ruled out.
  • In order to reduce trial complexity and facilitate blinding, patients were not allowed to receive aspirin. Thus, the comparative efficacy of either clopidogrel or ticagrelor compared to aspirin cannot be assessed.

Funding

  • Study supported by AstraZeneca.
  • Trial was designed by an independent executive committee that included members from the study sponsor.

Further Reading