ISAR-REACT 5

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Schupke S et al. "Ticagrelor or prasugrel in patients with acute coronary syndromes". New Engl J Med. 2019. (epub doi 10.1056/NEJMoa1908973):1-11.
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Clinical Question

In patients with acute coronary syndrome (ACS), for whom an invasive evaluation is planned, is antiplatelet therapy with ticagrelor superior to prasugrel with regard to a primary outcome of death, nonfatal MI, or stroke?

Bottom Line

In patients with acute coronary syndrome (ACS), for whom an invasive evaluation is planned, prasugrel was associated with a 2.4% absolute reduction in the primary outcome of death, nonfatal MI, and stroke, driven primarily by reduction in nonfatal myocardial infarction (although there was also numerically lower all-cause mortality). Stent thrombosis was rare in both groups, but numerically lower with prasugrel. Major bleeding rates were similar in both groups.

Major Points

Platelet inhibition using P2Y12 inhibitors (in addition to aspirin) is a cornerstone of contemporary therapy for acute coronary syndromes (ACS). The P2Y12 inhibitors most commonly utilized for patients presenting with ACS include clopidogrel, ticagrelor, and prasugrel. Of the three, clopidogrel is the least potent agent, with recent randomized trials suggesting that ticagrelor (see PLATO) and prasugrel (see TRITON-TIMI 38) are associated with significant decreases in adverse thrombotic outcomes including cardiovascular death. Whether ticagrelor or prasugrel is preferred over the other with regard to thrombotic and bleeding risk, however, remained unclear.

The 2019 Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5 (ISAR-REACT 5) trial randomized 4018 patients with ACS for whom invasive treatment was planned to receipt of ticagrelor versus prasugrel and assessed for a primary outcome of death, nonfatal MI, or stroke. At 1 year, prasugrel was associated with a 2.4% absolute reduction in the primary outcome, driven primarily by reduction in nonfatal myocardial infarction (although there was also numerically lower all-cause mortality). Definite stent thrombosis was lower with prasugrel as well, although the difference was not statistically significant in the setting of very low rates (0.6% with prasugrel, 1.1% with ticagrelor). Major bleeding was also numerically lower with prasugrel (4.8% versus 5.4%), but again this difference was not statistically significant.

The ISAR-REACT 5 trial is the first trial to provide strong evidence that prasugrel may be superior to ticagrelor with respect to reducing thrombotic outcomes without a clear tradeoff signal for increased bleeding. Although the mechanism of improved outcomes with prasugrel requires further investigation, it has been proposed that once daily dosing with prasugrel (as opposed to twice daily dosing with ticagrelor) may underlie much of the benefit. This is consistent with a slightly higher rate of drug discontinuation prior to 12 months in the ticagrelor group (15%) versus the prasugrel group (12%).

Notably, >80% of individuals in the trial underwent PCI. As a result, the degree to which study findings can be extended to those undergoing primary medical therapy is limited.

Guidelines

As of September 2019, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, randomized, open-label, trial
  • N=4018
    • Ticagrelor (n=2012)
    • Prasugrel (n=2006)
  • Setting: 23 centers in Germany and Italy
  • Period: September 2013 - February 2018
  • Analysis: Intention-to-treat
  • Duration of follow-up: 1 year
  • Primary outcome: Death, nonfatal MI, or stroke

Population

Inclusion Criteria

  • Hospitalization for ACS with planned invasive strategy
  • Age ≥ 18 years

Exclusion Criteria

  • Intolerance or allergy to study drug
  • History of stroke, TIA, or intracranial bleeding
  • Known intracranial neoplasm, intracranial AV malformation, or intracranial aneurysm
  • Active bleeding or clinical findings associated with increased risk of bleeding
  • Fibrin-specific fibrinolytic exposure < 24 hours before randomization or non-fibrin-specific fibrinolytic exposure < 48 hours before randomization
  • Known platelet count < 100,000uL, hgb < 10 g/dL, or INR > 1.5
  • Oral anticoagulant that cannot be discontinued for the duration of the study
  • Chronic kidney disease requiring dialysis
  • Moderate to severe liver dysfunction (CTP class B or C)
  • Increased risk of bradycardia events
  • Index event is an acute (< 30 days) complication of PCI
  • Life expectancy < 1 year
  • Concomitant oral or IV therapy with strong CYP3A inhibitors, CYP3A substrates with narrow therapeutic indices, or strong CYP3A inducers
  • ≥ dose of prasugrel or ticagrelor with 5 days prior to randomization

Baseline Characteristics

From the ticagrelor group.

  • Demographics: Age 64.5 years, female 23.8%
  • Comorbidities: diabetes 23.0%, smoker 34.1%, HTN 71.3%, HLD 58.7%, BMI 27.8
  • Coronary disease: past MI 15.5%, past PCI 22.5%, past CABG 5.7%
  • Presenting ACS: UA 12.4%, NSTEMI 46.2%, STEMI 41.4%, treatment with PCI 83.4%, treatment with CABG 2.3%, treatment with conservative therapies 14.2%

Interventions

  • Patients who met all inclusion criteria and no exclusion criteria were randomized 1:1 to receive prasugrel or ticagrelor
  • Patients were stratified according to clinical trial site and clinical presentation (i.e., ACS with or without STEMI)
  • Randomly permuted block sizes were used in each stratum
  • Ticagrelor dosing
    • Loaded at 180MG and maintained at 90MG twice daily
    • Load administered as soon as possible after randomization
  • Prasugrel dosing
    • Loaded at 60MG and maintained at 10MG daily
    • A reduced maintenance dose of 5MG daily was recommended in patients ≥ 75 years old and in those with body weight < 60kg
    • STEMI patients loaded with prasugrel as soon as possible after randomization. NSTEACS patients were loaded after coronary angiography (but before PCI if PCI was planned).
  • Clinical follow-up scheduled at 30 days, 6 months, and 12 months
  • All serious adverse events and primary and secondary endpoint events were monitored on-site
  • All analyses performed as intention-to-treat except for the safety end point which was analyzed as modified intention-to-treat (all patients who received at least one dose of assigned trial drug and were assessed for bleeding events up to 7 days after discontinuation of the trial drug)

Outcomes

Comparisons are ticagrelor versus prasugrel

Primary Outcome

Death, nonfatal MI, or stroke
184 (9.3%) vs. 137 (6.3%) [HR 1.36; 95% CI 1.09-1.70; P<0.01]

Secondary Outcomes

Death
90 (4.5%) vs. 73 (3.7%) [HR 1.23; 95% CI 0.91-1.68]
Myocardial infarction
90 (4.8%) vs. 60 (3.0%) [HR 1.63; 95% CI 1.18-2.25]
Stroke
22 (1.1%) vs. 19 (1.0%) [HR 1.17; 95% CI 0.63-2.15]
Definite stent thrombosis
22 (1.1%) vs. 12 (0.6%)

Subgroup Analysis (primary outcome)

Diabetes
51 (11.2%) vs. 55 (13.0%) [HR 0.84; 95% CI 0.58-1.24]
No diabetes
132 (8.6%) vs. 81 (5.2%) [HR 1.70; 95% CI 1.29-2.24]
  • Remainder of subgroup analyses (including those stratified by type of ACS and treatment strategy) revealed no compelling evidence of a treatment by subgroup interaction.

Adverse Events

BARC major bleeding
95 (5.4%) vs. 80 (4.8%) [HR 1.12; 95% CI 0.83-1.51, p=0.46]

Criticisms

  • Open-label design allows for potential bias in ascertainment of outcomes, although this is mitigated somewhat by blinded outcomes adjudication
  • There was a slight asymmetry in the proportion of individuals who stopped assigned therapy (15% in ticagrelor group, 12% in prasugrel group), which may be overestimated the benefit of prasugrel
  • Greater than 80% of individuals underwent PCI, limiting ability to extend findings reliably to those undergoing medical therapy for ACS

Funding

  • Authors with multiple ties to industry

Further Reading