ISAR-REACT 5: Ticagrelor vs prasugrel in ACS

Schupke S, et al. Ticagrelor or prasugrel in patients with acute coronary syndromes. NEJM 2019

Bottom line: In patients with ACS planned for invasive management (90% treated with new-gen drug-eluting stent), prasugrel reduced death/MI/stroke versus ticagrelor (NNT=42) at 1 year, which was driven by fewer MIs.

Patients (n=4018 randomized)

  • Enrolled from 21 centres in Germany & 2 centres in Italy

  • Included if:

    • Hospitalized for ACS (STEMI, NSTEMI or unstable angina)

    • Planned invasive strategy (i.e. scheduled for coronary angiogram)

  • Key exclusion criteria:

    • Hx of any stroke, TIA or intracranial hemorrhage

    • Intracranial abnormality at risk of bleeding

    • Lysis <24h before randomization

    • Ticagrelor or prasugrel <5 days before randomization

  • Average baseline characteristics

    • Age 65 y, female 24%

    • Diagnosis @ admission: STEMI 41%, NSTEMI 46%, UA 13%

    • Final diagnosis of ACS at discharge 91%

    • Index ACS managed with: PCI 84% (90% of which were drug-eluting stents), CABG 2%, medical management only 14%

    • Prior MI 16%, prior PCI 23%, prior CABG 6%

    • Cardiac risk factors: HTN 70%, diabetes 22%, dyslipidemia 58%

    • BMI 28, wt <60 kg 5%

Interventions: Ticagrelor ASAP vs Prasugrel x1 year

  • Ticagrelor: Loading dose of 180 mg x1 ASAP after randomization (i.e. pre-loading before coronary angiogram), then 90 mg PO BID

  • Prasugrel: Loading dose of 60 mg x1, then 10 mg once daily

    • If STEMI: Loading dose given ASAP after randomization

    • If NSTEMI/UA: Loading dose given after coronary angiogram

    • Lower maintenance dose of 5 mg daily given if age age 75+ or weight <60 kg

  • ~20% in both groups were not discharged on their assigned study P2Y12i (most because they were not confirmed to have obstructive CAD on angiography, had indication for oral anticoagulant, or underwent CABG)

  • Note: Patients did not get the medication for free as part of the trial; they had to obtain it as they otherwise would need to do in standard practice

Outcomes @ 1 year

  • Primary outcome (composite of all-cause death, MI, stroke): Ticagrelor 9.3% vs prasugrel 6.9%

    • Hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.09-1.70

    • NNT (using prasugrel instead of ticagrelor)=42 @ 1 year

  • Secondary outcomes

    • Death: 4.5% vs 3.7% (HR 1.23, 95% CI 0.91-1.68)

    • CV death: 3.2% vs 3.0%

    • MI: 4.8% vs 3.0% (HR 1.63, 1.18-2.25), NNT=56 in favor of prasugrel

    • Definite/probable stent thrombosis: 1.3% vs 1.0%

    • Stroke: 1.1% vs 1.0%

    • Major bleed (BARC 3, 4 or 5): 5.4% vs 4.8% (HR 1.12, 0.83-1.51)

  • Discontinued study intervention: Ticagrelor 15.2% vs prasugrel 12.5%

    • Median time to D/C: 84 vs 109 days

Risk of bias: Overall some concern

  • Some concerns re: bias arising from the randomization process (allocation bias)

    • Computer-generated random sequence

    • Allocation concealment only by sealed, opaque envelopes (no details on storage location, sequential numbering or assignment); prone to tampering & less robust than other methods

  • Some concerns re: bias due to deviations from intended interventions

    • Open-label design

    • Higher & earlier discontinuation of study drug in ticagrelor group, though no other evidence of differences in management between groups

    • Predicted direction of bias in favor of prasugrel for the primary efficacy outcome

  • Low risk of bias due to missing outcome data (attrition bias)

    • Low loss-to-follow-up: <1% in both groups

    • Analyzed the intention-to-treat population

  • Low risk of bias in measurement of the outcome (detection bias)

    • Open-label design; however objective outcome definition (especially for MI, the driver of the difference between ticagrelor & prasugrel), & outcomes adjudicators not aware of assigned intervention

  • Low risk of bias in selection of the reported result (outcome reporting bias)

Other considerations

  • The findings of this trial conflict with results of prior trials of prasugrel & ticagrelor:

    • The results of the primary outcome of ISAR-REACT 5 expressed as prasugrel vs ticagrelor are 6.9% vs 9.3%, HR 0.74 (0.59-0.92)

    • In the PLATO trial comparing ticagrelor to clopidogrel in ACS patients managed medically or with PCI, ticagrelor reduced death/MI/stroke vs clopidogrel.

      • 10.2% vs 12.3%, HR 0.84 (0.77-0.92)

      • Notably, ticagrelor also reduced death vs clopidogrel (HR 0.78)

    • Similarly, in the TRITON-TIMI 38 trial comparing prasugrel to clopidogrel in ACS patients managed almost exclusively with PCI, prasugrel reduced death/MI/stroke vs clopidogrel @ 15 months

      • 10.7% vs 12.7%, HR 0.83 (0.75-0.92)

      • Prasugrel did not reduce death vs clopidogrel (HR 0.96)

    • Conversely, in TRILOGY, in which only medically-managed ACS patients were randomized, prasugrel did not reduce CV death/MI/stroke vs clopidogrel, HR 0.96 (0.86-1.07)

    • Note: The previous PRAGUE-18 trial (n=1230) that also compared prasugrel to ticagrelor was severely underpowered & inconclusive.

  • In terms of pharmacodynamics, ticagrelor inhibits platelet function at least as well as prasugrel, irrespective of assay technique (e.g. Rollini et al., SWAP-2, SWAP-3).

  • Adherence to the P2Y12 inhibitor was apparently assessed (as briefly described in the protocol), but not reported in sufficient detail in this article. Of patients who discontinued the study P2Y12 inhibitor, those in the ticagrelor discontinued approximately 1 month earlier than prasugrel, which may explain at least in part the early higher MI rate with ticagrelor vs prasugrel.

  • Overall, it’s unclear how much the findings of this trial are attributable to:

    • A yet-unidentified pharmacodynamic benefit of prasugrel;

    • Lower adherence to ticagrelor due to BID dosing;

    • Greater & earlier discontinuation of ticagrelor due to dyspnea.

  • Arguably, it’s also unclear how the efficacy of prasugrel compares to clopidogrel in the era of modern drug-eluting stents with incredibly low rates of stent thrombosis, and in this emerging era of complete revascularization.