New England Journal of Medicine OCTOBER 17, 2019

Ticagrelor or Prasugrel in Patients with Acute Coronary Syndromes

Stefanie Schüpke, Franz-Josef Neumann, Massimiliano Menichelli, et al.

Bottom Line

In patients with acute coronary syndrome undergoing a planned invasive strategy, prasugrel was found to be superior to ticagrelor in reducing the composite endpoint of death, myocardial infarction, or stroke at one year without increasing the risk of major bleeding.

Key Findings

1. The primary endpoint (composite of death, myocardial infarction, or stroke) occurred in 6.9% of the prasugrel group compared to 9.3% in the ticagrelor group (hazard ratio, 1.36; 95% CI, 1.09 to 1.70; P=0.006).

2. The benefit for prasugrel was driven primarily by a lower rate of myocardial infarction (3.0% vs. 4.8%; hazard ratio, 1.63; 95% CI, 1.18 to 2.25).

3. Major bleeding (BARC types 3, 4, or 5) did not differ significantly between the groups (4.8% for prasugrel vs. 5.4% for ticagrelor; hazard ratio, 1.12; 95% CI, 0.83 to 1.51; P=0.46).

4. Rates of all-cause death (3.7% for prasugrel vs. 4.5% for ticagrelor) and stroke (1.0% vs. 1.1%) were not statistically different between the two arms.

Study Design

Design

RCT

Open-Label

Sample

4,018

Patients

Duration

1 yr

Median

Setting

Multicenter, Germany/Italy

Population Patients with acute coronary syndrome (STEMI, NSTEMI, or unstable angina) scheduled for an invasive strategy.

Intervention Prasugrel (60 mg loading dose, followed by 10 mg daily maintenance; 5 mg daily if ≥75 yr or <60 kg). In NSTE-ACS, loading was performed after coronary anatomy was known.

Comparator Ticagrelor (180 mg loading dose as soon as possible, followed by 90 mg twice daily maintenance).

Outcome Composite of death, myocardial infarction, or stroke at 1 year after randomization.

Study Limitations

• The trial was open-label, which introduces the potential for ascertainment bias, particularly in reporting non-fatal events.

• The study compared treatment strategies rather than just the drugs themselves, as the timing of the loading dose (pre-angiography for ticagrelor vs. post-angiography for prasugrel in NSTE-ACS) differed.

• A higher proportion of patients in the ticagrelor group discontinued the study drug by one year (15.2% vs. 12.5% in the prasugrel group), which may have confounded the results.

• The event rates in both arms were lower than initially assumed, which may have impacted the statistical power of the study.

Clinical Significance

The ISAR-REACT 5 trial challenged the prevailing practice of routine pre-treatment with ticagrelor in patients with acute coronary syndromes, suggesting that a strategy involving prasugrel with a deferred loading dose after coronary anatomy is known is both safer and more effective at reducing ischemic outcomes.

Historical Context

Prior to ISAR-REACT 5, prasugrel and ticagrelor had independently shown superiority over clopidogrel in the TRITON-TIMI 38 and PLATO trials, respectively. However, no direct head-to-head randomized comparison between the two potent P2Y12 inhibitors existed, leaving the choice of agent largely to physician preference and regional guidelines.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Prasugrel and ticagrelor both target the P2Y12 receptor on platelets. How do their mechanisms of action and pharmacokinetics differ, and why is this clinically relevant in the context of Acute Coronary Syndrome (ACS)?

Key Response

Prasugrel is a thienopyridine prodrug that irreversibly binds to the P2Y12 receptor, requiring a two-step hepatic metabolism process. Ticagrelor is a cyclopentyltriazolopyrimidine that binds reversibly and is direct-acting (does not require hepatic activation). These differences impact the speed of onset, duration of antiplatelet effect, and the potential for reversing the drug's effect before emergency surgery.

Resident

Despite the superiority of prasugrel over ticagrelor demonstrated in the ISAR-REACT 5 trial, what are the specific patient populations where prasugrel remains contraindicated or requires dose modification?

Key Response

Based on the TRITON-TIMI 38 trial data which informs current practice, prasugrel is contraindicated in patients with a history of stroke or TIA due to high risk of intracranial hemorrhage. Additionally, caution and dose reduction (5mg instead of 10mg) are recommended for patients weighing less than 60kg or those aged 75 years and older to mitigate bleeding risks.

Fellow

A major point of discussion in ISAR-REACT 5 is the 'pretreatment' strategy. Ticagrelor was administered as soon as possible after diagnosis, whereas prasugrel was delayed until coronary anatomy was known for NSTEMI patients. How does this study design impact our understanding of 'pretreatment' in ACS?

Key Response

The trial compared two different clinical strategies, not just two drugs. By delaying prasugrel until the time of PCI in NSTEMI, the investigators avoided the increased bleeding risk associated with pretreatment (as seen in the ACCOAST trial) while still achieving superior ischemic outcomes. This suggests that the pharmacological potency of the drug at the time of intervention may be more critical than the early initiation of therapy.

Attending

ISAR-REACT 5 challenged the 'ticagrelor-first' paradigm established by the PLATO trial. Given these findings, how should a health system justify the routine use of ticagrelor over prasugrel in an invasive ACS pathway, and what are the cost-effectiveness implications?

Key Response

Prasugrel is now available as a generic and demonstrated superior efficacy with no increase in major bleeding in ISAR-REACT 5. Transitioning to a 'prasugrel-first' strategy for patients intended for invasive management (who meet safety criteria) provides both better clinical outcomes and significant cost savings. Ticagrelor should likely be reserved for those with contraindications to prasugrel or those managed conservatively.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ISAR-REACT 5 trial used a PROBE (Prospective, Randomized, Open-label, Blinded-Endpoint) design. Critically evaluate how the open-label nature of this trial, specifically regarding treatment adherence and secondary event reporting, could have introduced bias in favor of one agent.

Key Response

Open-label trials are susceptible to performance bias. Differences in side-effect profiles (e.g., ticagrelor-induced dyspnea) could lead to higher discontinuation rates in one arm, which was observed in the ticagrelor group (15.2% vs 12.5%). This differential dropout can lead to an 'attrition bias' that may exaggerate the perceived efficacy of the more tolerable drug in an intention-to-treat analysis.

Journal Editor

As a peer reviewer, the 'trial-within-a-trial' nature of ISAR-REACT 5 (different loading protocols for NSTEMI vs STEMI) is a significant variable. Does this heterogeneity in drug administration timing weaken the study's internal validity, or does it enhance its external validity for real-world clinical practice?

Key Response

A tough reviewer would flag that the trial protocol 'stacked the deck' against ticagrelor by using a pretreatment strategy for it that had previously shown limited benefit, while using a more 'optimized' delayed strategy for prasugrel. However, the editorial significance lies in the fact that this design reflects the most common way these drugs are actually utilized in practice, thus providing high external validity despite the confounding of drug choice with drug timing.

Guideline Committee

The 2023 ESC Guidelines for the management of ACS now give a Class I recommendation for prasugrel over ticagrelor for patients undergoing PCI. How does the ISAR-REACT 5 evidence specifically support this preference, and what caveats must be included regarding patients managed without an invasive strategy?

Key Response

The guidelines shifted based on the primary endpoint superiority of prasugrel in ISAR-REACT 5 (HR 1.36 favoring prasugrel). However, the committee must specify that this recommendation is strictly for those with known coronary anatomy or a high likelihood of PCI. For patients managed medically (without PCI), ticagrelor or clopidogrel remain the preferred agents, as prasugrel has not demonstrated a net clinical benefit in non-invasive cohorts (TRILOGY-ACS).

Clinical Landscape

Noteworthy Related Trials

2001

CURE

n = 12,562 · NEJM

Tested

Clopidogrel

Population

Patients with acute coronary syndromes without ST-segment elevation

Comparator

Placebo

Endpoint

Composite of cardiovascular death, nonfatal myocardial infarction, or stroke

Key result: The addition of clopidogrel to aspirin therapy significantly reduced the rate of major cardiovascular events in patients with non-ST-elevation ACS.

2007

TRITON-TIMI 38

n = 13,608 · NEJM

Tested

Prasugrel

Population

Patients with acute coronary syndromes scheduled for PCI

Comparator

Clopidogrel

Endpoint

Composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke

Key result: Prasugrel significantly reduced the rate of ischemic events compared to clopidogrel but was associated with an increased risk of major bleeding.

2009

PLATO

n = 18,624 · NEJM

Tested

Ticagrelor

Population

Patients with acute coronary syndromes

Comparator

Clopidogrel

Endpoint

Composite of death from vascular causes, myocardial infarction, or stroke

Key result: Ticagrelor significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding.

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