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.

AUGUSTUS - Antithrombotic regimens including apixaban vs warfarin, & aspirin vs placebo, in patients with AFib plus PCI &/or ACS

Reference: Lopes RD, et al. Antithrombotic therapy after acute coronary syndrome or PCI in atrial fibrillation. NEJM 2019.

Bottom line: In patients with atrial fibrillation who either undergo PCI and/or have ACS, in combination with a P2Y12 inhibitor (almost always clopidogrel):

  • Apixaban reduces the risk of major or clinically-relevant non-major bleeding (NNT=24), hospitalizations (NNT=27), & stroke (NNT=84) compared to warfarin at 6 months;

  • Aspirin (beyond the first week) increases the risk major or clinically-relevant non-major bleeding (NNH=15), without a clear effect on hospitalization/death or ischemic events compared to placebo at 6 months;

  • Therefore, an antithrombotic regimen of apixaban + clopidogrel (without aspirin) should be routinely considered in these patients. Warfarin should be limited to patients for whom a DOAC is contraindicated, intolerable or unaffordable; & aspirin beyond the first week should be limited to patients with very high risk of stent thrombosis/recurrent coronary events.

Patients (n=4614 from 33 countries)

  • Included if (all of the following):

    • Age 18+ years

    • Known AF (paroxysmal, persistent or permanent) with planned long-term oral anticoagulation

    • Recent (<14 days) ACS &/or PCI with plan for 6+ months of P2Y12 inhibitor

  • Key exclusion criteria:

    • Other indication for anticoagulation (prosthetic valve, VTE, mitral stenosis, etc)

    • History of intracranial hemorrhage, ongoing bleeding or coagulopathy

    • Recent/planned CABG

    • “Severe” renal insufficiency

  • Average baseline characteristics:

    • Age 71 years, male (71%), white (92%)

    • Qualifying event: ACS+PCI (37%), medically-managed ACS (24%), elective PCI (39%)

      • ~6.6 days from ACS/PCI to randomization

    • CHA2DS2-VASc ~4, HAS-BLED ~3

    • Prior stroke/TIA/thromboembolism (14%), HF (43%), HTN (88%), diabetes (36%)

    • SCr >133 (8%)

    • Previous oral anticoagulant (49%)

Interventions x6 months

  • 2x2 factorial design: Patients were simultaneously randomized to apixaban vs warfarin & aspirin vs placebo within 14 days of ACS &/or PCI, so total of 4 different intervention groups.

  • Management prior to randomization: At the discretion of treating physicians according to local standard of care (likely that all at least received DAPT +/- anticoagulation leading up to randomization, though not recorded/reported)

  • Anticoagulation: Apixaban vs warfarin

    • Apixaban arm: 5 mg PO BID

      • Reduced to 2.5 mg PO BID if 2 of the following: Age >80 years, wt <60 kg, SCr >133 umol/L

      • Discontinued study regimen prematurely: 13%

    • Warfarin to target INR 2.0-3.0

      • Median time in therapeutic range (TTR)=59%; INR<2.0 23% of the time, INR>3.0 3% of the time

      • Discontinued study regimen prematurely: 14%

  • Antiplatelet: Aspirin 81 mg PO daily vs matching placebo

    • Discontinued study drug prematurely: 15-17%

  • All: P2Y12 inhibitor left at the discretion of the treating clinicians (clopidogrel 93%, prasugrel 1%, ticagrelor 6%)

  • After 6 months, anticoagulation & antiplatelets were managed according to local standard of care (i.e. not standardized for the trial)

Results @ 6 months

  • Primary outcome: Major or clinically-relevant non-major bleeding, ISTH definition

  • Key secondary outcomes: Composite of death or hospitalization; composite of death or ischemic events (stroke, MI, definite/probable stent thrombosis, or urgent revascularization).

Outcomes at 6 months of apixaban versus warfarin in combination with P2Y12 inhibitor +/- aspirin

Outcomes at 6 months of aspirin versus placebo in combination with P2Y12 inhibitor + apixaban or warfarin

Risk of bias

  • Low risk of: Allocation bias (allocation concealed via interactive voice-response system), attrition bias (low [0.3%] loss to follow-up & analyzed by intention-to-treat), outcome reporting bias (all outcomes of interest defined & reported).

  • Variable risk of performance/detection bias:

    • Apixaban vs warfarin comparison was open-label (i.e. patients & clinicians aware of treatment assignment):

      • All outcomes were adjudicated by a blinded clinical endpoint committee, therefore providing some protection against (but not eliminating) detection bias.

    • Aspirin vs placebo comparison was blinded (patients, clinicians, outcome adjudicators unaware of treatment assignment): Low risk of performance & detection bias.

ODYSSEY OUTCOMES - Alirocumab added to max-tolerated statins after ACS

Bottom line: In patients with ACS in the past 12 months & LDL-C >1.8 mmol/L on max-tolerated statin therapy, alirocumab reduced the risk of major adverse cardiovascular events (composite of death/MI/stroke) by 1.6% (NNT 63), versus placebo over 2.8 years. Alirocumab increased local injection-site reactions compared to placebo (NNH 59).

Context: FOURIER trial and prior evidence

Patients (n=18,924)

  • 1315 sites in 57 countries (15% from Canada/US), enrolling from Nov 2012 to Nov 2015

  • Included

    • 40+ y/o

    • Hospitalized for ACS 1-2 months ago

    • LDL-C 1.8+ mmol/L, non-HDL-C 2.6+ mmol/L, or ApoB 0.80+ g/L after 2+ weeks on stable high-intensity statin (atorvastatin 40-80 mg/d, rosuvastatin 20-40 mg/d), or max-tolerated statin (including no statin if documented intolerance)

  • Excluded

    • Uncontrolled HTN (>180/110 mm Hg)

    • HF with NYHA functional class 3-4

    • Hx hemorrhagic stroke

    • Fasting triglycerides >4.5 mmol/L

    • ALT/AST >3x ULN

  • Baseline characteristics

    • Age 59 y, female (25%), white (79%)

    • Randomized median 2.6 months (IQR 1.7-4.3) after ACS

    • Index ACS: STEMI (35%), NSTEMI (48%), UA (17%)

    • Prior MI (19%), PCI (17%), stroke (3%), HF (15%)

    • Smoker (24%), HTN (65%), DM (29%), FHx premature CAD (36%)

    • Labs: LDL-C 2.4 mmol/L, HDL-C 1.2, non-HDL-C 3.2, apoB 0.8 g/L, Lp(a) 40 mg/dL

    • Meds: Statin (97.5%; high-intensity 89%), ezetimibe (3%)

      • Antiplatelet (99%), ACEI/ARB (78%), beta-blocker (85%)

Intervention & control

  • I: Alirocumab 75 mg subcut every 2 weeks

    • Uptitrated to 150 mg every 2 weeks to target an LDL-C 0.65-1.3 mmol/L, or switch to placebo if <0.4 mmol/L

  • C: Matching placebo

Results @ median 2.8 years

Efficacy

  • 1o outcome (CHD death, non-fatal MI, fatal or non-fatal ischemic stroke, UA hospitalization): Alirocumab 9.5% vs placebo 11.1% (NNT=63, or NNT=~175/year)

    • Hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.78-0.93

    • No significant difference in efficacy between pre-defined subgroups

    • Non-fatal MI: 6.6% vs 7.6% (HR 0.86, 95% CI 0.77-0.96)

    • Non-fatal ischemic stroke: 1.2% vs 1.6% (HR 0.73, 0.57-0.93)

    • UA hospitalization: 0.4% vs 0.6% (HR 0.61, 0.41-0.92)

  • Composite of all-cause death, MI, stroke: 10.3% vs 11.9% (HR 0.86, 95% CI 0.79-0.93)

  • All-cause death: 3.5% vs 4.1% (HR 0.85, 95% CI 0.73-0.98)

    • Note: To minimize type 1 error in the secondary outcomes, the investigators performed hierarchical testing, which means they tested for statistical significance of several outcomes in a pre-defined sequence, and stopped testing once they reach an outcome that was not statistically significantly different. The difference between groups for CHD death was not different, & the hierarchical testing therefore stopped before all-cause death.

    • Regardless, the mortality findings are not statistically robust with a fragility index of only 6, & do not correspond with a reduction in CV death. For comparison to statin data, the fragility index for mortality was 33 in the 4S trial, 81 in the HPS trial.

  • HF hospitalization: 1.9% in both groups

Safety

  • Premature discontinuation: Alirocumab 14.2% vs placebo 15.8%

  • Adverse events

    • Serious (SAEs): 23.3% vs 24.9%

    • Local injection-site reaction: 3.8% vs 2.1% (NNH 59)

    • No difference in neurocognitive adverse effects, new-onset diabetes, diabetes worsening, or myopathy

  • Neutralizing antidrug antibodies: 0.5% vs <0.1%

Effect on LDL-C (ITT analysis that includes patients who D/Ced alirocumab/switched to placebo)

  • Baseline: 2.4 in both groups

  • Month 4: Alirocumab 1.0 vs placebo 2.4 (-58%)

  • Month 12: 1.2 vs 2.5 (-52%)

  • Month 48: 1.7 vs 2.7 (-37%)

Internal validity

  • Low risk of allocation, performance, detection & attrition bias:

    • Computer-generated randomized sequence with centralized allocation of study drug/placebo kits;

    • Patients & clinicians blind to study intervention & lipid panel;

    • Central, blinded outcome adjudication;

    • Loss-to-follow-up 0.2% for death & 0.9% for primary outcome;

    • Analyses based on intention-to-treat principle.

  • Pre-randomization run-in with placebo injection x2-16 weeks to ensure patients could use autoinjector & tolerate stable statin regimen.

GLOBAL LEADERS: Ticagrelor-based DAPT x1 month, then ticagrelor monotherapy vs 12 months of standard DAPT in PCI

GLOBAL LEADERS. Lancet 2018;392:940-9.

Bottom Line: In patients who undergo PCI for either ACS or stable CAD, a regimen of ticagrelor plus ASA for 1 month, followed by ticagrelor monotherapy for 23 months, did not reduce the risk of death or Q-wave MI versus standard DAPT at 2 years.

Although major bleeding rates were no different in the overall population, in patients with PCI for ACS, ticagrelor monotherapy after the first month may reduce the risk of bleeding versus ticagrelor plus ASA for 12 months followed by ASA monotherapy. Conversely, in patients with stable CAD, there was no benefit to the ticagrelor-based regimen studied here.

Patients (n=15,991)

  • Included: Scheduled for percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) or stable coronary artery disease (CAD)

  • Excluded:

    • Taking strong CYP3A4 inhibitor, oral anticoagulant;

    • Use of fibrinolytic <24h before PCI;

    • Planned for CABG within 12 months of randomization;

    • Hx of intracranial hemorrhage, known (current) major bleed, stroke/TIA in last 30 days.

  • Average patient at baseline:

    • Age 64.5 y

    • Female 23%

    • Presentation: ACS 47% (STEMI 13%), stable CAD 53%

    • Cardiac Hx: Prior myocardial infarction (MI) 23%, prior PCI 33%, prior CABG 6%

    • PMHx: Smoker 26%, HTN 74%, diabetes 25%, dyslipidemia 70%, eGFR<60 14%

    • Angiographic characteristics

      • Lesion treated: Left main 2%, LAD 41%, bypass graft 1%

      • Mean total stent length 24.8 mm, stent diameter 3.0 mm

Intervention & Control

  • Intervention (both ACS & stable CAD as indication for PCI)

    • First month: Dual antiplatelet therapy (DAPT) with ticagrelor (load, then 90 mg BID) + low-dose ASA (75-100 mg/d); then

    • Next 23 months: Ticagrelor 90 mg BID monotherapy

    • Adherent (among those assessed): @ 1 month (95%), @ 1 year (81%), @ 2 years (78%)

  • Control

    • ACS as indication for PCI: Ticagrelor (load then 90 BID) + low-dose ASA x12 months, then ASA x12 months

    • Stable CAD as indication for PCI: Clopidogrel (load then 75 mg/d) + low-dose ASA x12 months, then ASA x12 months

    • Adherent (among those assessed): @ 1 month (96%), @ 1 year (89%), @ 2 years (93%)

  • Co-interventions standardized to all patients:

    • PCI performed with biodegradable biolimus-eluting stents;

    • Bivalirudin was used as anticoagulant (not heparin/enoxaparin) during PCI.

Results (intervention vs control) @ 2 Years

  • Primary outcome (all-cause death or Q-wave MI): 3.8% vs 4.4% (hazard ratio (HR) 0.87, 95% confidence interval 0.75-1.01)

    • Death from any cause: 2.8% vs 3.2% (HR 0.95, 0.74-1.22)

    • New Q-wave MI: 1% vs 1.3% (HR 0.80, 0.60-1.07)

    • Subgroup by indication for PCI (no interaction; p=.93):

      • ACS: HR 0.86 (0.69-1.08)

      • Stable CAD: HR 0.87 (0.71-1.08)

    • Landmark analyses:

      • Up to day 30: HR 0.81 (0.52-1.27)

      • Up to year 1 (including first 30 days): HR 0.79 (0.64-0.98)

      • After year 1: HR 0.97 (0.77-1.22)

  • Any MI: 3.1% in both groups (HR 1.00, 0.84-1.19)

  • Stroke: 1% in both groups (HR 0.98, 0.72-1.33)

  • Major bleeding (BARC grade 3 or 5): 2.0% vs 2.1% (HR 0.97, 0.78-1.20)

    • Subgroup by indication for PCI (interaction p=.007):

      • ACS: HR 0.73 (0.54-0.98) - where control is ticagrelor+ASA

      • Stable CAD: HR 1.32 (0.97-1.81) - where control is clopidogrel+ASA

  • Dyspnea: 13.8% vs 6.5% (p<.0001)

Generalizability (External Validity)

GLOBAL LEADERS tested a very complex intervention in a heterogeneous population:

  • First, this trial evaluates two populations with distinct standards of care: Patients with ACS, and patients with stable CAD. In patients undergoing PCI for ACS, the standard-of-care antiplatelet regimen is ticagrelor plus low-dose ASA for 12 months based on the PLATO trial, followed by lifelong ASA. Conversely, there is no evidence that ticagrelor is superior to clopidogrel in patients undergoing PCI for stable angina; no trial has been done to address this question.

  • Second, the interventions in GLOBAL LEADERS differ at 3 timepoints:

    • Day 0-30: Antiplatelet intensity in ACS subgroup (intervention = control), stable CAD subgroup (intervention > control).

    • Day 31-365: Antiplatelet intensity in ACS subgroup (intervention < control), stable CAD subgroup (intervention ? control).

    • Day 366-730: Antiplatelet intensity: intervention ? (> or =) control.

    • Therefore, the neutral results at 2 years may be because of a true lack of difference, or they may be due to a mixture of benefit in some timepoints and harms in other timepoints for these 2 subpopulations.

  • Third, adherence to ticagrelor in this trial was similarly poor to what was seen in PLATO and in clinical practice, driven by a higher rate of dyspnea and nuisance bleeding.

Risk of Bias: Moderate

  • Low risk of allocation bias:

    • Computer-generated randomization by otherwise-uninvolved 3rd party;

    • Blocked randomization with permuted blocks of 2 or 4;

    • Central randomization using locked web-based system.

  • High risk of performance and detection bias:

    • Open-label (patients, caretakers & clinicians caring for patient aware of which intervention they were randomized to);

    • No adjudication of outcomes.

SMART-DATE - 6 vs 12 months of DAPT after PCI for ACS

Hahn JY, et al. 6-month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): a randomised, open-label, non-inferiority trial. Lancet 2018 [epub]

Bottom line: In patients with ACS who underwent PCI, shorter DAPT (~6 months) increased the risk of recurrent MI (NNH 100) without any clear reduction in bleeding versus a standard DAPT duration of 12+ months.

Patients (n=2712)

  • Setting: South Korea from Sept 2012 to Dec 2015
  • Included:
    • ACS (STEMI, NSTEMI or unstable angina)
    • At least 1 lesions in a native coronary vessel with stenosis >50% amenable to PCI with stents
  • Excluded: Contraindication to antiplatelets, drug-eluting stent coating, or contrast media; Active bleeding, major bleeding within 3 months, or major surgery within 2 months; History of bleeding diathesis or known coagulopathy; Planned elective surgical procedure within next 12 months
  • Baseline characteristics:
    • Age 62 y
    • Women 25%
    • ACS subtype: STEMI 38%, NSTEMI 31%, unstable angina 31%
    • Prior MI 2%, previous revasc 5%
    • Angiography: Multivessel CAD 45%, left main 2%, LAD 59%, bifurcation lesion 9%
    • Other PMHx: Smoker 39%, HTN 49%, diabetes 27%

Intervention & control

  • Intervention: Short DAPT duration (x6 months)
    • Median DAPT duration 6.1 months
    • Adherence to study protocol: 74%
    • Used clopidogrel as P2Y12 inhibitor: 80%
  • Control: Standard DAPT duration (x12+ months)
    • Median DAPT duration 17.7 months
    • Adherence to study protocol: 96%
    • Used clopidogrel as P2Y12 inhibitor: 82%
  • Both groups: DAPT consisted of ASA + P2Y12 inhibitor at standard doses

Results (from PCI to 18 months after PCI)

Efficacy

  • 1o outcome (composite of all-cause mortality, MI, stroke): DAPTx6months 4.7%, x12+ months 4.2%, hazard ratio (HR) 1.13 (0.79-1.62)
    • Absolute risk difference 0.5% (upper limit 1.8% < 2.0% non-inferiority margin, p=0.03 for non-inferiority)
    • Post-hoc landmark analysis from month 6 to 18: HR 1.69 (0.97-2.94)
  • Death: 2.6% vs 2.9%, HR 0.90 (0.57-1.42)
  • MI: 1.8% vs 0.8%, HR 2.41 (1.15-5.05) - number needed to harm (NNH) 100
    • Post-hoc landmark analysis from month 6 to 18: HR 5.06 (1.46-17.47)
  • Stroke: 0.8% vs 0.9%
  • Stent thrombosis: 1.1% vs 0.7%

Safety

  • BARC 2-5 bleeding: 2.7% vs 3.9%, HR 0.69 (0.45-1.05)
  • Major bleeding: 0.5% vs 0.8%, HR 0.60 (0.22-1.65)

Generalizability

  • This trial enrolled a generally representative group of Asian patients with ACS undergoing PCI predominantly treated with DAPT consisting of ASA + clopidogrel
  • Study investigators were hesitant to comply with the study protocol; 26% of patients in the 6-month group continued to receive DAPT beyond 6 months
  • Although the authors claimed to randomize at the time of PCI rather than 6 months later in order to avoid "selection bias, resulting in enrolment of low-risk patients," it's likely that any "high-risk patients" would not have been considered & therefore not enrolled into this trial.

Risk of bias

  • Low risk of allocation bias
    • Web-based randomization;
    • Computer-generated block randomization;
    • Stratified by (1) enrolment site, (2) ACS subtype, (3) diabetes (y/n), (4) type of P2Y12 inhibitor after prasugrel/ticagrelor became available, & randomized to 1 of 3 drug-eluting stents (eluting everolimus [Xience Prime], zotarolimus [Resolute Integrity], or biolimus [BioMatrix Flex]).
  • High risk of performance & detection bias
    • Randomization occurred immediately after PCI rather than at month 6, allowing for differences in performance & collection of outcomes prior to patients receiving allocated treatment (stopping or continuing DAPT at 6 months);
    • Participants & personnel not blinded to treatment allocation;
    • 26% of patients in 6-month group did not comply with the study intervention of stopping DAPT at month 6.
  • Low risk of attrition bias
    • 2.5% loss-to-follow-up (3.0% vs 1.9%);
    • ITT analysis.
  • Non-inferiority design not clearly justified
    • Wide non-inferiority margin of 2.0% absolute risk difference justified based on feasibility (assuming 4.5% incidence of 1o outcome @ 18 months in 12-month group);
    • Non-inferiority criteria based on above wide non-inferiority margin met for primary outcome, however, MI - key component of this composite - was clinically and statistically significantly higher in the short DAPT group;
    • Inclusion of period from PCI to month 6, when both groups were intended to receive DAPT, biases the results toward non-inferiority. The post-hoc landmark analysis evaluating outcomes from month 6 to 18 demonstrates a greater difference between groups, supporting the conclusion that DAPT x6 months is inferior to 12+ months;
    • Similar results between ITT & per-protocol analysis, although with the above limitations.