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.

TREAT - Ticagrelor vs clopidogrel after fibrinolytic therapy for STEMI

Berwanger O, et al. Ticagrelor vs clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: a randomized clinical trial. JAMA Cardiol 2018

Bottom line:

  • In patients <75 y/o who received fibrinolytic therapy plus a loading dose of clopidogrel for STEMI & already not actively bleeding from this, switching to ticagrelor with a loading dose 8-24h after administration of the fibrinolytic agent does not appear to increase the risk of major, fatal or intracranial bleeding at 30 days versus continuing with clopidogrel.

  • Follow-up in TREAT is ongoing; 12-month outcomes as well as meta-analysis with PLATO STEMI subgroup will likely be reported in 2019.

Patients (n=3799)

  • Setting: 10 countries including Canada, enrolled from Nov 2015 to Nov 2017
  • Included:
    • 18-75 y/o
    • STEMI presenting <24h after symptom onset
    • Received fibrinolytic therapy
  • Excluded:
    • Contraindication to clopidogrel, ticagrelor or fibrinolysis
    • Use of oral anticoagulant therapy
    • Increased risk of bradycardia (not further defined)
    • Concomitant use of a strong CYP3A4 inhibitor/inducer
    • Dialysis-dependent
    • Clinically-important anemia or thrombocytopenia, or active bleeding (therefore excluding those who bled early with the initial fibrinolytic+antiplatelet regimen)
  • Baseline characteristics:
    • Age 59 y
    • Female 23%
    • White 57%, Asian 33%
    • STEMI type: Anterior only (~34%), inferior only (~31%), LBBB only (1%)
    • Killip class 2-4: 8-9%
    • PMHx: MI (8-9%), stroke (4-5%), PCI (5-6%), CABG (<1%)
    • Meds (baseline + in-hospital):
      • ASA 99%
      • Anticoagulant: Heparin (40%), LMWH (69%), fondaparinux (4%), bivalirudin (~1%), warfarin (<1%)
      • ACEI ~60%, ARB ~10%
      • Beta-blocker 74%
      • Statin 93%
      • PPI ~55%
    • PCI during initial ACS hospitalization: ~56% (DES ~34%)

Intervention & control

  • Intervention: Ticagrelor 180 mg PO x1, then 90 mg BID (plan to continue 12+ months per standard ACS management)
    • Mean 90% of doses taken within 30 days
  • Control: Clopidogrel 300-600 mg PO x1, then 75 mg daily (plan to continue 12+ months per standard ACS management)
    • Mean 91% of doses taken within 30 days
  • Co-interventions:
    • Clopidogrel dose administered before randomization: >300 mg (3%), 300 mg (87%), none or <300 mg (10%)
    • All received ASA 75-100 mg daily unless intolerant
    • Fibrinolytic selection: TNK ~40%, alteplase ~20%, reteplase, 17%, other 23%
    • Median 2.6 h from symptom onset to fibrinolytic administration
    • Median 11.4 h from fibrinolytic administration to randomization
    • PCI during hospitalization in 56%, drug-eluting stent in 34%

Results @ 30 days (follow-up up to 12 months ongoing)

Bleeding

  • 1o outcome (major bleed, TIMI definition): Ticagrelor 0.7%, clopidogrel 0.7%
    • (95% confidence interval for absolute risk difference -0.5% to +0.6%, p<0.001 for non-inferiority based on a non-inferiority margin of 1.0%)
  • Other bleeding definitions:
    • Intracranial hemorrhage: 0.4% vs 0.4% (95% CI -0.35% to +0.45%)
    • Fatal bleeding: 0.2% vs 0.1% (95% CI -0.2% to +0.3%)
    • BARC type 3-5: 1.2% vs 1.4%
    • PLATO, major: 1.2% vs 1.4%
    • TIMI
      • Major non-CABG: 0.7% vs 0.6%, p=0.57
      • Requiring medical attention: 2.0% vs 1.3%, p=0.06
      • Minor: 0.4% vs 0.6%, p=0.47
  • TIMI major bleed based on time from fibrinolytic administration to administration of study antiplatelet
    • <4h: 1.5% vs 1.2%
    • 4-8h: 0.8% vs 1.2%
    • 8-16h: 0.5% vs 0.3%
    • 16+h: 0.5% vs 0.2%

Other safety outcomes

  • Dyspnea: 13.9% vs 7.6% (NNH 16)
  • Premature discontinuation of study drug <30 days: 8.1% vs 6.4%
    • Due to dyspnea: 1.2% vs 0%
    • Due to patient refusal: 1.5% vs 0.3%

Efficacy

  • Death from any cause: 2.6% in both groups (HR 0.99, 0.66-1.47)
  • Vascular death, MI, stroke: 4.0% vs 4.3% (hazard ratio [HR] 0.91, 95% CI 0.67-1.25)
    • MI: 1.0% vs 1.3% (HR 0.79, 0.44-1.42)

Generalizability

  • TREAT enrolled a representative population of STEMI patients who received fibrinolytic therapy.
  • Note that the logistics of this trial are key to interpretation and application. Fibrinolytic therapy is generally reserved for patients who cannot get to a PCI-capable hospital in a reasonable timeframe, & is therefore administered in the pre-hospital or community hospital setting. This trial was undertaken at academic sites, and therefore generally enrolled patients & administered the study therapy hours after administering a fibrinolytic, with 90% having already received a clopidogrel load.
    • This is therefore NOT a trial comparing SIMULTANEOUS fibrinolysis + ticagrelor vs fibrinolysis + clopidogrel, but rather a trial comparing a switch from clopidogrel to ticagrelor within 24h of administering a fibrinolytic. With a median time from fibrinolytic administration to study P2Y12 administration of 11.4h, the fibrinolytic was long-gone by the time they entered the study (e.g. half-life <30 min for 3 most-commonly-used fibrinolytics)
    • Therefore the most direct application of these results would be to administer a loading dose of clopidogrel 300 mg PO with the fibrinolytic, & then switch to ticagrelor by starting with a loading dose 8-24h later (ensuring that the fibrinolytic is eliminated, & therefore pharmacodynamic interaction & bleed risk is minimized)

Internal validity

  • Low risk of allocation bias due to use of an automated web-based system in permuted blocks of 4 stratified according to site
  • Unclear risk of performance and detection bias due to open-label design with blinded adjudication of outcomes (though low risk for important "hard" endpoints of death, major, fatal and intracranial bleeds)
  • Low risk of attrition bias due to very low loss-to-follow-up (0.1-0.2%) & use of ITT analysis
  • Non-inferiority design was appropriate, design decisions were well-justified & conclusion of non-inferiority is reasonable based on threshold set & consistency in analyses
    • Justified based on potential long-term benefits of ticagrelor as observed in the PLATO trial (i.e. to 12 months after ACS)
    • Non-inferiority margin for major bleed set at an absolute risk increase of 1.0%, which the authors justify empirically based on thresholds used in other non-inferiority RCTs
    • Analyzed 3 separate definitions of "major bleed" using both ITT & per-protocol analyses, which were all nearly identical & consistent