DECLARE-TIMI 58 - Dapagliflozin & CV events in type 2 diabetes

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Wiviott SD, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. NEJM

Bottom line: In patients with type 2 diabetes with existing ASCVD or with multiple CV risk factors, dapagliflozin did not reduce the risk of a composite of major adverse cardiovascular events; however, it did reduce the risk of HF hospitalizations (NNT 125) at 4.2 years. Dapaglifozin increases the risk of fungal genital infections (NNH 125) & DKA (NNH 500).

Overall assessment of the evidence for SGLT2 inhibitors shows several differences between agents in this class; empagliflozin appears to have the greatest potential for benefit, whereas canagliflozin has the highest potential for harm.

Context: Summaries of EMPA-REG with empagliflozin & CANVAS with canagliflozin

Patients (n=17,160)

  • Included

    • T2DM with HbA1c 6.5%-12.0%

    • + CrCl 60+ mL/min

    • + either

      • Established atherosclerotic cardiovascular disease (ASCVD; IHD, ischemic CVA, PAD) & 40+ y/o

      • Multiple risk factors: Male 55+ y/o or female 60+ y/o + tobacco use, HTN, or LDL >3.3 mmol/L

  • Key exclusion criteria:

    • Adherence <80% during run-in or considered “at risk for poor medication adherence”

    • Previous SGLT2 inhibitor use

    • Steroid use with equivalent of prednisone 10+ mg/d

    • ACS, decompensated HF or stroke within 8 weeks

    • BP >180/100

    • Recurrent UTIs

  • Baseline characteristics:

    • 64 y/o, male (63%), white (80%), North American (32%)

    • ASCVD (41%): CAD (33%), PAD (6%), CVA (8%)

    • HF (10%)

    • Diabetes duration median 11 y,

    • HbA1c median 8.3%

    • BP 135/85

    • eGFR 85 (7% with eGFR <60)

    • Meds

      • Antihyperglycemics: Metformin (82%), sulfonylurea (43%), insulin (41%), DPP-4i (17%), GLP1 agonist (4%)

      • ASA (61%), ACEI/ARB (81%), beta-blocker (53%), statin or ezetimibe (75%), diuretic (41%)

Intervention & control

  • I: Dapagliflozin 10 mg once daily

  • C: Matching placebo

  • Co-interventions: Other antihyperglycemics per standard of care, excluding SGTL2i or glitazones

Results @ median 4.2 years

Efficacy

  • No reduction in major adverse cardiovascular events (composite of CV death, MI or ischemic stroke): Dapagliflozin 8.8% vs placebo 9.4%

    • Hazard ratio (HR) 0.93, 95% confidence interval (CI) 0.84-1.03

    • CV death: 2.9% in both groups

    • MI: 4.6% vs 5.1% (HR 0.89, 95% CI 0.77-1.01)

    • Ischemic stroke: 2.7% in both groups

  • Reduction in composite of CV death or HF hospitalization: 4.9% vs 5.8%

    • HR 0.83 (95% CI 0.73-0.95)

    • Driven by a reduction in HF hospitalization: 2.5% vs 3.3% (NNT 125, HR 0.73, 95% CI 0.61-0.88)

    • Originally a secondary outcome; switched to co-primary outcome before unblinding of outcomes due to favorable results on this outcome in EMPA-REG & CANVAS.

  • No reduction in death: 6.2% vs 6.6% (HR 0.93, 95% CI 0.82-1.04)

Safety

  • Increased:

    • Diabetic ketoacidosis (DKA): 0.3% vs 0.1% (NNH 500; HR 2.18, 95% CI 1.10-4.30)

    • Genital infection (generally fungal): 0.9% vs 0.1% (NNH 125)

  • Reduced:

    • Serious adverse events: 34.1% vs 36.2% (HR 0.91, 95% CI 0.87-0.96)

  • No difference in

    • D/C due to adverse event: 8.1% vs 6.9% (HR 1.15, 95% CI 1.03-1.28)

    • Amputation: 1.4% vs 1.3%

    • Symptomatic volume depletion: 2.5% vs 2.4%

    • UTI: 1.5% vs 1.6%

Effect on surrogate endpoints:

  • HbA1c -0.4%

  • Wt -1.8 kg

  • SBP/DBP -2.7/-0.7

Internal validity

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

    • Computer-generated block-randomization sequence;

    • Centralized randomization by interactive voice/web response system to blinded kit containing intervention or matching placebo;

    • Low loss-to-follow-up (0.3%);

    • Analyzed by intention-to-treat.

  • Single-blind (patient) placebo run-in phase lasting 4-8 weeks to assess for non-adherence

    • Unclear risk of selection bias: 25,698 entered run-in phase -> 17,160 randomized (i.e. high rate of exclusion during placebo run-in)

Other Evidence

  • A meta-analysis of the 3 major CV outcome trials of SGLT2 inhibitors (CANVAS, DECLARE & EMPA-REG) shows the following overall patterns:

    • CV efficacy

      • Only empagliflozin clearly reduces all-cause & CV mortality (in patients with existing ASCVD, RRR 32%);

      • SGLT2 inhibitors reduce the risk of major adverse CV events (composite of CV death/MI/stroke) in patients with existing ASCVD (RRR 14%), but not in those without ASCVD;

      • SGLT2 inhibitors do not reduce/increase stroke;

      • All SGLT2 inhibitors reduce the risk of HF hospitalization (RRR ~30%), regardless of prior ASCVD or HF.

    • Safety

      • All SGLT2 inhibitors increase the risk of DKA (RR increase by 120%);

      • Only canagliflozin increases the risk of amputations (RR increase 26%) & fractures (RR increase by 11%).

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

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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

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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.

ASA vs rivaroxaban for extension of VTE prophylaxis after hip/knee arthroplasty

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Anderson DR, et al. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. NEJM 2018;378:699-707.

Bottom line: In patients who underwent elective hip or knee replacement with rivaroxaban 10 mg/d up until POD #5, switching to ASA 81 mg/d on POD #6 is no worse than continuing rivaroxaban 10 mg/d for preventing VTE, with similar rates of bleeding. 

Patients (n=3427)

  • Setting: 15 Canadian university-affiliated hospitals from Jan 2013 to April 2016
  • Included: Elective unilateral hip (THA) or knee arthroplasty (TKA), primary or revision
  • Excluded:
    • Hip or lower limb fracture in previous 3 months
    • Metastatic cancer
    • Did NOT exclude patients who received ASA pre-op (they could continue open-label ASA <100 mg/d in addition to blinded study drug)
  • Baseline characteristics:
    • Age 63 y
    • Male 48%
    • Joint operated: Hip (53%), knee (47%)
    • VTE risk factors: Prior VTE 2-3%, previous surgery ~3%, cancer 2-3%, smoker ~9%
    • BMI 31
    • Post-op mechanical compression: IPCs (50%), graduated stockings (42%), both (8%)
    • Hospital LOS 3.5 days
    • Peri-op tranexamic acid 54.5%
    • Pre-op ASA 25%

Intervention & control

  • All patients received rivaroxaban 10 mg once daily on POD #0 (starting >6h after wound closure) or POD #1, & was continued until POD #5
  • Intervention: Switched to ASA 81 mg daily on POD #6
  • Control: Continued Rivaroxaban 10 mg once daily
  • Duration of study drug in both groups:
    • Hips x30 days (total 35 days of VTE prophylaxis)
    • Knees x9 days (total 14 days of VTE prophylaxis) 

Results @ 90 days

  • Primary efficacy outcome (symptomatic DVT or PE): ASA 0.6% vs rivaroxaban 0.7%
    • Absolute risk difference -0.06% (upper end of 95% confidence interval [CI]: +0.55%), p<0.001 for non-inferiority
  • Mortality: 0.06% (1 death from PE) vs 0%
  • Primary safety outcome (major or clinically-relevant non-major bleed): 1.3% vs 1.0%
    • All consisted of overt bleeding at the surgical site; most occurred between POD #6-16
  • Major bleed: 0.5% vs 0.3%

Generalizability (external validity)

  • Widely applicable to patients who underwent elective THA/TKA (whether they received DOAC or LMWH from POD #0-5)

Risk of bias: Low (high internal validity)

  • Low risk of allocation, performance, detection or attrition bias
    • Random sequence generation: using permuted-block design, stratified by THA or TKA, centre, & use of open-label ASA
    • Allocation concealment: patients & personnel (central pharmacy staff aware)
    • Blinding of patients & personnel: ASA & rivaroxaban administered in identical-appearing opaque gelatin capsules
    • Blinding of outcome assessors: Independent adjudication committee unaware of treatment allocation
    • ITT analysis
    • 1 patient lost to follow-up of VTE, but vital status known (alive @ 90 days)
  • Non-inferiority trial design
    • Non-inferiority margin set at <1.0% absolute risk difference justified based on survey of Canadian thromboembolism specialists & orthopedic surgeons (reference not provided)
    • ITT analysis used for primary analysis; on-treatment analysis consistent with ITT analysis:
      • Primary outcome: 0.4% vs 0.4%
      • Bleeding: 0.9% vs 0.75%
    • No safety advantage for ASA demonstrated in this trial, however, non-inferiority design is justifiable based on substantially-lower cost of ASA (<$5 for 1 month) compared to rivaroxaban ($3/day for 10 mg-tab).

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

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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.