REDUCE-IT - Icosapent ethyl (EPA) to reduce CV events

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Bhatt DL, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. NEJM

Bottom line: In patients with existing ASCVD or diabetes + other CV risk factors, isocapent ethyl (esterified EPA) reduced the risk of CV events (NNT 21) versus placebo over 4.9 years. Conversely, icosapent increased the risk of AF (NNH 72), peripheral edema (NNH 67) and possibly serious bleeding (NNH 167) versus placebo.

It remains unclear how icosapent ethyl works to reduce CV events, or whether it benefits only patients with elevated triglycerides.

Patients (n=8179)

  • Enrolled in 11 countries from November 2011 to August 2016

  • 19,212 screened (10,429 did not meet inclusion criteria) -> 8179 randomized

  • Included

    • Either

      • Secondary prevention: 45+ y/o + established ASCVD, or

      • Primary prevention: 50+ y/o with diabetes + 1 other CV risk factor (male age 55+ y/o or female 65+ y/o; smoker; HTN; HDL-C <1 for men or <1.2 for women; hsCRP >3 mg/L; CrCl 30-60; retinopathy; albuminuria; ABI <0.9 without intermittent claudication)

    • Fasting triglyceride 1.7-5.6 mmol/L (amended in 2013 to 2.3-5.6)

    • LDL-C 1.0-2.6 mmol/L on a stable statin dose for at least 4 weeks

  • Key exclusion criteria

    • HF NYHA functional class 4; life-threatening condition other than CVD with expected prognosis <2y

    • BP >200/100 mm Hg; HbA1c >10.0%; CrCl <30 or need for peritoneal/hemodialysis

    • Planned PCI/CABG

    • Prior pancreatitis; ETOH abuse in past 6 months

    • Meds:

      • Lipid-lowering drugs other than statin +/- ezetimibe (niacin (>200 mg/d), fibrate, omega-3 supplements, bile acid sequestrants, PCSK9 inhibitors

      • Drugs that affect triglycerides & other lipids (tamoxifen, estrogen, progestins, thyroid replacement, systemic steroids.

    • Allergy to fish or shellfish

  • Typical baseline characteristics

    • 64 y/o, male (71%), white (90%)

    • Secondary prevention (71%), primary prevention (29%)

    • Type 2 diabetes (58%)

    • Labs

      • LDL-C 1.9 mmol/L, HDL-C 1.0 mmol/L, trigs 2.4 mmol/L

      • hsCRP 2.2 mg/L

    • Meds

      • Statin (100%): High-intensity (32%), moderate (62%), low (6%)

      • Ezetimibe 6%

Intervention & control

  • I: Icosapent ethyl 2 g PO BID

    • Purified formulation of eicosapentanoic acid (EPA), one of the main omega-3 fatty acids in fish oil;

    • Far exceeds doses found in over-the-counter (OTC) fish oil products, which are typically labeled to contain ~200 mg of EPA/capsule.

  • C: Matching “placebo” containing mineral oil

Results @ median 4.9 years

  • Reduction in primary CV outcome (composite of CV death, MI, stroke, PCI/CABG, or hospitalization for unstable angina [UA]): Icosapent ethyl 17.2% vs placebo 22.0% (NNT 21) & every individual component

    • Hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.68-0.83

    • Reduction in 3-point MACE (CV death, MI, stroke): 11.2% vs 14.8% (NNT 28), HR 0.74, 95% CI 0.65-0.83

      • CV death: 4.3% vs 5.2% (HR 0.80, 95%CI 0.66-0.98)

      • Non-fatal or fatal MI: 6.1% vs 8.7% (HR 0.69, 95%CI 0.58-0.81)

      • Stroke: 2.4% vs 3.3% (HR 0.72, 95%CI 0.55-0.93)

    • Urgent/emergent PCI/CABG: 5.3% vs 7.8% (HR 0.65, 95%CI 0.55-0.78)

    • UA hospitalization: 2.6% vs 3.8% (HR 0.68, 95%CI 0.53-0.87)

  • Death from any cause: 6.7% vs 7.6% (HR 0.87, 95%CI 0.74-1.02 - inconclusive)

Safety

  • Increased:

    • Atrial fibrillation: 5.3% vs 3.9% (NNH 72)

    • Hospitalization for afib/flutter: 3.1% vs 2.1% (NNH 100)

    • Peripheral edema: 6.5% vs 5.0% (NNH 67)

  • Possible increased risk of serious bleeding: 2.7% vs 2.1% (NNH 167; p=0.06)

    • No difference in GI bleeds (1.5% vs 1.1%) or CNS bleeds (0.3% vs 0.2%)

Effect on surrogate outcomes

  • Trigs at year 1: -0.4 vs +0.05 mmol/L (-20% [-0.5 mmol/L] from baseline vs placebo

  • LDL-C at year 1: +0.05 vs 0.18 mmol/L (0.13 mmol/L lower vs placebo)

  • hsCRP at year 2: -0.2 vs +0.5 mg/L (-38% [0.8 mg/L] lower vs placebo

Internal validity

  • Low risk of allocation, performance and detection bias

    • Computer-generated randomization sequence stratified by CV risk group (2o or 1o prevention), use of ezetimibe & geographic region

    • Allocation concealment maintained by central allocation via interactive voice response system

    • Blinding of patients, investigators, clinicians maintained by use of mineral oil “placebo” in control group, which is similar in appearance to the intervention

  • Unclear (potentially high) risk of attrition bias

    • Low loss to follow-up (0.2%) for death

    • High loss to follow-up for non-fatal outcomes, with similar frequency between groups (icosapent ethyl 9.3%, placebo 10.0%)

    • Intention-to-treat analysis.

Other considerations

  • This is not a study of fish oil/omega-3 fatty acid supplements

    • High-quality evidence is exceptionally clear that fish oil/omega-3 fatty acid supplements, such as those sold at pharmacies, health food stores or over the Internet, do NOT reduce the risk of CV events in patients with or without CVD. This has been shown in a meta-analysis of 20 RCTs including 68,680 patients, as well as 2 other recent RCTs (ASCEND & VITAL).

  • The mechanism of action for CV event reduction with icosapent ethyl is unclear

    • Unlikely to be explained by triglyceride reduction

      • Identical CV relative risk reduction (RRR) regardless of baseline triglyceride concentration (<1.7 vs >1.7 or <2.3 vs >2.3 mmol/L);

      • Identical CV RRR regardless of whether achieved trigs <1.7 or 1.7+ mmol/L.

    • Not fully explained by LDL-C increase caused by mineral oil within placebo in comparator group

      • Identical RRR vs placebo patients who had LDL-C increase, decrease, or no change;

      • LDL-C difference of 0.13 mmol/L would only explain a ~3% RR difference based on estimates from the Cholesterol Treatment Trialists’ Collaboration meta-analysis of statins (where 1 mmol/L reduction in LDL-C associated with a ~25% RRR in CV events)

    • Other possible mechanisms include

      • Anti-inflammatory effect (or pro-inflammatory effect of mineral oil in placebo)?

      • Antiarrhythmic effect, or stabilization of cellular membranes?

        • Reduced tertiary outcomes of cardiac arrest (HR 0.52, 95% CI 0.31-0.86) & sudden cardiac death (HR 0.69, 95% CI 0.50-0.96)

      • Antithrombotic effect?

        • Reduced MI, stroke, as well as sudden cardiac events & likely increased risk of bleeding

  • Ongoing trials with EPA +/- DHA: STRENGTH (International) , RESPECT-EPA (Japan)

CARMELINA - Linagliptin in type 2 diabetes

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Rosenstock J, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: The CARMELINA randomized clinical trial. JAMA

Bottom line: In patients with type 2 diabetes with additional risk for CV or renal adverse events, linagliptin did not reduce the risk of CV events, nephropathy or retinopathy vs placebo over 2.2 years. Linagliptin may increase the risk of acute pancreatitis (NNH 500).

This is consistent with all other trials of DPP-4 inhibitors showing no clinical benefit from this class of medications.

Patients (n=6991)

  • Included

    • Adults with T2DM with HbA1c 6.5-10.0%

    • + antihyperglycemic meds stable for at least 2 months

    • + either high CV or renal risk

      • High CV risk: Existing CAD/stroke/PAD, or micro/macroalbuminuria (urinary albumin:creatinine ratio [UACR] >30 mg/g)

      • High renal risk: eGFR 15-45, or eGFR 45-75 + UACR >200 mg/g

  • Key exclusion criteria

    • ACS/PCI/CABG in last 2 months or PCI/CABG planned

    • Stroke/TIA in last 3 months

  • Typical baseline characteristics

    • 66 y/o, male (62%), white (80%)

    • Diabetes mean duration 15 y, HbA1c 8.0%

    • Ischemic heart disease (27%), HF (27%)

    • eGFR mean 55 mL/min/1.73 m^2: 30-45 (28%), <30 (15%)

    • Meds:

      • Antihyperglycemics: Insulin (58%), metformin (54%), sulfonylurea (32%)

      • ASA (62%), statin (72%), ACEI/ARB (81%)

Intervention & control

  • I: Linagliptin 5 mg PO daily

  • C: Matching placebo

  • Co-interventions: Glycemic control using most available antihyperglycemics (no DPP-4i, SGLT2i or GLP-1 receptor agonists)

Results @ median 2.2 years

Efficacy

  • No reduction in the original primary outcome (“4-point MACE” a composite of CV death, MI, stroke, or hospitalization for unstable angina): Linagliptin 13.3%, placebo 13.2%

    • Hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.88-1.13

    • CV death: 7.3% vs 7.6%

    • Non-fatal MI: 4.5% vs 3.9%

    • Non-fatal stroke: 1.9% vs 2.1%

    • UA hospitalization: 1.2% vs 1.4%

    • Consistent lack of benefit in all subgroups (if anything, HR 1.20 in pts with baseline HbA1c >8%)

  • No effect on death from any cause: 10.5% vs 10.7% (HR 0.98, 95% CI 0.84-1.13)

  • No reduction in kidney outcomes (composite of death due to kidney disease, end-stage renal disease, or sustained -50% eGFR): 6.6% vs 6.5% (HR 0.98, 0.82-1.18)

  • No reduction in retinopathy: 1.0% vs 1.4% (HR 0.73, 95% CI 0.47-1.12)

Safety

  • Serious adverse events: 37.0% vs 38.5%

  • D/C due to adverse event: 10.3% vs 11.5%

  • Possible increase in acute pancreatitis: 0.3% vs 0.1% (NNH 500)

  • No increase in HF hospitalizations: 6.0% vs 6.5% (HR 0.90, 0.74-1.08)

Surrogate outcomes vs placebo

  • HbA1c: At month 3: -0.5%; over entire trial: -0.36%

  • No difference in weight, SBP, DBP, LDL-C, HDL-C

Internal validity

  • Low risk of allocation, performance, detection bias:

    • Computer-generated random sequence;

    • Block-randomized by interactive phone/web system;

    • Participants, clinicians & investigators blinded;

    • Central adjudication of CV & renal events by committee unaware of treatment allocation.

  • Low risk of attrition bias for CV outcomes & death, but unclear for renal outcomes:

    • Low loss-to-follow-up (LTFU) of 0.3% for mortality & 1.3% for CV events, but high (12%) LTFU for kidney outcomes;

    • Modified intention-to-treat (mITT) including all patients as randomized who received study drug for at least 1 dose.

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

in ,

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.