PIONEER AF-PCI - Antithrombotics in patients with AF after PCI

PIONEER: Gibson CM, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;online

Secondary analysis of PIONEER: Gibson CM, et al. Recurrent hospitalization among patients with atrial fibrillation undergoing intracoronary stent treated with 2 treatment strategies of rivaroxaban or a dose-adjusted oral vitamin K antagonist treatment strategy. Circulation 2016;online

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Bottom line: In patients with AF undergoing PCI, a novel antithrombotic regimen (reduced-dose rivaroxaban + P2Y12 inhibitor, or ATLAS trial-like triple therapy regimen) reduces the risk of hospitalization, bleeding requiring medical attention and study discontinuation (NNT ~10-15 each).

This trial does not answer whether these novel regimens retain stroke efficacy for AF (either regimen versus full anticoagulation) or MI/stent thrombosis efficacy for CAD (modified double therapy versus DAPT). While ongoing trials will provide further guidance on the ideal regimen and dose, the best available evidence suggests that dual therapy with clopidogrel plus full-dose anticoagulation provides the best balance of benefit and safety.

 

Patients (n=2124)

• Inclusion
  • Age 18+ y
  • AFib (documented within 1 y before enrolment or taking OAC for at least 3 months before PCI)
  • Underwent PCI with stent placement (randomized within 3 days of PCI)
• Exclusion
  • Prior stroke/TIA
  • Significant GI bleed within 1 year
  • Anemia of unknown cause with Hb <100 g/L
  • "Any other condition known to increase bleed risk"
  • CrCl <30 mL/min
• Screened 2236 -> randomized 2124 -> analyzed 2099
• "Average" patient
  • Age 71 y (36% 75+ y)
  • Female 26%
  • White 94%
  • Indication for PCI: Unstable angina (21%), NSTEMI (18%), STEMI (12%), non-ACS (49%)
  • Drug-eluting (2/3), bare-metal (1/3) stent
  • CHA2DS2-VASc score: 0 (<2%), 1 (9%), 2 (15%), 3 (18%), 4 (20%), 5 (20%), 6 (13%), 7 (3%)
  • CrCl 78 mL/min
  • P2Y12 inhibitor: Clopidogrel (93%), prasugrel (<2%), ticagrelor (~5%)
  • PPI used in ~40%

Generalizability

• Represents the target population at the time when the decision on antithrombotics would be made.
• Similar to WOEST and ISAR-TRIPLE, ACS was the indication for PCI in <50% of patients
  • Due to their higher risk of MI, stent thrombosis & CV death, thes benefit-risk profile of different antithrombotic regimens (& DAPT duration) likely differs in this subgroup. This trial is underpowered to evaluate this subgroup.
• ~90% of patients had a CHA2DS2-VASc of 2 or more, corresponding to a risk of stroke or systemic thromboembolism of >1.5%/year & indication for anticoagulation by all major guidelines (AHA, CCS, ESC).
• This trial included only patients without major bleeding risk factors (i.e. no recent GI bleed, intracranial hemorrhage, eGFR <30 mL/min, or chronic NSAID use)
  • The bleeding rates in this trial therefore represent a minimum risk that would be expected to increase substantially in the presence of any of these risk factors.

 

Interventions & co-interventions

• I 1: Modified "double therapy" for trial duration
  • Rivaroxaban 15 mg daily + P2Y12 inhibitor at standard dose
    • If CrCl 30-50: Decrease rivaroxaban to 10 mg daily
  • Comments about this intervention:
    • Rivaroxaban dose 75% of the 20 mg/d dose determined to be non-inferior to warfarin in ROCKET-AF trial of non-valvular AF. It is unclear if the addition of 1 antiplatelet drug to this reduced dose provides similar ischemic stroke risk reduction compared to full-dose anticoagulation monotherapy
    • Full-dose apixaban may have been a better option, since it has demonstrated similar risk of major bleeding compared to ASA, with greater reduction in ischemic stroke in non-valvular AF (AVERROES)
• I 2: Rivaroxaban 2.5 mg BID + DAPT (ATLAS trial regimen)
  • DAPT consisted of ASA 75-100 mg/d indefinitely + a standard dose of any of clopidogrel, prasugrel, ticagrelor x1 to 12 months (decided before randomization)
  • Comments about this intervention:
    • Rivaroxaban dose 25% of the 20 mg/d dose determined to be non-inferior to warfarin in ROCKET-AF trial. There is no prior evidence suggesting that this dose is adequate to reduce the risk of stroke in AF, nor is there evidence that adding DAPT to this reduced dose will reduce the risk of ischemic stroke.
• C: Warfarin-based triple therapy
  • Warfarin to INR 2.0-3.0 (mean time in the therapeutic range 65%) + ASA 75-100 mg/d + P2Y12 inhibitor
    • Warfarin & ASA continued for trial duration
    • P2Y12 inhibitor continued x1 to 12 months (decided before randomization)

 

Outcomes @ 1 year

• Efficacy
  • Death or hospitalization: Modified double therapy 35%, ATLAS regimen 32%, triple therapy 42%
    • Modified double therapy vs triple therapy: Hazard ratio (HR) 0.79 (95% confidence interval 0.66-0.94), NNT 10
    • ATLAS regimen vs triple therapy: HR 0.75 (0.62-0.90), NNT 15
    • Note: The lower risk of hospitalization in the 2 rivaroxaban-based regimens vs triple therapy were due to reductions in both CV- and bleeding-related hospitalizations
  • Death: 2.3-2.7% (no statistically significant differences)
  • Composite CV death, MI or stroke: 6.5% vs 5.6% vs 6.0%
    • Double vs triple therapy: HR 1.08 (0.69-1.68)
    • ATLAS regimen vs triple therapy: HR 0.93 (0.59-1.48)
  • Stent thrombosis: 0.8% vs 0.9% vs 0.7%
    • Double vs triple therapy: HR 1.20 (0.32-4.45)
    • ATLAS regimen vs triple therapy: HR 1.44 (0.40-5.09)
  • Stroke: 1.3% vs 1.5% vs 1.2%
    • Double vs triple therapy: HR 1.07 (0.39-2.96)
    • ATLAS regimen vs triple therapy: HR 1.36 (0.52-3.58)
• Safety
  • Primary outcome (major + minor bleeding based on TIMI criteria or bleeding requiring medical attention): 16.8% vs 18.0% vs 26.7%
    • Double vs triple therapy: HR 0.59 (0.47-0.76), NNT 11
    • ATLAS regimen vs triple therapy: HR 0.63 (0.50-0.80), NNT 12
  • Major bleeding: 2.1% vs 1.9% vs 3.3%
    • Double vs triple therapy: HR 0.66 (0.33-1.31)
    • ATLAS regimen vs triple therapy: HR 0.57 (0.28-1.16)
• Discontinuation before study termination: 21.0% vs 21.1% vs 29.4% (NNT ~12 for either double therapy or the ATLAS regimen versus triple therapy)

Context

• ~1 in 20 patients undergoing PCI also have AF
• The ideal antithrombotic regimen AF patients undergoing PCI remains elusive
  • In AF, oral anticoagulants (OACs) provides better stroke prevention than dual antiplateletet therapy (DAPT), with no difference in the risk of major bleeds
  • In PCI with stent placement, DAPT reduces the risk of MI, stent thrombosis and revascularization more than ASA + oral anticoagulants, with no difference in the risk of major bleeds
• Some clinicians have elected to treat these patients with "triple therapy" with an OAC + DAPT to reduce both ischemic stroke and MI/stent thrombosis. Observational studies provide conflicting results:
  • Triple therapy confers a 12% annual risk of hospitalization or death due to bleed, though so does clopidogrel + OAC
  • Triple therapy is associated with double the risk of major bleed compared to OAC + single antiplatelet, but with a reduced risk of death
• 2 prior RCTs have evaluated the ideal antithrombotic therapy in AF patients with PCI:
  • The open-label WOEST trial randomized 573 patients undergoing PCI with an indication for OAC to either double therapy (clopidogrel + warfarin to target INR 2.0-3.0) or triple therapy (clopidogrel + ASA + warfarin). Notably, only ~1/3 of patients underwent PCI for MI, & only ~70% took an OAC for AF. At a median 1 year, double therapy had a lower risk of any bleeding (19% vs 44%, NNT 4) and death (2.5% vs 6.3%, NNT 27). The differences in major bleeding (3.2% vs 5.6%) and stent thrombosis (1.4% vs 3.2%) were not statistically significant.
    • Bottom line: Lower risk of any bleed & death; No statistically significant difference in major bleeding or other outcomes.
  • The open-label ISAR-TRIPLE randomized 614 patients undergoing PCI with drug-eluting stent who were taking OAC for at least 1 year to either 6 weeks or 6 months of clopidogrel (added to ASA + OAC). ACS was the indication for <20% of stent placements, and AF was the indication for OAC in ~85% of patients. There was no statistically significant difference in the primary outcome of death, MI, stent thrombosis, stroke or major bleeding from week 6 to month 9 (6-week 4.6%, 6-month 6.4%). There were also no statistically significant differences in CV endpoints of CV death, MI, stent thrombosis or ischemic stroke (6-week 1.4% vs 6-month 3.4%) or major bleeding (2.4% in both groups). The only statistically significant difference was a lower risk of any bleeding (BARC definitions; 20.5% vs 27.9%, NNT 14) with the shorter course of clopidogrel.
    • Bottom line: Lower risk of any bleeding; No statistically significant difference in major bleeding or other outcomes.

Internal validity

• Low risk of allocation bias (central randomization)
• Unclear risk of certain biases
  • Performance bias
    • Open-label
    • Anticipated DAPT duration selected & recorded prior to randomization
    • PPI/H2RA use for gastroprotection encouraged but not mandated for all trial participants
  • Detection bias:
    • Open-label
    • Most outcomes included in the primary safety outcome were subjective "soft" outcomes ("bleeding requiring medical attention" accounted for >90% of bleeding outcomes reported) & prone to biased reporting from patients, and subsequently from the treating clinician
    • The more important & objective outcomes such as major hemorrhage or death occurred infrequently (~2-3%), with too few events to provide firm conclusions about differences or lack thereof
    • Blinded adjudication: All efficacy endpoints & a portion of bleeding events reported by patients & their clinicians were subsequently adjudicated by investigators blind to assigned intervention
  • Attrition bias:
    • Analyzed only patients who took at least 1 dose of the study drug (modified intention-to-treat [mITT] population)
    • None in the mITT population were lost-to-follow-up, but more patients in the triple therapy group discontinued the study regimen prematurely
• Low risk of reporting bias (all clinically-important outcomes reported)

 

 

Interpretation of study outcomes

• Study underpowered to demonstrate superiority or non-inferiority of any intervention to each other for the outcomes of cardiovascular events or major hemorrhage
  • Could not rule out a 3-fold increased risk of stroke in the double therapy/ATLAS regimen versus triple therapy.
• Contrary to WOEST, PIONEER did not demonstrate a lower risk of death with the modified double therapy regimen vs triple therapy. Due to the low number of events, either finding could be due to chance (false-negative in PIONEER or false-positive in WOEST).
• The risk of major hemorrhage over 1 year with triple therapy (3.3%) was comparable to that in the ISAR-TRIPLE trial (2.4% at 9 months), & substantially lower than in the Danish registry (12.2%) and the WOEST trial (5.6%).

DAPT Score - Risk stratifying for DAPT x12 vs >12 months after PCI

Yeh RW, et al. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016;315:1735-49.

Bottom line: The DAPT Score is an easy-to-use tool to help select patients for extended DAPT duration after PCI, but it hasn't yet been sufficiently validated in a real-world population to use in practice.

Particularly important issues that may crop up in future validation include poor discrimination in a real-world heterogeneous population (& already fairly low with c-statistic ~0.70 or less in RCT populations), poor calibration, & over-simplification from combining ischemic & bleeding risk into a single score.

Context

• Until publication of the DAPT trial in 2014, limited evidence to guide optimal dual antiplatelet therapy (DAPT) duration following acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) with drug-eluting stent (DES) placement, so guidelines routinely recommended 12 months for all patients.

• Numerous subgroup analyses looked at patient characteristics that could be used to identify patients that could obtain a net benefit from prolonged DAPT, but these only look at 1 characteristic at a time;

  • Decisions on DAPT duration are complex and require integration of multiple characteristics.

• The newest AHA guidelines on DAPT recommend using a risk prediction tool such as the DAPT Score to aid in deciding on DAPT duration.

DAPT score

• Available here

• Score-based risk calculator ranging from -2 to 10, with lower scores representing an unfavorable benefit/risk ratio from extended DAPT and higher scores representing a greater net benefit from extended DAPT.

• The investigators divided the score into 2 categories:

  • With a DAPT Score <2 (-2 to 1), extending DAPT >1 yearr:

    • NNT 167 for MI/stent thrombosis

    • NNH 72 for GUSTO moderate-severe bleed

  • With a DAPT Score >2 (2-10), extending DAPT >1 year resulted in:

    • NNT 53 for MI/stent thrombosis

    • NNH 250 for GUSTO moderate/severe bleed

Level of evidence

• Derivation, internal validation & external validation: 2a (level of evidence ranges from 1 [highest] to 4 [lowest])
• Hierarchy of evidence for clinical prediction rules: Level 3 (validated in only 1 narrow prospective sample)

Study population

• Data sources:
  • Derivation & internal validation: RCT (DAPT trial)
  • External validation: RCT (PROTECT trial)
• Study setting: Outpatient cardiology follow-up
• Patient population: Individuals undergoing PCI with DES (elective or urgent)
• Adequate proportion of patients with each predictor variables?
  • es, in DAPT ~300 patients (3%) with rarest included predictor variable (stent in vein graft); other characteristics present in >2000 (>20%) of patients

Predictor variables

• 37 predictor variables initially considered
  • Demographics: Age, sex, race
  • CV history: HF or LVEF <30%; prior CABG, PCI or MI; PAD; stroke/TIA; AF
  • Comorbidities: BMI; cancer at time of randomization; current smoking; diabetes; history of major bleed; hypertension; renal insufficiency (SCr >2 mg/dL)
  • Procedural characteristics: >2 lesions/vessel; bifurcation stenting; coronary lesion class C; number of stents; number of treated vessels; presentation with MI; pre-procedural stenosis; prior brachytherapy; prior in-stent thrombosis; severe coronary calcification; stenting of vein graft; stent diameter; stent type; thrombus-containing lesion; TIMI grade flow post-procedure; total stent length; unprotected left main stenting
  • Meds: Randomization arm (DAPT 12 vs >12 months); clopidogrel vs prasugrel; statin at time of randomization
• Checklist for what makes good predictor variables (all were met):
  • Clear & reproducible predictor definition
  • Reliable 
  • Available at time of decision
• Assessors were blind to the outcome at time of predictor variable determination (inherent in prospective design of these RCTs)
• Predictor variable definition consistent between derivation, internal validation & external validation cohorts

Outcome

• Composites of:
  1. Death/MI/stroke
  2. MI/stent thrombosis
  3. Moderate/severe bleed (GUSTO definitions)
• Checklist for what makes good outcomes (all were met):
  • Clinically important
  • Clear & reproducible definition
• Caveat: Adjudicators not blind to predictor variables at time of outcome assessment (though blind to the existence of the DAPT Score derivation & related hypotheses)

Accuracy

• Analysis appropriate & well-described: Hazards ratios derived using Cox multivariable regression
• Handling of missing data: Unclear
• Overfitting? Low risk (far more than rule-of-thumb 10 outcome events/predictor variable included in statistical model)
• Discrimination (tool's ability to distinguish between patients who do & those who don't experience the outcome, using the c-statistic, where a c-statistic of 0.50 = model is as good as chance, & a c-statistic of 1.00 = perfect discrimination): Good, not great
  • Internal validation (DAPT):
    • Ischemic outcome: 0.70 (moderate)
    • Bleeding outcome: 0.68 (moderate)
  • External validation (PROTECT): c-statistics = 0.64 for ischemic & bleeding outcomes
• Calibration (tool's ability to correctly estimate the incidence of an outcome in a population)
  • Internal validation (DAPT): Good
  • External validation (PROTECT): Overestimated risks of outcomes (because PROTECT enrolled a lower-risk population than the DAPT trial). Good after re-calibration for this lower incidence in the overall study population.

Generalizability (also known as transportability)

• To RCT populations similar to the DAPT & PROTECT trials: Excellent
• To different geographical areas, clinical settings, providers (e.g. GPs, internists, pharmacists, nurses. etc): Unknown
• To different follow-up intervals (e.g. extended DAPT beyond 3 years): Unknown
• To patients with different spectra of coronary artery disease or comorbidities: Unknown
• To patients on different antiplatelet agents (e.g. ticagrelor) or on anticoagulant therapy (e.g. DOAC for AF): Unknown

DAPT - Comparison of 12 vs >12 of DAPT after drug-eluting stent placement

Mauri L, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155-66.

Bottom line: In patients who go 1 year after drug-eluting stent placement with good adherence to DAPT without a CV or bleeding event, extending DAPT for another 18 months will reduce the risk of MI (NNT 50), but increase the risk of death (NNH 200) & moderate-to-severe bleeding (NNH 112). Benefits are far less impressive in patients receiving 2nd generation drug-eluting-stents, which are the sole drug-eluting stents implanted in current practice.

Context

• Concerns were raised in 2006 about an increased risk of late (month 1-12 after stent placement) & very late (>1 year) stent thrombosis with 1st generation drug-eluting stents (Cypher, Taxus) versus bare-metal stents
  • DAPT duration recommendations at the time were 3-6 months
  • End of 2006: Label change & AHA recommendations for 12 months of DAPT after drug-eluting stent placement
  • True ideal duration of DAPT unknown; further reduction of very late stent thrombosis & resulting MI with durations >12 months?
• From 2008 onward, newer "2nd generation" drug-eluting stents with faster endothelial healing over the stent & decreased thrombogenicity entered the market
  • Includes everolimus-eluting (Xience) & zotarolimus-eluting (Endeavor, Resolute) stents

Issues with internal validity?

• Low risk of allocation, performance and detection bias: Randomized, allocation-concealed, double-blind trial analyzed using the intention-to-treat population
• Unclear risk of attrition bias: ~5% of patients were lost-to-follow-up or withdrew consent

Patients (n=9961)

• Inclusion
  • >18 y/o
  • PCI with drug-eluting stent placement
  • Received 12 months of DAPT after stent placement
  • Adherence 80%+ during 1st year of DAPT
  • No adverse events during 1st year of DAPT (MI, stroke, repeat coronary revascularization, stent thrombosis, major bleed)
• Exclusion
  • Life expectancy <3 y
  • Planned surgery in next 30 months requiring antiplatelet discontinuation >14 days
  • Stent diameter <2.25 mm or >4.0 mm
  • Need for oral anticoagulation
  • Switched P2Y12 inhibitor type or dose in first 6 months of DAPT
• 22.866 screened (11% had events within 1 year) -> 9961 randomized -> 9499 analyzed
• "Average" patient
  • Age 62 y
  • Female 25%
  • White 91%
  • Indication for PCI: STEMI (10%), NSTEMI (15%), unstable angina (17%), stable angina (38%), other (20%)
  • CV history
    • Prior MI 22%
    • Prior PCI 31%
    • Prior CABG 11%
    • Stroke/TIA 3%
    • HF <5%
    • PAD 6%
  • CV risk factors
    • Current smoker 25%
    • HTN 75%
    • Diabetes 31%
  • PCI characteristics
    • Type of stent
      • 1st generation: Paclitaxel (27%), sirolimus (11%)
      • 2nd generation: Everolimus-eluting (47%), zotarolimus (13%)
    • Other PCI characteristics
      • Treated vessel: Left main (<1%), LAD (41%), RCA (33%), LCx (22%), graft (3%)
      • 1.5 stents
      • Minimum diameter <3 mm 47%
      • Total length 28 mm

Intervention

• I: DAPT with clopidogrel (2/3) or prasugrel (1/3) x30 months
  • Investigator's choice: Clopidogrel 75 mg/d or prasugrel 10 mg/d (5 mg/d if weight <60 kg)
• C: DAPT x12 months, then matching placebo
• Co-interventions
  • Drug-eluting stents used in this trial: 1st generation (Cypher, TAXUS), 2nd generation (Endeavor, Xience)
  • ASA 75-162 mg/d

Generalizability

• Population: Limited to a relatively low-risk population; individuals with stent placement (for ACS or stable angina) without any CV or bleeding event x12 months
  • Patients with a CV event in this timeframe would inherently be at higher risk & therefore have a larger absolute benefit from prolonged DAPT
  • Patients with a bleeding event in this timeframe would inherently be at higher bleed risk, & therefore have a higher risk of harm from prolonged DAPT
• Intervention: Most used clopidogrel, but ~1/3 of patients used prasugrel (investigator's choice)
  • Ticagrelor not used in this trial, but risk/benefit of prolonged ticagrelor-based DAPT likely similar to prasugrel (extrapolating from PLATO & PEGASUS ), with additional adverse events with ticagrelor (dyspnea & gout)

Results during months 12-30 from stent placement (randomized period)

• Death, MI, stroke (primary outcome 1): 4.3% with DAPT x30 months, 5.9% with DAPT x12 months, hazard ratio 0.71 (0.59-0.85)
  • Death: 2.0% vs  1.5% (NNH 200, p=0.05)
  • MI: 2.1% vs 4.1% (NNT 50), HR 0.47 (0.37-0.61)
    • Stroke: 0.8% vs 0.9% (p=0.32)
• Stent thrombosis, definite or probable (primary outcome 2): 0.4% vs 1.4% (NNT 100), HR 0.29 (0.17-0.48)
  • Safety
    • Discontinued study drug: 21.4% vs 20.3% (p=0.18)
    • Moderate-severe bleed (GUSTO definition): 2.5% vs 1.6% (NNH 112)
• Subgroup analyses: Newer stents have lower risk of CV events & stent thrombosis, as well as lower relative & absolute benefit from prolonged DAPT
  • Benefit of prolonged DAPT on CV events based on stent type:
    • 1st generation NNT <32
    • 2nd generation NNT >77

Other consideration

• 11 RCTs (n=33,051) have compared DAPT durations ranging from 3 to 48 months following drug-eluting stent placement
  • In 1 meta-analysis of 10 RCTs, "longer" vs "shorter" DAPT duration resulted in
    • Decreased risk of MI by -0.8%/year (NNT 125)
    • Increased risk of 
      • Death by +0.2%/year (NNH 500)
      • Major bleed by +0.6%/year (NNH 167)
• Subgroups analyses
  • Patients based on presenting for MI vs no MI, benefit on death/MI/stroke
    • MI: NNT 35
    • No MI: NNT 112 (p=0.08)
  • Patients with everolimus-eluting stent confirms a general unfavorable benefit-risk profile in patients with 2nd generation stents:
    • Increased risk of death (NNH 91) & moderate-severe bleed (NNH 84)
    • Reduced risk of MI (NNT 112) & stent thrombosis (NNT 250)
    • No difference in composite death/MI/stroke

PEGASUS - Long-term ticagrelor in patients with prior MI

Bonaca MP, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791-800.

Bottom line: In patients with prior MI >1 year ago + 1 additional CV risk factor, ticagrelor 60 mg PO BID reduced the risk of MI (NNT 125) & stroke (NNT 250) over 2-3 years, though this was offset by an increased risk of adverse events, including major bleed (NNH 84), dyspnea (NNH 11) and gout attacks (NNH 200).

The "full PLATO" dose of 90 mg BID further increased the risk of adverse events without increasing efficacy over the 60 mg BID dose.

 

Patients (n=21,162)

• Inclusion
  • Age 50+ years
  • MI 1-3 y before enrollment
  • 1 or more additional risk factors:
    • Age 65+ years
    • >1 prior MI
    • Multivessel CAD
    • CKD with eGFR <60
    • Diabetes (requiring meds)
• Exclusion
  • Prior ischemic stroke, intracranial hemorrhage, CNS tumor, intracranial vascular abnormality (e.g. AVM, aneurysm)
  • Prior GI bleed within 6 months
  • Major surgery in past 30 days
  • Bleeding disorder
  • Planned use of oral anticoagulant, P2Y12 inhibitor, dipyridamole, or cilostazol
• "Average" patient
  • Age 65 y
  • Female 24%
  • White 86%
  • CV history
    • 1.7 y since last MI
    • >1 prior MI 16%
    • Multivessel CAD 59%
    • Prior PCI 83%
    • PAD 5%
  • CV risk factors
    • Current smoker 17%
    • HTN 78%
    • CKD (eGFR <60) 23%
    • Dyslipidemia 77%
    • Diabetes 32%

Interventions

• I 1: Ticagrelor 90 mg PO BID (PLATO dose)
• I 2: Ticagrelor 60 mg PO BID (reduced dose)
• Control: Placebo
• Co-interventions:
  • ASA 75-150 mg PO daily 100%
  • Statin 93%
  • ACEI/ARB 80%
  • Beta-blocker 83%

Results @ mean 2.75 years

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• Efficacy
  • Death from any cause: Ticag90 5.2%, ticag60 4.7%, placebo 5.2%
    • Ticag90 vs placebo: Hazard ratio (HR) 1.00 (95% confidence interval 0.86-1.16)
    • Ticag60 vs placebo: HR 0.89 (0.76-1.04)
  • Primary outcome (CV death, MI or stroke): Ticag90 7.8%, ticag60 7.8%, placebo 9.0%
    • Ticag90 vs placebo: HR 0.85 (0.75-0.96; NNT 85)
    • Ticag60 vs placebo: HR 0.84 (0.74-0.95; NNT 85)
  • MI: 4.4% vs 4.5% vs 5.3%
    • Ticag90 vs placebo: HR 0.81 (0.69-0.95, NNT 112)
    • Ticag60 vs placebo: HR 0.84 (0.72-0.98, NNT 125)
  • Any stroke: 1.6% vs 1.5% vs 1.9%
    • Ticag90 vs placebo: HR 0.82 (0.63-1.07)
    • Ticag60 vs placebo: HR 0.75 (0.57-0.98; NNT 250)
• Safety
  • Premature discontinuation: 32.0% vs 28.7% vs 21.4% (NNH 11 & 14, respectively) 
  • Major bleed (TIMI definition): 2.6% vs 2.3% vs 1.1%
    • Ticag90 vs placebo: HR 2.69 (1.96-3.70; NNH 67)
    • Ticag60 vs placebo: HR 2.32 (1.68-3.21; NNH 84)
  • Dyspnea: 18.9% vs 15.8% vs 6.4%
    • Ticag90 vs placebo: HR 3.55 (3.16-3.98; NNH 8)
    • Ticag60 vs placebo: HR 2.81 (2.50-3.17; NNH 11)
    • Severe dyspnea: 0.4% vs 0.4% vs 0.1%
  • Gout: 2.3% vs 2.0% vs 1.5%
    • Ticag90 vs placebo: HR 1.77 (1.32-2.37; NNH 125)
    • Ticag60 vs placebo: HR 1.48 (1.10-2.00; NNH 200)

Issues with internal validity?

• No: Randomized, allocation-concealed, double-blind trial with low loss-to-follow-up (~1%) analyzed using the intention-to-treat population

Additional PEGASUS publications

• A secondary analysis evaluated the impact of timing of enrolment into PEGASUS relative to previous P2Y12 inhibitor use
  • Test for interaction p<0.001 for primary outcome, no difference in relative risk increase of bleeding
    • Greatest relative risk reduction seen for those within 30 days of previous P2Y12 inhibitor use (HR 0.73, 0.61-0.87 for either ticagrelor dose vs placebo)
      • Primary outcome @ 3 years: Ticagrelor 7.7%, placebo 9.9% (NNT 46)
      • TIMI major bleeding @ 3 years: Ticagrelor 2.5%, placebo 0.7% (NNH 56)
    • No statistically significant benefit in those who discontinued P2Y12 inhibitor 30-365 days before PEGASUS (HR 0.86, 0.71-1.04) & >1 year before pegasus (HR 1.01, 0.80-1.27)
  • Despite a greater relative & absolute risk reduction in those with P2Y12 inhibitor discontinuation <30 days prior to PEGASUS enrolment, ischemic benefit still mostly offset by increased risk of major bleed

EMPA-REG - Empagliflozin for CV risk reduction in T2DM with hx of CVD

Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.

Bottom line: In patients with T2DM and CVD, empagliflozin (at either dose of 10 mg or 25 mg daily) reduced the risk of death (NNT 39) & CV events (NNT 63) over 3 years.

Patients

• Inclusion
  • Adults with T2DM
    • No glucose-lowering agents in previous 12 weeks: 7-9%
    • Receiving glucose-lowering agents, stable x12 weeks: 7-10%
  • Established CVD, defined as any of the following:
    • MI >2 months ago
    • CAD (confirmed with angiography)
    • Stroke >2 months ago
    • PAD documented by
      • Limb revascularization or amputation
      • Peripheral artery stenosis >50% on angiography or non-invasive evaluation
      • ABI <0.9 on at least 1 side
• Key exclusion criteria
  • Cancer within last 5 y
  • Stroke/TIA within 2 months
  • Planned cardiac surgery or PCI in next 3 months
  • BMI >45
  • Blood dyscrasias or any disorder causing hemolysis or unstable RBCs
  • eGFR <30 mL/min/1.73 m^2
  • ALT, AST or ALP >3x ULN
• 11,531 individuals screened across 590 sites in 42 countries -> 7028 randomized -> 7020 analyzed
• "Average" patient
  • Age 63 y
  • Male 72%
  • White 72%, Asian 22%, Black 5%, other 1%
  • Geography: Europe 41%, North America 20%, Asian 19%, Latin America 15%, Africa 4%
  • CV risk factors
    • CAD 76% (multivessel 47%)
    • MI 46%
    • CABG 24%
    • Stroke 24%
    • PAD 20%
  • Time since T2DM dx: >10 y (57%), 5-10 y (25%), 1-5 y (16%)
  • Wt 87 kg, BMI 31
  • BP 136/77
  • Lipids: total 4.2, LDL 2.2, HDL 1.1 mmol/L
  • A1c 8%
  • Meds
    • Metformin 74%
    • Insulin 49%
    • Sulfonylurea 43%
    • DPP-4 inhibitor 11%
    • Antihypertensives 95%
      • ACEI 80%
      • Beta-blocker 64%
    • ASA 83%
    • Statin 76%

Interventions & co-interventions (median 2.6 y)

• I: Empagliflozin 10 mg or 25 mg
  • A1c lowered by 0.5-0.6% at 12 weeks vs placebo
• C: Matching placebo
• Co-interventions:
  • 1st 12 weeks after randomization: No change to glycemic management unles fasting glucose >13.3 mmol/L
  • After 12 weeks: Adjustment to glucose-lowering therapy according to local guidelines

Results @ median 3.1 y

• Results for both doses of empaglifozin were similar, and therefore pooled
• Statistically significant reduction in:
  • The primary outcome (CV death, MI, stroke): Hazard ratio (HR) 0.86, 95% confidence interval 0.74-0.99 (p=0.04)
    • 10.5% vs 12.1% (NNT 63)
  • Death: HR 0.68 (0.57-0.82)
    • 5.7% vs 8.3% (NNT 39)
  • HF hospitalization: HR 0.65 (0.50-0.85)
    • 2.7% vs 4.1% (NNT 72)
• No statistically significant difference:
  • MI: HR 0.87 (0.70-1.09) - 4.8% vs 5.4%
  • Stroke: HR 1.18 (0.89-1.56) - 3.5% vs 3.0%
  • Coronary revascularization: HR 0.86 (0.72-1.04) - 7.0% vs 8.0%
• Safety
  • Serious adverse events: 38.2% vs 42.3% (NNT 25, p<0.001)
  • Premature discontinuation: 23.4% vs 29.3%
  • Hypovolemia: 5.1% vs 4.9%
  • Acute kidney injury: 1.0% vs 1.6%
  • UTI: 18.0% vs 18.1% (complicated 1.7% vs 1.8%)
  • Genital infection: 6.4% vs 1.8% (NNH 22)
  • DKA: 0.1% vs <0.1%
  • Hypoglycemia (glucose <3.9 mmol/L or requiring assistance): 27.8% vs 27.9%
• Numerous subgroup analyses were performed, which demonstrated inconsistent subgroup interactions with the primary outcome and CV death

Issues with internal validity?

• No: Randomized, allocation-concealed, blinded trial with low loss-to-follow-up (<0.1%) analyzed using intention-to-treat principles 
• Run-in: 2-week open-label placebo run-in

Additional considerations

• The reduction of CV events became apparent after only 3 months. Previous trials of diabetes drugs or glycemic control goals have never demonstrated a benefit this early, suggesting that the apparent benefit of empagliflozin may have resulted from another mechanism. 
• The reduction int the primary CV event resulted mainly from a reduction in CV death, but not MI or stroke. This further argues against glycemic control as the beneficial mechanism of empagliflozin.