Statin dose & CV events

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Bottom-line:

  • In patients with CAD, high-dose statin therapy vs low/moderate statin doses further reduces the risk of CV events by an ~15% (relative risk reduction).

  • In Japanese patients with CAD, moderate-dose statin reduces the risk of CV events and death versus a very low dose by ~19% (relative risk reduction).

 

    Summary of 6 largest trials (n=52,666) 

    statin dose.png

    Latest trial: REAL-CAD summarized below:

    • Design: RCT with open-label, blinded-outcome-adjudication design
    • 13,054 randomized -> 12,413 analyzed in ITT population
    • Included: 
      • Age 20-80 y/o +
      • CAD (history of ACS, prior PCI/CABG, or angiographic coronary artery stenosis >75%) +
      • LDL-C >2.6 mmol/L (excluded if LDL-C >3.0 mmol/L on pitavastatin 1 mg/d during run-in phase)
    • Excluded: Known FH, contraindication to statin, HF NYHA 3-4 or LVEF <30%
    • Baseline characteristics:
      • Age 68 y, male 83%
      • Prior MI 52% (mean 5 years ago), HF 5%, ischemic stroke 7%
      • Statin before run-in: 91%, ASA 92%, ACEI/ARB 67%, beta-blocker 42%
      • LDL-C: before run-in 2.4 mmol/L, after run-in on pitavastatin 1 mg/d: 2.2 mmol/L
    • Interventions: Pitavastatin 4 mg/d (equivalent to ~atorvastatin 20-40 mg/d)
      • Reduced LDL-C by an additional 0.4 mmol/L (18%) vs lower dose
    • Control: Pitavastatin 1 mg/d (equivalent to ~atorvastatin 5 mg/d)
    • Follow-up: 3.9 years (median)

    Results from 5 largest RCTs

    statin dose outcomes.png

    Results from REAL-CAD

    • Primary outcome (CV death, MI, ischemic stroke or unstable angina requiring hospitalization):
      • Higher dose 4.3%, lower dose 5.4% - 1.1% absolute risk reduction (ARR)
      • HR 0.81, 95% CI 0.69-0.95
    • Death: 3.3% vs 4.2% - 0.9% ARR; HR 0.81, 0.69-0.98
    • MI: 0.6% vs 1.2% - 0.6% ARR; HR 0.57, 0.38-0.83
    • Any muscle complaints: 1.9% vs 0.7% - 1.2% absolute risk increase
    • No difference in rhabdo (<0.1%), CK increase >5xULN (0.7% vs 0.6%) or liver enzyme elevations (2.9% vs 2.7%, p=0.46)

    Meta analysis comparing high- to moderate-dose statins @ mean 2.5 years

    • Systematic review of 10 databases (including MEDLINE, Embase, CENTRAL) to Dec 2010
    • Included 10 RCTs enrolling 41,778 patients
    • Results
      • Statistically significant reduction with higher dose in
        • Coronary death or MI: Relative risk 0.90 (0.84-0.96), low heterogeneity (I^2=0%) in 9 trials
        • Stroke (excluding TIA): RR 0.86 (0.77-0.96), I^2=0% in 10 trials
          • Non-fatal MI: RR 0.82 (0.76-0.90), I^2=0% in 5 trials
      • No statistically significant difference in
        • Death: RR 0.92 (0.83-1.03), I^2=38% in 10 trials
      • Lab abnormalities, elevated
        • Liver enzymes, for ALT: RR 1.57 (1.29-1.91)
        • CK: RR 2.86 (2.02-4.04)
      • Subgroup analysis limited to 3 trials of patients with recent ACS (A-Z, PROVE-IT, Colivicchi et al) found possible reduction in death with higher dose (RR 0.75, p=0.005)

    Article links

    de Lemos JA, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: Phase Z of the A to Z Trial. JAMA 2004;292:1307-16.

    Cannon CP, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.

    Pedersen TR, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: The IDEAL study: A randomized controlled trial. JAMA 2005;294:2437-45.

    LaRosa JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35.

    SEARCH Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin dialy in 12 064 survivors of myocardial infarction: A double-blind randomised trial. Lancet 2010;376:1658-69.

    Taguchi I, et al. High-dose versus low-dose pitavastatin in Japanese patients with stable coronary artery disease (REAL-CAD): a randomized superiority trial. Circulation 2018;137:1997-2009.

    MIRACL - High-dose statin early post-ACS

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    Schwartz GG, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: The MIRACL study: A randomized controlled trial. JAMA 2001;285:1711-8.

    Bottom line: In patients with ACS (without Q wave formation & not treated with PCI), high-dose atorvastatin reduced the short-term risk of symptomatic ischemia (NNT 46) or stroke (NNT 125).

    Reporting of safety events was limited, but high-dose atorvastatin increased the likelihood of liver enzyme elevation >3x ULN, which has unknown clinical significance.

     

    Patients (n=3086)

    • Included
      • Age 18+ y
      • Within 24-96h after hospital admission for ACS (unstable angina or non-Q-wave MI)
    • Excluded
      • Total cholesterol >7 mmol/L
      • Coronary revascularization planned or anticipated
      • Hx of Q-wave MI within 4 weeks, CABG within 3 months, PCI within 6 months
      • LBBB or paced ventricular rhythm
      • HF with NYHA functional class IIIb-IV
      • Treatment with other lipid-lowering agents or vitamin E
      • Severe anemia, renal failure requiring dialysis, ALT >2x ULN, insulin-dependent diabetes
    • ? screened -> 3086 randomized & analyzed
    • Typical patient in study
      • Age 65 y
      • Female 35%
      • ACS: UA 46%, non-Q-wave MI 54%
      • PMHx
        • Prior MI 25%, CABG 7%, PCI 3%
        • HF 8%
        • CVA 9%
        • Peripheral vascular disease 9%
        • Smoker 28%
        • HTN 55%
        • Diabetes 23%
      • Meds
        • ASA ~90%, OAC 8%
        • ACEI or ARB ~50%
        • Beta-blocker 77%
        • Used in hospital: Heparin 75%, fibrinolytic 8%

    Intervention

    • I: Atorvastatin 80 mg PO once daily
      • Patients on average took 86% of all doses
      • 11.2% discontinued prematurely
    • C: Matching placebo
      • 10.3% discontinued prematurely

    Results @ 4 months

    • LDL
      • @ baseline: 3.2 mmol/L
      • @ 4 months: Atorvastatin 1.9 mmol/L, placebo 3.5 mmol/L (46% reduction vs placebo)
    • Statistically significant reduction in
      • Primary outcome (death, non-fatal MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization): 14.8% vs 17.4% (hazard ratio 0.84, 0.70-1.00), NNT 39
      • Symptomatic ischemia with objective evidence: 6.2% vs 8.4% (HR 0.74, 0.57-0.95), NNT 46
      • Stroke (fatal or non-fatal): 0.8% vs 1.6% (HR 0.50, 0.26-0.99), NNT 125
    • No statistically significant difference in
      • Coronary revascularization: 16.5% vs 16.1%
      • Non-fatal MI: 6.6% vs 7.3%
      • Worsening angina without new objective evidence of ischemia: 5.9% vs 6.8%
      • Death: 4.2% vs 4.4%
      • New/worsening HF requiring hospitalization: 2.6% vs 2.8%
      • Resuscitated cardiac arrest: 0.5% vs 0.6%
    • Safety
      • Liver enzymes >3x ULN at any time: 2.5% vs 0.6% (NNH 53)
      • Myalgias, muscle weakness, CK changes or rhabdo: Not reported

    Generalizability

    • Representative ~intermediate-risk ACS population
      • Despite exclusion of patients Q-wave MI, likely included some STEMI patients, particularly since ~8% received lytic therapy
      • Likely included an ACS population at low-intermediate risk by excluding Q-wave MI, patients planned for revascularization, recent CV event, or any significant non-CV comorbidity
    • Short-term follow-up intended only to evaluate acute effects of high-dose statin therapy; 4-month follow-up precludes meaningful evaluation of long-term benefit, particularly for "secondary prevention"

    Internal validity

    • Allocation & performance bias
      • Insufficient description of random-sequence generation, allocation concealment - likely low risk
    • Low risk of detection bias
      • Assuming proper allocation concealment & blinding, though not sufficiently described
      • Endpoints adjudicated by committee of cardiologists unaware of treatment allocation
    • Low risk of attrition bias
      • Intention-to-treat analysis including all randomized patients
      • <1% lost to follow-up

    Corroborating evidence from other studies

    • A secondary analysis of the PROVE IT trial evaluating the early and late benefit of high-intensity statin (atorvastatin 80 mg/d) versus low-intensity statin (pravastatin 40 mg/d) found a statistically significant improvement in the first 30 days:
      • 30-day risk of composite CV outcome (death, MI or ACS hospitalization): High-intensity 3.0% vs low-intensity 4.2%, HR 0.72 (0.52-0.99)

    ACE inhibitors post-MI (CCS-1, CONSENSUS II, GISSI-3, ISIS-4, SMILE; AIRE, SAVE, TRACE)

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    Bottom line:

    • Short-term use of ACE inhibitors reduces the risk of death post-MI regardless of HF signs/symptoms or LVEF at time of initiation (NNT 125-200).

      • Note: The previously-reviewed HOPE trial then supports continuing ACE inhibitors in patients without HF or LV dysfunction. 

    • In patients with either clinical HF or reduced LVEF post-MI, long-term use of ACE inhibitors reduce the risk of death (NNT 14-20) and severe HF.

     

    Short-term use of ACEI in MI all-comers:

    • Oral captopril versus placebo among 13,634 patients with suspected acute myocardial infarction: Interim report from the Chinese Cardiac Study (CCS-1). Lancet 1995;345:686-7.
    • ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995;345:669-85.
    • Swedberg K, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med 1992;327:678-84.
    • Gruppo Italiano per lo Study della Sopravvivenza nell'infarcto Miocardico. GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after myocardial infarction. Lancet 1994;343:1115-22.
    • The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995;332:80-5.

    Long-term use of ACEI started shortly post-MI with LV dysfunction or clinical HF:

    • Pfeffer MA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: Results of the Survival and Ventricular Enlargement trial. N Engl J Med 1992;327:669-77.
    • The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-8.
    • Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995;333:1670-6.

    Issues with internal validity?

    • No: All but 1 trial double-blind (GISSI-3) with measurement of objective outcome (all-cause mortality) and consistency between all trials.

    Patients

    5 trials enrolled "all-comer" acute MI patients, regardless of the presence/absence of clinical HF or LVEF

    About 20% of patients in the "all comer" trials had clinical HF. LVEF was not routinely measured & is not reported in the original trial reports

    3 trials enrolled patients early after an MI if they had either clinical HF (AIRE) or reduced LVEF (SAVE, TRACE) for enrolment

    The majority of patients in the 2 trials of patients with LV dysfunction (SAVE, TRACE) did not have any clinical signs of HF at baseline despite an average LVEF ~30%

    Generalizability: Who do these results apply to?

    • Taken together, these 8 trials enrolled any patient within ~2 weeks of an MI with or without clinical HF or LV dysfunction in the fibrinolytic/pre-early invasive management era, as long as they did not have an absolute contraindication to ACEI such as SBP <90, AKI or hyperkalemia (exclusion criteria common to 2+ trials)
    • Baseline use of concomitant medications (ASA, beta-blockers, etc) was variable, & overall suboptimal (ASA use ranged 55-94%)

    Interventions

    • Captopril studies
      • CCS-1: 6.25 mg PO test dose, followed by 12.5 mg PO TID x28 days
      • ISIS-4: 6.25 mg PO test dose, then 12.5 mg 2h later, then 25 mg 10h later, then 50 mg PO BID x28 days
        • 17% discontinued captopril before discharge
      • SAVE: Initial dose 6.25-12.5 mg PO TID, titrated up to 25 mg PO TID by hospital discharge, then increased to 50 mg PO TID & continued for trial duration (mean 3.3 y)
    • Enalaprilat/enalapril (CONSENSUS II)
      • Enalaprilat 1 mg IV over 2h, then enalapril 2.5 mg PO BID, doubled daily as tolerated up to 20 mg PO BID on day 5 onward & continued for trial duration (41-180 days)
    • Lisinopril (GISSI-3)
      • 5 mg PO daily x2 days, then 10 mg PO daily x6 weeks
      • 18% discontinued by week 6
    • Ramipril (AIRE)
      • 2.5 mg PO BID x2 days, then 5 mg PO BID for trial duration (mean 1.25 y)
        • 86% discharged on 10 mg/d
    • Trandolapril (TRACE)
      • 1 mg PO daily x2 days, then 2 mg PO daily x4 weeks, then 4 mg PO daily for trial duration (2-5.1 y)
    • Zofenopril (SMILE)
      • 7.5 mg PO BID x1 day, doubled daily to target 30 mg PO BID, continued for total 6 weeks

    Results

    The 5 all-comer trials all evaluated outcomes in the short term, & all but CONSENSUS II (which initiated ACEI therapy as IV) demonstrated a reduction in the incidence of death +/- HF with NNT ~125-200 for death at 4-6 weeks

    The trials of patients with clinical HF/LV dysfunction post-MI all evaluated outcomes beyond 1 year, with all trials demonstrating a mortality benefit that ranged from NNT 14-20 at ~1-5 y. Superficially, the greatest absolute benefit was seen in the AIRE trial, which enrolled only patients with clinical HF

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

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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

     

    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%).

      PEGASUS - Long-term ticagrelor in patients with prior MI

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      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

        • 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