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

    in ,

    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

      PLATO - Ticagrelor in ACS

      in

      Wallentin L, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndrome. N Engl J Med 2009;361:1045-57.

      Bottom line: In patients with ACS (excluding STEMI treated with fibrinolysis, or low-risk unstable angina), ticagrelor reduced the risk of death (NNT 72) or MI (NNT 91) compared to clopidogrel at 1 year. Conversely, ticagrelor increased the risk of certain adverse events compared to clopidogrel, including non-CABG major bleed (NNH 143) and dyspnea (NNH 17).

       

        Patients

        • Inclusion:
          • ACS with symptom onset <24h, including:
            • STEMI treated with primary PCI
            • NSTE-ACS with at least 2 of the following:
              • EKG - ST-segment changes suggesting ischemia
              • Troponin or CK-MB positive
              • 1+ additional risk factor (age 60+ y; previous MI, CABG or ischemic stroke/TIA; CAD with stenosis at least 50% in 2+ vessels; carotid stenosis of at least 50% or cerebral revascularization; CKD with eGFR <60 mL/min; diabetes; PAD)
        • Exclusion:
          • Fibrinolytic <24h before randomization
          • Need for oral anticoagulation
          • Increased risk of bradycardia
          • Taking medication that is a strong CYP 3A inhibitor/inducer
        • ? screened -> 18,624 randomized & analyzed for efficacy (18,421 analyzed for safety outcomes)
        • "Average" patient
          • Age 62 y (75+ y - 15%)
          • Female 28%
          • White 92%
          • ACS final diagnosis
            • STEMI 38%
            • NSTEMI 42%
            • Unstable angina 17%
          • CV history
            • MI 21%
            • PCI 13%
            • CABG 6%
            • HF 5%
            • Non-hemorrhagic stroke 4%
            • PAD 6%
          • CV risk factors
            • Smoker 36%
            • HTN 65%
            • CKD 4%
            • Dyslipidemia 47%
            • Diabetes 25%

        Interventions & co-interventions

        • I: Ticagrelor x up to 12 months (median 9 months)
          • Loading dose of 180 mg PO x1, followed by
          • Maintenance dose of 90 mg PO BID
          • Started at median 11 hours from start of chest pain
          • % of patients taking at least 80% of study drug: 83%
        • C: Clopidogrel x up to 12 months (median 9 months)
          • Loading dose of 300 mg PO x1 (additional 300 mg for total loading dose 600 mg could be given prior to PCI), followed by
          • Maintenance dose of 75 mg PO once daily
          • Started at median 11 hours from start of chest pain
          • % of patients taking at least 80% of study drug: 83%
        • Co-interventions
          • ASA 75-100 mg PO daily (could be increased to 325 mg PO daily for 1st 6 months after stent placement)
          • Procedures
            • Coronary angiography 81%
            • PCI during index hospitalization 61%
          • Other meds at discharge
            • Statin, ACEI/ARB, beta-blocker ~90%
            • PPI 45%

        Results @ median 9 months

        • Statistically significant reduction with ticagrelor in:
          • Death from any cause: 4.5% vs 5.9% (NNT 72)
          • Primary outcome (vascular death, MI, stroke): Ticagrelor 9.8%, clopidogrel 11.7% (NNT 53)
          • MI 5.8% vs 6.9% (NNT 91)
          • Stent thrombosis (probable or definite): 2.2% vs 2.9% (NNT 143)
        • No statistically significant difference in:
          • Ischemic stroke: 1.1% in both groups
          • Hemorrhagic stroke: 0.2% vs 0.1% (p=0.10)
          • Recurrent ischemia: 5.8% vs 6.2% (p=0.22)
        • Safety:
          • Premature discontinuation: 23.4% vs 21.5% (NNH 53)
            • Because of adverse event: 7.4% vs 6.0% (NNH 72)
          • Major bleed: 11.6% vs 11.2% (p=0.43)
            • Not related to CABG: 4.5% vs 3.8% (NNH 143)
          • Dyspnea: 13.8% vs 7.8% (NNH 17)
            • Requiring study drug discontinuation: 0.9% vs 0.1% (NNH 125)
          • Bradycardia requiring pacemaker insertion: 0.9% in both groups
          • Transient reversible increases in SCr & uric acid greater in ticagrelor group
        • Subgroup analyses: 3 of 25 subgroups had a positive test for interaction (each with p=0.05 or lower). Of interest:

        Issues with internal validity?

        • Unclear risk of bias: Incompletely described as a "randomized, double-blind trial". No description of sequence generation, allocation concealment, blinding method.
        • Low risk of attrition bias (loss-to-follow-up <0.5%), and analysis properly included all randomized patients (intention-to-treat population).

        COGENT - PPI added to DAPT in patients after ACS/PCI

        in ,

        Bhatt DL, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010;363:1909-17

        Bottom Line: In patients on clopidogrel + ASA following ACS or stent placement, the addition of omeprazole reduced the risk of clinical GI events (NNT 56 over 6 months), including overt upper GI bleed (NNT 100 over 6 months) with no increase in CV events. Because this trial was stopped early, the benefits (& reported NNTs) may be overestimated.

         

        Integrating This Study Into Practice

        Despite this uncertainty caused from stopping the trial early, it's reasonable to consider a PPI for the duration of dual antiplatelet therapy in patients without prior GI bleed, especially if they have other risk factors or medications that further increase their risk. PPIs should be mandatory in those with prior GI bleed while taking dual antiplatelet therapy unless contraindicated.

         

        Design

        Allocation-concealed "superiority" RCT with all (patients, clinicians, outcome adjudicators) blinded, low loss-to-follow-up (3%), analyzed using the intention-to-treat population. 

        Study stopped early due to abrupt loss of funding (sponsor went bankrupt), leading to accumulation of only ~1/3 of planned GI primary outcome events.

         

        Patients and Setting

        • 15 countries, 393 centers
        • Enrolled between January-December 2008
        • Inclusion criteria:
          1. Age 21+ y/o
            • (designed to have >60% of patients 65+ y/o)
          2. Required DAPT (ASA + clopidogrel) x 12+ months, specifically
            • NSTE-ACS
            • STEMI
            • Coronary stent implantation
        • Key exclusion criteria:
          • Erosive esophagitis, esophageal or gastric varices, non-endoscopic gastric surgery
          • Hx of hemorrhagic stroke, intracranial neoplasm, AVM, aneurysm
          • Active pathological bleeding or hx of hereditary/acquired hemostatic disorder
          • Other indication for gastroprotection (PPI, H2RA, sucralfate, misoprostol)
          • CABG <30 days prior to randomization
          • Cardiogenic shock, refractory ventricular arrhythmias or HF with NYHA class IV at time of randomization
          • Meds
            • >21 days of clopidogrel or another thienopyridine prior to randomization
            • Needs oral anticoagulation
            • Recent fibrinolytic therapy
            • Steroids equivalent to >5 mg/d of prednisone
          • Labs
            • Hemoglobin <100 g/L
            • Platelets <100
        • 4444 screened for eligibility -> 3873 randomized -> 3761 analyzed
        • Average patient:
          • 66 y/o
          • Female 32%
          • Race: White 94%
          • BMI 28
          • CV hx
            • PCI 72%
            • ACS 42%
            • MI 30%
            • PAD 12%
            • Stroke 8%
            • Other vascular disease 50%
          • Hx of GI bleed/ulcer 4%
          • PMHx
            • Current smoker 13%
              • HTN 80%
              • Diabetes 30%
              • Dyslipidemia 78%

         

        Intervention and Control

        • Intervention: Omeprazole 20 mg/d
          • Note: Part of proprietary product CGT-2168, which is a fixed-dose combination of clopidogrel 75 mg + omeprazole 20 mg
        • Control: Placebo
        • Co-interventions common to both groups:
          • ASA 75-325 mg/d + clopidogrel 75 mg/d (planned duration of at least 12 months)

         

        Outcomes

        • Median follow-up 106 days (max 341 days)
          • Note: Outcomes standardized to 180 days
        • Primary efficacy outcome: Composite upper GI events (ulcer complications [perforation, obstruction, bleed], occult bleeds presumed to be from GI, symptomatic non-bleeding ulcer or erosions
        • Primary safety outcome: Composite CV events (CV death/ischemic stroke/non-fatal MI/coronary revascularization)
        • Subgroup analysis: Outcomes did not differ based on baseline H pylori status or use/non-use of non-ASA NSAIDs (randomization stratified based on these 2 factors)

        Outcomes in COGENT trial

         

        Key Considerations & Interpretation

        Trial stopped early: This trial with otherwise low risk of bias was truncated (stopped early) due to loss of funding. Truncated trials tend to exaggerate effect sizes (overestimate benefits/harms), especially when few events have occurred. It's therefore possible that the observed 1.8% absolute risk reduction (NNT 56) in clinical GI events over 6 months seen with omeprazole versus clopidogrel in COGENT based on only 55 GI events may be an overestimate of the real benefit.

        Who does this apply to? 

        • COGENT enrolled patients with new indication for 12 months of DAPT (3/4 PCI, 1/4 ACS), without high-risk features for GI bleed. This is therefore a trial to determine whether routine use of PPIs with DAPT is beneficial in patients at otherwise low risk of GI bleed. Given the issue with stopping early described above, the GI benefits of routinely adding a PPI to DAPT in patients without previous GI bleed/ulcer remain uncertain.
        • This doesn't apply to patients with prior upper GI bleed, where previous trials have demonstrated a large reduction in GI events when adding a PPI to antiplatelet therapy in patients who've previously bled (1, 2). 

        Does this trial prove that PPIs don't increase CV risk? 

        • COGENT wasn't designed to demonstrate the absolute CV safety of omeprazole (or to dispel the possible interaction with clopidogrel), and in isolation can't be used to demonstrate safety. Despite this, omeprazole did not numerically increase the risk of CV events in this population at high risk of CV events (4.9% versus 5.7% with placebo).
        • Interpreted in the context of all of the observational and pharmacokinetic evidence, it appears that the association between PPIs & increased CV events may be due to confounding factors (i.e. weight, smoking, and other lifestyle factors that predispose a patient to be prescribed a PPI) rather than a true cause-and-effect.