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.
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:
- Age 21+ y/o
- (designed to have >60% of patients 65+ y/o)
- Required DAPT (ASA + clopidogrel) x 12+ months, specifically
- Coronary stent implantation
- Age 21+ y/o
- 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
- >21 days of clopidogrel or another thienopyridine prior to randomization
- Needs oral anticoagulation
- Recent fibrinolytic therapy
- Steroids equivalent to >5 mg/d of prednisone
- 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%
- Current smoker 13%
- HTN 80%
- Diabetes 30%
- Dyslipidemia 78%
- Current smoker 13%
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)
- 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)
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.