ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use
Conclusions are:
1. The Assessment of Epidemiologic Evidence Supporting a Significant Clinical Interaction Between PPIs and Thienopyridines.
a. The magnitude of association in positive observational studies reviewed is small to moderate (HR or OR: <2), but associations of this magnitude in nonrandomized observational studies may be due to residual differences in patient characteristics between study groups. The only available randomized trial showed no significant association of omeprazole with CV events, but the confidence limits on this null finding include the possibility of up to a 44% relative increase in CV risk.
b. A significant association between PPI use and increased CV events has been inconsistently demonstrated in observational studies, with the majority of studies showing no association.
c. Although clinical studies with CV events as endpoints are not definitive, the proposed mechanism is biologically plausible, given that a) clopidogrel users with reduced-function genetic polymorphisms in CYP2C19 metabolism have increased rates of CV events; and b) in vitro testing suggests that PPIs may inhibit CYP2C19 metabolism.
d. Experimental pharmacodynamic data consistently indicate that omeprazole diminishes the effect of clopidogrel on platelets. Other pharmacodynamic studies have failed to demonstrate a significant effect of other PPIs on clopidogrel.
2. Risk/Benefit Balance: GI Bleed Risk Versus CV Event Risk. All prescription drugs have favorable and unfavorable effects, and treatment decisions must be based on whether the potential for benefit outweighs the potential for harm.
PPIs are coprescribed with antiplatelet drugs for 1 reason—to reduce the increased risk of GI complications caused by antiplatelet drugs. Prior upper GI bleeding is the strongest and most consistent risk factor for GI bleeding on antiplatelet therapy. Patients with ACS and prior upper GI bleeding are at substantial CV risk, so dual antiplatelet therapy with concomitant use of a PPI may provide the optimal balance of risk and benefit.
Among stable patients undergoing coronary revascularization, a history of GI bleeding should inform the choice of revascularization method; if a coronary stent is selected to treat such patients, the risk/benefit tradeoff may favor concomitant use of dual antiplatelet therapy and a PPI.
Advanced age; concomitant use of warfarin, steroids, or NSAIDs; or H. pylori infection all raise the risk of GI bleeding with antiplatelet therapy. The risk reduction with PPIs is substantial in patients with risk factors for GI bleeding and may outweigh any potential reduction in the CV efficacy of antiplatelet treatment because of a drug–drug interaction. Patients without these risk factors for GI bleeding receive little if any absolute risk reduction from a PPI, and the risk/benefit balance would seem to favor use of antiplatelet therapy without concomitant PPI. The reduction of GI symptoms by PPIs (i.e., treatment of dyspepsia) may also prevent patients from discontinuing their antiplatelet treatment. The discontinuation of antiplatelet therapy in patients with GI bleeding may increase the risk of CV events.
3. Are H2RAs a Reasonable Alternative and in Which Population?. Available data suggest PPIs are superior to H2RAs, but H2RAs may be a reasonable alternative in patients at lower risk for GI bleeding, and in those who do not require PPI for refractory gastroesophageal reflux disease. Cimetidine can competitively inhibit CYP2C19, so other H2RAs might be a better choice in patients treated with clopidogrel.
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