Dual antiplatelet therapy (DAPT) has become the standard of care for patients after acute coronary syndrome (ACS) . It is important, however, to consider the risk of gastrointestinal (GI) bleeding with DAPT and whether proton pump inhibitors (PPIs) should be prophylactically prescribed to prevent these events. This article will explore the clinical evidence, rationale, and guidelines for using PPI prophylaxis in ACS patients on DAPT to prevent GI bleeding.
The two components of DAPT, aspirin and a P2Y12 receptor inhibitor, act synergistically to decrease platelet activation and aggregation, and consequently, reduce propagation of coronary thrombosis. Specifically, aspirin inhibits COX-1 from facilitating the conversion of arachidonic acid to thromboxane A2, an important platelet activating factor. P2Y12 receptor inhibitors impair the binding of ADP, another mediator of platelet activation .
Strong evidence exists for using DAPT in ACS patients to prevent major cardiovascular events and death . Patients with ST-segment elevation myocardial infarction receiving aspirin and the P2Y12 receptor inhibitor clopidogrel, compared to those receiving aspirin and placebo, had less cardiovascular death, recurrent myocardial infarction (MI), or recurrent ischemia requiring urgent revascularization (OR 0.64, 95% CI 0.53 to 0.76) in one study . Similarly, patients with unstable angina or non-ST segment elevation myocardial infarction who received aspirin and clopidogrel, compared to those receiving aspirin and placebo, had significantly less cardiovascular death, nonfatal MI, or stroke (RR 0.80, 95% CI 0.72 to 0.90) .
However, both components of DAPT contribute to the risk of GI bleeding, which is associated with patient mortality. Aspirin directly damages gastric mucosa and also inhibits production of prostaglandin, which normally exerts a protective effect by suppressing gastric acid secretion, increasing secretion of mucus and bicarbonate, and increasing mucosal blood flow; inhibition of these processes can result in ulceration and bleeding . Platelet activation and aggregation are further inhibited by aspirin and P2Y12 inhibitors, which prevent resolution of bleeding events [3,7,8]. In the United States general population, the incidence of upper GI bleeding is 0.061% and for lower GI bleeding is 0.032% . However, among patients on DAPT after recent PCI, the incidence of GI bleeding is 2.7%, and those patients with GI bleeds have significantly higher mortality at 30 days (3.7% vs 0%, p<0.01) and at 1 year (18.9% vs 0%, p<0.001) compared to those without the event . Additional risk factors for GI bleeding applicable to this patient population include age over 75 years, prior GI bleeding, H. pylori infection, and concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, or steroids [3,10,11].
When comparing the risk of GI bleeding among different P2Y12 inhibitors, one meta-analysis found that prasugrel was associated with significantly higher risk of GI bleeding than clopidogrel (RR 1.40, 95% CI 1.10 to 1.77) but ticagrelor was not (RR 1.15, 95% CI 0.94 to 1.39) . Incidence of GI bleeding for patients on DAPT may rise in the future, since prasugrel and ticagrelor are increasingly being favored by clinicians over clopidogrel .
Studies suggest that the risk of GI bleeding for patients on DAPT can be reduced by the use of PPIs. The Clopidogrel and Optimization of Gastrointestinal Events (COGENT) trial found that patients on aspirin and clopidogrel randomized to receiving omeprazole, compared to those receiving placebo, had significantly fewer GI events (bleeding, ulceration, erosion, obstruction, or perforation) after 180 days (HR 0.34, 95% CI 0.18 to 0.63) . Similar findings have been confirmed over longer follow up and in settings where other P2Y12 inhibitors and PPIs were used. For example, a retrospective cohort study based on Danish nationwide registries found that for patients on DAPT after MI, PPI prophylaxis, compared to no therapy, was associated with a significant reduction in upper GI bleeding (RR 0.62, 95% CI 0.48 to 0.77) after 1 year of follow up . While both PPIs and H2 receptor antagonists (H2RAs) suppress gastric acid secretion, PPIs have been proven to be the more effective of the two in reducing GI bleeding. A meta-analysis found that patients on DAPT with prophylactic PPI, compared to those with prophylactic H2RA, had significantly less GI bleeding and ulceration (OR 0.28, 95% CI 0.17 to 0.48) .
While PPIs are effective at reducing risk of GI bleeding for patients on DAPT, there is concern that PPIs also reduce the therapeutic effects of DAPT. Clinical studies so far have shown mixed results, and this link does not appear to have been established by randomized controlled trials (RCTs). Both components of DAPT may be affected by PPIs. An observational study based on Danish national registries found that patients after MI on aspirin and PPI, compared those on aspirin alone, had significantly more events of recurrent MI, stroke, or cardiovascular death (HR 1.46, 95% CI 1.33 to 1.61). A proposed mechanism for how PPIs interfere with aspirin is that aspirin absorption becomes reduced in the less acidic environment induced by PPIs [16,17].
Meanwhile, PPIs likely interfere with clopidogrel and prasugrel through a different mechanism. Both clopidogrel and prasugrel require the enzyme CYP2C19 for conversion into its active metabolites; PPIs are also metabolized by CYP2C19 and can exert competitive inhibition on other drugs requiring the enzyme. Ticagrelor’s metabolism does not involve CYP2C19, so it is not affected by PPIs .
Multiple studies have been performed to determine if PPI use in patients on DAPT is associated with ischemic events or mortality. However, results have been mixed depending on the type of study performed, as seen through the results of two meta-analyses. Observational studies generally showed that PPIs significantly increased all-cause and cardiovascular mortality, MI, and stroke while RCTs did not [18,19]. This discrepancy may be explained by selection bias. Although observational studies often attempt to reduce it by adjusting for baseline patient characteristics, unmeasured baseline differences may continue to have effects on the outcome [8,17].
It is also important to note that long-term PPI use has been associated with several other adverse effects including Clostridium difficile infection, kidney disease, pneumonia, and fractures . However, most of these associations were uncovered through observational studies rather than RCTs. A recent RCT of 17,598 patients on aspirin, rivaroxaban, or both randomized to receiving either PPI or placebo found that the only adverse effect associated with PPI use was enteric infections other than Clostridium difficile infection (OR 1.33, 95% CI 1.01 to 1.75). No associations were found between PPI use and Clostridium difficile infection, gastric atrophy, kidney disease, pneumonia, fracture, or dementia .
What are the actual guidelines regarding PPI prophylaxis for patients on DAPT? The European Society of Cardiology recommends that PPI prophylaxis be used in all patients on DAPT (class I recommendation, level of evidence B) . Meanwhile, the American College of Cardiology and the American Heart Association state that in patients on DAPT, PPI prophylaxis is indicated for those with prior GI bleeding (class I recommendation); is reasonable for those at higher risk of GI bleeding due to advanced age or concurrent use of NSAIDs, steroids, or warfarin (class IIa); and is not recommended for those at low risk of GI bleeding (class III) . The decision to start PPI prophylaxis in patients on DAPT primarily depends on weighing the effect of PPIs in reducing GI bleeding against possible increases in ischemic events or other adverse effects. In patients on DAPT at high risk of GI bleeding, professional societies seem to agree that PPI prophylaxis is warranted. Further studies, especially with prasugrel or ticagrelor as the P2Y12 inhibitor component in DAPT, are needed to determine the optimal strategy regarding PPI prophylaxis with DAPT in the general population.
Dr. Peter Sheng is a second-year resident in the NYU Langone Internal Medicine Residency
Peer reviewed by Michael Poles, MD, associate professor, Department of Medicine (Division of Gastroenterology)
Image courtesy Wikimedia Commons
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