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Antiplatelet therapy and GI risk

Strategies for primary and secondary prevention of cardiovascular events constitute a multitude of interventions including use of antiplatelet therapy. Commonly used antiplatelet agents include aspirin (ASA) and clopidogrel. Although their cardiovascular benefits are well known, the gastrointestinal (GI) risks of using antiplatelet therapy with non-steroidal anti-inflammatory drugs (NSAIDS) or in high risk patients are less well recognized and/or addressed. In conjunction with the American College of Gastroenterology (ACG) and the American Heart Association (AHA), the American College of Cardiology (ACC) has published recommendations on identifying and reducing GI risk associated with antiplatelet therapy.¹

Identifying risk
As defined by the consensus document, upper gastrointestinal events (UGIE) include symptomatic ulcer (dyspepsia along with an ulcer) or ulcer complications such as bleeding or perforation.¹ For patients receiving antiplatelet therapy, risk factors for UGIE include:

And/or more than 1 of the following:

Aspirin and NSAIDs cause local irritation to the GI tract as well as systemic effects through reduction in the production of GI protective prostaglandins via inhibition of cyclooxgenase COX-1 and 2 enzymes.¹ A COX-2 inhibitor, such as celecoxib, selectively blocks the COX-2 enzyme leading to the reduction in prostaglandins involved in pain, inflammation and fever and spares the COX-1 enzyme involved in producing GI protective prostaglandins. Some evidence suggests gastric ulceration may require inhibition of both COX-1 and COX-2 enzymes. Therefore, the addition of aspirin to a COX-2 inhibitor potentially negates any reduced GI risk associated with use of a COX-2 inhibitor. Although clopidogrel does not cause direct injury to the GI mucosa, it does interfere with angiogenesis involved in repair and healing of erosions and ulcers. Similarly, anticoagulants do not cause direct GI ulceration but can exacerbate existing GI lesions caused by aspirin, NSAIDs or Helicobacter pylori infection. Table 1 below provides a description of the UGIE and bleeding risks associated with antiplatelet therapy alone and in combination with other agents

Table 1. Description of UGIE risk associated with aspirin and clopidogrel.¹

Reducing risk
Gastrointestinal risk should be evaluated in all patients deemed to be candidates for antiplatelet therapy.¹ When single antiplatelet therapy is required, aspirin 81 mg per day should generally be the antiplatelet agent and dose of choice unless a patient has a history of aspirin hypersensitivity. Patients on antiplatelet therapy who have a history of UGIE or are receiving concomitant anticoagulant, antiplatelet, NSAID or COX-2 therapy should receive gastroprotection with a proton pump inhibitor (PPI). Although misoprostol may be effective for preventing GI events in patients receiving aspirin plus either an NSAID or COX-2 inhibitor, its side effects (primarily, diarrhea) limit its use. The guidelines do not recommend use of clopidogrel alone as an alternative to aspirin in patients with a history of UGIE since the combination of aspirin and a PPI has demonstrated superior efficacy in reducing GI events compared to clopidogrel alone. Prior to initiation of antiplatelet therapy, patients with a GI history should be tested and treated, if infected, for H. pylori infection. Other patient populations that qualify for addition of a PPI to antiplatelet therapy include those with 1 or more of the risk factors discussed above (i.e. age ≥ 60 years, corticosteroid use, or dyspepsia). The guidelines also recommend a target International Normalized Ratio (INR) of 2 to 2.5 in patients started on warfarin that are also receiving aspirin and clopidogrel.

Although a reduction in the risk of UGIE may occur with concomitant use of clopidogrel and PPIs in high GI risk patients, there is some evidence to suggest that omeprazole may reduce the antiplatelet efficacy of clopidogrel.² The Omeprazole Clopidogrel Aspirin (OCLA) study compared the effects of clopidogrel on platelet activity in post-stent patients receiving aspirin, clopidogrel and omeprazole to patients receiving aspirin and clopidogrel alone.  Clopidogrel’s effect on decreasing platelet activity was significantly reduced in patients receiving omeprazole compared to those who did not receive gastroprotection.  On the other hand, a recent study found no decrease in clopidogrel’s antiplatelet activity in patients undergoing percutaneous coronary intervention (PCI) that received either pantoprazole or esomeprazole.³  The impact of these findings on clinical outcomes, however, were not evaluated.  An ongoing clinical trial, Clopidogrel and the Optimization of Gastrointestinal Events (COGENT-1), is prospectively evaluating the clinical outcomes of concomitant omeprazole with aspirin and clopidogrel and should help delineate the significance of the omeprazole-clopidogrel interaction.¹  A retrospective review of an Aetna database compared the incidence of myocardial infarction (MI) in clopidogrel treated patients that received a PPI to those that did not receive PPIs.⁴  After adjusting for various cardiac risk factors, the MI rates were significantly higher in patients that received PPIs compared to those who did not (11.3% vs. 2.6%, p<0.05).  Another review of the Medco Integrated Database presented at the recent AHA meeting also found a greater number of cardiac events in patients receiving both a PPI and clopidogrel compared to patients on clopidogrel alone.⁵ In contrast, results of a subgroup analysis of patients from the CREDO (Clopidogrel for the Reduction of Events During Observation) study also presented at the recent AHA meeting found no increase in cardiac events in patients receiving a PPI and clopidogrel compared to clopidogrel alone. Based on conflicting data presented at the meeting, the ACC, AHA and ACG released a joint statement suggesting that no changes in clinical practice can be recommended based on the limited and conflicting evidence available.⁵

Clopidogrel is a prodrug that requires conversion to active drug via cytochrome P450 (CYP450) enzymes.² The CYP2C19 isoenzyme is involved in the activation of clopidogrel. Omeprazole is metabolized by this same isoenzyme and is also known to be a CYP2C19 enzyme inhibitor. Therefore, a proposed mechanism of the interaction between omeprazole and clopidogrel is inhibition of the metabolic activation of clopidogrel. It is unknown if this is the true mechanism of the interaction. Currently, providers should be made aware of the potential interaction and may consider use of other PPIs such as pantoprazole or esomeprazole.

Summary
Assessment and management of GI risk is recommended when antiplatelet therapy for primary or secondary cardiovascular disease prevention is initiated. Patients determined to be at risk for GI events should receive gastroprotection, preferably with a PPI. The antiplatelet agent of choice is low dose aspirin (81 mg per day). Clopidogrel alone is not sufficient at reducing GI risk in high risk patients and is not considered an acceptable alternative to aspirin in patients with previous GI events. The addition of a PPI to aspirin is considered to have greater efficacy in reducing GI events compared to clopidogrel alone. Similarly, the use of a COX-2 inhibitor instead of an NSAID in patients receiving aspirin does not lower GI risk and gastroprotection is still recommended for patients receiving both aspirin and a COX-2 inhibitor. The guidelines do not specifically address the GI risk of concomitant clopidogrel and COX-2 inhibitor therapy or whether gastroprotection is required with such a regimen. Preliminary evidence suggests a potential reduction in antiplatelet activity of clopidogrel when combined with omeprazole. However, the clinical significance of this interaction is currently under study. Clinicians may consider the use of other PPIs, such as pantoprazole and esomeprazole, which have recently demonstrated no effects on clopidogrel’s antiplatelet activity.

References

Update (3/30/2009)

In late January 2009, the Food and Drug Administration (FDA) released an early communication regarding the need for further studies evaluating effects of genetic factors on clopidogrel efficacy as well as the drug interaction between PPIs and clopidogrel. The FDA at that time suggested clinicians reassess GI risk and the need for PPI use for patients prescribed clopidogrel and a PPI. 1 Several recent reports have provided additional information on the potential interaction between proton pump inhibitors (PPIs) and clopidogrel.

The hospitalization and death rates due to acute coronary syndrome (ACS) were evaluated in a retrospective cohort study of approximately 8200 Veterans Affairs (VA) patients prescribed clopidogrel with or without a PPI. 2 Of the 5244 patients prescribed clopidogrel with a PPI, 1561 (29.8%) experienced death or hospitalization due to ACS compared to 615 of 2961 (20.8%) patients taking clopidogrel without a PPI. After adjusting for multiple variables, the use of clopidogrel and a PPI was found to be associated with an increased risk of hospitalization or death due to ACS compared to use of clopidogrel without a PPI (adjusted odds ratio, 1.25; 95% confidence interval [CI], 1.10 to 1.46). Of the secondary outcomes of all-cause mortality, revascularization procedures, and recurrent hospitalizations, the risk of the latter 2 was found to be significantly higher with clopidogrel and PPI use. In addition, no significant increase risk in outcomes was detected in patients who received only a PPI. Although close to 60% of the patients who received a PPI were prescribed omeprazole, the study was not designed to detect whether outcomes were related to a specific PPI.

A case control study evaluated the impact of PPI use on recurrent MI in patients receiving clopidogrel within 3 days of hospital discharge. 3 Cases were defined as those patients who were hospitalized for recurrent MI within 90 days of the first MI. Controls included patients who did not experience a recurrent event within 90 days. Over 13,000 post-MI patients filled a prescription for clopidogrel within 3 days of discharge. Of these patients, 734 cases and 2057 matched controls were identified. A greater number of cases were current users of a PPI compared to controls (26.4% vs. 20.6%) and PPI use was found to be significantly associated with recurrent MI (adjusted OR 1.27, 95% CI 1.03 to 1.57). No significant association was identified with pantoprazole use and recurrent MI (adjusted OR 1.02, 95% CI 0.70 to 1.47), which is in contrast to the association found with use of other PPIs including omeprazole, lansoprazole, or rabeprazole (adjusted OR 1.40, 95% CI 1.10 to 1.77). The authors explained this difference by the lack of pantoprazole’s effect on cytochrome (CYP) 2C19.

As discussed previously, clopidogrel is a prodrug that requires activation by CYP P450 enzymes including the isoenzyme CYP2C19. Certain forms of the genes encoding for CYP2C19 have been shown to cause reduced function of this isoenzyme. This would theoretically lead to reduced enzymatic conversion of clopidogrel to its active form and therefore, decreased antiplatelet activity. A recent study by Mega and colleagues reported approximately 30% of healthy subjects (n=162) administered clopidogrel carried a reduced function allele for CYP2C19. 4 These patients demonstrated a 32% relative risk reduction in plasma exposure to the active form of clopidogrel compared to subjects who did not carry the reduced function allele (p<0.001). In addition, maximal platelet aggregation decreased by 9% in patients who carried the reduced function allele compared to non-carriers (p<0.001). The study also evaluated clinical outcomes in acute coronary syndrome (ACS) patients who were randomized to receive clopidogrel in the TRITON-TIMI 38 study and who carried the reduced function allele. Of 1477 subjects in whom a sample was obtained, approximately 27% carried a CYP2C19 reduced function allele. Death from cardiovascular causes, MI, or stroke was significantly higher in these patients compared to non-carriers (12.1% vs. 8%; hazard ratio for carriers 1.53, 95% CI 1.07 to 2.19; p=0.01).

A second study by Simon and colleagues further demonstrated a reduced response to clopidogrel in patients who carry variant alleles for genes involved in clopidogrel metabolism (CYP2C19). 5 In this study, the 1 year rates of death, nonfatal MI, or stroke were determined for over 2200 French patients who were admitted for MI and discharged on clopidogrel. Two hundred ninety four patients experienced the primary outcome. Patients with 2 reduced function alleles of CYP2C19 had a higher rate of events compared to those who did not carry the alleles (21.5% vs. 13.3%; adjusted hazard ratio, 1.98; 95% CI, 1.10 to 3.58). However, outcomes were not significantly increased by concomitant PPI use.

The suggestion is that proton pump inhibitors, such as omeprazole, that are also CYP2C19 inhibitors, may diminish the activation of clopidogrel and therefore, reduce plasma exposure to the active form of clopidogrel as well as its antiplatelet effect. However, what has not been confirmed in randomized controlled trials is whether CYP2C19 inhibition by PPIs or presence of reduced function alleles of CYP2C19 results in similar adverse clinical outcomes in patients who are taking clopidogrel. A secondary outcome of the study, the effect of omeprazole in combination with clopidogrel and aspirin on cardiovascular events in the COGENT-1 study would have provided further information on clinical outcomes; however, the study has been terminated. Although an increasing amount of data suggests a potential interaction between PPIs and clopidogrel, caution is still advised in interpreting these results due to limitations of retrospective and case control studies.

If patients are determined to be at high risk for GI events and a proton pump inhibitor is deemed necessary, selection of a PPI such as pantoprazole may be preferred as it does not exhibit inhibition of the CYP2C19 enzyme. This recommendation, however, is based on the limited data available and the effect of pantoprazole on adverse clinical outcomes in patients who are receiving clopidogrel needs to be further studied. Histamine receptor antagonists (H2 receptor antagonists), with the exception of cimetidine, can also be considered. 6 Cimetidine, similar to PPIs, is a CYP2C19 inhibitor. Clinicians, however, should be aware that H2 receptor antagonists do not confer similar protection against GI ulcers and bleeding as do PPIs in patients taking clopidogrel.

References

1. Anon. Early communication about an ongoing safety review of clopidogrel bisulfate (marketed as Plavix). CDER News. Available at: http://www.fda.gov/cder/drug/early_comm/clopidogrel_bisulfate.htm. Accessed March 30, 2009.
2. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009;301(9):937-944.
3. Juurlink, DN, Gomes T, Ko DT, et al. A population based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009;180(7):713-718.
4. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(4):354-362.
5. Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360(4):363-375.
6. Hester SA. Proton pump inhibitor and Plavix interaction: does it exist? Pharmacist's Letter/Prescriber's Letter. 2009;25(4):250401.