Common Questions Regarding Antiplatelet Therapy in Primary Care
The preceding discussion confirms that many patients with ACS benefit from antiplatelet therapy. However, the use of antiplatelet agents in primary care can be challenging. The following are some of the evolving issues and questions regarding antiplatelet therapy faced by family physicians.
If a patient has experienced gastrointestinal bleeding while taking low-dose aspirin in the past and has an acute coronary syndrome, what course of action should be taken?
Dual antiplatelet therapy is still recommended in this setting, but therapy with a proton pump inhibitor (PPI) for gastrointestinal (GI) protection is recommended.2,3,17 For patients at low risk of upper GI bleeding, routine PPI prophylaxis is not recommended. Currently available data do not demonstrate the prophylactic superiority of one PPI over another, but do show that PPI therapy is more effective in decreasing GI bleeding associated with aspirin and is, therefore, preferred over a histamine H2 receptor antagonist.17 For instance, high-dose famotidine has been shown to be less effective than pantoprazole in patients with aspirin-related peptic ulcers/erosions.18
Can a proton pump inhibitor be used for gastrointestinal protection in conjunction with clopidogrel?
Yes, although the evidence is conflicting about whether specific PPIs should be avoided because of reduced clinical efficacy of clopidogrel. The results of a meta-analysis of 23 studies demonstrated a clinically significant interaction that reduces the antiplatelet effectiveness of clopidogrel when combined with some PPIs.19 The results of 4 prospective, crossover pharmacokinetic studies in healthy subjects (N = 282) also suggest an interaction between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.20 A subanalysis of PLATO showed that the use of a PPI was independently associated with a higher rate of CV events in patients with ACS treated with clopidogrel or ticagrelor.21 The observed effect with both agents, as well as a higher rate of major bleeding among PPI vs non-PPI users suggests that PPI use may be more of a marker for rather than a cause of higher rates of CV events. In fact, data from the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) found that in patients treated with clopidogrel and aspirin, the addition of omeprazole reduced the rate of a GI event, compared with placebo at 180 days (1.1% vs. 2.9%, respectively;
P < .001).22 Overt upper GI bleeding occurred less frequently in the omeprazole group (hazard ratio, 0.13; 95% confidence interval, 0.03 to 0.56; P = .001). A CV event was observed in 4.9% of patients treated with omeprazole and 5.7% of placebo patients (P = .96). While limited, these prospective data do not suggest a detriment to clopidogrel efficacy when used in combination with a PPI. The dose of PPI to use for GI protection is not well-established; the following drugs and doses have been used: omeprazole 20 to 40 mg once daily; esomeprazole 20 mg once or twice daily; pantoprazole 20 mg once daily; or lansoprazole 30 mg once daily.18,23-28
Should I avoid starting clopidogrel in patients with acute coronary syndrome because of concerns about “poor metabolizers”?
Clopidogrel is a prodrug, requiring CYP450 metabolism to its active metabolite. Because of genetic CYP450 variations, as many as one-third of patients lack fully active CYP450 pathways, resulting in reduced (or even absent) conversion from the parent drug to the active metabolite, with a corresponding diminution of antiplatelet effects.3,29 Recent recommendations about dealing with these genetic polymorphisms include direct measurement of CYP450 pathway status and selection of alternative pharmacologic agents which are not dependent upon similar CYP pathway activation. There are, unfortunately, no prospective clinical trials based upon CYP2C19 genotyping confirming that patient selection based upon genotyping is associated with improved outcomes.
In terms of alternative antiplatelet therapy in clopidogrel nonresponders, the Response to Ticagrelor in Clopidogrel Nonresponders and Responders (RESPOND) study shows ticagrelor to be beneficial, at least as measured in vitro.30 Following laboratory assessment of patients’ responsiveness to clopidogrel, both responders and nonresponders were randomized to clopidogrel or ticagrelor. After 14 days, all clopidogrel nonresponders and half of the responders switched treatment. The antiplatelet effects of ticagrelor were similar whether the patient was a clopidogrel responder or not. The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) showed higher inhibition of platelet aggregation (IPA) with prasugrel 60 mg compared with clopidogrel 600 mg 6 hours after initiation.31 Following crossover, IPA was higher in subjects receiving prasugrel 10 mg/d compared with clopidogrel 150 mg/d (61% vs 46%, respectively; P < .0001). While not measuring clopidogrel responsiveness, this suggests that prasugrel might be effective in clopidogrel nonresponders. Not all patients treated with prasugrel achieve optimal inhibition of platelet reactivity. In patients who underwent successful PCI for ACS (N = 301) 25.2% were observed to have high on-treatment platelet reactivity following a 60 mg loading dose of prasugrel.32 Such patients had a significantly higher risk for a major adverse cardiovascular event after PCI. The clinical trials which demonstrate improved clinical outcomes when clopidogrel is compared with other antiplatelet agents suggest that the above-mentioned in vitro metrics are clinically relevant.