Clopidogrel Dosing in Overweight Patients: Does One Size Fit All?

Finding the “right dose” of a medication for an individual patient remains an illusive challenge for the practicing clinician. As part of the drug approval process, drug developers use randomized controlled trials to determine the general safety and efficacy profiles of a drug using a standard dosing regimen. However, it is clear that pharmacokinetics and dynamics of a drug can vary markedly based on the patient’s age, body size and composition, renal and hepatic function, concomitant medications used and other factors. These issues are particularly relevant with anti-thrombotic or anti-coagulant therapy where the therapeutic window for efficacy and safety may be narrow. The current study by Angiolilio and colleagues addresses whether the “standard” dose of clopidogrel following percutaneous coronary intervention needs to be “super-sized” in larger patients. See Angiolillo, et al. on pages 169–174 Coronary stents provide an effective means of decreasing the incidence of restenosis.^1,2 However, the introduction of a metal stent into a coronary artery is also thrombogenic, and presents risks for acute and subacute stent thrombosis.³ After numerous combinations of anti-thrombotic and anticoagulant regimens were tested, the combination of an adenosine diphosphate P2Y12 receptor antagonist and aspirin was found to effectively prevent thrombotic complications following percutaneous intervention with a coronary stent.^4–6 While the initial trials tested ticlopidine and aspirin, subsequent studies demonstrated that clopidogrel was better tolerated, had fewer side effects, and was at least as efficacious as ticlopidine.^7–9 This combination quickly became the standard of care in patients undergoing percutaneous coronary intervention with stent implantation. In terms of dosing, these early studies tested 75 mg/day of clopidogrel with or without a loading dose.^10-12 Subsequent studies confirmed that a “loading dose” of clopidogrel can speed the onset of action of the drug as assessed by platelet inhibition. In a recent randomized trial, patients receiving a 300 mg clopidogrel load at least 6 hours prior to percutaneous intervention had decreased rates of death, myocardial infarction, and urgent target vessel revascularization.¹³ This loading dose was increased to 600 mg in another recent randomized trial of PCI.14 While there has been intensive study, there remains considerable debate as to the appropriate clopidogrel loading dose (300 mg, 450 mg, or 600 mg).^15,16 In this issue of the Journal of Invasive Cardiology, Angiolillo et al. address the relationship between body weight and clopidogrel loading dose. Forty-eight consecutive patients undergoing percutaneous intervention with coronary stent implantation were included in the analysis. The patients were divided into two groups according to BMI: overweight BMI > 25 kg/m² and normal weight BM 2. In addition to 300 mg of clopidogrel as a loading dose followed by 75 mg/day for one month, patients received aspirin (100–250 mg/day) for at least seven days. Glycoprotein IIb/IIIa receptor blockers were not used before, during, or after the intervention in any of the patients. All patients had platelet aggregation tested at baseline, 10 minutes, 4 hours, and 24 hours following clopidogrel administration using ADP induced platelet aggregation assessed by light transmittance. The investigators defined platelet inhibition of less than 10% as clopidogrel resistance, less than 40% as “semi-responders,” and greater than 40% as adequate response. Platelet aggregation was found to be significantly higher in the overweight patients at all measurements, and significantly higher at baseline and at 24 hours when compared to normal weight patients. The investigators conclude that overweight patients may require a higher loading dose of clopidogrel at the time of coronary intervention. The investigators involved in this study should be commended for addressing a clinically important issue for the interventional community. While the study was performed well and provides new information, it has limitations. The study included a relatively small number of patients, making it difficult to find meaningful clinical differences among the patient subgroups. Instead, the authors used a surrogate endpoint, platelet aggregation as its main outcome measure. Unfortunately, it is not clear that achieving platelet inhibition level of 40% or more is closely linked with clopidogrel’s ability to prevent acute thrombotic events. In particular, in addition to platelet inhibition, clopidogrel has multiple potential mechanisms of action including inhibiting platelet activation and other inflammatory processes. Also, the authors did not assess the effectiveness or safety (bleeding risks) of higher loading doses of clopidogrel 600 mg. Thus, while 300 mg may have achieved less inhibition in larger patients, whether another strategy would have been more successful remains unknown. Indeed, in addition to patient weight, other factors can alter the cytochrome P450 (CYP3A4) system and subsequent activation of the clopidogrel pro-drug to its active form. These include individual genetic variation as well as the concomitant use of drugs that affect the (CYP3A4) system (such as statin therapy).^17–19 Finally, the safety and efficacy profiles of clopidogrel therapy may be altered by other anti-thrombotic therapies used during PCI including unfractionated or low-molecular weight heparin, direct thrombin inhibitors, and glycoprotein IIb/IIIa receptor blockers. So how should one proceed? Ideally, patients who are to undergo elective percutaneous coronary intervention would receive 75 mg of clopidogrel three days prior to the procedure or more so that steady state drug levels would be achieved by the procedure date. As this is often not possible, it seems reasonable to suggest that a clopidogrel loading dose of at least 300mg be begun at least 6 hours prior to the procedure based on data from CREDO and other studies. Based on the current study and others,¹⁴ it seems reasonable to consider higher loading doses (600 mg) when the patient is large or the time window to the procedure is less than 6 hours. Although intriguing, individual patient dosing regimens should not be based on platelet aggregation studies until clear correlation between therapeutic range and clinical outcomes have been established as with other anti-thrombotic therapies, such as unfractionated heparin. Clearly, further research is needed to help clinicians identify and use the best dosing strategy for clopidogrel, one that provides the best efficacy to risk balance for each patient. This strategy should incorporate patient specific factors in addition to simultaneous therapies. Until then, as with many therapies, clinicians must continue to judiciously apply the information from clinical trials in order to find the ‘“right dose” for the each individual patient they are treating.