Wei C. Lau

Atorvastatin Reduces the Ability of Clopidogrel to Inhibit Platelet Aggregation A New Drug–Drug Interaction

Background—We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing. Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4. Methods and Results—Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated with clopidogrel and either erythromycin or troleandomycin, CYP3A4 inhibitors, or rifampin, a CYP3A4 inducer. Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner. Percent platelet aggregation was 34±23, 58±15 (P =0.027), 74±10 (P =0.002), and 89±7 (P =0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively. Erythromycin attenuated platelet aggregation inhibition (55±12 versus 42±12% platelet aggregation;P =0.002), as did troleandomycin (78±18 versus 45±18% platelet aggregation;P <0.0003), whereas rifampin enhanced platelet aggregation inhibition (33±18 versus 56±20% platelet aggregation, P =0.001). Conclusions—CYP3A4 activates clopidogrel. Atorvastatin, another CYP3A4 substrate, competitively inhibits this activation. Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel.

Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance

Background—Interindividual variability of platelet inhibition after aspirin or clopidogrel administration has been described. Additionally, aspirin resistance and clopidogrel resistance occur in some individuals. Because the prodrug clopidogrel is activated by hepatic cytochrome P450 (CYP) 3A4, we hypothesized that interindividual variability in clopidogrel efficacy might be related to interindividual differences in CYP3A4 metabolic activity. Methods and Results—Platelet aggregation was measured before and after clopidogrel treatment in 32 patients undergoing coronary artery stent implantation and in 35 healthy volunteers. The erythromycin breath test was used to measure CYP3A4 activity in vivo in 25 of the healthy volunteers. Individual platelet aggregation was studied in 10 healthy volunteers after the coadministration of clopidogrel and rifampin (a CYP3A4 inducer). Clopidogrel nonresponders, low responders, and responders were defined by a relative inhibition of adenosine diphosphate (20 &mgr;mol/L)–induced platelet aggregation of <10%, 10% to 29%, and ≥30%, respectively. Among patients, 22% were clopidogrel nonresponders, 32% were low responders, and 47% were responders. Among volunteers, 16% were nonresponders, 12% were low responders, and 72% were responders. Percent platelet aggregation after clopidogrel inversely correlated with CYP3A4 activity (r =−0.6, P =0.003). Improved platelet inhibition in volunteers resistant to clopidogrel was observed with the coadministration of clopidogrel and rifampin. Conclusions—Clopidogrel administration results in interindividual variability in platelet inhibition, which correlates with CYP3A4 metabolic activity. Measurement of antiplatelet drug efficacy with a point-of-care device and alternative antithrombotic strategies for aspirin or clopidogrel nonresponders and low responders could reduce the incidence of thrombotic events that continue to occur despite oral antiplatelet therapy.

Clopidogrel-Drug Interactions

Multidrug therapy increases the risk for drug-drug interactions. Clopidogrel, a prodrug, requires hepatic cytochrome P450 (CYP) metabolic activation to produce the active metabolite that inhibits the platelet P2Y₁₂ adenosine diphosphate (ADP) receptor, decreasing platelet activation and aggregation processes. Atorvastatin, omeprazole, and several other drugs have been shown in pharmacodynamic studies to competitively inhibit CYP activation of clopidogrel, reducing clopidogrel responsiveness. Conversely, other agents increase clopidogrel responsiveness by inducing CYP activity. The clinical implications of these pharmacodynamic interactions have raised concern because many of these drugs are coadministered to patients with coronary artery disease. There are multiple challenges in proving that a pharmacodynamic drug-drug interaction is clinically significant. To date, there is no consistent evidence that clopidogrel-drug interactions impact adverse cardiovascular events. Statins and proton pump inhibitors have been shown to decrease adverse clinical event rates and should not be withheld from patients with appropriate indications for therapy because of concern about potential clopidogrel-drug interactions. Clinicians concerned about clopidogrel-drug interactions have the option of prescribing either an alternative platelet P2Y₁₂ receptor inhibitor without known drug interactions, or statin and gastro-protective agents that do not interfere with clopidogrel metabolism.

The drug-drug interaction between proton pump inhibitors and clopidogrel

The efficacy of clopidogrel in combination with acetylsalicylic acid (ASA) therapy has been clearly established in well-designed randomized controlled trials that have shown a reduction in recurrent coronary events following acute myocardial infarction, as compared with ASA monotherapy.[1][1]

The Effect of St John's Wort on the Pharmacodynamic Response of Clopidogrel in Hyporesponsive Volunteers and Patients: Increased Platelet Inhibition by Enhancement of Cyp3a4 Metabolic Activity

Clopidogrel is metabolically activated by cytochrome P450 (CYP) isoenzymes. We evaluated whether St. Johns wort (SJW), a CYP2C19 and CYP3A4 inducer, enhances the pharmacodynamic response of clopidogrel. Volunteers (n = 45) were screened for clopidogrel hyporesponsiveness after a 300-mg load. After a 7-day washout, hyporesponders (n = 10) received 14 days of SJW (300 mg 3 times a day) followed by a second 300-mg clopidogrel. Platelet aggregation was measured at 0, 2, 4, and 6 hours postloading; hepatic CYP3A4 activity was simultaneously determined at 0 and 4 hours by the erythromycin breath test. A prospective, randomized, double-blind pilot study was conducted in postcoronary stent patients (n = 85) on clopidogrel 75 mg/d screened for clopidogrel hyporesponsiveness. Hyporesponders (n = 20) were randomized to SJW (n = 10) or placebo (n = 10); platelet aggregation was measured before and after 14 days of therapy. In volunteers, SJW decreased platelet aggregation (59% ± 14% vs. 40% ± 15% at 2 hours, P = 0.02; 56% ± 10% vs. 44% ± 13% at 4 hours, P < 0.03; and 55% ± 14% vs. 37% ± 14% at 6 hours, P = 0.01) and increased CYP3A4 activity (2.1% ± 0.4% 14CO2 exhaled per hour before vs. 2.9% ± 0.6% 14CO2 exhaled per hour after SJW, P = 0.002). In patients, SJW decreased platelet reactivity (226 ± 39 vs. 185 ± 49 P2Y12 reactivity units, P = 0.0002) and increased platelet inhibition (23% ± 11% vs. 41% ± 16%, P = 0.002). SJW may be a future therapeutic option to increase CYP metabolic activity and antiplatelet effect of clopidogrel in hyporesponders.

Loading, pretreatment, and interindividual variability issues with clopidogrel dosing

Clopidogrel, a thienopyridine, decreases adenosine diphosphate (ADP)–induced platelet aggregation. Clopidogrel is an inactive prodrug that requires in vivo conversion in the liver by the cytochrome P450 (CYP) 3A4 enzyme system to an active metabolite that exerts its antiplatelet effect by noncompetitive inhibition of the platelet ADP receptor subtype P2Y12.1 The 75-mg once-daily dose was approved by the US Food and Drug Administration (FDA) in November 1997 after the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial2 showed superior reduction of adverse cardiovascular events with clopidogrel versus aspirin. The 75-mg once-daily dose had been used in CAPRIE because it produced inhibition of platelet aggregation equivalent to that produced by ticlopidine 250 mg administered twice daily. FDA approval for the 300-mg loading dose in patients with acute coronary syndromes was granted in February 2002 after the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial3 demonstrated a reduction of adverse cardiovascular events with dual antiplatelet therapy versus aspirin. Clopidogrel is not approved by the FDA for adjunctive antiplatelet therapy in percutaneous coronary intervention (PCI), although it has become the standard of care. It is curious that investigations into the optimal loading and maintenance doses of clopidogrel have been pursued only recently. See p 2560 In this issue of Circulation , Hochholzer et al4 performed optical platelet aggregometry and flow cytometry before and after a 600-mg oral dose of clopidogrel in 1001 potential PCI candidates undergoing cardiac catheterization. The findings are consistent with previous observations from small studies with regard to the 600-mg clopidogrel loading dose: Maximal inhibition of ADP-induced platelet aggregation was achieved ≈2 hours after ingestion,5 interindividual variability of platelet response was considerable,6 and there was no significant effect of concomitant statin therapy on platelet inhibition.7,8 Although …

Antiplatelet Drug Resistance and Drug-Drug Interactions: Role of Cytochrome P450 3A4

Antiplatelet therapy provided pivotal advances in the treatment of cardiovascular disease. Aspirin and thienopyridine, clopidogrel, is currently the treatment of choice in acute coronary syndromes and the prevention of thrombosis after coronary stent implantation. Despite the efficacy of this dual antiplatelet therapy in reduction of adverse coronary events in patients with acute coronary syndromes, complications persist in a subgroup of these patients. Emerging causes of aspirin and clopidogrel resistance may translate to increase risk for recurrent myocardial infarction, stroke, or cardiac related mortality. However, the mechanism of antiplatelet drug resistance remains incompletely characterized, and a sensitive and specific assay of aspirin and clopidogrel effect that reliably predicts treatment failure has not emerged. To date, evidence supporting antiplatelet drug resistance are pharmacokinetic response variability, drug-drug interaction through competitive inhibition a specific enzymatic pathway, genetic variability, and variability in the induction of enzymatic pathway in metabolic activation of prodrugs, like clopidogrel. Further investigation or guidelines are needed to optimize antiplatelet treatment strategies to identify and treat patients resistant to aspirin and/or clopidogrel.

Omeprazole: A Possible New Candidate Influencing the Antiplatelet Effect of Clopidogrel⁎

Clopidogrel is a prodrug activated in the liver to a metabolite that is a specific and irreversible inhibitor of the platelet P2Y12 receptor. The P2Y12 receptor mediates the amplification of aggregation induced by adenosine diphosphate (ADP) and also other agonists. In addition, P2Y12 inhibition

Intrathecal sufentanil for extracorporeal shock wave lithotripsy provides earlier discharge of the outpatient than intrathecal lidocaine.

Many anesthetic techniques are currently used for extracorporeal shock wave lithotripsy (ESWL).This randomized, prospective, double-blind study was designed to examine postoperative recovery with two anesthetic techniques for unilateral ESWL; i.e., intrathecal sufentanil versus intrathecal 5% lidocaine. The incidence of adverse effects was also assessed. Twenty-two ASA physical status I-III patients, 18-70 yr of age who were scheduled for unilateral ESWL under spinal anesthesia were studied. Patients were randomized to receive either intrathecal sufentanil 20 micro g + saline (n = 11) or intrathecal 5% lidocaine (n = 11) based on their height. Both patients and observers were blinded to the treatment groups. Patients were assessed for intraoperative and postoperative pain via a 10-cm verbal analog pain scale (VAPS) (0 = no pain, 10 = extreme pain). Stone sizes, number of shock waves, and voltages were also compared. The recovery profile-time to ambulate, void, oral intake, and home discharge-was documented. Antiemetic requirements in the postanesthesia care unit (PACU) and incidence of postoperative nausea and vomiting (PONV), pruritus, and sedation were also recorded. This study showed no differences in VAPS between groups at any time in the perioperative period. Patients who received intrathecal sufentanil ambulated (79 +/- 16 vs 146 +/- 57 min mean +/- SD; P < 0.05), voided (80 +/- 18 vs 152 +/- 54 min, P < 0.05), and were discharged home (98 +/- 17 vs 166 +/- 50 min, P < 0.005) significantly sooner than the patients who received intrathecal lidocaine. Although 27% (3 of 11) of the patients who received sufentanil reported pruritus, respiratory depression was not found. There were no differences in PONV between the two groups. Intrathecal sufentanil provided an enhanced recovery profile with significantly earlier home discharge when compared with intrathecal lidocaine. In conclusion, intrathecal sufentanil is a safe and effective method of anesthesia for outpatient unilateral ESWL. (Anesth Analg 1997;84:1227-31)

Impact of Adding Aspirin to Beta-Blocker and Statin in High-Risk Patients Undergoing Major Vascular Surgery

BACKGROUND Beta-blockers (BB) and statins (S) independently have been shown to reduce perioperative mortality and myocardial infarction (MI) in patients undergoing vascular surgery. In this study we evaluated the benefits of adding aspirin (A) to BB and S (ABBS), with/without angiotensin-converting enzyme inhibitor (ACE-I) on postoperative outcome in high-risk patients undergoing major vascular surgery. METHODS Analysis of consecutive patients undergoing elective vascular surgery at the University of Michigan Cardiovascular Center was performed. Univariate and multivariate analyses were done using cardiac risk index [Revised Cardiac Risk Index (RCRI), coronary artery disease (CAD), insulin-dependent diabetes mellitus (IDDM), cerebral vascular disease, renal dysfunction, congestive heart failure, and major surgery]; pulmonary disease; and A, BB, S (ABBS)±ACE-I use. Baseline clinical characteristics and medication were adjusted using propensity scores. Endpoints were bleeding, 30-day MI, stroke, and 12-month mortality. RESULTS Between 2003 and 2010, 4,149 arterial procedures were performed, 819 of which were risk stratified as RCRI≥3. The incidence of MI was 3-fold lower (2.5% vs. 7.8%, OR 0.31, 95% CI 0.15-0.61, P=0.001) in ABBS±ACE-I (n=513) as compared with non-ABBS±ACE-I (n=306). The 12-month mortality was 8-fold lower in ABBS±ACE-I as compared non-ABBS±ACE-I (5.9% vs. 37.5%, HR 0.13, 95% CI 0.08-0.20, P<0.0001). After adjustment for the propensity to use various therapies, A (HR 0.35, 95% CI 0.24-0.53, P<0.0001), BB (HR 0.65, 95% CI 0.43-1.0, P=0.05), and S (HR 0.36, 95% CI 0.25-0.53, P<0.0001) remained associated with improved 12-month survival. ACE-I use (HR 0.80, 95% CI 0.54-1.19, P=0.27) was not predictive. Aspirin did not predict severe/moderate bleeding. CONCLUSIONS In high-risk patients undergoing major vascular surgery, ABBS therapy has superior 30-day and 12-month risk reduction benefits for MI, stroke, and mortality as compared with A, BB, or S independently. ACE-I did not demonstrate additional risk-reduction benefits.