Antiplatelet Therapy in Patients with Acute Coronary Syndrome

Anaheim—To decrease the risk of patients with acute coronary syndrome (ACS) experiencing future coronary episodes, researchers are looking at the effectiveness of dual antiplatelet therapy. There are also emerging strategies such as triple antiplatelet therapy and additional antiplatelet agents in the pipeline that may help ACS patients. At the ASHP meeting, speakers discussed recent clinical trials and oral antiplatelet therapies during a symposium titled Optimizing Oral Antiplatelet Therapy in Acute Coronary Syndrome. Toby Trujillo, PharmD, BCPS, associate professor of clinical pharmacy at the University of Colorado Denver School of Pharmacy, Aurora, classified ACS into 2 categories: ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI). The NSTEMI group also included unstable angina. According to guidelines from the American Heart Association and the American College of Cardiology, several therapies are used to treat NSTEMI ACS, among them beta-blockers, nitrates, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone antagonists, statins, anticoagulants, and antiplatelet therapy. Patients with STEMI use the same treatments, and they may also undergo reperfusion therapy. Dr. Trujillo discussed the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, which included 12,562 patients with NSTEMI ACS who took clopidogrel plus acetylsalicylic acid (ASA) (n=6259) or placebo plus ASA (n=6303). Clopidogrel is an oral antiplatelet agent intended to prevent strokes and heart attacks. The clopidogrel group had significantly fewer instances of myocardial infarction, stroke, or cardiovascular death compared with the placebo group (P=.00009; relative risk reduction, 20%). Patients taking clopidogrel plus ASA were significantly more likely to experience major bleeding (3.7% vs 2.7%; P=.001) and minor bleeding (5.1% vs 2.4%; P<.001) compared with the placebo group. Dr. Trujillo also discussed the CURRENT-OASIS 7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions) study of 25,087 patients who either had STEMI or NSTEMI ACS. Patients were assigned to take 300 or 600 mg of clopidogrel as well as 75 to 100 mg or 300 to 325 mg of ASA per day. The authors found that 522 of the 12,520 patients taking the double dose of clopidogrel died from cardiovascular causes, experienced myocardial infarction, or had a stroke compared with 557 of the 12,566 patients taking the single dose (P=.30). In addition, 530 of the 12,507 patients taking the higher dose of ASA died from cardiovascular causes, experienced myocardial infarction, or had a stroke compared with 549 of the 12,579 patients taking the lower dose (P=.61), Dr. Trujillo said. Dr. Trujillo said there are many advantages of utilizing dual antiplatelet therapy to treat patients with ACS. However, some studies have indicated the limits of dual antiplatelet therapy, such as combining clopidogrel and ASA. Potential problems include increased bleeding, delayed onset or offset, variable response, irreversible mechanisms of action, and residual clinical events. Next, Julie Oestreich, PharmD, PhD, assistant professor in the University of Nebraska Medical Center’s College of Pharmacy, Omaha, discussed challenges associated with oral antiplatelet therapy. She mentioned that patients vary in their response to taking clopidogrel as well as their on-treatment platelet reactivity. In a trial of 192 patients undergoing elective percutaneous coronary intervention (PCI) and having a stent while taking clopidogrel, 20% experienced major adverse cardiac events after 6 months. Dr. Oestreich said additional studies found that platelet function tests indicate clopidogrel variability correlates with clinical outcomes in patients undergoing PCI with a good negative predictive value but a poor positive predictive value. Dr. Oestreich also spoke about the interaction between clopidogrel and proton pump inhibitors (PPIs). She said pharmacokinetic and pharmacodynamic evidence shows that an interaction exists between clopidogrel and PPIs, although significant effects with platelet function tests do not always match clinical outcomes. In addition, Dr. Oestreich mentioned that pharmacokinetic, pharmacodynamic, and clinical evidence has shown that a cytochrome P450 2C19 metabolizer has a significant effect on clopidogrel effectiveness, although genetic testing has demonstrated a low positive predictive value. She said cardiology groups do not recommend genetic testing for clopidogrel and that no one knows how to optimize clopidogrel therapy or improve clinical outcomes. Finally, Paul Dobesh, PharmD, FCCP, BCPS, associate professor of pharmacy practice at the University of Nebraska Medical Center, Omaha, discussed emerging treatment strategies, including increasing the clopidogrel dose, switching to another P2Y12 inhibitor (ticlopidine, prasugrel, or ticagrelor), or undergoing triple antiplatelet therapy by adding cilostazol or protease activated receptor-1 inhibitors. He mentioned numerous trials, including the PLATO (Platelet Inhibition and Patient Outcomes) study of 18,624 patients who received clopidogrel or ticagrelor, a platelet aggregation inhibitor. The authors found that 9.8% of the 9333 patients in the ticagrelor group died from cardiovascular events, had myocardial infarction, or suffered from a stroke compared with 11.7% of the 9291 patients in the clopidogrel group (P<.001). The PLATO trial did not show statistical differences in major bleeding between the groups: 11.6% of the ticagrelor group experienced major bleeding versus 11.2% of the clopidogrel group (P=.43). The TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction) phase 3 study compared clopidogrel with prasugrel, a novel platelet inhibitor. Of the prasugrel group, 9.9% of patients died from cardiovascular causes, had a nonfatal myocardial infarction, or had a nonfatal stroke compared with 12.1% of the clopidogrel cohort (P=.0004). Dr. Dobesh also mentioned 2 drugs under development: cangrelor, a parenteral adenosine diphosphate (ADP) P2Y12 receptor antagonist, and elinogrel, the first available intravenous and oral ADP P2Y12 receptor antagonist. Dr. Dobesh presented a meta-analysis comparing 6 trials that evaluated clopidogrel with prasugrel, cangrelor, ticagrelor, and elinogrel, all novel P2Y12 inhibitors. In patients undergoing any PCI, those taking the novel P2Y12 inhibitors were significantly less likely to die or experience major bleeding compared with those taking clopidogrel. Of the 21,337 patients in the novel P2Y12 inhibitor group, 519 died, compared with 602 deaths in the 20,861-person clopidogrel group (P=.008). In addition, 332 patients in the novel P2Y12 inhibitor group had major bleeding compared with 268 in the clopidogrel group (P=.01). Another meta-analysis focused on death and major bleeding for patients undergoing PCI for STEMI and compared clopidogrel with novel P2Y12 inhibitors. Of the 6489 patients in the novel P2Y12 inhibitor group, 272 died, compared with 346 deaths in the 6539-person clopidogrel group (P=.003). In addition, 413 of the 6002 patients in the novel P2Y12 inhibitor group had major bleeding compared with 425 of the 6030 patients in the clopidogrel group (P=.76). Dr. Dobesh concluded by discussing trials involving triple antiplatelet therapy, including ACCEL-AMI (Adjunctive Cilostazol versus High Maintenance Dose Clopidogrel in Patients with AMI). The study examined 90 patients who had STEMI after undergoing PCI and stenting. The authors looked at 3 arms, with patients receiving 75 mg of clopidogrel daily (standard group), 150 mg of clopidogrel daily (high maintenance dose group), or 75 mg of clopidogrel daily plus 100 mg of cilostazol twice daily (triple group). The triple group was statistically superior when measuring the inhibition of maximal platelet aggregation after adding 5 micrometers ADP (P<.001 in both cases when comparing the triple group vs the standard group and the high maintenance dose group). The triple group was also statistically superior after adding 20 micrometers ADP (P<.001 in both cases when comparing the triple group vs the standard group and the high maintenance dose group), Dr. Dobesh said. The researchers also measured platelet reactivity by looking at the change of P2Y12 reaction units. The triple group was statistically superior to the standard group (P<.001), but the difference was not statistically significant compared with the high maintenance dose group (P=.071).