Antiplatelet Therapy Continues to Take Center Stage - ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non–ST-elevation myocardial infarction

The 2012 update of the guidelines for management of patients with unstable angina/Non-ST-Elevation Myocardial infarction serves as an update to the 2007 guideline¹ and replaces the 2011 focused update.² The writing committee organized the 2012 focused update around early hospital care; late hospital care/discharge/post-hospital care; and special groups. As with previous guidelines on this topic, antiplatelet therapy continues to take center stage. This underscores the contributions of platelet adhesion, activation, and aggregation in the pathophysiology of acute coronary syndromes. The vast majority of the recommendations and supporting text deals with the pharmacology and clinical trial findings of the P2Y12 antagonists. Although antiplatelet therapy will also be the focus of this commentary, it must be emphasized that there is networking between platelet aggregation and the coagulation cascade. The prothrombinase complex, consisting of coagulation factors Xa and Va, along with calcium, assembled on a phospholipid surface converts prothrombin to thrombin (ultimately catalyzing the conversion of fibrinogen to fibrin). Platelet aggregates provide a surface for assembly of the prothrombinase complex---the larger the platelet aggregate, the greater the surface area for assembly of the prothrombinase complex, and the greater the amount of thrombin formation. Also, thrombin is a potent activator of platelets, thereby contributing to thrombus formation. Thus, antiplatelet therapy, which is typically administered in conjunction with anticoagulants during the early phase of hospital care, should be thought of more broadly as antithrombotic therapy and not exclusively antiplatelet therapy. The challenge is striking the balance of decreasing the thrombus burden in the affected coronary vessel(s) without causing so much antithrombotic activity that bleeding ensues.³

The 2012 focused update includes recommendations on the latest addition to the P2Y12 antagonist portfolio---ticagrelor, studied in the PLATO trial.⁴ Ticagrelor joins prasugrel, studied in the TRITON-TIMI 38 trial, as alternatives to the more familiar compound clopidogrel.⁵ On May 17, 2012 the FDA approved the generic versions of clopidogrel from several companies setting the stage for interesting decision-making by clinicians. Clopidogrel will be available in a less expensive formulation in the near future, while two alternatives---prasugrel and ticagrelor---are now available and have both been shown to be superior to clopidogrel for prevention of the composite primary endpoint of cardiovascular death/nonfatal MI/ or nonfatal stroke. Of note, both prasugrel and ticagrelor are associated with an increased risk of non-CABG associated bleeding compared with clopidogrel.

The writing committee did not recommend one P2Y12 antagonist over another. This is quite reasonable, since prasugrel and ticagrelor have only been compared to clopidogrel and not to each other and were studied in different populations (acute coronary syndrome with planned PCI in the case of prasugrel versus acute coronary syndrome without the requirement for planned PCI in the case of ticagrelor---resulting in 99% of subjects undergoing PCI in the prasugrel study compared with 64% in the ticagrelor study). As with any new therapy introduced into clinical medicine, it is important to realize that the efficacy and safety established in the confines of a randomized trial may not be reflective of the effectiveness and safety when the drug is used in routine clinical practice.

A concern raised by the writing committee was the risk of bleeding with both new agents. While non-CABG associated bleeding is increased with all P2Y12 antagonists (clopidogrel versus placebo; prasugrel and ticagrelor versus clopidogrel), it is the risk of intracranial bleeding that concerns clinicians most. The risk of intracranial bleeding is always to be considered when contemplating antiplatelet therapy---its incidence increases along the spectrum of progressively of more potent regimens from aspirin alone, to aspirin plus clopidogrel, to aspirin plus a more potent P2Y12 antagonist. As pointed out by the Writing Committee, the risk of intracranial bleeding with dual antiplatelet therapy is of particular concern in patients with a prior stroke. The concern is supported by evidence from studies of dual antiplatelet therapy involving clopidogrel, dipyridamole, prasugrel, and vorapaxar.^6-10 As mentioned in this focused update, the data from the PLATO trial appear underpowered to definitively detect increased intracranial bleeding in patients with a prior stroke. In an editorial on this topic, but not covered in the focused update, Dr. Freek Verheugt argues from the totality of the evidence, the perspective of biologic plausibility, and the decision by trialists to exclude patients with prior stroke from ongoing studies (the PEGASUS trial is evaluating the benefits of long term treatment with ticagrelor) that there is “…no safe ground to treat ACS patients with a previous stroke or TIA routinely with the novel platelet P2Y12 receptor antagonists prasugrel or ticagrelor rather than with clopidogrel.”¹¹ Clinicians should also note that the secondary prevention guidelines for management of patients with stroke recommend against prescribing the combination of aspirin with clopidogrel (Class III) unless there are compelling cardiovascular indications.¹²

A particularly helpful feature of the 2012 focused update is the series of tables and figures in the Appendix. Table 3 provides the details of the dosing recommendations for both antiplatelet and anticoagulant therapy. Table 4 is relatively unique among Guidelines documents---it summarizes virtually all of the recommendations for P2Y12 antagonists. The pharmacology section of the table reminds clinicians that both clopidogrel and prasugrel are pro-drugs and the active metabolite binds irreversibly to the P2Y12 receptor (covalent bonds are formed between the sulfhydryl groups on the drugs with cysteine residues on the receptor) while ticagrelor is an active parent compound and binds reversibly to the receptor. Since ticagrelor is administered twice daily, patients need to be reminded to establish a reliable system for remembering to take the drug to avoid periods of diminished inhibition of the P2Y12 receptor. When patients transition to surgery both clopidogrel and ticagrelor should be stopped for 5 days, while prasugrel should be stopped for 7 days.

The issue of variability of response to clopidogrel is addressed in the focused update and the key information is also found in Table 4. The clinical utility of platelet function testing is not rigorously established but may be useful in selected patients with ischemic or thrombotic events while compliant with a clopidogrel regimen. The development programs for prasugrel and ticagrelor included extensive pharmacokentic and pharmacodynamic studies and the anticipated level of antiplatelet activity with a given dose is reasonably well established. This fact coupled with the much lower degree of variability of response to prasugrel and ticagrelor makes platelet function testing with those agents unnecessary in routine practice. Genotyping of patients to identify carriers of a deficient allele that limits their ability to generate the active metabolite of clopidogrel can be helpful, but its role in clinical management is a subject of ongoing study. While the FDA warning in the package insert for clopidogrel advises clinicians to consider alternative dosing strategies in patients who are poor metabolizers of clopidogrel, it does not give specific recommendations. Subsequent to placement of the black box warning on clopidogrel’s label, the results of the ELEVATE-TIMI 56 study were reported.¹³ This double-blind study of patients with stable coronary artery disease linked genotyping with platelet function testing across a range of clopidogrel maintenance doses. Patients who were heterozygous for the CYP2C19*2 allele required 225 mg per day to achieve the same level of platelet inhibition as that achieved by patients with the wild type allele who received 75 mg per day. Of note, for patients who were homozygous for the CYP2C19*2 allele even a 300 mg per day maintenance dose did not achieve comparable degrees of platelet inhibition to the wild type patients on the standard maintenance dose of clopidogrel.

The material on antiplatelet therapy in this focused update will help clinicians each step along the way in managing a patient with UA/NSTEMI – from initial selection of a drug during the early hospital phase through long-term care after hospital discharge.