ACUTE CORONARY SYNDROME UNDERSTANDING TREATMENT GUIDELINES SANDEEP DEVABHAKTHUNI, PHARM.D.

Transcription

1 ACUTE CORONARY SYNDROME UNDERSTANDING TREATMENT GUIDELINES SANDEEP DEVABHAKTHUNI, PHARM.D.

2 ACUTE CORONARY SYNDROME UNDERSTANDING TREATMENT GUIDELINES ACTIVITY DESCRIPTION Pharmacist can make a critical difference in the treatment of acute coronary syndrome, particularly in the areas of adherence and prevention of premature discontinuation of therapy. This program will educate pharmacists on ACS treatment guidelines, provide an update on pharmacotherapy, and the challenges associated with ACS treatment so they can more comfortably respond to patients and providers in their role as a pharmacist. TARGET AUDIENCE The target audience for this activity is pharmacists and nurses in hospital, community, and retail pharmacy settings. LEARNING OBJECTIVES After completing this activity, the pharmacist and nurse will be able to: Outline the evidence and guideline-based role of antiplatelet therapy in the prevention of coronary attacks in patients with acute coronary syndromes (ACS) Compare and contrast the safety and efficacy of oral antiplatelet therapies for long-term prevention of coronary attacks in ACS patients to include bleeding risks associated with antiplatelet therapy Review the pharmacist s role in counseling patients to increase understanding of treatment guidelines and medication adherence as a critical component of longterm maintenance of ACS patients ACCREDITATION PHARMACY PharmCon, Inc. is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NURSING PharmCon, Inc. is approved by the California Board of Registered Nursing (Provider Number CEP 13649) and the Florida Board of Nursing (Provider Number ). Activities approved by the CA BRN and the FL BN are accepted by most State Boards of Nursing. CE hours provided by PharmCon, Inc. meet the ANCC criteria for formally approved continuing education hours. The ACPE is listed by the AANP as an acceptable, accredited continuing education organization for applicants seeking renewal through continuing education credit. For additional information, please visit Universal Activity No.: H01-P Credits: 2 contact hours (0.2 CEU) Release Date: August 1, 2014 Expiration Date: August 1, 2016 ACTIVITY TYPE Knowledge-Based Home Study Monograph FINANCIAL SUPPORT BY AstraZeneca 1

3 ABOUT THE AUTHOR Dr. Sandeep Devabhakthuni is an Assistant Professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy. He graduated with a Bachelor of Engineering in Biomedical Engineering degree from University of Pittsburgh School of Engineering and a Doctor of Pharmacy degree from the University of Pittsburgh School of Pharmacy. He then completed his pharmacy practice residency at the University of Maryland Medical Center. He also completed his specialty residency in Cardiology and Critical Care at the University of Pittsburgh Medical Center. Currently, Dr. Devabhakthuni is a board certified pharmacotherapy specialist at the University of Maryland Medical Center, and he has a clinical practice on the Cardiology and Medical Intensive Care services. Sandeep Devabhakthuni, PharmD, BCPS Assistant Professor, University of Maryland School of Pharmacy FACULTY DISCLOSURE It is the policy of PharmCon, Inc. to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer of any commercial product(s) and/or service(s) discussed in an educational activity. Sandeep Devabhakthuni reports no actual or potential conflict of interest in relation to this activity. Peer review of the material in this CE activity was conducted to assess and resolve potential conflict of interest. Reviewers unanimously found that the activity is fair balanced and lacks commercial bias. Please Note: PharmCon, Inc. does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced and objective. Occasionally, authors may express opinions that represent their own viewpoint. Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient or pharmacy management. Conclusions drawn by participants should be derived from objective analysis of scientific data presented from this monograph and other unrelated sources. 2

4 Introduction Acute coronary syndrome (ACS) has a substantial economic and societal impact in the United States. An estimated 620,000 Americans have a new coronary attack (defined as first hospitalized MI or death) and 295,000 people have a recurrent attack. 1 From 2000 to 2010, death rates attributable to cardiovascular disease has declined by 31.0% due to major advancements in treatment for initial and secondary prevention after myocardial infarction (MI), heart failure treatment, and therapies for management of hypertension and hyperlipidemia. Despite the decline in deaths, one death occurs every minute from coronary events, which confirms the need to improve on evidence-based recommended therapies. 2, 3 Thrombosis, the catalytic event that leads to the cardiovascular morbidity and mortality associated with ACS, is predominantly caused by partial or complete coronary artery occlusion due to plaques that are vulnerable to rupture or erosion. 4.5 The spectrum of ACS events ranges from unstable angina (UA) to non-st-segment elevation myocardial infarction (NSTEMI) and STsegment elevation myocardial infarction (STEMI). Once a plaque ruptures, an occlusive thrombosis forms on top of the plaque, initiating the pathway for platelet adhesion and activation. 5 Because platelet adhesion, activation, and aggregation are key steps in the development of an occlusive thrombosis, a major pharmacological strategy is to mitigate the damage caused by atherothrombosis. Platelet activation persists well after the onset of ACS, requiring both short- and long-term antiplatelet therapy to prevent further damage. The pharmacotherapy for ACS includes combinations of fibrinolytic, anticoagulant, and antiplatelet agents to decrease incidence of cardiovascular events. Oral antiplatelet agents are 3

5 essential for primary and secondary prevention of ACS. 2,3 Studies provide strong evidence for dual antiplatelet therapy with aspirin and P2Y12 receptor antagonists (i.e., clopidogrel, prasugrel, and ticagrelor), demonstrating significant reduction in cardiovascular events in patients with all types of ACS with or without percutaneous coronary intervention (PCI). 6,7 On the basis of this evidence, antiplatelet therapies are generally considered standard of care for primary and secondary prevention of ACS. Antiplatelet Agents Development of adjunctive pharmacotherapy that includes antithrombotic and antiplatelet therapies has increased the use of invasive management (i.e., PCI) to treat ACS. The role of platelet activation in the pathogenesis of ACS has become a primary focus for therapy. The ACC/AHA practice guidelines for both NSTEMI/UA and STEMI provide strong recommendations for antiplatelet use in ACS (Table 1). 2,3 Although the efficacy of antiplatelet agents such as aspirin and clopidogrel has been wellestablished for ACS, instances of ischemic events have occurred as a result of suboptimal inhibition of platelets, also known as aspirin and clopidogrel resistance. 8,9 Other significant limitations, such as delayed platelet inhibition, individual variability in response, and adverse events, have resulted in the investigation of novel antiplatelet agents such as prasugrel and ticagrelor. 8,10,11 Based on the recent clinical evidence, the ACC/AHA practice guidelines now include prasugrel and ticagrelor in the recommendations for patients with NSTEMI/UA receiving conservative and invasive management or STEMI who are undergoing primary PCI or nonprimary PCI without previous fibrinolytic therapy. The differences in the pharmacokinetic 4

6 and pharmacodynamic profiles among clopidogrel, prasugrel, and ticagrelor are summarized in Tables 2 and 3. 12,13 Aspirin Because of the strong evidence for long-term prognostic effects in patients with coronary disease, aspirin is currently indicated to reduce the risk of MI or ischemic stroke. 14 Aspirin plays an essential role in treating atherothrombosis by inhibiting arachidonic acid metabolism by irreversible acetylation of a single serine residue on cyclooxygenase, an enzyme that produces a thromboxane A2 precursor. 9 Therefore, aspirin exerts its antiplatelet effect by irreversibly inhibiting platelet cyclo-oxygenase. This inhibition of platelet release and the impairment of platelet aggregation could prolong bleeding time. Based on several metaanalyses, aspirin use has been associated with the risk of gastrointestinal and intracranial hemorrhage The risk of major bleeding, especially gastrointestinal bleeding, appears to be significantly less with the use of low-dose aspirin. Despite gastrointestinal bleeding risk, the benefit of reducing ischemic events clearly outweighs the risk of bleeding. 17 Available clinical data supports the use of aspirin as a secondary preventive agent for ACS. The Canadian Multi-center Trial demonstrated a significant reduction in cardiac death and nonfatal MI by 51% compared with placebo when aspirin was initiated within the first 8 days after unstable angina. 18 Additional trials, including the Second International Study of Infarct Survival (ISIS-2) 19 trial and Research on Instability in Coronary Artery Disease (RISC) 20 trial, confirmed these results. The Antithrombotic Trialists Collaboration investigated various doses 5

7 of aspirin for secondary prevention and determined no significant differences between doses of , , or mg in preventing serious cardiovascular events. 14 First- and Second-Generation Thienopyridines The thienopyridine antiplatelet agents represent a second major therapeutic class of agents that inhibit platelet activation through a mechanism that is different from the effect exerted by aspirin. The first available thienopyridine, ticlopidine is now a last-line alternative because of its significant adverse effect profile, which includes neutropenia ( %) and thrombotic thrombocytopenic purpura (0.02%). 21 Clopidogrel, a second-generation thienopyridine, is more commonly used than ticlopidine because it is a safer alternative. Both clopidogrel and ticlopidine are irreversible inhibitors of platelets, rendering the targeted platelets inactive throughout their life span. These agents are prodrugs (pharmacologically inert precursors), which are converted to their active forms through hepatic metabolism. The active metabolites bind to the adenosine 5 - diphosphate (ADP) P2Y12 receptors on platelets, resulting in platelet inactivation and inhibited aggregation. 9 An overview of pertinent clinical data regarding the P2Y12 receptor antagonists is provided in Table 4. A landmark clinical trial, the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, demonstrated the clinical efficacy of clopidogrel 75mg/d compared with aspirin 325 mg/d in patients with recent MI, ischemic stroke, or symptomatic peripheral arterial disease (PAD). 22 Furthermore, clopidogrel was an independent predictor for the reduction of this combined end point. The CAPRIE investigators determined a reduction in 6

8 need for hospitalization due to recurrent ischemia and bleeding for clopidogrel when compared to aspirin. Combination therapy with aspirin and thienopyridines creates a synergistic effect on platelet inhibition. Several investigations have demonstrated a significant reduction in ischemic events associated with dual antiplatelet therapy when compared with aspirin therapy alone. 23 Recently, the Clopidogrel for High Atherothombotic Risk, Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial determined that the use of clopidogrel provided significant benefit only for patients with established cardiovascular disease (Table 4). 6,23,30 This benefit was not observed in the asymptomatic high-risk patients (i.e., primary prevention), indicating that dual antiplatelet therapy may be beneficial only for secondary prevention. 23 The superior efficacy of dual antiplatelet therapy with a thienopyridine and aspirin compared with use of aspirin alone in patients with cardiovascular disease is well established. 6,7,23,30 However, many investigators have discovered that the adjunctive use of clopidogrel has significant limitations, including delayed onset of action and a wide interpatient variability in antiplatelet action and treatment response, possibly because of the inefficient conversion of clopidogrel to its active metabolite. 8,10 The delayed onset (usually 2-4 hours) can be critical in patients with ACS who are in urgent need of catheterization. 31 Because of the unpredictable onset of action, many clinicians administer a high loading dose (e.g., 300 or 600mg) to achieve an earlier and higher inhibition of platelet function with better response profiles. 32 However, data on the clinical impact of a high loading dose are limited, and this regimen has not been approved by the Food and Drug Administration (FDA). 31 7

9 A further limitation is irreversible platelet inhibition, which means that clopidogrel must be withheld at least 5-7 days (lifespan of platelets) before a scheduled surgical intervention to decrease risk of serious bleeding. An antiplatelet medication that allows platelet function to return to baseline rapidly would enable the patient to undergo surgery more promptly. 31 Another concern about the unpredictable response of clopidogrel has emerged regarding the potential drug-drug interactions with medications that inhibit CYP2C19 activity such as proton pump inhibitors. Proton pump inhibitors are often prescribed for patients taking clopidogrel to prevent gastrointestinal complications such as ulceration or gastrointestinal hemorrhage due to the recommended dual antiplatelet therapy with aspirin and a thienopyridine such as clopidogrel. Recently, proton pump inhibitors (e.g., omeprazole, pantoprazole, and lansoprazole) have been reported to interfere with the metabolism of clopidogrel. 2 According to the ACC/AHA 2009 guidelines for STEMI, no convincing clinical trial data indicate an important clinical drug-drug interaction to date. Moreover, additional data from randomized clinical trials is needed in order to evaluate the use of DAPT with proton pump inhibitors. However, no evidence indicates that other acid-reducing medications, such as histamine2 receptor blockers or antacids, interfere with the antiplatelet activity of clopidogrel. The wide variability in treatment response could lead to enhanced platelet reactivity and potentially serious vascular complications such as atherothrombosis, hematoma, and ischemic stroke. 32 Potential mechanisms of clopidogrel resistance include noncompliance, variability in absorption, dug-drug interactions (e.g., atorvastatin), and genetic polymorphisms in hepatic cytochrome P450 3A4 metabolic activity and P2Y12 ADP receptors. 9 Several laboratory methods exist for determining clopidogrel response, which include light transmission 8

10 aggregometry (gold standard), vasodilator-associated stimulated phosphoprotein phosphorylation, and the point-of-care VerifyNow P2Y12 assay. 33,34 The purpose of these assays is to measure residual platelet aggregation or P2Y12 receptor activity as markers of clopidogrel efficacy. One of the major limitations of these assays is that there is no accepted level of antiplatelet activity in which safety and/or efficacy outcomes can be predicted, introducing further confusion when evaluating the literature to determine appropriate antiplatelet regimen. 33 Because of inconclusive prospective data and considerable variation in assays and definitions for high post-treatment platelet reactivity, it remains unclear whether altering the maintenance dose of clopidogrel can reduce risk of cardiovascular events Compared to other P2Y12 receptor antagonists, clopidogrel is the most widely studied agent in the spectrum of ACS and has shown significant benefit in all presentations regardless of selected treatment strategy. In patients undergoing PCI within 6 hours, a loading dose of 600mg should be used to ensure appropriate antiplatelet effects. The major limitations of clopidogrel include variable effects on platelet function due to genetic polymorphisms and drug interactions. 33,34 Yet, genetic testing appears to provide little benefit over platelet reactivity testing. 33,39,40,43 Although high post-treatment platelet reactivity has been linked with increased risk of ischemic events, no data exists to support increases in clopidogrel maintenance dose. 38,41-43 Drug interactions have not been shown to lead to worse clinical outcomes. Prasugrel Prasugrel received FDA approval in 2009 for patients with UA, NSTEMI, or STEMI managed with PCI to reduce the number of cardiovascular events, including stent 9

11 thrombosis. 8,10,44 This orally active agent was designed to overcome many of the limitations of clopidogrel treatment. Prasugrel is classified as a third-generation thienopyridine derivative because of its similarities to the chemical structure of ticlopidine and clopidogrel. Like clopidogrel, prasugrel is a prodrug that requires hepatic metabolism to be converted to its active metabolite. This active form binds irreversibly to the platelet ADP P2Y12 receptor, causing a permanent blockade of ADP-mediated P2Y12 receptor signaling and the inhibition of glycoprotein IIb/IIIa receptor activation, thereby preventing platelet aggregation. 44 After oral administration, prasugrel has a rapid absorption and metabolism, with a median time of 30 minutes for maximal concentrations of the active metabolite. 45 Prasugrel is rapidly de-esterified to an inactive metabolite, then transformed to the active metabolite through the hepatic cytochrome P450 system. 8 In contrast to clopidogrel metabolism, much of the prodrug is activated in the early stages, which leads to 10-fold higher levels of active metabolite and explains the difference in pharmacokinetics between the 2 agents. 46 However, in equal concentrations, the active metabolites of both prasugrel and clopidogrel have similar potency in inhibition of platelet aggregation (IPA). 47 In a major phase I trial, Brandt et al compared a 300mg loading dose of clopidogrel with a 60mg loading dose of prasugrel in healthy persons not taking aspirin. 45 The investigators reported that prasugrel had a more rapid onset of antiplatelet action (maximal effect in 60 minutes for prasugrel vs. 4-6 hours for clopidogrel), significantly higher peak IPA (78.8% vs. 35%, p < 0.001), and less interpatient variability when compared with clopidogrel. Thienopyridine resistance, defined as 20% IPA at 24 hours, was also measured. When receiving clopidogrel, 42% of participants met this criterion for resistance; however, patients receiving 10

12 prasugrel did not experience any resistance. 45 Other pharmacodynamic studies confirmed an earlier onset and higher IPA during the loading phase, which persisted throughout the maintenance therapy for prasugrel compared with clopidogrel. 48,49 A major phase II trial, the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trail (Table 4) evaluated the safety of low, intermediate, and high doses of prasugrel compared to clopidogrel in patients with ACS receiving elective or urgent PCI. 26 Subjects were monitored for 30 days for bleeding and clinical events. There was no significant difference in the primary end point, which was the rate of clinically significant (TIMI major plus minor) non-cabg-related bleeding events. In the prasugrel group, there were significantly lower incidences of primary efficacy composite end-point (30-day major adverse cardiac events) and of the secondary end points (MI, recurrent ischemia, and clinical target vessel thrombosis). The findings demonstrated that prasugrel has a suitable safety profile to allow phase III investigations of both short- and long-term safety and efficacy focusing on major cardiovascular clinical outcomes. The efficacy of prasugrel was compared extensively with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON-TIMI 38 trial). 24,25 This trial compared prasugrel (60mg loading dose and 10mg maintenance dose) with clopidogrel (300mg loading dose and 75mg maintenance dose) in 13,608 patients with ACS scheduled for PCI. This multicenter phase III trial led to the FDA approval of prasugrel for the management of patients with ACS undergoing PCI because prasugrel had a significant reduction in composite end point of cardiovascular death, nonfatal MI, or stroke compared to clopidogrel (9.9% vs. 12.2%; hazard ratio (HR) 0.82; 95% confidence 11

13 interval (CI) ; p < 0.001). This trial also examined safety outcomes associated with prasugrel, particularly bleeding not associated with CABG. An increased risk of major hemorrhage was documented for prasugrel, including both fatal and nonfatal bleeds. The findings of a pre-specified analysis of net clinical benefit showed that prasugrel did not offer an advantage over clopidogrel. Patients with a history of stroke or TIA experienced net harm with prasugrel compared with clopidogrel (23% vs. 16%; HF 1.54; 95% CI ; p = 0.04). Those that were 75 years or older (HR 0.99; 95% CI ; p = 0.92) or weighing less than 60 kg (HR 1.03; 95% CI ; p = 089) experienced no net benefit. Several pre-specified subgroup analyses from TRITON-TIMI 38 trial have been conducted to identify patient populations that may benefit from prasugrel. A major limitation of these analyses is that they cannot directly link the subgroup characteristics to differences in response to prasugrel and clopidogrel. The TRITON study included a subgroup analysis of 3534 patients with STEMI. 50 Compared with the overall study, patients with STEMI had a significant reduction in the incidence of primary composite outcome when they received prasugrel compared to clopidogrel (10.0% vs. 12.4%, HR 0.79; 95% CI ; p = ). Thrombotic events in the subgroup of patients receiving stents in TRITON were reported. 51 The primary end point in patients with stents was consistent with the overall trial showing that prasugrel was superior (10% vs. 12%; HR 0.8; 95% CI ; p = 0.003). Incidence of definite stent thrombosis was lower with prasugrel in patients receiving stents (0.88% vs. 2.03%; HR 0.42; 95% CI ; p < ). The impact of diabetes on outcomes in TRITON study was also studied because of poor responses with clopidogrel in this population. 52 There were 3146 patients with diabetes enrolled in the study that had higher 12

14 rates of all ischemic outcomes. Prasugrel reduced the incidence of primary end point compared with clopidogrel in patients with diabetes (12.2% vs. 17.0% HR 0.7; 95% CI ; p < 0.001) and in patients without diabetes (9.2% vs. 10.6%; HR 0.86; 95% CI ; p = 0.02). The subgroup of patients in TRITON who underwent PCI without stenting had similar clinical outcomes compared to all patients enrolled in the trial, and they had higher bleeding rates, resulting in a neutral net clinical benefit. 53 More recently, the TaRgeted platelet Inhibition to clarify the Optimal strategy to medically manage Acute Coronary Syndromes (TRILOGY ACS) trial evaluated the role of prasugrel in patients with UA/NSTEMI who received medical management. 54 Patients were randomized to receive either clopidogrel (300mg loading dose and 75mg maintenance dose) or prasugrel 5mg maintenance dose if 75 years or older or weight less than 60 kg or 10mg maintenance dose for younger patients with higher body weight. The rate of primary efficacy end point was similar among the groups. These data do not support the use of the reduced 5mg dose in those with either low body weight or advanced age or use of prasugrel in patients receiving medical management. Due to irreversible action of prasugrel on platelets and increased risk of bleeding, prasugrel should be discontinued at least 7 days before any surgery. 44 Prasugrel is contraindicated in patients with active bleeding or a history of stroke or transient ischemic stroke (no clinical data regarding hemorrhagic stroke reported). 24,25 Other adverse events not related to hemorrhage include dizziness (20%), cellulitis (16%), facial edema (16%), headache (13%), dyspepsia (9%), thrombocytopenia (0.3%), neutropenia (< 0.1%), and colonic neoplasms (0.2%). 24,25, 44, 45 Unlike clopidogrel, prasugrel has minimal drug-drug interactions, including with 13

15 drugs metabolized by the hepatic CYP450 system. Although concomitant administration of prasugrel with other antiplatelet or antithrombotic agents has not been adequately studied, this combination should be carefully monitored because of the potential for increased bleeding risk. Although more clinical data are needed, prasugrel does not need to be adjusted for renal or hepatic impairment. However, the risk of bleeding is higher for severe hepatic disease. When compared to clopidogrel, prasugrel has a more rapid onset of action, less interpatient variability in pharmacokinetics and pharmacodynamics, and a higher rate of platelet inhibition. Phase III trial results demonstrated the efficacy and safety of prasugrel for the management of patients with ACS who receive PCI. 24, 25 The role of prasugrel in preventing ischemic events is clear in specific populations including diabetic patients; however, the increased incidence of bleeding should be considered, especially in patients older than 75 years or low body weight (< 60 kg) where there is no net clinical benefit. Also, patients with a history of stroke or TIA should not receive prasugrel since there is evidence of net clinical harm. Ticagrelor Ticagrelor is an oral direct-acting, reversible P2Y12 receptor antagonist, which is the first of a new therapeutic class of antiplatelet agents, the cyclopentyltriazolo-pyrimidines. 55 Ticagrelor and its active metabolite bind selectively and reversibly to platelet P2Y12 receptors at a site distinct from the adenosine 5 -diphosphate (ADP). 12 Beneficial effects beyond platelet inhibition include inhibition of ADP-mediated vasoconstriction of vascular smooth muscle and enhancement of adenosine-induced coronary blood flow through inhibition of adenosine uptake by erythrocytes. 56,57 Unlike clopidogrel and prasugrel, ticagrelor does not require 14

16 hepatic activation. 12,58 Also, due to its reversible effect, it does not need to be withheld for 5 to 7 days prior to a planned major procedure like clopidogrel or prasugrel. Recent evidence suggests that patients may undergo a major surgical intervention after withholding ticagrelor for hours. 55 The product label states that ticagrelor should be held for 5 days prior to surgery when possible. Ticagrelor has one active metabolite (AR-C124910XX), which has been shown to have relatively equal potency to the parent compound at the P2Y12 receptor. 59 Ticagrelor is rapidly absorbed following oral administration, with an onset of antiplatelet effect within 30 minutes. 9,60 Peak plasma levels of ticagrelor are reached within 1.5 to 3 hours of administration, while the peak levels of the active metabolite occur within 2 to 4 hours. The active metabolite is further metabolized and undergoes glucuronidation before elimination in the urine. Both ticagrelor and its active metabolite are primarily excreted in the feces, with < 1% eliminated in the urine. The elimination half-life of ticagrelor is 6-12 hours, and steady state is attained after 2 to 3 days. The elimination half-life of the active metabolite is 8.5 to 10 hours. Pharmacokinetics do not appear to be influenced by age or gender. While no formal drug-drug interaction studies have been conducted, patients taking inhibitors, inducers, or substrates of CYP3A were excluded from clinical trials. Within two hours of oral administration of ticagrelor 100 to 400mg, IPA is at least 95%. Ticagrelor inhibits platelet aggregation in a dose-dependent manner up to mg twice daily. 55, 59 The effect peaks at 2 to 4 hours and diminishes over the next 24 hours. The reversible binding of ticagrelor is shown by a decrease in IPA within 24 hours post steady-state dose, which can be explained by a reduction in plasma drug concentrations. 55, 59 However, the IPA at 15

17 24 hours post-dose is still higher than or at least equivalent to clopidogrel 75mg daily, which may mean that a missed dose may not be as problematic. 59 Full platelet function is recovered 5 days after the last dose of ticagrelor. 55 A study conducted by Gurbel et al., called the ONSET/OFFSET study, determined the onset and offset of the antiplatelet effect of ticagrelor with a loading dose of 180mg followed by 90mg twice daily as the maintenance dose for 6 weeks compared with high-dose clopidogrel and placebo in stable coronary artery disease (CAD) patients given background aspirin therapy. 61 Ticagrelor was shown to have a rapid onset of a marked increase of platelet inhibition compared to clopidogrel. At 24 hours after stopping ticagrelor, the degree of platelet inhibition with ticagrelor was similar to the platelet inhibition of clopidogrel. At day 3 after the last dose, the inhibition with ticagrelor was similar to the platelet inhibition of clopidogrel at day 5. Finally, at day 5 after the last dose, the inhibition with ticagrelor was similar to the platelet inhibition of clopidogrel at day 7. These findings suggested that ticagrelor had a more rapid offset compared to clopidogrel, which may allow patients to undergo a major surgical intervention more quickly. Gurbel et al. conducted another study, called the RESPOND study, to investigate the antiplatelet efficacy of ticagrelor in patients who were considered to be nonresponders to clopidogrel therapy and studied the platelet function during switching from one agent to the other one. 62 The authors determined that ticagrelor was associated with increased platelet inhibition in either clopidogrel responders or nonresponders, suggesting that the antiplatelet efficacy of ticagrelor is not affected by clopidogrel response status. During switching, ticagrelor achieved a rapid enhancement in platelet inhibition for both clopidogrel responders and 16

18 nonresponders. Conversely, changing from ticagrelor to clopidogrel resulted in a reduction in platelet inhibition. The Dose confirmation Study assessing anti-platelet Effects of AZD6140 vs. clopidogrel in non-st-segment Elevation myocardial infarction (DISPERSE)-2 trial was a randomized, multicenter, double-blind, double-dummy phase 2 study comparing ticagrelor to clopidogrel in patients with NSTEMI. 27 This trial confirmed that ticagrelor has similar safety and efficacy profile when compared to clopidogrel in patients with ACS being managed with standard pharmacotherapy and interventional therapy. Based on the results, this study provided the rationale for conducting a larger, randomized, controlled trial in all patients with ACS to assess efficacy and safety of ticagrelor. The Study of Platelet Inhibition and Patient Outcomes (PLATO) trial was a Phase 3 trial that was conducted to determine whether ticagrelor is superior to clopidogrel for the prevention of vascular events and death in a broad population of patients presenting with an acute coronary syndrome. 28, 29 This multicenter, double-blind, randomized, double-dummy trial included 18,624 patients who were admitted to the hospital with an ACS with or without a ST-segment elevation. Eligible patients were randomized to receive ticagrelor (loading dose of 180mg followed by 90mg twice daily) or clopidogrel (loading dose of 300mg if not received within 5 days before randomization followed by 75mg once daily). Patients received another loading dose if they underwent a PCI 24 hours after randomization with ticagrelor 90 mg or clopidogrel 300mg (600mg dose optional). 17

19 The primary efficacy end point (composite of death from vascular causes, nonfatal MI, or nonfatal stroke) occurred significantly less often in the ticagrelor group than in the clopidogrel group (9.8% vs. 11.7% at 12 months; p < 0.001). This difference appeared at 30 days after initiation of therapy (4.8% vs. 5.4%, p = 0.045) and persisted throughout the study period. Also, patients receiving ticagrelor had a lower rate of MI, vascular death, and death from any cause but had a similar rate of stroke compared to those receiving clopidogrel. More patients receiving ticagrelor had a hemorrhagic and cryptogenic stroke. The incidence of major bleeding was similar between ticagrelor and clopidogrel. However, when assessed as a composite outcome, major and minor bleeding was higher in the ticagrelor group. More patients receiving ticagrelor discontinued study drug due to an adverse event compared to those receiving clopidogrel (7.4% vs. 6.0%, p < 0.001). There was a higher incidence of dyspnea but low rate of discontinuation (0.9% vs. 0.1%, p < 0.001) associated with ticagrelor. Ticagrelor also had increased rates of ventricular pauses compared to clopidogrel after the first week, but the rates were comparable after the first month of therapy (2.1% vs. 1.7%, p = 0.52). Also, ticagrelor was found to have increases in serum uric acid and creatinine levels at 1 month and 12 months, but these increases resolved 1 month after discontinuation of therapy. A post-hoc subgroup analysis was performed that focused on renal function of the patients enrolled in the PLATO trial based on serum creatinine levels measured on admission to the hospital (values available for 15,202 patients). 63 The results found that in patients with chronic kidney disease (creatinine clearance < 60 ml/min, n = 3237), patients receiving ticagrelor had a significant reduction in the primary end point from 22.0% to 17.3% (HR 0.77; 18

20 95% CI 0.65 to 0.9) with an absolute risk reduction greater than that of 11,965 patients with normal renal function (7.9% vs. 8.9%, HR 0.90; 95% CI 0.79 to 1.02). Also, patients with chronic kidney disease who received ticagrelor had a significant reduction in mortality compared to those receiving clopidogrel (10.0% vs. 14.0%, HR 0.72; 95% CI 0.58 to 0.89). Major bleeding rates, fatal bleedings, and non-coronary bypass-related major bleedings were not significantly different between the two study groups. There were no significant interactions between creatinine clearance and either study treatment on any of the outcome variables. The authors concluded that patients with chronic kidney disease who received ticagrelor compared to clopidogrel had significant reductions in ischemic end points and mortality without a significant increase in major bleeding but with numerically more incidences of non-procedure related bleeding. Patients with diabetes mellitus have high platelet reactivity and are at an increased risk of ischemic events and bleeding post-acs. 64 A post-hoc analysis examined patients enrolled in the PLATO study to investigate the outcome with ticagrelor vs. clopidogrel in patients with diabetes or poor glycemic control. The investigators, James et al., analyzed 4662 patients with pre-existing diabetes, including 1036 patients on insulin, and subgroups based on admission levels of hemoglobin A1c (n = 15,150). In patients with diabetes, the reduction in the primary composite endpoint (HR: 0.88, 95% CI: ), all-cause mortality (HR: 0.82, 95% CI: ), and stent thrombosis (HR: 0.65, 95% CI: ) with no increase in major bleeding (HR: 0.95, 95% CI: ) with ticagrelor was consistent with the overall cohort and without significant diabetes status interactions. The authors concluded that ticagrelor significantly 19

21 reduced ischemic events in ACS patients without an increase in major bleeding events compared to clopidogrel, regardless of diabetic status or glycemic control. Since ticagrelor and its active metabolites are metabolized by CYP3A4 and inhibit the P- glyoprotein system, there is potential for drug interactions, especially strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) and inducers (e.g. rifampin). Concomitant use of strong CYP 3A4 inhibitors or inducers should be avoided with ticagrelor. Ticagrelor significantly increases the concentration of simvastatin and lovastatin so dose adjustment by at least 50% is advised when using these agents. Despite ticagrelor increasing the concentration, no dose adjustment is needed for concomitant use of atorvastatin and digoxin. A retrospective analysis of the PLATO trial determined that there is an interaction between ticagrelor and aspirin that is dose-related. It is unclear whether this interaction is pharmacokinetic, pharmacodynamic, or other type of interaction. Patients treated with aspirin doses of 300mg daily or higher had better clinical outcomes with clopidogrel compared to ticagrelor (HR 1.45; 95% CI ). Those treated with 100mg or less of aspirin had better clinical outcomes with ticagrelor (HR 0.77; 95% CI ). Due to these findings, the FDA recommended a boxed warning that the maintenance dose of aspirin should be 100mg or less when administered with ticagrelor. Ticagrelor is an attractive option as a P2Y12 antagonist for management of ACS. The favorable clinical outcomes associated with ticagrelor compared with clopidogrel in patients receiving either medical or invasive management due to significant reductions in MI and cardiovascular death with minimal increase in bleeding. Ticagrelor overcomes some of the 20

22 limitations of the other P2Y12 antagonists such as prodrug activation, irreversibility, variable antiplatelet response, delated onset, and suboptimal degree of platelet inhibition. The aspirin dose should be 100mg or less when given concomitantly with ticagrelor. One major limitation with ticagrelor is the high drug acquisition cost, whereas a generic product exists for clopidogrel that is more affordable. Several cost-effectiveness analyses have attempted to account for these factors, but determining the role of the three available P2Y12 antagonists remains challenging. Antiplatelet Guidelines The recommendations for antiplatelet regimens for management of ACS are summarized in Table 1. 2,3 The 2012 American College of Cardiology/American Heart Association (ACC/AHA) focused update for NSTEMI/UA recommends the use of a P2Y12 receptor antagonist in addition to aspirin. When using clopidogrel, the recommendation is to provide a loading dose of mg followed by a 75mg maintenance dose with therapy duration dependent on the intervention strategy used. Both prasugrel and ticagrelor are considered as alternatives to clopidogrel for PCI-managed patients with the same duration. However, only ticagrelor is approved as an alternative for patients receiving medical management since prasugrel has not been studied in this setting. If ticagrelor is selected, the maintenance dose of aspirin must be 81mg. The 2013 American College of Cardiology Foundation (ACCF)/AHA focused update for STEMI also recommends any of the P2Y12 receptor antagonists in combination with aspirin for a duration of dual antiplatelet therapy (DAPT) of at least 12 months. 21

23 The American College of Chest Physicians also provided guidelines on antithrombotic therapy and prevention of thrombosis. 65 These guidelines do not differentiate between the type of ACS to determine the DAPT. All the currently available oral antiplatelet agents are considered; however, ticagrelor is preferred over clopidogrel regardless of stent use and duration of DAPT consistent with ACC/AHA guidelines. For patients with ACS not receiving PCI, either clopidogrel or ticagrelor is recommended for at least 12 months. For patients with ACS receiving PCI, DAPT is recommended for 12 months after a bare metal stent (BMS) and at least 3-6 months after a drug-eluting stent (DES) up to 12 months. Regardless of the decision to perform PCI, single antiplatelet therapy is recommended after 12 months of DAPT. Patient Education Despite significant advances in pharmacotherapy to manage patients with ACS, many patients lack compliance when prescribed DAPT due to poor understanding of the medications. Thus, pharmacists play a crucial role in educating patients so that they understand the need to prevent further cardiovascular events by adhering to the prescribed antiplatelet regiment. When determining the selection and monitoring of antiplatelet agents for management of ACS, pharmacists must consider the clinical characteristics of the patient in relation to the available clinical evidence and their preferences to ensure medication adherence. Pharmacists must weigh the risks of increased bleeding events and costs of the newer antiplatelet agents compared with clopidogrel. Also, pharmacists should pay close attention to contraindications and drug-drug interactions and educate patients on these warnings (e.g., appropriate maintenance dose of aspirin when dispensing ticagrelor). Pharmacists should also assess the need for anticoagulant therapy in combination with antiplatelet therapy and determine 22

24 appropriate duration of DAPT after intervention (Table 1). Finally, pharmacists can improve patient adherence by reviewing evidence-based clinical guidelines. Conclusion In the past decade, antiplatelet therapy for management of patients with ACS has evolved due to continued incidence of clinical atherosclerotic events including recurrent MI. This concern has led to the development of novel antiplatelet agents to overcome limitations of clopidogrel, especially interpatient variability in platelet inhibition due to genetic factors. Pharmacists play a crucial role in educating patients on the novel antiplatelet agents so it is necessary to understand the place in therapy for each. In general, treatment strategy is dependent on whether the patient is presenting for medical or invasive management. Clopidogrel is still an accepatable option in most scenarios. Prasugrel is contraindicated in patients with a history of stroke or TIA, and it is not beneficial for medical management, patients greater than 75 years, and patients with weights < 60 kg. Ticagrelor shows great promise due to significant reductions in clinical atherosclerotic events compared to clopidogrel, but it is limited by high drug acquisition costs. Ticagrelor should be avoided in patients with severe hepatic impairment, and drug interactions should be considered, especially aspirin, which should be limited to a dose 100mg. Title: You Take My Breath Away - Understanding and Treating COPD 23

25 Table 1. Guideline-Recommended Antiplatelet Regimen for Acute Coronary Syndromes ACC/AHA Guidelines Aspirin Clopidogrel Prasugrel NSTEMI/UA 1. Medical Management Initial: mg once Maintenance: mg daily indefinitely 2. PCI Initial: mg once Maintenance: mg daily indefinitely STEMI (with or without stent) Initial: mg once Maintenance: mg daily indefinitely (81mg daily is preferred to minimize bleeding risk) NSTEMI/UA 1. Medical Management Load: mg once Maintenance: 75mg daily for 1-12 months 2. PCI Load: mg once Maintenance: 75mg daily for 1-12 months after BMS or at least 1 year after DES STEMI 1. Primary PCI Load: mg once Maintenance: 75mg for at least 12 months 2. Nonprimary PCI Load: mg once (continue maintenance dose if already received load after fibrinolytic) Maintenance: 75mg for at least 12 months 3. No PCI Maintenance: 75mg daily for at least 14 days NSTEMI/UA 1. Medical Management Not recommended 2. PCI Load: 60mg once Maintenance: 10mg daily up to 12 months after BMS or at least 1 year after DES; Avoid with history of stroke and/or TIA 24

26 STEMI 1. Primary PCI Load: 60mg once Maintenance: 10mg for at least 12 months 2. Nonprimary PCI Load: 60mg once without fibrinolytic once coronary anatomy known instead of clopidogrel Maintenance: 10mg for at least 12 months Ticagrelor NSTEMI/UA 1. Medical Management Load: 180mg once Maintenance: 90mg twice daily up to 12 months 2. PCI Load: 180mg once Maintenance: 90mg twice daily up to 12 months after BMS or at least 1 year after DES ACC, American College of Cardiology; AHA, American Heart Association; ACCP, American College of Chest Physicians; NSTEMI, non-st-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; BMS, bare metal stent; DES, drug-eluting stent; TIA, transient ischemic attack. Table 2. Comparison of antiplatelet agents for acute coronary syndrome Characteristic Clopidogrel Prasugrel Ticagrelor Receptor P2Y12 P2Y12 P2Y12 Prodrug Yes Yes No CYP isoenzymes responsible for metabolism No. of CYPdependent steps Genetic polymorphisms affecting generation of active metabolites 3A, 2B6, 1A2, 2C9, 2C19 3A, 2B6 3A4/ CYP2C19, CYP2C9 None None 25

27 Onset of action 300mg: 6 h 30 min 1.5 h after load 600mg: 4 h Offset 5 days 7 days 3 days Maximum IPA 300mg: 50% 80% 95% 600mg: 69% Reversible No No Yes Excretion 50% renal 68% renal 58% fecal 46% fecal 27% fecal Drug interactions CYP2C19 inhibitors may decrease effects (avoid omeprazole and esomeprazole); concomitant administration with NSAIDs or Concomitant administration with warfarin or NSAIDs increase risk of bleeding Concomitant administration of strong CYP3A4 inhibitors or inducers with ticagrelor should be avoided. Aspirin dose should be 100mg/day or less. warfarin increases risk of bleeding CYP, cytochrome P450; IPA, inhibition of platelet aggregation; NSAIDs, non-steroidal antiinflammatory drugs. Table 3. Contraindications and adverse effects of antiplatelet agents Medication Contraindications Adverse Effects Monitoring Aspirin Hypersensitivity Bleeding Gastrointestinal: ulceration, nausea, vomiting, dyspepsia Headache Clopidogrel Children and adolescents with chickenpox or flu symptoms (risk of Reye syndrome) Syndrome of asthma, rhinitis, and nasal polyps Hypersensitivity Active pathological bleeding: peptic Bleeding Gastrointestinal: hemorrhage, diarrhea Signs of bleeding or gastrointestinal intolerance Complete blood cell count and platelet count at discharge and every 6 months Signs of bleeding Complete blood cell count and platelet 26

28 Prasugrel Ticagrelor ulcer, intracranial hemorrhage Hypersensitivity Active pathological bleeding: peptic ulcer, intracranial hemorrhage Transient ischemic attack or stroke Hypersensitivity Active pathological bleeding: peptic ulcer, intracranial hemorrhage Severe hepatic impairment Rash Hematological: neutropenia (rare), thrombocytopenia (rare) Bleeding Dyspepsia Headache Dizziness Cellulitis Hematological: neutropenia (rare), thrombocytopenia (rare) Bleeding Headache Elevated creatinine Cough Dyspnea Atrial Fibrillation Syncope count at discharge and every 6 months Signs of bleeding Complete blood cell count and platelet count at discharge and every 6 months Signs of bleeding Complete blood cell count and platelet count at discharge and every 6 months Table 4. Overview of selected trials of P2Y12 receptor antagonists Trial Clopidogrel CAPRIE trial 22 Study Design Randomized, double blind, international, placebocontrolled Population Patients with recent MI, ischemic stroke, or PAD Number of Patients Clinical Outcomes % risk reduction versus aspirin in composite end point of ischemic stroke, myocardial infarction, or rehospitalization Limitations Analysis of patients with previous history of CABG that 27

29 CHARISMA trial 23 Randomized, double blind, multicenter, placebocontrolled Patients with established cardiovascul ar disease or multiple cardiovascul ar risk factors For patients with established cardiovascular disease, significant benefit in secondary end point including cardiovascular death, first occurrence of MI or stroke, hospitalization, or revascularization was not prespecified No 3-month follow-up data available for some stroke events No benefit in asymptomatic patients with multiple cardiovascular risk factors Prasugrel TRITON-TIMI 38 trial 24,25 Randomized, double blind, active control Patients with moderate to high risk of ACS undergoing PCI Combination therapy with aspirin had similar outcomes in primary end point of cardiovascular death, MI, or stroke Significantly lower outcomes in cardiovascular events for prasugrel compared with clopidogrel (9.9% vs. 12.1%, p < 0.001) Significant reductions in urgent target revascularization (2.5% vs. 3.7%, p < 0.001) and stent thrombosis (1.1% vs. 2.4%, p < 0.001) Overall mortality between the 2 groups did not differ significantly Comparison of prasugrel with lower loading dose (300mg) of clopidogrel Only 27% of patients in clopidogrel arm were preloaded within 24 hours prior to procedure Prasugrel had significantly higher incidence of TIMImajor bleeding (2.4% vs. 1.8%, p = 0.03) and fatal 28

30 JUMBO-TIMI 26 trial 26 Ticagrelor DISPERSE-2 trial 27 PLATO trial Randomized, multi-center, doubleblind, doubledummy Randomized, doubleblind, multicenter, doubledummy Patients undergoing elective or urgent PCI with stenting Patients with NSTEMI Patients with or without a ST-segment elevation bleeding events (0.4% vs. 0.1%, p = 0.002) 904 Combined prasugrel groups (low, intermediate, and high doses) had nonsignificant higher incidence of bleeding not associated with CABG compared with clopidogrel (1.7% vs. 1.2%, p = 0.59) 990 Incidence of major or minor bleeding at 4 weeks was not different among the 3 groups (8.1% in clopidogrel group vs. 9.8% in ticagrelor 90mg BID group vs. 8.0% in 180mg BID group, p = 0.43 and p =0.96 vs. clopidogrel, respectively) Rate of all-cause death was similar among the groups (1.3% vs. 2.4% vs. 1.7%, p = 0.38 and p = 0.72 vs. clopidogrel, respectively). Rate of cardiovascular death was not different Primary composite end point of death from vascular causes, nonfatal myocardial infarction, or nonfatal stroke was significantly less in ticagrelor group (9.8% vs. Use of lower loading dose (300mg) for clopidogrel Double blind, doseranging Antithrombotic drugs may not have been preloaded prior to PCI at optimal time Small sample size Short study duration of 12 weeks, precluding complete description of clinical and safety outcomes Exclusion of STEMI patients More patients in clopidogrel group received 300mg loading dose (600mg 29