Prasugrel a step ahead in antiplatelet therapy

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1 Prasugrel a step ahead in antiplatelet therapy VS Srinath, MD (Med), DNB (Cardiology) The burden of atherosclerotic disease in the United States and across the world is vast. Although the symptoms of atherosclerosis may manifest in several different ways, the most urgent and life-threatening are acute coronary syndromes (ACS). The use of percutaneous coronary intervention (PCI) has evolved to be the optimal treatment for many patients experiencing acute coronary syndromes, both as an elective and an emergency option. 1 Although bare-metal and drug-eluting stents used during PCI provide rapid revascularization, short-term and long-term dual antiplatelet therapy with aspirin and a thienopyridine is required to help ensure that the stents remain patent and free from thrombosis. 1 Thienopyridine antiplatelet drugs have been used for 15 years for the prevention of coronary stent thrombosis in patients undergoing percutaneous coronary intervention with stent placement. Ticlopidine, the first approved thienopyridine, has in large part been replaced by clopidogrel, a more potent and better tolerated thienopyridine. Clopidogrel has since remained the recommended thienopyridine by the American College of Cardiology American Heart Association guidelines. 1 Unfortunately, there are limitations associated with clopidogrel use, including potential drug-drug interactions, slow onset of action, irreversibility of platelet inhibition, and wide variability of patient response, including no response. A large fraction of the population carries a gene that may account for some of the inter-patient variation in platelet inhibition with clopidogrel. Carriers of a reduced-function CYPC19 allele approximately 3% of people in one study have significantly lower levels of the active metabolite of clopidogrel, less platelet inhibition from clopidogrel therapy, and a 53% higher rate of death from cardiovascular causes, myocardial infarction (MI), or stroke. To achieve levels of the active metabolite sufficient to inhibit the PY1 receptor around the time of PCI, the thienopyridine dosing strategy begins with a loading dose followed by longterm therapy with a daily maintenance dose that should not be discontinued prematurely to avoid ischemic complications. Despite its established effectiveness as the thienopyridine element of the dual antiplatelet regimen, clopidogrel has several limitations, including only a modest antiplatelet effect with a delayed onset of action and considerable inter-patient variability. 3 Consultant Cardiologist. Correspondence: Dr. VS Srinath, Krishna Institute of Medical Sciences, Hyderabad. It would be desirable to have a thienopyridine that lacked significant drug-drug interactions but also provided a quick onset of action, a consistent patient response, and minimal risk of bleeding. Prasugrel is a new thienopyridine antiplatelet agent approved by the United States Food and Drug Administration (FDA) on July 1, 9, for the treatment of patients with acute coronary syndromes who are undergoing PCI. Prasugrel is more potent, more rapid in onset, and more consistent in inhibiting platelet aggregation than clopidogrel. PHARMACOLOGY OF PRASUGREL AND CLOPIDOGREL Like clopidogrel, prasugrel is a prodrug that requires conversion to an active metabolite prior to binding to the platelet PY1 receptor for ADP to confer antiplatelet activity. Prasugrel is metabolized more efficiently than clopidogrel, allowing for faster activation and superior bioavailability to produce a greater and more consistent antiplatelet effect. The active metabolites of clopidogrel and prasugrel are no different in their ability to inhibit platelet aggregation, but approximately 85% of clopidogrel is inactivated by esterases, with the remaining 15% being converted to the active metabolite using the cytochrome P45 pathway via two successive oxidative steps in the liver. In contrast, esterases facilitate the transformation of prasugrel to its active metabolite. This activation requires only one oxidative step that can occur in either the liver or the gut through cytochrome P45. The active metabolite has an elimination half-life of about 7 hours (range 15 hours). Healthy subjects, patients with stable atherosclerosis, and patients undergoing PCI show similar pharmacokinetics. 4 Important pharmacokinetic and pharmacodynamic parameters of prasugrel and clopidogrel loading doses are displayed in Table 1. Both prasugrel and clopidogrel are irreversible PY1 receptor blockers. For this reason, one must wait approximately 5 days after the last dose of either medication for generation of a sufficient number of new platelets to allow restoration of normal platelet-mediated hemostasis. Both prasugrel and clopidogrel are pro-drugs requiring bio-activation through the hepatic cytochrome P45 (CYP) system before producing their antiplatelet effects. Once active, the metabolites of these agents antagonize the PY1 receptor of platelets, inhibiting the ability of adenosine diphosphate (ADP) to induce platelet aggregation. Both agents are noncompetitive antagonists of PY1 and therefore block the effects of ADP for the life of the platelet ( 1 days), an action independent of (and additive to) aspirin. The streamlined metabolism and activation of prasugrel likely account for its more rapid onset of action compared with clopidogrel. Onset of Action and Antiplatelet Efficacy Conversion of clopidogrel to its active metabolite is a two-step, CYP45-dependent process. However, prasugrel requires only one CYP45 dependent oxidative step to generate the thiol containing active metabolite. This difference may underlie the more rapid metabolic conversion and onset of action of prasugrel JICC Vol 1 Issue 1 17

2 Srinath Table 1 Pharmacokinetic and pharmacodynamic properties of clopidogrel and prasugrel. Parameter Clopidogrel Prasugrel 3 mg LD, 75 mg MD 6 mg LD, 75 mg MD 6 mg LD, 1 mg MD Time to peak plasma concentration (hrs) Time to peak platelet inhibition (hrs) > Time to platelet aggregation steady state (days) a Accumulation of metabolites No No No a Without loading dose. LD = loading dose; MD = maintenance dose without loading dose. compared with clopidogrel. The active metabolite of prasugrel was detected in plasma within 15 min of dosing and reached a maximum plasma concentration approximately 3 min after dosing. In a randomized crossover ex vivo study healthy subjects received a single loading dose of prasugrel (6 mg) or clopidogrel (3 mg). Inhibition of platelet aggregation with prasugrel was evident after 15 min. Platelet inhibitory effects of a 6 mg loading dose of prasugrel 3 min after administration was greater than the maximum antiplatelet effects of clopidogrel 1 hours after a 3 mg loading dose. 4 In patients with stable atherosclerosis, prasugrel (6 mg loading dose) achieved quicker and greater inhibition of ADP induced platelet aggregation, compared to a 6 mg loading dose of clopidogrel. The difference in the IPA between clopidogrel and prasugrel was observed in as little as 3 min following drug administration. Within 3 minutes, prasugrel had achieved antiplatelet effects superior to the maximum antiplatelet effects attained by 6 mg of clopidogrel over the 4-hour long observation period. 4 Prasugrel O CH 3 Liver O S O N F Platelet activation decreased Oxidation by cytochrome P-45 Active metabolite Platelet Hydrolysis by esterases ADP PY1 receptor Rapid absorption after oral ingestion ADP Mechanism of Action Prasugrel is a prodrug with rapid and almost complete absorption after oral ingestion of a loading dose. It is metabolized into its active form, which binds irreversibly to the adenosine diphosphate (ADP) PY1 receptor on platelets for their lifespan, thereby inhibiting their activation and decreasing subsequent platelet aggregation. Hydrolysis by intestinal carboxylesterases; and oxidation by intestinal and hepatic cytochrome P45 enzymes, convert prasugrel into its active metabolite (Figure 1). Prasugrel has a greater antiplatelet effect than clopidogrel because it is metabolized more efficiently. Genetic polymorphisms affecting the cytochrome P45 system may explain some of the differences in metabolism between prasugrel and clopidogrel. 4 The data from the PRINCIPLE-TIMI 44 (prasugrel in comparison to clopidogrel for inhibition of platelet activation and aggregation thrombolysis in myocardial infarction) study extend the results to patients undergoing cardiac catheterization for planned percutaneous coronary intervention. This trial compared the same dose regimen of prasugrel with high-dose clopidogrel (6 mg loading dose and 15 mg/d maintenance dose). Substantially and statistically significant greater platelet inhibition with prasugrel was observed at all time points studied during the loading dose and maintenance dose phases. Prasugrel was more potent and consistent in comparison to clopidogrel in the PCI setting. Figure 1 Prasugrel mechanism of action. The active metabolites of prasugrel and clopidogrel have similar potency at the platelet level. The greater potency of prasugrel to inhibit platelet PY1 receptors in patients with coronary artery disease, compared with clopidogrel, has been linked to more efficient generation of prasugrel s active metabolite, to higher peak plasma levels and greater exposure of platelets to the active metabolite. Interindividual Variability Studies including patients with coronary artery disease have documented inter-individual variability relative to clopidogrel s capacity to inhibit platelet aggregation. A substantial proportion (4% non-responders with the clopidogrel 3 mg and 11% nonresponders with the clopidogrel 6 mg) of the patients undergoing elective PCI were evaluated as non-responders to clopidogrel treatment. The proportion of patients, with limited clopidogrel efficacy, was even higher in patients with acute myo cardial infarction. The percentage of prasugrel non-responders, in patients with stable coronary artery disease (using the same definition for non-response; IPA < % in response to μm ADP), was only 3% after the 4 and 6 mg doses of prasugrel. A crossover JICC Vol 1 Issue 1 18

3 Prasugrel a step ahead in antiplatelet therapy Clopidogrel Prasugrel Genetic variation in CYPC19 can impair metabolism Concomitant medications that interfere with CYPC19 can impair metabolism Two CYP-mediated oxidation steps One esterase-mediated hydrolysis step One CYP-mediated oxidation step No relevant effect of genetic variation in CYPC19 Can be administered with drugs that are inducers or inhibitors of CYP enzymes Active metabolite Active metabolite Figure Effect of genetic variation and concomitant medications. 1, Source: study in healthy, aspirin-free subjects demonstrated that all individuals who responded poorly to the clopidogrel 3 mg achieved robust platelet inhibition when switched to prasugrel. PRASUGREL A CRITICAL COMPARISON WITH CLOPIDOGREL DRUG INTERACTIONS Possible drug-drug interactions with clopidogrel have been a hot topic recently. An additional class of drugs that have received a considerable amount of recent attention is the proton pump inhibitors (PPIs). The PPIs, including omeprazole, esomeprazole, rabeprazole, lansoprazole, and to a lesser extent pantoprazole, may have inhibitory activity on the CYPC19 hepatic enzyme, which is involved in the bio-activation of clopidogrel and prasugrel platelet aggregation studies evaluating this interaction have differed in their outcome, but clinical data showing an association between concomitant clopidogrel and PPI use and worse clinical outcome are mounting. A recent study comparing the effects of lansoprazole on the pharmacokinetics and pharmacodynamics of clopidogrel 3 mg and prasugrel 6 mg loading doses concluded that lansoprazole decreased the inhibition of platelet aggregation with clopidogrel but not prasugrel (Table ). 1 Most clinical data comparing prasugrel with clopidogrel come from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction (TRITON-TIMI 38). The aim of this randomized double-blind double-dummy clinical trial was to determine if the more potent antiplatelet activity of prasugrel would translate to improved clinical outcomes in moderate to high-risk patients with acute coronary syndromes undergoing PCI when compared with clopidogrel. The study randomly assigned 6813 patients to a prasugrel 6 mg loading dose followed by 1 mg/day and 6795 patients to a clopidogrel 3 mg loading dose followed by 75 mg/day for upto 15 months. Both groups also received aspirin mg/day. Patients were eligible for study inclusion if they had unstable angina or non-st segment elevation myocardial infarction occurring within 7 hours of randomization, a TIMI risk score of 3 or greater, and electrocardiographic (ST segment deviation 1 mm) or laboratory (elevated levels of Table Major clinical trials comparing clopidogrel and prasugrel. JUMBO-TIMI 6 PRINCIPLE-TIMI 44 TRITON-TIMI 38 TRITON-TIMI 38, Diabetes Mellitus Group TRITON-TIMI 38, STEMI Group TRILOGY- ACS (ongoing) a cardiac biomarker of necrosis) evidence of myocardial ischemia. The primary efficacy end point was a combination of death from cardiovascular causes, nonfatal myocardial infarction (defined by symptoms suggestive of ischemia or infarction, electrocardiographic data, cardiac biomarker, or pathologic evidence of infarction dependent on the clinical situation), or nonfatal stroke (defined as the rapid onset of new, persistent neurologic deficit lasting at least 4 hrs). To assess safety, major and life-threatening bleeding, not associated with CABG, was evaluated. Bleeding was assessed by using the TIMI scale, by which major bleeding is defined as either clinically overt hemorrhage plus a decrease in hemoglobin level of 5 g/dl or greater and minor bleeding is clinically overt bleeding plus a decrease in hemoglobin level of < 3 g/dl. 5 Prasugrel was found to have a significantly lower rate of the primary combined efficacy end point compared with clopidogrel (9.9% vs. 1.1%, HR.81, 95% CI.73.9, p <.1). This beneficial effect favoring prasugrel could be seen as soon as 3 days after PCI (HR.8, 95% CI.71.96, p =.1) and persisted throughout the follow-up period (HR.8, 95% CI.7.93, p =.3). The authors reported that the number needed to treat for the primary efficacy end point over the 15 months followup period was 46. This beneficial effect was mainly driven by a significant reduction in nonfatal myocardial infarction with prasugrel compared with clopidogrel (7.3% vs. 9.5%, HR.76, 95% CI.67.85, p <.1). 5 Some bleeding events that were observed with prasugrel like prasugrel also had a significantly higher rate of the primary safety end point of non-cabg related TIMI major bleeding compared with clopidogrel (.4% vs. 1.8%, HR 1.3, 95% CI , p =.3). The number needed to harm this end point was 167. This included not only a significant increase in nonfatal JICC Vol 1 Issue 1 19

4 Srinath life-threatening bleeding events with prasugrel (HR 1.5, 95% CI , p =.1), but fatal TIMI major bleeding events as well (HR 4.19, 95% CI , p =.). Intracranial hemorrhage occurred at a similar rate between prasugrel and clopidogrel (.3% vs..3%, p =.74). It is worth noting that patients who underwent subsequent CABG, albeit only 1% of the population, experienced significantly higher rates of TIMI major bleeding with prasugrel compared with clopidogrel (13.4% vs. 3.%, HR 4.73, 95% CI , p <.1). 5 The TRITON-TIMI 38 investigators also conducted a net clinical benefit analysis looking at improvements in efficacy end points (death from any cause, nonfatal myocardial infarction, nonfatal stroke) while also accounting for risks of bleeding in each group (non-cabg related TIMI major hemorrhage). Prasugrel had a lower rate of 1.% of this combined end point compared with clopidogrel, which had a rate of 13.% (p =.4). The authors did report that for every 1 patients treated with prasugrel versus clopidogrel, a total of 3 myocardial infarctions would be prevented at the expense of 6 additional non-cabgrelated TIMI major hemorrhages. 5 Regarding the observations in the elderly and underweight, the pharmacokinetic data suggest that in patients who are 75 years of age or older or who weigh < 6 kg, reducing the prasugrel dose would probably mitigate the bleeding risk. Instead of the usual maintenance dose of 1 mg a day, 5 mg is recommended in patients who weigh < 6 kg. It is hoped that even at lower doses, prasugrel will still be more effective than clopidogrel; confirmation may be forthcoming from an ongoing phase 3 clinical trial. Prasugrel would generally not be recommended for patients 75 years of age or older, though it might be considered if they were at high risk because of diabetes or previous MI. 4 The option of using a lower dose of prasugrel is appealing for example, for patients who have frequent nuisance bleeding when taking the higher dose. 4 NEWER TRIALS OPTIMUS-3, SWAP AND ACAPULCO Optimus-3 Randomized studies specifically designed to evaluate the pharmacodynamic effects of prasugrel in the patients with diabetes and CAD have not been previously performed. This represented the rationale for performing the OPTIMUS-3 study, where the primary objective was to compare the pharmacodynamic effects of a 6 mg loading dose (LD) of prasugrel vs. a 6 mg LD of clopidogrel in patients with diabetes and CAD, using inhibition of platelet aggregation (IPA) as measured by the VerifyNow PY1 assay (Accumetrics, San Diego, California) at 4 hours after the LD. This is the trial design. This was a randomized prospective crossover double-blind study, in which 35 patients were enrolled and randomized on one hand to the standard dose of prasugrel (6 mg LD, and 1 mg maintenance dose [MD]), vs. high dose clopidogrel (6 mg LD and 15 mg MD). Platelet function was measured at several time points: at baseline, 1 hour after the LD, 4 hours after the LD, 4 hours after the LD, and then 1 week afterwards. After this initial analysis, the patients underwent a week washout period. During this washout period, platelet function testing was performed at 1 week, and then again the treatment was re-initiated in the crossover fashion with all the platelet function testing time points. 6 Results Prasugrel 6 mg LD demonstrated significantly higher levels of IPA as measured by the VerifyNow PY1 assay, as early as 1 hour following the LD, and was maintained over the subsequent 4 hours in patients with diabetes and CAD compared with a 6 mg LD. The 1 mg prasugrel MD maintained a higher IPA than clopidogrel 15 mg after 1 week of therapy. These measures were consistent using different assays, including light transmittance aggregometry (LTA) with 5 and μm adenosine diphosphate (ADP) as well as VASP. In conclusion, in patients with diabetes and CAD, prasugrel is associated with significantly greater inhibition of platelet function than double-dose regimens of clopidogrel. 6 SWAP Switching Antiplatelet Study As stated before, prasugrel is associated with greater PY1 receptor blockade, greater platelet inhibition, and the reduction of ischemic complications compared with clopidogrel in ACS patients undergoing PCI. Pharmacodynamic studies have shown that treatment with prasugrel results in higher and more consistent levels of platelet inhibition than clopidogrel, even when higher than approved LDs or MDs of clopidogrel are used. However, the effects of switching ACS patients during the maintenance phase of clopidogrel therapy to prasugrel on their pharmacodynamic effects remain unknown. Therefore, this fell within the objectives of the SWAP study to evaluate the pharmacodynamic effects of switching patients who were on the clopidogrel 75 mg MD, following an ACS event, to prasugrel 1 mg MD, with or without the use of a 6 mg LD. This was the primary objective. There were many secondary objectives. One was to evaluate the effect of switching from clopidogrel to prasugrel, on the rate of poor pharmacodynamic response to thienopyridines. This is the study design. These were patients who had an ACS within the past 3 33 days and who were on treatment with aspirin and clopidogrel at the standard doses. The first phase of the study was a run-in phase, which lasted approximately weeks, where all patients were on 75 mg MD of clopidogrel. One hundred and thirty nine patients were randomized into 3 groups. Patients either continued with clopidogrel at 75 mg MD for approximately weeks, or were treated with prasugrel. Within the prasugrel arms, patients were either on treatment with the 1 mg MD for approximately weeks, without a LD, or received prasugrel with a 6 mg LD, and then continued with the 1 mg MD. So, we have these 3 switching approaches. 6 Results Prasugrel resulted in significantly lower MPA by 7 days following the switch from clopidogrel. When switching to a prasugrel 6 mg LD, more rapid platelet inhibition was obtained within hours and maintained to 4 hours, compared with switching to JICC Vol 1 Issue 1

5 Prasugrel a step ahead in antiplatelet therapy Open-label loading dose phase Daily maintenance dose (MD) phase (1st MD at 16 8 hours after the loading dose [LD]) Informed consent Prasugrel 1 mg MD + 1 mg aspirin Prasugrel 1 mg MD + 1 mg aspirin Clopidogrel 9 mg LD (cumulative) and 5 5 mg of aspirin LD R + Clopidogrel 15 mg MD + 1 mg aspirin Crossover Clopidogrel 15 mg MD + 1 mg aspirin Optional coronary angiography/pci Visit 1 Day 1 Visit Day Visit 3 Day 15 ± Visit 4 Day 9 ± 4 Randomization 48 hours from onset of ischemic symptoms Figure 3 ACAPULCO study design and methodology. a prasugrel 1 mg MD. Switching ACS patients during the maintenance phase of clopidogrel therapy to prasugrel is associated with reduced rates of poor responders with or without an LD. In conclusion, switching ACS patients during maintenance phase clopidogrel therapy to prasugrel resulted in significantly lower platelet aggregation by 1 week, regardless of platelet function tests used, and achieved more rapid platelet inhibition within hours using an LD of prasugrel than without using an LD. 6 ACAPULCO In ACS, however, platelet reactivity is enhanced; whether the results of the PRINCIPLE-TIMI 44 study could be extrapolated from stable to ACS patients is questionable. The ACAPULCO study was designed to address this issue (Figure 3). Results Of 51 patients enrolled, 37 underwent PCI. Mean MPA (mixed data from pre-crossover, visit 3 and post-crossover phase, visit 4) was 6.% for the prasugrel group and 39.1% for the clopidogrel group (p <.1). Patients were judged as thienopyridine nonresponders (defined as a MPA under 5%) in % of the cases with prasugrel and 6% with clopidogrel. 7 Conclusion Compared even to a higher dose of clopidogrel as used in the TRITON-TIMI 38 and CURRENT-OASIS 7 studies, prasugrel resulted in higher overall platelet inhibition in the setting of ACS. More specifically, a prasugrel 6 mg loading dose shows more results in lowering platelet reactivity than a clopidogrel 9 mg loading dose; and a prasugrel 1 mg maintenance dose results in lower platelet reactivity than a clopidogrel 15 mg maintenance dose (Figure 4). 7 DIABETICS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION ROLE OF PRASUGREL Diabetic patients have been shown to be poor responders to clopidogrel. Moreover, a high clopidogrel loading dose (6 mg) has been unable to satisfactorily inhibit platelet reactivity in diabetics undergoing elective PCI. Prasugrel treatment (6 mg loading dose) results in a significantly lower proportion of diabetic patients with weak inhibition of ADP induced platelet activation, compared with 6 mg of clopidogrel. The relationship between insufficient inhibition of platelet reactivity in diabetic patients, on dual antiplatelet therapy, and a greater risk of adverse cardiovascular events has been demonstrated. Subgroup analysis from the TRITON-TIMI 38 reports that the composite of cardiovascular death, myocardial infarction, and stroke, was significantly reduced with prasugrel, among subjects without diabetes mellitus, and even more significantly in patients with diabetes mellitus, particularly in those taking insulin. 4 CLINICAL EVIDENCE OF PRASUGREL IN DIABETIC PATIENTS WITH ACUTE CORONARY SYNDROMES The study classified 13,68 subjects on the basis of pre-existing history of diabetes mellitus (DM) and further according to insulin use. Pre-specified analyses of the primary (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) and JICC Vol 1 Issue 1 1

6 Srinath A Primary end point (%) DM HR.7 (.58.85), p <.1 No DM HR.86 (.76.98), p <. Clopidogrel Clopidogrel Prasugrel 1. 8 Prasugrel Days Days P interaction =.9 Primary end point (%) B MI (%) DM HR.6 (.48.76), p < Days No DM HR.8 (.7.95), p < Clopidogrel Clopidogrel Prasugrel 8. 6 Prasugrel Days P interaction =. MI (%) Figure 4 Kaplan Meier curves for prasugreal vs. clopidogrel stratified by diabetes status. (A) Primary efficacy and point (cardiovascular death/ nonfatal MI/nonfatal stroke) stratified by diabetic status (B) MI (fatal or nonfatal). 8 DM: diabetes mellitus, HR: hazard ratio, MI: myocardial infarction. key secondary end points, including net clinical benefit (death, nonfatal myocardial infarction, nonfatal stroke, and nonfatal TIMI major bleeding) were compared. Three thousand one hundred forty six subjects had a pre-existing history of DM, including 776 receiving insulin. The primary end point was reduced significantly with prasugrel among subjects without DM (9.% vs. 1.6%; hazard ratio [HR],.86; p =.) and with DM (1.% vs. 17.%; HR,.7; p <.1, P interaction =.9). A benefit for prasugrel was observed among DM subjects on insulin (14.3% vs..%; HR,.63; p =.9) and those not on insulin (11.5% vs. 15.3%; HR,.74; p =.9). Myocardial infarction was reduced with prasugrel by 18% among subjects without DM (7.% vs. 8.7%; HR,.8; p =.6) and by 4% among subjects with DM (8.% vs. 13.%; HR,.6; p <.1, P interaction =.). TRANSITION FROM CLOPIDOGREL TO PRASUGREL DURING MAINTENANCE THERAPY A study, assessing the safety, time-course, and level of platelet inhibition when switching directly from clopidogrel 75 mg maintenance dose (MD) to a prasugrel 6 mg LD/1 mg MD or 1 mg MD regimen, was undertaken. Healthy subjects (n = 39) on aspirin (81 mg/d) received a clopidogrel 6 mg LD followed by 1 days of clopidogrel MD (75 mg/d). Subjects were then randomized without a washout period to prasugrel 6 mg LD (n = 16) followed by 1 days of prasugrel MD (1 mg/d) or to prasugrel MD (1 mg/d, n = 19) for 11 days. Maximal platelet aggregation (MPA) to μm ADP was measured by turbidimetric aggregometry. In subjects on clopidogrel 75 mg MD, mean MPA decreased from 39% to 1% by 3 minutes, and to 5% by 1 hour after a prasugrel 6 mg LD (p <.1 for both) and from 3% to 8% (p <.1) by 1 hour after a prasugrel 1 mg MD. During prasugrel MD, a new pharmacodynamic steady state MPA of 4% (p <.1 vs. clopidogrel MD) occurred within 4 5 days of switching from clopidogrel. Changing from clopidogrel to prasugrel did not increase bleeding episodes or other adverse events. Switching directly from clopidogrel MD to either prasugrel LD or MD was well tolerated and resulted in significantly greater levels of platelet inhibition than a clopidogrel 75 mg MD. 9 Role of Prasugrel in Medically Managed Acute Coronary Syndrome The TRILOGY ACS study is a global Phase III, double-blind, double-dummy, parallel-group, randomized controlled trial. TRILOGY ACS is designed to test the hypothesis that the combination of aspirin and prasugrel, a novel thienopyridine inhibiting the PY1 platelet receptor, is superior to aspirin and clopidogrel JICC Vol 1 Issue 1

7 Prasugrel a step ahead in antiplatelet therapy in the treatment of medically managed patients enrolled within 1 days of the unstable angina/non-st-segment elevation myocardial infarction (UA/NSTEMI) index event. The total study population of 1,3 patients will be enrolled at 8 sites globally, with an estimated 78 patients < 75 years of age and 5 patients 75 years of age. TRILOGY ACS is the first study to investigate the clinical efficacy of prasugrel in medically managed patients with UA/NSTEMI. 1 Prasugrel s Role in Therapy Overall, data demonstrate that patients with acute coronary syndromes undergoing PCI have fewer events, most notably nonfatal myocardial infarction, as well as stent thrombosis, with prasugrel compared with clopidogrel, although a higher risk for bleeding was also reported. Due to its improved pharmacokinetic and pharmacodynamic profile, prasugrel is likely to have a role in treating patients who require immediate intervention, as its onset of action is faster than that of clopidogrel. Subgroups of patients who seem to have particularly favorable responses to prasugrel versus clopidogrel in terms of reducing adverse clinical events without significant increases in bleeding are patients experiencing a STEMI and those with a history of diabetes mellitus. Data from TRITON TIMI 38 suggested that patients older than 75 years or with a body weight < 6 kg seem to have similar outcomes between prasugrel and clopidogrel; however, those with a history of stroke or transient ischemic attack seem to have worse outcomes with prasugrel versus clopidogrel. In addition, although few patients in TRITON TIMI 38 underwent CABG, a significantly higher proportion of the patients receiving prasugrel experienced major bleeding compared with those receiving clopidogrel. This suggests that these patients should have their antiplatelet therapy discontinued before surgery, if required. Thus, the choice between prasugrel and clopidogrel in patients with acute coronary syndromes undergoing PCI should be based on the risk of bleeding balanced with the potential clinical benefits. BALANCE OF SAFETY AND EFFICACY 11 The stronger antiplatelet effect of prasugrel when compared with clopidogrel caused a significant increase in major bleeding (.4 vs. 1.8%, p =.3) including a significant increase in life-threatening bleeding (1.4 vs..9%, p =.1) and in fatal bleeding (.4 vs..1%, p =., Figure ). 5 Balancing safety and efficacy, it is conspicuous that a.% reduction in the composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke was achieved at the expense of an.6% increase in major non- CABG bleed. The numbers needed to treat were 46, whereas the numbers needed to harm were 167. It can be calculated that for every 1 patients treated 3 myocardial infarctions were prevented at the expense of 6 major non-cabg bleed (Figure 5). Considering the net clinical effect, i.e. the composite of death, nonfatal myocardial infarctions, nonfatal stroke, and major non-cabg bleed, a significant benefit of prasugrel Number of events per 1 patients Myocardial infarction Major non-cabg bleed 6 Figure 5 Balance of safety and efficacy in TRITON-TIMI 38: number of myocardial infarctions prevented vs. number of severe non-cabg bleedings incurred. CABG: Coronary artery bypass graft. Prior Stroke/TIA Age Weight Hazard ratio Yes No P w =.6 75 < 75 < 6 kg 6 kg Overall P w =.18 P w = Prasugrel better Clopidogrel better Figure 6 Net clinical benefit (composite of primary efficacy and safety endpoint) in three subgroups that do no drive benefit from prasugrel. TIA: transient ischemic attack. is maintained with an incidence of the composite safety and efficacy endpoint of 13.9% in the clopidogrel group and 1.% in the prasugrel group (p =.4). 5 As published recently, patients with diabetes mellitus and patients with AMI derived the largest net clinical benefit from prasugrel when compared with clopidogrel (Figure 6). CONCLUSIONS Prasugrel represents an advance in antiplatelet therapy for acute coronary syndromes. It appears to be a promising antiplatelet agent, with emerging clinical data in direct comparison with clopidogrel supporting its role in reducing recurrent ischemic events. TRITON TIMI 38 supports its use in patients with such syndromes when there is a very high probability of PCI, such as in myocardial infarction with ST-segment elevation or after coronary angiography in patients with non-st-segment myocardial infarction. Use in the elderly should be avoided except in high-risk situations. 5 JICC Vol 1 Issue 1 3

8 Srinath Lower maintenance doses in the underweight appear to be warranted, though prospective confirmation of this strategy is necessary. 5 Thus, the choice between prasugrel and clopidogrel in patients with acute coronary syndromes undergoing PCI should be based on the risk of bleeding balanced with the potential clinical benefits. REFERENCES 1. Reinhart KM, White CM, Baker WL. Prasugrel: a critical comparison with clopidogrel. Pharmacotherapy 9;9: Lazar LD, Lincoff AM. Prasugrel for acute coronary syndromes: faster, more potent, but higher bleeding risk. Cleve Clin J Med 9;76: Antman EM, Wiviott SD, Murphy SA, et al. Early and late benefits of prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: a TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction) analysis. J Am Coll Cardiol 8;51: Motovska Z, Widimsky P. Improving outcomes in patients undergoing percutaneous coronary intervention: role of prasugrel. Vasc Health Risk Manag 9;5: Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 7;357:1 15. Epub 7 Nov Montalescot G, Sideris G, Cohen R, Meuleman C, Bal dit Sollier C, Barthélémy O, et al. Prasugrel compared with high-dose clopidogrel in acute coronary syndrome. The randomised, double-blind ACAPULCO study. Thromb Haemost 1;13:13 3. Epub 9 Oct Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel thrombolysis in myocardial infarction. Circulation 8; 118: Payne CD, Li YG, Brandt JT, Jakubowski JA, Small DS, Farid NA, et al. Switching directly to prasugrel from clopidogrel results in greater inhibition of platelet aggregation in aspirin-treated subjects. Platelets 8;19: Neumann F-J. Balancing efficacy and safety in the TRITON-TIMI 38 trial. Eur Heart J Suppl 9;11(Suppl G):G14 7. JICC Vol 1 Issue 1 4