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Prasugrel – Clinical Implications in Current Anesthesia Practice

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Drug & innovation Update

Prasugrel – Clinical Implications in Current Anesthesia Practice

By Jason Voigt, MD and Philip Greilich, MD
University of Texas Southwestern Medical Center
Dallas, TX

Prasugrel (Effient), a new thienopyridine antiplatelet agent produced by Daiichi Sankyo Company and marketed in the United States by Eli Lilly and Company, was approved for use by the FDA July 10, 2009. Prasugrel is indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with acute coronary syndrome (ACS) who are to be managed with primary or delayed percutaneous coronary intervention (PCI).1

Prasugrel, chemically related to ticlopidine and clopidogrel, is a thienopyridine derivative which binds to the P2Y12 receptor on platelet membranes effectively preventing ADP-induced platelet activation and subsequent aggregation.2 Prasugrel is a prodrug, similar to other thienopyridines, which requires the cytochrome p450 system (predominately CYP3A and CYP2B6) for active and inactive metabolite generation.2 The rapidly generated active metabolite of Prasugrel causes irreversible ADP inhibition by forming disulfide bridges between the reactive thiol group of the drug metabolite and a cysteine residue on the platelet P2Y12 receptor.2

The pharmacokinetics of Prasugrel’s active metabolite are not known to be affected by genetic variations in CYP2C19. This is in contrast to clopidogrel where active metabolite generation is affected by the CYP2C19 genotype. Approximately 30% of Caucasians are reduced-metabolizers of clopidogrel.1

Several phase I and II trials (included in this review are 4 trials, 1330 patients) have been performed to test the safety, dosing and clinical effectiveness of Prasugrel.4-8 Pharmacokinetic studies demonstrate that effective plasma levels of active metabolite can be achieved with a 60mg loading dose (LD) and 10mg per day maintenance dose (MD).4,5,7 A single oral dose of Prasugrel is 79% absorbed and the time to maximum plasma concentration of the active metabolite was 0.5 hours.1 The elimination half-life of Prasugrel’s active metabolite is approximately 7 hours (range 2-15 hours).1 Prasugrel should be taken concurrently with aspirin.1

The pharmacodynamic studies utilize the degree of platelet inhibition to ADP-induced aggregation to establish efficacy. A Prasugrel LD of 60mg and MD of 10mg inhibits platelet aggregation more effectively than currently recommended doses of clopidogrel.4,5,7 The incidence of non-responsiveness (resistance) was also found to be lower with Prasugrel compared to clopidogrel.4 Platelet aggregation returns to baseline values within 5-9 days after drug discontinuation. This recovery of aggregation is primarily a result of new platelet production rather than the pharmacokinetic profile of Prasugrel.1 The incidence of TIMI major and minor bleeding following PCI did not appear to be significantly different in those receiving Prasugrel compared to clopidogrel.6

The TRITON-TIMI 38 trial (trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with Prasugrel) was the pivotal phase III trial in patients with ACS undergoing PCI. This double-blind, randomized controlled trial compared Prasugrel (60mg LD, 10mg MD) with clopidogrel (300mg LD, 75mg MD) in patients with ACS scheduled to undergo PCI. The study enrolled 13,608 patients. Primary end point was a composite of death from cardiovascular causes, non-fatal MI, or non-fatal stroke. Safety outcomes included TIMI major or minor bleeding. The absolute reduction in the primary endpoint in the Prasugrel group was 2.2% (9.9% vs. 12.1% compared to clopidogrel). Significant reductions were also found in the rates of myocardial infarction, urgent target vessel revascularization and stent thrombosis. Of note, overall mortality did not differ significantly between treatment groups.9

The trade-off for improvement in the primary endpoint was an absolute increase in major (0.6%) and life-threatening (0.5%) bleeding in the Prasugrel group compared to those receiving clopidogrel.9 In addition, approximately 3% (n=437) of patients enrolled in this trial required CABG surgery. An absolute increase of 9.6% in the rate of excessive bleeding was observed in the Prasugrel group (14.1% vs. 4.5% compared to clopidogrel).1 For those receiving Prasugrel within three days of CABG surgery, TIMI major or minor bleeding was 26.7%. Those who received their last dose of Prasugrel 4-7 days prior to CABG had their frequency of major or minor bleeding reduced to 11.3%.1

The anesthetic concerns regarding the perioperative use of Prasugrel are similar to those involving clopidogrel. These involve stent thrombosis and subsequent cardiac events with abrupt discontinuation and bleeding if significant platelet inhibition remains. Prasugrel should be continued perioperatively in patients who have undergone PCI with recent stent placement. If lapses in therapy are unavoidable due to the nature of the operative intervention, therapy should be resumed as soon as possible. Prasugrel should not be instituted in patients expected to undergo CABG and if started, therapy should be discontinued seven days prior to surgery.1 There are no agents available to reverse the effects of Prasugrel and the drug effect remains for the lifetime of the platelet (7-10 days). It is unlikely that Prasugrel’s active metabolite can be removed by dialysis.1 The manufacturer recommends restoring hemostasis by administering exogenous platelets. Platelet administration will be less effective at restoring hemostasis if given within six hours of a loading dose or four hours of a maintenance dose.1 If urgent surgical procedures are necessary while therapeutic on Prasugrel, it seems reasonable to delay surgery for 24-48 hours to allow the pharmacologic elimination of Prasugrel’s active metabolite. As with clopidogrel, the use of P2Y12 point-of-care monitors or whole blood aggregometry for assessing Prasugrel induced platelet inhibition might have a future role in the timing of surgical interventions.10-11 Additional clinical investigation will be needed in this area as no established Prasugrel protocols currently exist.

Due to the higher incidence of bleeding events in Prasugrel treated patients the authors of the TRITON-TIMI 38 trial performed a series of analyses to identify subgroups that did not have net clinical benefit. They identified several groups – those who had a previous stroke or TIA (absolute contraindication), patients greater than 75 years of age, and those weighing less than 60kg in whom the risk:benefit ratio of Prasugrel administration should be carefully weighed.9 In the absence of these risk factors there was greater efficacy with Prasugrel and no difference in the rate of major bleed in comparison to clopidogrel.9 The manufacturer has identified risk factors in addition to those stated above with regard to bleeding while using Prasugrel. Those with active bleeding, at high risk for bleeding (trauma, recent surgery), or those anticipated to present for CABG should not receive Prasugrel.1

In summary, Prasugrel represents a significant advance in antiplatelet therapy and evidence exists for its use in certain high-risk patient populations. The anesthetic implications of Prasugrel are mainly those pertaining to abrupt discontinuation with subsequent ischemic cardiac events and bleeding. Dual antiplatelet therapy should continue, if practical, throughout the perioperative period. If this is not possible, lapses in dosing should be minimized and therapy should be reinstituted as soon as reasonably possible. Cardiac surgery should be delayed seven days to allow sufficient return of platelet function. If excessive surgical bleeding is encountered and thought to be secondary to Prasugrel’s platelet inhibiting effects, attempts to restore hemostasis by administering exogenous platelets should be undertaken. Increasing perioperative experience with Prasugrel might lead to established protocols that will attempt to correlate the degree of platelet inhibition with the risk of clinical bleeding. The current and future roles of Prasugrel are evolving and with increasing market penetration the anesthesiologist must be aware of its clinical utility and prepared to address the complications that arise secondary to its use.

References:

  1. Prasugrel online prescribing information. www.effient.com. Eli Lilly and Company.
  2. Baker WL, White CM. Role of Prasugrel, A Novel P2Y12 Receptor Antagonist, in the Management of Acute Coronary Syndromes. Am J Cardiovasc Drugs 2009; 9: 213-229.
  3. Bhatt DL. Prasugrel in Clinical Practice. N Eng J Med 2009; 361:940-942.
  4. Jernberg T, Payne CD, Winters KJ, et al. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart Journal 2006; 27: 1166-73.
  5. Brandt JT, Payne CD, Wiviott SD, et al. A comparison of Prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007; 153: e9-16.
  6. Wiviott SD, Antman EM, Winters KJ, et al. For the JUMBO-TIMI 26 Investigators. Randomized comparison of Prasugrel, a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO-TIMI 26 Trial). Circulation 2005; 111: 33673.
  7. Wiviott SD, Trank D, Frelinger AL, et al. For the PRINCIPLE-TIMI 44 Investigators. Prasugrel compared with high loading and maintenance dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in comparison to clopidogrel for inhibition of platelet activation and aggregation – Thrombolysis in myocardial infarction 44 trial. Circulation 2007; 116: 2923-32.
  8. Montalescot G, Sideris G, Cohen R, et al. Prasugrel 10mg provides greater platelet inhibition than clopidogrel 900/150 in UA/NSTEMI ACS – the ACAPULCO study. Eur Heart J 2008; 29: 716.
  9. Wiviott SD, Braunwald E, McCabe CH, et al. For the TRITON-TIMI 38 investigators. Prasugrel versus clopidogrel in patients with acute coronary syndrome. N Eng J Med 2007; 357: 2001-15.
  10. Velik-Salchner C, Maier S, et al. Point of care whole blood impedance aggregometry versus classical light transmission aggregometry for detecting aspirin and clopidogrel: the results of a pilot study. Anesth Analg 2008; 107(6):1798-806.
  11. Jakubowski JA, Li YG, Small DS, et al. A comparison of VerifyNow P2Y12 Point-of-Care Device and Light Transmission Aggregometry to Monitor Platelet Function with Prasugrel and Clopidogrel: An Integrated Analysis. J Cardiovasc Pharmacol 2010 March 24th [Epub ahead of print] www.ncbi.nlm.nih.gov/pubmed/20351563

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