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The Ohio State University 1 Question 5A: Prepare a report that evaluates the overall quality of the dossier. That is, how well did the manufacturers follow the AMCP Format for Formulary Submissions Version 2.1? Briefly discuss what was done well, what content was missing, and where the instructions were not followed. The dossier assembled for prasugrel was completed in August 2009 following the AMCP Format for Formulary Submissions Version 2.1. Overall, the dossier is fairly adequate in following the format with some exceptions. The product information is clear and concise but lacks information on off-label indications, market share information, and pharmacogenomic evidence. It includes clinical studies on the disease state, minor economic studies and one costeffectiveness economic study but lacks other key studies such as systematic reviews and metaanalyses. Most studies did not abide by the page limitations set up by the AMCP Format for Formulary Submissions Version 2. One cost-effectiveness study is included but does not follow the format suggestion of placing it under modeling report with the BIM. The overall product cost was included but not clearly stated. In general the dossier allows for adequate analysis of prasugrel’s strengths and weaknesses but could be improved by including more concise clinical information. 1. Product Information REQUESTED BY VERSION 2.1 COMPLETE INFORMATION IN DOSSIER Section 1.1 a. Generic, brand name and therapeutic class Yes b. Dosage forms, strengths, package sizes Includes forms and strengths but not package sizes c. NDC number Yes d. Copy of product labeling/literature Yes. This can be found in the Appendix e. The AWP and WAC cost per unit size Yes f. AHFS or other drug classification Yes g. FDA Approved and other Studied Yes Indications h. Current or pending off-label indications No. No current data available. i. Pharmacology Yes The Ohio State University 2 j. Pharmacokinetics/Pharmacodynamics Yes k. Contraindications Yes l. Warnings/Precautions/Adverse Effects Yes m. Interactions Partial. Drug/drug information was included. The manufacturer did not include drug/food and drug/disease interactions. n. Dosing and Administration Yes o. Access Yes p. Current or anticipated market share No. Not available at this time information q. Co-Prescribed/Concomitant Therapies Yes r. Comparison with primary comparator Yes products REQUESTED BY VERSION 2.1 COMPLETE INFORMATION IN DOSSIER Section 1.2 1.2.1 Disease Description Description of specific patient subpopulations No. The dossier includes how different subpopulations in which the drug is expected to be most react to the disease state but not where prasugrel is effective (Markers, diagnostic or generic expected to be most effective. criteria to identify) a. Epidemiology and relevant risk factors Yes b. Pathophysiology Yes c. Clinical presentation Yes d. Societal and/or economic impact Yes 1.2.2 Approaches to Treatment a. Approaches to treatment – principal Yes options/practice patterns b. Description of alternative treatment options Yes (both drug and non-drug) c. Place and anticipated use of therapy in Yes The Ohio State University 3 treatment d. Proposed ancillary disease or care Yes management intervention strategies that are intended to accompany the product at launch e. Relevant treatment guidelines from national Yes or international bodies f. Expected outcomes of therapy Yes g. Other key assumptions and their rationale Yes Section 1.3 Evidence for Pharmacogenomic No. The manufacturer did not include any data Tests and Drugs 2. Supporting Clinical and Economical Information The prasugrel dossier includes three summaries of key clinical studies: one safety trial, one efficacy and safety trial, and one efficacy comparison to clopidogrel. All three trials were double blind, randomized trials and included all of the required items listed in the format. The dossier also includes five outcome studies and economic supporting data: four retrospective cost studies and one cost-effectiveness study. No studies regarding off-label uses or prospective effectiveness were included. Systematic reviews, meta-analyses and prospective studies examining health status or quality of life were not included. Each study had an evidence table spreadsheet that included both negative and positive findings. All but one of the studies exceeds the maximum pages allowed. 3. Modeling Report The manufacturer included one budget impact model (BIM). The model includes an overview, parameters, analyses and results of the model. The payer perspective is included for both the managed care organization and the hospital. However, no results on discounting were included; the manufacturer stated that ongoing clinical trials are assessing whether discounting is associated with negative clinical outcomes. The model includes assumptions associated with the findings but does not account for multiple aspects of care such as consequences and indirect costs to the patient. The Ohio State University 4 A cost-effectiveness model is not included in the modeling report but the costeffectiveness of prasugrel was compared to the cost-effectiveness of clopidogrel in section 2 of the dossier. This economic study only includes prasugrel and clopidogrel as treatment options; other therapies and clinical pathways were not discussed when considering cost-effectiveness. 4. Product Value and Overall Cost The manufacturer summarizes all clinical and economic information presented in pervious sections. The section includes key information on prasugrel and several evidence tables that summarize the drug’s therapeutic efficacy and economic evaluation. A summary of pharmacoeconomic studies is included but it did not clearly state the value of the product. The unit daily cost of prasugrel as well as total absolute savings is clearly stated in the projected impact on budget section. 5. Supporting Information Relevant clinical and pharmacoeconomic references are made in each section and a model is included with the dossier. The Ohio State University 5 \ Question 5B: Analyze the manufacturers’ value proposition for prasugrel (Effient®). Does the clinical and economic data presented in the dossier and model support the manufacturer’s value arguments? Has the manufacturer excluded any information that would refute their value argument? Include an analysis of the economic model, key studies not included and any potentially misleading information contained in the dossier. The Effient ® (prasugrel) dossier provides extensive clinical evidence which concluded a decrease in ACS rehospitalization events. Furthermore, the economic model provides a thorough account of potential costs to Pitt Street Health. The evaluation of the dossier provides sufficient evidence through numerous clinical trials for recommending prasugrel in certain patient populations. Clinical Evidence Evaluation The overall value proposition of prasugrel for patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI) is not directly stated in the dossier. Through interpretation of the dossier’s clinical data, the overall product value can be argued to reduce the rate of combined endpoints of cardiovascular death, nonfatal myocardial infarction (MI) or nonfatal stroke in comparison to clopidogrel. The evaluation of the published clinical trials were graded using the Delfini Validity & Usability Grading Scale for Summarizing the Evidence for Interventions and is presented below. Table 1. Evidence based on Effient® Dossier Reference Study Limitations Strengths Parameters LTA requires precise Sample size large Wiviott, et RCT, DB al. 20071 multicenter, sample conditions for enough to detect double- processing and a 90% power dummy, significant portion did Multicenter active not meet standards Similar baseline comparator- and were excluded characteristics controlled, 2-phase Exclusions potentially reduced the power of among participants Delfini Clinically Grade Useful? B Yes The Ohio State University 6 crossover study the study No washout period Frequent endpoint measurements and between MD various laboratory treatments analyses were Funding by Eli Lilly used. Wiviott et Multicenter, 77% of subjects male Large sample size al. 20052 RCT, No statistical power with 80% power parallel- to detect clinically in order to detect group, ITT, meaningful significant DB, active differences in differences in comparator- efficacy endpoints safety outcomes controlled trial A Yes A Yes Reduced power for primary safety endpoint due to low bleeding rates Short study period, one clopidogel arm, funding from Eli Lilly Wiviott et RCT, DB, al. 20073 double Funding from Eli Lilly Sample size adequate for 90% dummy, Did not use highest parallel- possible dose of Length of study group with clopidogrel Randomized active comparator, Mostly white males power Double-blinded participated in study ITT, multicenter RCT = randomized controlled trial, DB = double blind, PC = placebo controlled, ITT = intent to treat LTA= Light Transmission Aggregometry MD = maintenance dose The Ohio State University 7 The evidence presented in the clinical trials of the dossier provides strong evidence sufficient for use in making health care decisions. The conducted studies were all large, double bind, randomized control trials. Each trial also had a power of at least 80% to have the ability to detect clinically significant differences in either safety or efficacy outcomes. Although all clinical trials were thought to be of some use in making clinical decisions, there were a few limitations. The TRITON-TIMI 38 trial used standard doses of clopidogrel whereas physicians have adopted using higher loading and maintenance doses. While this is a limitation to TRITON-TIMI 38, PRINCIPLE-TIMI 44 addressed this limitation and proved the high loading and maintenance doses of clopidogrel are not superior in efficacy to standard doses of prasugrel. The JUMBO-TIMI 26 trial was predominately male, which was viewed as a limitation, but the occurrence of an ACS event is more common among the male population. The manufacturer of prasugrel, Eli Lily, conducted all studies. Summary of pharmacoeconomic evidence: In order for prasugrel to be economical for Pitt Street Health, a decrease in ACS-related rehospitalization would be essential. Most economic outcome studies present in the dossier consist of costs of ACS events in a managed care setting. The only trial that took into account the cost-effectiveness of prasugrel came from the results from the TRITON-TIMI 38 trial. The clinical trial endpoints are index hospitalization resource use and cost, follow-up, life expectancy projections, and cost-effectiveness analysis versus clopidogrel. The trial found the index hospitalization cost to not differ between treatment groups.4 Follow-up costs for rehospitalization were estimated to be $221/patient lower with prasugrel than clopidogrel (P=0.20). Life expectancy due to cardiovascular death, nonfatal MI or nonfatal stroke was found to be higher for prasugrel as well. The overall cost-effectiveness analysis conducted found treatment with prasugrel to decrease overall costs due to lower rate of rehospitalization involving PCI, making prasugrel the economically dominant treatment strategy.4 Additional ongoing studies are being conducted to determine whether discontinuing treatment with a thienopyridine after one year is associated with negative clinical outcomes. When this data becomes available, reevaluation will be necessary to determine the effect on outcomes. Also, it is projected that clopidogrel will lose patent at the end of 2011 and therefore The Ohio State University 8 needs to be taken into consideration when analyzing the economical effectiveness of prasugrel. Since only one trial for cost-effectiveness has been presented, additional cost-effectiveness and cost-benefit trials are needed. Economic Evidence Evaluation of prasugrel The manufacturer developed a budget impact model (BIM) for a managed care organization (MCO) or hospital. The model was designed to estimate the impact of including prasugrel on the formulary in addition to clopidogrel. The model design is flexible and helpful within the context of the Pitt Street formulary. The BIM can be used to assess prasugrel’s potential budget impact of Pitt Street using MCO-specific and hospital-specific demographics and costs. The model concludes addition of prasugrel to the formulary for people hospitalized with a diagnosis of ACS and undergoing a PCI reduces the total annual costs for Pitt Street.5 Furthermore, adding prasugrel to the formulary would decrease the number of disease-related events, but would increase the number of bleeding events. The model anticipates the use of prasugrel in treatment of patients hospitalized with ACS prior to undergoing PCI and will receive a once-daily maintenance dose thereafter. This place in therapy is supported by clinical trial data presented in the dossier and analysis of class review of thienopyridine agents. The BIM allows adjustments to provide estimates for relevant populations who are to be treated with a thienopyridine drug. Clinical trials are currently being conducted to determine treatment with a thienopyridine after one year to be beneficial. With this assumption, patients took the thienopyridine for up to 15 months after PCI.5 The limitations of the model can be found in some of the assumptions made. The model assumes a 100% adherence rate of clopidogrel and prasugrel. The BIM only accounts for prasugrel and clopidogrel and therefore lacks consideration of other thienopyridine agents. Additionally, it does not take into account other medications required to prevent an additional ACS event from occurring. The BIM uses clinical outcomes per patient characteristics observed in TRITON TIMI 38 trial, which was 75% male with a median age of 61 years. A major weakness of the model is that it did not thoroughly take into account clopidogrel going generic at the end of 2011 and how this will impact the MCO and hospital. The Ohio State University 9 Overall, the economic information provided for the treatment of ACS managed with PCI was thorough and could be applied to Pitt Street Health for formulary decision. References 1. Wiviott S, Trenk D, Frelinger A, O’Donoghue M, Neumann FJ, Michelson AD, Angiolillo DJ, Hod H, Montalescot G, Miller D, Jakubowski JA, Cairns R, Murphy SA, McCabe CH, Antman EM, Braunwald E. 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 Dec 3;116:2923-32. 2. Wiviott S, Antman EM, Winters KJ, Weerakkody G, Murphy S, Behounek BD, Carney RJ, Lazzam C, McKay RG, McCabe CH, Braunwald E. Randomized comparison of prasugrel (CS-747, LY640315), 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 Jun 20;111:3366-73. 3. Wiviott S, Braunwald E, McCabe C, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy S, Riesmeyer J, Weerakkody G, Gibson C, Antman E. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. 4. Mahoney KM, Wang K, Arnold SV, et al. Cost-effectivess of prasugrel vs. clopidogrel in patients with acute coronary syndromes and planned percutaneous coronary intervention: results from the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel thrombolysis in myocardial infarction TRITON-TIMI-38. Circulation. 2010;121:71-79. 5. Effient® (prasugrel) Dossier. Eli Lilly and Daiichi-Sankyo. Prepared using AMCP format for formulary submissions, version 2.1. The Ohio State University 10 Question 5C: How does the recent emergence of non-responders to antiplatelet therapy (both those determined by platelet function testing and genetic testing) play into an appropriate formulary decision? Currently, the recommended treatment for acute coronary syndromes (ACS) is dual antiplatelet therapy with aspirin and Plavix® (clopidogrel). However, a major concern in recent years concerning this standard of care is the recent emergence of non-responders to clopidogrel. Since clopidogrel is a prodrug, it requires biotransformation to its active metabolite via the cytochrome P-450 (CYP) enzymes, most notably by CYP3A4, 3A5, 2C9, 2B6 and 2C19.1,2 CYP2C19 is the major enzyme involved in clopidogrel nonresponsiveness, and the *2, *3, *4 and *5 alleles have all been known to cause decreased metabolism of clopidogrel and are termed loss-of-function alleles. The *2 allele is most frequent in Caucasians (13%), African Americans (18%) and Asians (30%).2 It has been suggested that patients with these loss-of-function alleles have reduced conversion of clopidogrel to its active metabolite and therefore have an increased risk of cardiovascular events. Nonresponsiveness to clopidogrel was first reported in a prospective study that evaluated clopidogrel responsiveness in 60 consecutive patients with ST-segment-elevation acute myocardial infarction (STEMI) within six hours of onset. All 60 patients received primary percutaneous coronary intervention (PCI) and were treated with 300 mg of clopidogrel followed by 75mg/day for the next 3 months. There was a 35-60% reduction in ex-vivo platelet aggregation, and no significant inhibition of platelets as detected by the thrombin-related activating peptide (TRAP). These results suggest that clopidogrel is less effective in the presence of high-thrombin, which is characteristic of ACS. While this study has many limitations, such as being observational with a small sample size, it has led to further investigation regarding variable response to clopidogrel.3 In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38, 1,477 patients provided a DNA sample that allowed for further investigation in their response to clopidogrel versus prasugrel. Primary efficacy outcomes of the trial include a composite of death from cardiovascular causes, MI, or stroke. Secondary outcomes include definite or probable stent thrombosis. Of the 1,477 patients who gave a DNA sample, 34% had at least one CYP2C19 reduced-function allele. When comparing the carriers to non-carriers, carriers of the The Ohio State University 11 reduced function allele had a relative reduction of 32.4% in exposure to the active metabolite of clopidogrel. These results confer strong evidence between CYP genetic variations and reduced platelet inhibition which theoretically leads to an increased risk for recurrent ischemic events in patients taking clopidogrel. While this study does demonstrate that patients with CYP2C19 lossof-function alleles have less exposure to active metabolite, it does not prove that these patients are at an increased risk of recurrent MI.1 In a meta-analysis including 23 studies, carriers of the *2 loss-of-function allele exhibited a significant increase (42%) in the rate of major adverse cardiovascular events (MACE), the primary endpoint. Furthermore, there was a three to six fold increase in the risk of definite or probable stent thrombosis in carriers versus non-carriers. In addition, CYP2C19 gene variant showed an increase in all-cause and cardiovascular mortality, leading to a 20% increase risk for death. The meta-analysis concluded that among patients that carry the loss-of-function allele, those with a high baseline cardiovascular risk are at the highest risk for experiencing MACE when treated with clopidogrel. Many of the studies evaluated were observational and came from prospective or retrospective registries. Further limitations were observed, leading to questionable confidence in the reported results.4 In addition to CYP2C19, clopidogrel is also subject to efflux from P-glycoprotein encoded by ABCB1. Polymorphisms in ABCB1, most notably 3435C→T, affect drug transport and efficacy and, when combined with variants in CYP2C19, lead to increased risk in cardiovascular outcomes in patients treated with clopidogrel or prasugrel. The patient population studied came from the TRITON-TIMI 38 trial and were divided into four groups based on their ABCB1 3435C→T genotype and CYP2C19 status. When considering both ABCB1 and CYP2C19, variants demonstrated independent increased risk of cardiovascular death, MI or stroke. While these results strongly suggest an increased risk of MACE in patients with genetics variants, patients studied were largely Caucasian and healthy. Furthermore, there was restricted power to detect association between ABCB1 variants and outcomes reported.5 A prospective cohort study looked at 259 young patients who survived one MI. Those possessing the *2 allele compared with wild-type homozygotes displayed a significant increase in the primary endpoint, including death from any cause, non-fatal stroke or MI and stent thrombosis. Any patient who possessed two loss-of-function alleles of CYP2C19 or ABCB1 variant allele were at the highest risk for developing the primary outcome. However, this study The Ohio State University 12 was not randomized and genotyping was only performed for the *2 and *1 alleles. While genotyping is currently available, it is very costly and requires the use of specialty laboratory equipment. Furthermore, it requires 6-10 days for processing; this would significantly delay the administration of clopidogrel and in order for clopidogrel to be effective it should be started immediately. In comparison to prasugrel, clopidogrel requires two steps for activation compared to prasugrel’s one. Studies have displayed little susceptibility for drug interactions in patients taking prasugrel.2 Another meta-analysis looked at the results of loss-of-function alleles in the CURE study as well as the ACTIVE A study. In the CURE study, results show clopidogrel’s effect was consistent in all subgroups for primary and secondary endpoints between carriers of loss-offunction alleles and non-carriers. In addition, major bleeding rates were also similar. In the ACTIVE A study, results were consistent in all subgroups regardless of functional allele carrier status. This led to the conclusion that efficacy and safety of clopidogrel is not altered by CYP2C19 loss-of-function allele status. This study had limitations which include a small population, limited power, and mostly Latin American or European patient involvement.6 As a result of the data presented here, the Food and Drug Administration (FDA) mandate that clopidogrel include a black box warning in its label to notify prescribers and patients about the possible reduced effectiveness.6 While it is apparent that patients taking clopidogrel are exposed to less active metabolite, there are no randomized trials to confirm that this affects clinical outcomes. Because prasugrel is not activated in the same manner as clopidogrel, it is not subject to the same possibility of decreased effectiveness, leading to the question if it should be used over clopidogrel. Because of the lack of data proving that clopidogrel users suffer an increase in MACE resulting from less active metabolite generation, we cannot rule out its use in practice. It does, however, support the addition of a more consistent and stronger antiplatelet agent to formulary in cases where high platelet inhibition is necessary. In conclusion, when determining which therapy is more appropriate for patients, a riskbenefit analysis is necessary. In low to medium risk patients, the use of clopidogrel may be acceptable because a lower platelet inhibition level may be all that is required to see effect. If it is known that the patient has a loss-of-function allele, this would be taken into account as another risk factor for recurrent ischemic events. If, however, the patient is considered high risk, prasugrel may be more appropriate since higher levels of platelet inhibition are necessary. The Ohio State University 13 References 1. Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt, JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360(4):354-62. 2. Momary KM, Dorsch MP, Bates ER. Genetic causes of clopidogrel nonresponsiveness: which ones really count? Pharmacotherapy. 2010;30(3):265-74. 3. Matetzky S, Shenkman B, Guetta V, Shechter M, Bienart R, Goldenberg I, Novikov I, Pres H, Savion N, Varon D, Hod H. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. 2004 Jun 7;109:3171-75. 4. Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthelemy O, Cayla G, Beygui F, Montalescot G. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450*2 loss-of-function allele or proton pump inhibitor coadministration. J Am Coll Cardiol. 2010 July 6;56(2):134-43. 5. Mega JL, Close SL, Wiviott SD, Shen L, Walker JR, Simon T, Antman EM, Braunwald E, Sabatine MS. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010 Oct 16;376:1312-19. 6. Pare G, Mehta SR, Yusuf S, Phil D, Anand SS, Connolly SJ, Hirsh J, Simonsen K, Bhatt DL, Fox KAA, Eikelboom JW. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. 2010 Oct 28;363(18):1704-14. The Ohio State University 14 Question D: What consideration, if any, should be given to patients who are taking Effient or other antiplatelet agents and concomitantly taking a PPI? Proton Pump Inhibitors (PPIs) are often administered to patients in combination with thienopyridines to help reduce the risk of gastrointestinal bleeding after Acute Coronary Syndrome (ACS) or percutaneous coronary intervention (PCI). The role of thienopyridine-class antiplatelet drugs such as Plavix® (clopidogrel) and Effient® (prasugrel) are well established in the treatment of ACS by various clinical trials and meta-analyses, and as a result, their use has increased exponentially in recent times. Clopidogrel is currently the second-best-selling drug in the world.1 However, its range of potential interactions with other drugs is yet to be fully explored because of its fast introduction to the market.2 Several studies have shown that PPIs, such as omeprazole, lansoprazole etc., can diminish the antiplatelet effects of clopidogrel, and questions have been raised regarding the safety of using these drugs in combination. It is necessary to look at what ways the use of PPIs interfere with the antiplatelet effects and clinical benefits of thienopyridines. One hypothesis is that absorption of thienopyridines is increased in an acidic environment, and therefore the use of PPIs could diminish drug absorption.3 The second and more controversial concern is the possible competitive inhibition by PPIs of the cytochrome P450 isoenzyme CYP2C19, which is responsible for metabolic activation of clopidogrel. Genetic polymorphisms of the CYP2C19 allele are associated with an increased risk of adverse effects for patients treated with clopidogrel, thereby supporting the concept that diminished CYP2C19 activity can have a detrimental effect on outcomes. PPIs are thought to be converted by CYP2C19 as well, which reduces bioavailability of the enzyme. The resulting effect would be a reduced antiplatelet activity and the emergence of clopidogrel resistance in patients.4 Many experiments have been conducted to test this second hypothesis regarding CYP2C19 activity. Cohort studies from the U.S. and Canada provided data on the clinical effectiveness of clopidogrel in combination with PPIs.5,6 Both studies demonstrate that concomitant therapy of clopidogrel with PPIs is associated with increased risk of rehospitalization for ACS.7 In response to these findings, both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency advised physicians to re-evaluate the need for treatment with a PPI in patients taking clopidogrel and discouraging their combined use without a compelling indication. The Ohio State University 15 However, at this time scarce data is available that shows a definitive interaction between PPI use and the clinical benefit of clopidogrel. Because there is no data from randomized trials, there is controversy that patients prescribed a PPI and thienopyridine have high risk baseline characteristics compared to patients not in need of a PPI. This leads to the question of whether PPIs are decreasing the effectiveness of clopidogrel or if these patients on PPIs are more likely to develop ischemic events regardless. More limitations arise in the fact that risks have been overestimated due to incomplete control of confounding variables and biased patient selection. Other studies such as the one Gilard et. al performed indicated only a partial reduction in the antiplatelet action of clopidogrel and concluded that even if a drug-drug interaction was occurring, clopidogrel still provides some benefit.8 More recent studies have been conducted on a larger scale and take into account limitations from past studies. O’Donoghue et al. analyzed a subgroup of the TRITON-TIMI 38 trial and the PRINCIPLE-TIMI 44 trial, concluding that the concurrent use of PPIs did not attenuate the clinical efficacy of clopidogrel.3 Preliminary results of a randomized double-blind trial of the PPI omeprazole versus placebo in patients taking clopidogrel plus aspirin showed no evidence for clinically relevant adverse cardiovascular interactions with PPIs.9 In the TRITON TIMI-38 trial, the primary endpoint was the composite of a myocardial infarction (MI) or cardiovascular death. Approximately 13,600 patients with ACS were randomly assigned to prasugrel or clopidogrel. Thirty-three percent of these patients were on a PPI at randomization, and the result show that no association exists between PPI use and risk of the primary endpoints mentioned for patients treated with clopidogrel or prasugrel.3 The PRINCIPLE-TIMI 44 consisted of 201 patients undergoing elective PCI that were randomly assigned to prasugrel or high-dose clopidogrel. Results for this trial suggest mean inhibition of platelet aggregation was lower for patients on a PPI than for those not on a PPI after a 600 mg clopidogrel loading dose. A more modest difference was seen with and without a PPI after a 60 mg loading dose of prasugrel. It is important to note that prasugrel showed more potent and consistent inhibition of platelet aggregation than high-dose clopidogrel, and almost no patients experienced significantly less platelet inhibition when combining prasugrel with a PPI. Despite the observed attenuation of the in-vitro antiplatelet effects of clopidogrel and prasugrel in patients treated with a PPI, there were no clear indications of the use of a PPI to be associated with an increased risk of adverse clinical outcomes. Modest inhibition of antiplatelet effects of The Ohio State University 16 either clopidogrel or prasugrel are likely to have been insufficient to translate into an increased risk of adverse outcomes.3 Finally, higher risk of adverse outcomes was not observed for patients on PPIs with diminished CYP2C19 activity caused by a reduced-function allele. This refutes the hypothesis that reduced activity of the cytochrome enzyme contributes to increased risk of ACS or other cardiovascular outcomes. In conclusion, there is no clear evidence that taking thienopyridines with PPIs results in decrease efficacy of the antiplatelet agents. Physicians and pharmacists should keep in mind the interaction possibly exists and monitor patients appropriately; however, no evidence suggests that clopidogrel cannot be used with PPIs effectively. While older studies detected concomitant use of PPIs with clopidogrel lead to increased risk of MI or other cardiovascular adverse outcomes, they failed to take into account an inherently biased patient selection. Most patients taking PPIs with antiplatelet drugs have a higher likelihood to develop cardiovascular disorders to begin with compared to those not taking PPIs. Data provided by recent studies like those mentioned above demonstrate that the diminished function of CYP2C19 activity does not associate with increased adverse outcomes for patients on PPIs, and that while antiplatelet activities of clopidogrel and prasugrel are attenuated, this does not affect clinical outcomes. On the part of the health-care practitioner, a risk-benefit analysis is necessary to choose which antiplatelet therapy is more appropriate in the setting of a PPI. Because prasugrel has been proven to be more efficacious in the presence of a PPI, it may be more appropriate for higher risk patients. However, in low risk patients that do not require as much platelet inhibition, clopidogrel may be a suitable alternative. References 1. IMS Health [internet]. Top ten global pharmaceutical products. IMS Health Inc.; c2010. Updated periodically. 2. Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation. 2009 Nov 23;120:2322-29. 3. O’Donoghue ML, Braunwald E, Antman EM, Murphy SA, Bates ER, Rozenman Y, Michelson AD, Hautvast RW, Ver Lee PN, Close SL, Shen L, Mega JL, Sabatine MS, Wiviott SD. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with The Ohio State University 17 or without a proton-pump inhibitor: an analysis of two randomized trials. Lancet. 2009 Sep 1;374:989-97. 4. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. Journal of the American College of Cardiology. 2005;45:1157-64. 5. Ho PM, Maddox TM, Wang L et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009 Jul 1;301:937-44. 6. Juurlink DN, Gomes T, Ko DT et al. A population based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009 Mar 31;180:713-8. 7. Boxel OS, Oijen MGH, Hagenaars MP, Smout AJPM, Siersema PD. Cardiovascular and gastrointestinal outcomes in clopidogrel users on proton pump inhibitors: results of a large Dutch cohort study. American Journal of Gastroenterology. 2010 Aug 24;105:2430-36. 8. Gilard M, Arnaud B, Cornily JC, Le Gal G, Lacut K, Le Calvez G, Mansourati J, Mottier D, Abgrall JF, Boschat J. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin. Journal of the American College of Cardiology. 2008;51:256-60. 9. Kwok CS, Loke YK. Meta-analysis: the effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel. Alimentary Pharmacology and Therapeutics. 2010 Apr 31;31:810-23.