Abstract: Objective. To determine the safety and efficacy of administering prasugrel at the time of percutaneous coronary intervention (PCI), and switching to clopidogrel, without reloading. Background. Prasugrel has faster onset of action and appears to be of greater benefit than clopidogrel, particularly early after PCI. However, long-term prasugrel increases bleeding. Many physicians at Geisinger Medical Center (GMC) administer prasugrel before PCI and switch to clopidogrel afterward. The safety and efficacy of this strategy has not been studied. Methods. We performed a retrospective study using electronic medical records and identified patients at GMC who underwent PCI between February 1, 2009 and January 31, 2012 and received a loading dose of prasugrel with a subsequent switch to clopidogrel, without reloading. The primary endpoint was major adverse cardiovascular event (MACE), defined as death, myocardial infarction (MI), stroke, or stent thrombosis, 7 days after the first dose of clopidogrel. Secondary endpoints included MACE at 30 days, individual MACE components at 7 and 30 days post procedure, and bleeding as defined by the Bleeding Academic Research Consortium (BARC) at 1 day and 30 days. Results. A total of 151 patients met inclusion criteria. One patient suffered a MACE on day 7 (0.7%; 95% confidence interval, 0.03%-3.33%). One patient had an MI between 8-30 days. Two patients had BARC bleeding (type 2 and type 3b) 30 days post PCI. Conclusions. In this small, retrospective analysis, the results of loading patients with prasugrel for PCI and switching them to clopidogrel without a loading dose appear to be encouraging.
J INVASIVE CARDIOL 2015;27(12):543-546. Epub 2015 September 15.
Key words: balloon angioplasty, antiplatelet therapy, platelet biology
Dual-antiplatelet therapy improves patient outcomes following percutaneous coronary intervention (PCI), particularly if a coronary stent is deployed. Clopidogrel has a slower onset of action and inhibits platelet aggregability less than prasugrel.1 Prasugrel reduces thrombotic events in recently stented patients more effectively than clopidogrel, but increases the risk of life-threatening bleeding, particularly over the long term.2 As a result, prasugrel may be the drug of choice for treatment of acute coronary syndrome (ACS) in the setting of PCI, particularly when pretreatment with clopidogrel has not been accomplished. Many physicians at Geisinger Medical Center (GMC) administer prasugrel around the time of PCI and switch to clopidogrel shortly thereafter. However, little is known about the safety and efficacy of such a strategy. Accordingly, we performed this retrospective study to assess the clinical outcomes of patients who received a loading dose of prasugrel immediately prior to a PCI, and were discharged on clopidogrel.
We retrospectively analyzed data from our cardiac catheterization database and electronic health records to electronically identify all patients at GMC who underwent PCI with at least 1 bare-metal or drug-eluting stent between February 1, 2009 (when prasugrel first became available) and January 31, 2012, who were loaded with prasugrel 60 mg for the procedure, and who were switched to clopidogrel before or upon discharge. All patients switched to clopidogrel received Plavix, since this study was conducted prior to the availability of generic clopidogrel. The electronic charts of patients meeting the inclusion criteria were then manually reviewed for exclusion criteria, baseline characteristics, demographics, and clinical outcomes. A total of 238 patients who underwent PCI were initially identified. A total of 87 patients were excluded for the following reasons: they were in cardiogenic shock at the time of the PCI (n = 5); they were taking other antithrombotic medications (warfarin, dabigatran, rivaroxaban, or cilostazol) at the time of the procedure or on discharge (n = 19); they received a loading dose of clopidogrel within 7 days prior to the PCI (n = 30); they did not receive a loading dose of prasugrel (n = 13); they had no stents placed at the end of the procedure (n = 6); they were referred to GMC from another institution and there was no follow-up at 7 days (n = 1); or they met other exclusion criteria (n = 13). A total of 2942 PCIs were performed at GMC during the period analyzed; the remaining 151 patients represent 5.1% of patients who underwent PCI during the study period. Of the 2942 PCI procedures, a total of 4339 stents were placed. This retrospective analysis was approved by the Geisinger Institutional Review Board.
Analysis and outcomes. The primary endpoint of this study was the rate of all-cause death, myocardial infarction (MI), stroke, or stent thrombosis in the 7 days after the first dose of clopidogrel. Secondary endpoints included the rate of these events at 30 days; the rate of each component of the primary endpoint at 7 days and 30 days (analyzed separately); the rate of type 0 to type 5 bleeding as defined by the Bleeding Academic Research Consortium (BARC)3 at 1 day and 30 days; and the rate of major and minor bleeding using the Thrombolysis in Myocardial Infarction (TIMI) definition4 at 1 day and 30 days.
Data sources. The main source of the data was Geisinger’s electronic health record system, EpicCare. Geisinger’s internal PCI database was used as a secondary data source. Additionally, follow-up data on 9 patients were obtained via phone call by the primary investigator of the study. The EpicCare system is an effective source for capturing clinical outcomes on the study population. Epic was initially implemented at Geisinger in outpatient settings in 1996, with all clinics fully implemented by 2001. Since 2007, all inpatient clinical information has been captured in Epic as well. At Geisinger, the entire patient’s health information, including outpatient, inpatient, and emergency room encounters, medication orders, and laboratory orders throughout our 40+ outpatient clinics and 5 hospital systems are available in Epic.
Statistical analysis. Data were analyzed using simple statistics to calculate means with standard deviations or medians with 25th and 75th percentiles. Confidence intervals (CIs) were calculated using normal approximation to the binomial distribution using StatXact software (Cytel software version 9.0).
Clinical and procedural characteristics. The baseline clinical characteristics of the study population are summarized in Table 1. Their average age was 59 years; 76% were male. There were 25 patients who were on antiplatelet maintenance therapy (clopidogrel 75 mg) prior to the PCI. Overall, 33 patients (22%) had a previous MI, 36 (24%) had a previous PCI, and 8 patients (5%) had previous coronary artery bypass graft (CABG) surgery. Overall, the left ventricular systolic function was preserved in the study population.
Procedural characteristics are summarized in Table 2. A total of 240 stents (84 bare-metal stents and 156 drug-eluting stents) were placed in these 151 patients.
Medications. Among the 151 patients, 140 (92.7%) were switched to clopidogrel the day after they had been loaded with 60 mg of prasugrel; the remaining 11 patients received one dose (7 patients), two doses (3 patients), or three doses (1 patient) of prasugrel 10 mg before the switch to clopidogrel. Other medications prescribed at discharge are listed in Table 3. At 1 month, all patients (100%) indicated to their clinician that they were still taking clopidogrel daily.
Clinical outcome. There was 1 death (0.7%) in the 7 days post procedure (95% CI, 0.03%-3.33%). This patient was being transported to the hospital for progressive shortness of breath thought to be caused by his documented severe emphysema, and passed away before arrival in the emergency department. He was not thought to have suffered an MI, although an autopsy was not performed.
Thirty-day follow-up was not available for 1 patient. Of the 149 remaining patients, 1 patient (0.7%) suffered an MI during days 8-30 post procedure (95% CI, 0.03%-3.37%); angiography of this patient revealed an edge dissection with a severe stenosis not evident at the time of stent placement. No other adverse events occurred in any other patients in the 30 days after initiation of clopidogrel.
Regarding bleeding, 1 patient had a BARC type-2 bleed (an upper gastrointestinal bleed) within 30 days post procedure. Another patient had a BARC type-3b bleed (which also met criteria for TIMI major bleed) within 30 days of the first clopidogrel dose. The patient developed a large right groin hematoma. Both patients were continued on uninterrupted dual-antiplatelet therapy.
The most important finding of this study is that in a consecutive series of patients who underwent PCI after receiving a loading dose of prasugrel, switching to clopidogrel immediately or very shortly after the PCI procedure without a loading dose appears to be safe and effective.
Background. Tremendous strides have been made in the medical treatment of ACS over the past two decades, in part due to advances in antiplatelet therapy. The efficacy of clopidogrel has been well established for the prevention of stent thrombosis.5-10 Although clopidogrel is one of the most studied cardiovascular drugs ever, with proven benefit in multiple clinical settings, it has a number of important limitations. Individual variability in response, unpredictable absorption, and delayed onset even after large loading doses have created the need for more rapidly acting, predictable, and potent P2Y12 antagonists.11,12
Prasugrel, like clopidogrel, is an inactive pro-drug that requires conversion to an active metabolite that irreversibly binds to P2Y12 receptors.8 However, prasugrel requires fewer intrahepatic metabolic conversions, leading to a higher concentration of its active metabolite. As a result, prasugrel is a more potent inhibitor of platelet aggregation (at the approved doses of prasugrel and clopidogrel). Since higher concentrations of the same metabolite are bound to the same P2Y12 receptor bound by the active metabolites of clopidogrel, it is not believed that a loading dose of clopidogrel is necessary. Prasugrel has a much faster onset of action.1
In the landmark TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38) trial, prasugrel outperformed clopidogrel in 13,608 ACS patients undergoing PCI.2 However, there was a significant increase in non-CABG related major bleeding (2.4 vs 1.8%; hazard ratio, 1.32; P=.03) as well as spontaneous, life-threatening, and fatal bleeding in the prasugrel arm. And while the majority of the benefit from prasugrel was seen in the first 5 days, the majority of the bleeding events occurred more than 30 days after the procedure.13 This raises the issue of whether early treatment with prasugrel followed by later treatment with clopidogrel might be beneficial in some patients, ie, might maximize the likelihood of benefit while reducing the risk of harm. Many other drugs are switched from one to another in ACS patients; short-acting beta-blockers are often changed to once-a-day drugs at discharge, as are angiotensin-converting enzyme inhibitors, and less expensive generic statins are often administered during hospitalization for an ACS, while more expensive and more potent agents are administered after discharge. However, the safety of using a more rapidly acting and potent antiplatelet agent around the time of a PCI followed by a safer antiplatelet agent after discharge, and the safety of doing so without administering a loading dose of clopidogrel, is unknown.
The current retrospective analysis suggests that such a strategy, combined with what we know about the pharmacology of these two drugs, might possibly be safe and effective during short-term follow-up, and requires further study. The 1 major event among the 151 patients in this study (a death that occurred within 7 days) appeared not to be coronary in origin. The duration of follow-up at which the primary endpoint was assessed (7 days) is sufficient for clopidogrel to achieve steady state without a loading dose. However, we believe that the density of receptor occupancy gradually drifts down and that patients are never exposed to a greater risk of thrombosis had they initially received a 600 mg clopidogrel loading dose followed by clopidogrel post discharge.
Furthermore, because both prasugrel and clopidogrel bind to the same platelet receptor site, and have similar modes of action, the switch to maintenance-dose clopidogrel would not warrant a reloading strategy after the initial prasugrel loading dose. Our clinical data contrast from a smaller trial by Kerneis et al, where the switch from prasugrel to clopidogrel in 31 ACS patients was evaluated by measuring platelet reactivity with the VerifyNow P2Y12 assay, light transmission aggregometry, and the vasodilator-stimulated phophoprotein platelet reactivity index. The authors in that study concluded that switching from prasugrel to clopidogrel might unmask a group of non-responders to clopidogrel with unknown clinical outcomes.14
Study limitations. This is a retrospective study, subject to the limitations of all such studies. The majority of the patients in this study were Caucasian (98.7%); caution should be used when extrapolating to other races. The study is small; the ability to detect rare events in such a trial is limited, and the CI ranges up to 3.51% at the upper boundary if we include the 1 death as possibly caused by a thrombotic event. In this study, nearly one-half of the patients had stable angina as the indication for PCI. Prasugrel has not been studied for this indication, and accordingly, this is an off-label use. However, it is often used in clinical practice in patients undergoing PCI for stable angina who had not been treated with clopidogrel before the procedure. Whether administering prasugrel to such patients is more effective than administering a 600 mg loading dose of clopidogrel (which is believed to take at least 2 hours before maximal inhibition of aggregation), or some other strategy of antiplatelet therapy, is not known and cannot be determined from this study.
These data suggest that switching to clopidogrel without a loading dose after the initial administration of prasugrel in order to take advantage of its greater efficacy and more rapid onset of action is a strategy that requires further study. This strategy may be beneficial in some patients by maximizing the more potent agent, prasugrel, during the very highest-risk period and utilizing the safer agent, clopidogrel, during the lower-risk period. Further large, randomized control trials are needed to confirm this strategy.
- 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;153:66.e9-66.e16.
- Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001-2015.
- Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation. 2011;123:2736-2747.
- TIMI definitions for commonly used terms in clinical trials. Available at: http://www.timi.org/wp-content/uploads/2010/10/TIMI-Definitions.pdf. Accessed June 12, 2014.
- Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345:494-502.
- Sabatine MS, Cannon CP, Gibson CM, et al. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. JAMA. 2005;294:1224-1232.
- 7. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomized placebo-controlled trial. Lancet. 2005;366:1607-1621.
- Sabatine MS, Cannon CP, Gibson CM, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:1179-1189.
- Mehta SR, Yusuf S, Peters RJG, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet. 2001;358:527-533.
- Steinhubl SR, Berger PB, Mann III JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. The CREDO trial. JAMA. 2002;288:2411-2420.
- Cattaneo M. New P2Y(12) inhibitors. Circulation. 2010;121:171-179.
- Barn K, Steinhubl SR. A brief review of the past and future of platelet P2Y12 antagonist. Coron Artery Dis. 2012;23:368-374.
- Kaul S, Shah PK, Diamond GA. Abstract 4014. Timing of benefit with prasugrel in patients with acute coronary syndromes undergoing percutaneous coronary intervention: reanalysis of TRITON-TIMI 38 results. Circulation. 2008;118:S818-S819.
- Kerneis M, Silvain J, Abtan J, et al. Switching acute coronary syndrome patients from prasugrel to clopidogrel. JACC Cardiovasc Interv. 2013;6:158-165.
From the 1Department of Cardiology, 2General Internal Medicine, and 3Cardiovascular Center for Clinical Research, Geisinger Medical Center, Danville, Pennsylvania; and 4North Shore LIJ Health Care System, Great Neck, New York.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Berger reports consultant fees from Medicure and Janssen; research funding from Janssen for Geisinger Clinic studies on which he was the Principal Investigator. The remaining authors report no conflicts of interest regarding the content herein.
Manuscript submitted June 5, 2015 and accepted June 10, 2015.
Address for correspondence: Peter B. Berger, MD, North Shore-LIJ System Administration, 145 Community Drive, Great Neck, NY 11021. Email: firstname.lastname@example.org