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Trends in P2Y12 Inhibitor Use in Patients Referred for Invasive Evaluation of Coronary Artery Disease in Contemporary US Practice

Open AccessPublished:February 16, 2016DOI:https://doi.org/10.1016/j.amjcard.2016.02.012
      Practice in patients undergoing invasive evaluation for coronary artery disease is variable regarding choice of P2Y12 inhibitor and timing of treatment initiation and is usually dictated by institutional or even individual operator preference. Limited data are available on the actual patterns of P2Y12 inhibitor use in contemporary practice in the United States. We used electronic medical records from the Cerner “Health Facts” database of adults who underwent coronary angiography with or without percutaneous coronary intervention (PCI) from January 2008 to June 2013 and who received a loading dose of clopidogrel, prasugrel, or ticagrelor at any time from 48 hours before the start of procedure up to 6 hours after. Timing of P2Y12 inhibitor administration was categorized as >2 hours before, 0 to 2 hours before (pretreatment groups), or after the start of procedure. Results were also evaluated according to type of P2Y12 inhibitor and patient clinical presentation. A total of 37,964 patients underwent coronary angiography, and 28,306 proceeded to PCI. Pretreatment with a P2Y12 inhibitor was observed in 28% and 23% in the overall and PCI populations, respectively. Moderate variability of pretreatment rates was noted relative to clinical presentation and P2Y12 inhibitor type. Pretreatment rates remained fairly constant over time with the exception of a decreasing trend with prasugrel. In conclusion, among patients referred for invasive evaluation of coronary artery disease, P2Y12 inhibitor pretreatment was low in contemporary US practice, an observation consistent over time and for all available agents and clinical presentations.
      All patients undergoing a percutaneous coronary intervention (PCI) require treatment with a platelet P2Y12 inhibitor.
      • Levine G.N.
      • Bates E.R.
      • Blankenship J.C.
      • Bailey S.R.
      • Bittl J.A.
      • Cercek B.
      • Chambers C.E.
      • Ellis S.G.
      • Guyton R.A.
      • Hollenberg S.M.
      • Khot U.N.
      • Lange R.A.
      • Mauri L.
      • Mehran R.
      • Moussa I.D.
      • Mukherjee D.
      • Nallamothu B.K.
      • Ting H.H.
      American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions
      2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines and the Society for Cardiovascular Angiography and Interventions.
      PCI usually follows diagnostic coronary angiography in the same setting (ad hoc PCI), a practice that is followed in over 80% of PCI performed in the United States and is endorsed by the Society of Cardiac Angiography and Interventions.
      • Blankenship J.C.
      • Gigliotti O.S.
      • Feldman D.N.
      • Mixon T.A.
      • Patel R.A.
      • Sorajja P.
      • Yakubov S.J.
      • Chambers C.E.
      Ad hoc percutaneous coronary intervention: a consensus statement from the Society for Cardiovascular Angiography and Interventions.
      The delayed bioavailability of oral P2Y12 inhibitors has prompted the practice of initiating treatment before coronary angiography (pretreatment) to ensure that antiplatelet activity would be present should a PCI be required. Randomized trials comparing pretreatment to treatment initiated only after the coronary anatomy is defined, and the decision to proceed with PCI has been made have not conclusively demonstrated a benefit and have even suggested possible harm.
      • Bellemain-Appaix A.
      • Kerneis M.
      • O'Connor S.A.
      • Silvain J.
      • Cucherat M.
      • Beygui F.
      • Barthelemy O.
      • Collet J.P.
      • Jacq L.
      • Bernasconi F.
      • Montalescot G.
      ACTION Study Group
      Reappraisal of thienopyridine pretreatment in patients with non-ST elevation acute coronary syndrome: a systematic review and meta-analysis.
      • Widimsky P.
      • Motovska Z.
      • Simek S.
      • Kala P.
      • Pudil R.
      • Holm F.
      • Petr R.
      • Bilkova D.
      • Skalicka H.
      • Kuchynka P.
      • Poloczek M.
      • Miklik R.
      • Maly M.
      • Aschermann M.
      PRAGUE-8 Trial Investigators
      Clopidogrel pre-treatment in stable angina: for all patients >6 h before elective coronary angiography or only for angiographically selected patients a few minutes before PCI? A randomized multicentre trial PRAGUE-8.
      In addition, pretreatment may complicate the process of care for the patients who will require coronary bypass grafting surgery (CABG) because they will either have to experience delays to allow for platelet function to return or alternatively proceed to surgery at increased bleeding risk. Guideline recommendations vary, with pretreatment generally considered reasonable in patients with acute coronary syndromes (ACS), except when prasugrel is used. The most recent non–ST-elevation myocardial infarction guidelines released by the European Society of Cardiology reflect the lack of definitive data to support universal pretreatment –“As the optimal timing of ticagrelor or clopidogrel administration in NSTE-ACS patients scheduled for an invasive strategy has not been adequately investigated, no recommendation for or against pretreatment with these agents can be formulated. Based on the Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction (ACCOAST) trial results, pretreatment with prasugrel is not recommended.”
      • Roffi M.
      • Patrono C.
      • Collet J.P.
      • Mueller C.
      • Valgimigli M.
      • Andreotti F.
      • Bax J.J.
      • Borger M.A.
      • Brotons C.
      • Chew D.P.
      • Gencer B.
      • Hasenfuss G.
      • Kjeldsen K.
      • Lancellotti P.
      • Landmesser U.
      • Mehilli J.
      • Mukherjee D.
      • Storey R.F.
      • Windecker S.
      • Baumgartner H.
      • Gaemperli O.
      • Achenbach S.
      • Agewall S.
      • Badimon L.
      • Baigent C.
      • Bueno H.
      • Bugiardini R.
      • Carerj S.
      • Casselman F.
      • Cuisset T.
      • Erol C.
      • Fitzsimons D.
      • Halle M.
      • Hamm C.
      • Hildick-Smith D.
      • Huber K.
      • Lliodromitis E.
      • James S.
      • Lewis B.S.
      • Lip G.Y.
      • Piepoli M.F.
      • Richter D.
      • Rosemann T.
      • Sechtem U.
      • Steg P.G.
      • Vrints C.
      • Luis Zamorano J.
      for the Task Force Members
      2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC).
      We performed this analysis to describe trends of P2Y12 inhibitor use in contemporary US practice.

      Methods

      This study used electronic medical records from the Cerner Health Facts database (Cerner, Kansas City, Missouri). Health Facts collects comprehensive, time-stamped clinical and pharmacy records from approximately 300 hospitals and hospital-affiliated outpatient facilities, of diverse size and affiliation (teaching or nonteaching), throughout the US. Patient records in this database have been deidentified in compliance with the Health Insurance Portability and Accountability Act. Adults undergoing diagnostic coronary angiography with or without PCI from January 2008 to June 2013 who received a loading dose of clopidogrel (300 or 600 mg), prasugrel (60 mg), or ticagrelor (180 mg) at any time from 48 hours before the start of procedure up to 6 hours after were included. Procedure time was determined using a proxy of pharmacy dispense times for anesthetics, anxiolytics, contrast media agents, sedatives, or analgesics (in hierarchical order) in a similar manner as has been adopted by the CathPCI registry

      NCDR® CathPCI Registry® v4.4 Coder's Data Dictionary. Available at: http://cvquality.acc.org/∼/media/QII/NCDR/Data%20Collection%20Forms/cathpci_v4_codersdictionary_4-4.ashx. Accessed on July 23, 2015.

      and published previously.
      • Dean B.B.
      • Yu H.
      • Bae J.P.
      • Fiske S.
      • Meadows E.
      • Xiong Y.
      • Emons M.F.
      Pattern of clopidogrel use in hospitalized patients receiving percutaneous coronary interventions.
      Timing of P2Y12 inhibitor administration was calculated according to pharmacy dispense time of P2Y12 inhibitor and procedure time and was further divided into 3 periods: >2 hours before, 0 to 2 hours before, or any time after the start of the procedure. Pretreatment rates (first 2 time categories) were evaluated for the overall study population, but also according to the type of P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and clinical presentation (stable coronary artery disease [SCAD], non–ST-elevation ACS [NSTE-ACS], and ST-elevation ACS [STE-ACS]). This is a descriptive analysis, without a prespecified statistical hypothesis. All analyses were conducted using SAS, version 9.2 (SAS Institute Inc., Cary, North Carolina).

      Results

      A total of 37,964 patients from 77 hospitals (18, 27, 25, and 7 hospitals from the 4 census regions

      United States Census Bureau. Available at: https://www.census.gov/geo/reference/gtc/gtc_census_divreg.html. Accessed on July 23, 2015.

      of the Midwest, Northeast, South, and West, respectively) met the entry criteria and were included in the analysis. The patient breakdown according to clinical presentation was 22,631 (59.6%) with SCAD, 8,885 (23.4%) with NSTE-ACS, and 6,448 (17.0%) with STE-ACS. A total of 28,306 patients (74.6%) underwent angiography and PCI, whereas 9,658 patients (25.4%) underwent only diagnostic coronary angiography.
      Overall, 27.8% of patients included in this analysis received pretreatment (14.6% >2 hours, 13.2% within 0 to 2 hours). Although there was moderate variability relative to P2Y12 inhibitor type, overall, pretreatment was more frequent in STE-ACS and NSTE-ACS than in SCAD (Figure 1, Top ). Pretreatment rates were also low at 23.1% in the subgroup of the 28,306 patients that proceeded to PCI with similar patterns of distribution according to P2Y12 inhibitor type or clinical presentation as observed in the overall study population (Figure 1, Bottom).
      Figure thumbnail gr1
      Figure 1Timing of P2Y12 inhibitor loading dose administration for all patients (Top) and patients who proceeded to PCI (Bottom).
      Practice patterns remained fairly consistent over time without important difference in pretreatment rates from 2008 to 2013. This stable pattern of pretreatment over time was true for all clinical presentations (Figure 2, Left ). There seemed to be a trend toward lower rates of pretreatment over time with the newer agents, especially prasugrel, but in the case of clopidogrel pretreatment rates remained stable over time (Figure 2, Right).
      Figure thumbnail gr2
      Figure 2Pretreatment rates of P2Y12 inhibitor over time according to clinical presentation (Left) and agent selection (Right).
      Finally, our analysis showed that clopidogrel had been and still was the most commonly used P2Y12 inhibitor in this population and even as recently as 2013 was still used in over 3/4 of patients in this database. The use of prasugrel appeared to have stabilized at about 13%, whereas the adoption of ticagrelor appeared to be slowly increasing over time and was at about 10% by 2013 (Figure 3, Top Left). Consistent with product labels
      and practice guidelines, the use of prasugrel and ticagrelor was higher in patients with STE-ACS and NSTE-ACS (15.6% and 11.8%, respectively) compared with patients with SCAD (11.6% and 7.3%, respectively; Figures 3, Top Right and Bottom).
      Figure thumbnail gr3
      Figure 3Type of P2Y12 inhibitor selection over time for all patients (Top Left), ACS patients (Top Right) and SCAD patients (Bottom).

      Discussion

      Despite the universal need for P2Y12 inhibitor therapy in all patients undergoing PCI, there is clinical equipoise regarding the optimal timing of treatment initiation.
      • Levine G.N.
      • Bates E.R.
      • Blankenship J.C.
      • Bailey S.R.
      • Bittl J.A.
      • Cercek B.
      • Chambers C.E.
      • Ellis S.G.
      • Guyton R.A.
      • Hollenberg S.M.
      • Khot U.N.
      • Lange R.A.
      • Mauri L.
      • Mehran R.
      • Moussa I.D.
      • Mukherjee D.
      • Nallamothu B.K.
      • Ting H.H.
      American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Society for Cardiovascular Angiography and Interventions
      2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines and the Society for Cardiovascular Angiography and Interventions.
      • Roffi M.
      • Patrono C.
      • Collet J.P.
      • Mueller C.
      • Valgimigli M.
      • Andreotti F.
      • Bax J.J.
      • Borger M.A.
      • Brotons C.
      • Chew D.P.
      • Gencer B.
      • Hasenfuss G.
      • Kjeldsen K.
      • Lancellotti P.
      • Landmesser U.
      • Mehilli J.
      • Mukherjee D.
      • Storey R.F.
      • Windecker S.
      • Baumgartner H.
      • Gaemperli O.
      • Achenbach S.
      • Agewall S.
      • Badimon L.
      • Baigent C.
      • Bueno H.
      • Bugiardini R.
      • Carerj S.
      • Casselman F.
      • Cuisset T.
      • Erol C.
      • Fitzsimons D.
      • Halle M.
      • Hamm C.
      • Hildick-Smith D.
      • Huber K.
      • Lliodromitis E.
      • James S.
      • Lewis B.S.
      • Lip G.Y.
      • Piepoli M.F.
      • Richter D.
      • Rosemann T.
      • Sechtem U.
      • Steg P.G.
      • Vrints C.
      • Luis Zamorano J.
      for the Task Force Members
      2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC).
      In this analysis, more than 70% of patients referred for invasive evaluation of coronary artery disease did not get a loading dose of a P2Y12 inhibitor before coronary angiography. Rates of pretreatment appeared to be modestly higher in patients presenting with STE-ACS and NSTE-ACS but were still well below 50% for all time points included in this analysis and across all the types of P2Y12 inhibitors.
      These results suggest that clinical practice patterns are heavily influenced by the practical and safety considerations of administering P2Y12 inhibitors before the coronary anatomy is defined and the treatment plan is finalized. The most obvious consideration is that many of these patients will not require PCI because they may not have significant coronary artery disease, or if they do, may be best treated with medical management or CABG. Specifically, the number of patients who will eventually undergo PCI after diagnostic coronary angiography ranges greatly according to clinical presentation: close to 90% for patients presenting with STE-ACS,
      • Stone G.W.
      • Witzenbichler B.
      • Guagliumi G.
      • Peruga J.Z.
      • Brodie B.R.
      • Dudek D.
      • Kornowski R.
      • Hartmann F.
      • Gersh B.J.
      • Pocock S.J.
      • Dangas G.
      • Wong S.C.
      • Kirtane A.J.
      • Parise H.
      • Mehran R.
      HORIRIZONS-AMI Trial Investigators
      Bivalirudin during primary PCI in acute myocardial infarction.
      approximately 60% for patients with NSTE-ACS,
      • Stone G.W.
      • McLaurin B.T.
      • Cox D.A.
      • Bertrand M.E.
      • Lincoff A.M.
      • Moses J.W.
      • White H.D.
      • Pocock S.J.
      • Ware J.H.
      • Feit F.
      • Colombo A.
      • Aylward P.E.
      • Cequier A.R.
      • Darius H.
      • Desmet W.
      • Ebrahimi R.
      • Hamon M.
      • Rasmussen L.H.
      • Rupprecht H.J.
      • Hoekstra J.
      • Mehran R.
      • Ohman E.M.
      ACUITY Investigators
      Bivalirudin for patients with acute coronary syndromes.
      and <50% for patients evaluated for SCAD.
      • Dehmer G.J.
      • Weaver D.
      • Roe M.T.
      • Milford-Beland S.
      • Fitzgerald S.
      • Hermann A.
      • Messenger J.
      • Moussa I.
      • Garratt K.
      • Rumsfeld J.
      • Brindis R.G.
      A contemporary view of diagnostic cardiac catheterization and percutaneous coronary intervention in the United States. A report from the CathPCI registry of the national cardiovascular data registry, 2010 through june 2011.
      It is therefore reasonable to understand why clinicians do not feel comfortable with universal pretreatment of their patients.
      Importantly, among those patients who will require CABG surgery, pretreatment with a long-acting P2Y12 inhibitor may complicate their care because they would either need to wait for 3 to 9 days, depending on the agent used, until sufficient platelet function is restored or proceed to surgery at an increased bleeding risk.
      • Ebrahimi R.
      • Dyke C.
      • Mehran R.
      • Manoukian S.V.
      • Feit F.
      • Cox D.A.
      • Gersh B.J.
      • Ohman E.M.
      • White H.D.
      • Moses J.W.
      • Ware J.H.
      • Lincoff A.M.
      • Stone G.W.
      Outcomes following pre-operative clopidogrel administration in patients with acute coronary syndromes undergoing coronary artery bypass surgery: the ACUITY (Acute Catheterization and Urgent Intervention Triage strategy) trial.
      • Biancari F.
      • Airaksinen K.E.
      • Lip G.Y.
      Benefit and risks of using clopidogrel before coronary artery bypass surgery: systematic review and meta-analysis of randomized trials and observational studies.
      In addition to the safety concerns for either scenario, there are also substantial economic implications with large increases in hospitalization costs.
      • Chu M.W.
      • Wilson S.R.
      • Novick R.J.
      • Stitt L.W.
      • Quantz M.A.
      Does clopidogrel increase blood loss following coronary artery bypass surgery?.
      Finally, our analysis shows that clopidogrel remains the most commonly prescribed agent in US practice, whereas ticagrelor and prasugrel are slowly exhibiting increased use in patients with ACS. It is possible that the recent availability of generic clopidogrel may further ensure its dominant position in the future.
      Several limitations of this analysis should be considered. First, procedure times were not captured in the database but were instead inferred by proxy; a method previously adopted and validated by the National Cardiovascular Data Registry CathPCI registry.

      NCDR® CathPCI Registry® v4.4 Coder's Data Dictionary. Available at: http://cvquality.acc.org/∼/media/QII/NCDR/Data%20Collection%20Forms/cathpci_v4_codersdictionary_4-4.ashx. Accessed on July 23, 2015.

      • Dean B.B.
      • Yu H.
      • Bae J.P.
      • Fiske S.
      • Meadows E.
      • Xiong Y.
      • Emons M.F.
      Pattern of clopidogrel use in hospitalized patients receiving percutaneous coronary interventions.
      Second, pharmacy dispense times were used as proxy for time of P2Y12 administration, so accordingly, hospitals dispensing drugs directly in the catheterization laboratory were not included in this analysis. Third, data included in this analysis are limited to the June 2013 and may therefore underrepresent the current usage of newer P2Y12 inhibitors. Finally, clinical outcomes were not captured in this analysis; and therefore, the clinical significance of our findings remains unknown.
      Accordingly, these results should be interpreted in lieu of the previously mentioned limitations and in the context of local practice patterns; however, the inclusion of a large number of hospitals with broad geographic distribution does add substantial external validity to the results.

      Disclosures

      The authors have no conflicts of interest to disclose.

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        • Feit F.
        • Colombo A.
        • Aylward P.E.
        • Cequier A.R.
        • Darius H.
        • Desmet W.
        • Ebrahimi R.
        • Hamon M.
        • Rasmussen L.H.
        • Rupprecht H.J.
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        • Rumsfeld J.
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