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Pre-treatment with dual antiplatelet therapy in patients with non-ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention M. B. Yudi,1 D. Eccleston,2 N. Andrianopoulos,3 O. Farouque,1 S. J. Duffy,4 A. Brennan,3 C. Reid,3 D. J. Clark,1 A. E. Ajani2,3,5 on behalf of the Melbourne Interventional Group 1 Department of Cardiology, Austin Health, 2Department of Cardiology, Royal Melbourne Hospital, 3Centre of Cardiovascular Research and Education in Therapeutics (CCRE), Monash University, 4Department of Cardiology, Alfred Hospital, and 5The University of Melbourne, Melbourne, Victoria,
Australia
Key words pre-treatment, clopidogrel, NSTEACS, PCI. Correspondence Andrew E. Ajani, Royal Melbourne Hospital, Grattan Street, Parkville, Vic. 3050, Australia. Email: [email protected] Received 19 March 2015; accepted 12 May 2015. doi:10.1111/imj.12818
Abstract Background: Although dual antiplatelet therapy is the standard of care in non-STsegment elevation acute coronary syndromes (NSTEACS), it remains unclear when a second antiplatelet agent should be initiated. We sought to assess the safety and efficacy of pre-treatment with clopidogrel in patients with NSTEACS undergoing percutaneous coronary intervention (PCI). Methods: We analysed baseline clinical and procedural characteristics of 6817 patients with NSTEACS who underwent PCI from the Melbourne Interventional Group registry from 2005 to 2012. Patients were included in the pre-treatment group if clopidogrel was administered prior to cardiac catheterisation. We assessed 30-day mortality, myocardial infarction (MI) and major adverse cardiovascular events. The safety endpoint was in-hospital bleeding. Results: Of the 6817 patients, only 2951 (43%) received pre-treatment with clopidogrel. Patients in the pre-treatment group were more likely to present with unstable angina (70.8% vs 68.2%, P = 0.02) and have a history of MI (35.6% vs 23.6%, P < 0.01) but were less likely to have PCI within 24 h of admission (17.2% vs 25.2%, P < 0.01). There was no difference between the groups in 30-day mortality (0.9% vs 1.4%, P = 0.06), MI (2.0% vs 2.2%, P = 0.52) or major adverse cardiovascular event (3.7% vs 4.2%, P = 0.25). There was no difference in bleeding complications (1.9% vs 1.9%, P = 0.94). Conclusions: Pre-treatment with dual antiplatelet therapy in NSTEACS is not routine clinical practice in Australia. Pre-treatment appears safe but is not associated with improved short-term clinical outcomes.
Introduction Dual antiplatelet therapy is an integral component of the management of non-ST-segment elevation acute coronary syndromes (NSTEACS). The addition of a P2Y12 antagonist to aspirin reduces cardiovascular morbidity1,2 and mortality.3 Although international guidelines4,5 rec-
Funding: The Melbourne Interventional Group acknowledges funding from Abbott, Astra-Zeneca, Biotronik, Boston Scientific, Bristol-Myers Squibb, Cordis Johnson & Johnson, CSL, Medtronic, MSD, Pfizer, Sanofi-Aventis, Servier, ScheringPlough and The Medicines Company. These companies do not have access to data and do not have the right to review manuscripts or abstracts before publication. Conflict of interest: None.
ommend dual antiplatelet therapy be initiated as early as possible in NSTEACS, there is genuine clinical equipoise regarding the efficacy of this treatment strategy in preventing ischaemic events and reducing mortality. Furthermore, there are concerns regarding bleeding, which itself is an independent risk factor for mortality.6 The CURE study1 established the benefit of dual antiplatelet therapy with the addition of clopidogrel to aspirin in patients with NSTEACS. In the percutaneous coronary intervention (PCI)-CURE substudy,7 pretreatment for a mean period of 10 days prior to PCI also showed a significant improvement in major adverse cardiac events. This result was pivotal in the recommendation of dual antiplatelet pre-treatment in current guidelines.4,5 © 2015 Royal Australasian College of Physicians
1032
Pretreatment in NSTEACS
However, in the two randomised studies designed to assess the effect of clopidogrel pre-treatment in NSTEACS, there was no clinical benefit associated with this strategy.8,9 Prasugrel and ticagrelor are newer P2Y12 inhibitors that are more efficacious and have a more rapid onset of action than clopidogrel in patients with ACS.2,3 Given the trial design and positive result of the PLATO study,3 ticagrelor is recommended as upfront treatment in NSTEACS. Prasugrel pre-treatment however is associated with increased bleeding without improvement in efficacy.10 A recent meta-analysis11 did not show mortality benefit with dual antiplatelet pre-treatment in NSTEACS patients. Furthermore, pre-treatment was associated with excess major bleeding. This result is contrary to current guidelines and emphasises the need to re-evaluate clinical practice. We aim to describe the clinical characteristics and frequency of patients receiving clopidogrel pre-treatment in NSTEACS. In addition, we will assess the safety and efficacy of this treatment strategy.
Methods The cohort included consecutive patients undergoing PCI from January 2005 until December 2012 enrolled in the Melbourne Interventional Group (MIG) registry. The MIG registry is a multicentre PCI registry and has been previously described in detail.12 Briefly, demographic, clinical, procedural and in-hospital outcome data are prospectively recorded on case-report forms using standardised definitions for all fields with follow up performed at 30 days and 12 months.13 The registry is coordinated by the Centre of Cardiovascular Research and Education in Therapeutics, an independent research body within the School of Public Health and Preventive Medicine at Monash University (Melbourne, Australia). An audit of several verifiable fields from 5% of randomly selected procedures at each institution is undertaken periodically.14 In the most recent audit, 27 fields were assessed with an accuracy of 98%. This compares favourably to audits from other large registries. The ethics committee in each participating hospital has approved the MIG registry, including the use of ‘opt-out’ consent. Patients who underwent PCI for NSTEACS during the index admission were included. NSTEACS is defined as a clinical spectrum ranging from unstable angina, where cardiac biomarkers are negative, to non-ST-segment elevation myocardial infarction (NSTEMI), where cardiac biomarkers are elevated. The exclusion criteria for this study were as follows: out-of-hospital cardiac arrest; cardiogenic shock; patients transferred from a non-PCI
capable hospital; and patients who were loaded with prasugrel or ticagrelor. Eligible patients were included in the pre-treatment group if they received clopidogrel loading before coronary angiography. Patients who were loaded with clopidogrel during or after the procedure were included in the no pre-treatment group. Interventional strategy, stent selection and antithrombotic therapy were left at the discretion of the operator in all procedures. The efficacy end points assessed were 30-day mortality, myocardial infarction (MI) and major adverse cardiovascular events (MACE). MACE is the composite of death, MI and/or target vessel revascularisation. Additionally, we analysed in-hospital bleeding. In-hospital bleeding was defined as requiring a transfusion and/or prolonged hospital stay and/or a drop in hemoglobin >3 g/dL. In-hospital complications were recorded at the time of discharge or death. Thirty-day follow up was undertaken either by telephone or record review. Patient medical records were reviewed to verify events where available. MI was defined as: an increase in creatine kinase or creatine kinase-MB ≥3 times the upper limit of normal; and/or a significant ST-segment change, development of new Q waves in ≥2 contiguous electrocardiographic leads or new left branch bundle block pattern. Continuous variables are expressed as mean ± SD, and categorical data are expressed as numbers/percentages. Continuous variables were compared using Student’s t test. Categorical variables were compared using Fisher’s exact or chi-squared tests as appropriate. Multivariate logistic regression was used to estimate the adjusted odds ratio and 95% confidence interval of preloading for 30-day mortality using the pre-specified factors of unstable angina, procedure within 24 h, glycoprotein IIb/IIIa use, age ≥75 years, female gender, diabetes and estimated glomerular filtration rate (eGFR) < 60 mL/min/m2 for covariate adjustment. All statistical analyses were performed using STATA 13.1 (StataCorp LP, College Station, TX, USA). P values < 0.05 were considered to be statistically significant.
Results Of the 8231 consecutive NSTEACS cases during the specified time period, 6817 met the inclusion criteria for this study. There were 2951 (43%) patients included in the pre-treatment group and 3866 (57%) patients in the no pre-treatment group. There were differences in baseline clinical characteristics (Table 1). The pre-treatment group was younger (64.9 ± 12.3 vs 65.4 ± 2.1, P = 0.04) and more likely to have a history of MI (35.6% vs 23.6%, P < 0.01), hypertension
© 2015 Royal Australasian College of Physicians
1033
Yudi et al.
Table 1 Clinical characteristics of n = 6817 patients undergoing PCI by clopidogrel pre-treatment Pre-treatment (n = 2951)
Clinical characteristics Age (years ± SD) Age > 75 years Male Hypertension Hypercholesterolemia Diabetes mellitus Current smoker Previous MI Previous CABG eGFR ≥ 60 mL/min/m2 eGFR < 60 mL/min/m2 Presentation and angiographic characteristics Unstable angina NSTEMI Balloon angioplasty only Bare metal stent Drug eluting stent Glycoprotein IIb/IIIa use PCI within 24 h of admission
P value
%
No pre-treatment (n = 3866) %
64.9 ± 12.3 25.4 73.1 69.9 75.6 27.9 23.4 35.6 10.9 76.4 23.6
65.4 ± 12.1 27.0 72.4 67.1 71.8 26.4 25.1 23.6 9.6 74.9 25.1
0.04 0.15 0.5 0.02
Pre-treatment with dual antiplatelet therapy in patients with non-ST-segment elevation acute coronary syndromes undergoing percutaneous coronary intervention M. B. Yudi,1 D. Eccleston,2 N. Andrianopoulos,3 O. Farouque,1 S. J. Duffy,4 A. Brennan,3 C. Reid,3 D. J. Clark,1 A. E. Ajani2,3,5 on behalf of the Melbourne Interventional Group 1 Department of Cardiology, Austin Health, 2Department of Cardiology, Royal Melbourne Hospital, 3Centre of Cardiovascular Research and Education in Therapeutics (CCRE), Monash University, 4Department of Cardiology, Alfred Hospital, and 5The University of Melbourne, Melbourne, Victoria,
Australia
Key words pre-treatment, clopidogrel, NSTEACS, PCI. Correspondence Andrew E. Ajani, Royal Melbourne Hospital, Grattan Street, Parkville, Vic. 3050, Australia. Email: [email protected] Received 19 March 2015; accepted 12 May 2015. doi:10.1111/imj.12818
Abstract Background: Although dual antiplatelet therapy is the standard of care in non-STsegment elevation acute coronary syndromes (NSTEACS), it remains unclear when a second antiplatelet agent should be initiated. We sought to assess the safety and efficacy of pre-treatment with clopidogrel in patients with NSTEACS undergoing percutaneous coronary intervention (PCI). Methods: We analysed baseline clinical and procedural characteristics of 6817 patients with NSTEACS who underwent PCI from the Melbourne Interventional Group registry from 2005 to 2012. Patients were included in the pre-treatment group if clopidogrel was administered prior to cardiac catheterisation. We assessed 30-day mortality, myocardial infarction (MI) and major adverse cardiovascular events. The safety endpoint was in-hospital bleeding. Results: Of the 6817 patients, only 2951 (43%) received pre-treatment with clopidogrel. Patients in the pre-treatment group were more likely to present with unstable angina (70.8% vs 68.2%, P = 0.02) and have a history of MI (35.6% vs 23.6%, P < 0.01) but were less likely to have PCI within 24 h of admission (17.2% vs 25.2%, P < 0.01). There was no difference between the groups in 30-day mortality (0.9% vs 1.4%, P = 0.06), MI (2.0% vs 2.2%, P = 0.52) or major adverse cardiovascular event (3.7% vs 4.2%, P = 0.25). There was no difference in bleeding complications (1.9% vs 1.9%, P = 0.94). Conclusions: Pre-treatment with dual antiplatelet therapy in NSTEACS is not routine clinical practice in Australia. Pre-treatment appears safe but is not associated with improved short-term clinical outcomes.
Introduction Dual antiplatelet therapy is an integral component of the management of non-ST-segment elevation acute coronary syndromes (NSTEACS). The addition of a P2Y12 antagonist to aspirin reduces cardiovascular morbidity1,2 and mortality.3 Although international guidelines4,5 rec-
Funding: The Melbourne Interventional Group acknowledges funding from Abbott, Astra-Zeneca, Biotronik, Boston Scientific, Bristol-Myers Squibb, Cordis Johnson & Johnson, CSL, Medtronic, MSD, Pfizer, Sanofi-Aventis, Servier, ScheringPlough and The Medicines Company. These companies do not have access to data and do not have the right to review manuscripts or abstracts before publication. Conflict of interest: None.
ommend dual antiplatelet therapy be initiated as early as possible in NSTEACS, there is genuine clinical equipoise regarding the efficacy of this treatment strategy in preventing ischaemic events and reducing mortality. Furthermore, there are concerns regarding bleeding, which itself is an independent risk factor for mortality.6 The CURE study1 established the benefit of dual antiplatelet therapy with the addition of clopidogrel to aspirin in patients with NSTEACS. In the percutaneous coronary intervention (PCI)-CURE substudy,7 pretreatment for a mean period of 10 days prior to PCI also showed a significant improvement in major adverse cardiac events. This result was pivotal in the recommendation of dual antiplatelet pre-treatment in current guidelines.4,5 © 2015 Royal Australasian College of Physicians
1032
Pretreatment in NSTEACS
However, in the two randomised studies designed to assess the effect of clopidogrel pre-treatment in NSTEACS, there was no clinical benefit associated with this strategy.8,9 Prasugrel and ticagrelor are newer P2Y12 inhibitors that are more efficacious and have a more rapid onset of action than clopidogrel in patients with ACS.2,3 Given the trial design and positive result of the PLATO study,3 ticagrelor is recommended as upfront treatment in NSTEACS. Prasugrel pre-treatment however is associated with increased bleeding without improvement in efficacy.10 A recent meta-analysis11 did not show mortality benefit with dual antiplatelet pre-treatment in NSTEACS patients. Furthermore, pre-treatment was associated with excess major bleeding. This result is contrary to current guidelines and emphasises the need to re-evaluate clinical practice. We aim to describe the clinical characteristics and frequency of patients receiving clopidogrel pre-treatment in NSTEACS. In addition, we will assess the safety and efficacy of this treatment strategy.
Methods The cohort included consecutive patients undergoing PCI from January 2005 until December 2012 enrolled in the Melbourne Interventional Group (MIG) registry. The MIG registry is a multicentre PCI registry and has been previously described in detail.12 Briefly, demographic, clinical, procedural and in-hospital outcome data are prospectively recorded on case-report forms using standardised definitions for all fields with follow up performed at 30 days and 12 months.13 The registry is coordinated by the Centre of Cardiovascular Research and Education in Therapeutics, an independent research body within the School of Public Health and Preventive Medicine at Monash University (Melbourne, Australia). An audit of several verifiable fields from 5% of randomly selected procedures at each institution is undertaken periodically.14 In the most recent audit, 27 fields were assessed with an accuracy of 98%. This compares favourably to audits from other large registries. The ethics committee in each participating hospital has approved the MIG registry, including the use of ‘opt-out’ consent. Patients who underwent PCI for NSTEACS during the index admission were included. NSTEACS is defined as a clinical spectrum ranging from unstable angina, where cardiac biomarkers are negative, to non-ST-segment elevation myocardial infarction (NSTEMI), where cardiac biomarkers are elevated. The exclusion criteria for this study were as follows: out-of-hospital cardiac arrest; cardiogenic shock; patients transferred from a non-PCI
capable hospital; and patients who were loaded with prasugrel or ticagrelor. Eligible patients were included in the pre-treatment group if they received clopidogrel loading before coronary angiography. Patients who were loaded with clopidogrel during or after the procedure were included in the no pre-treatment group. Interventional strategy, stent selection and antithrombotic therapy were left at the discretion of the operator in all procedures. The efficacy end points assessed were 30-day mortality, myocardial infarction (MI) and major adverse cardiovascular events (MACE). MACE is the composite of death, MI and/or target vessel revascularisation. Additionally, we analysed in-hospital bleeding. In-hospital bleeding was defined as requiring a transfusion and/or prolonged hospital stay and/or a drop in hemoglobin >3 g/dL. In-hospital complications were recorded at the time of discharge or death. Thirty-day follow up was undertaken either by telephone or record review. Patient medical records were reviewed to verify events where available. MI was defined as: an increase in creatine kinase or creatine kinase-MB ≥3 times the upper limit of normal; and/or a significant ST-segment change, development of new Q waves in ≥2 contiguous electrocardiographic leads or new left branch bundle block pattern. Continuous variables are expressed as mean ± SD, and categorical data are expressed as numbers/percentages. Continuous variables were compared using Student’s t test. Categorical variables were compared using Fisher’s exact or chi-squared tests as appropriate. Multivariate logistic regression was used to estimate the adjusted odds ratio and 95% confidence interval of preloading for 30-day mortality using the pre-specified factors of unstable angina, procedure within 24 h, glycoprotein IIb/IIIa use, age ≥75 years, female gender, diabetes and estimated glomerular filtration rate (eGFR) < 60 mL/min/m2 for covariate adjustment. All statistical analyses were performed using STATA 13.1 (StataCorp LP, College Station, TX, USA). P values < 0.05 were considered to be statistically significant.
Results Of the 8231 consecutive NSTEACS cases during the specified time period, 6817 met the inclusion criteria for this study. There were 2951 (43%) patients included in the pre-treatment group and 3866 (57%) patients in the no pre-treatment group. There were differences in baseline clinical characteristics (Table 1). The pre-treatment group was younger (64.9 ± 12.3 vs 65.4 ± 2.1, P = 0.04) and more likely to have a history of MI (35.6% vs 23.6%, P < 0.01), hypertension
© 2015 Royal Australasian College of Physicians
1033
Yudi et al.
Table 1 Clinical characteristics of n = 6817 patients undergoing PCI by clopidogrel pre-treatment Pre-treatment (n = 2951)
Clinical characteristics Age (years ± SD) Age > 75 years Male Hypertension Hypercholesterolemia Diabetes mellitus Current smoker Previous MI Previous CABG eGFR ≥ 60 mL/min/m2 eGFR < 60 mL/min/m2 Presentation and angiographic characteristics Unstable angina NSTEMI Balloon angioplasty only Bare metal stent Drug eluting stent Glycoprotein IIb/IIIa use PCI within 24 h of admission
P value
%
No pre-treatment (n = 3866) %
64.9 ± 12.3 25.4 73.1 69.9 75.6 27.9 23.4 35.6 10.9 76.4 23.6
65.4 ± 12.1 27.0 72.4 67.1 71.8 26.4 25.1 23.6 9.6 74.9 25.1
0.04 0.15 0.5 0.02
