- Email: [email protected]
Double-dose clopidogrel in patients undergoing PCI for ACS – Authors' reply
Correspondence
Authors’ reply Francois Schiele questions how best to incorporate the results of the CURRENTOASIS 7 trial into clinical practice given the clear benefit of the doubledose clopidogrel regimen in those undergoing percutaneous coronary intervention (PCI) reported in The Lancet1 and the neutral results in the overall cohort of patients simultaneously reported in the New England Journal of Medicine.2 The report in The Lancet focused on the 17 263 patients enrolled in the CURRENT-OASIS 7 study who underwent PCI, and it showed that the double-dose regimen reduced definite stent thrombosis by 46% (p=0·0001) and the primary outcome of cardiovascular death, myocardial infarction, or stroke by 15% (p=0·039). Of the remaining patients who did not undergo PCI, 5379 did not have clinically significant coronary artery disease or received only one dose of study drug because of planned coronaryartery bypass graft surgery and thus could not be expected to benefit from a more potent antiplatelet dosing regimen. However, administration of an initial 600 mg of clopidogrel in these patients at the time of presentation did not increase bleeding in the lead-up to coronary angiography,2 supporting our interpretation that all patients presenting with acute coronary syndromes (ACS) who are planned for early invasive management should be considered for a 600 mg loading dose at first medical contact. Double-dose clopidogrel can be discontinued after coronary angiography in patients who do not proceed to PCI. This approach will maximise the benefit and minimise the harm associated with the higher dosing regimen. On the basis of the finding of a statistical interaction between aspirin and clopidogrel in the CURRENTOASIS 7 trial, Schiele concludes that the benefits of double-dose clopidogrel are confined to patients also receiving aspirin at a dose of 300–325 mg per day. An interaction between two treatments in a 2×2 factorial design 298
trial is not same as an additive effect of the two treatments. We believe that a conservative interpretation of this interaction is warranted since it lacks a known biological mechanism and was only nominally significant. For those who wish to interpret the results of the trial according to the four randomised groups, we agree that there seems to be no major downside to treating patients with ACS with the higher dose of aspirin for the first 30 days plus the double dose of clopidogrel for 7 days. Vassilis Vassiliou questions the separate publication of the PCI cohort in the CURRENT-OASIS 7 trial, but we believe that these data merit full disclosure because they are compelling, important for patients’ care, and instructive on how best to dose clopidogrel in patients with ACS. We are also pleased that we were able to include data on use of proton-pump inhibitors (PPIs) in the final consecutive 18 430 patients enrolled in the trial, including 12 365 patients undergoing PCI.1,2 Because the question of an interaction between PPIs and clopidogrel was not apparent until after the trial had started, PPIs were not included as a data point in the case report forms in the first 6656 patients enrolled in the trial. Our findings of no interaction between PPI and clopidogrel treatment in this large cohort of patients is consistent with the results of other large-scale observational analyses3 as well as those of the COGENT randomised trial4 and support the conclusions of a 2010 expert consensus document5 that the pharmacodynamic drug interaction between clopidogrel and PPIs is not clinically relevant. SRM reports receiving institutional research grants from Sanofi-Aventis and Bristol-Myers Squibb; and consulting fees or honoraria from AstraZeneca, Astellas, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Pfizer, and Sanofi-Aventis. JWE reports receiving institutional research grants from Bristol-Myers Squibb and Sanofi-Aventis; consulting fees or honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, and Sanofi-Aventis; and is a member of the advisory board for Bristol-Myers Squibb and Sanofi-Aventis. SY reports receiving institutional research grants from Sanofi-Aventis and Bristol-Myers Squibb; and consulting fees or honoraria
from Sanofi-Aventis, Bristol-Myers Squibb, Novartis, AstraZeneca, Boehringer Ingelheim, and Novartis.
*Shamir R Mehta, John W Eikelboom, Salim Yusuf [email protected] McMaster University, Hamilton, ON L8L 2X2, Canada 1
2
3
4
5
Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010; 376: 1233–43. CURRENT-OASIS 7 Investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010; 363: 930–42. O’Donoghue ML, Braunwald E, Antman EA, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet 2009; 374: 989–97. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363: 1909–17. Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. J Am Coll Cardiol 2010; 56: 2051–66.
Watch out for the even eviler cousin—sorbitolfermenting E coli O157 Hugh Pennington’s thorough review (Oct 23, p 1428)1 focuses on classic (ie, non-sorbitol-fermenting) enterohaemorrhagic Escherichia coli O157:H7, the main cause of haemolytic uraemic syndrome (HUS) worldwide. However, its phylogenetically close relative, sorbitol-fermenting E coli O157:NM (non-motile), warrants note. Sorbitol-fermenting E coli O157 accounts for 17% of sporadic cases of HUS2 and caused seven outbreaks in Germany between 1988 and 2009, the largest of which involved 38 cases of HUS.3 A large outbreak also occurred recently in the UK.4 Several features distinguish sorbitol-fermenting E coli O157 from its prominent cousin, E coli O157:H7. First, outbreaks caused by sorbitol-fermenting O157 strains www.thelancet.com Vol 377 January 22, 2011
Authors’ reply Francois Schiele questions how best to incorporate the results of the CURRENTOASIS 7 trial into clinical practice given the clear benefit of the doubledose clopidogrel regimen in those undergoing percutaneous coronary intervention (PCI) reported in The Lancet1 and the neutral results in the overall cohort of patients simultaneously reported in the New England Journal of Medicine.2 The report in The Lancet focused on the 17 263 patients enrolled in the CURRENT-OASIS 7 study who underwent PCI, and it showed that the double-dose regimen reduced definite stent thrombosis by 46% (p=0·0001) and the primary outcome of cardiovascular death, myocardial infarction, or stroke by 15% (p=0·039). Of the remaining patients who did not undergo PCI, 5379 did not have clinically significant coronary artery disease or received only one dose of study drug because of planned coronaryartery bypass graft surgery and thus could not be expected to benefit from a more potent antiplatelet dosing regimen. However, administration of an initial 600 mg of clopidogrel in these patients at the time of presentation did not increase bleeding in the lead-up to coronary angiography,2 supporting our interpretation that all patients presenting with acute coronary syndromes (ACS) who are planned for early invasive management should be considered for a 600 mg loading dose at first medical contact. Double-dose clopidogrel can be discontinued after coronary angiography in patients who do not proceed to PCI. This approach will maximise the benefit and minimise the harm associated with the higher dosing regimen. On the basis of the finding of a statistical interaction between aspirin and clopidogrel in the CURRENTOASIS 7 trial, Schiele concludes that the benefits of double-dose clopidogrel are confined to patients also receiving aspirin at a dose of 300–325 mg per day. An interaction between two treatments in a 2×2 factorial design 298
trial is not same as an additive effect of the two treatments. We believe that a conservative interpretation of this interaction is warranted since it lacks a known biological mechanism and was only nominally significant. For those who wish to interpret the results of the trial according to the four randomised groups, we agree that there seems to be no major downside to treating patients with ACS with the higher dose of aspirin for the first 30 days plus the double dose of clopidogrel for 7 days. Vassilis Vassiliou questions the separate publication of the PCI cohort in the CURRENT-OASIS 7 trial, but we believe that these data merit full disclosure because they are compelling, important for patients’ care, and instructive on how best to dose clopidogrel in patients with ACS. We are also pleased that we were able to include data on use of proton-pump inhibitors (PPIs) in the final consecutive 18 430 patients enrolled in the trial, including 12 365 patients undergoing PCI.1,2 Because the question of an interaction between PPIs and clopidogrel was not apparent until after the trial had started, PPIs were not included as a data point in the case report forms in the first 6656 patients enrolled in the trial. Our findings of no interaction between PPI and clopidogrel treatment in this large cohort of patients is consistent with the results of other large-scale observational analyses3 as well as those of the COGENT randomised trial4 and support the conclusions of a 2010 expert consensus document5 that the pharmacodynamic drug interaction between clopidogrel and PPIs is not clinically relevant. SRM reports receiving institutional research grants from Sanofi-Aventis and Bristol-Myers Squibb; and consulting fees or honoraria from AstraZeneca, Astellas, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Pfizer, and Sanofi-Aventis. JWE reports receiving institutional research grants from Bristol-Myers Squibb and Sanofi-Aventis; consulting fees or honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, and Sanofi-Aventis; and is a member of the advisory board for Bristol-Myers Squibb and Sanofi-Aventis. SY reports receiving institutional research grants from Sanofi-Aventis and Bristol-Myers Squibb; and consulting fees or honoraria
from Sanofi-Aventis, Bristol-Myers Squibb, Novartis, AstraZeneca, Boehringer Ingelheim, and Novartis.
*Shamir R Mehta, John W Eikelboom, Salim Yusuf [email protected] McMaster University, Hamilton, ON L8L 2X2, Canada 1
2
3
4
5
Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial. Lancet 2010; 376: 1233–43. CURRENT-OASIS 7 Investigators. Dose comparisons of clopidogrel and aspirin in acute coronary syndromes. N Engl J Med 2010; 363: 930–42. O’Donoghue ML, Braunwald E, Antman EA, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet 2009; 374: 989–97. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363: 1909–17. Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. J Am Coll Cardiol 2010; 56: 2051–66.
Watch out for the even eviler cousin—sorbitolfermenting E coli O157 Hugh Pennington’s thorough review (Oct 23, p 1428)1 focuses on classic (ie, non-sorbitol-fermenting) enterohaemorrhagic Escherichia coli O157:H7, the main cause of haemolytic uraemic syndrome (HUS) worldwide. However, its phylogenetically close relative, sorbitol-fermenting E coli O157:NM (non-motile), warrants note. Sorbitol-fermenting E coli O157 accounts for 17% of sporadic cases of HUS2 and caused seven outbreaks in Germany between 1988 and 2009, the largest of which involved 38 cases of HUS.3 A large outbreak also occurred recently in the UK.4 Several features distinguish sorbitol-fermenting E coli O157 from its prominent cousin, E coli O157:H7. First, outbreaks caused by sorbitol-fermenting O157 strains www.thelancet.com Vol 377 January 22, 2011