- Email: [email protected]
Prevention of vascular events in atrial fibrillation – Authors' reply
Correspondence
[email protected] The Allen Pavilion, Columbia University Medical Center, 5141 Broadway, New York, NY 10034-1159 1
2
3
The ACTIVE Writing Group on behalf of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367: 1903–12. Levine MN, Raskob G, Beyth RJ, et al. Hemorrhagic complications of anticoagulant treatment-the seventh ACCP conference on antithromotic and thrombolytic therapy. Chest 2004; 126: 287S–310S. Gage BF, Birman-Deych E, Kerzner R, et al. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med 2005; 118: 612–17.
The ACTIVE investigators1 found oral anticoagulation to be superior to dual antiplatelet therapy for prevention of vascular events in atrial fibrillation. Although not a primary outcome measure, the investigators place some store on the lower risk of major bleeding with oral anticoagulants in patients already taking them. Freek Verheugt, in the accompanying Comment,2 is right to point out the seminal trials illustrating the increased bleeding sequelae of dual therapy. In comparison with other large cardiovascular trials, we note that the ACTIVE investigators are assiduous in excluding patients with documented peptic ulcer disease. They have shown a significant reduction in minor bleeding in those receiving oral anticoagulants (568 vs 481, p=0·0009). The CURE trial found that any excess bleeding in patients treated with clopidogrel was due to gastrointestinal bleeding and bleeding at an arterial puncture site.3 We suggest that the criteria for classifying bleeding (both major and minor) does not accurately reflect the diverse range of complications included. Major bleeding includes causes as diverse as intracranial haemorrhage, substantial hypotension, and a haemoglobin drop of more than 50 g/L. The TIMI classification4 is equally hampered in this regard. Anticoagulation and antiplatelet therapy both remain mainstays of 106
the management of many vascular entities. Previous studies have shown the efficacy of proton-pump inhibitors for aspirin-induced ulcers.5 We feel that inclusion of such gastroprotective agents should be considered in clinical trials and real life. We would argue that gastrointestinal, and not just vascular, outcomes are a priority and that complete studied breakdown of the ensuing complications is essential. We declare that we have no conflict of interest.
Andrew King, *Neeraj Bhala [email protected] Department of Gastroenterology, Walsgrave Hospital, University Hospital of Coventry and Warwick, Coventry CV2 2DX, UK 1
2
3
4
5
The ACTIVE Writing Group on behalf of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367: 1903–12. Verheugt FWA. Good old warfarin for stroke prevention in atrial fibrillation. Lancet 2006; 367: 1877–78. The CURE investigators. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (CURE). N Engl J Med 2001; 345: 494–502. Committee for Acute Coronary Syndromes Clinical Data Standards. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. J Am Coll Cardiol 2001; 38: 2114–30. Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med 2005; 352: 238–44.
intolerance to warfarin. Among those older than 80 years, falling was the most common contraindication to warfarin therapy. ACTIVE has collected extensive information on history of falling and falling during followup. These data will be analysed in a subsequent paper. We agree with Andrew King and Neeraj Bhala that understanding bleeding outcomes is a priority and that major haemorrhage can have serious long-term consequences. A detailed analysis and evaluation of all bleeding outcomes in ACTIVE W is planned for future publication. SC and SY received a research grant from SanofiAventis and Bristol Myers Squibb to perform the ACTIVE study.
*Stuart Connolly, Salim Yusuf, on behalf of the ACTIVE Investigators [email protected] Division of Cardiology, McMaster University, Hamilton, Ontario L8L 2X2, Canada 1
Hylek EM, D’Antonio J, Evans-Molina C, Shea C, Henault LE, Regan S. Translating the results of randomized trials into clinicalpractice: the challenge of warfarin candidacy aong hospitalized elderly patients with atrial fibrillation. Stroke 2006; 37: 1075–80.
Authors’ reply Huai yong Chen draws attention to the interesting finding in ACTIVE W that, compared with clopidogrel plus aspirin, oral anticoagulation reduces ischaemic stroke but increases the risk of haemorrhagic stroke. As patients age, the risk of major haemorrhage also increases, and ACTIVE W, with relatively short follow-up, might have failed to capture the adverse potential of both treatments that might occur in very elderly patients. Hylek and colleagues1 have reported that half of patients older than 65 years with atrial fibrillation, admitted to hospital not on warfarin, had contraindications to warfarin or previously documented
Department of Error GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico). Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSIPrevenzione trial. Lancet 1999; 354: 447–55—In this Article (Aug 7, 1999), the third sentence of the Introduction (p 447) should have read: “Although no consensus existed on the underlying mechanism of action, focus was placed on the ability of high-dose n-3 PUFA to lower triglycerides (registration approval was given for this indication), and to modify membrane composition.”
www.thelancet.com Vol 369 January 13, 2007
[email protected] The Allen Pavilion, Columbia University Medical Center, 5141 Broadway, New York, NY 10034-1159 1
2
3
The ACTIVE Writing Group on behalf of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367: 1903–12. Levine MN, Raskob G, Beyth RJ, et al. Hemorrhagic complications of anticoagulant treatment-the seventh ACCP conference on antithromotic and thrombolytic therapy. Chest 2004; 126: 287S–310S. Gage BF, Birman-Deych E, Kerzner R, et al. Incidence of intracranial hemorrhage in patients with atrial fibrillation who are prone to fall. Am J Med 2005; 118: 612–17.
The ACTIVE investigators1 found oral anticoagulation to be superior to dual antiplatelet therapy for prevention of vascular events in atrial fibrillation. Although not a primary outcome measure, the investigators place some store on the lower risk of major bleeding with oral anticoagulants in patients already taking them. Freek Verheugt, in the accompanying Comment,2 is right to point out the seminal trials illustrating the increased bleeding sequelae of dual therapy. In comparison with other large cardiovascular trials, we note that the ACTIVE investigators are assiduous in excluding patients with documented peptic ulcer disease. They have shown a significant reduction in minor bleeding in those receiving oral anticoagulants (568 vs 481, p=0·0009). The CURE trial found that any excess bleeding in patients treated with clopidogrel was due to gastrointestinal bleeding and bleeding at an arterial puncture site.3 We suggest that the criteria for classifying bleeding (both major and minor) does not accurately reflect the diverse range of complications included. Major bleeding includes causes as diverse as intracranial haemorrhage, substantial hypotension, and a haemoglobin drop of more than 50 g/L. The TIMI classification4 is equally hampered in this regard. Anticoagulation and antiplatelet therapy both remain mainstays of 106
the management of many vascular entities. Previous studies have shown the efficacy of proton-pump inhibitors for aspirin-induced ulcers.5 We feel that inclusion of such gastroprotective agents should be considered in clinical trials and real life. We would argue that gastrointestinal, and not just vascular, outcomes are a priority and that complete studied breakdown of the ensuing complications is essential. We declare that we have no conflict of interest.
Andrew King, *Neeraj Bhala [email protected] Department of Gastroenterology, Walsgrave Hospital, University Hospital of Coventry and Warwick, Coventry CV2 2DX, UK 1
2
3
4
5
The ACTIVE Writing Group on behalf of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367: 1903–12. Verheugt FWA. Good old warfarin for stroke prevention in atrial fibrillation. Lancet 2006; 367: 1877–78. The CURE investigators. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (CURE). N Engl J Med 2001; 345: 494–502. Committee for Acute Coronary Syndromes Clinical Data Standards. American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes. J Am Coll Cardiol 2001; 38: 2114–30. Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med 2005; 352: 238–44.
intolerance to warfarin. Among those older than 80 years, falling was the most common contraindication to warfarin therapy. ACTIVE has collected extensive information on history of falling and falling during followup. These data will be analysed in a subsequent paper. We agree with Andrew King and Neeraj Bhala that understanding bleeding outcomes is a priority and that major haemorrhage can have serious long-term consequences. A detailed analysis and evaluation of all bleeding outcomes in ACTIVE W is planned for future publication. SC and SY received a research grant from SanofiAventis and Bristol Myers Squibb to perform the ACTIVE study.
*Stuart Connolly, Salim Yusuf, on behalf of the ACTIVE Investigators [email protected] Division of Cardiology, McMaster University, Hamilton, Ontario L8L 2X2, Canada 1
Hylek EM, D’Antonio J, Evans-Molina C, Shea C, Henault LE, Regan S. Translating the results of randomized trials into clinicalpractice: the challenge of warfarin candidacy aong hospitalized elderly patients with atrial fibrillation. Stroke 2006; 37: 1075–80.
Authors’ reply Huai yong Chen draws attention to the interesting finding in ACTIVE W that, compared with clopidogrel plus aspirin, oral anticoagulation reduces ischaemic stroke but increases the risk of haemorrhagic stroke. As patients age, the risk of major haemorrhage also increases, and ACTIVE W, with relatively short follow-up, might have failed to capture the adverse potential of both treatments that might occur in very elderly patients. Hylek and colleagues1 have reported that half of patients older than 65 years with atrial fibrillation, admitted to hospital not on warfarin, had contraindications to warfarin or previously documented
Department of Error GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico). Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSIPrevenzione trial. Lancet 1999; 354: 447–55—In this Article (Aug 7, 1999), the third sentence of the Introduction (p 447) should have read: “Although no consensus existed on the underlying mechanism of action, focus was placed on the ability of high-dose n-3 PUFA to lower triglycerides (registration approval was given for this indication), and to modify membrane composition.”
www.thelancet.com Vol 369 January 13, 2007