Kamal, Ayeesha Kamran

Khan, Maria

eCommons@AKU

eCommons@AKUDepartment of Medicine Department of MedicineMarch 2011Atrial fibrillation, is warfarin the only option forstroke prevention?Maria KhanAga Khan UniversityAyeesha Kamran KamalAgha Khan University, ayeesha.kamal@aku.eduFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_med_medPart of the Neurology CommonsRecommended CitationKhan, M., Kamal, A. (2011). Atrial fibrillation, is warfarin the only option for stroke prevention?. JPMA. The Journal of the PakistanMedical Association, 61(3), 301-302.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_med_med/383Atrial Fibrillation Clopidogrel Trialwith Irbesartan for prevention ofvascular events-activeWhy is this study important andnoteworthy?Atrial fibrillation is the most common cardiacarrhythmia with a potential for serious adverse events likestroke. The annual rate of stroke with AF is around 4.5% andincreases in patients older than 75 years of age. Warfarin haslong been established as the treatment of choice for strokeprevention in patients with AF. However, there are severalissues with oral anticoagulation. Firstly, there is an increasedrisk of haemorrhagic complications, secondly INR'scommonly fall out of range due to drug and food interactionsand require major lifestyle adjustment to accommodatefrequent testing. As a result investigators have tried to exploreoptions other than Warfarin to prevent cerebrovascularevents. Several studies have compared varying doses ofAspirin to oral anticoagulation and a meta-analysis concludedthat Warfarin was superior in terms of preventingcerebrovascular events but increased the risk of haemorrhage.Clopidogrel added to aspirin had been found superiorto aspirin in some cardiology trials. Therefore theinvestigators for ACTIVE also decided to explore whetherthe combination of clopidogrel and aspirin was any match towarfarin in patients with AF.The trial had a third arm in which irbesartan which isan ACE inhibitor was given to half the patients in a factorialdesign, on the pretext that hypertension increases the risk ofstroke in patients with AF. The results of this trial are stillawaited.Who were the participants?ACTIVE included three separate interrelated trials.ACTIVE W was an open label non-inferiority trial in whichclopidogrel plus ASA was compared to oral anticoagulationin patients with AF and at least 1 risk factor for stroke.ACTIVE A included patients with AF and at least 1 risk factorfor stroke who received ASA because they had acontraindication to oral anticoagulation or because they wereunwilling to take an oral anticoagulant and half of themreceived clopidogrel in a double blind placebo controlledmanner. ACTIVE I was a partial factorial, double-blind,placebo-controlled trial of irbesartan in patients participatingin ACTIVE A or ACTIVE W.The study was a multicenter trial performed at 580centers in 33 countries. Patients were eligible if they hadECG evidence of AF and at least one risk factor for stroke. Ifthey were less than 75 years of age, they had to have eitherDM or CAD. They were excluded from ACTIVE A if theyhad any contraindication to clopidogrel and from ACTIVE Wif they had contraindication to oral anticoagulation. ACTIVEI is not described here as the results from it are still awaited.What was the intervention?In ACTIVE W, 3371 patients were assigned to oralanticoagulation (keeping INR between 2 and 3) and 3335 toa combination of Aspirin 75-100mg and Clopidogrel 75mg.They were followed up for a median of 1.28 years.ACTIVE A included patients who had had AF andwere at increased risk for stroke but were consideredunsuitable for oral anticoagulation. In ACTIVE A, 3772patients were randomized to receive clopidogrel 75mg plusaspirin 75-100mg and 3782 were assigned to placebo plusaspirin 75-100mg. Both groups were followed up for amedian of 3.6 years.What was the outcome?In ACTIVE W there were 164 primary outcomeevents (stroke, non-CNS systemic embolus, myocardialinfarction, or vascular death) on oral anticoagulation therapy(annual risk 3.9%) compared with 234 events on clopidogrelplus aspirin (annual risk 5.6%; relative risk [RR] 1.44, 95%CI 1.18-1.76; p=0.0003).Oral anticoagulation was mostprotective against stroke (RR 1.72, 95% CI 1.24-2.37;p=0.001) and non-CNS systemic embolism (4.66, 1.58-13.8;p=0.005). Rates of major haemorrhage were similar in thetwo groups. However, total as well as minor bleeds weresignificantly more common with clopidogrel plus aspirin thanwith oral anticoagulation therapy (RR 1.21 and 1.23 andp=0.001 and p=0.0009 respectively).In ACTIVE A there were 832 primary outcome events(stroke, MI, systemic embolism and death) in the aspirin plusclopidogrel arm and 924 events in the aspirin plus placeboarm (RR 0.89, p=0.01). The greatest benefit of thecombination was seen in stroke with a RR of 0.72 andVol. 61, No. 3, March 2011 301Evidence Based MedicineAtrial Fibrillation, is Warfarin the only option for stroke prevention?Maria Khan, Ayeesha Kamran KamalDirector Stroke Service and Vascular Fellowship Program, Aga Khan University Hospital, Karachi, Pakistan.p<0.001. However, the rate of major haemorrhage alsoincreased significantly with the combination. Therefore, oncombining the major vascular events and majorhaemorrhages, the number of events in the two groups werenot significantly different (A+C 968 vs. A 996 events; p =0.54). The addition of clopidogrel to aspirin reduced the rateof major vascular events from 7.6% per year to 6.8%, but therate of haemorrhage increased from 1.3% to 2.0% per year. What were the conclusions?ACTIVE W concluded that oral anticoagulationtherapy is superior to clopidogrel plus aspirin for preventionof vascular events in patients with atrial fibrillation at highrisk of stroke who do not have contraindications to oralanticoagulation therapy. The trial failed to show mortalitybenefit with Warfarin. The number needed to be treated for 1year with anticoagulation to prevent one stroke is about 100.ACTIVE A concluded that a combination of aspirinand clopidogrel is superior to aspirin alone for preventing allvascular events and particularly strokes. However, thisadvantage is offset by the risk of excess bleeding with thecombination.How does this impact our clinical practice?The clear advantage of oral anticoagulation for AFwas re-demonstrated in ACTIVE W. Therefore for patientswith AF at risk of stroke, and with no contraindications toanticoagulation, Warfarin remains the drug of choice.In our setting, putting patients on Warfarin is perhapsa bigger challenge than it is in the West. Reasons for thisinclude lack of education regarding the drug, lack of properfollow up, and sub standard medicines and laboratory testing.For all these reasons, oral anticoagulation is often notsafe. For those with a clear cut contraindication to Warfarin,a combination of aspirin and clopidogrel confers greaterprotection against vascular events compared to aspirin alone.However, given the increased risk of haemorrhage with thecombination, this decision should be based upon the absoluterisks of stroke and bleeding and the relative risk and benefitfor an individual patient.Recommended Reading1. The ACTIVE steering committee. Rationale and design of ACTIVE: the atrialfibrillation clopidogrel trial with irbesartan for prevention of vascular events.Am Heart J 2006; 151: 1187-93. 2. Connolly SJ, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Yusuf S.Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in theAtrial fibrillation clopidogrel trial with irbesartan for prevention of vascularevents (ACTIVE). Lancet 2006; 367: 1903-12.3. Healey JS, Hart RG, Pogue J, Pfeffer MA, Hohnloser SH, De Caterina R,Flaker G, Yusuf S, Connolly SJ. Risks and benefits of oral anticoagulationcompared with clopidogrel plus aspirin in patients with atrial fibrillationaccording to stroke risk: the atrial fibrillation clopidogrel trial withirbresartan for prevention of vascular events (ACTIVE-W). Stroke 2008;39: 1482-6.4. Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M, Chrolavicius S, YusufS. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. NEngl J Med 2009; 360: 2066-78.302 J Pak Med Assoc

English

Atrial fibrillation, is warfarin the only option for stroke prevention?

eCommons@AKUSection of Neurology Department of MedicineMarch 2011Atrial fibrillation, is warfarin the only option forstroke preventionMaria KhanAga Khan UniversityAyeesha Kamran KamalAga Khan UniversityFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_med_neurolPart of the Neurology CommonsRecommended CitationKhan, M., Kamal, A. (2011). Atrial fibrillation, is warfarin the only option for stroke prevention. Journal of the Pakistan MedicalAssociation, 61(3), 301-2.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_med_neurol/15Atrial Fibrillation Clopidogrel Trialwith Irbesartan for prevention ofvascular events-activeWhy is this study important andnoteworthy?Atrial fibrillation is the most common cardiacarrhythmia with a potential for serious adverse events likestroke. The annual rate of stroke with AF is around 4.5% andincreases in patients older than 75 years of age. Warfarin haslong been established as the treatment of choice for strokeprevention in patients with AF. However, there are severalissues with oral anticoagulation. Firstly, there is an increasedrisk of haemorrhagic complications, secondly INR'scommonly fall out of range due to drug and food interactionsand require major lifestyle adjustment to accommodatefrequent testing. As a result investigators have tried to exploreoptions other than Warfarin to prevent cerebrovascularevents. Several studies have compared varying doses ofAspirin to oral anticoagulation and a meta-analysis concludedthat Warfarin was superior in terms of preventingcerebrovascular events but increased the risk of haemorrhage.Clopidogrel added to aspirin had been found superiorto aspirin in some cardiology trials. Therefore theinvestigators for ACTIVE also decided to explore whetherthe combination of clopidogrel and aspirin was any match towarfarin in patients with AF.The trial had a third arm in which irbesartan which isan ACE inhibitor was given to half the patients in a factorialdesign, on the pretext that hypertension increases the risk ofstroke in patients with AF. The results of this trial are stillawaited.Who were the participants?ACTIVE included three separate interrelated trials.ACTIVE W was an open label non-inferiority trial in whichclopidogrel plus ASA was compared to oral anticoagulationin patients with AF and at least 1 risk factor for stroke.ACTIVE A included patients with AF and at least 1 risk factorfor stroke who received ASA because they had acontraindication to oral anticoagulation or because they wereunwilling to take an oral anticoagulant and half of themreceived clopidogrel in a double blind placebo controlledmanner. ACTIVE I was a partial factorial, double-blind,placebo-controlled trial of irbesartan in patients participatingin ACTIVE A or ACTIVE W.The study was a multicenter trial performed at 580centers in 33 countries. Patients were eligible if they hadECG evidence of AF and at least one risk factor for stroke. Ifthey were less than 75 years of age, they had to have eitherDM or CAD. They were excluded from ACTIVE A if theyhad any contraindication to clopidogrel and from ACTIVE Wif they had contraindication to oral anticoagulation. ACTIVEI is not described here as the results from it are still awaited.What was the intervention?In ACTIVE W, 3371 patients were assigned to oralanticoagulation (keeping INR between 2 and 3) and 3335 toa combination of Aspirin 75-100mg and Clopidogrel 75mg.They were followed up for a median of 1.28 years.ACTIVE A included patients who had had AF andwere at increased risk for stroke but were consideredunsuitable for oral anticoagulation. In ACTIVE A, 3772patients were randomized to receive clopidogrel 75mg plusaspirin 75-100mg and 3782 were assigned to placebo plusaspirin 75-100mg. Both groups were followed up for amedian of 3.6 years.What was the outcome?In ACTIVE W there were 164 primary outcomeevents (stroke, non-CNS systemic embolus, myocardialinfarction, or vascular death) on oral anticoagulation therapy(annual risk 3.9%) compared with 234 events on clopidogrelplus aspirin (annual risk 5.6%; relative risk [RR] 1.44, 95%CI 1.18-1.76; p=0.0003).Oral anticoagulation was mostprotective against stroke (RR 1.72, 95% CI 1.24-2.37;p=0.001) and non-CNS systemic embolism (4.66, 1.58-13.8;p=0.005). Rates of major haemorrhage were similar in thetwo groups. However, total as well as minor bleeds weresignificantly more common with clopidogrel plus aspirin thanwith oral anticoagulation therapy (RR 1.21 and 1.23 andp=0.001 and p=0.0009 respectively).In ACTIVE A there were 832 primary outcome events(stroke, MI, systemic embolism and death) in the aspirin plusclopidogrel arm and 924 events in the aspirin plus placeboarm (RR 0.89, p=0.01). The greatest benefit of thecombination was seen in stroke with a RR of 0.72 andVol. 61, No. 3, March 2011 301Evidence Based MedicineAtrial Fibrillation, is Warfarin the only option for stroke prevention?Maria Khan, Ayeesha Kamran KamalDirector Stroke Service and Vascular Fellowship Program, Aga Khan University Hospital, Karachi, Pakistan.p<0.001. However, the rate of major haemorrhage alsoincreased significantly with the combination. Therefore, oncombining the major vascular events and majorhaemorrhages, the number of events in the two groups werenot significantly different (A+C 968 vs. A 996 events; p =0.54). The addition of clopidogrel to aspirin reduced the rateof major vascular events from 7.6% per year to 6.8%, but therate of haemorrhage increased from 1.3% to 2.0% per year. What were the conclusions?ACTIVE W concluded that oral anticoagulationtherapy is superior to clopidogrel plus aspirin for preventionof vascular events in patients with atrial fibrillation at highrisk of stroke who do not have contraindications to oralanticoagulation therapy. The trial failed to show mortalitybenefit with Warfarin. The number needed to be treated for 1year with anticoagulation to prevent one stroke is about 100.ACTIVE A concluded that a combination of aspirinand clopidogrel is superior to aspirin alone for preventing allvascular events and particularly strokes. However, thisadvantage is offset by the risk of excess bleeding with thecombination.How does this impact our clinical practice?The clear advantage of oral anticoagulation for AFwas re-demonstrated in ACTIVE W. Therefore for patientswith AF at risk of stroke, and with no contraindications toanticoagulation, Warfarin remains the drug of choice.In our setting, putting patients on Warfarin is perhapsa bigger challenge than it is in the West. Reasons for thisinclude lack of education regarding the drug, lack of properfollow up, and sub standard medicines and laboratory testing.For all these reasons, oral anticoagulation is often notsafe. For those with a clear cut contraindication to Warfarin,a combination of aspirin and clopidogrel confers greaterprotection against vascular events compared to aspirin alone.However, given the increased risk of haemorrhage with thecombination, this decision should be based upon the absoluterisks of stroke and bleeding and the relative risk and benefitfor an individual patient.Recommended Reading1. The ACTIVE steering committee. Rationale and design of ACTIVE: the atrialfibrillation clopidogrel trial with irbesartan for prevention of vascular events.Am Heart J 2006; 151: 1187-93. 2. Connolly SJ, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Yusuf S.Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in theAtrial fibrillation clopidogrel trial with irbesartan for prevention of vascularevents (ACTIVE). Lancet 2006; 367: 1903-12.3. Healey JS, Hart RG, Pogue J, Pfeffer MA, Hohnloser SH, De Caterina R,Flaker G, Yusuf S, Connolly SJ. Risks and benefits of oral anticoagulationcompared with clopidogrel plus aspirin in patients with atrial fibrillationaccording to stroke risk: the atrial fibrillation clopidogrel trial withirbresartan for prevention of vascular events (ACTIVE-W). Stroke 2008;39: 1482-6.4. Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M, Chrolavicius S, YusufS. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. NEngl J Med 2009; 360: 2066-78.302 J Pak Med Assoc

Atrial fibrillation, is warfarin the only option for stroke prevention

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Atrial fibrillation, is warfarin the only option for stroke prevention

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