Eugene Crystal, Stuart J Connolly

Transcription

1 General ardiology ROLE OF ORAL ANTICOAGULATION IN MANAGEMENT OF ATRIAL FIBRILLATION PREVENTION See end of artile for authors affiliations Correspondene to: Eugene Crystal, MD, Division of Cardiology, Sunnybrook and Womens College Health Siene Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada; eugene. A Eugene Crystal, Stuart J Connolly Heart 2004; 90: doi: /hrt trial fibrillation (AF) is the most ommon serious ardia arrhythmia, with an estimated prevalene of two million in the USA. 1 AF arries signifiantly inreased risk of morbidity and mortality, a major omponent of whih is a fivefold inrease in the frequeny of stroke. 2 Non-rheumati AF is probably responsible for 15 20% of erebrovasular aidents of ishaemi origin. 3 w1 The risk of emboli stroke in the general population inreases with age; in people over the age of 75 years AF is one of the most important auses of emboli stroke. 4 A majority of the erebrovasular events in AF patients are ishaemi. 5 A prinipal mehanism responsible for ishaemi stroke in AF is embolism seondary to the stasis in the left atrium, speifially in the left atrial appendage. Thrombogenesis in AF patients is orrelated with low flow veloities in the appendage. w2 The left atrial appendage is the almost exlusive loation of intraardia thrombus in patients with AF. w3 Overall in AF, two thirds of the ishaemi erebrovasular events and perhaps half of all vasular events are related to the atrial thrombi. 4 The other impliated ause of stroke in AF patients is oexisting atheroslerosis of the large arteries and valvar abnormalities. Indeed, many of the patients with AF are at inreased risk of signifiant arotid disease. w4 Notably, the major risk fators for stroke in patients with AF are the same as the risk fators for aelerated atheroslerosis (table 1). Clinially ative atherosleroti disease is very ommon in patients with AF. In the SPAF (stroke prevention in atrial fibrillation) trial (mean age of patients 67 years) 10% of patients had ative angina, 8% had had a myoardial infartion, and 12% had signifiantly dereased left ventriular funtion. 6 The overall mortality in plaebo treated patients with AF was 3.1% annually, with seven out of eight fatal events being of ardiovasular origin. Some experimental data suggest that AF related haemodynamis may atually inrease the propensity for arterial thrombosis in narrowed vessels. w5 The risk of stroke varies signifiantly between patients with AF. The main risk fators identified in two major studies addressing the issue in AF patients are presented in table 1. The history of prior emboli event and age are the two most powerful preditors of inreased risk of stroke in non-valvar AF. OF STROKE IN AF PATIENTS The goal of dereasing the risk of stroke in AF has been approahed with two treatment onepts: antiarrhythmi therapy (aimed at suppression of AF, also known as rhythm ontrol), and antithromboti treatment (aimed at suppression of oagulation asade and platelet ativation). w6 Mehanial approahes, based on the obstrution of the left atrial appendage, are now w3 w7 w8 also under evaluation. Four very reent randomised trials examined whether rhythm ontrol is able to derease the risk of death or emboli stroke in AF 6 9 when ompared to rate ontrol alone. All of these trials onsistently reported failure to derease the risk of emboli events in AF patients. Therefore, the only urrently redible option for preventing vasular events in AF patients is antithromboti treatment, whih is the fous of this review. ORAL ANTICOAGULANTS The oumarin antioagulants inlude warfarin, diumarol, and several related ompounds. Their main mehanism of ation is prevention of the intrahepati metabolism of vitamin K epoxides, and an indution of vitamin K defiieny. As a result, thrombin generation slows, and lot formation beomes impaired due to dereased biologi ativity of the prothrombin omplex proteins. The effet of vitamin K antagonists is gradual and reversible. It takes several days before an adequate level of antioagulation is ahieved, and for the antioagulant effet to disappear after drug disontinuation. The therapeuti effet of oral antioagulants (OACs) is measured by monitoring the prothrombin time. OAC dosage must be adjusted to ahieve a narrow range of the desired prothrombin time values, usually expressed as the international normalised ratio (INR). Thromboplastins, the essential reagent for prothrombin time testing, vary in animal soure and 813 Heart: first published as /hrt on 14 June Downloaded from on 3 April 2019 by guest. Proteted by opyright.

2 814 Table 1 Risk fators of embolism in AF patients (only independently signifiant fators inluded) Risk fator Assoiated relative risk by AFI investigators w23 Assoiated relative risk by SPAF investigators 19 Prior stroke or transient ishaemi event Diabetes mellitus 1.7 Age 1.6/deade 1.8/deade Hypertension Alohol onsumption 0.4 Female sex 1.6 SPAF, stroke prevention in atrial fibrillation. method of preparation, whih result in differing sensitivities to fator defiienies. Differenes in instrumentation, methodology, and ontrol plasmas also ontribute to inter- and intra-laboratory variability. To ontrol for this the World Health Organization has established a referene thromboplastin derived from human brain that is now used to alibrate seondary standards, and is available to manufaturers and laboratories for the evaluation of thromboplastin reagents. In an effort to standardise the monitoring of OAC, the INR was adopted worldwide. The INR onverts the prothrombin (PT) patient/pt mean normal ratio to the value expeted if the test had been performed with the WHO referene thromboplastin. The OAC antagonists have multiple interations with other drugs and some food omponents. The most ommon agents assoiated with enhaned antioagulant effet are allopurinol, ommon analgesis, antiarrhythmis, antidepressants, antidiabetis, antimalarials, antiplatelets, anxiolytis, disulfiram, levothyroxine, lipid regulating agents, testosterone, and alohol. Oral ontraeptives, raloxifene, retinoids, rowahol, and vitamin K have the opposite, reduing effet on antioagulation. The most ommon ontraindiations for OACs inlude evidene of any ative bleeding, unontrolled severe hypertension, reent brain, eye or spinal ord surgery or injury, propensity for reurrent falling, inability for INR monitoring, and patient non-ompliane. w9 ORAL ANTICOAGULANTS IN AF By the late 1990s, six randomised linial trials addressing the effiay of OACs in non-valvar AF by omparison to plaebo or no treatment had been published (table 2). The data from these and other trials of OACs were reently summarised in a meta-analysis. 15 In all these trials OAC treatment was assoiated with dereased risk of ishaemi ThreeoneptsofstrokepreventioninAF 1. Antithromboti treatment antioagulant or antiaggregant effets aimed at diminishing the pro-thromboti effets of atrial fibrillation 2. Antiarrhythmi treatment aimed at eliminating atrial fibrillation or signifiantly dereasing the burden of atrial fibrillation 3. Mehanial means aimed at the olusion of the left atrial appendage, or proteting the internal arotid artery from thrombi stroke in patients with AF, with a relative risk redution in the range of 33 75%, mean 62% (95% onfidene interval (CI) 48% to 72%). The effet of OAC was onsistent and was ahieved despite overall 20% dropout rates. The absolute benefit of OAC in patients with AF varies in the plaebo ontrolled studies aording to the risk of emboli events in the patient population enrolled: the higher the risk of ardioemboli event, the stronger the absolute preventive benefit from antioagulation (fig 1). The overall effet of OAC was a 59% redution in stroke in the primary prevention trials and 68% in the seondary prevention trial. The absolute annual risk redution for all strokes was 2.7% for the primary prevention and 8.4% for the seondary prevention trials (number needed to treat for one year to prevent one stroke was 37 and 12, respetively). Total mortality also dereased with OAC signifiantly, with relative risk redution of 26% (95% CI 4% to 43%) and an absolute risk redution of 1.6% per year. 15 The range of effiay of the oral antioagulants evaluated in the randomised trials differed signifiantly (with a lower INR range of , and an upper range of ). When estimated in a ase ontrol study, the lower threshold of intensity of antioagulation in patients with a history of emboli stroke was an INR of 2.0. w10 The probability of stroke inreases steeply in patients having an INR, 2.0. The upper limit of safe INR is between , varying signifiantly with the risk of intraranial haemorrhage. The INR ratios reommended by the most reent guidelines are , with 16 w6 a target level of 2.5. WARFARIN IN AF COMPARED TO OTHER REGIMENS Antiplatelet regimens are another prophylati modality available for treating patients with AF whih have been evaluated in randomised linial trials and subsequent metaanalyses. w11 w12 In primary prevention trials aspirin redues stroke and major vasular events in non-valvar AF by 22%. w11 A single seondary prevention trial demonstrated a Table 2 Adjusted dose warfarin ompared with plaebo, or no treatment in non-rheumati AF (modified from Hart and olleagues 15 ) Study Prevention Target INR Warfarin group: strokes/ person-years Plaebo group: strokes/ person-years Relative risk redution (%) Petersen 10 Primary /413 19/ SPAF 5 Primary /263 19/ BAATAF 11 Primary /487 13/ Connolly 12 Primary /237 9/ Ezekowitz 13 Primary /489 23/ EAFT 14 Seondary /507 50/ All trials 53/ / (48 to 72)* 3.1 Absolute risk redution per year (%) BAATAF, Boston area antioagulation trial for atrial fibrillation; EAFT, European atrial fibrillation trial; INR, international normalised ration; SPAF, stroke prevention in atrial fibrillation. *95% onfidene interval. 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3 Figure 1 Absolute benefit in stroke prevention by antioagulation versus plaebo. AFASAK, Copenhagen atrial fibrillation, aspirin and antioagulant therapy study; BAATAF, Boston area antioagulation trial for atrial fibrillation; CAFA, Canadian atrial fibrillation antioagulation trial; EAFT, European atrial fibrillation trial; SPAF, stroke prevention in atrial fibrillation trial; SPINAF, Veterans Affairs stroke prevention in non-rheumati atrial fibrillation trial. non-signifiant redution in the risk of reurrent stroke from 12% to 10% per year (odds ratio (OR) 0.89, 95% CI 0.64 to 1.24). w12 More then 10 randomised omparative trials ompared dose adjusted OACs with other drug regimens for the stroke prevention in AF. Three reent meta-analyses have reviewed these data. w13 The results of these meta-analyses are onsistent in regard to the superiority of OAC over antiplatelet treatment, but differed in regard to the extent of this superiority. This differene may be explained by the inlusion of trials omparing OAC to the ombination of low dose warfarin and aspirin 17 and inlusion of antiplatelet regimens other than aspirin. w13 The only individual patient data based meta-analysis 17 was limited to the omparisons of warfarin and aspirin (exluding trials on other antiplatelets drugs and inluding two trials whih used a ombination of aspirin and low dose warfarin). This meta-analysis reported a signifiant superiority of the OAC over aspirin in the prevention of all strokes (hazard ratio (HR) 0.55, 95% CI 0.43 to 0.71) and ardiovasular events (HR 0.71, 95% CI 059 to 0.85) (fig 2). It did not find a signifiant redution of mortality (HR 0.93, 95% CI 0.76 to 1.13). OAC (ompared to aspirin) prevented 2.1 strokes (derease of stroke rate from 4.5/100 patient-years to 2.4/100 patient-years) at a ost of approximately 1.1 major bleeds (inrease in the major bleeding rate from 1.3/100 patientyears in aspirin group to 2.2/100 patient-years (relative risk (RR) 1.17, 95% CI 1.21 to 1.41)). Interestingly, another reent meta-analysis ompared OAC with any evaluated antiplatelet agents (exluding trials where the ombination of aspirin and warfarin was ompared to warfarin) and showed no signifiant differene between OAC and antiplatelet treatment with regard to vasular death or fatal strokes, with only statistially borderline superiority of OAC for outome of non-fatal stroke (OR 0.68, 95% CI 0.46 to 0.99). w13 The inidene of the major bleeding event was higher with OACs (OR 1.45, 95% CI 0.93 to 2.27). Major bleeding in the aspirin arm in this metaanalysis may be inflated due to inlusion of low dose warfarin in this arm. Thus, the aumulated evidene ertainly indiates the superiority of oral antioagulation over aspirin treatment alone in patients with AF at inreased risk of stroke. However, the magnitude of the benefit of OAC over antiplatelet agents remains slightly unertain. Data suggest that the effet on stroke is more powerful than against other vasular events. OAC is urrently the gold standard for prevention of stroke and other vasular events in AF patients. LIMITATIONS OF ORAL ANTICOAGULATION The limitations of OAC are signifiant and the main onerns are safety and adherene to the treatment. Chroni OAC use is assoiated with a signifiant inrease in the risk of major bleeding, inluding haemorrhagi stroke. The absolute of this inrease depends on the level of Figure 2 Comparison of oral antioagulants and aspirin Heart: first published as /hrt on 14 June Downloaded from on 3 April 2019 by guest. Proteted by opyright.

4 OAC versus plaebo OAC versus antiplatelet treatment 816 Signifiant stroke redution in primary and seondary prevention Signifiant redution in total mortality. antioagulation, but in partiipants of randomised ontrolled trials reeiving ative drug it is generally estimated as 0.2% per year for haemorrhagi stroke (from 0.1% in the plaebo group to 0.3% in the OAC group), and 0.3% for major extraranial haemorrhage (from 0.6% to 0.9%). The overall rate of haemorrhagi events has been reported to be as high as 1.8% per year in AF patients over 75 years of age. 18 The risk of major haemorrhage during OAC when ompared to aspirin was 2.2 versus 1.3 per 100 patient-years (HR 1.71, 95% CI 1.21 to 2.41) (note that the annual risk with aspirin was atually lower then that of plaebo). 17 The inrease in risk of brain haemorrhage in the same meta-analysis was not signifiant (0.5 v 0.3 per 100 patient-years (HR 1.84, 95% CI 0.87 to 3.87)). The risk of the brain haemorrhage is higher in routine w14 w15 pratie than in rigorously ontrolled linial trials. Reognised independent risk fators for major bleeding events are elevated INR, history of stroke, history of gastrointestinal bleeding, and serious o-morbid onditions. w15 w16 Poor patient adherene to the treatment, drug interations, and multiple dietary restritions make it diffiult to remain in the reommended range of INR. Chroni antioagulant therapy plaes the patient under a number of restritions, inluding delays of urgent invasive proedures, ontraindiation for thrombolyti treatment for myoardial infartion, and potentially serious bleeding after ommon trauma. Many patients need to disontinue antioagulants for other treatments and proedures during whih time they are at risk. In spite of the evidene and reommendations, only about half of all patients with AF are orretly treated. w17 19 Old and disabled AF patients are even less likely to reeive OAC. w17 19 Even in patients who have no ontraindiations to OAC, there are several patient, physiian, and health are system related barriers to the presription of OACs. w18 Patients with AF before the first stroke are less likely to reeive adequate OAC than after having one. w18 Speifially oriented linis of antioagulation have been reported to make OAC more effetive, safe, and even ost effetive. w20 The greater use of self monitoring devies ould further improve safety and effiay of this treatment. w21 RECOMMENDATIONS Two major guidelines addressing the use of OAC in patients with AF are available. 16 w22 Both indiate that AF in ombination with one or more risk fators for a thromboemboli event is a lass I indiation for OAC administration. Risk fators inlude history of prior erebrovasular or other systemi emboli event, hypertension, age. 75 years, poor left ventriular funtion, rheumati heart disease, or a prostheti valve. Both guidelines are targeting the same levels of antioagulation in these patients (INR ). Management of those patients at moderate risk (with one of the indiators of moderate risk: diabetes, age years, thyrotoxiosis, oronary artery disease) is learly addressed in the Amerian College of Chest Physiians onsensus, where use of either OAC or aspirin is reommended. Signifiant redution of all strokes Signifiant redution of ardiovasular events CONCLUSION Currently, hroni OAC treatment is the most effetive available prophylati approah in patients with AF at high risk of thromboemboli events. Aspirin, the only available proven alternative to hroni OAC, is signifiantly less effetive, and therefore is only indiated in patients at moderate and low risk, or in patients with major ontraindiations to OAC. Chroni OAC, however, is underused, due to ontraindiations and diffiulties in its use. Therapeuti agents as effetive as OACs, with greater ease of use and fewer ontraindiations, are being tested and may offer improved antithromboti protetion for patients with AF in the future.... Authors affiliations E Crystal, Department of Mediine, Faulty of Mediine, University of Toronto, Toronto, Ontario, Canada S J Connolly, Department of Mediine, Faulty of Health Sienes, MMaster University, Hamilton, Ontario, Canada REFERENCES 1 Amerian Heart Organization Heart and stroke statistial update. Dallas, Texas: Amerian Heart Assoiation, 2001:18. 2 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk fator for stroke: the Framingham study. Stroke 1991;22: Flegel KM, Shipley MJ, Rose G. Risk of stroke in non-rheumati atrial fibrillation. Lanet 1987;i: Hart RG, Halperin JL. Atrial fibrillation and stroke: onepts and ontroversies. Stroke 2001;32: Comprehensive editorial review of the onepts behind the use of oral antioagulants, with in-depth disussions of assoiated ontroversies. 5 SPAF Investigators. Stroke prevention in atrial fibrillation study. Final results. Cirulation 1991;84: Hohnloser SH, Kuk KH, Lilienthal J. Rhythm or rate ontrol in atrial fibrillation pharmaologial intervention in atrial fibrillation (PIAF): a randomised trial. Lanet 2000;356: Van Gelder IC, Hagens VE, Bosker HA, et al. A omparison of rate ontrol and rhythm ontrol in patients with reurrent persistent atrial fibrillation. N Engl J Med 2002;347: Wyse DG, Waldo AL, DiMaro JP, et al. A omparison of rate ontrol and rhythm ontrol in patients with atrial fibrillation. N Engl J Med 2002;347: Largest of existing trials on the rhythm versus rate ontrol. The study showed no survival benefit of rhythm ontrol strategy by pharmaologial means over rate ontrol approah. 9 Carlsson J. STAF a randomized trial of strategies in atrial fibrillation. JAm Coll Card 2001;38:603A. 10 Petersen P, Boysen G, Godtfredsen J, et al. Plaebo-ontrolled, randomised trial of warfarin and aspirin for prevention of thromboemboli ompliations in hroni atrial fibrillation. The Copenhagen AFASAK study. Lanet 1989;i: BAATAF Investigators. The effet of low-dose warfarin on the risk of stroke in patients with nonrheumati atrial fibrillation. The Boston area antioagulation trial for atrial fibrillation investigators. N Engl J Med 1990;323: Connolly SJ, Laupais A, Gent M, et al. Canadian atrial fibrillation antioagulation (CAFA) study. J Am Coll Cardiol 1991;18: Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke assoiated with nonrheumati atrial fibrillation. Veterans Affairs stroke prevention in nonrheumati atrial fibrillation investigators. N Engl J Med 1992;327: European Atrial Fibrillation Trial Study Group. Seondary prevention in nonrheumati atrial fibrillation after transient ishaemi attak or minor stroke. EAFT (European atrial fibrillation trial) study group. Lanet 1993;342: Hart RG, Benavente O, MBride R, et al. Antithromboti therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131: Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: exeutive summary. A report of the Amerian College of Cardiology/Amerian Heart Assoiation task fore on pratie guidelines and the European Soiety of Cardiology ommittee for pratie guidelines and poliy onferenes (ommittee to develop guidelines Heart: first published as /hrt on 14 June Downloaded from on 3 April 2019 by guest. Proteted by opyright.

5 for the management of patients with atrial fibrillation) developed in ollaboration with the North Amerian Soiety of Paing and Eletrophysiology. Cirulation 2001;104: The most reent omprehensive guidelines on the management of the atrial fibrillation, inluding use of oral antioagulants. 17 van Walraven C, Hart RG, Singer DE, et al. Oral antioagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. JAMA 2002;288: Individual patient data meta-analysis omparing oral antioagulation and antiplatelet regimens demonstrated signifiant superiority of oral antioagulation in end points of stroke and all ardiovasular events. 18 Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major ontributor to stroke in the elderly. The Framingham study. Arh Intern Med 1987;147: Hart RG, Peare LA, MBride R, et al. Fators assoiated with ishemi stroke during aspirin therapy in atrial fibrillation: analysis of 2012 partiipants in the SPAF I III linial trials. The stroke prevention in atrial fibrillation (SPAF) investigators. Stroke 1999;30: Additional referenes appear on the Heart website LEARNING ON THE WEB... Case 6: Aorti valve replaement in the elderly Roger Hall, Professor of Clinial Cardiology, University of East Anglia, Norwih, Norfolk, UK Mark Earley, St Bartholomew s Hospital, London, UK A 90 year old man was found at home by his daughter, slumped at the bottom of his stairs. He realled quite severe tight entral hest pain assoiated with breathlessness and sweating while going up stairs whih was not relieved by taking a spray of sublingual glyeryl trinitrate (GTN). He sensed that he was about to die before ollapsing with loss of onsiousness. He was sent to the aident and emergeny department (emergeny room) of his loal hospital by ambulane. The patient had a five year history of angina petoris that limited him to one flight of stairs within the house and light housework only. Over the two weeks preeding his admission to hospital he had experiened inreasing frequeny of these symptoms and used his GTN spray more often than usual. He had not smoked for over 50 years and there were no other risk fators for ardiovasular disease. There was no other notable past medial history and he was otherwise fit, living ompletely independently. The signifiane of these signs and symptoms, the diagnosis, and the short and long term treatment of these problems are disussed in an interative ase presentation. 817 Heart: first published as /hrt on 14 June Downloaded from on 3 April 2019 by guest. Proteted by opyright.