In defence of current treatment options: where are we now?

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management of AF-associated stroke represents a major ..... Table 1 The clinical outcomes of patient INR self-monitoring and INR monitoring via usual care.
European Heart Journal Supplements (2005) 7 (Supplement E), E4–E9 doi:10.1093/eurheartj/sui029

In defence of current treatment options: where are we now? ¨ller* Heinz Vo ¨dersdorf bei Berlin, Germany Klinik am See, Rehabilitation Clinic for Cardiovascular Diseases, Ru

Introduction Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia worldwide, with an estimated prevalence of 0.4% in the general population. In the United States, for example, this equates to approximately 2.3 million adults with AF.1–3 The major clinical consideration in AF is the substantial increase (five-fold) in the risk of ischaemic stroke, resulting from embolization of thrombi within the fibrillating left atrial appendix.1,4 In the United States, AF is responsible for approximately 50 000 strokes annually,2,5 leading to a 1.5–1.9-fold increase in the risk of mortality among affected individuals.6 Known risk factors for AF include diabetes, hypertension, prior stroke, and increasing age.7 Increasing age is a particularly powerful risk factor for AF, with the incidence of AF increasing dramatically after 55 years of age8—approximately doubling for every decade of life. The estimated prevalence of AF in the United States has been shown to increase from 0.5% in the sixth decade of life (50–59 years) to 10% in the ninth decade of life (80–89 years).4 Results from the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study have further demonstrated that, as a result of an increasingly elderly population, the number of adults affected by AF is likely to increase to more than 5.6 million in the United States by 2050.3 In patients with acute ischaemic stroke, the presence of AF doubles the probability of permanent disability or handicap.9 Furthermore, the risk of early death is increased, reflecting the greater age of patients and larger infarcts typical of AF. It can, therefore, clearly be seen that AF represents an increasingly important public health issue, and that the prevention and management of AF-associated stroke represents a major

*Corresponding author. Tel: þ49 33638 78 623; fax: þ49 33638 78 624. E-mail address: [email protected]

challenge for healthcare systems. How can we reduce the burden of AF-associated stroke? First and foremost, we can reduce it through appropriate use of antithrombotic therapy in patients with AF. Of the therapeutic options available to us, the oral vitamin K antagonist (VKA) warfarin is the most effective agent for stroke prophylaxis in AF, yet it is an agent that is clearly underused.10–12 This article presents the case for warfarin, reviewing the evidence supporting its efficacy and examining how we can maximize the benefits of this highly effective agent.

The case for warfarin: unequivocal evidence of efficacy in primary and secondary stroke prevention in AF A pooled analysis of five randomized primary prevention trials that compared dose-adjusted warfarin with placebo has demonstrated that warfarin is highly effective in the prevention of stroke in AF (Figure 1 ). The annual rate of ischaemic stroke was 1.4% in patients receiving warfarin and 4.5% in placebo patients—an absolute reduction in risk of 3.1% and a relative reduction in risk of 68% [95% confidence interval (CI), 5–79%].1 Warfarin provided greater benefits in women than in men, producing a relative risk reduction of 84% (95% CI, 5–95%), compared with 60% in men (95% CI, 35–76%). In terms of bleeding events, no significant increase in major bleeding was observed in any of the five trials, and the pooled analysis reported an annual rate of major bleeding of 1.3% in warfarin-treated patients and 1.0% in the placebo group. Warfarin is also unequivocally superior to antiplatelet therapy with aspirin. A subsequent meta-analysis of six primary prevention trials of dose-adjusted warfarin vs. aspirin reported a 36% relative reduction in the risk of stroke when compared with aspirin.13 The effects of warfarin were even greater when only ischaemic strokes were considered—a risk

& The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: [email protected]

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Figure 1 Primary prevention: the relative risk of stroke in patients with AF treated with warfarin when compared with placebo—data from five randomized studies separately and combined. AFASAK, Atrial Fibrillation, Aspirin, Anticoagulation Study; BAATAF, Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA, Canadian Atrial Fibrillation Anticoagulation; SPINAF, Stroke Prevention in Non-rheumatic Atrial Fibrillation. Adapted with permission from the Atrial Fibrillation Investigators.1

reduction of 46% relative to aspirin-treated patients (95% CI, 27–60%). VKAs have also proven effective in the secondary prevention of stroke in AF. Results from the European Atrial Fibrillation Trial (EAFT) study group demonstrated a reduction in the annual risk of stroke in patients treated with VKAs when compared with those receiving placebo. This study involved 1007 patients with non-rheumatic AF and a recent transient ischaemic attack (TIA) or minor ischaemic stroke. The annual stroke risk was 4% in patients receiving a VKA when compared with 12% with placebo (hazard ratio, 0.34; 95% CI, 0.20–0.57)—a 66% relative reduction in risk.14 These data mean that one vascular event was prevented for every 12 patients treated or 90 vascular events (mainly strokes) per year were prevented if 1000 patients were treated with anticoagulation therapy. With respect to the risk of major bleeding, this was 2.8% per year in VKAtreated patients when compared with 0.7% per year in the placebo group. No intracranial bleeds were seen in the VKA group.

Optimal intensity of anticoagulation in AF As described earlier, the VKAs are highly effective agents in preventing stroke in AF. However, the intensity of anticoagulation with the VKAs must be optimized to achieve the greatest benefit, without increasing the risk of bleeding complications. What is the optimal intensity of anticoagulation in AF? This question was

examined in a subanalysis of the EAFT study where the international normalized ratio (INR)-specific incidence of major bleeding events, strokes, and ischaemic events was calculated (Figure 2 ).15 The data show that as INR increased, there was an increase in the risk of major bleeding, such that at an INR 5.0, the risk of bleeding increased 3.6-fold relative to an INR of ,2.0. The rate of thromboembolic events was lowest at INRs between 2.0 and 3.9. The optimal intensity of anticoagulation that achieved maximum therapeutic effect with minimum risk was determined to be at an INR of 3.0. There was no evidence of a therapeutic effect below an INR of 2.0. Conversely, if the intensity of anticoagulation is too low, the risk of thromboembolic events is increased. This was highlighted in a case–control study conducted by Hylek et al. 16 This study examined 74 consecutive patients with AF admitted to hospital with an ischaemic stroke despite receiving warfarin therapy. The INR for each of these patients was compared with that of three control patients with AF receiving warfarin and with no history of prior stroke. The risk of stroke was found to increase dramatically at INRs ,2.0 (Figure 3 ), with the odds ratio for stroke increasing from 2.0 at an INR of 1.7, to 6.0 at an INR of 1.3 (relative to an INR of 2.0). These data, along with recommendations from recent American College of Chest Physician (ACCP) guidelines, indicate that the optimal intensity of anticoagulation in AF for balancing efficacy in preventing stroke, while minimizing the risk of bleeding, is within the INR range of 2.0–3.0.17

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Figure 3 The odds ratio of stroke for a given INR value in patients treated with anticoagulation.

Figure 2 INR-specific incidence rates for ischaemic or haemorrhagic complications in patients with AF treated with anticoagulation therapy.

Maximizing the benefit of warfarin in AF: using risk stratification schemes Although warfarin is an effective anticoagulant, the risk of bleeding complications associated with its use highlights the need to target warfarin at those individuals with AF most likely to benefit, based on their individual risk of stroke and bleeding. Several risk stratification schemes have been developed and validated that can aid in the appropriate selection and treatment of eligible patients. These schemes include those from the ACCP,18 the Atrial Fibrillation Investigators (AFI) trial,1 the Stroke Prevention in Atrial Fibrillation (SPAF) study,19 the joint American College of Cardiology/American Heart Association Task Force on Practice Guidelines and European Society of Cardiology Committee for Practice Guidelines and Policy (ACC/AHA/ESC),20 the Framingham Heart study,21 and the Congestive Heart Failure, Hypertension, Age, Diabetes, and Stroke (CHADS2) scoring system.22 In all cases, previous TIA or stroke, increasing age, and history of hypertension, diabetes, or left ventricular dysfunction identify individuals at high risk of stroke.1,18–22 Figure 4 shows the risk stratification scheme developed by the ACCP.18 Patients are stratified primarily by age, and subsequently by risk factors considered to confer a high or moderate risk on the patient. A patient with AF, aged ,65 and with no risk factors does not require drug therapy, or only requires aspirin at most, whereas a patient of the same age with one high-risk factor or more (e.g. a prior TIA or hypertension) requires warfarin therapy. Patients with AF, aged .75, are at high risk of stroke and require warfarin therapy, regardless of the presence of any other risk factors. Those aged 65–75 may require warfarin or aspirin therapy, depending on the number of moderateor high-risk factors present (Figure 4 ).

Maximizing the benefit of warfarin in AF: changing physician perceptions Stroke risk outweighs bleeding risk in elderly patients with AF In the AFI trial, the benefit–risk ratio for warfarin was calculated as a function of age.3 Patients aged .75 (with multiple risk factors) had a stroke incidence of 8.1% per year when untreated, compared with 1.2% when treated with warfarin. The data from the AFI trial showed that in this patient group, only 14 patients needed to be treated to prevent one ischaemic stroke. Conversely, in patients aged ,65 (with multiple risk factors), the untreated and treated stroke incidence was 4.9 and 1.7%, respectively, such that the number needed to treat to prevent one stroke was 30—more than twice the figure in the older patients. In contrast, the 0.3% absolute increase in the risk of bleeding in all warfarin-treated patients compared with all untreated patients (a relative increase in risk of 30%) corresponded to a number needed to harm of 333. As shown in the AFI trial, elderly patients with AF (.75 years) clearly benefit from anticoagulation. Despite this fact, numerous studies have shown that elderly patients, the group most likely to benefit from anticoagulation, are the least likely to receive it.10,12,23,24 For example, in a subgroup analysis of the Cardiovascular Health Study, in which warfarin use was examined in 172 patients with AF, overall, warfarin was used in 63 patients (37%).12 However, warfarin use decreased substantially with increasing age—from 47% usage in patients aged 69–79 to 24% in patients aged 80–89, with only 15% of patients aged 90 using warfarin. Concerns over bleeding risk with oral anticoagulants are the primary reason for physician hesitation to initiate treatment in elderly patients.12 These concerns, however, are largely unjustified if target INR levels are

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Figure 4 Stratification for antithrombotic therapy by risk factor (RF) in patients with AF according to the ACCP. ASA, acetyl salicylic acid; Rx, treatment. Reproduced with permission from Hylek et al. 16 An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Eng J Med 1996;335:540–546. & 1996 Massachusetts Medical Society.

maintained in eligible patients. This was highlighted in a study by Copeland et al. demonstrating no increase in the rate of major haemorrhage in elderly patients with AF receiving warfarin treatment.25 In this retrospective follow-up study, anticoagulant control (target INR, 2.5) and the incidence of major haemorrhage in patients aged .75 were compared with those in patients aged 60–69 attending a hospital anticoagulation outpatient clinic. No significant difference between the elderly (.75 years) and the control groups (60–69 years) was seen with respect to the incidence of major haemorrhages per year (2.8 vs. 2.9%, respectively; P ¼ 0.13) or the level of anticoagulation control (per cent of INR in range, 71 vs. 66.1%, respectively; P ¼ 0.96). In general, fear of haemorrhagic complications is largely unjustified in most elderly patients if the target INR is maintained, whereas the benefits of oral anticoagulation outweigh the risks of haemorrhage.

Improving awareness and acceptance of treatment guidelines The gap between patient eligibility and treatment is not restricted to elderly patients. Numerous studies have shown that in clinical practice, many eligible patients with AF do not receive anticoagulant treatment, despite the publication of guidelines prompting their use.26–29 In the UK, for example, studies have reported that less than one-third of eligible patients were appropriately treated with anticoagulants.25,26 In the United States, the situation is little better, with use of anticoagulation in eligible patients varying between 30 and

60%.30,31 Evidence-based treatment guidelines such as those from the ACCP and the ACC/AHA/ESC are not being followed, because physicians either are unaware of what the guidelines say or are unaware of the benefits of anticoagulation in AF.18,20 If we are to maximize the benefits of warfarin in clinical practice, then one approach is clearly to increase the awareness and use of these guidelines.

Maximizing the benefit of warfarin in AF: patient self-management as a strategy to improve INR monitoring The effectiveness and safety of the VKAs are critically dependent on maintaining the INR in the therapeutic range. Potential strategies to improve INR control include greater use of anticoagulation management services (AMS) and patient self-management (PSM) to manage therapy.32 Readers are referred to the recent seventh ACCP guideline article by Ansell et al. 32 for an overview of AMS. Focusing here on PSM, a number of studies have been conducted comparing PSM with usual care (Table 1 ).33–39 The data demonstrate that when patients self-manage their VKA therapy, they are more likely to achieve their target INR. PSM provides an average increase of 20–25% in the proportion of patients achieving their target INR, and a substantial reduction in the rate of complications.33–37 The reason for these improvements lies in the fact that with PSM, patients are able to control their therapy on a weekly basis when compared with substantially longer intervals (3–4 weeks) during usual care.

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Table 1 The clinical outcomes of patient INR self-monitoring and INR monitoring via usual care Study (year)

Ansell et al. (1995)33 Bernardo (1996)34 Hasenkam et al. (1997)35 Horstkotte et al. (1998)36 Ko ¨rtke et al. (2001)37 Vo ¨ller et al. (2005)39 a

INR within target range (per cent of patients)

Incidence of complicationsa (per cent per patient-year)

Usual care

Self-monitoring

Usual care (all/severe)

Self-monitoring (all/severe)

68.0 50.0 53.0 58.8 62.0 58.5

88.6 83.1 77.0 92.4 80.0 67.8

1 case 6.31/0.97 — 14.51/2.72 —/5.8 1 case

3 cases 3.38/0.00 — 4.58/0.00 —/5.2 1 case

Major bleeding or thromboembolic events.

In Germany, we have had considerable success with PSM strategies. Vo ¨ller et al. 40 have reported a PSM study involving 353 patients assigned to anticoagulation self-management (n ¼ 197) or usual care (n ¼ 156). At the end of a 1-year follow-up period, INR variability was lower in self-managed patients (SD, 0.57 + 0.31) than in patients undergoing usual care (SD, 0.70 + 0.36; P ¼ 0.02). These data clearly show that in suitable patients, PSM provides greater adherence to INR targets and, therefore, improved anticoagulation control and a reduced risk of bleeding complications.

Conclusions The major risk factor for AF is increasing age, and with an increasingly elderly population, the prevalence of this already relatively common arrhythmia is set to increase substantially. An increase in the prevalence of AF will bring an increase in the number of ischaemic strokes because AF represents a powerful risk factor for these events. Consequently, it is important that patients with AF receive appropriate therapy to reduce the risk of ischaemic stroke, in either the primary or the secondary prevention setting. The available data show that oral anticoagulation therapy with warfarin and other VKAs is effective in clinical practice, providing a dramatic reduction in the risk of ischaemic stroke in patients with AF at INRs between 2.0 and 3.0. However, VKA use is associated with a potential increase in the risk of bleeding complications, leading to hesitation among physicians to administer these agents to eligible patients, particularly the elderly. This risk is largely unfounded, however, even in elderly patients, and careful patient selection and control of INR, as can be achieved through PSM, substantially reduces the risk of complications, while providing protection from stroke. Anticoagulation therapy is effective and well tolerated in the prevention of AF-associated stroke. Raising awareness of the benefits of the VKAs among physicians is a priority in order to address the underuse of these agents and reduce the heavy burden of morbidity and mortality associated with AF. This should result in a

greater number of high-risk patients with AF receiving appropriate treatment with what are ultimately highly effective agents if used optimally—the VKAs.

References 1. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154: 1449–1457. 2. Feinberg WM, Blackshear JL, Laupacis A et al. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch Intern Med 1995;155:469–473. 3. Go AS, Hylek EM, Phillips KA et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA 2001;285:2370–2375. 4. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22: 983–988. 5. Albers GW, Atwood JE, Hirsh J et al. Stroke prevention in nonvalvular atrial fibrillation. Ann Intern Med 1991;115:727–736. 6. Benjamin EJ, Wolf PA, D’Agostino RB et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 1998;98:946–952. 7. Benjamin EJ, Levy D, Vaziri SM et al. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA 1994;271:840–844. 8. Kannel WB, Abbott RD, Savage DD et al. Coronary heart disease and atrial fibrillation: the Framingham Study. Am Heart J 1983;106: 389–396. 9. Lamassa M, Di Carlo A, Pracucci G et al. Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: data from a multicenter multinational hospital-based registry (The European Community Stroke Project). Stroke 2001;32:392–398. 10. Cohen N, Almoznino-Sarafian D, Alon I et al. Warfarin for stroke prevention still underused in atrial fibrillation: patterns of omission. Stroke 2000;31:1217–1222. 11. Antani MR, Beyth RJ, Covinsky KE et al. Failure to prescribe warfarin to patients with nonrheumatic atrial fibrillation. J Gen Intern Med 1996;11:713–720. 12. White RH, McBurnie MA, Manolio T et al. Oral anticoagulation in patients with atrial fibrillation: adherence with guidelines in an elderly cohort. Am J Med 1999;106:165–171. 13. Hart RG, Benavente O, McBride R et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131:492–501. 14. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993;342:1255–1262.

In defence of current treatment options 15. The European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995;333:5–10. 16. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996;335:540–546. 17. Singer DE, Albers GW, Dalen JE et al. Antithrombotic therapy in atrial fibrillation: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:429S–456S. 18. Albers GW, Dalen JE, Laupacis A et al. Antithrombotic therapy in atrial fibrillation. Chest 2001;119:194S–206S. 19. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84:527–539. 20. Fuster V, Ryden LE, Asinger RW et al. ACC/AHA/ESC Guidelines for the management of patients with atrial fibrillation: executive summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation), developed in collaboration with the North American Society of Pacing and Electrophysiology. Circulation 2001;104:2118–2150. 21. Wang TJ, Massaro JM, Levy D et al. A risk score for predicting stroke or death in individuals with new-onset atrial fibrillation in the community: the Framingham Heart Study. JAMA 2003;290:1049–1056. 22. Gage BF, Waterman AD, Shannon W et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–2870. 23. Gurwitz JH, Monette J, Rochon PA et al. Atrial fibrillation and stroke prevention with warfarin in the long-term care setting. Arch Intern Med 1997;157:978–984. 24. Stafford RS, Singer DE. National patterns of warfarin use in atrial fibrillation. Arch Intern Med 1996;156:2537–2541. 25. Copland M, Walker ID, Tait RC. Oral anticoagulation and hemorrhagic complications in an elderly population with atrial fibrillation. Arch Intern Med 2001;161:2125–2128. 26. Lip GY, Tean KN, Dunn FG. Treatment of atrial fibrillation in a district general hospital. Br Heart J 1994;71:92–95. 27. Gottlieb LK, Salem-Schatz S. Anticoagulation in atrial fibrillation. Does efficacy in clinical trials translate into effectiveness in practice? Arch Intern Med 1994;154:1945–1953.

E9 28. Albers GW. Atrial fibrillation and stroke. Three new studies, three remaining questions. Arch Intern Med 1994;154:1443–1448. 29. Sudlow M, Thomson R, Thwaites B et al. Prevalence of atrial fibrillation and eligibility for anticoagulants in the community. Lancet 1998;352:1167–1171. 30. Samsa GP, Matchar DB, Goldstein LB et al. Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities. Arch Intern Med 2000;160:967–973. 31. Jencks SF, Cuerdon T, Burwen DR et al. Quality of medical care delivered to Medicare beneficiaries: A profile at state and national levels. JAMA 2000;284:1670–1676. 32. Ansell J, Hirsh J, Poller L et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126: 204S–233S. 33. Ansell JE, Patel N, Ostrovsky D et al. Long-term patient self-management of oral anticoagulation. Arch Intern Med 1995; 155: 2185–2189. 34. Bernardo A. Post-conference session: experience with patient self-management of oral anticoagulation. J Thromb Thrombolysis 1996;2:321–325. 35. Hasenkam JM, Kimose HH, Knudsen L et al. Self management of oral anticoagulant therapy after heart valve replacement. Eur J Cardiothorac Surg 1997;11:935–942. 36. Horstkotte D, Piper C, Wiemer M. Optimal frequency of patient monitoring and intensity of oral anticoagulation therapy in valvular heart disease. J Thromb Thrombolysis 1998;5(Suppl. 1):19–24. 37. Ko ¨rtke H, Minami K, Breymann T et al. INR self-management after mechanical heart valve replacement: ESCAT (Early Self-Controlled Anticoagulation Trial). Z Kardiol 2001;90(Suppl. 6):118–124. 38. Heidinger KS, Bernardo A, Taborski U et al. Clinical outcome of self-management of oral anticoagulation in patients with atrial fibrillation or deep vein thrombosis. Thromb Res 2000;98:287–293. 39. Vo ¨ller H, Glatz J, Taborski U et al. Self-Management of Oral Anticoagulation in Nonvalvular Atrial Fibrillation (SMAAF study). Z Kardiol 2005;94:182–186. 40. Vo ¨ller H, Dovifat C, Glatz J et al. Lower INR variability through self-management of oral anticoagulation. Ann Hematol 2003; 306(Suppl.):S87.