What is best and safest method to anticoagulate a patient who has had atrial fibrillation and a TIA related to SSS? Do the risks of warfarin in this type of patient outweigh the benefits? Are aspirin, aspirin /dipyridamole, or clopidogrel potentially effective and safer alternatives?

Submitted by Joseph Upson, MD

Response by Carol Howe, MD, MLS

This topic has been the subject of many studies. There are two excellent Cochrane Reviews:

Segal, JB. McNamara, RL. Miller, MR. Powe, NR. Goodman, SN. Robinson, KA. Bass, EB. Anticoagulants or antiplatelet therapy for non-rheumatic atrial fibrillation and flutter. Cochrane Database of Systematic Reviews. 4, 2006. 

and

Saxena, R. Koudstaal, PJ. Anticoagulants versus antiplatelet therapy for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischemic attack. Cochrane Database of Systematic Reviews. 4, 2006.

Both reviews confirm that “multiple trials have established that antithrombotic therapy dramatically decreases the risk of cardioembolic stroke associated with AF….In a pooled analysis, adjusted-dose warfarin reduced the risk of stroke by about two thirds vs. control. The magnitude of benefit associated with warfarin was consistent among trials despite variations in design and intensity of anticoagulation. Compared with aspirin, adjusted-dose warfarin reduces the risk of ischemic stroke by 46%…” (Halperin, 2005).

Despite this seeming unanimity, as well as the fact that the prevalence of both atrial fibrillation and stroke increase with age, most studies under-represent the elderly—the population most at risk.

The age-associated variation in prevalence of AF is not truly reflected in the population base of these trials. Around 50% of patients with AF are over 75 of age…whereas only 20% of the trial patients were in this age bracket, 32% of patients are over 80 years and were not included in the trials. Exclusion criteria included old age (>75) years, serious illness (liver, kidney, brain or malignancy), alcoholism, risk of falls, forgetfulness, use of non-steroidal anti-inflammatories and uncontrolled hypertension. Over all, the studies tended to select younger patients at a lower risk of harm from treatment than the population with AF encountered in clinical practice. (Morgan, 2004, pp.544-5)

Of all the major atrial fibrillation trials, only the Second Stroke Prevention in Atrial Fibrillation (SPAF-II) trial actually looked specifically at older patients (“data were analysed separately for patients aged 75 years or less (n=715) or more than 75 years (n = 385) at the time of enrollment”) and, in this group, the investigators found “The rate per year of all strokes with residual deficit (haemorrhagic and ischaemic) was similar in patients assigned to warfarin (4.6%) and aspirin (4.3%, table 2).” They further found that “in older patients assigned to warfarin, the annual rate of intracranial haemorrhage (71% fatal, 29% with residual deficit) was significantly higher than in younger patients assigned to warfarin (1.8%, 95% CI 0.8 to 3.7 vs 0.5%, p = 0.05).”

In general, however, most studies have indeed found that warfarin is superior to aspirin in terms of stroke reduction. Halperin reports that “On balance, treating 1000 patients with AF for 1 year with adjusted-dose oral anticoagulants rather than aspirin avoided 23 ischemic strokes while causing 9 additional major bleeding events” (p. 82). The importance of maintaining an INR between 2.0 and 3.0 (as close to 2.5 as possible) is stressed. Below an INR of 2.0, the benefits of warfarin resemble those of aspirin. Above an INR of 3.0, the risks of intracranial bleeding outweigh any risk reduction of ischemic stroke

Halperin concludes that, “although adjusted-dose warfarin carries the risk of hemorrhage, the stoke-prevention benefit in patients with AF justifies this therapy, particularly for secondary prevention” (pp83-4).

Given the data that is available (and as we have seen—the data collected so far is not necessarily representative of the frail elderly), most authors find that warfarin is tremendously under prescribed. In their article, “Anticoagulation in the elderly” Dhond et al (2003) analyze some of the “barriers to anticoagulation.” They find that among physicians, “an outcome due to an ‘act of commission’ is regretted more than a similar outcome due to an ‘act of omission’ (p.247):

Thus physicians may be unwilling to take the risk, for example, of an elderly patient falling. Interestingly, a recent study demonstrated that the risk of an adverse event from falling is far less than the risk for stroke in many elderly patients with AF, and that patients must fall more than 295 times a year to justify not giving them anticoagulation therapy (p.247).

The authors also discuss patient factors and health care system factors in decisions not to use warfarin. Patient factors include age, “the perceived embolic risk or perceived risk of hemorrhage, the patient’s medical history, the patient’s risk of falling, and patient refusal of therapy or nonadherence to treatment” (p.247).

Three significant patient/physician factors in decisions regarding treating elderly patients with warfarin are: the patients’ cognitive status; functional capabilities; and social situation. It would clearly make no sense to prescribe warfarin to a community dwelling elder with little outside support who may or may not remember to take his or her medications. Warfarin therapy in particular, also involves substantial investment on the part of both patient and physician in that the therapeutic window is narrow and the patient requires constant surveillance in terms of INR testing, dosage adjustment etc. Several articles mentioned, with hopeful anticipation, oral agents such as ximelagratran, which would require no routine monitoring and which it is hoped will have few medication or food interactions (and not be too expensive!) Unfortunately, “none of the trials of these agents have yet generated sufficient data to justify clinical use for this indication” (Halperin p.82).

This search has concentrated primarily on the comparison of aspirin with warfarin. I do include the abstract for DeSilvey ‘s (2006) article reporting on “Clopidogrel Plus Aspirin vs Oral Anticoagulation for Atrial Fibrillation: The ACTIVE W Trial,” because, to a large extent, it summarizes the state of current research in this arena, as well as addresses some of the larger questions asked by Dr. Upson.

Atrial fibrillation is a common cardiac arrhythmia in the elderly population. Estimates have placed the frequency of atrial fibrillation at between 6%–8% in the population older than 80 years. With the onset of atrial fibrillation, the risk of embolic stroke (thought to originate from the left atrium) increases such that 50% of patients with atrial fibrillation will suffer an event over their lifetime. Oral anticoagulation with warfarin is known to reduce the risk of stroke by 45%.1 Compared with other therapies, such as aspirin, this reduction is significant and has led to the recommendation that warfarin therapy be considered in all patients over the age of 70 with known episodes of atrial fibrillation. 2 Therapy with warfarin is not without risk, and estimates for the increase in major bleeding are 70%. 3 Finding an alternative to warfarin for the prevention of stroke in the elderly population has challenged the clinician since the recommendations for its use were first published. Having a drug or drug combination that would be equivalent or better than warfarin without the need for monitoring would be ideal. The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE W) 4 was developed to test the hypothesis that the combination of aspirin plus clopidogrel, known potent platelet inhibitors that have been proven to be effective in acute coronary syndromes, 5 would be equally effective in preventing stroke in patients with atrial fibrillation. Patients were enrolled in the trial if they had documented atrial fibrillation plus one or more additional risk factors for stroke. Patients were randomly assigned to receive oral anticoagulation therapy with warfarin (target international normalized ratio, 2–3) according to guidelines or clopidogrel (75 mg/d) plus aspirin (75–100 mg/d). The population in the study was elderly (aged 70±9 years in both groups). The primary outcome was the first occurrence of stroke, systemic embolus not of the central nervous system, myocardial infarction, or vascular death. The study was terminated early because of evidence of superiority of oral anticoagulation therapy over the aspirin plus clopidogrel combination. The annual risk for an event in the patients on oral anticoagulation was 3.93%, and the risk in the aspirin plus clopidogrel group was 5.60%. One very interesting result was that patients who were already on oral anticoagulation therapy at the start of the trial had an even greater reduction in vascular events (relative risk 1.50) and a significantly lower risk of major bleeding. While the study authors did not explore this result in depth, it raises 2 issues. One is whether the maximum risk of vascular events occurs in the first year of oral anticoagulation and longer duration of therapy results in atrial events that reduce the risk of thrombus formation. The other is whether the first year of therapy may select out those patients who are at greatest risk of bleeding. We also await the results of the two remaining arms of the trial: ACTIVE A, in which clopidogrel is being compared with placebo in patients receiving aspirin, and ACTIVE I, in which irbesartan is being compared with placebo in eligible patients from ACTIVE W and ACTIVE A. These studies are ongoing, and I suspect that we will be most interested in the results of ACTIVE A. What we do know, from ACTIVE W, is that conventional oral anticoagulation with warfarin remains the standard of care for patients with atrial fibrillation who are candidates for such therapy.

 

 

References

DeSilvey, D. L. (2006). Clopidogrel plus aspirin vs oral anticoagulation for atrial fibrillation: The ACTIVE W trial. The American Journal of Geriatric Cardiology, 15(5), 326-327.

Dhond, A. J., Michelena, H. I., & Ezekowitz, M. D. (2003). Anticoagulation in the elderly. The American Journal of Geriatric Cardiology, 12(4), 243-250.

Economides Munoz, C., & Singh, B. N. (2004). Antithrombotic therapies for stroke prevention in atrial fibrillation. Minerva cardioangiologica, 52(2), 125-139.

Flaker, G. C., & Schutz, J. (2004). Why is warfarin underutilized in patients with atrial fibrillation? Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing, 10 Suppl 1, 21-25.

Halperin, J. L. (2005). Anticoagulation for atrial fibrillation in the elderly. The American Journal of Geriatric Cardiology, 14(2), 81-86.

Kamath, S., & Lip, G. Y. (2002). Atrial fibrillation in the elderly: Anticoagulation strategies and indications in the very elderly. The American Journal of Geriatric Cardiology, 11(6), 357-62; quiz 363-4.

Krishnan, K. (2005). Atrial fibrillation: Management for the geriatric patient. The American Journal of Geriatric Cardiology, 14(5), 242-7; quiz 248-9.

Morgan, S. V. (2004). Between the devil and the deep blue sea--balancing the risks and potential benefits of warfarin for older people with atrial fibrillation. Age and Ageing, 33(6), 544-547.

Nattel, S., & Opie, L. H. (2006). Controversies in atrial fibrillation. Lancet, 367(9506), 262-272.

Oden, A., Fahlen, M., & Hart, R. G. (2006). Optimal INR for prevention of stroke and death in atrial fibrillation: A critical appraisal. Thrombosis research, 117(5), 493-499.

Ross, H. M., Kocovic, D. Z., & Kowey, P. R. (2005). Pharmacologic therapies for atrial fibrillation. The American Journal of Geriatric Cardiology, 14(2), 62-67.

Saxena, R., & Koudstaal, P. J. (2006). Anticoagulants versus antiplatelet therapy for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischemic attack. Cochrane Database of Systematic Reviews, 4.