Ischemic stroke (cerebrovascular event), heart attack (myocardial infarction), and pulmonary embolism are major
causes of death and disabling disease. Ischemic stroke is caused by an embolism, that is, the lodging of a
blood clot (thrombus) or a fragment of atherosclerotic plaque in a small artery of the brain, resulting in the cutting
off of blood supply to part of the brain. Pulmonary embolism is caused by a thrombus formed in the veins
(usually in the legs) that is carried to the lungs in the blood stream and gets stuck there. Heart attack is caused
by the build-up of atherosclerotic plaque or a blood clot in the coronary arteries.
Thrombi can form in both the arterial system (the supply side involving the left side of the heart) and in the venous system (the return side involving the right side of the heart and the lungs). The formation of a blood clot involves platelet activation, platelet aggregation, and blood coagulation. The body has a built-in process for dealing with clotted blood that no longer serves its purpose of preventing excessive bleeding. This process is called fibrinolysis.
Stroke, heart attack, and pulmonary embolism are extremely common and often fatal conditions. It is estimated that about 700,000 strokes (mostly ischemic), 650,000 cases of pulmonary embolism, and 1.5 million heart attacks occur every year in the United States alone[1-3]. Not surprisingly, this state of affairs has spawned the development of several drugs designed to reduce the natural tendency of blood to coagulate when flowing too slowly (in the veins) or when exposed to a damaged blood vessel wall. The most popular drug for preventing platelet activation and aggregation is aspirin and the most popular drug for preventing blood coagulation is warfarin (Coumadin). Heparin is also effective in preventing coagulation, but is much less used as it needs to be given by injection.
Several trials have shown that aspirin is quite effective in protecting against heart attack, particularly a second one. It is less effective in protecting against stroke and for "serious" stroke protection in high-risk individuals warfarin is currently the drug of choice. Warfarin is also more effective in preventing deep vein thrombosis, a condition often leading to pulmonary embolism.
Warfarin was first isolated in the 1920s after farmers noted that their cows often bled to death after eating spoiled sweet clover. It was patented as a powerful rat poison in 1948. By the mid-fifties it was beginning to be used as an anticoagulant in humans. The drug lost in popularity during the 1970s when it was realized that it probably caused as many deaths from bleeding as it prevented deaths from stroke. One of the major problems was the need to adjust the dosage for each individual patient. This, combined with the fairly unreliable test methods used at the time, resulted in a less than sterling experience with the drug. For the last 20 years warfarin has experienced a resurgence, partly because of the development of an improved test for bleeding time (International Normalized Ratio) and partly because of a superb marketing campaign by the manufacturer of Coumadin.
Several studies were carried out in the early 1990s to determine the effectiveness of warfarin in preventing stroke in atrial fibrillation patients. Unfortunately, these studies did not distinguish between AF with underlying heart disease and AF without heart disease (lone atrial fibrillation). One major trial (SPAF II) specifically excluded lone afibbers and all trials included a large proportion of patients not only with heart disease, but also with one or more risk factors for stroke (hypertension, diabetes, heart failure or a prior stroke or TIA). Thus the applicability of the trial data to lone afibbers, and in particular lone afibbers without risk factors, is very much in doubt. The average annual rates of ischemic stroke among all patients included in the five trials were as follows:
It is clear that there is no reason to prescribe warfarin for afibbers below the age of 65 years who have no additional risk factors for stroke and indeed this is fully recognized in the current guidelines for the management of atrial fibrillation.
The data would, however, indicate that prescribing warfarin for afibbers over the age of 75 years having one or more risk factors might be prudent. The SPAF II trial found that the risk of an ischemic stroke in this age group was 3.6% when on warfarin and 4.8% when on aspirin. However, when looking at the combined total of fatal and disabling ischemic and hemorrhagic strokes there was little difference – 4.6% in the warfarin group and 4.3% in the aspirin group. So again, the wisdom of prescribing warfarin rather than aspirin for older afibbers is by no means clear-cut. It should also be kept in mind that the SPAF II trial was a clinical trial with frequent and accurate monitoring of INR levels. Even though close monitoring would presumably reduce the risk of major bleeding, the SPAF II study found the risk of major internal bleeding in patients over 75 years to be 4.2%, thus largely cancelling out the benefit of ischemic stroke protection.
More recently, a group of American researchers evaluated stroke risk among 700 elderly participants (mean age of 75 years) in the Framingham Heart Study and concluded that afibbers with a predicted annual stroke risk of 2% or less (irrespective of age) may not realize additional benefit from warfarin compared with aspirin and their risk of stroke may not exceed the risk of life-threatening bleeding with warfarin. Thus anticoagulation therapy may not be justified in individuals with low predicted rates of stroke[7,8].
A team of American, Canadian, Dutch, and Danish medical researchers looked at the effectiveness of warfarin therapy among participants in six major trials. The annual rate of stroke in the low-risk group (no hypertension, angina or diabetes and no history of stroke or TIA) was 1.5% on warfarin as compared to 1.0% with aspirin and 1.2% in an age and gender matched cohort without afib. The stroke risk in the remaining moderate- to high-risk group was 3.4% per year with warfarin, 4.2% with aspirin, and 1.3% in an age and gender matched cohort without afib or risk factors. The researchers conclude that, irrespective of age, afibbers who satisfy the criteria for low risk can safely take aspirin for stroke prevention and would not benefit from oral anticoagulation. They estimate that about one quarter of all afibbers would fall in the low-risk group.
Researchers at Kaiser Permanente in northern California recently concluded that results regarding warfarin efficacy obtained in tightly controlled clinical trials may not necessarily be indicative of what is going on in the "real world". They followed 11,526 patients with nonvalvular atrial fibrillation for an average of 2.2 years (25,341 person years). About half the patients (6,320) were treated with warfarin while the remainder (5,089) took daily aspirin or used no drugs for stroke prevention. The average age of the patients was 71 years with about 40% being over the age of 74 years and about 24% being below the age of 65 years. Most of the participants had one or more risk factors for stroke (previous ischemic stroke [8%], heart failure [28.5%], hypertension [50.1%], diabetes [16.8%], and coronary heart disease [27.7%]). Almost half (43%) of patients were women. This survey population thus has little in common with a representative group of lone afibbers.
During the follow-up period the researchers observed 141 ischemic strokes, 59 hemorrhagic strokes (intracranial bleeding), and 118 major gastrointestinal bleeds in the warfarin group and 231 ischemic strokes, 29 hemorrhagic strokes, and 119 major gastrointestinal bleeds in the aspirin/no drug therapy group. Results are detailed below.
* Assuming that these rates are independent of ischemic stroke risk factors
In reviewing the above results it should be kept in mind that a hemorrhagic stroke can be just as devastating as an ischemic stroke, so what really matters to the patient is the combined incidence of the two. The incidence of major gastrointestinal hemorrhage (defined as death or hospitalization requiring blood transfusion) was similar in the two groups at about 1% per year. This is no doubt due to the fact that the non-warfarin group included patients taking aspirin. Regular aspirin usage has been associated with a 2.5% annual bleeding risk in other studies.
It is clear that warfarin does indeed have a moderate overall beneficial effect on the incidence of stroke (ischemic and hemorrhagic) in patients with non-valvular atrial fibrillation. For every 100 patients treated with warfarin for a year 0.53 strokes are avoided. This corresponds to a relative risk reduction of 25% when compared to patients taking aspirin or using no drug therapy. The benefit of warfarin therapy is substantial for patients having suffered a prior ischemic stroke (4.85 strokes per year avoided or a 63% benefit), but non- existent for afibbers with no risk factors for stroke (zero strokes per year avoided or a 0% benefit). This finding, of course, is in line with numerous previous studies. The benefit of warfarin therapy for afibbers with hypertension is 0.73 strokes avoided per year for a relative benefit of 26%. This is significant, but not impressive.
Overall, it is apparent that 1,000 patients need to be treated with warfarin for a year in order to prevent 5.3 strokes. Treating one patient for a year would cost an estimated $830 (8 lab tests @ $50/test + 4 doctor's visits per year @ $75/visit + drug cost @ $130). Thus treating 1,000 patients would cost $830,000 or $157,000 per annual stroke avoided. The cost per annual stroke avoided in patients with a prior stroke would be $20,000 and that for patients with hypertension $86,000 per stroke per year. The cost would, of course, be astronomical for patients with no risk factors.
The Kaiser Permanente researchers conclude that, "Warfarin is very effective in preventing ischemic stroke in patients with atrial fibrillation in clinical practice while the absolute increase in the risk of intracranial hemorrhage is small".
I find this conclusion hard to reconcile with the actual data presented in the report. I would conclude that warfarin therapy is contraindicated for afibbers without risk factors, is quite effective for patients with heart failure and for those who have suffered a stroke previously, and is marginally effective for afibbers with hypertension. However, the cost of warfarin therapy to the healthcare system is considerable with an estimated annual cost of about $86,000 per stroke avoided among afibbers with hypertension.
A group of 7500 California Medicaid recipients with afib and one or more of the following conditions – hypertension (58%), congestive heart failure (48%), diabetes (34%), prior stroke (17%) or prior heart attack (14%) participated in a recent study to evaluate the effectiveness of warfarin therapy. During follow-up stroke occurred in 514 patients with a rate of 3.4 per 100 person-years in patients treated with warfarin and a rate of 4.1 per 100 person-years for those not on warfarin. This corresponds to an overall absolute risk reduction of 0.7% per year. Bleeding occurred in 302 patients with a rate of 3.0 per 100 person-years in patients treated with warfarin and a rate of 2.2 per 100 person-years for those not on warfarin. This corresponds to an absolute increase in bleeding risk of 0.8% per year. The researchers conclude that, "Warfarin therapy, in clinical practice, has a relatively modest benefit in terms of reducing stroke rates, with the greatest benefit occurring among patients with moderate stroke risk. However, this benefit is somewhat offset by the increased risk of bleeding events".
Unfortunately, quite apart from its limited efficacy, warfarin also has other significant shortcomings:
The many shortcomings of warfarin and the relative under-utilization of anticoagulation for prevention of thrombosis and embolism have led to a concerted effort to find an effective replacement. It now appears that the search may have succeeded with the development of the new oral anticoagulant ximelagatran.
Ximelagatran (Exanta) was developed by the Swedish arm of AstraZeneca and by now is probably one of the most carefully tested of all pharmaceutical drugs. Ximelagatran or rather its metabolite, melagatran, prevents blood coagulation by directly inhibiting the final step in the coagulation process – namely, the conversion of fibrinogen to insoluble fibrin by thrombin. Warfarin, on the other hand, works less directly by reducing the blood level of vitamin K-dependent coagulation factors. Early clinical trials of ximelagatran concluded that it has many advantages over warfarin.
It is clear that ximelagatran has many advantages over warfarin, but is it equally effective?
Clinical trials of ximelagatran
Ximelagatran in heart disease patients
Ximelagatran in prevention of venous thromboembolism
Ximelagatran after knee replacement
A group of researchers from Brazil, Canada, Israel, Mexico and the United States has just completed a study to determine the relative efficacy of warfarin and ximelagatran in the prevention of venous thromboembolism after total knee replacement. The 1851 study participants were randomized to receive warfarin (INR = 2.0-3.0) or 24 mg or 36 mg of oral ximelagatran twice daily for 7-12 days following surgery. At the end of the trial 128 patients in the 36 mg ximelagatran group (20%) had either died or developed venous thromboembolism while 168 patients in the warfarin group (28%) had done likewise. Minor or major bleeding occurred in 5.3% of the patients in the 36 mg ximelagatran group and in 4.5% of those in the warfarin group. (NOTE: This after only 7-12 days of therapy). Levels of alanine aminotransferase were not noticeably elevated in either group after this short treatment. The researchers conclude that 36 mg of ximelagatran administered twice daily is superior to warfarin in preventing venous thromboembolism following total knee replacement.
Ximelagatran in atrial fibrillation
Ximelagatran is superior to warfarin in ease of administration and control. The dosage is fixed at 24 or 36 mg twice daily and no monitoring of coagulation parameters is required. It also has the great advantage of not being affected by different foods, herbs and supplements and not interacting with other commonly used drugs. However, liver enzymes do need to be checked monthly for the first 6 months of therapy.
Ximelagatran has now successfully passed phase III trials and is awaiting approval in Europe, the USA and Canada.
While ximelagatran would likely be advantageous for afibbers with one or more risk factors for stroke, I do not believe it would be any more appropriate for afibbers with no risk factors than is warfarin.
International Health News and The AFIB Report are published 10 times a year by Hans R. Larsen MSc ChE
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International Health News and The AFIB Report do not provide medical advice. Do not attempt self- diagnosis or self-medication based on our reports. Please consult your health-care provider if you wish to follow up on the information presented.