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

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[4]:

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[5].

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[6].

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[9].

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[10].

* Assuming that these rates are independent of ischemic stroke risk factors
A = ischemic + hemorrhagic stroke
B = ischemic + hemorrhagic stroke + major bleeding

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[11].

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"[12].

Unfortunately, quite apart from its limited efficacy, warfarin also has other significant shortcomings:

• Reliably maintaining an INR within the customary range of 2.0 to 3.0 is still a very dicey proposition. Two recent, tightly-controlled clinical trials found that only 57% and 66% respectively of participants were consistently within the desired range during the trial[13,14]. The number of patients within the range in a much less controlled actual daily practice would be considerably lower. Having an INR above 3.0 increases the risk of internal bleeding while having an INR below 2.0 significantly increases the risk of thrombus formation.

• Appropriate monitoring of INR levels requires frequent visits to a testing laboratory resulting in considerable inconvenience to the patient and a significant financial burden on the health care system.

• INR levels are strongly affected by many foods and herbs adding further to the difficulty of maintaining the desired ratio.

• Warfarin interacts with at least 60 common drugs. Some of the interactions, particularly with acetaminophen (Tylenol, Paracetemol), can be fatal as a combination of warfarin and acetaminophen can raise INR to 6.0 or higher[15-17].

• Warfarin can cause hemorrhagic stroke, gastrointestinal bleeding, osteoporosis and bone fractures (with long-term use), skin necrosis in some cases involving amputation of breast or penis, and no doubt a host of other less common complications[15,18].

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

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.

• One size fits all. Two 36 mg tablets of ximelagatran taken daily provide anticoagulation equivalent to or better than that afforded by warfarin. There is no need for periodic monitoring of clotting time.

• Ximelagatran is not metabolized by the cytochrome P450 enzyme system in the liver so it's effect is not altered by foods, herbs or supplements. There is no need to be concerned about what foods or supplements are safe to take when on ximelagatran.

• There are no known interactions between ximelagatran and other pharmaceutical drugs.

• Ximelagatran does increase bleeding risk, but the increase in risk is no greater than what is experienced with warfarin in the 2.0-3.0 INR range.

• Ximelagatran has no known major adverse effects in the short-term (about 18 months); however, it is not known whether it may have adverse effects in the long-term. A significant elevation in liver enzymes has been noticed in about 5% of patients, but this increase usually disappears with continued use or can be reversed by discontinuing the drug.

It is clear that ximelagatran has many advantages over warfarin, but is it equally effective?

Clinical trials of ximelagatran
Several clinical trials have evaluated the effectiveness of ximelagatran as compared to warfarin. For ethical reasons, ximelagatran has not been evaluated against placebo. One trial involved heart attack patients, two trials involved patients with venous thromboembolism while the five SPORTIF (Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation) trials involved patients with atrial fibrillation.

Ximelagatran in heart disease patients
This trial (ESTEEM) involved 1833 patients who had suffered a heart attack. The patients were randomized to placebo or 24 mg, 36 mg, 48 mg or 60 mg of ximelagatran twice daily. All participants also received 160 mg of aspirin daily. During the 6-month duration of the trial 16.3% of the placebo group members suffered another non-fatal heart attack, died or developed severe recurrent ischemia. The corresponding number for the combined ximelagatran groups was 12.7% indicating that adding ximelagatran to a daily aspirin can reduce risk by an absolute 3.6% or a relative reduction of 22% over and above the protection provided by aspirin alone. The incidence of major bleeding was 1.8% in the combined ximelagatran group and 0.9% in the aspirin only (placebo) group. The concentration of the liver enzyme, alanine transaminase, was more than 3 times the upper normal limit in 4% of the participants receiving 24 mg of ximelagatran twice daily as compared to 1% in the placebo group. The underlying mechanism for this increase is under investigation. No major adverse effects were observed during the 6-month trial. The researchers conclude that aspirin plus 24 mg of ximelagatran twice daily provides an absolute additional risk reduction of 4% over aspirin alone, has an acceptable risk of major bleeding, and a manageable rise in liver enzymes. It is of interest to note that the total incidence of internal bleeding (minor and major) was 22% in the combined ximelagatran group versus 13% in the aspirin only group[19].

Ximelagatran in prevention of venous thromboembolism
This Swedish trial involved 1233 patients from 18 countries with confirmed venous thromboembolism who had been treated for 6 months with anticoagulant therapy without reoccurrence of thromboembolism. The participants were randomized to receive placebo or 24 mg of ximelagatran twice daily for an 18-month period after discontinuing warfarin therapy. No coagulation tests were carried out during the trial period. At the end of the period 12 patients (2%) in the ximelagatran group had experienced a new thromboembolism versus 71 patients (12%) in the placebo group – a 10% absolute and an 84% relative risk reduction. The risk of minor or major internal bleeding was 22% and 18% in the ximelagatran and placebo groups respectively. Major hemorrhage accounted for about 1% in each group. The cumulative incidence of elevation of alanine aminotransferase to more than 3 times upper normal level was 6.4% in the ximelagatran group and 1.2% in the placebo group. The researchers conclude that oral ximelagatran is effective in extended prevention of venous thromboembolism[20].

Ximelagatran after knee replacement
Venous thromboembolism occurs in 40 to 84% of patients undergoing total knee replacement if they do not receive anticoagulation therapy. About 7% of patients experience a pulmonary embolism and in about 0.2 to 0.7% of cases the embolus is fatal. Anticoagulation with warfarin reduces the incidence of venous thromboembolism to about 47%.

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[21].

Ximelagatran in atrial fibrillation
Following a small preliminary trial (SPORTIF II) to investigate optimal dosing and alleviate safety concern two major trials were undertaken to evaluate the efficacy of ximelagatran in stroke prevention among patients with non-valvular atrial fibrillation[4]. SPORTIF III involved 3407 patients from 23 countries and SPORTIF V involved 3922 patients from 409 locales in North America. All study participants had one or more risk factors for stroke (about 40% had coronary artery disease and about 75% had hypertension) and 89% of participants had persistent rather than paroxysmal afib. Thus results are not directly applicable to paroxysmal afibbers with no risk factors for stroke. The 7300 high-risk patients were randomized to receive either 36 mg of ximelagatran twice daily or warfarin adjusted to an INR of 2.0-3.0. After an average follow-up of about 18 months 91 patients (1.6%) in the combined ximelagatran groups (SPORTIF III and V) had suffered an ischemic or hemorrhagic stroke or had experienced a systemic thromboembolic event. The corresponding figure for the combined warfarin groups was 93 patients (1.6%). Minor and major bleeding events were significantly lower in the ximelagatran groups at 37% versus 47% in the warfarin groups (NOTE: A rate of 37% or 47% of patients experiencing internal bleeding during an 18-month period is still, or ought to be, a major cause for concern). If deaths, strokes and major bleeding events were combined the incidence was 5.2% in the ximelagatran groups compared to 6.2% with warfarin. A significant relative risk reduction of 16%. Elevated liver enzyme levels (alanine aminotransferase) were noted in about 6% of ximelagatran users and in about 1% of warfarin users. The investigators conclude that fixed dose ximelagatran is at least as effective as well-controlled warfarin in preventing stroke and systemic embolism in high-risk patients with atrial fibrillation[14,22,23].

Conclusion
Trials involving close to 10,000 patients have shown that ximelagatran is equivalent or superior to warfarin in preventing stroke and systemic embolism. Bleeding rates are similar, although, in my opinion, unacceptably high if applied to patients at low risk for stroke. Significant elevation of liver enzymes occurs in about 5% of patients on ximelagatran, but appears to be fully reversible. No major adverse effects have been observed in trials lasting up to 20 months, but longer term effects are unknown.

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.

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