SPORTIF V: Ximelagatran noninferior to warfarin for stroke prevention in AF

Susan Jeffrey

November 11, 2003

Orlando, FL - Eagerly awaited results of a randomized, double-blind trial comparing dose-adjusted warfarin with the oral direct thrombin inhibitor ximelagatran (Exanta®, AstraZeneca) in high-risk patients with nonvalvular atrial fibrillation show that the new agent met criteria for noninferiority, suggesting that it is at least as effective as well-controlled warfarin for the prevention of stroke and systemic embolic events.

There was no difference in major bleeding between groups, but major and minor bleeding combined was significantly less frequent in patients treated with ximelagatran.

Elevations in liver enzymes seen in previous studies with the new agent were again evident in 6% of patients during the first two to six months of treatment, compared with 0.8% among those on warfarin. However, levels generally returned toward baseline whether or not treatment was continued.

The results, from the fifth Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF V) trial, were presented here today at the American Heart Association Scientific Sessions.

"The encouraging findings in the SPORTIF program support a role for ximelagatran as a new treatment option for prevention of thromboembolism," Dr Jonathan L Halperin (Mount Sinai School of Medicine, New York, NY) concluded during his presentation. "Oral direct thrombin inhibition offers an exciting new opportunity to extend treatment more broadly and reduce the threat of stroke faced by millions of people with atrial fibrillation."

Definitive result

The SPORTIF trials in patients with AF are part of a larger program of research by AstraZeneca with this new agent in a variety of indications, including prophylaxis of venous thromboembolic events (VTE) after orthopedic surgery, chronic VTE prophylaxis after a first episode of deep venous thrombosis or pulmonary embolism, and acute coronary syndromes.

Warfarin has been shown in many studies to effectively reduce the risk of stroke in patients with AF, but the cumbersome process of anticoagulation monitoring means that many don't comply with therapy. Those who do take warfarin often are not within therapeutic INR ranges, putting them at continued risk for thrombotic complications if INRs are too low or for bleeding if they are too high.

The hope for ximelagatran is that it can be given as a fixed dose, without the need for either titration or ongoing anticoagulation monitoring. However, findings in previous studies with the agent have raised some concern about elevations in liver enzymes with ximelagatran; if liver-enzyme monitoring were required on an ongoing basis, it might undermine the advantage of fixed dosing.

SPORTIF III, for example, a study first presented at the American College of Cardiology annual meeting in March 2003 and reported at that time by heartwire , was a randomized but open-label comparison of ximelagatran with warfarin in patients with AF. Results suggested that the new drug was as effective as warfarin in preventing stroke and systemic embolic events, with less overall bleeding. However, elevated liver enzymes were seen significantly more often with ximelagatran than with warfarin, although all elevations resolved either spontaneously or with withdrawal of the drug, the researchers noted. SPORTIF V, a double-blind, randomized study, was meant to be the definitive trial of ximelagatran in this indication.

SPORTIF V

SPORTIF V included 3922 patients from 409 sites in the US and Canada. Eligible patients had nonvalvular AF and one other stroke risk factor, including age 75 or older, prior stroke, or history of congestive heart failure or hypertension.

Participants were randomized to receive either a fixed dose of ximelagatran, 36 mg twice daily, or dose-adjusted warfarin with a target INR of 2.0-3.0. To preserve blinding for this trial, patients receiving ximelagatran underwent sham testing and dosage changes for placebo warfarin. The dose of ximelagatran did not change.

The primary objective was to show whether ximelagatran is noninferior to dose-adjusted warfarin for the prevention of all strokes (ischemic and hemorrhagic) and systemic embolic events, with an absolute rate of events within a margin of 2% per year.

Warfarin was given with "extreme care" in this trial, Halperin said: The INR on warfarin was within the target range 68% of the time and within an extended INR range (1.8-3.2)where no dose adjustment would be deemed necessary 83% of the time.

The difference in primary-event rates by intention-to-treat analysis fell within the noninferiority parameters, with an absolute difference of 0.45% per year between groups (p=0.13).

SPORTIF V: Primary end point

End point

Ximelagatran

Warfarin

Absolute difference (95% CI)(%/yr)

Stroke/SEE 51 (1.6%/year) 37 (1.2%/year) 0.45% (-0.13%-1.03%)
SEE=systolic embolic events

By on-treatment analysis, the absolute difference was +0.55% per year (95% CI -0.06%-1.16%, p=0.089) for ximelagatran vs warfarin, and when all-cause mortality was included with the primary events, the rate difference between groups by intention to treat was +0.10% per year (95% CI -0.97%-1.18%, p=0.86) with the new agent compared with warfarin.

Rates of intracerebral hemorrhage and major bleeding—defined as bleeding that was fatal, affected a critical anatomical site, required transfusion, or decreased hemoglobin by 2 g/dL—were low and not significantly different between groups, with a trend for major bleeding that favored ximelagatran. When all bleeding was considered, there was a statistically significantly lower rate of major and minor bleeding with ximelagatran compared with warfarin.

SPORTIF V: Safety

End point

Ximelagatran (%/y)

Warfarin (%/y)

p

  0.06 0.06 NS
  2.4 3.1 0.16
  37 47 <0.0001
 
Ximelagatran is noninferior to warfarin for the prevention of stroke and systemic thromboembolism and was associated with less bleeding.
 

Halperin noted that the results were similar to those seen in SPORTIF III in that "both trials show that ximelagatran is noninferior to warfarin for the prevention of stroke and systemic thromboembolism and was associated with less bleeding."

The researchers also calculated the net clinical benefit of treatment with ximelagatran vs warfarin by comparing the combined rates of the primary end point, major bleeding and death, he added. "These are similar for both treatment groups in the SPORTIF V cohort, but pooling the data from the two studies (SPORTIF III and V) yields a statistically significant reduction favoring ximelagatran."

Liver-enzyme elevations

Elevations of serum transaminase enzymes in the ximelagatran group reached beyond three times the upper limit of normal in 6% of ximelagatran patients, compared with 0.8% in the warfarin group, he noted. "This typically occurred within two and six months after initiation of treatment and then normalized whether or not treatment was continued," Halperin said. "Clinical sequelae are rare, but one patient developed fatal gastrointestinal hemorrhage after corticosteroid treatment for hepatitis associated with ximelagatran."

As seen in SPORTIF III, he added, serum bilirubin levels rose above twice the upper limit of normal in a small number of those with serum transaminase enzyme elevations in each treatment group. In SPORTIF V, there were nine such cases in those assigned to ximelagatran and one on warfarin, he said.

"Based on the global experience and information available from trials of ximelagatran in other thromboembolic disease states, surveillance of serum enzyme activity seems appropriate during the early months of treatment," Halperin added.

He noted, though, that like many safety issues, this would not be adequately studied until the drug is brought to market and used more widely in practice.

"We can't speak yet to what the recommendations will be when the drug is finally approved, and we also can't speak to what the experience will be with this drug when it's more widely used," Halperin told a press conference here. "But I will say that I think it's prudent to monitor liver function tests, about once a month from the beginning of treatment with ximelagatran, for about the first six months."

On balance, an advance over warfarin

Discussant for the trial after the presentation was Dr Michael D Ezekowitz (MCP Hahnemann University School of Medicine, Philadelphia, PA). He called SPORTIF V a "landmark study," noting that it is the largest trial conducted to date in AF, and he congratulated the researchers on "getting the dose right" for ximelagatran so quickly, a feat that took about 50 years with warfarin.

Ezekowitz pointed out that stroke rates in this trial with both warfarin and ximelagatran were in the range of 1% to 2% and "remarkably low." Without treatment, high-risk patients like those included in the study would have an expected risk of "somewhere in the 6% to 7% per year range," he noted.

 

I think...this is a huge advance on what we currently have, all things being considered.

 

The biggest issue that still needs to be addressed in his view, however, relates to the liver-function abnormalities. The researchers presented the data in a balanced fashion, he noted, but added, "I do think, though, that we need more data on these abnormalities. As has been pointed out, they seem to resolve, even with continuation of the drug, and certainly with withdrawal of the drug."

In the future, drugs that would not produce this liver function signal or that could be given once a day would be preferable, leaving open future opportunities for efforts to develop other alternatives to warfarin, Ezekowitz said.

Still, he concluded, "I think, in summary, this is a huge advance on what we currently have, all things being considered. I have no role in whether the drug will be approved or not, but my impression is that it should be approved, and the suggestion that the [liver function] abnormalities be monitored closely I think is a good one."

In a press release, AstraZeneca vice president Hamish Cameron is quoted saying that the SPORTIF program will be the key element in the company's regulatory submissions supporting use of the drug for the prevention of stroke and systemic embolic events in patients with AF. The submission, planned for the end of the current year, will include evaluation of the drug's risk/benefit profile from studies in more than 30,000 patients.

 

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