SPORTIF V: Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation V

Linda Brookes, MSc

Disclosures

December 30, 2003

Editorial Collaboration

Medscape &

Presenter: Jonathan L Halperin, MD (Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, NY)

The results of the latest phase 3 trial with the novel oral direct thrombin inhibitor (DTI) ximelagatran (Exanta; AstraZeneca, United Kingdom) appear to provide further support for the drug as an alternative to warfarin for prevention of stroke and systemic embolic events (SEE) in patients with atrial fibrillation (AF) -- but without warfarin's well-known limitations, which include serious drug interactions, the need for coagulation monitoring, dose titration, and concerns over bleeding.[1] Questions about liver toxicity associated with the drug were again voiced, but in the opinion of the trial investigators, these effects are transitory and can be managed with careful monitoring.

SPORTIF Program

The Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) program has been investigating the safety and efficacy of ximelagatran for the prevention of stroke in patients with AF. A phase 2 study, SPORTIF II, and its extension trial, SPORTIF IV, demonstrated the safety and efficacy of ximelagatran compared with warfarin in patients with nonvalvular AF. The program also included 2 long-term, phase 3 clinical trials of the safety and efficacy of ximelagatran compared with warfarin in patients with AF at high risk of ischemic stroke (SPORTIF III and SPORTIF V).[2] The results of SPORTIF III, a trial carried out in Asia, Australia, and Europe, were presented at the American College of Cardiology Annual Scientific Sessions earlier this year.[3]

SPORTIF V, a North American trial, has now reported the same findings. The protocols of SPORTIF III and SPORTIF V were identical, except that SPORTIF III had an open-label design with blinded event assessment and SPORTIF V had a double-blind design. In both trials, patients were randomized to warfarin (dose-adjusted to maintain the INR between 2.0 and 3.0 based on monthly measurements of prothrombin time) or to ximelagatran at a fixed dose of 36 mg twice daily.

SPORTIF V

SPORTIF V enrolled a total of 3922 patients (1960 randomized to ximelagatran and 1962 randomized to warfarin), aged ≥ 18 years, at 409 sites in the United States and Canada. Eligibility for the trials was based on clinical indications for anticoagulation for patients with nonvalvular AF, including at least 1 additional risk factor for stroke: eg, previous stroke, previous systemic embolism, hypertension, left ventricular dysfunction, age ≥ 75 years or age ≥ 65 years if coronary artery disease or diabetes mellitus was present. The population consisted mainly of white males, the mean age was 72 years (40% were older than 75 years), about 25% had a history of stroke or transient ischemic attack, about 40% had heart failure or left ventricular systolic dysfunction, and 80% had hypertension.

Follow-up included regular screening for stroke symptoms and multiple levels of blinded endpoint assessment, including evaluation by local, study-affiliated neurologists and a review of all detected events by a central events adjudication committee. The protocol stipulated a minimum of 12 months/patient exposure, an aggregate follow-up of > 4000 patient-years, and accumulation of at least 80 primary events.

Patients were treated for a mean of 20 months (> 6400 patient-years). Warfarin was well controlled during the study, similar to the controls in SPORTIF III, but within INR limits seldom achieved in clinical practice: mean INR on warfarin during the study was 2.4 ± 0.8 and was within the target range (2.0-3.0) for 68% of the time and in the extended range of 12.8-3.2 for 83% of the time.

Outcome Analyses

The primary analysis was based on intention-to-treat and compared the combined rates of all strokes (ischemic or hemorrhagic) and systemic thromboembolic events in patients on ximelagatran compared with those on warfarin. Sensitivity analyses were based on primary events plus all-cause mortality and assessment of efficacy by on-treatment analysis. Since the established efficacy of warfarin made a placebo-controlled design unethical, the trial was carried out with the objective of evaluating whether ximelagatran was at least as effective as warfarin within a prespecified margin of 2% for the difference in rates of primary events. This "noninferiority" design differs from the conventional superiority trial design and from a comparison based on proving equivalence to an active control.

The primary efficacy endpoint was met, showing that fixed-dose, twice-daily oral ximelagatran at a dose of 36 mg is noninferior to dose-adjusted warfarin in preventing stroke and SEE. Fifty-one events occurred in the patients on ximelagatran (1.6% per year) vs 37 in those on warfarin (1.2% per year) (Table).

Table. Primary Analyses
Warfarin Ximelagatran
No. of primary events 37 51
Primary event rate (%/yr) 1.2 1.6
Absolute difference in primary event rates (ITT) 0.45 (95% CI -0.13,1.03); P = .13
Absolute difference in primary event rates (OT) 0.55 (95% CI -0.06,1.16); P = .089
ITT, intention to treat; OT, on treatment.

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 = .86).

The design of both SPORTIF III and V allowed for a pooled analysis of the results. In the combined studies, a total of 91 on ximelagatran had primary events compared with 93 on warfarin (1.6% vs 1.6% per year; absolute difference in event rates, -0.03).

Rates of disabling or fatal stroke, hemorrhagic stroke, and major bleeding did not differ significantly between the ximelagatran and warfarin groups, but combined major and minor bleeding events were significantly lower with ximelagatran than with warfarin (37% vs 47%, respectively, P < .0001).

Overall, a statistically significant net clinical benefit is seen for ximelagatran from the pooled data of both the SPORTIF V and SPORTIF III studies. In an assessment of the combined rates of deaths, primary events, and major bleeding while on treatment, 5.2% events were seen with ximelagatran compared with 6.2% with warfarin (P = .038), amounting to a relative risk reduction of 16% (Figure 1).

Figure 1. SPORTIF: net clinical benefit of death, primary events, and major bleeding with on-treatment analysis).
Liver Enzyme Elevations

An elevation of liver enzymes (serum alanine aminotransferase (ALT) beyond 3 times the upper limit of normal (> 3 × ULN) was observed in 6% of patients treated with ximelagatran in SPORTIF V compared with 0.8% of patients on warfarin (P < .001). This typically occurred 2-6 months after initiation of treatment, after which ALT levels returned to normal, whether or not treatment was continued. One patient in SPORTIF V developed fatal gastrointestinal hemorrhage after corticosteroid treatment for hepatitis associated with ximelagatran. An incidence of elevated bilirubin > 2 × ULN following ALT > 3 × ULN was seen in 9 ximelagatran patients vs 1 warfarin patient.

The experience in SPORTIF V was consistent with that of SPORTIF III (Figure 2). In SPORTIF III, more than half the patients who developed the liver abnormality continued the drug, and their liver enzymes returned to normal.

Figure 2. SPORTIF: liver enzyme elevation (ALT > 3 x ULN).

Dr Halperin declined to comment on what recommendations would be made if ximelagatran is approved or what the experience will be when the drug is used more widely. However, he recommended liver function tests about once per month at the beginning of treatment with ximelagatran and for the first 6 months thereafter. If elevations in liver enzymes occur, then the drug should be interrupted. He would expect liver function then to normalize. The serum ALT elevation is a transient phenomenon, he believes.

Investigators Are Optimistic

"If a person can take warfarin and take it well, it is highly effective at preventing strokes. It is a real problem, however, to deliver the drug consistently to patients, particularly the elderly, as it requires close coagulation monitoring and dose titration," Dr. Halperin commented. "The risk of stroke, as well as the difficulties of using warfarin, particularly the increased risk of bleeding, increase with age, leaving too many patients undertreated. Ximelagatran represents an exciting new approach to anticoagulation, as the SPORTIF V results show. We may be able to offer our patients a much-needed, consistently efficacious alternative to warfarin treatment that does not have the limitations inherent in coagulation monitoring or dose titration," Dr. Halperin concluded.

Ximelagatran Seen as "Huge Advancement"

Congratulating the SPORTIF V investigators, the officially AHA-designated discussant Michael D Ezekowitz, MD (MCP/Hahnemann University, Philadelphia, Pennsylvania) praised them for having established the correct dose for ximelagatran in such a short time compared with the 50 years it took to do so for warfarin. He noted that stroke rates in SPORTIF V were very low -- he had himself calculated the risk in these high-risk patients as being 6% to 7%.

He cautioned that the issue of ALT elevations should be addressed and more data obtained on the liver function test abnormalities. There is still the potential for developing alternatives to warfarin that do not have this problem, he suggested. Since the drug is renally excreted, patients with severe renal disease would need dose adjustments, he added.

For the treatment of AF, a drug that can be given once daily would probably be preferable to ximelagatran, which is given twice daily, he suggested. He added, however, that the twice-daily drug is clearly a major advance over what is currently available.

Dr. Ezekowitz praised ximelagatran as a huge advance over warfarin and, noting that he himself had no interest or role in the drug's development, said that he believed it should be approved by the regulatory authorities.

Regulatory Submissions for Ximelagatran

The combined data from SPORTIF III and SPORTIF V are expected to form the basis for regulatory submissions in the United States and Europe supporting the use of the drug for the prevention of stroke in patients with AF.

References
  1. Halperin JL, for the Executive Steering Committee on behalf of the SPORTIF V Investigators. Stroke Prevention Using the Oral Thrombin Inhibitor Ximelagatran in Patients with Nonvalvular Atrial Fibrillation V – SPORTIF V. Program and abstracts from the American Heart Association Scientific Sessions 2003; November 9-12, 2003; Orlando, Florida. Plenary Session VII: Late Breaking Clinical Trials.

  2. Halperin JL, for the Executive Steering Committee, SPORTIF III and V Study Investigators. Ximelagatran compared with warfarin for prevention of thromboembolism in patients with nonvalvular atrial fibrillation: Rationale, objectives, and design of a pair of clinical studies and baseline patient characteristics (SPORTIF III and V). Am Heart J. 2003;146:431-438.

  3. Halperin JL. SPORTIF III: A long-term randomized trial comparing ximelagatran with warfarin for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Program and abstracts from the American College of Cardiology 62nd Annual Scientific Sessions; March 30-April 2, 2003; Chicago, Illinois. Late Breaking Clinical Trials III. #421-9.

processing....