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DewDiligence

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Re: DewDiligence post# 52404

Saturday, 01/26/2008 5:47:49 PM

Saturday, January 26, 2008 5:47:49 PM

Post# of 252819
Idraparinux Causes Excess Bleeding in A-Fib Patients

[This is a big story insofar as biotinylated idraparinux (SSR126517), an injectable FXa inhibitor, was one of the drugs with which SNY had hoped to replace Lovenox revenue when Lovenox generics eventually hit the market. In the phase-3 trial reported here, idraparinux had efficacy similar to warfarin in preventing stroke and embolism, but it caused statsig greater bleeding. This outcome puts the further development of idraparinux very much in doubt, IMO.]

http://www.medpagetoday.com/Cardiology/Arrhythmias/tb/8108

>>
By Todd Neale
January 25, 2008

AMSTERDAM, Jan. 25 -- Significant excess bleeding (P<0.0001) halted a trial of idraparinux for stroke prevention in patients with atrial fibrillation.

Before the trial was stopped, idraparinux had efficacy similar to that of the vitamin K antagonists, the standard treatment for preventing thromboembolism in these patients (HR 0.71, 95% CI 0.39 to 1.30, P=0.007 for noninferiority), reported Harry Buller, M.D., of Academic Medical Center here, and colleagues in the Jan. 26 issue of The Lancet.

In an accompanying comment, Alan Go, M.D., of Kaiser Permanente in Oakland, Calif., and Daniel Singer, M.D., of Harvard and Massachusetts General Hospital in Boston, wrote that the push to find new medications to prevent thromboembolism in atrial fibrillation patients is fueled by the problems associated with vitamin K antagonists, particularly the need for constant monitoring, despite their effectiveness.

The safety and efficacy of vitamin K antagonists depend on maintaining a narrow range of anticoagulation intensity, they wrote. "This goal is complicated by the fact that the effect of these drugs is altered by underlying genotype, coexisting illnesses, dietary intake, and exposure to other drugs, which necessitates frequent INR testing and dose adjustment."

Idraparinux, which inhibits activated factor X, would require only fixed weekly dosing without constant coagulation monitoring, Dr. Buller and colleagues theorized.

So they initiated the Amadeus trial, a multicenter, randomized, open-label, noninferiority trial with a blinded outcome assessment. The researchers randomized 2,283 participants to 2.5 mg of subcutaneous idraparinux once a week and 2,293 participants to the vitamin K antagonists warfarin or acenocoumarol with INR of 2.0 to 3.0.

For patients with calculated creatinine clearance at baseline of 10 to 30 mL/min, dosing with idraparinux was changed to 1.5 mg from the second dose through the end of the study.

All participants (mean age 70.1) had atrial fibrillation with an indication for long-term anticoagulation.

Primary efficacy outcome was the cumulative incidence of all stroke and systemic embolism and the principal safety outcome was clinically relevant bleeding.

After a mean follow-up of 10.7 months, the trial was stopped because of an excess of clinically relevant bleeding in the idraparinux group compared with the vitamin K antagonist group (346 cases versus 226, HR 1.74, 95% CI 1.47 to 2.06, P<0.0001).

Non-major but clinically relevant bleeding also occurred more frequently in the idraparinux group than in the vitamin K antagonist group (HR 1.60, CI 1.34 to 1.91, P<0.0001).

Intracranial bleeding occurred more in the idraparinux group (21 occurrences versus 9 in the control group, HR 2.58, 95% CI 1.18 to 5.63, P=0.014).

Older patients and those with renal impairment were at increased risk for additional bleeding.

Hazard ratios for clinically relevant bleeding with idraparinux varied by creatinine clearance rates, despite adjustment of idraparinux dose according to renal function. For rates:

• of 80 mL/min or more, the hazard ratio was 1.4 (95% CI 1.0 to 1.9)

• of 30 to 50 mL/min, HR was 3.0 (1.9 to 4.6)

• of less than 30 mL/min, HR was 3.9 (1.3 to 11.7)

The idraparinux to vitamin K antagonist hazard ratio for clinically relevant bleeding also varied by age. It was 1.5 (95% CI 1.2 to 1.8) in patients under 75 years and 2.4 (95% CI 1.8 to 3.1) in those 75 or older.

Despite the excessive bleeding, mortality did not differ between the two groups (62 deaths with idraparinux versus 61 with the vitamin K antagonists, P=0.49).

Taking antiplatelet medications such as aspirin, clopidogrel, or ticlopidine, in addition to either idraparinux or one of the vitamin K antagonists, increased clinically relevant bleeding, prompting the researchers to advise avoiding these combinations.

Irrespective of treatment allocation, clinically relevant bleeding was more frequent in the 971 patients (21%) who took aspirin in combination with the anticoagulant (30.5 per 100 patient-years with idraparinux versus 17.7 per 100 patient-years with vitamin K antagonists) and in the 126 (3%) who took clopidogrel or ticlopidine (42.7 per 100 patient-years with idraparinux and 23.4 per 100 patient-years with vitamin K antagonists) than in those not taking concurrent platelet inhibitor medication (16.4 per 100 patient-years with idraparinux and 9.3 per 100 patient-years with vitamin K antagonists).

Dr. Buller and colleagues were not ready to give up on idraparinux altogether, despite the failure of the Amadeus trial. "An idraparinux dose regimen adjusted to patients' characteristics -- e.g., age and renal clearance -- might preserve efficacy without an increased hemorrhagic risk, and should be addressed by further studies," they said.

Drs. Go and Singer suggested that the search for alternatives to vitamin K antagonists would eventually bear fruit, even though attempts so far have been unsuccessful.

"We believe that on the basis of positive features of recent trial experiences, one or more approaches (e.g., inhibition of factor Xa, thrombin, or other clotting factors) will emerge as an alternative to vitamin K antagonists and facilitate more widespread use of effective and acceptably safe stroke prevention in patients with atrial fibrillation," they wrote.

"Yet, while we wait for the new antithrombotics to emerge, we still need dedicated innovative efforts to improve the delivery of vitamin K antagonists for the growing population with atrial fibrillation," they concluded.
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