Good and bad news for possible warfarin competitors

by Lisa Nainggolan

Boston, MA - An investigational factor Xa inhibitor, edoxaban (Daiichi-Sankyo), is being tested as a once-daily drug in a phase 3 trial in over 16 000 patients with atrial fibrillation, following unexpected results from a pharmacokinetic analysis of the agent in a phase 2 study. The latter was presented at the International Society of Thrombosis and Haemostasis (ISTH) 2009 Congress this week [1].

The phase 2 pharmacokinetics data, which was a subanalysis of an international phase 2 study presented at the American Society of Hematology 2008 Annual Meeting, were reported at ISTH by Dr Robert P Giugliano (Brigham and Women's Hospital, Boston, MA). The findings were "a little surprising," Giugliano told heartwire, because "what we learned was that once-daily dosing caused less bleeding than twice-daily dosing, even when you used the same total dose."

Delivering a compound twice a day generally allows for more consistent drug levels in the blood, he explains, because the C_min (trough) levels of the agent do not dip as low and the C_max (peaks) do not go as high as when the drug is given once daily. But "we found the most important parameter that predicted bleeding was the C_min, the trough level," he noted.

Consequently, in the multinational phase 3 study, known as ENGAGE-AF TIMI 48, patients will be randomized either to 30 mg or 60 mg of edoxaban once daily or to warfarin, dosed once daily with adjustments to maintain an internalized normalized ratio (INR) between 2.0 and 3.0. Giugliano said that the 30-mg once-daily dose of edoxaban "looks to have less bleeding than warfarin and the 60-mg dose looks to have bleeding similar to warfarin."

The primary end point of ENGAGE-AF will be the prevention of stroke and systemic embolic events (SEE), and the primary safety assessment will be the incidence of bleeding. The trial is expected to conclude in the first half of 2012.

Learning from the mistakes of others

Giugliano says he feels "pretty confident" about this drug. "Because it's not the first one out, we've been able to learn from other people's mistakes, and right from the get-go we wanted to pick two doses. We realized it would be difficult to beat warfarin, so we're happy to be just as good as warfarin but to have equal or less bleeding. Even if we have equal bleeding to warfarin and are as good as it on the efficacy side, you don't have to monitor [edoxaban], it doesn't have a lot of drug-drug interactions, and it doesn't matter what you eat, so it's easier to use."

Another investigational, once-daily factor Xa inhibitor, rivaroxaban (Xarelto, Johnson & Johnson), is currently in limbo in the US after the FDA declined to approve it for the prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing hip- or knee-replacement surgery, despite a recommendation for approval from its Cardiovascular and Renal Drugs Advisory Committee earlier this year, as reported by heartwire. Bristol-Myers Squibb also has a factor Xa inhibitor in development, apixaban.

Warfarin analog disappoints in phase 2

Meanwhile, tecarfarin (Aryx Therapeutics), another new potential competitor to warfarin, has disappointed in a recent phase 2/3 trial [3]. Tecarfarin, like warfarin, is a selective inhibitor of vitamin-K epoxide reductase (VKOR), but unlike warfarin, it is not dependent upon cytochrome P450 enzymes for metabolism.

In the study, EmbraceAC, in 600 patients with a variety of underlying conditions—such as AF, implanted prosthetic heart valves, and a history of venous thromboembolic disease—tecarfarin failed to show superiority (as measured by time in the therapeutic INR range) over warfarin. The company says this is because the warfarin patients did much better than expected in the trial, due to the centralized dosing control center employed. It is still analyzing the data to determine a future strategy for tecarfarin.

Sources

1. Giugliano R, Rohatagi S, Kastrissios H, et al. The relationship between oral factor Xa inhibitor DU-176B pharmacokinetics and the probability of bleeding events (BE) in patients with atrial fibrillation (AF). International Society of Thrombosis and Haemostasis 2009 Congress; July 11-16, 2009; Boston, MA. Abstract OC-WE-003.
2. Daiichi Sankyo. Analysis of edoxaban phase II data provides insight into reduced bleeding events seen in once-daily dosing [press release]. July 15, 2009.
3. Aryx Therapeutics. Efficacy of tecarfarin mirrors earlier studies while primary end point missed [press release]. July 8, 2009.

Technorati Tags: warfarin,Clopidogrel,coronary,coronary heart disease,edoxaban,rivaroxaban,apixaban,tecarfarin

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Reducing bleeding risk in patients who need triple antithrombotic therapy

The review, published in the July 7, 2009, issue of the Journal of the American College of Cardiology, was written by a group led by Dr David Holmes (Mayo Clinic, Rochester, MN).

They explain that dual antiplatelet therapy (aspirin plus clopidogrel [Plavix, Sanofi-Aventis/Bristol-Myers Squibb]) is given routinely in the treatment of ACS and after coronary stent deployment, and anticoagulant therapy might be indicated for stroke prevention in a variety of conditions that include atrial fibrillation and profound left ventricular dysfunction as well as after mechanical prosthetic heart valve replacement. Triple antithrombotic therapy may be needed when a patient has multiple diseases, the most common situations being patients with AF and or mechanical prosthetic heart valves who also have coronary artery disease and require a stent.

Coauthor Dr Dean Kereiakes (Christ Hospital, Cincinnati, OH) commented to heartwire: "This is a growing problem in the context of the aging population. Both atrial fibrillation and the need for prosthetic heart valves rise with age, and so does the risk of falling, which further increases bleeding risk. ACS is very common, and given the increasingly widespread use of drug-eluting stents (for which dual antiplatelet therapy is recommended for at least one year), the significant bleeding hazards associated with triple antithrombotic therapy is a real issue, which will become worse in the future."

The authors note that before committing a patient to triple therapy for an indefinite period, the physician should carefully consider alternative approaches. For example, in patients who require long-term oral anticoagulation who are undergoing stenting, serious consideration should be given to the use of bare-metal stents, for which dual antiplatelet treatment is recommended for a shorter time. And for AF patients, thought should be given to left atrial appendage occlusion devices or pulmonary vein ablation that could avoid the need for long-term warfarin.

Kereiakes added that for patients needing a heart valve, the new On-X valve (On-X Life Technologies, Austin, TX) should be considered; it has lower warfarin requirements than other valves. "New valve technology such as this will help immensely to reduce levels of anticoagulation needed," he said.

Balancing the need for treatment with bleeding risk

Holmes et al say that patients who are treated with triple therapy present significant clinical challenges because of the imperative to balance bleeding risks against the risk of stopping one of the therapies. They point out that there is very limited published information regarding use of triple antithrombotic therapy, so concrete recommendations are difficult.

Data that are available suggest that up to 21% of patients receiving triple antithrombotic therapy need a transfusion (a figure that might increase with longer treatment durations), and the relative risk of major bleeding is three- to fivefold higher than in patients receiving dual antiplatelet therapy alone. But this is confounded by the fact that patients receiving triple therapy are typically older and have multiple comorbidities, which might increase bleeding potential. Short-term use of triple therapy (for one month) is associated with at least a twofold lower risk of major bleeding compared with prolonged use (more than six months). But patients receiving dual antiplatelet therapy only after PCI (prolonged warfarin interruption) have a threefold increase in stroke or thromboembolic events, compared with patients receiving triple therapy or warfarin plus a single antiplatelet agent.

Keep aspirin dose and INR low

Holmes et al advise that for patients receiving triple therapy, the dose of aspirin should be kept as low as possible (75 to 81 mg), clopidogrel should be given at its standard dose of 75 mg/day, and warfarin should be administered under tight control to achieve a slightly lower target international normalized ratio (INR) of 2.0 to 2.5. They also suggest that proton-pump inhibitors (PPIs) should be considered as prophylaxis against gastric bleeds.

The issue of using PPIs with clopidogrel has been fraught with controversy as it is thought that there may be an interaction between these agents. But Kereiakes commented to heartwire: "The latest consensus of experts is that there is no good evidence events are increased when PPIs are given with clopidogrel. The studies suggesting increased events are confounded. I do give PPIs as prophylaxis to patients on triple antithrombotic therapy, but I tend to use pantoprazole and esomeprazole, which have the least incriminating data regarding an interaction with clopidogrel."

PCI in patients taking warfarin

In patients on warfarin who need PCI, the authors suggest that it may be better to choose a bare-metal stent and commit the patient to a short course of clopidogrel, rather than to an extended course of triple therapy. They suggest that bare-metal stents should be considered for use in target vessels less likely to benefit from drug-eluting stents (eg, vessels >3 mm in diameter, short lesions <15 mm, and de novo stenoses). They note that clopidogrel regimens as short as two to four weeks have been reported to offer adequate protection from early stent thrombosis with bare-metal stents, but current guidelines recommend approximately three to six months of triple therapy, after which patients may continue on aspirin and warfarin alone.

One alternative they mention is to use a drug-eluting stent for very high-risk lesions and accept the increased risk of bleeding. For patients with high bleeding risk treated with a drug-eluting stent, they advise that triple therapy may be limited to three to six months, with warfarin plus clopidogrel and a prophylactic PPI continued thereafter.

How to cope with bleeding

The authors note that bleeding on triple therapy is a particularly difficult problem. Severe or life-threatening bleeding usually requires reversal of warfarin therapy and, in some cases, platelet transfusions to counteract clopidogrel therapy. If dual antiplatelet therapy requires urgent discontinuation, the patient should be closely monitored for the risk of stent thrombosis. In patients with mild or moderate bleeding, every effort should be made to maintain the INR as close to 2.0 as possible, and the aspirin dose should be kept at <100 mg.

If bleeding persists, they advise that aspirin be discontinued first, as clopidogrel seems to be more important than aspirin in preventing stent thrombosis after PCI.

New drugs and stent designs

Holmes et al point out that all these uncertainties will be further compounded by the imminent arrival on the market of new anticoagulant and antiplatelet drugs and new stent designs. The factor Xa antagonists rivaroxaban (Xarelto, Johnson & Johnson) and apixaban (Bristol-Myers Squibb), which might replace warfarin, also dramatically increase bleeding risk when combined with aspirin plus clopidogrel and so may not much help patients requiring triple therapy. The new antiplatelet drug prasugrel (Lilly/Daiichi Sankyo) is more potent than clopidogrel and associated with higher bleeding rates and so is not likely to be suitable for use in combination with warfarin, but the AstraZeneca compound AZD 6140 is shorter acting and reversible, which might be advantageous when used in patients who also require warfarin, they note.

The new protease-activated receptor 1 (PAR-1) antagonist SCH 530348 (Schering-Plough) has shown promising results in preliminary trials, with no increase in bleeding yet seen, and the authors suggest that if this drug becomes clinically available, it may replace clopidogrel in patients who require warfarin, giving a modified triple combination that might have an improved safety profile.

Finally, the cyclooxygenase inhibitor triflusal (Uriach Pharma) is potentially associated with lower bleeding risk and has been demonstrated as safe and effective in combination with warfarin in patients with AF and so could prove useful in patients requiring oral anticoagulation and undergoing PCI, but randomized studies are needed, they add.

In addition, new stents are being introduced with thinner struts and polymer coatings, which are thought to be associated with better endothelialization and less vascular inflammation than previous drug-eluting stents. And another new generation of stents that employ bioabsorbable polymers or are designed to capture circulating endothelial precursor cells to promote vascular healing are in development, and the hope is that these stents could be less subject to late thrombosis and might require shorter durations of dual antiplatelet therapy.

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New meta-analysis updates benefits of antithrombotics in AF

by Sue Hughes

San Antonio, TX - For patients with atrial fibrillation, taking adjusted-dose warfarin reduces the risk of stroke by approximately 60%, and antiplatelet agents reduce the risk by about 20%, a new meta-analysis estimates.

The authors conclude: "These results reaffirm recommendations for adjusted-dose warfarin for patients with atrial fibrillation who are deemed to be at high risk for stroke, with antiplatelet therapy for low-risk patients and for those who cannot safely receive warfarin." But they add that a substantial unmet need remains for antithrombotic agents that are more efficacious than aspirin and that are safer or more easily administered than adjusted-dose warfarin.

The meta-analysis, published in the June 19, 2007, issue of the Annals of Internal Medicine, was conducted by a team led by Dr Robert Hart (University of Texas Health Science Center, San Antonio). They note that nonvalvular atrial fibrillation is an important cause of disabling stroke, the incidence of which can be reduced by using antithrombotic prophylaxis. They previously conducted a meta-analysis of 16 randomized clinical trials testing antithrombotic therapies for stroke prevention in approximately 10 000 participants. But since publication of that meta-analysis, another 13 randomized trials in 18 140 additional patients have been reported. They therefore conducted a new meta-analysis of all currently available randomized trials.

They included 29 trials with a total of 28 044 participants (mean age 71 years; mean follow-up 1.5 years). Results showed that adjusted-dose warfarin is the most effective antithrombotic therapy at preventing stroke, being around 40% more efficacious than antiplatelet therapy.

Main results of meta-analysis of antithrombotic therapy in AF patients

Comparison	Trials (n)	Patients (n)	Reduction in stroke (%)	95% CI (%)
Warfarin vs control	6	2900	64	49-74
Antiplatelet agents vs control	8	4876	22	6-35
Warfarin vs antiplatelet agents	12	12 963	39	22-52

Other randomized comparisons were inconclusive. Absolute increases in major extracranial hemorrhage were small (less than 0.3% per year) and were less than the absolute reductions in stroke.

Hart et al note that they have confirmed the main findings of their previous meta-analysis but have improved the precision of the estimates of benefits and risks, because of the addition of 13 trials and the more than doubling of the total number of participants and strokes. "Major new evidence includes comparisons of adjusted-dose warfarin with the combination of clopidogrel plus aspirin (one trial with 6706 participants) and a more precise estimate of anticoagulation therapy compared with all antiplatelet therapies (six additional trials with 8911 participants)."

What is the best INR?

They note that the substantial relative risk reduction in stroke with adjusted-dose warfarin is consistent for all patient subgroups over a wide range of absolute stroke risks. Achieved INRs in randomized trials ranged from 2.0 to 2.9, and while direct randomized comparisons of different intensities of adjusted-dose warfarin are limited, the authors say that achieved INRs between 2.0 and 2.5 offer large relative risk reductions for primary stroke prevention and that the absolute increase in intracerebral hemorrhage during anticoagulation therapy remains relatively small if the INR is 3.5 or less.

They point out that the estimate of a 20% reduction in stroke with antiplatelet agents is less consistent among trials than the estimate for adjusted-dose warfarin, and another recent analysis suggested a larger estimate of the efficacy of aspirin, with a 35% risk reduction, but that aspirin seems to have a larger effect on nondisabling, noncardioembolic strokes than on cardioembolic infarctions.

Any role for clopidogrel?

Hart et al further report that the relative benefit of any specific antiplatelet agent or combinations of antiplatelet agents is unclear from the available data and that there is no evidence favoring any one dosage of aspirin over another. They add that the point estimate of the relative risk reduction with adjusted-dose warfarin was similar when compared with clopidogrel plus aspirin and with pooled results from eight trials of aspirin alone, suggesting that there is no major benefit of adding clopidogrel to aspirin, but these antiplatelet agents are being directly compared in the ongoing ACTIVE-A trial.

They further report that the two available randomized trials that added antiplatelet therapy to full-dose anticoagulant therapy were too small and had too few events to adequately characterize the efficacy and safety of such therapy.

Hart et al say the finding of only small increases in major extracranial hemorrhage during anticoagulation is reassuring, but the design of recent randomized trials may result in more favorable estimates of bleeding than those that can be anticipated in clinical practice for warfarin-naive patients and for older patients. However, they add that recent, large, practice- and population-based studies report reassuringly similar results.

But warfarin not best for everyone

The authors conclude by pointing out that the impressive relative risk reduction in stroke with adjusted-dose warfarin does not imply clinically important benefits for all patients who have atrial fibrillation. Noting that the intrinsic risk for stroke among such patients varies 20-fold, they advise that many low-risk patients do not benefit substantially from warfarin, whereas high-risk patients (particularly those with previous stroke or transient ischemic attack) have large absolute reductions in stroke rate with anticoagulation therapy.

They add that the choice of antithrombotic prophylaxis is best individualized and should consider the patient's inherent stroke risk and the best estimate of the absolute benefits, as well as bleeding risk, access to high-quality anticoagulation monitoring, and patient preferences.

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