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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