Strategies aimed at reducing bleeding risk in patients who need treatment with
dual antiplatelet therapy as well as an anticoagulant such as warfarin are
examined in a new review [1].

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.