Dr. Garrett is a clinical pharmacist practitioner at Cornerstone Health Care in High Point, NC.
Macugen (pegaptanib sodium; Pfizer) is a treatment for age-related macular degeneration(AMD) that is given in a series of intravitreal injections. A retrospective reviewof patients on warfarin who received pegaptanib injections for AMD demonstrated thatpatients could safely receive the treatment without stopping warfarin therapy. Thereview identified 31 patients (32 eyes) who underwent 102 intravitreal pegaptanibinjections while receiving warfarin. The mean number of pegaptanib injections perpatient was 3. No intraoperative or immediate postoperative hemorrhagic complicationswere noted. One patient experienced an acute submacular hemorrhage 35 daysafter the third pegaptanib injection. There were no other hemorrhagic events amongthe remaining patients.
Results of the Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) studysuggest that elderly patients (75 years of age or older) with atrial fibrillation may haveless risk with warfarin treatment than previously thought. The study demonstrated theefficacy and safety of warfarin, compared with aspirin. Patients were randomized toreceive warfarin (international normalized ratio [INR] target 2.5) or aspirin (75 mg/day).Warfarin was more than twice as effective at preventing strokes and did not causemore major bleeding. Major bleeding rates increased with age, but the rate in the groupaged ≥85 years was actually lower with warfarin (2.9%/yr) than with aspirin (3.7%/yr).
These results conflict with other recent studies that found a substantially higher riskof bleeding in the elderly. Several differences in study design and patient populationmay account for the different bleeding rates, however. The BAFTA study excludedpatients with a recent bleed, certain bleeding risk factors, or hypertension, all of whichare risk factors for stroke. INR control was also better (67% in range) than in previousstudy populations. The authors suggested that the low prevalence of risk factors andthe large population of patients already taking a vitamin K antagonist (40%) when theyentered the study may explain why thrombotic events were lower than anticipated.
Atherosclerotic peripheral arterial disease (PAD) is associatedwith an increased risk of myocardial infarction (MI), stroke, anddeath from cardiovascular (CV) causes. Antiplatelet drugs reducethis risk, but the role of oral anticoagulant agents in the preventionof CV complications in patients with PAD is unclear.
The New England Journal of Medicine recently published a studyto determine the benefits of adding warfarin to antiplatelet therapy in this patient population.Patients received combination therapy with an antiplatelet agent and warfarin(target international normalized ratio, 2.0 to 3.0) or antiplatelet therapy alone. Outcomesstudied were MI, stroke, death from CV causes, or severe ischemia. No statistically significantdifferences in outcomes occurred between the 2 groups; however, the risk oflife-threatening bleeding was higher (4% for combination, 1.2% for single agent). Theauthors concluded that combination therapy did not reduce CV complications but didincrease a patient's chances of significant bleeding.
A recent case report suggests that theinternational normalized ratio (INR) maybe lowered significantly when the proteaseinhibitor (PI) lopinavir/ritonavir(Kaletra; Abbott Laboratories) is added toexisting warfarintherapy.The report describeda patientwith HIVwho had a PIadded to his existingwarfarintherapy. His doseof warfarin wasultimately increasedfrom5.5 mg/day to13 mg/day beforestabilizing.
Previous case reports have describeda potential interaction between warfarinand other PIs, largely due to their effectson the cytochrome P-450 (CYP450) system.Lopinavir is enzymatically inactivatedby the CYP450 3A4 isoenzyme; however,ritonavir inhibits CYP3A4 activityand thus increases the plasma concentrationof lopinavir and other CYP3A4substrates.
Warfarin is metabolized by CYP2C9,CYP1A2, and CYP3A4. Recent evidencesuggests that lopinavir/ritonavir therapyresults in modest induction of CYP1A2and CYP2C9 activity. Pharmacokineticanalysis in healthy participants foundthat 10 days of lopinavir/ritonavir therapyresulted in a 43% increase in CYP1A2activity and a 29% increase in CYP2C9activity. The increase in enzymatic activitymay reduce warfarin levels, thusaccounting for the reduction in INR andthe increased warfarin dose required tomaintain the patient's INR in the therapeuticrange.