AUGUST 17, 2010
Anna D. Garrett, PharmD, BCPS, CPP
Rt-PA Benefits Seen Up To 4.5 Hours after Onset of Stroke Symptoms
Early administration of intravenous recombinant tissue plasminogen activator (rt-PA) after ischemic stroke improves outcomes, but a clearly defined treatment window has not been established. Previous analysis of combined data from individual patients suggests a potential benefit beyond 3 hours from stroke onset, but there are little data regarding the point at which risks exceed benefits of treatment.
A recently published article examined the effect of time to treatment with intravenous rt-PA (alteplase) on therapeutic benefit and clinical risk by adding more recent trial data to earlier analyses. This meta-analysis combined data from 2 recent trials with data from 6 older ones.
A total of 3670 patients with ischemic stroke were included in the study. Patients were randomized to receive either rt-PA alteplase or placebo infused over 1 hour. Each patient had a clearly defined time of stroke onset. Patients with hemorrhagic stroke or high risk of bleeding were excluded.
Outcomes were evaluated for patients who were within a window of 0 to 6 hours from stroke onset to start of treatment (OTT). Odds of a favorable 3-month outcome increased as OTT decreased, and no benefit of alteplase treatment was seen after approximately 270 minutes. Large parenchymal hemorrhage was seen in 96 (5.2%) of 1850 patients assigned to alteplase and 18 (1.0%) of 1820 controls, but there was no clear relation to OTT.
The authors concluded that there was benefit of alteplase administration up to 4.5 hours after onset of symptoms, but that every effort should be made to shorten the time between onset and drug administration, since outcomes improve with shorter time frames. Beyond 4.5 hours, risks of administration may outweigh benefits.
Overcoming Warfarin Resistance
Some patients need higher-than-expected doses of warfarin (Coumadin) to get their international normalized ratio (INR) into the therapeutic range. The cause of warfarin resistance can be either acquired (eg, poor compliance, drug interactions, dietary interactions) or hereditary. Warfarin resistance is different than warfarin failure, which is defined as a new thrombotic event despite a therapeutic prothrombin time and INR. This situation is commonly seen in patients with malignant diseases.
The most common cause of warfarin resistance is nonadherence. Others include poor absorption, high vitamin K intake, hypersensitivity to vitamin K, and rapid drug deactivation. Patient education is necessary to improve adherence and to minimize the adverse effects of warfarin therapy, regardless of the dose.
In true hereditary warfarin resistance, there are 2 approaches to treatment: increase the warfarin dosage (perhaps to as high as 100 mg/day or more), or switch to another anticoagulant. Testing is available to determine if the patient has a vitamin K epoxide reductase complex subunit 1 genetic mutation, which confers warfarin resistance. The cost of the test is approximately $300, is not covered by Medicare, and may not be covered by insurance.
PPI/Clopidogrel Combination Increases Risk of Rehospitalization
Studies have suggested that proton pump inhibitors (PPIs) may modify the antiplatelet effects of clopidogrel bisulfate (Plavix) due to the effects on cytochrome P450 2C9. The true clinical risks of this interaction have not been well described, however.
Researchers have now conducted a retrospective cohort study of patients enrolled in a multistate health insurance plan with commercial and Medicare clients. The study was designed to evaluate adverse clinical outcomes in patients using clopidogrel plus a PPI, compared with clopidogrel alone. Patients who were discharged from the hospital after myocardial infarction (MI) or coronary stent placement and treated with clopidogrel plus a PPI (n = 1033) were matched 1:1 with patients with similar cardiovascular risk factors treated with clopidogrel alone. Rehospitalizations for MI or coronary stent placement were evaluated for up to 360 days. Patients who received clopidogrel plus a PPI had a 93% higher risk of rehospitalization for MI and a 64% higher risk of rehospitalization for MI or coronary stent placement than did patients receiving clopidogrel alone. Of note, the risk for rehospitalization was not lower in patients treated with pantoprazole. Previous studies had suggested that pantoprazole did not have the same effects on clopidogrel; however, the results of this study suggest otherwise. More studies are warranted to further evaluate the effect of PPIs on clopidogrel.
Dr. Garrett is manager of the Health Education Center at Mission Hospitals in Asheville, North Carolina.