Does Recombinant t-PA Have a Role in AIS?
An estimated 700,000 patientsexperience a new or recurrentstroke each year. Approximately500,000 of these cases are firstattacks, and 200,000 of them are recurrentstrokes. Although the incidencerates are higher in men than in womenat a younger age, that difference disappearsas people approach 75 years ofage. The national impact of stroke canbe devastating. It has been estimatedthat stroke currently costs the UShealth care system about $56.8 billionper year. The latest data calculate themean lifetime cost per patient forischemic stroke in the United States at$140,048, which includes inpatientcare, rehabilitation, and follow-up carenecessary for lasting deficits.1
Acute ischemic stroke (AIS) is adiverse disease process; prediction ofcourse, recovery, disability, or death isdifficult. Diagnostic procedures forAIS—such as cerebral angiography—performed after event onset demonstratethat the majority of acute infarctionsare arterial occlusions. In AIS,recombinant tissue plasminogen activator(t-PA) has been evaluated toreduce the risk of intracerebral hemorrhage(ICH) and to maximize thepotential of recovery. Evidence supportingt-PA in AIS comes from 2 large,multicentered trials.
The National Institute of NeurologicalDisorders and Stroke (NINDS) rt-PAStroke Study was a double-blind, placebo-controlled, randomized trial thatevaluated the safety and efficacy oft-PA in patients presenting with acutestroke, and it discerned the appropriatetime to administer t-PA.2 The trial randomized624 patients into 2 parts. Part1 tested whether t-PA had clinicalactivity, as indicated by an improvementof 4 points over baseline valuesin the score on the National Institutesof Health Stroke Scale (NIHSS) or theresolution of the neurologic deficitwithin 24 hours of the onset of stroke.Part 2 used a global test statistic toassess clinical outcome at 3 months,according to scores on the Barthelindex (BI), the modified Rankin scale(MRS), the Glasgow outcome scale(GS), and the NIHSS. Favorable outcomeswere defined as a BI score of≥95, an MRS score of ≤1, a GS score of1, and an NIHSS score of ≤1. Eachgroup was assessed according to thetime from the onset of stroke to thebeginning of treatment: 0-90 minutes,91-180 minutes, and 0-180 minutes.
For part 1, the investigators foundno statistically significant differencesbetween groups in the primary outcome.In part 2, the number of patientswith favorable outcomes foreach of the 4 primary outcome measures3 months after stroke was higherin the t-PA group than in the placebogroup, and only statistically significantin the patients randomized to receivet-PA in the <3-hour window. Eventhough benefit was demonstrated inpatients who were treated with t-PA at3 to 12 months after stroke, there wasa 6.4% incidence of ICH in the treatmentgroups.
Despite endorsements by expert panels,such as the American College ofChest Physicians, there was great concernthat the incidence of ICH in routineclinical practice may be higher. The FDAmandated that the Standard Treatmentwith Alteplase to Reverse Stroke (STARS)study be conducted to assess the safetyprofile and clinical outcomes obtainedfollowing the administration of intravenoust-PA therapy for acute strokepatients in clinical practice.3 This multicentered,prospective study followed theclinical course of nearly 400 patientswith AIS. Primary outcome measureswere the time intervals between strokesymptom onset, hospital arrival, andtreatment with t-PA; pretreatment computedtomographic (CT) scan results;ICH; and major systemic bleeding. Thetrial revealed that the median time fromstroke onset to treatment was 2 hours 44minutes, and the median NIHSS scorewas 13. A baseline CT without stroke-specificabnormalities of the middlecerebral artery, a less severe baselineNIHSS score, an age of ≤85 years, andlower mean arterial pressure at baselineall were found to be predictors of favorableoutcomes. Only 3% of the participantsexperienced symptomatic ICH,and the 30-day mortality rate was 13%.At 30 days after treatment, 35% hadfavorable outcomes, and 43% werefunctionally independent.
In contrast, other trials have notdemonstrated findings similar to thoseof the NINDS and STARS studies. Infact, the following prospective, multicentered,randomized, double-blind,placebo-controlled trials could not distinguisha clinical benefit from thet-PA treatment groups and placebogroups. The European CooperativeAcute Stroke Study (ECASS) I and IIwere trials that used the same outcomemeasures and time strata as theNINDS.4,5 Both studies showed that the3-hour cohort did not display any significantdifferences because of thesmall patient numbers (n = 80/group).Furthermore, the safety analysis ofthese 2 trials showed no significantdifference in mortality between thegroups and a significantly higher incidenceof fatal ICH.
The Alteplase Thrombolysis forAcute Noninterventional Therapy inIschemic Stroke trial tested the efficacyand safety of t-PA at 3 to 5 hours poststroke symptoms, using the NIHSS ≤1at 90 days as the primary outcomemeasure. Secondary end points includedexcellent functional recovery atdays 30 and 90 on the MRS, the BI,and the GS.6 The study was an intention-to-treat design that had 2 differentarms, placebo and treatment. Thepatients, however, were randomized to1 of 3 different time strata. There were39 patients who were treated within 3hours of symptom onset, 547 patientswho were treated within 3 to 5 hoursof symptom onset, and 24 patientswho were treated >5 hours after symptomonset. This trial failed to find asignificant difference in overall mortalitybetween the t-PA group and theplacebo group at 3 to 5 hours, despitean increased neurologic recovery inthe treatment group between days 30and 90.
Despite some question as to theexact magnitude of clinical benefitand the practicality that t-PA can offerin patients presenting with AIS, thegeneral consensus is that the benefits,if given to specific patients, outweighthe risk. This sentiment is probablywhy the American Academy of Neurology,the American Heart Association,and the American College ofChest Physicians granted a grade 1Arecommendation to the use of t-PA,but with strict inclusion and exclusioncriteria. Most of the inclusion criteriacan be generalized to the time fromonset of symptoms to treatment,which should be <180 minutes; andbaseline CT showing no evidence ofICH. The exclusion criteria are morespecific for physiologic parameters,such as systolic blood pressure >185mm Hg, diastolic blood pressure >110mm Hg, and platelets <100,000/μL.7
Therefore, pharmacists either dispensingor recommending t-PA in thesetting of AIS should obtain the mostaccurate time line from the onset tothe point of treatment, gather patient-specificparameters to assist withappropriate patient selection, and consultwith the neurologist to ensure thata CT has been performed, with theresults being unremarkable for ICH.
Dr. Owen is a pharmacy practice residentat the University of Colorado Hospital.Dr. Page is an associate professor ofclinical pharmacy and physicalmedicine/rehabilitation at Universityof Colorado Health Sciences Center,Schools of Pharmacy and Medicine.
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