Journal Club. 1. Develop a PICO (Population, Intervention, Comparison, Outcome) question for this study

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1 Journal Club Articles for Discussion Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-pa Stroke Study Group. N Engl J Med Dec 14;333(24): The IST-3 Collaborative Group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. Elsevier Ltd; 2012 Jun 23;379(9834): The Original NINDS Paper METHODS 1. Develop a PICO (Population, Intervention, Comparison, Outcome) question for this study In patients with an ischemic stroke with clearly defined time of onset and CT that shows no ICH, does the administration of tpa result in (Part 1) increased rates of early improvement as defined by complete resolution of neurologic symptoms or an improvement of NIHSS by 4 or more points 24 hours after the stroke and (Part 2) is there a consistent improvement at 3 months as defined by minimal or no deficit as compared to placebo? 2. What is the null hypothesis for this study? tpa provides no early improvement in neurologic outcome (Part 1). At 3 months the rate of patients with minimal or no deficit is the same between the tpa group and placebo. The NINDS article was a publication of two studies within a single article. 3. What was the stated purpose of Part 1? What were the two primary outcomes of interest to measure this? The purpose of NINDS1 is to determine if tpa had any clinical activity at 24 hours. 1. Complete resolution of neurologic deficit 2. Improvement of NIHSS by 4 or more points 1

2 4. What was the stated purpose of Part 2? What were the four primary outcomes of interest to measure this? To determine if there was a sustained difference in the proportion of patients with minimal or no deficit at 3 months. 1. Barthel Index: Measure of ability to perform ADLs. scored from Modified Rankin Scale: Simplified overall assessment of function. 0 is no impairment. 6 is dead. 3. Glasgow Outcome Scale: Global assessment of function. 1 = Death, 5 = Good recovery. 4. NIH Stroke Scale: 42-point scale that quantifies neurologic deficits in 11 categories 5. What were the inclusion criteria? Ischemic stroke with: Clearly defined time of onset Deficit measurable on NIHSS Baseline CT scan of brain that showed no evidence of ICH 6. What were the exclusion criteria? Stroke or serious head trauma within previous 3 months Major surgery within 14 days History of ICH or symptoms suggestive of SAH SBP >185mmHg or DBP >110mmHg; or aggressive treatment required to reduce BP Rapidly improving or minor symptoms Symptoms suggestive of SAH GI or GU bleeding within previous 21 days Arterial puncture at noncompressible site within previous 7 days Seizure at onset of stroke Anticoagulants or antithrombotics within 48 hours preceding onset of stroke Elevated PTT/PT or platelets <100k Glucose <50 or >400 mg/dl 2

3 7. Was the study blinded? The study clearly states that the study is blinded but this could just apply to the patient and the initial treating clinician. It is not clearly stated that the certified examiner that is performing the 24-hour and 3-month assessments is also blinded. 8. Did the study receive financial support from industry? The study was funded by The National Institute for Neurologic Disorders and Stroke Genentech supplied and distributed both the t-pa and the placebo and monitored the clinical sites. 9. Patients in both parts were further subdivided based on time from onset of symptoms. What were the times of each of these two groups? Why does this matter? 0-90 min and min. If there is a large effect in the early group but the final data is pooled than it seems that the results (if still positive) could be generalized to include the latter group. 10.How were the patients randomized? A permuted-block design with blocks of various sizes was used for randomization, with patients stratified according to clinical center and time from the onset of stroke to the start of treatment (0 to 90 or 91 to 180 minutes). Permuted block design is where a "block size" and "allocation ratio" (number of subjects in one group versus the other group) are specified, and subjects are allocated randomly within each block. For example, a block size of 6 and an allocation ratio of 2:1 would lead to random assignment of 4 subjects to one group and 2 to the other 11.The patients were examined at 24-hours and 3 months. Who performed this examination? Was the examiner blinded? The patient was examined by a certified examiner. It is unclear what role the examiner had, if any, in the original care of the patient. It is not clearly stated if the examiner was blinded. STATISTICAL ANALYSES 1. In part 1, what tests were used to compare the proportion of patients with improvement in the NIHSS 24 hours after the onset of stroke? What is this test? Mantel Haenszel tests (aka Cochran-Mantel-Haenszel tests), which allows the comparison of two groups on a dichotomous/categorical response. 3

4 2. The authors state, There was no adjustment for multiple comparisons, since the three hypotheses were prespecified. Is this valid? Why or why not? When multiple comparisons are made any increase in the number of comparisons leads to increased rate of witnessing a rare event and thus rejecting the null hypothesis when it is true (a Type 1 Error). A comparison is considered significant when the p-value is less than the pre-stated alpha. By convention the alpha is The probability of making such an error is the Family Wise Error Rate (FWER). The Bonferroni correction is a method used to counteract the problem of multiple comparisons. 3. In Part 2, what test was used to simultaneously tests for effect in all four outcome measures specified in the primary hypothesis? The primary hypothesis was tested with a global statistic (the Wald test) derived from a general linear model with logit-link function, computed with the use of generalized estimating equations. This allows for the simultaneous testing of all 4 outcome measures RESULTS 1. How many patients were randomized in Part 1? Part 2? Total? Part 1: N=291, tpa (n=144) vs. placebo (n=147) Part 2: N=333, tpa (n=168) vs. placebo (n=165) Total: N= Were there any significant differences between the treatment and placebo groups at baseline? The authors state, The treatment groups were well matched with respect to all base-line characteristics except weight in part 1 of the trial and age and aspirin use in part 2. P-values were not given in Table 2 to verify this. There does seem to be some large variation in the stroke subtypes. 3. What were the primary outcome results for Part 1? No statistically significant differences were detected between groups in the primary outcome (improvement by 4 or more points in the NIHSS score or a complete resolution of the neurologic deficit) (Table 3). 4. Did this result allow the researchers to reject the null hypothesis? No, these results did not. 5. What was the odds ratio for a favorable outcome at 3 months in the tpa group? In part 2 the number of patients with favorable out- comes for each of the four primary outcome measures three months after stroke was higher in the t-pa group than in the placebo group (Table 4). 4

5 As evaluated by the global test statistic, the odds ratio for a favorable outcome in the t-pa group was 1.7. (95 percent confidence interval, 1.2 to 2.6; P=0.008) 6. Was there a mortality benefit seen in the tpa group? There were no significant differences in mortality between the groups. By 90 days after the onset of stroke, 54 of the 312 t-pa treated patients had died (17 percent), as compared with 64 of the 312 placebo-treated patients (21 percent) (P=0.30). 7. What was the rate of Intracerebral hemorrhage in the 2 groups at 36 hours? ICH within 36 hours of stroke treatment 6.4% vs. 0.6% (P<0.001), of which 45% were fatal ICH within 3 months of stroke treatment 7.7% vs. 1.3% (P<0.001), of which 61% were fatal 5

6 The IST-3 Paper METHODS 1. Develop a PICO (Population, Intervention, Comparison, Outcome) question for this study For patients with an acute stroke who did not exactly meet license criteria for thrombolysis, would administration of et-pa at a dose of 0.9 mg/kg IV within 6 hours of symptom onset result in an increase in the proportion of patients alive and independent at 6 months. 2. What is the null hypothesis for this study? The administration of rt-pa to patients who did not already meet eligibility criteria does not result in increased survival or independence at 6 months. 3. What was the primary outcome measured? 3. What was the primary outcome measured? 4. What were the inclusion criteria? proportion of patients alive and independent as measured by the Oxford Handicap Score (OHS), a commonly used variant of the modified Rankin score. Patients with an OHS of 0, 1, or 2 were classed as independent. 5. What were the exclusion criteria? 4. What were the inclusion criteria? Symptoms and signs of clinically definite acute stroke. Time of stroke onset is known and treatment can be started within six hours of this onset. CT or MRI brain scanning has reliably excluded both intracranial hemorrhage and structural brain 6. lesions Was the which study can blinded? mimic stroke (e.g cerebral tumor). The trial was governed by the uncertainty principle : If, for whatever reason, the clinician is convinced that a patient fulfilling the above criteria should be treated, the patient should be 7. treated The study with originally rt-pa and planned NOT randomized. to enroll 6000 If the patients clinician based is convinced a power that a analysis patient to should show not a 10% be treated difference (for whatever in the primary reason), outcome the patient measure. should How NOT did be this included change? in the trial. 5. What were the exclusion criteria? Major surgery, trauma or gastrointestinal or urinary tract hemorrhage within the previous 21 days. RESULTS Arterial puncture at a non-compressible site within the previous 7 days. 4. Any How known many defect patients in coagulation were enrolled (e.g. in currently each arm on of oral the study? Vitamin in K total? antagonists with an INR > 1.3 OR other oral anticoagulant OR current treatment with heparin [unless APPT within normal laboratory limits] OR treatment with low molecular weight heparin or heparinoid). 5. What was the result of the primary outcome? Known defect of clotting or platelets (patients on antiplatelet agents can be randomized). The patient is female and of childbearing potential or breast feeding. 6

7 Hypo- or hyperglycemia sufficient to account for the neurological symptoms Symptoms considered likely to resolve completely within the next few hours (i.e. a TIA) Patient has had a stroke within the previous 14 days or has had treatment for acute ischemic stroke with thrombolytic therapy within the past 14 days. Patient was already dependent in activities of daily living before the present acute stroke Patient has life threatening illness (eg advanced cancer) likely to lead to death within a few months. Likely to be unavailable for follow-up e.g. no fixed home address. Systolic Blood Pressure < 90 or > 220 or Diastolic Blood Pressure < 40 or > Was the study blinded? Not really. The initial pilot phase was double blinded. The main part of the study was an open treatment trial. The design and enrollment of the double blinded portion is not thoroughly explained in the article. Referencing the protocol it appears that the first 300 patients enrolled comprised the pilot phase. 7. The study originally planned to enroll 6000 patients based on a power analysis to show a 10% difference in the primary outcome measure. How did this change? The main trial began in 2005 with recruitment scheduled to end in In 2007, it became clear that recruitment of 6000 patients by 2009 was not realistic. A revised recruitment target of 3100 which would yield 80% power to detect an absolute difference of 4.7% in the primary outcome. RESULTS 1. How many patients were enrolled in each arm of the study? in total? Control: 1520 Study: 1515 Total: What was the result of the primary outcome? The primary outcome measured was the proportion of patients alive and independent, as defined by an Oxford Handicap Score (OHS) of 0-2 at 6 months. 554/1515 (36.57%) of study group and 534/1520 (35.13%) of control group were alive and independent at 6 months. P = Absolute difference of 1.44%. 7

8 3. What did the authors use to prove a benefit? How was this justified? They used a secondary ordinal analysis to provide evidence of a favorable shift in the distribution of OHS scores at 6 months in the tpa group. The scores were adjusted for age, NIHSS, time, and presence of ischemic changes on imaging. What the adjustments were was not explained 4. Did this adjustment to the data show a benefit to the primary outcome measure? If not, did it show a benefit to any measures? No, even after adjustment the p value was Testing the group of alive and favorable as defined as OHS of 0 or 1 was significant with a p value of after adjustment. The p value for the OHS of 0 only was not determined. 5. What was the rate of death at 7 days in the tpa group compared to placebo? Did this hold true at 6 months? 11% VS 7% at 7 days. By 6 months this had evened out at 26.9% and 26.8%. 6. What was the overall impression of the authors about the use of tpa in this study? For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome. 7. What were they smoking? No seriously, what were they smoking? Do you consider this to be a trial of high quality that you can use to apply to your clinical practice? This was a (mostly) open-label study that failed to reject it null hypothesis. It significantly changed its recruitment goals mid-study. It used unusual statistical methods to find a statistically significant result. When reviewing the data based on time to randomization it appeared beneficial at 0-3 hours, harmful from 3 to 4.5 hours and then beneficial again from 4.5 to 6 hours. This suggests random events occurring. 8