Tissue Plasminogen Activator for Acute Ischemic Stroke National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group

Summarise the paper in 200 words

Aims – Compare intravenous tissue plasminogen activator (t-PA) with placebo in treatment of acute ischaemic stroke. Method – 2 part double blinded multi-centre randomised controlled trial – Patients with ischaemic stroke (no intracranial haemorrhage on CT) within 3 hours of onset were included – Stratified block randomisation to treatment with placebo or t-PA

Summarise the paper in 200 words Outcome measures: – Part 1: Complete resolution of neurological deficit or improvement in NIHSS score >4 within 24 hours of onset of stroke – Part 2: Recovery with minimal or no deficit 3 months after treatment, measured using a combination of 4 outcome measures (Barthel index, modified Rankin scale, Glasgow outcome scale, NIHSS)

Summarise the paper in 200 words Results – Part 1 (n=291): no significant difference in percentage of patients with neurological improvement at 24 hours (relative risk =1.2 (95% CI )) – Part 2 (n=333): Odds ratio for favourable outcome in combined test statistic at 3 months in t-PA group =1.7 (95% CI , p=0.008) – No significant difference in mortality, but higher rate of symptomatic intracerebral haemorrhage within 36hrs seen in t-PA group (p<0.001)

Summarise the paper in 200 words Conclusion – Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with t-PA within 3 hours onset of ischemic stroke improved clinical outcome at 3 months.

Abstract

The Good... Multi-centre RCT Clear power calculation performed Few patients lost to follow up Intention to treat analysis

The Bad... Patient selection – were all eligible patients randomised? No CONSORT diagram Differences between placebo and treatment groups – No mean given for NIHSS score - makes comparison difficult – Higher rate of “Large-vessel occlusive stroke” in placebo group – Higher rate of edema and mass effect in placebo group Unconventional statistical tests applied – (Mantel-Haenszel test and Wald test) No p-value given for differences in adverse events – (symptomatic intracerebral haemorrhage and serious systemic bleeding)

The Bad... Dichotomous end-point in part 2 – No assessment of magnitude of effect of treatment can be made Randomisation method – Permuted block design with blocks of various sizes. Stratified by clinical centre (8 centres) and time to treatment Was part 2 only done because part 1 failed to deliver a significant outcome?

Definitions Control event rate (CER) = C/(C+D) = outcome event rate in control group Experimental event rate (EER) = A/(A+B) = outcome event rate in experimental group Outcome PositiveNegative Exposure PositiveAB NegativeCD

Definitions Control event rate (CER) = C/(C+D) Experimental event rate (EER) = A/(A+B) Absolute risk reduction (ARR) = CER-EER Relative risk (RR) = EER/CER Relative risk reduction (RRR) = (CER-EER)/CER Outcome PositiveNegative Exposure PositiveAB NegativeCD

Definitions Number needed to treat (NNT) – The number of subjects that must be treated with the intervention, compared with the control, for one extra subject to experience the beneficial effect. – NNT = 1/ARR

Definitions Control event rate (CER) = C/(C+D) Experimental event rate (EER) = A/(A+B) Absolute risk reduction (ARR) = CER-EER Relative risk (RR) = EER/CER Relative risk reduction (RRR) = (CER-EER)/CER Number needed to treat (NNT) = 1/ARR Outcome PositiveNegative Exposure PositiveAB NegativeCD

Bonus Points Using the numbers given for the Barthel index in part 2 of the study (Table 4), calculate the number needed to treat (NNT) in order to get a favourable functional outcome. Absolute risk reduction = =12% NNT= 1/ARR = 1/0.12 = 8.3

Bonus Points Using the data given in Table 6, calculate the overall number needed to harm (NNH) for symptomatic intracranial haemorrhage (parts 1 and 2 of the study combined). Risk of symptomatic intracranial haemorrhage – t-PA group = (8+12)/( ) = = 6.4% – Placebo = (0+2)/( ) = = 0.6% Absolute risk reduction = = 5.8% NNH = 1/ARR = 1/0.058 = 17.2

Further analysis of stroke thrombolysis: