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

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 0.9-1.6))

– Part 2 (n=333): Odds ratio for favourable outcome in combined test statistic at 3 months in t-PA group =1.7 (95% CI 1.2-2.6, 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

OutcomePositive Negative

ExposurePositive A BNegative C D

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

Positive Negative

ExposurePositive A B

Negative C D

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

Positive Negative

ExposurePositive A B

Negative C D

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 = 50-38 =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)/(144+168) = 0.064 = 6.4%– Placebo = (0+2)/(147+165) = 0.006 = 0.6%

• Absolute risk reduction = 6.4-0.6 = 5.8%• NNH = 1/ARR = 1/0.058 = 17.2

• Further analysis of stroke thrombolysis:www.thennt.com/thrombolytics-for-stroke/