NNT: Thrombolytics have a long way to go to be proven effective

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Q: Does administering aspirin in the acute stages of ischemic stroke reduce death and disability?

Q: Does administration of thrombolytic agents for acute ischemic stroke patients reduce morbidity and mortality?


by Paul Roszko, MD & Anthony M. Napoli, MD

Q: Does administering aspirin in the acute stages of ischemic stroke reduce death and disability?
A: Yes

79 patients must be treated for one to see the benefit of this intervention

245 for causing a major hemorrhage; 574 for causing an intracranial hemorrhage

Color Code
Green: Proven to benefit

Take Home Message: Aspirin is beneficial for patients with acute ischemic stroke

Details: Ischemic stroke is thought to occur by the activation of platelets or by plaque rupture in the cerebral arterial circulation leading to the formation of a platelet clot. Interventions that prevent the clotting of platelets may therefore reduce the incidence and severity of acute ischemic stroke.

The Cochrane review included twelve randomized trials encompassing >43000 stroke patients and, in aggregate, the review clearly suggests a benefit on death or dependency (NNT=79), death alone (NNT=108), and recurrent stroke within 30 days (NNT=140) Included trials compared an antiplatelet agent to control (placebo or no therapy with adequate blinding) for acute stroke, initiated within 14 days of onset.

The review included trials of all antiplatelet agents including COX-2 inhibitors, thienopyridine derivatives, phosphodiesterase inhibitors, thromboxane A2 antagonists, and GP IIb/IIIa receptor antagonists, but 94% of the data came from two trials, CAST and IST, which evaluated 160mg and 300mg of once daily aspirin continued for either two or four weeks.

Caveats: Not all subjects in the review had a CT scan to exclude hemorrhagic stroke prior to randomization, which would lead to an underestimate of benefit when compared to a setting where imaging is obtained before therapy is started. Also, not all of the trials used aspirin, however aspirin is likely the cheapest and most feasible medication for most settings. Because of the small scale of the other trials included in the meta-analysis, there is limited evidence to recommend the use of other antiplatelet agents other than aspirin in patients who cannot tolerate aspirin. Finally, a significant interaction between aspirin and streptokinase was noted in the MAST-I trial, leading to an increase in early and late mortality, thus it is unclear if and when aspirin should be administered to those patients who receive thrombolytic therapy.

Data source: Sandercock PAG, Counsell C, Gubitz GJ, Tseng MC. Antiplatelet therapy for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2008, Issue 3. Art No.: CD000029.


by David H Newman, MD

Q: Does administration of thrombolytic agents for acute ischemic stroke patients reduce morbidity and mortality?
A: No

No consistent or reproducible benefits were found

5% were harmed by suffering an intracranial hemorrhage

Color Code
Red: Intervention NOT proven to be beneficial

Take Home Message: Thrombolytics should be tested further in randomized trials to help determine which patients will be helped and which will be harmed

Details: Thrombolysis has been rigorously studied for myocardial infarction, and is proven to reduce deaths, although it took >60,000 patients to demonstrate consistent benefits and to clearly define the subgroup that benefits (those with ST elevations). Thrombolysis may also benefit ischemic stroke patients, though only about 8000 subjects have been studied in relevant trials thus far.

There are 12 major relevant trials, and we believe they are clinically (and also statistically) much too different to be combined into a single number. The different trials enrolled patients with different anatomic stroke regions, small- versus large-vessel occlusions, different clinical severities, varying age ranges, different vital sign exclusions, different stroke scale cutoffs, and different times of administration. Therefore we chose to review them individually. We found that six of the trials demonstrated no overall benefit, two suggested a benefit, and five were stopped early because of an increase in deaths in the thrombolytic group. To us, this means that thrombolytics have a long way to go before they can be considered proven safe and effective. As with any drug we would like to see multiple consecutive trials that show a definite benefit in a clearly defined group of patients before we consider this a beneficial intervention.

Caveats: There is, however, a Cochrane review that pooled the data from many trials. We don’t endorse this choice, but for completeness: The Cochrane review suggests a 5% reduction in ‘death or disability’ with thrombolytics (NNT=20), but a 3% increase in deaths (NNH=33) and a 5% increase in major intracranial hemorrhage (NNH=20).

Data source: Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD000213. DOI: 10.1002/14651858.CD000213.pub2.


The NNT Explained

The NNT offers a measurement of the impact of a medicine or therapy by estimating the number of patients that need to be treated in order to have an impact on one patient. The concept is statistical, but intuitive. After all, we know that not everyone is helped by a medicine or intervention—some benefit, some are harmed, and some are unaffected. The NNT and the NNH (number-needed-to-harm) tell us how many.

TheNNT.com is a project designed to make these estimates available for decisions at the bedside, and in conversations with patients. There’s a lot of data out there, TheNNT.com is just a place where it’s easy to find, and easy to use.

-David Newman, MD
Editor-in-Chief, TheNNT.com


David H. Newman, MD is author of Hippocrates’ Shadow: Secrets From The House Of Medicine

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