Pro/Con Should tPA be Administered at 4.5 hours?

 

In ECASS III, Benefits Outweigh Risk

The question of whether t-PA is the right choice for stroke patients has been controversial since the day the NINDS (National Institute of Neurological Disorders and Stroke) trial was published. Fourteen years and several additional studies haven’t brought us any closer to confirming the real-world effectiveness and safety of t-PA in acute ischemic stroke. 

Here’s the history. For those in support of t-PA, the basis for this support is the NINDS trial from 1995. This study should have only provoked more investigation and not prompted widespread acceptance of t-PA administration in stroke. So, how many patients did this landmark study test, “proving” t-PA’s benefits: 100,000? 50,000? 20,000? How about 1000? None of the above. NINDS conclusions are based on the treatment of 624 patients, with only about half receiving t-PA. If this study had adequate power, then why do we keep asking the same question in follow-up studies? The results suggest that patients treated with t-PA are 30% more likely to experience complete or nearly complete neurological recovery. At what expense? The expense to the patient is the risk of intracranial hemorrhage. Although this risk is substantial, pro-t-PA investigators frequently minimize it. NINDS discovered a 6.4% “symptomatic intracranial hemorrhage” rate for those treated with t-PA. What isn’t often mentioned is the additional 4.4% that are “asymptomatic,” totaling a 10.8% intracranial hemorrhage rate. So, for a 30% chance of resolving or partially resolving your stroke symptoms, 10.8% of patients will suffer a major complication. When you consider the possibility that some of the patients claimed by NINDS, as successes from t-PA, must have been TIAs that would have resolved anyway and strokes that may have substantial improvement without the administration of t-PA, the 30% more likely to improve number is overstated.

So, if NINDS, unveiled, is not so convincing, why did the American Heart Association give t-PA in stroke a glowing endorsement, a Class I recommendation, in its 2000 guidelines, which they further stated “Saves lives”? Following the money often brings clarity to things that don’t make sense. Genentech is known to have donated more than $10 million over 10 years to the AHA, including 2.5 million dollars to build a new headquarters in Dallas, Texas. The AHA maintained that the panel of nine physicians that drafted the recommendation were not biased and had submitted conflict-of-interest forms. Unfortunately, the AHA does not publish those forms for public review. Eight of the panelists endorsed this recommendation and one, Jerry Hoffman, dissented.

 

Interestingly, six of the eight supporters had financial ties to Genentech, and Dr. Hoffman’s testimony in dissent was not included in the guidelines and his name was subsequently removed from the group of panelists. Of further interest is that Genentech attempted to duplicate the NINDS data with the ATLANTIS trial. In part A of the trial, there was no benefit and the 30-day mortality rate was 18% vs. 4% for those not treated with t-PA. A 0-6 hour time window was used. However, a 0-3 hour cohort was studied as well. Interestingly, analysis of that subgroup was never included in the final publication. The final publication, released in 1999, was published six years after completion of the part A data (Jeanne Lenzer. Alteplase for stroke: money and optimistic claims buttress the “brain attack” campaign, BMJ. 2002 March 23; 324(7339): 723–729.).Am I a t-PA skeptic? You bet I am. There are external validity issues with the NINDS trial. This is probably why more studies are being done by t-PA supporters to prove its efficacy. If the question has been answered, why do we keep studying the concept? There are many studies casting doubt on the safety of t-PA in stroke patients. The Cleveland Area Experience, JAMA 2000, had to be stopped due to a 17% intracranial hemorrhage rate. Furthermore, two large registries, one of nearly 250,000 stroke victims and the other of nearly 100,000, report that those treated with t-PA have almost twice the mortality rate as those not treated with the drug, 11.4% v. 6.8% and 10.1% v. 5.8%. (Bateman, B.T., et al, Stroke 37:440, February 2006; Dubinsky, R., et al, Neurology 66:1742, June 2006). These registries also concur that about 1% of stroke victims, 13% of those eligible, actually receive t-PA.The goal of the ECASS investigators was to extend t-PA to more patients by expanding the treatment window to 4.5 hours. In short, ECASS 3, the European Cooperative Acute Stroke Study 3, in my opinion, is a new spin on a bad idea. What hasn’t worked and has harmed patients at 3 hours, will certainly pose similar risks at 4.5.  This study really hasn’t proved safety or efficacy any better than any of its predecessors.

The investigators report that expanding the time window provided benefit to “substantially more patients,” without increasing the rate of intracranial hemorrhage (ICH). The odds ratio for a “favorable outcome” at 90 days was 1.34. An odds ratio of 1 would mean that the treatment group and the placebo group had the same chance to of experiencing the favorable outcome at 90 days. Thus, 1.34 really isn’t much benefit over placebo at all.  Although they reported that the intracranial hemorrhage rate was higher in the treatment group, they stated that it was the same as noted in previous studies for patients treated within three hours. What is not widely publicized is that the investigators changed the definition of symptomatic ICH. They stated that in order to be considered symptomatic, it must be identified as the predominant cause of the deterioration. Nonetheless, they report an overall ICH rate of 27.0% vs. 17.6% for placebo. The change in definition artificially reduced the symptomatic group to 2.4%. Thus, we aren’t comparing apples to apples, with respect to prior data. More importantly, is the fact that 27% of patients bled in their head! This ICH rate is 10% higher that in the placebo group. At least this data is consistent with most recently published articles on this topic (Lansberg MG, Bluhmki E, Thijs VN Efficacy and safety of tissue plasminogen activator 3 to 4.5 hours after acute ischemic stroke: a metaanalysis.Stroke. 2009 Jul;40(7):2438-41.).

 However, If this data is true, and ischemic stroke patients are so likely to experience ICH, then why would we consider giving a systemic thrombolytic to any of them?

 

Based on the ECASS 3 definitions, the symptomatic ICH rate is no greater than that previously reported. However, what they really proved, once again, is that t-PA causes a lot of intracranial hemorrhages with marginal benefit at best.