Interview with Ralph L. Sacco, MD.
Ralph L. Sacco, MD, professor and Olemberg Family Chair in Neurological Disorders and Miller Professor of Neurology, Epidemiology, and Human Genetics at the University of Miami Miller School of Medicine, Florida; neurologist-in-chief at University of Miami Jackson Memorial Hospital; and president-elect of the AHA, discusses the evidence supporting this new recommendation and some of the issues that still stand in the way of rapid use of tPA for patients with stroke.
Dr. Ralph Sacco
How widely has tPA been used for stroke patients within the US Food and Drug Administration (FDA)-approved 3-hour window?
Dr. Sacco: Well, it is increasing in use, but still it’s underutilized as an acute stroke therapy. I would say overall the numbers are maybe 3% to 5% of the 750,000 strokes per year actually get tPA. In some areas it’s used in greater proportions, where acute stroke care is more organized.
What were the main limitations to its use?
Dr. Sacco: Number 1 is still the number of people in the public with acute symptoms getting to urgent medical attention. There are still too many people who don’t call 911 quickly enough to get in during that very tight time window to be eligible for tPA.
The second issue is the organization of stroke care. Not every hospital in the United States is equipped with 24/7 capability of providing acute tPA for stroke patients. Over the last few years, with the certification of primary stroke centers, the number of primary stroke centers is rapidly growing, but there are still segments of the population in the United States that don’t have adequate access to rapid stroke care.
What is the new evidence that prompted the updated AHA/ASA Science Advisory?
Dr. Sacco: The publication of the ECASS 3 [European Cooperative Acute Stroke Study 3] trial in Europe was new with randomized clinical trial evidence of the efficacy of tPA in the 3-to-4.5-hour window.
To put it into perspective, in Europe, the regulatory authorities requested that another trial be done to broaden the safety and the efficacy information about tPA. So there was both a large registry that’s published now, called SITS-MOST [Safe Implementation of Thrombolysis in Stroke — Monitoring Study, Lancet. 2007;369:275-282], which basically I think confirmed the safety of tPA within the 3-hour time window, and then ECASS 3, which was a very large randomized European trial that looked at patients within the 3-to-4.5-hour window and confirmed the risk-benefit ratio being in favor of intravenous tPA up to 4.5 hours after stroke [N Engl J Med. 2008;359:1317–1329].
Now this was also on top of meta-analysis that had shown [that] when you combine all the clinical trials in the past together, it looked like there was a window of positive benefit for tPA up to 4.5 hours [Lancet. 2004;363:768–774]. Moreover, the safety of giving tPA in the 3-to-4.5-hour window was confirmed in another large European registry [Safe Implementation of Treatments in Stroke — International Stroke Thrombolysis Registry, Lancet. 2008;372:1303–1309]. The ECASS 3 was a very well conducted trial that confirmed, I think, both safety and efficacy in the 3-to-4.5-hour window with tPA.
What are the main recommendations of the new advisory?
Dr. Sacco: This new evidence from ECASS 3, in conjunction with the prior meta-analysis and in conjunction with the SITS-MOST study and other publications that have shown that tPA is safe and efficacious up to 4.5 hours after acute stroke, led the AHA/ASA to issue this new advisory, giving tPA a class 1, level B recommendation for use in the 3-to-4.5-hour window.
The big issue is we don’t want clinicians to delay treatment. So even though we now can treat with intravenous tPA out to 4.5 hours, that doesn’t mean you should wait. We don’t want to send the wrong message to the public. It’s still clear to everyone, and all the data shows, that the earlier you treat the better the outcomes.
Not all stroke patients will be eligible for consideration for treatment within the 3-to-4.5-hour window. Which patients are these?
Dr. Sacco: The exclusion criteria for ECASS 3, that mirrored the exclusion criteria mandated by European regulatory authorities for the approval of tPA [in Europe], now are exclusions in the new AHA/ASA recommendations. Eligibility criteria for treatment in the 3-to-4.5-hour time window are similar to those for the 3-hour window, but excluding those who are older than 80 [years], those taking oral anticoagulants, patients with a National Institutes of Health Stroke Scale of greater than 25, or patients with a history of stroke or diabetes.
In ECASS 3 they tried to select a population to maximize benefit and minimize risk, so they used a variety of definitions of intracerebral hemorrhage, which is the most-feared complication of tPA, and when they used a modified definition of intracerebral hemorrhage, they actually found a lower risk than previous studies. When they used the National Institute of Neurological Disorders and Stroke criteria to define hemorrhage risk, they found a similar risk as the 3-hour patients, so this also provides confirmatory safety data.
There still seems to be some resistance to the use of tPA this late in the time window. Is the caution fair, and can you outline some of the reasons for this?
Dr. Sacco: I think the resistance still comes from the fear of causing hemorrhage. What we try to educate clinicians about is — even accounting for this risk of hemorrhage, which is there with tPA — there is still clear and substantial benefit. But you know clinicians always want to avoid causing harm, and therefore minimize risk, and so to me that is one of the main reasons that people may not use tPA. But it’s so clear from all of the trials — the trials that preceded the guidelines and this more recent trial that confirms the efficacy and reasonable safety in the expanded time window — that tPA is of clear benefit for acute stroke, despite the risk of hemorrhage.
The other issue, of course, is the availability of acute stroke teams. If physicians don’t have, for example, the ability to read acute computed tomography (CT) scans in the middle of the night when patients come in with acute ischemic stroke, they will feel reluctant to start a drug if they aren’t absolutely clear about what the CT scan is showing. And you do need a brain image and a variety of other tests done before one gives tPA. It’s not as simple as giving an aspirin. It does require an orchestrated team and a well-developed acute stroke protocol when the drug is used. So because it’s not easy and because there is risk, I believe there is sometimes reluctance, despite the clear benefits.
Do you think this will change with the new Science Advisory?
Dr. Sacco: Well, I hope so, but there have been other Scientific Advisories. Our acute stroke guidelines from the ASA have given intravenous tPA within the 3-hour time window a class 1, level A rating for some time now. I think with the increasing numbers of primary stroke centers and with the increasing awareness in the public of stroke warning symptoms, and awareness in the public that there are potential therapies, we are beginning to see an increase in the proportion of stroke patients who receive tPA, but it’s still not as much as we’d like.
The uptake of these results into guidelines from the Europe Stroke Organization was very rapid. Why was the AHA/ASA more cautious in its assessment of the new evidence?
Dr. Sacco: I think there are a number of reasons there. First, the principal investigators in the ECASS 3 trial were also some of the key people on the guideline-writing committee in Europe, so they were well-poised and knowledgeable about the results to make rapid changes in the European Stroke Organization’s guidelines.
Second, they have a different review process. The AHA has multiple layers of review when a scientific statement is issued; from getting peer reviewed, to getting the scientific advisory council to sign off on it, there are a number of levels that the AHA goes through, and it often takes longer. The European Stroke Organization has a little different protocol and organization, which allowed them to more rapidly approve changes in their guidelines. And I think they approved it online, and we don’t actually have that rapid online process available yet, so we had to issue a written statement.
There is also still some reluctance in the United States because I don’t believe the FDA has changed any labeling for tPA. In Europe that was less of an issue, since their regulatory authority actually requested the ECASS 3 trial be done. Here I don’t know yet how the FDA will deal with European data and Genentech — the company that markets tPA — what their plan is in working with the FDA.
Information for this interview came from Medscape Medical News