Anticoagulation in patients with microbleeds and TPA for stroke beyond 3 hours

The 3rd World Congress on Controversies in Neurology, held in Prague October 8-11, used an all-debate format to highlight areas of uncertainty and disagreement in current neurological practice. With three concurrent sessions to choose from, I wasn’t able to attend everything of interest, but here are some highlights from two of the sessions:

Should patients who have brain microbleeds on MRI be anticoagulated for secondary prevention of cardiovascular or cerebrovascular disease?

Dr. Charlotte Cordonnier of France defended the position that, in general, advantages outweigh drawbacks. MRI techniques are improving, so small bleeds that previously would have gone unrecognized now are apparent. Their presence, Dr. Cardonnier says, tells us nothing about when the bleeds occurred and there is no good evidence that they predict future haemorrhage. Thus, for the moment, patients with cerebral microbleeds should not be managed differently than those without microbleeds when it comes to anticoagulation for secondary prevention. She acknowledged the need for more research, however.

Michael Russell from Norway agreed that cerebral microbleeds are more often detected with improved MRI techniques. He noted that they are associated with 2 distinct pathologies, namely amyloid angiopathy and hypertensive vasculopathy. The topography of the 2 processes seems different, but he suggested that the presence of microbleeds may in fact signal underlying problems that raise the risk of haemorrhage, making caution about anticoagulation appropriate. He called for individualized decision-making, and suggested that the size and quantity of the bleeds might be important modifiers of risk.

Should tissue plasminogen activator (TPA) be given to patients with ischemic stroke beyond 3 hours from onset of symptoms?

Dr. Peter Schellinger of Germany acknowledged that he was taking an extreme position for the purpose of fostering debate, and so defended the proposition that IV TPA beyond three hours from stroke onset was suitable for most patients with ischemic stroke. He commented that “in a better organized world we could give IV TPA to as many as eighty percent of all ischemic stroke victims and do good.” He suggested that the biggest problem is logistics: patients are slow to present for medical care after onset of symptoms suggestive of stroke, emergency departments are slow to evaluate them, and neurologists and neuroradiologists are slow to respond as well. He opined that the low percentage of patients eligible for TPA who receive it is “one of the biggest health scandals on the planet.” He suggested that the results of a recent study, ECASS 3, clearly indicate that the time window for TPA could be expanded to 4.5 hours and that “there is no doubt that patients who fulfill the inclusion criteria of ECASS 3 will benefit from TPA. In addition to expanding the time window for TPA, he suggested that older patients and those who show perfusion-reperfusion mismatch on imaging studies might also be candidates for TPA. He noted that studies clearly show that TPA increases the chance for early reperfusion, and that although the link between this outcome and infarct size has not been firmly established, it stands to reason the two are correlated. He concluded by saying that, in his opinion, TPA should probably be given to 80 percent of all ischemic stroke patients based, as suggested by results of National Institute of Neurological Disorders and Stroke (NINDS), ECASS and MRI criteria. He reiterated his view that it is a scandal that TPA is currently given to only 2-4% of all patients with ischemic stroke.

Dr. Peter Sandercock, of the University of Edinburgh, took the opposite view, saying that further evidence is still necessary before recommending significantly more widespread use of TPA. He agreed that even under the current conservative criteria for TPA, most eligible patients don’t get it, though the percentage who do varies form a high of 6.3% in Sweden to a low of 1% in the UK. The US rate of 2.4%, though higher than the UK rate, is still a “scandal”, he said, given that the drug has been licensed there for much longer than elsewhere. In the EU, he said, approval of the drug restricts its use to a narrow range of patients.  The US average is a scandal given drug licensed there longer than anywhere else.

He noted that the debate stems from a number of causes. Meta-analysis has not provided a clear answer because there is significant heterogeneity among trials, for reasons that are not clear. He also noted that while TPA may limit stroke size and thus reduce disability, it doesn’t seem to save lives and in fact, “it probably kills a few people” through hemorrhage. He compared this state of affairs to surgery for carotid stenosis, in which the short-term risks of surgery cause early mortality for some patients, but improve outcome for those who survive the procedure. He noted that if TPA were used in a wider variety of patients, there might be an excess of deaths.

He is involved with an ongoing trial, IST3, which is a randomized, open study with blinded outcomes of TPA vs control in patients with acute ischemic stroke less than six hours. Recruitment has been slow, though, which he blames on the introduction of the European Clinical Trials Directive. This, in what probably could have been a separate talk, he suggested was a huge barrier to investigator-led trials that slowed the study down immensely. He suggested that rather than use TPA outside its current indications, physicians should consider randomizing patients into this trial. In summary, he concluded, TPA s effective within approved criteria, but underused. Further study is needed to determine whether a wider variety of patients may benefit. Rather than just tackle slow doctors, though, he suggested “we need to tackle the slow regulators. We must protest at the overregulation of clinical research. This is really what’s killing our patients.”

Elizabeth Loder is clinical editor (secondary care), BMJ