Thrombolysis will continue to be the mainstay for acute stroke treatment, despite the recent revolution in neurointerventional clot retrieval. However, as there are ongoing limitations of thrombolysis of bleeding risk and reduced efficacy in large clots – what possible therapeutic advancements can complement or act as an adjuvant to thrombolysis?
Neurointervention – effective, but limited to a small subset of stroke patients
The latest evidence has renewed confidence in neurointervention, which has been proven to be a highly effective treatment in a sub-population of ischemic stroke sufferers in relation to a large occlusion of a proximal intracerebral vessel – the ‘reperfusion responder’. Overall, about 80% of all strokes are ischemic (caused by a blockages of a blood vessel in the brain), and those with large clots and residual viable brain tissue, the so called ‘reperfusion responders’, comprise about 15% of this group.
Whilst an exciting advancement in acute stroke treatment, unfortunately the overall impact of this development in absolute terms is likely to be small. There are a host of challenges that must be overcome to ensure that neurointervention is accessible to people who experience an acute ischemic stroke. Advanced infrastructure in brain imaging is required to identify suitable patients, as is the deployment of highly skilled doctors supported by trained nurses and technicians, available 24/7. Therefore, it is likely that neurointervention will only ever be effectively delivered to a small fraction of potentially eligible patients. Currently, only a very small number of these patients actually receive neurointervention, although the exact number is still unknown.
Globally, in emerging countries, the lack of advanced infrastructure to deliver neurointervention becomes more palpable. Even now, less than 1-2% are receiving thrombolysis in Asian urban centers, and hardly any are receiving neurointervention at all, save for the well-organized health care delivery systems in some Korean and Japanese cities. Accessible treatments are still unknown to the rest of stroke patients in Asia, so it is important that new developments in stroke therapy are meaningful to this vast population.
As it is unlikely that the massive infrastructure and resource challenges facing neurointervention can be overcome globally, thrombolytic treatment is still the most effective and practical way to treat patients with acute ischemic stroke, now and into the near future.
Thrombolytic treatment, and more specifically recombinant tissue plasminogen activator (rtPA), is the only approved treatment for ischemic stroke, it is estimated that only 4-5% of patients receive this therapy in Australia. In good centers, this figure may reach 20% but still this is nowhere near enough. The brain deteriorates rapidly at the onset of stroke. In order to be eligible for thrombolysis, the patient needs to have sufficient salvageable tissue when they are presented to hospital. This time window is estimated to be only 3 to 4.5 hours in most patients, with patients on the latter end of this scale being eligible if they meet a number of pathophysiological criteria based on their imaging results. There are also significant limitations to rtPA – it sometimes does not achieve rapid reperfusion and has relatively low recanalization rates. It also increased the risk of major hemorrhage within the brain and early death.
It is estimated that 5% of ‘on time’ patients do not receive rtPA due to bleeding risks. This group of patients include those who have had recent operations, anticoagulants, blood thinners or diseases/conditions that increase the risk of bleeding such as renal failure. The risk for patients who fall under this category is very significant – there is a 2% chance of early death from brain hemorrhage in at-risk patients who receive rtPA. As approximately 10% of ischemic strokes occur in hospital, it is likely that this group of people would be largely excluded.
The case for improved healthcare delivery services must be pursued, however we should also ask what therapeutic strategies can meet healthcare delivery at the other end in order to increase the number of eligible patients for thrombolysis.
A number of healthcare delivery factors such as detection, ambulance time, time in triage etc. impacts the time between stroke onset and time of treatment.
One of the most obvious strategies is to ‘stun’ the brain or hold it in stasis to preserve the ischemic tissue whilst the clot is addressed. Many neuroprotectant drugs have been pursued over the past 20 years but without any success, potentially due to their limited ability to control rapidly the accelerated metabolic changes that occur in the brain after ischemic injury. Cooling was also considered as a strategy to hold the brain in stasis, however there are many complexities on how to apply cooling efficiently and safely.
However, the Los Angeles Fast-MAG trial does pave the way for future neuroprotectant trials to be undertaken in the ambulance with the patient on-route to hospital. Fast-Mag showed the practicality of subject recruitment within an hour after the onset of symptoms, obtaining informed consent, and provision of a treatment in advance of recanalization are all possible – application of these strategies may demonstrate benefits of future neuroprotectant trials.
One of the more useful strategies is to increase thrombolysis with more effective lytic agents. Of the newer thrombolytic agents – the most promising appears to be tenecteplase, which is already available on the market for coronary events. It is a potentially stronger lytic with a longer duration of effect from a single bolus injection, staying in the circulation longer.. This is in contract to rtPA which requires both intravenous bolus and continuous infusion over 1 hour. The evidence on whether or not tenecteplase is safe and effective for treatment of stroke is still several years away.
Another recently trialed lytic, demesteplase, was also promising and showed good safety data with lower bleeding. However, it was tested unsuccessfully in situations where rtPA could not be used (up to 9 hours), and for commercial reasons, was not evaluated directly against rtPA, which may have been an error. Ultimately, the trials of demesteplase have been abandoned after neutral results being shown.
Repurposing lytics that are already available
We should also consider re-evaluating older lytics. Urokinase, which is derived from urine, is prescribed for breakdown of pulmonary emboli, which are clots in the lungs. It is discontinued in the United States, but is still being manufactured in China and India. It is very affordable and still being used to treat blocked clots in many emerging countries, and in some cases where patients can’t afford to pay for rt-PA, ischemic stroke. However, as urokinase is not licensed to treat ischemic stroke and there is certainly no randomized controlled trials that proves it does, clinicians are very wary of it. There is a possibility that it is effective for ischemic stroke, but more data is required. Streptokinase is another example of a discontinued lytic that was widely used for coronary events. It was evaluated in ischemic stroke at a higher ‘cardiac’ dosage and caused bleeding problems. There is an opportunity here to re-evaluate whether a lower dose of streptokinase is as good as rtPA, but more affordable in a low resource setting, however clinicians will clearly be apprehensive due to its bleeding history.
An evaluation of the safety and efficacy of a lower dose or rtPA is currently being performed by the Australian led ENCHANTED study involving over 3000 patients, with results expected to be published in May 2016. It is the first study to randomize a lower dose (0.6mg) of intravenous rtPA versus the current standard dose (0.9mg) of rtPA used in most countries around the world. The hypothesis is that a lower dose is safer with less bleeding risk but just as efficacious. The lower dose of 0.6mg rtPA was approved by the Japanese health authorities, PMDA, based on a non-randomized open arm clinical trial showed equivalent outcomes to other rtPA trials. This lower dose is used quite widely in Asian countries with the background influence of Japan, such as Korea and Taiwan. Whilst the eligibility criteria is still limited to 4 hours, it may pose less bleeding risk, which as highlighted earlier – is a significant danger to a large group of patients. It could be that all patients who are eligible for rtPA could be switched to a lower dose rtPA to retain the efficacy but reduce the risk. Or, the full dose can be used for larger clots and the lower dose used for smaller clots – utilizing a tailored approach rather than the current ‘one size fits all’. This approach would affect approximately half of the eligible patients for rtPA.
In addition, if a lower dose of rtPA is proven to be efficacious or safer, it opens up the possibility of combination with other existing and new antithrombotic agents, such as the novel anticoagulants or other antiplatelet agents. The reaction to clots in our circulation is complex, made up of many levels of varying components. For example, rtPA works to dissolve the fibrin strands in order to puncture the clot. Other drugs can also be used to work on clotting’s other components. By working together, complementary treatments can ‘crack’ then ‘smooth’ the clot from all sides. There are also new types of antithrombotics being tested that help open up the clot with low bleeding risk. Whether this is on top of rtPA or on its own remains to be seen. Approximately 5% of patients receiving rtPAhave major bleeds in the brain, and 2% of patients with major bleeds die.
Blood flow augmentation
Lytics also work much better if it gets to the clot, so adequate blood flow is required. Another strategy is blood flow augmentation – a simple one being tested now is the position of the patients head in HeadPoST. It is hypothesized that lying patients flat down may enhance blood flow to the brain and preserve the ischemic position, slowing down the decline and may also assist with perfusion. Other devices, such as external counter pulsation and compressive bandages that enhance venous circulation from the lower torso and limbs in synchrony with heart rate; could augment blood flow to the brain.
Twenty years ago was an exciting time in stroke with improved outcomes for patients with acute stroke being demonstrated with the results of the pivotal NINDS stroke trial of rtPA and a systematic review with meta-analysis of small trials of well organized, expert, acute stroke unit care. Now, with the results of neurointervention, there is considerable opportunity to expand acute stroke care. However, this should not distract from the opportunity (and challenges) that continue in the organization of acute stroke services and new thrombolysis regimes to improve access and benefits of acute treatments in stroke.