Date: November 1st, 2021
Reference: Katsanos et al. Utility of Intravenous Alteplase Prior to Endovascular Stroke Treatment: A Systematic Review and Meta-analysis of RCTs. Neurology 2021
Guest Skeptic: Dr. Michal Krawczyk is in his fifth year of neurology residency at Western University in London, Ontario, Canada. He is interested in acute neurological illness, including cerebrovascular disease and epilepsy. Next year he will be beginning a Neurohospitalist fellowship at the University of Texas at Houston.
Case: A 70-year-old male with a past medical history of hypertension and peripheral artery disease, last seen normal 1.5 hours ago, presenting with acute onset of aphasia and right sided face and arm weakness. He has a National Institute of Health Stroke Scale (NIHSS) score of 7. At 1am a CT angiogram is obtained that demonstrated a left M2 occlusion, and an Alberta Stroke Program Early CT Score (ASPECTS) of 10. Given the recent publications of trials assessing if mechanical thrombectomy alone is non-inferior to a bridging approach with tPA in addition to mechanical thrombectomy, you wonder whether these trials apply to your patient and what is the best course of action.
Background: There are two treatments for acute ischemic stroke, systemic tPA and mechanical thrombectomy (MT). We have covered some studies looking at both treatment modalities on the SGEM.
- SGEM#29: Stroke Me, Stroke Me
- SGEM#70: The Secret of NINDS (Thrombolysis for Acute Stroke)
- SGEM#85: Won’t Get Fooled Again (tPA for AIS)
- SGEM#137: A Foggy Day – Endovascular Treatment for Acute Ischemic Stroke
- SGEM#292: With or Without You – Endovascular Treatment with or without tPA for Large Vessel Occlusions
- SGEM#297: tPA Advocates Be Like – Never Gonna Give You Up
- SGEM#333: Do you Gotta Be Starting Something – Like tPA before EVT?
Mechanical thrombectomy is indicated only for patients with large vessel occlusions (LVOs) on imaging. There were a few earlier studies on MT that failed to demonstrate superiority, but it was the study MR CLEAN published in NEJM 2015 that really changed practice. It was a multicenter, randomized, unblinded trial treating 500 patients with an anterior circulation LVO within six hours of symptom onset. The primary outcome was mRS 0-2 at 90 days and it showed an absolute difference of 14% favoring MT. This gives a NNT of 7.
For patients with LVOs it is unclear whether there is any additional benefit with administering tPA before thrombectomy, also known as a bridging approach, in contrast to skipping tPA and directly proceeding with MT.
There are several theoretical advantages of a bridging approach. These potential advantages include thrombus debulking allowing easier clot retrieval, distal emboli lysis, recanalization prior to MT, and it may be beneficial in cases of unsuccessful MT. Conversely, a direct to MT approach may lead to fewer intracerebral hemorrhages (ICH) and quicker initiation of endovascular thrombectomy.
Recently, three randomized control non-inferior trials on this topic have been published, two from China (DIRECT-MT, and DEVT) and one from Japan (SKIP). Two trials demonstrated non-inferiority while one trial failed to show that direct MT was non-inferior.
Clinical Question: What is the best strategy for treating patients with an acute large vessel occlusion stroke, direct to mechanical thrombectomy or a bridging approach with tPa followed by mechanical thrombectomy?
Reference: Katsanos et al. Utility of Intravenous Alteplase Prior to Endovascular Stroke Treatment: A Systematic Review and Meta-analysis of RCTs. Neurology 2021
- Population: Randomized controlled trials of patients with acute large vessel occlusion stroke qualifying for MT
- Exclusions: Observational studies and non-randomized trials
- Intervention: MT alone
- Comparison: MT bridged with tPA
- Primary Outcome: mRS score 0-2 at three months
- Secondary Outcomes: mRS 0-1 and ordinal shift at three months, successful recanalization before MT, successful recanalization after MT, randomization to puncture time, symptomatic intracranial hemorrhage (sICH), any ICH and all-cause mortality
Authors’ Conclusions: “We detected no differences in functional outcomes of IV thrombolysis–eligible patients with an acute LVO receiving dEVT compared to BT. Because uncertainty for most endpoints remainslarge and the available data are not able to exclude the possibility of overall benefit or harm, further RCTs are needed.”
Quality Checklist for Therapeutic Systematic Reviews:
- The clinical question is sensible and answerable. Yes
- The search for studies was detailed and exhaustive. Yes
- The primary studies were of high methodological quality. No
- The assessment of studies were reproducible. Yes
- The outcomes were clinically relevant. Yes
- There was low statistical heterogeneity for the primary outcomes. Yes
- The treatment effect was large enough and precise enough to be clinically significant. No
Results: The three RCTs included a total of 1,092 patients. Median age was in the early 70’s and 42% were female.
Key Results: No statistical difference in good neurologic outcome
- Primary Outcome: mRS score 0-2 at three months
- OR 1.08 (95% CI 0.85 to 1.38) and adjusted OR 1.11 (95% CI 0.76 to 1.63)
- Secondary Outcomes:
- mRS score 0-1 at three months OR 1.10 (95% CI 0.84 to 1.43) and adjusted OR 1.16 (95% CI 0.84 to 1.61)
- Successful recanalization before EVT: OR 0.37 (0.18-0.77) Moderate certainty
- Successful recanalization after EVT: OR 0.77 (0.54-1.08) Low certainty
- sICH: OR 0.75 (0.45-1.25) Low certainty
- Any ICH: OR 0.67 (0.49-0.92) Moderate certainty
- All-cause mortality: OR 0.93 (0.68-1.29) Low certainty
1. External Validity: All three trials were from Asia and as such may not be directly applicable to North American populations and healthcare systems. In one of the trials, they used 0.6mg/kg of tPA (SKIP) instead of the standard 0.9mg/kg. This could bias the trial to finding non-inferiority. In addition, these studies were all conducted at stroke centres with MT availability and do not address a drip and ship model of care.
2. Non-Inferiority Margins: All three studies included in the SRMA were non-inferiority trial designs. They were asking if direct to MT was non-inferior to the standard bridging with tPA before MT. Two out of three trials (DIRECT-MT and DEVT) the non-inferiority was met, but the non-inferiority margin was set at ≤10% absolute clinical effect in DEVT, and 20% effect size in odds ratio in DIRECT-MT. Even if non-inferiority is demonstrated, it does not mean there is no clinical benefit from a bridging approach if the non-inferiority margin is too large, which may represent a clinically important difference. Many argue that the non-inferiority claim should only be reserved when a less conservative margin of 5% is utilized. None of the trials met this less conservative margin.
3. Performance Bias: We have discussed different forms of bias many times on the SGEM. This is the first time we have mentioned performance bias. This type of bias is defined by Cochrane Risk of Bias (RoB) Tool as the result of “systematic differences between groups in the care that is provided, or in exposure to factors other than the interventions of interest.”
As highlighted in this SRMA, there was a performance bias in the DIRECT-MT trial with 9.4% of patients in the bridging group not receiving MT, while only 5.2% in the direct group did not receive MT. This 4.2% difference may have resulted in worse outcomes in the bridging group, favoring direct MT and a finding of non-inferiority.
3. Selection Bias: This is a type of bias we have discussed many times on the SGEM. The Cochrane RoB Tool defines selection bias as the result of “systematic differences between baseline characteristics of the groups that are compared.” Selection bias may affect the estimate of the per-protocol effect and/or the intention-to-treat effect. It depends on the definition that is used for the groups that are being compared.
In the DEVT trial, an exclusion criterion was “arterial tortuosity and/or other arterial disease that would prevent the device from reaching the target vessel.” This exclusion criterion may effectively ‘cherry-pick’ patients, excluding those where thrombectomy would have been difficult, potentially resulting in less favorable outcome in the direct MT group. It is unclear how many patients were excluded from the DEVT trial for this reason. In the DIRECT-MT trial approximately 5.8% (38/654) of patients intended to undergo thrombectomy did not due to technical reasons, highlighting that even in specialized academic centers thrombectomy remains technically challenging.
4. Timing of tPA: In the SKIP trial, 21% of patients in the bridging group had tPA started after groin puncture for MT. It is likely that in a significant proportion of these patients MT was completed even before the tPA infusion was finished. In the DIRECT-MT trial 87% of patients had a tPA infusion ongoing during MT, and 9% of patients in the bridging group did not receive the full dose of tPA. This could have biased the study towards finding non-inferiority for MT alone.
5. Subgroups: Certain subgroups that may benefit more from a bridging approach were underrepresented in the three trials. In the study design of the DEVT and SKIP trials they did not include patients with M2 occlusions. After final adjudication the percentage of M2 occlusions in the DEVT trail was 1.7%, SKIP 19%, and DIRECT-MT 10.1%. It is known that compared to M1/ICA occlusions, tPA is much more effective at lysing M2 clots. In the INTERRSeCT study, the odds ratio of recanalization with tPA of an ICA occlusion is 1, proximal M1 occlusion is 1.99, and M2 occlusion is 3.61 (1).
It is unclear which approach is better for M2 occlusions. The argument is that two out of the three trials did not include M2 occlusions based on their inclusion criteria, and as a result the amount of M2 occlusions overall was low. Therefore, it may be unwise to expect for patients with M2 occlusions as they were excluded from the majority of the trials we are discussing, and there is a rationale based on previous research to suggest that patients with M2 occlusions “may/may not” do better with a bridging approach (1).
In addition, recanalization would be a surrogate marker for good neurologic function. Just because blood flow is restored does not mean function will improve. This would be true if the damage was too great regardless of the time (futile recanalization). However, recanalization is a variable strongly associated with better outcome (2), after all the entire point of thrombectomy is to pull out the clot, there is no conceivable benefit of thrombectomy without recanalization.
The benefits of tPA are strongly associated with earlier time to treatment (3), neither the DIRECT-MT or DEVT trial had any patients receiving tPA under two hours, the approximate median for both trials from symptom onset to tPA treatment was 3 hours. This is contrast to the HERMES meta-analysis (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) the symptom onset to tPA treatment was 2.08 hours (interquartile range, 90-170) (4), approximately one hour shorter compared to DIRECT-MT or DEVT. A partial explanation is the less-than-ideal door-to-needle times of approximately 60 minutes in the DIRECT-MT and DEVT trials. The HERMES investigators demonstrated that a 1-hour delay in door-to-needle times is associated with 53% lower odds of functional independence in LVO patients treated with tPA (4). The unfavorable effect of such a delay may have led to an underestimation of the benefit of a bridging approach.
We need to be cautious not to over-interpret observational data. There are no RCT randomizing patients into early vs late treatment. There could be unmeasured confounders responsible for the association between faster times and better outcomes. Perhaps those teams that perform faster also do several other things better that are responsible for the observed improvement.
The concept of “time is brain” is initially based on animal studies (5-7). If the middle cerebral artery (MCA) is occluded in monkeys (5) or other animals (6), the duration of ischemia is directly related to volume of infarct up to a certain time point but not longer. These experiments formed the basis of our understanding of core and penumbra physiology and defined thresholds of cerebral ischemia (7).
Dr. Camilo Gomez coined the term “time is brain” back in 1993. He has since modified his position: “It is no longer reasonable to believe that the effect of time on the ischaemic process represents an absolute paradigm. It is increasingly evident that the volume of injured tissue within a given interval after the estimated time of onset shows considerable variability in large part due to the beneficial effect of a robust collateral circulation.” (J Stroke Cerebrovasc Dis 2018)
We agree with Dr. Gomez that time to treatment is not an absolute paradigm, and there are other important variables such as collateral circulation that can perfuse the ischemic penumbra and slow core progression. Currently, at stroke onset we cannot predict which patients are slow or fast progressors. Even in patients that are slow progressors, over time the ischemic core grows. From DAWN and DEFUSE-3 we know that the limit is 24 hrs, but some argue that in a minority of slow progressors benefit from reperfusion can be up to 48 hrs (8).
Besides animal studies, advances in neuroimaging such as PET also demonstrated that time is a critical predictor of tissue fate (9) and allowed for the quantification of how much brain tissue is lost over time (10). Dr. Saver published an article in 2006 that quantified how much brain is lost over time and determined 1.9 million neurons are destroyed each minute (10).
1.9 million neurons sounds impressive, but we need to consider how many total neurons are in the brain. Our current best estimate is 86 billion (J Comp Neuro 2009). To put it another way, it would take over 750 hours or 31 days to lose all your neurons. No one is advocating for the loss of neurons but how many neurons must be lost and in what area of the brain to be clinically significant?
In the same study by Dr. Saver, it was estimated that each hour without recanalization the ischemic brain ages 3.6 years (10). Based on this scientific rationale, time to treatment is a critically important variable predicting outcome. This has been reported both in a pooled meta-analysis of RCTs on tPA (3) and MT (11, 12), not to mention multiple well designed observational studies (13, 14).
Again, we need to be careful not to over-interpret observational data. Pushing the system to go too fast can lead to increased potential harm. This has been reported in the STEMI literature in trying to reduce door-to-balloon time (Fanari et al 2015). We do not want to be too slow or to be too fast.
Acute ischemic stroke treatments needs to be provided in a safe manner. Some stroke centers have achieved excellent door-to-needle times of 20-25 minutes (15, 16) and they did not report any compromise of safety. The rate of thrombolyzed stroke mimic was low at 1.4% (15) and sICH post-thrombolysis was also low at 2.1% (16).
Comment on Authors’ Conclusion Compared to SGEM Conclusion: We agree with the authors conclusion.
SGEM Bottom Line: Currently there is insufficient evidence to know what the best strategy for patients with large vessel occlusions is, direct to mechanical thrombectomy or bridging with tPA.
Case Resolution: Our case highlights the nuances of the application of these trials to individual care. There are many factors that may suggest a bridging approach is the preferred option.
First, the patient is presenting at 1.5 hours from stroke onset, and earlier time to treatment with tPA is strongly associated with better outcome (3). Neither the DIRECT-MT or DEVT trial randomized patients in this early time window.
It is true that there is a strong association, but tissue factors are probably more important than the clock. In terms of tissue viability, the patient has an ASEPCTS of 10, with no early ischemic changes, that is as good as it gets.
Second, the evaluation of this patient is occurring at 1am and not during standard working hours. All three trials had very quick work workflow with MT occurring after tPA in DEVT and DIRECT-MT trials in approximately 30 minutes, while SKIP trial in 8 minutes. If considerable delays to MT are expected, such as on call, or transfer from a community hospital, a bridging approach may be preferred.
Standard working hours for emergency medicine is 24/7/365. Patients can have acute ischemic stroke at any time of day. If there is a more effective/safer therapy, why should it be only offered during “banking hours”? Perhaps that means that the revascularization team needs to be available 24/7/365 in a timely fashion like we have with STEMI patients. We still do not know if a drip and ship model will have a patient oriented net benefit.
In many centers MT is available 24/7/365, but the reality is that, many of those centers the interventionalist and techs are at home and it takes time for everyone to arrive to the hospital and set up. Not to mention there is one interventionalist on call, rarely they may be busy with another case. These are the realities that we face and need to be cognizant of them when we are applying the results of trials with excellent workflow characteristics for mechanical thrombectomy.
A study published in 2017 by Prasanna Venkatesan Eswaradass et al in CMAJ Open looked at eight Canadian provinces and estimated that 84.7%-99.8% have access to a current or proposed endovascular thrombectomy site within six hours by ground EMS.
Third, the patient has an M2 occlusion, which is more frequently recanalized with tPA compared with M1/ICA occlusions (1). Moreover, MT may be more challenging the more distal the clot.
Lastly, the patient has a history of peripheral artery disease, if severe may make it challenging to gain vascular access and may even preclude a transfemoral approach.
We cannot forget about the potential increase in harms. There is no doubt that the bridging approach using tPA increases the risk of sICH. The excess risk of sICH in all three included RCTs was just under 2%. However, it was not statistically significant and there was no increase in all-cause mortality.
The risk of sICH needs to be strongly considered before deciding on a bridging approach. There are many clinical (i.e., high NIHSS, uncontrolled hypertension, dual anti-platelet therapy), radiological (i.e., CT hypodensity), and laboratory (i.e., hyperglycemia, thrombocytopenia) risk factors for sICH (17).
There are many scoring tools used to predict sICH post-tPA that have not been applied clinically for two reasons. First, the scores have only moderate predictability, and second, the variables that predict sICH are also associated with benefit from tPA. For instance, high NIHSS is a consistent predictor of sICH, but patients with high NIHSS also benefit from tPA. I think with the publications of these trials, we have evidence that both approaches are not considerably different in terms of outcome. There may indeed be subgroups that benefit more from one approach versus another which remains to be seen. But overall, the outcome appears similar. Therefore, we really should consider a direct approach in patients with multiple risk factors for sICH. For instance, in a patient with high NIHSS, a large clot burden from a tandem occlusion, on DAPT, hypertensive, and hyperglycemic. In a patient like this, do we want to risk a sICH with tPA administration?
The patient presented at the start of this SGEM episode had minimal risk factors for sICH. Therefore, the decision is made to go ahead and offer treatment with tPA, while you wait for the endovascular team.
Clinical Application: It would be premature for a general application of a direct MT approach, and more data is required. Importantly, as was mentioned by the authors, these trials are only applicable to a mothership model of stroke care.
Intervention bias is recognized as an issue in medicine (Foy and Filippone Yale J Biol Med 2013). They defined this type of bias as “bias on the part of physicians and the medical community to intervene, whether it is with drugs, diagnostic tests, non-invasive procedures, or surgeries, when not intervening would be a reasonable alternative.” It is too bad we don’t have more high-quality evidence to guide whether we should be using tPA as a bridging therapy for MT. This is not an unusual problem in medicine. There is a lack of high-quality evidence to help inform our care in emergency medicine and often need to rely upon our good clinical judgment (Parish et al AEM 2021).
We need to be guided by evidence and need to be careful in rushing too quickly applying RCTs to clinical care, when as we have been discussing there are major limitations in these studies.
It can take over ten years for high-quality, clinically relevant information to reach the patients’ bedside (Morris et al J RSM 2011). However, new practices can be adapted too quickly as we have seen with targeted temperature management (TTM) for out-of-hospital cardiac arrest (OHCA) or TXA for epistaxis.
It is unlikely that there will be a general application of a direct MT approach to all cases of LVOs. This prediction is based upon the results of two European trials, MR CLEAN-NO IV (ISC 2020) and SWIFT-DIRECT (ESOC 2021), which were presented, both failed to show that a direct MT approach was non-inferior to the standard of care. Therefore, there are now three out of five trials that failed to demonstrate non-inferiority. All the European trials failed to show non-inferiority, which highlights the limitation we addressed about the external validity of the trials conducted in Asia.
The fact that multiple trials are failing to show non-inferiority suggests some subgroups may be benefiting from a bridging approach. There is one other study pending called DIRECT-SAFE. Ultimately, a patient level meta-analysis of all studies may address which patients benefit from a direct MT versus bridging approach, likely necessitating an individualized treatment strategy.
We will have to be skeptical of the SRMA and consider the quality of the included studies. Putting together several open label (non-blinded) trials may not get us any closer to the “truth” (best point estimate of an observed effect size).
Lastly, in the near future tenecteplase (TNK), which has greater fibrin selectivity, and the full dose is administered as a single bolus, may be adopted as the standard care. There is also suggestion that TNK may be more effective in lysing LVOs compared to tPA (18). In an RCT called EXTEND-TNK (2018) patients with LVOs prior to MT were randomized to either TNK or tPA. The primary outcome was vessel recanalization and secondary outcome was mRS. With an average time of thrombolytic administration of 42 min prior to MT, TNK was statistically associated with double the recanalization rate prior to MT (22% vs. 10%), and better clinical outcomes (18). If TNK does in fact replace tPA in the near future, the question will remain should we administer TNK prior to MT?
We seem to be moving towards using TNK for acute ischemic stroke. The STEMI literature does not support TNK being superior to tPA for efficacy. The large ASSENT-2 trial (n=16,949) reported no difference in revascularization, equivalence for 30 mortality between TNK and tPA but less bleeding with TNK (19).
The previously mentioned EXTEND-IA TNK trial was a relatively small trial (n=202). The trial was partially funded by industry and multiple authors declared financial conflicts of interest. This does not make the data or conclusions wrong, but it should make us more skeptical. They had a composite primary outcome of reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. Both are surrogate markers and not patient oriented outcomes. There were baseline differences between groups reported in their supplementary appendix (ex. atrial fibrillation, diabetes, and smoking). While the median score on ordinal analysis was statistically better with TNK none of the other three patient-oriented secondary outcomes were shown to be statistically different (early neurologic improvement, functional independence, or excellent outcome at 90 days).
What Do I Tell the Patient? Our patient is aphasic. If possible, a family member should be called to inform them that their loved one is having a stroke. Explaining that there is a blood clot in one of their vessels blocking blood from reaching part of their brain. This is causing them to have severe problems with language and weakness in their face and arm. There are two treatments currently available to treat his stroke. The first is a clot busting medication called tPA that has been shown to reduce risk of disability in three months, but there is also a risk of a serious complication of a brain bleed (2-7%) that could be life threatening. The second treatment is to give the clot busting drug and then try to retrieve the clot. The clot retrieval procedure where doctors put a tube inside a blood vessel in the leg. This is then threaded all the way up to the brain. The end of the tube has a special device to remove the clot. The usual practice is to give the combination therapy. The third option would be to go to directly try clot retrieval without using the clot busting drug. There is insufficient evidence to know what the best strategy is. What do you want to do?
Keener Kontest: Last weeks’ winner was Erik Iszkula. He knew the half-life of dalbavancin is longer that one week. The range is between 6 and 10 days (Zhanel et al Drugs 2010).
Listen to the SGEM podcast for this weeks’ question. If you know, then send an email to firstname.lastname@example.org with keener in the subject line. The first correct answer will receive a cool skeptical prize.
Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.
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- Read et al. The fate of hypoxic tissue on 18F-fluoromisonidazole positron emission tomography after ischemic stroke. Ann Neurol. 2000 Aug;48(2):228-35. PMID: 10939574.
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