A guest post by Rory Spiegel (@EMNerd_) who blogs on nihilism and the art of doing nothing at emnerd.com.
Nothing sparks controversy quite like a discussion on the utility of thrombolytics. No sooner had the wave of debate brought on by the publication of the PEITHO trial and its finding of no overall mortality benefit died down, did JAMA stoke these flames with the publication of a meta-analysis including the entirety of the literature on thrombolytic use for pulmonary embolism. Examining 16 trials, the authors found a statistically significant absolute mortality benefit of 1.12% or an NNT of 59 patients. This benefit was offset by the increase in major bleeding events observed in those given thrombolytics (9.24% vs 3.42%) with a 1.27% absolute increase in ICH.
The cascade of incendiary events continued when one week later a second meta-analysis examining the very same question was published in Journal of Thrombosis and Haemostasis. Only these authors claimed to find the exact opposite of their JAMA counterparts. In this case the authors found no statistical improvement in mortality in the patients given thrombolytics when compared to those given a placebo. Despite these contradictory claims, a more comprehensive inspection reveals these meta-analyses are extensively saying the same thing. A comparison of the two serves as a timely reminder that conclusions reached from any meta-analysis is primarily dependent on the trials selected for inclusion. The JAMA meta-analysis included 2115 patients in 16 trials, while the Journal of Thrombosis and Haemostasis examined only 1510 patients in 6 trials. Interestingly, the absolute risk reduction in mortality was 1.12% in the JAMA publication vs 1.4% in the Journal of Thrombosis and Haemostasis publication. Though the JAMA analysis had an overall smaller absolute risk reduction, the result reached statistical significance due to the larger sample size.
More importantly the results of these publications should not come as a surprise. Before the publication of PEITHO the data on thrombolytics for PE was sparse. Most of the trials suffered from small sample sizes and questionable methodology. It is the amalgamation of these small trials that accounts for the mortality benefit in both meta-analyses. In the JAMA publication the mortality difference consisted of 17 fewer deaths in the thrombolytic arm compared to the placebo. All of which originated from these small underpowered studies. Conversely, the two large high quality trials (PEITHO and MSPPE) consisting of 1005 and 256 patients respectively made up the majority of patients meta-analyzed, neither of which found a mortality benefit with the use of thrombolytics. Moreover the 2% absolute increase in ICH seen in the PEITHO cohort is only diluted by the inclusion of these small trials, whose sample sizes were not powered to detect such rare events. A more elegant design would be to utilize a weighted average or one of the various statistical methods that takes into account each study’s sample size and event rate, allocating a greater weight to the hardier cohorts. Though one might argue an equally elegant solution would be to not include such flawed trials in the first place.
The publication of these dueling meta-analyses highlights the flaws of such statistical endeavors. Small trials with flawed methodological designs are prone to fall victim to publication bias and the fluctuating whims of chance. Collecting this data and attaching a statistical judgment to it does not correct these imperfections, it augments them. The overall benefit of thrombolytics in PE is yet undetermined, but the answer will not be elucidated in such analysis. We require further large randomized controlled trials like the PEITHO trial. Adding small flawed cohorts to this robust dataset does nothing but muddy the already murky waters.
“Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis.”
http://www.ncbi.nlm.nih.gov/pubmed/24938564
“Impact of the efficacy of thrombolytic therapy on the mortality of patients with acute submassive pulmonary embolism: a meta-analysis.”
http://www.ncbi.nlm.nih.gov/pubmed/24829097
Rory,
As always a fantastic and sophisticated analysis. You are one smart dude.
One point of clarification however… The vast majority of the patients included in the meta-analysis are for MODERATE pulmonary embolism. This is usually defined as some form of RV dysfunction on echocardiogram or CT along with a large PE. Less controversial is the generally accepted indication for thrombolysis of massive PE. How many patients with MASSIVE PE (i.e. big PE with hypotension) have been enrolled in RCT"S? Take a guess then look below…
Just over 30.
The most recent study was in 1995 and was stopped early for ethical reasons after only including 8 patients. So I guess we will never really get a proper large RCT to give us the answer about massive PE. Nevertheless, I think most people would feel comfortable about thrombolysis in someone dying from a massive PE. Having said this, the last patient I thrombolysed with massive PE two weeks ago got better but then dropped dead 13 hours later after her massive intracranial haemorrhage.
Rory,
As always a fantastic and sophisticated analysis. You are one smart dude.
One point of clarification however… The vast majority of the patients included in the meta-analysis are for MODERATE pulmonary embolism. This is usually defined as some form of RV dysfunction on echocardiogram or CT along with a large PE. Less controversial is the generally accepted indication for thrombolysis of massive PE. How many patients with MASSIVE PE (i.e. big PE with hypotension) have been enrolled in RCT"S? Take a guess then look below…
Just over 30.
The most recent study was in 1995 and was stopped early for ethical reasons after only including 8 patients. So I guess we will never really get a proper large RCT to give us the answer about massive PE. Nevertheless, I think most people would feel comfortable about thrombolysis in someone dying from a massive PE. Having said this, the last patient I thrombolysed with massive PE two weeks ago got better but then dropped dead 13 hours later after her massive intracranial haemorrhage.
Thank you so much Brian for your kind words. Great points on the paucity of literature that exists for massive PE. So we have to extrapolate from the literature we do have. You are right, I doubt we will ever know for certain the efficacy of thrombolytics for massive pulmonary embolism. My personal experience with its use had similar results to your own. Then again the plural of anecdote does not equal evidence…
Thanks again for your support!
Brian,
Sorry to hear about your last case.
TPA has a half-life measured in minutes, so its difficult to ascribe a massive intracranial hemorrhage 13 hours afterwards to the TPA alone. I've seen similar cases of delayed bleeding, and I think these delayed bleeds are often due to use of heparin or other anticoagulants following TPA. After receiving TPA patients usually have decreased levels of fibrinogen and other coagulation factors, which may not entirely be reflected in standard coagulation studies. Adding heparin or other anticoagulants at this point can be risky.
So, the question is whether we should be avoiding TPA, or whether we should be avoiding heparin in the first 12-24 hours following TPA? For further speculation on this see http://www.pulmcrit.org/2014/04/submassive-pe-do-we-have-it-backwards_18.html
Best, Josh
Brian,
Sorry to hear about your last case.
TPA has a half-life measured in minutes, so its difficult to ascribe a massive intracranial hemorrhage 13 hours afterwards to the TPA alone. I've seen similar cases of delayed bleeding, and I think these delayed bleeds are often due to use of heparin or other anticoagulants following TPA. After receiving TPA patients usually have decreased levels of fibrinogen and other coagulation factors, which may not entirely be reflected in standard coagulation studies. Adding heparin or other anticoagulants at this point can be risky.
So, the question is whether we should be avoiding TPA, or whether we should be avoiding heparin in the first 12-24 hours following TPA? For further speculation on this see http://www.pulmcrit.org/2014/04/submassive-pe-do-we-have-it-backwards_18.html
Best, Josh
Excellent article Rory! I was just reviewing the conflicting results a couple days back and agree with your analysis. I would also add there is significant heterogeneity between these studies, notably in terms of inclusion criteria (including the very definition of intermediate risk/sub massive PE) and thrombolytic doses which I think makes pooling their results extremely problematic. I too think there is little to be added by these meta-analyses and we must wait till further large trials come out. Even if you believed there was a small mortality reduction the trade off, of producing living disabled people from ICH who mostly would have survived in good shape without treatment makes the decision very difficult. I think the future will be examining a higher risk cohort within this intermediate group eg excluding those in the intermediate risk group who are quite likely to do well regardless off their troponin rise/RVD dysfunction based on other prognostic factors such as sPESI score. Also I totally with Josh that it's a mistake to give heparin after we give the thrombolysis. We actually have no good evidence that heparin is even beneficial for PE so it seems bizarre that we are not withholding it for a period after giving the thrombolytic. Finally if we can get the thrombolytic systemic dose down eg through catheter directed therapy which is being studied that also might be beneficial. I do think we will identify a group who will clearly have a net benefit from thrombolysis in some form (with heparin withheld) but we are not there yet.
Excellent article Rory! I was just reviewing the conflicting results a couple days back and agree with your analysis. I would also add there is significant heterogeneity between these studies, notably in terms of inclusion criteria (including the very definition of intermediate risk/sub massive PE) and thrombolytic doses which I think makes pooling their results extremely problematic. I too think there is little to be added by these meta-analyses and we must wait till further large trials come out. Even if you believed there was a small mortality reduction the trade off, of producing living disabled people from ICH who mostly would have survived in good shape without treatment makes the decision very difficult. I think the future will be examining a higher risk cohort within this intermediate group eg excluding those in the intermediate risk group who are quite likely to do well regardless off their troponin rise/RVD dysfunction based on other prognostic factors such as sPESI score. Also I totally with Josh that it's a mistake to give heparin after we give the thrombolysis. We actually have no good evidence that heparin is even beneficial for PE so it seems bizarre that we are not withholding it for a period after giving the thrombolytic. Finally if we can get the thrombolytic systemic dose down eg through catheter directed therapy which is being studied that also might be beneficial. I do think we will identify a group who will clearly have a net benefit from thrombolysis in some form (with heparin withheld) but we are not there yet.
Thanks Josh for your, as always, much welcome thoughts and perspective. You may in fact be right about the about the half-dose tPA being a safer option than full dose TNK. Holding the heparin after administration of tPA is also an interesting concept. I'd like to see both these concepts played out in a trial powered to detect a 2% bleed rate (similar to the PEITHO trial).
Thanks again, as alway I appreciate your support!
Thanks Josh for your, as always, much welcome thoughts and perspective. You may in fact be right about the about the half-dose tPA being a safer option than full dose TNK. Holding the heparin after administration of tPA is also an interesting concept. I'd like to see both these concepts played out in a trial powered to detect a 2% bleed rate (similar to the PEITHO trial).
Thanks again, as alway I appreciate your support!
Thanks Anand! I agree in a cohort like PEITHO, it would be almost impossible see a significant mortality benefit what with the overall mortality in the placebo group being 1.8%. If we could identify a higher risk population the small signal observed in PEITHO may become a clinically significant benefit. Then again it may just turn out to be noise…
I think if thrombolytics do turn out to be helpful in pulmonary embolism it will not be in the method they are now given. If anything works it is likely to be the catheter directed therapy. Though like you said the trick will be identifying the population at a high enough risk of deterioration to overcome the increased rate of serious bleeding.
Thanks again Anand, I appreciate the support!!
Thanks Anand! I agree in a cohort like PEITHO, it would be almost impossible see a significant mortality benefit what with the overall mortality in the placebo group being 1.8%. If we could identify a higher risk population the small signal observed in PEITHO may become a clinically significant benefit. Then again it may just turn out to be noise…
I think if thrombolytics do turn out to be helpful in pulmonary embolism it will not be in the method they are now given. If anything works it is likely to be the catheter directed therapy. Though like you said the trick will be identifying the population at a high enough risk of deterioration to overcome the increased rate of serious bleeding.
Thanks again Anand, I appreciate the support!!
I'm cautious in my belief that catheter directed lytics will be better. Makes sense physiologically, but so did endovascular intervention in stroke. Not the same process but I'll wait for the data.
I agree that another trial is needed based off of what we've found so far. Interested to see who will take this on since Jeff Kline has said that he's not interested in redoing TOPCOAT with a larger n.
In the meantime, we will have to continue to act in a vacuum. Before TOPCOAT and PEITHO, I think many of us were using shared decision making to guide management. What I told patients with submassive PE (usually both right heart strain on echo/CT and Troponin) was that lytics wouldn't save their lives but may make them more functional long term in regards to things like exercise tolerance (using pulmonary HTN as a surrogate). The caveat, I told them, was there is an increased risk of ICH. I didn't, and still don't, offer the intervention to patients over 60 or younger but frail as I interpret the data to say more harm in these groups. The problem with this is the more you dissect the studies, the more problems in the endpoints.
If I saw a young, otherwise healthy patient today with a submassive PE, I'd probably say something similar but may be even more cautious with the benefit side.
As far as heparin, agree with Anand that the benefit is unclear (Barrit + Jordan study a must read but tiny and not that helpful) and I hold while administering and don't restart after administration of lytics for at least 6 hours (which usually means they've left my ED and gone to the ICU).
I'm cautious in my belief that catheter directed lytics will be better. Makes sense physiologically, but so did endovascular intervention in stroke. Not the same process but I'll wait for the data.
I agree that another trial is needed based off of what we've found so far. Interested to see who will take this on since Jeff Kline has said that he's not interested in redoing TOPCOAT with a larger n.
In the meantime, we will have to continue to act in a vacuum. Before TOPCOAT and PEITHO, I think many of us were using shared decision making to guide management. What I told patients with submassive PE (usually both right heart strain on echo/CT and Troponin) was that lytics wouldn't save their lives but may make them more functional long term in regards to things like exercise tolerance (using pulmonary HTN as a surrogate). The caveat, I told them, was there is an increased risk of ICH. I didn't, and still don't, offer the intervention to patients over 60 or younger but frail as I interpret the data to say more harm in these groups. The problem with this is the more you dissect the studies, the more problems in the endpoints.
If I saw a young, otherwise healthy patient today with a submassive PE, I'd probably say something similar but may be even more cautious with the benefit side.
As far as heparin, agree with Anand that the benefit is unclear (Barrit + Jordan study a must read but tiny and not that helpful) and I hold while administering and don't restart after administration of lytics for at least 6 hours (which usually means they've left my ED and gone to the ICU).
Hey Swami, great stuff! I love the shared decision-making! My optimism for the catheter guided interventions lies more in my pessimistic view of our current thrombolytic strategy, rather than any overwhelming belief in the technological advancements of modern medicine. Unlike the other processes in which we utilize thrombolytics, pulmonary embolism is not an ischemic problem. In both CVA and MI the issue is decreased perfusion to the end organs distal to the blockage. Conversely in PE the problem lies in the obstruction to flow proximal to the blockage causing an increased workload for the heart. If we accept thrombolytics have no mortality benefit in patients with sub-massive PE, in order to avoid the long-term functional deficits caused by the clot burden, it is important to discern how quickly thrombolytics have to be given.
If the initial increase in pulmonary blood pressures is not fatal (very rare the case in sub-massive PE) how long before the increased pressure causes chronic changes to the pulmonary circulation? More importantly is there a temporal benefit to administering thrombolytics in the ED? I, like you, am always cynical and doubt the overall utility of thrombolytics in PE. Even more I question applying the same strategy utilized for MI and CVA. This artificial urgency we've created by applying our treatment models of ischemic disease processes to a seemingly far more chronic obstructive pathology is conceptually flawed.
Maybe studies will show there is a hyper-acute nature to the administration of thrombolytic therapy in sub-massive PE, but if not the decision to administer them becomes far easier (at least for us in the Emergency Department).
Thanks again Swami, I appreciate the support!!
Hey Swami, great stuff! I love the shared decision-making! My optimism for the catheter guided interventions lies more in my pessimistic view of our current thrombolytic strategy, rather than any overwhelming belief in the technological advancements of modern medicine. Unlike the other processes in which we utilize thrombolytics, pulmonary embolism is not an ischemic problem. In both CVA and MI the issue is decreased perfusion to the end organs distal to the blockage. Conversely in PE the problem lies in the obstruction to flow proximal to the blockage causing an increased workload for the heart. If we accept thrombolytics have no mortality benefit in patients with sub-massive PE, in order to avoid the long-term functional deficits caused by the clot burden, it is important to discern how quickly thrombolytics have to be given.
If the initial increase in pulmonary blood pressures is not fatal (very rare the case in sub-massive PE) how long before the increased pressure causes chronic changes to the pulmonary circulation? More importantly is there a temporal benefit to administering thrombolytics in the ED? I, like you, am always cynical and doubt the overall utility of thrombolytics in PE. Even more I question applying the same strategy utilized for MI and CVA. This artificial urgency we've created by applying our treatment models of ischemic disease processes to a seemingly far more chronic obstructive pathology is conceptually flawed.
Maybe studies will show there is a hyper-acute nature to the administration of thrombolytic therapy in sub-massive PE, but if not the decision to administer them becomes far easier (at least for us in the Emergency Department).
Thanks again Swami, I appreciate the support!!
I'm not holding my breath on catheter directed thrombolysis either based on prior experience with such tech advancements as you mention Swami but the feeling I get from the data is that using the lowest dose possible in the most targeted way is going to move the risk/benefit equation in our favour … but yes let's wait for the data. I also agree with Rory that the urgency is probably not there for PE like with MI (and I dispute the whole "time is brain" concept behind thrombolysis in CVA). End of the day, we know that fibrinolysis (delivered not that early) dissolves PE's and improves pulmonary outcomes, we just need to optimise the equation to overcome the negatives and improve net patient outcomes.
Swami addresses the key question as to what do we do now in the relative EBM vacuum. My thoughts are that first we must identify the highest risk cohort you can within the submassive/intermediate risk group. As a starter as Swami said, they should have RVD AND positive troponin but then we need to exclude those people who will likely do well anyway. At the risk of repeating some of my prior comments, my preference is simplied PESI score (sPESI) =0 but can potentially could use other scoring systems like the more complex PESI or even lactate which is quite promising as a prognosticator in PE (Vanni 2013). Then I also agree, should exclude the older group eg 65+.
Then from this remaining group, we should probably target those that you clinically believe are at risk of deterioration and becoming haemodynamically unstable (but aren't now obviously as they'd be massive PE). This would be an individualized clinical decision based on a variety of factors but primarily their clinical parameters such as sats, HR, BP and cormorbidities. Finally I absolutely 100% agree that the actual decision should involved shared decision making which I think has a particularly large place in the PE decision making world given the lack of certainty in many areas eg the investigation of low risk patients.
So for example if I had an intermediate risk person who had RVD and positive troponin and they were NOT sPESI=0 (+/- not having a normal lactate) AND they were under 65y.o and I was concerned about their likelihood of clinical deterioration I would then conduct a shared decision making process regarding thrombolysis. The beauty of sPESI is that it actually encompasses most of the clinical features that I would take into account when judging if they were at higher risk of clinical deterioration ie HR >110, sats <90%, SBP 90-100 (note <90 would be massive PE), cardiopulmonary comorbidities.
Until the evidence backs up this approach you'd still only be guided by these parameters and ultimately make an individualised decision based on the actual patient – you know how you could have 2 different people with HR 125 and the same other obs/co-morbidities but you worry about one more than the other based on how they look to you. My point is clinical intuition will have to guide you cause I really want to be selective on who I would even offer this super risky treatment to. So I also can't really suggest clear criteria for which patients to definitely thrombolyse within this intermediate risk/submassive group while we wait for more evidence except to say:
– "RVD & positive trop AND not elderly AND not those patients who are likely to do well anyway (eg sPESI=0) AND you are concerned that they are likely to clinically deteriorate and become haemodynamically unstable" – partially objective and partially subjective .
Of course if you don't thrombolyse them, they should be closely watched in case things change and they now they fall into the above group. For the majority of this intermediate risk/submassive group that will probably be the safest approach.
Oh … AND I'd use the half dose thrombolysis.
Apologies for the lengthy response.
I'm not holding my breath on catheter directed thrombolysis either based on prior experience with such tech advancements as you mention Swami but the feeling I get from the data is that using the lowest dose possible in the most targeted way is going to move the risk/benefit equation in our favour … but yes let's wait for the data. I also agree with Rory that the urgency is probably not there for PE like with MI (and I dispute the whole "time is brain" concept behind thrombolysis in CVA). End of the day, we know that fibrinolysis (delivered not that early) dissolves PE's and improves pulmonary outcomes, we just need to optimise the equation to overcome the negatives and improve net patient outcomes.
Swami addresses the key question as to what do we do now in the relative EBM vacuum. My thoughts are that first we must identify the highest risk cohort you can within the submassive/intermediate risk group. As a starter as Swami said, they should have RVD AND positive troponin but then we need to exclude those people who will likely do well anyway. At the risk of repeating some of my prior comments, my preference is simplied PESI score (sPESI) =0 but can potentially could use other scoring systems like the more complex PESI or even lactate which is quite promising as a prognosticator in PE (Vanni 2013). Then I also agree, should exclude the older group eg 65+.
Then from this remaining group, we should probably target those that you clinically believe are at risk of deterioration and becoming haemodynamically unstable (but aren't now obviously as they'd be massive PE). This would be an individualized clinical decision based on a variety of factors but primarily their clinical parameters such as sats, HR, BP and cormorbidities. Finally I absolutely 100% agree that the actual decision should involved shared decision making which I think has a particularly large place in the PE decision making world given the lack of certainty in many areas eg the investigation of low risk patients.
So for example if I had an intermediate risk person who had RVD and positive troponin and they were NOT sPESI=0 (+/- not having a normal lactate) AND they were under 65y.o and I was concerned about their likelihood of clinical deterioration I would then conduct a shared decision making process regarding thrombolysis. The beauty of sPESI is that it actually encompasses most of the clinical features that I would take into account when judging if they were at higher risk of clinical deterioration ie HR >110, sats <90%, SBP 90-100 (note <90 would be massive PE), cardiopulmonary comorbidities.
Until the evidence backs up this approach you'd still only be guided by these parameters and ultimately make an individualised decision based on the actual patient – you know how you could have 2 different people with HR 125 and the same other obs/co-morbidities but you worry about one more than the other based on how they look to you. My point is clinical intuition will have to guide you cause I really want to be selective on who I would even offer this super risky treatment to. So I also can't really suggest clear criteria for which patients to definitely thrombolyse within this intermediate risk/submassive group while we wait for more evidence except to say:
– "RVD & positive trop AND not elderly AND not those patients who are likely to do well anyway (eg sPESI=0) AND you are concerned that they are likely to clinically deteriorate and become haemodynamically unstable" – partially objective and partially subjective .
Of course if you don't thrombolyse them, they should be closely watched in case things change and they now they fall into the above group. For the majority of this intermediate risk/submassive group that will probably be the safest approach.
Oh … AND I'd use the half dose thrombolysis.
Apologies for the lengthy response.
Hi Josh and Rory
I would caution against being reassured by the short half-life of alteplase when considering potential haemorrhagic complications.
Alteplase half-life is probably much less important than the time it takes for the liver to reconstitute fibrinogen. This may take many hours.
For instance, in the case of Australian snakebite, recovery from venom-induced consumptive coagulopathy (VICC) can up to 12–18 h due to the time needed to resynthesis consumed clotting factors. This is the case despite antivenom adminstration and the fact than the venom components responsible for VICC are likely only in circulation for <1 hour.
Cheers
Chris
Hi Josh and Rory
I would caution against being reassured by the short half-life of alteplase when considering potential haemorrhagic complications.
Alteplase half-life is probably much less important than the time it takes for the liver to reconstitute fibrinogen. This may take many hours.
For instance, in the case of Australian snakebite, recovery from venom-induced consumptive coagulopathy (VICC) can up to 12–18 h due to the time needed to resynthesis consumed clotting factors. This is the case despite antivenom adminstration and the fact than the venom components responsible for VICC are likely only in circulation for <1 hour.
Cheers
Chris