“The Adventure of the Greek Interpreter Revisited”

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If our affair with thrombolytics had not started off with the success it did, we may not still be trying to nostalgically relive our yesteryears of throbolytic glory. Whether it was streptokinase, alteplase or tenectoplase (TNK), thrombolytics have consistently demonstrated a mortality benefit when used in patients experiencing an ST-elevation infarction (1). If it was not for the superiority of PCI in both measures of efficacy and financial gain, our romance with thrombolytics might still be in full swing.  Our initial triumph with STEMI patients has led us to believe in the efficacy of thrombolytics in all hypercoagulable disease states, despite its mediocre performance outside the confines of ACS.

When thrombolytics fell out of favor in the management of STEMI, supplanted by mechanical reperfusion therapy, it seemed only natural we turned our focus to the treatment of acute ischemic stroke to fill our thrombo-philic void. Though the efficacy of thrombolytics in CVA is still under debate, it is clear they have never demonstrated the mortality benefits as exhibited in myocardial infarction (2). What we are left debating is small differences on scales measuring functional neurological outcomes. Scales that are so unreliable, two neurologists grading the very same patient one after another, often disagree by one or more points (3).  Whether these potential improvements in neurological outcome are of clinical relevance or not, they are a far cry from the life saving benefits thrombolytics provide in STEMI management.

Pulmonary embolism was another likely candidate for thrombolytic intervention. As clinicians, we have become hyperaware and preoccupied by diagnosing even the most clinically irrelevant pulmonary emboli.  When we do happen to stumble upon emboli of clinical import we ironically have very little to offer the patient other than a hospital bed, IV heparin and the promise of a six month course of coumadin therapy. So the idea that thrombolytics may help dissolve these larger clots is an appealing one to say the least.  Despite the sparse evidence supporting their utility and no mortality benefit demonstrated in patients with massive pulmonary embolism (4), thrombolytics have gained general acceptance in this subgroup. And though this “standard of care” is based more on our fear of watching the patient decompensate in front of us, and less upon proof of benefit, their role in the management of massive pulmonary embolism is now a IIA recommendation in the AHA guidelines of the management of pulmonary embolism (5).

A looming question is whether patients with sub-massive pulmonary embolism are candidates for lytic therapy. The PEITHO trial was the largest RCT to have examined this question to date (6). PEITHO’s results, originally released in abstract form last year, were finally published in totality on April 10th 2014 by Meyer et al in the NEJM.  This study randomized normotensive patients with radiographic evidence of PE with concern for right heart strain (positive troponin, BNP or evidence of right heart strain on CT or ECHO) to either a thrombolytic strategy (TNK) or placebo. In the “The Adventure of the Greek Interpreter”, I discussed the results of this trial, but in brief it was disappointing. The authors claim success in a number of surrogate endpoints they categorized as “hemodynamic collapse”.  As a reader we cannot help but feel cheated, as the mortality between the groups was statistically equivalent. What the PEITHO trial did illustrate was that when patients are given thrombolytics, they bleed.  Overall there was an approximate 9% difference in major bleeding between the TNK and placebo group (11.5% vs 2.4%). Additionally there was an approximate 2% increase in ICH in those patients given TNK.

And so, since the acute benefits of thrombolytics in pulmonary embolism are nothing less than sub-tacular, the debate on the utility of thrombolytics in sub-massive pulmonary emboli hinges on their ability to improve functional outcomes in the long-term. The evidence supporting thrombolytics’ efficacy in preventing post-embolic pulmonary hypertension is unconvincing at best. Unfortunately the authors of the PEITHO trial failed to publish long-term functional outcomes. In the PEITHO’s trial design published in the American Heart Journal in 2012, the authors report that 6-month functional outcomes would be recorded, including NYHA classification and echocardiographic findings.  A second publication on the PEITHO cohort including these results may very well answer some of the uncertainties we currently have (7).

Until then, the best evidence we have supporting the practice of thrombolytic therapy in acute pulmonary embolism is the MOPPET trial (8). In this trial, comprised of 121 patients diagnosed with sub-massive pulmonary embolism and evidence of right heart strain, patients were randomized to either placebo or 50 mg of tPA (“half-dose” tPA). The authors found a staggering 41% absolute difference in their primary endpoint, the number of patients with pulmonary hypertension at 2 years post enrollment. As discussed in the original post, “The Adventure of the Greek Interpreter”, the rate of pulmonary hypertension in the placebo arm was far higher than the rate of pulmonary hypertension observed in similar cohorts (9,10,11). These impressive results are far more likely due to the surrogate outcome the authors chose as their primary endpoint rather than the efficacy of thrombolytics. Whereas most trials define pulmonary hypertension by echocardiographic evidence of pulmonary hypertension in the symptomatic patient, the authors of the MOPPET trial chose to use echocardiographic findings alone.  In the asymptomatic patient we are unsure of the clinical relevance this radiographic information provides in isolation.

A recently published trial by Jeff Kline, the man who defined pulmonary embolism for the past decade, hoped to delineate the clinical effect of thrombolytic therapy on the incidence of pulmonary hypertension after sub-massive pulmonary embolism (12). Named TOPCOAT, this trial examined thrombolytics’ effects on 3-month post-pulmonary embolism functional outcomes. Unfortunately interpreting the results is difficult due to its premature stoppage (after only 83 patients) and its convoluted primary endpoint, a composite outcome of recurrent PE, poor functional capacity (RV dysfunction with either dyspnea at rest or exercise intolerance) or an SF36 Physical Component Summary (PCS) score <30 at 90 day follow-up. Patients were randomized to either a single bolus of 30-50 mg of tenectoplase (TNK) or placebo. The authors examined the composite outcome of functional capacity and perception of wellness at 3-months. The authors also examined the rate of pulmonary hypertension as defined by echocardiographic findings.

In the TOPCOAT trial, the TNK arm certainly seemed to have slightly better functional outcomes at 90 days. The TNK group had lower rates of patients with a New York Heart Association Functional (NYHA) class greater than 3 (8 vs 2) and the number of patients with a low perceptional wellness score under 30 (2 vs 0). None of these differences reached statistical significance, and overall the groups’ functional outcomes were fairly similar, both arms of the trial had almost identical mean NYHA score, VEINES-QOL score, and SF-36 Mental Component score. In fact the number of patients with poor functional outcome at 3-months, defined as NYHA >3 and evidence of right heart hypertrophy on echo (the traditional definition of post-embolic hypertension), was identical (approximately 7.5%).  If echocardiographic findings alone (similar to the MOPPET definition) were used to diagnosis post-embolic pulmonary hypertension the incidence would have increased to 32.5%.
TOPCOAT like MOPPET demonstrated that thrombolytics may provide some benefit in long-term outcomes after sub-massive pulmonary embolism.  Just how relevant these benefits are is still unclear. TOPCOAT further reinforces that the unrealistic findings in MOPPET were just that, too good to be true. Whether these benefits outweigh the 2% risk of ICH that PEITHO revealed is still unknown. Furthermore it is still unclear as to who truly benefits from acute thrombolytic therapy. It may very well be that the young healthy patient with no comorbidities and a significant pulmonary reserve is unlikely to develop pulmonary hypertension, while the older patient with COPD or chronic heart failure, are more at risk and likely to benefit from thrombolytic therapy.  Ironically according to the PEITHO cohort these are the very same patients that are at the highest risk for ICH.

Finally the question arises of whether the differences in the doses and the protocols used in the MOPPET, TOPCOAT and PEITHO trials alter clinical outcomes and the incidence of ICH. Was the “half-dose” strategy that was used in the MOPPET trial the reason for this cohort’s low rate of ICH or was it just random chance and a small population size?  From the existing data we are unable to resolve these uncertainties. Historically these lines of inquiry have always proved fruitless. As far back as the GISSI-2 trial (13)examining thrombolytics in acute myocardial infarction, a particular thrombolytic agent failed to demonstrate superiority over any other agents. Not only were the authors unable to demonstrate superiority of any particular agent, it didn’t matter whether these clot busters were administered with or without heparin. Additionally, when the Cochrane Group examined thrombolytic therapy for acute ischemic stroke, they were unable to find a difference in efficacy between the individual thrombolytic agents or in the various dosing strategies utilized (14).

Like Thrombolytics in acute ischemic stroke, their use in sub-massive pulmonary embolism has failed to demonstrate the objective benefits that we saw with acute myocardial infarction. Thus like in CVA we are left deciphering the relevance of subjective endpoints of uncertain value. At least in the area of acute ischemic stroke we are familiar with the methods used to evaluate functional outcomes and there are accepted standards (an mRS >2) for poor outcomes, with which we can judge performance. The outcomes used to evaluate functional outcomes in post-pulmonary embolism patients are as of yet alien. Furthermore, there has yet to be a consistent set of metrics or time period utilized when measuring these outcomes. There does seem to be a consistent signal throughout the thrombolytic literature for pulmonary embolism. Whether it is clinically relevant or outweighs the obvious harms is still uncertain. At least in theory “half-dose” thrombolytic therapy seems physiologically plausible, but it is important and healthy that we maintain a robust state of skepticism until we have more than physiological reasoning and the warm memories of the golden years of thrombolytics supporting their use in sub-massive pulmonary embolism.

Sources Cited:

  1. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet. 1994 Feb 5;343(8893):311-22.
  2. Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database of Systematic Reviews 2009, Issue 4. Art. No.: CD000213. DOI: 10.1002/14651858.CD000213.pub2.
  3. Banks et al. Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke. 2007 Mar;38(3):1091-6. Epub 2007 Feb 1.
  4. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. 2004; 110: 744–749
  5. Jaff et al. Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension  A Scientific Statement From the American Heart Association. Circulation. 2011; 123: 1788-1830
  6. Meyer et al. Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism N Engl J Med 2014; 370:1402-1411 April 10, 2014
  7. Steering Committee. Single-bolus tenecteplase plus heparin compared with heparin alone for normotensive patients with acute pulmonary embolism who have evidence of right ventricular dysfunction and myocardial injury: rationale and design of the Pulmonary Embolism Thrombolysis (PEITHO) trial. Am Heart J. 2012 Jan;163(1):33-38.e1. doi: 10.1016/j.ahj.2011.10.003.
  8. Sharifi et al.  Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013 Jan 15;111(2):273-7
  9. Vittorio Pengo, M.D., Anthonie W.A. Lensing, M.D., Martin H. Prins, M.D., Antonio Marchiori, M.D., Bruce L. Davidson, M.D., M.P.H., Francesca Tiozzo, M.D., Paolo Albanese, M.D., Alessandra Biasiolo, D.Sci., Cinzia Pegoraro, M.D., Sabino Iliceto, M.D., and Paolo Prandoni, M.D. for the Thromboembolic Pulmonary Hypertension Study Group. Incidence of Chronic Thromboembolic Pulmonary Hypertension after Pulmonary Embolism. N Engl J Med 2004; 350:2257-2264
  10. Kline JA, Steuerwald MT, Marchick MR, Hernandez-Nino J, Rose GA. Prospective evaluation of right ventricular function and functional status 6 months after acute submassive pulmonary embolism: frequency of persistent or subsequent elevation in estimated pulmonary artery pressure. Chest. 2009; 136: 1202–1210.
  11. Becattini C, Agnelli G, Pesavento R, et al. Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism. Chest 2006;130(1):172-175.
  12. Kline et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost. 2014 Apr;12(4):459-68.
  13. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico . GISSI-2: a factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12 490 patients with acute myocardial infarction. Lancet 1990; 336: 65-71
  14. Wardlaw JM, Koumellis P, Liu M. Thrombolysis (different doses, routes of administration and agents) for acute ischaemic stroke. Cochrane Database Syst Rev. 2013 May 31

 

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Comments

  1. says

    Great article Rory
    Thrombolysis for sub-massive PE is essentially an experimental treatment, and there is equipoise for its use right now. This, I guess, is where the art of medicine comes in.
    Until we know more we have to weigh up markers of severity, biological plausibility (often not worth much), physiological response (watching the RV improve before your eyes on Echo is persuasive, but looking better doesn’t mean getting better a la FEAST) and the body of research published to date. I consider thromobolysis for submassive PE on a case-by-case basis and try to be honest with patients and their families about the considerable uncertainties.
    Stroke thrombolysis, on the other hand, is not viewed as an experimental therapy by its proponents (though it should be). That is the key difference between the two scenarios IMO.
    There may well be both stroke and PE patients that benefit from thrombolysis, but much work needs to be done to define this (which patients? what dose? etc). There has been much more stroke research, but – similar to the NASCIS studies – the research agenda has rolled out assuming benefits based on flawed studies in isolation that were not necessarily proven, instead of trying to go back and prove them.
    The sub-massive PE thrombolysis story has only just begun. Skepticism must reign, but here and now we must still choose to do, or not do, something when a patient with submassive PE is in front of us needing help.
    Chris

    • says

      Thanks Chris, great commentary!
      I agree, we are currently in the infancy of our understanding of the long-term effects of pulmonary embolism and how thrombolytics influence these outcomes. As you said there is far more data on stroke. And yet, because of the “research agenda”, despite this quantity of research, we are incapable of determining which stroke patients in particular will benefit from thrombolytic therapy. Most of the time we spend arguing for or against the benefits of tPA in stroke is spent debating small differences in stroke scales of questionable reliability.I hope we don’t fall into this same trap as we continue to examine the long term benefits of thrombolytics in PE. As of now, the endpoints we use to judge success are schizophrenic. Both the metrics we use and the time period at which we measure these outcomes are inconsistent. We need to settle on a standard method for measuring long-term function after pulmonary embolisms. From my reading of the limited literature I would say NYHA score combined with echocardiographic features of pulmonary hypertension is as good as any method to date. AS far as when to measure, I would guess the two year mark is probably the most accurate (time by which most people who are going to develop pulmonary hypertension will present- Pengo et al).

      Thanks again Chris for your words of wisdom. I always appreciate your support!

      Vittorio Pengo, M.D., Anthonie W.A. Lensing, M.D., Martin H. Prins, M.D., Antonio Marchiori, M.D., Bruce L. Davidson, M.D., M.P.H., Francesca Tiozzo, M.D., Paolo Albanese, M.D., Alessandra Biasiolo, D.Sci., Cinzia Pegoraro, M.D., Sabino Iliceto, M.D., and Paolo Prandoni, M.D. for the Thromboembolic Pulmonary Hypertension Study Group. Incidence of Chronic Thromboembolic Pulmonary Hypertension after Pulmonary Embolism. N Engl J Med 2004; 350:2257-2264

  2. says

    Rory – great post. The comments from Chris and you are well put. Clearly, there are differences in the current trajectory of lytics in PE research versus lytics in CVA research and recommendations. One of the major ones is that we (EPs and ICU docs) are driving the agenda to a certain degree. As such, we must set an example for how this should be done. Over-reliance on small studies (MOPETT), benefit in non-patient centered outcomes (PEITHO – HD decompensation) and blindly trusting experts in the field (TOPCOAT) are traps. Much like in CVA, I believe there is a group of PE patients that should get lytics. These studies start the ball rolling but more is needed. Kline is correct in his statement that mortality in submassive PE is low and an inordinately large number of patients would have to be enrolled to see a difference. As a result, we should pick a hard, patient centered outcome. Functional status seems reasonable, especially in the young or previously active patient.
    For now, Chris is correct that we need to make a decision on the patient in front of us without all the information being known. Careful selection of appropriate patients with 1/2 dose lytics is a reasonable approach based on what we currently know but we must stay flexible and ready to adapt to new information.

    • says

      Thanks Swami for your comments!
      Great summation of how little we truly know on this important topic. I think even which patients will benefit from thrombolytics is still uncertain. If we use criteria similar to those in the PEITHO trial we may cast our net to wide and end up hurting as many patients as we help. On the other hand if we wait for more clinically obvious signs we may miss the window to intervene effectively. We obviously need more subtle markers to identify which patients will benefit from this intervention.

      I hope when the PEITHO’s 6-month outcomes are published we will have a better idea of how thrombolytic therapy effects the rates pulmonary hypertension in a large cohort measuring clinically relevant outcomes. I’m interested how you’ll incorporate all this into your talk on May 7th :)

      Thanks again!!
      Rory

  3. says

    Rory

    Great post. One question and a comment-

    PEITHO had a 2% higher ICH rate in the treatment group versus the control group. MOPPETT had no ICH in either group with 121 patients total. I am not so great with stats- how close did MOPPETT come in regards to sample size that would have a reasonable chance of detecting a 2% higher rate of ICH? Would you have to get another 1,000 patient study the size of PEITHO to figure that out?

    Good arguments that the differences in lytics and protocols may not make a difference. I guess I am just not ready to throw in the towel on this yet- I would still like to see a larger study with a half dose TPA drip compared to the full dose TNK bolus.

    Steve

    • says

      Thanks Steve,

      Great point, how many patients would be required to determine if half-dose thrombolytics were a safer option than full dose therapy? If you assume the rate of ICH in the placebo group would be similar to that in the PEITHO trial (0.2%) then to power a trial to detect a 2% increase in the rate of ICH would require a little over 1,000 patients (1,056 as per my back of the napkin calculation).

      More importantly we have to determine the best way to accurately measure the potential benefits. Certainly the surrogate endpoint MOPPET used does not provide us with the answer we want. Hopefully the 6-month followup data from PEITHO will give us some guidance both on the true benefits of thrombolytics and how best to assess these benefits.

      Thanks again for the support. I’m a big fan of your work!!

  4. Matt Anderson says

    Any thoughts on onset of signs/symptoms to treatment with lytics? If I remember AHA past guidelines right, up to 12 hours for intervention for STEMI — but this trial allowed treatment within 15 days, which seems significantly outside the realm of the ‘penumbra’ or salvageable lung tissue. Thinking about it — the brain gets 3-4.5 hours and the lung gets up to 15 days — is there any studies that have been done on reversible ischemia time to the lung. Moreover, if it’s right sided heart failure related to the stress on the heart — how long before this right heart injury is no longer reversible? Lots of questions — not sure if you have the answers or if the studies have even been performed to evaluate this? Kind of like the recent endovascular studies on stroke that were done that showed the penumbra (ie identified on CT angio perfusion) in the brain during stroke is likely not all that salvageable after all making reperfusion unlikely to have any benefit even if clot is retrieved and the vessel is completely free flowing again.

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