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PEITHO Trial: Fibrinolysis for Intermediate-Risk Pulmonary Embolism

2016-11-20T07:21:33+00:00

Pulmonary embolism
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Most of us would agree that massive PE is treated with fibrinolysis and non-massive PE is treated with anticoagulation. The area of great debate has been the optimal treatment for sub-massive PE. The MOPETT Trial was published in January 2013 and although the patient population was small, it did show a huge benefit in pulmonary pressures at 28 months with fibrinolysis. The next study we have all been waiting for is the Pulmonary Embolism Thrombolysis (PEITHO) trial, which was just published yesterday in the NEJM, evaluating fibrinolysis for patients with intermediate-risk PE.

Background

Half of the cases of pulmonary embolism (PE) in the United States are diagnosed in the Emergency Department and follow ACS as the second most common cause of sudden unexpected death in outpatients. PE is typically broken down into three major categories:

  • Massive PE: Hemodynamic compromise with a systolic blood pressure of <90 mmHg
  • Sub-Massive PE: No hypotension but right ventricular strain or myocardial necrosis
  • Non-Massive PE: No hemodynamic compromise and no RV strain

Article Overview1

The purpose of this study was to determine the clinical efficacy and safety of fibrinolytic therapy with a single-bolus injection of tenecteplase, in addition to standard anticoagulation therapy in normotensive patients with an intermediate-risk PE.

Intermediate-risk PE was defined as acute RV dysfunction and myocardial injury without overt hemodynamic compromise.

What they did:

  • Randomized, double-blind, placebo-controlled trial of 1,005 patients with “intermediate-risk” PE
  • 76 sites in 13 countries
  • Tenecteplase plus heparin vs placebo plus heparin
  • Patients were eligible if they had ALL of the following:
    • Age ≥ 18 years
    • Confirmed PE with onset within 15 days
    • RV dysfunction (diagnosed on echocardiography and/or CT)
    • Myocardial injury (diagnosed with positive cardiac troponin I or T)

Treatment regimens:

  • Treatment arm: Weight-based tenecteplase (range: 30 – 50 mg) given as an IV bolus + standard anticoagulation
  • Control arm: Placebo + standard anticoagulation

Primary outcomes:

  • Death or hemodynamic decompensation within 7 days after randomization

Safety outcomes:

  • Extracranial major bleeding within 7 days after randomization
  • Ischemic or hemorrhagic stroke within 7 days 
  • Serious adverse events within 30 days

Results:

Outcome Tenecteplase Group Placebo Group P Value
Death at 7 days 1.2% 1.8% 0.42
Hemodynamic compromise at 7 days 1.6% 5.0% 0.002
Extracranial bleeding at 7 days 6.3% 1.2% <0.001
Stroke at 7 days 2.4% 0.2% 0.003
Death at 30 days 2.4% 3.2% 0.42

Limitations:

  • There is no mention of pulmonary pressures in the results

Conclusion:

In normotensive patients with intermediate-risk PE, death and hemodynamic decompensation are reduced with treatment of tenecteplase, but there is also a significant associated risk for intracranial and other major bleeding.

My thoughts

  • Fewer patients in the tenecteplase group developed persistent hypotension (1.5% vs 3.6%), required catecholamines (0.59% vs 2.8%), mechanical ventilation (1.6% vs 3.0%), or cardiopulmonary resuscitation (0.19% vs 1.0%).
  • The paper states that the risk of bleeding in younger patients is lower compared to older patients; however, patient subgroup analysis used an arbitrary pre-specified age (≤ 75 years vs > 75 years) showing a slightly greater risk for major extracranial bleeding in older patients. This risk, however, was not statistically significant (p=0.09).
  • Although the risk of EXTRAcranial bleeding was lower in the ≤ 75 years group, there was no mention of decreased INTRAcranial hemorrhage in this group as well. So it is unclear if there was a difference in overall bleeding complications between the age groups.
  • Would have liked to see a “safe dose” or “reduced dose” strategy studied here.

Clinical Bottom Line

Per these PEITHO results, there was a significant increase in hemorrhagic complications with full dose tenecteplase in intermediate-risk PEs. The treatment, however, was also associated with a slight clinical benefit.

We concur with the accompanying NEJM editorial.2 In brief, the results suggest that acute PE patients WITHOUT overt hemodynamic compromise should be carefully monitored and receive standard anticoagulation only (despite demonstrating RV dysfunction and myocardial injury) given the low mortality rate of 1.8% in the placebo group. Rescue thrombolytics can be considered once patients demonstrate hemodynamic instability. The risk of GIVING thrombolytics may be lower than NOT GIVING thrombolytics at this point.

1.
Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-1411. [PubMed]
2.
Elliott C. Fibrinolysis of pulmonary emboli–steer closer to Scylla. N Engl J Med. 2014;370(15):1457-1458. [PubMed]

Expert Peer Review

The treatment of submassive PE has long been discussed and debated. The heart of the argument centers on the role of thrombolytic agents. The basic logic for using these medications is straightforward; there’s a large clot impeding the right ventricular outflow tract so let’s use a clot-busting medication to open it up. The application of the drug, however, has been much more convoluted.

The MOPETT trial, published just last year, showed a marked reduction in pulmonary hypertension (57% in placebo vs 16% in lytic group) with the use of half or “safe” dose alteplase [1]. However, this study was relatively small (n=121) and was underpowered to detect a difference in mortality.

Enter PEITHO. The PEITHO trial has many of the characteristics we look for in a study. It was randomized and blinded. There was a placebo arm and it was performed in multiple sites. The results from PEITHO temper the excitement that came out of MOPETT. PEITHO showed no overall mortality benefit but a reduction in hemodynamic compromise during the 7-day period. These modest benefits come at a 10-fold increase in intracranial hemorrhage (ICH) and a 5-fold increase in major bleeding. A prespecified subgroup analysis found that patients < 75 years of age had improved mortality (but not statistically significant) and a lower overall (but not intracranial) bleed rate [2]. Early criticisms of the PEITHO trial point to the use of tenectaplase instead of alteplase, full dose lytics as a push and the concomitant starting of heparin; features that differentiate PEITHO from MOPPET. It should be noted, however, that no study has shown a significant difference in ICH rate between different lytic agents in other disease processes [3].

So where does this leave us? MOPETT and PEITHO are different trials with different protocols and different primary outcomes. They aren’t comparable. I would still use lytics in submassive PE following the MOPETT protocol. A young patient with signs of right heart strain and/or pulmonary hypertension may have a lot to gain in functional status from thrombolysis. However, the patient should be part of the discussion. It should be clear in the discussion that the drug has not been shown to save people’s lives but that it appears to improve the quality of life for those who survive.

Future research should focus on replicating the MOPETT protocol in a larger number of patients. This would allow us to see smaller mortality differences and give us more information on the intracranial hemorrhage an major bleeding rates.

References

  1. Sharifi M et al. Moderate pulmonary embolism treated with thrombolysis (from the “MOPPETT trial). J Cardiol 2013; 111: 273-7.
  2. Meyer G. Fibrinolysis for patients with intermediate-risk pulmonary embolism. NEJM 2014; 370(15): 1402-1411.
  3. Wardlaw JM, Koumellis P, Liu M. Thrombolysis (different doses, routes of administration and agents) for acute ischemic stroke (Review). Coch Data Syst Rev 2013; 5: Art No CD000514.
Anand Swaminathan, MD MPH
Assistant Residency Director and Assistant Professor of Emergency Medicine, Bellevue/NYU ; Faculty Editor of EM Lyceum
Salim Rezaie, MD

Salim Rezaie, MD

ALiEM Associate Editor
Clinical Assistant Professor of EM and IM
University of Texas Health Science Center at San Antonio
Founder, Editor, Author of R.E.B.E.L. EM and REBEL Reviews
  • PB

    It is interesting that patient classified as sub-massive (USA) or intermediate risk (Europe) by definition (clinical, echo, trop, BNP) can have a type A right atrial thrombus and risks in facts are other (and benefits with thrombolytics). RA thrombus must be putt in risk score…in my view.

    • Salim R. Rezaie

      Hello PB,

      In the end as long as we all agree what signs of RV dysfunction or myocardial necrosis are….i.e. Clinical, echo, troponin, BNP. I agree that RA thrombus should be included. It is well cited that a RA thrombus can have a 21% 14day mortality and a 26% 3 month mortality, but even scarier is the treatment chosen also affects outcome/prognosis:

      No tx: 100% mortality

      Anticoagulation: 28.6% mortality

      Surgical Embolectomy 23.8% mortality

      Thrombolysis: 11.3% mortality.

      For source checkout this blog post that actually discussed Thrombus in Transit.

      http://rebelem.com/diagnosis-right-ventricular-strain-transthoracic-echocardiography/

      TY for reading and your comments.

      Salim

  • Nilesh Patel

    This trial gives us no information on outcomes 6 months down the line, i.e., which patients developed heart failure etc. I thought that was the main reason we were giving lytics to submassive PE–not only b/c there is a trend toward improvement in mortality but more importantly, to improve the patient oriented outcome of less dyspnea and better cardiac function at 6 months.

    • Salim R. Rezaie

      Hello Nilesh,
      That has been my point. First of all comparing apples to oranges (tenecteplase vs tPA), secondly “safe dose” tPA was used with tPA and full dose with tenecteplase, finally, no comment on pulmonary pressures at 28 months commented on in PEITHO trial. That is exactly why I don’t think this study will change my practice with informed consent and offering tPA in “safe dose” for young pts with good functional outcome. I would like to see a study looking at 1/2 dose tenecteplase and 1/2 dose tPA looking at 6 month and 28month pulmonary pressures. TY for reading and commenting.

      Salim

  • Corey Heitz

    I thought it showed an increase in EXTRAcranial hemorrhage, but didn’t mention INTRAcranial?

    • Nilesh Patel

      I think showed increased rate of hemorrhagic stroke as well vs placebo.

      • Salim R. Rezaie

        Hello Corey,

        Yes in the 7 day follow up there was increased INTRAcranial hemorrhage, which they called stroke, but in the subgroup analysis of age greater than or less than 75 years, there was less EXTRAcranial bleeding in the younger age group compared to the older age group, but no mention of INTRAcranial in this group.

        Salim

        • Corey Heitz

          Yep. I misread initially. Thanks

          • Corey Heitz

            #readingcomprehension

  • Nilesh Patel

    Salim or Anand,
    Correct me if I am wrong. MOPPETT data was good, especially the fact that there was no bleeding complications with the 1/2 dose tPA group comparatively. However, my understanding is that even if you give full dose tPA to submassive PE, minor bleeding rates significantly increased but ICH rates pretty low (around 1% or less). And some trials have looked at full dose tPA in submassive PE. So I’m still on the tip (in the right patient–submassive, younger, less bleeding risk) to give full dose tPA to improve functional outcomes and potentially improve mortality.
    My question–in the right patient with submassive PE, are you going to give 1/2 dose or full dose tPA?

    Nilesh

    • Salim R. Rezaie

      Hello Nilesh,

      True that 100% of Cardiac Output goes to lungs….but if “1/2 dose” works, why risk bleeding complications from “full dose?” Also the studies you are referring to all had very small number of patients if I recall correctly. Checkout this article:

      http://circ.ahajournals.org/content/123/16/1788.full

      I can’t speak for Anand, but I think best evidence currently is for 1/2 dose.

      Salim

      • Anand Swaminathan

        Agreed. At this point, I’m on board with 1/2 dose until someone shows a difference with full dose.

        • Justin McNamee

          How are you giving the 1/2 dose tPA in these cases? With alteplase, it was previously recommended for 100 mg IV over two hours, then along came MOPPETT and the dosing regimen of half dose was oddly similar to tPA for stroke as far as administration. Are you giving the half- dose over an hour with an initial small bolus or running it in over 1-2 hours without a bolus?

          Justin

          • Sorry we didn’t reply sooner – somehow didn’t get notified. Apologies! here’s what the methods section of the MOPPETT paper stated:

            “In the present study, tPA was the only thrombolytic drug used. The dose of tPA was 50% of the standard dose (100 mg) commonly used for the treatment of PE, which we termed “safe dose” thrombolysis. For patients weighing 50 kg, the total dose was 50 mg, which was given as a 10-mg bolus by an intravenous push within 1 minute followed by infusion of the remaining 40 mg within 2 hours. For those weighing <50 kg, the total dose was calculated as
            0.5 mg/kg, which was given as a 10-mg initial bolus followed by the remainder within 2 hours."

            Contrast that to full dose TPA which is 100 mg IV infused over 2 hours; may administer as 10 mg bolus followed by 90 mg over 2 hr.

  • Jon Jones

    Thanks for the post – really interesting reading. Not been able to read the full article on NEJM but 2 points I’d like to make:

    1/ In your peer review it seems odd that you have presented the complications in terms of an (overly dramatic) relative risk increase.

    2/ I’m surprised at the inclusion criteria of the study: PE within last 15 days? Seems an awfully long time scale within which to expect thrombolysis to work!

    Jon (@jmjleeds)

  • Andy Neill

    aw damnit… i was really optimistic about this trial. Bleeding higher than i expected ( i always figured, the big bleeding risk was with stroke) and while not huge, the benefit just doesn’t seem to be there to justify the risk.

    Half dose it is, though I don’t think MOPPET was the greatest trial in the world to justify it….

    • Nilesh Patel

      I agree with Andy’s comments on MOPPET. Although MOPPET showed no bleed rate, I’m not sold on 1/2 dose lytics yet. MOPPET is a small trial and one trial.
      I do think the higher risk subset of submassive’s–borderline vs, + trop, RV strain, younger subset–are good candidates for full dose lytics (essentially these patients are likely massive PE with compensated vitals). Per limited data, a nice portion of them go on to have in hospital events and I just don’t believe giving them Heparin does anything.

  • Mac Walter

    Thank you Salim for the nice summary of the PEITHO Trial.

    Since many on this post are advocating for the use of half-dose lytics in submassive PE, I think it is important to emphasize both the limitations of the MOPETT Trial and what the trial does not show.

    Limitations
    – Single center study
    – Open label (as opposed to trials like PEITHO and MAPPET which were double-blinded)
    – Small number of patients (PEITHO had >1,000, MOPETT had 121)
    – ***The study protocol enrolled patients with “moderate pulmonary embolism.” Their criteria have not been followed in any other trial and do not follow the consensus definition
    of submassive PE. Indeed, many in the trial likely did not have a true submassive PE (PE w/o overt hypotension but with RV dysfunction or myocardial necrosis). RV enlargement was only seen in 20% of pts, RV hypokinesis in 5%, and elevation of trop or BNP in ~65%. It is worth considering whether the trial actually enrolled a patient group you are
    interested in. I think there is a reason that every other notable submassive PE trial (MAPPET, PEITHO, ULTIMA, the not yet published SEATTLE trial of catheter-directed therapy, etc) enrolled patients who met the definition for submassive PE.

    What the trial does not show
    – The trial does not show that patients with submassive PE treated with ½ dose TPA have better outcomes than those treated with anticoag alone because patients did not have to meet the accepted definition for submassive PE to be enrolled in the trial. Indeed, there is no evidence that I am aware of that looks at ½ dose lytics for patients who meet the accepted definition for submassive PE. As a result, I would urge caution in using statements like “I would still use lytics in submassive PE following the MOPETT protocol” as is found in Anand’s review as the word “submassive” is not anywhere in the MOPETT protocol and if you are really following the MOPETT protocol you will be offering ½ dose lytics to some patients without a submassive PE.

    – The expert peer review mentions lytics “appear to improve quality of life for those who survive.” If you are advocating for the use of ½ dose lytics rather than full dose (given the
    bleeding complications seen in PEITHO) this is not true. MOPETT does not show improved quality of life from ½ dose lytics. It shows a difference in PASP at 28 months of 28mmHg +/- 7 vs 43mmHg +/-6 in patients treated with ½ dose lytics vs not.
    There is no mention of quality of life or functional outcomes. The recently published TOPCOAT trial (using full dose tenecteplase) actually looks at quality of life but is so flawed in its methodology that it is almost not worth reading. This might be nitpicking but I think it is an important distinction when having a discussion with a patient about the
    potential use of ½ dose lytics. Saying “this drug at the dose I would like to give you has been shown to make people live a happier and more active life” is very different than “I think this drug at the dose I would like to give you may make you live a more active life but this has actually not been proven in a clinical trial.”

    Being an early adopter of a therapy prior to large randomized trials is certainly reasonable if you believe it may offer significant benefit to your patients but I think it is crucial in situations like ½ dose TPA (where the therapy has significant potential harms and is not
    yet endorsed by any consensus guidelines) to be crystal clear about what the available data says and does not say.

    As always, thanks for an informative post and a great site.

    • William Soares

      First, thanks to all for the great discussion! It benefits everyone to critically think and discuss these topics.

      This is a very thoughtful summary above of the limitations of MOPETT that I think many of us share. Thanks for taking the time. Some recent thoughts our group has discussed regarding MOPETT:

      – This is not OUR clinical population of submassive PE’s (per inclusion criteria)
      – Open Label studies are notorious for bias in favor of treatment. In addition, we dont know how they randomized or how many patients with PE were not screened for the study.
      – The fact that neither group had any bleeding is hard to imagine, since every other study has some bleeding complication. Given only 61 patients in tPA group, the study may not have had the power to detect significant bleeding.
      – The primary outcome is a surrogate outcome. Pulmonary hypertension measured by Echo, which is known to be a test with significant variability, with a subjective cutoff of 40mmHg. There is no mention of patient symptoms / morbidity.
      – There is also a composite outcome which reaches significance, but only because their primary outcome reaches significance – mortality is unchanged.

      Although tPA may ultimately have some benefit in a carefully selected population, those with low risk of bleeding and high risk submassive PE characteristics, comparing the body of literature to date, it seems hard to justify current use of 1/2 dose TPA based on MOPETT. The study was small, open label, with different inclusion criteria, a novel therapeutic regimen and measured subjective surrogate outcomes.

      Thanks again

      Bill Soares
      Research Fellow
      Baystate Medical Center

  • jlmcdurango

    Should the thrombolytic administration be followed by a heparin infusion as we do with STEMI?

    • You should give unfractionated or low molecular weight heparin:

      PEITHO trial with tenecteplase:
      https://clinicaltrials.gov/ct2/show/NCT00639743

      “Unfractionated heparin (UFH) at a dose of 80 IU/Kg as an intravenous bolus, followed by an infusion of 18 IU/Kg/hr, to be administered immediately after randomization in all patients for at least 48 hours following randomization. Beyond this period, intravenous UFH may be substituted with subcutaneous heparin (LMWH) treatment”

      MOPPETT trial with tPA: [from methods of paper]
      “All patients received either unfractionated heparin or subcutaneous enoxaparin, with initial preference given to the latter drug. Enoxaparin was given to 48 of 61 (79%) of the patients in the thrombolysis group (TG) and 49 of 60 (81%) in the control group (CG). Administration of unfractionated heparin was determined by the presence of renal insufficiency or patient preference. In the TG, enoxaparin was given as 1 mg/kg subcutaneously twice daily, with the initial dose not to exceed 80 mg. For unfractionated heparin in the same group, it was given at 70 U/kg as a bolus but not to exceed 6,000 U, with subsequent dose adjustment to keep the activated partial thromboplastin time at 1.5 to 2 times the baseline value. Although tPA was infused, the maintenance dose of unfractionated heparin was kept at 10 U/kg/hour and not to exceed 1,000 U/hour. At 3 hours after termination of thrombolysis, the dose of unfractionated heparin was increased to 18 U/kg/hour. In the CG, enoxaparin was given at 1 mg/kg subcutaneously twice daily and unfractionated heparin at 80 U/kg as a bolus followed by 18 U/kg/hour, with the same partial thromboplastin time target.”