Skip to content

Lytics for sub-massive PE: Ready for primetime?

2016-11-11T18:39:33+00:00

PulmonaryembolismThere was recently a great study published in the American Journal of Cardiology (2012) by Sharifi et al1, questioning whether we should be considering tPA in patients other than those patients with massive pulmonary embolism (PE)? You know the big “Saddle Embolus” we all fear? Well it turns out this is only about 5% of all PEs.

Should we be considering tPA in patients with sub-massive PEs?

Sharifi and colleagues hypothesized that “1/2 dose tPA” could be used for PEs.

Why half dose of tPA you ask?

It turns out that pulmonary blood flow is 100% of cardiac output, making pulmonary arteries very sensitive to lysis. In considering that the brain only uses about 15% of the cardiac output and the heart even less than that at 5%, do we really need to use “full dose” tPA (100 mg) in the lungs?

Methodology

This was a prospective, randomized clinical trial looking at 121 patients, which were randomized to treatment group or control group. The 61 treatment group patients received tPA 10 mg over one minute followed by the rest of the dose over two hours, followed by lovenox or heparin. The control group received no lytics and the treatment dose of lovenox or heparin.

Results

There was a decrease in baseline pulmonary artery systolic pressure (PASP) of 22 mmHg in the treatment arm and 8 mm Hg in the control arm at 28 month follow up. This led to an absolute risk reduction (ARR) of 41%.

Not bad you say. Well, there was NO statistical improvement in overall mortality. As far as the secondary outcomes, there was no major bleeding or intracranial hemorrhage in either group and the hospital length of stay was also shortened in the treatment group by about 2.7 days.

Bottom line on MOPETT study

Half-dose tPA is likely safe and but of questionable clinical benefit.

But wait! Hot off the press: PEITHO study

The PEITHO (Pulmonary EmbolIsm THrOmbolysis) study data was just presented at the American College of Cardiology 2013 Scientific Sessions. This is the largest study looking at sub-massive PEs and use of thrombolytics, conducted over 10 years. In this study, sub-massive PE comprised about 15 to 20% of all PEs, and patients were at high risk for death and cardiovascular collapse.

This was a prospective, multicenter study of just over 1000 patients who were randomized to a FULL, weight-dosed bolus of tenecteplase plus heparin (treatment arm) versus just heparin alone (control arm). The primary endpoint evaluated was the combined endpoint of death from any cause and hemodynamic collapse at 7 days.

The relative risk reduction (RRR) of the primary endpoint was about 56%, but as we are always cautioned about RRR, the actual numbers show primary endpoint rates of 2.6% in the treatment arm and 5.6% in the control arm, which is an ARR of only 3%. Unfortunately, the rate of major bleeding was significantly higher in the treatment arm (6.3%) compared to the control arm (1.5%).

So are lytics in sub-massive PE ready for primetime?

My opinion is we are not there yet. Several studies now have shown the risk of major bleeding with lytics, but no real significant improvement in mortality. Let’s see what else we have coming up in the pipeline in the near future. Remember our job as physicians is to do no harm, and right now the evidence says we are doing more harm than good with full-dose lytics in sub-massive PE.

1.
Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M, “MOPETT” I. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273-277. [PubMed]
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
  • Fantastic first point, and great that it coincided with the bay area journal club, it really lit up the twitter universe last night!

    At heart, I am a minimalist, and I really fear the risk of ICH with TPA, and its an interesting point you bring up with the two articles about the full dose vs the half dose.

    Ultimately it comes down to, do no harm; consider the pt’s baseline health status, and really have true informed consent discussion with the pt and family if at all possible prior to administration. Although we don’t need actual consent, it is so much better to discuss with the family the pros and cons, especially when things to south.

    • Great points, Niki. Everything in medicine is all about pros/cons and risks/benefits. There’s no higher-risk scenarios than the tPA discussion with family. I too err on the size of “doing no harm” especially if the patient is older (>75 years) because of the increased hazard ratio with lytics.

  • I agree with these thoughts. This is definitely not ready for prime time. My feeling is that lytics for PE are only indicated for the peri-arrest patient. This is the only point, in my opinion, that the benefits of lytics outweigh the risks for the PE patient. I have used lower dose tPa in several cardiac arrest patients with variable results. Each time was with family involvement/discussion.

  • Too bad about this not being ready for prime time. The study took 10 YEARS!! Funny that you mention PE in peri-arrest. See tomorrow’s post by Bryan on “code dose” of tPA.

  • I appreciate all the feedback. I think the authors of the MOPETT Trial were onto something with this “safe dose” or “1/2 dose” lytics and the theory that the lungs receive 100% of Cardiac Output. I would love to see more trials looking at this evaluation in sub-massive PE. We know the mortality and risk of cardiovascular collapse is already higher in this group, it seems that heparin or lovenox alone is not the answer, although obviously better than placebo alone. Hopefully more trials in the works looking at this “safe dose” concept.

  • More comments from the Google Docs demographic form:

    1. Good post. We do not use tPA in general for undifferentiated cardiac arrest; for PE, if coding, I use the 50 mg bolus, which seemed to be best supported by literature last time I reviewed.

    2. Excellent review of the literature. I think the key here is, if you clinically suspecting PE as the culprit, it is really the only diagnosis that seems to benefit from lyrics peri-arrest. That being said, people need to remember that MI/ACS is the number one killer, followed by PE as number two for out of hospital unexpected arrest.
    – Salim R. Rezaie, MD

    3. Pharmacy ED PGY-2 trained:
    Love the site- on my daily reading list; started following many of the contributors on twitter; recommend to all my students to get involved in the FOAMed movement and use social media to their advantage while learning; PV cards are awesome, as are the TOTs….I have recommended some non-medication TOTs to my physician colleagues who ask where I got this info (as I am “”just a pharmacist””)”

  • Nice post Salim, and congrats on writing for the blog!

    I do not think we should can this just because of the mortality argument. All comers with PE and normal BP have a mortality rate of about 0.9%. Limit that to submassive PE, and you still only see 3% mortality (https://docs.google.com/file/d/0B6V8oX3x0l-0cXRtOXB3Q0ZTVHc/edit). So even a 30% mortality reduction in this population doesn’t get you past 2% mortality. Mortality, in my mind, is not the only endpoint we should care about and should not be the deciding factor in shelving this treatment.

    What I really care about are young, active healthy people becoming crippled by PE induced pulmonary hypertension. The primary endpoints of the MOPETT trial were pulmonary hypertension and pulmonary HTN + recurrent PE at 28 months. In this light, it did wonderfully (41% ARR in pulmonary HTN and 47% ARR in the combined endpoint) with no ICH events. ICH happens about 2-6% of the time in tPA administration, but giving it for non-stroke events and being a young healthy person with no contraindications and no comorbidities should put you toward the lower end of that spectrum (Kline says just under 1%). Granted, I am not going to give lytics to the older person with relative tPA contraindications and comorbidities, but if I had a submassive PE and RV dysfunction I would want lytics. In a young, healthy population with the right risk factor profile, I think lytics give you a better change at long term improvement of pulmonary function.

    I need to read the PEITHO trial, but again it is another trial that focuses on death as the primary endpoint. I would be interested to see the patient profile (comorbidities, age, etc), as well as their definitions of major bleeding. Subgroup analysis would be interesting in the bleeders as well. Even before the MOPETT trial came out, I was of the opinion that in the low risk, young healthy patient, the benefit of lytics on pulmonary hypertension in the right patient population outweighed the risks (with a careful discussion with patient and family of course). I think the trial should at least make us think twice about this treatment in the patient with the right risk/benefit profile. Here is a link to a podcast I did on the topic with my opinion: http://emrespodcast.libsyn.com/case-conference-submassive-pe

    • Great summary of your thoughts. I agree that while it’s not ready for “primetime”, it is worth considering on a case-by-case basis. Interestingly at the Bay Area JC, when the residents were asked whether they’d want to receive at least half-dose tPA if they got a submassive PE, almost all raised the hands. The question now is at what dose (half vs full vs somewhere in between).

      Thanks for your podcast link, Bob. Will check it out.

  • Hey Bob,
    Thanks for the fantastic post. By no means was I saying we should not consider lytics in all patients with sub-massive PE. It is an informed consent and discussion with family and patient. I agree in a young, otherwise healthy person it certainly reasonable to consider. The main point I was trying to make was that it is not ready to be used in ALL patients with sub-massive PE. Your points are well taken, and I also thank you for the link to your podcast. Great to run into you again, this time via the ALiEM blog. Hope you are well.

  • Question for the group: How would you word your informed consent for a young healthy person with a submassive PE?

  • Something like…there is no proven mortality benefit, but there is some evidence that pulmonary pressures and therefore quality of life may be improved. Again, it is something I would offer, but not necessarily state there is strong evidence for at this time.
    One caveat, the pulmonary pressure improvement was recorded with echo, not rt heart cath which is the gold standard test. That being said, I would say there has been some echo evidence of improved pulmonary pressures and therefore cardiopulmonary function.
    Even though the MOPETT study did not show any increase in intracranial bleeding, I still think it is a risk, and one study with 1/2 dose tPA in 60 pts is not enough for me to not consider this a risk.
    I don’t know if this helps, but would like to hear others thoughts on the subject.