EM – Critical Care Journal Club
Topic: Use of Thrombolytics in Submassive PE
Article (2 of 4): Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M. Moderate Pulmonary Embolism Treated With Thrombolysis (from the “MOPETT” Trial). J Cardiol. 2013; 111: 273-277.
Resident Reviewer: Benjamin Bautz, MD
Case / Problem
Thrombolysis with tPA is a well-recognized and effective tool for treatment of “massive” PE (i.e. PE with hemodynamic instability). Accordingly, there has been interest in expanding the use of tPA to patients with “submassive” PE (i.e. PE with hemodynamic stability but evidence of right heart strain), as these patients are known to have increased morbidity/mortality compared to patients with “nonmassive” PE. And while some data have suggested efficacy of thrombolysis in patients with submassive PE (see Konstantinides et al. (1997) Circulation, and Konstantinides et al. (2002) NEJM), many physicians remained reluctant to give tPA to these relatively stable patients due to the risk of catastrophic hemorrhage. Could use of a lower dose of tPA offer a lower risk of hemorrhage while also providing a treatment benefit?
How was article selected?
This study is one of only several published in the last decade to evaluate the efficacy and safety of thrombolysis in submassive PE on a randomized, controlled basis.
Study Description and Research Question
Prospective, controlled, randomized, single-center open-label study to answer the question:
Does administration of “low dose” tPA (i.e. 0.5 mg/kg up to 50 mg) to patients with “moderate” PE (defined radiographically in this study as PE with thrombus in 2 or more lobar arteries or in the main pulmonary artery or V/Q scan with mismatch in 2 or more lobes) affect long-term development of pulmonary hypertension (as evidenced by elevated PA systolic pressure). Secondary outcomes of total mortality, duration of hospital stay, bleeding during hospitalization, and recurrent PE.
As discussed above, there is a desire for a more aggressive treatment approach to intermediate-risk PE due to increased morbidity/mortality in this group. While previous studies have demonstrated efficacy of tPA in this patient group, the rates of catastrophic bleeding remain significant. The MOPETT investigators postulated that a lower dose of tPA could offer an attractive approach if it could be shown to have a clinical benefit and reduced bleeding risk.
Population: 121 adult patients with symptomatic (defined as 2 or more signs/symptoms – chest pain, RR >22, HR >90, dyspnea, cough, PaO2 < 95, JVP >12) “moderate” (defined radiographically as above) PE at a single center in Arizona. [Note: unclear from article which center, and if ED vs. all hospital.] Exclusion criteria: Symptoms > 10 days, anticoagulated > 8 hrs already, SBP <95 or >200, eligible for full-dose thrombolytics, contra-indication to heparin, platelets < 50K, major bleeding requiring transfusion in last 2 months, major surgery or trauma in last 2 weeks, brain mass, neurosurgery/ICH/SDH in last year, end-stage illness.
Intervention: Randomized to thrombolysis (0.5 mg/kg tPA given as 10 mg bolus and remainder over 2 hours) plus heparin (LMWH or UFH).
Comparison: Standard treatment with heparin and warfarin alone.
Outcomes: Primary – development of pulmonary hypertension (by PA systolic pressure on echo at 28 wks) and composite of pulmonary hypertension plus recurrent PE. Secondary – all-cause mortality, recurrent PE, hospital LOS, bleeding events, and composite of all-cause mortality plus recurrent PE.
Appraisal of Internal Validity
Did the experimental and control groups starts out with a similar prognosis?
- Were inclusion/exclusion criteria well-defined and replicable? YES Appropriate?
- These inclusion criteria break from standard definition of “submassive” PE
- Were exposures well-defined? YES Replicable? YES
- Were measurements of variables similar and valid between groups? YES
- Were exposure and comparison groups otherwise similar? YES
- Other than exposures, were groups treated equally? YES
- Were outcomes well-defined? YES Measurable? YES
- Was follow-up complete? YES (3 and 4 patients lost to follow-up in intervention and comparison groups respectively) Sufficient? YES for research question.
These authors used a clear and reproducible set of inclusion and exclusion criteria, and randomization of participants was effective in producing groups with similar characteristics. They had clear outcomes and good follow-up. While the study was open-label, outcomes were clearly defined and evaluators of outcomes (e.g. Cardiologists reading echocardiograms) were appropriately blinded, so bias was likely reduced. Accordingly this study has good internal validity.
Rate of pulmonary hypertension at 28 wks: 16% (TG) vs 57% (CG) P < 0.001, NNT = 2
Composite pulmonary hypertension plus recurrent PE: 16% vs 63% P <0.001, NNT = 2
Recurrent PE: 0% vs 5% (P=0.08)
All-cause mortality: 1.6% vs 5% (P=0.30)
All-cause mortality or recurrent PE: 1.6% vs 10% (P=0.049, NNT 12)
Hospital length of stay: 2.2 vs 4.9 days (P<0.001)
Major or minor bleeding: 0 in both groups
- The use of composite outcome pulmonary HTN + recurrent PE here is probably not useful, since the statistically significant difference here is driven by pulmonary hypertension and not a significant decline in rate of recurrent PE.
- These bleeding rates of 0 are different from the previously reported bleeding rates in studies of DVT/PE treated with heparin and studies of tPA. This may be related to the small sample size and low overall event rate.
- The results of this study suggest that use of a lower dose of tPA along with heparin and warfarin reduces long-term pulmonary hypertension and hospital length of stay in certain patients with symptomatic, acute PE. The study did not show any mortality benefit, however, and the broad clinical significance of pulmonary hypertension at 28 weeks is unclear in this setting.
- Most importantly, the authors’ definition of “moderate” PE is different from the now widely-accepted standard of “submassive” PE. Accordingly, the results of this study are not helpful in answering the question of how to treat patients with submassive PE.
- Because there were no bleeding events, the study is also not useful in answering the question – which in my opinion was central to the impetus for the study – of whether or not a lower dose tPA could be recommended based on a favorable safety profile.
Utility to Practice
In my opinion, this study alone is not practice-changing. While it suggests a low dose of tPA may have benefit in some PE patients, it does not offer direct guidance regarding efficacy or safety of low dose tPA in submassive PE patients.
Resident Reviewer: Benjamin Bautz, MD
Faculty Review: Alex Sheng, MD