Case:

A 50 year old female with a PMH of DM presents to your department with 4 days of dyspnea on exertion. She states that she was recently hospitalized for DKA and discharged just 3 days ago. Since discharge she has had progressively worsening SOB with pleuritic chest pain. On presentation she is hypoxic to 88% and tachycardia at 105 bpm. Her blood pressure is stable at 124/83.

Laboratory investigation was significant for an elevated D Dimer, troponin, and BNP. CXR showed no acute process, EKG showed sinus tachycardia. CTA of the Chest was significant for multiple segmental filling defects involving multiple lobes as well as the right and left main pulmonary arteries as well as a saddle embolus.

You wonder if there is any benefit to thrombolitic therapy in this patient.

Background:

The treatment of submassive PE (defined as PE without hypotension, but with evidence of RV dysfunction or myocardial necrosis) has been a focus within the medical literature over the past few years with two larger trials (PEITHO, a large multi center study, and MOPETT, a single center study) evaluating the use of TPA for treatment receiving much attention. Unlike massive PE, where patients present with hemodynamic instability and the use of a thrombolytic such as TPA is recommended (level B, ACEP), the use of TPA for submassive PE has been more controversial.

An early trial, the TOPCOAT trial, evaluated patients with submassive PE. In this small, multicenter RCT of 83 patients, showed that treatment with tenecltplase had a increase in the probability of a favorable outcome. (1)  In the PEITHO study(2), high risk, submassive PE were evaluated using two criteria, RV dysfunction on imaging and elevated cardiac biomarkers (troponin I or T).  The primary outcome of death or hemodynamic decompensation within 7 days was seen in 2.6% of the intervention group (N=13) versus 5.6% of the placebo group (N=28) OR 0.44 (95% CI 0.23-0.87) P= 0.02. However, major extracranial bleeding was seen in 6.3% of the intervention group versus 1.2% of the placebo group OR 5.55 (2.3-13.39) P = <0.001 and stroke risk was 2.4% in the intervention group versus 0.2% in the placebo group (OR 12.1 (1.57-93.39) P =0.003). The authors concluded that administration of TPA decreased the all cause mortality and hemodynamic decomponsation, but was offset by the large risk of hemorrhage.

Given no clear evidence towards benefit for TPA in the initial period of treatment, newer studies aimed to investigate whether there may be benefit when studying patients for longer intervals.

Reference 1: Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. (3)

This long anticipated follow up to the PEITHO study by Konstantinides et al attempts to evaluate the impact of thrombolytic therapy on the long term prognosis of intermediate risk PE and the effect on treatment on persistence of symptoms. This follow up study to PEITHO captured approximately 70% of the original study participants and evaluated them at 24 months to see if there was any long term improvement.

Study: A large, double blind, multi center randomized control trial

Population: Patients older than 18 with confirmed PE and less than 15 days of symptoms with RV dysfunction confirmed by ECHO or CT and myocardial injury.

Intervention: comprised of a weight based tenecteplase bolus + heparin.

Comparison: comprised of a placebo and heparin

Outcome: Evaluation of long term mortality rates, clinical function including dyspnea, functional limitations, RV dysfunction, and incidence of chronic thromboembolic pulmonary hypertension at 24 months.

Key Results

There was no difference in mortality at 30 days and 24 months. At 30 days there was a 2.2 % all cause mortality in the tenectaplace group (N=8) and 2.9% in the Control Group (N=10). At 24 months all cause mortality was 18.1% in the tenectaplase group (N-65) and 15.1% in the control group (N=53).

There was no difference in the development of RV dysfunction or pulmonary hypertension.

No differences in persistent dyspnea or functional limitation were seen (36% versus 30.1% p = 0.23). A subset of the patients were evaluated (175 patients in intervention arm and 183 patients in control)

No statistical differences in chronic thromboembolic pulmonary hypertension (2.1% versus 3.6%).

Limitations

Long term follow up was only performed in approximately 2/3rds of the randomized population due to only 28 of 76 PEITHO sites being involved. However, given that randomization was performed in blocks and stratified by centers, there is low concern for selection bias from improperly randomized samples. Many causes of death past 30 days was not identified. Follow up echocardiography was not standardized and not competed in all patients.

Bottom Line

This study does not show any advantage for the use of submassive PE in improving long term outcomes.

Reference 2: Moderate Pulmonary Embolism Treated With Thrombolysis (MOPPETT Trial). (4)

These conclusions are in contrast to the MOPPETT trial, which used a similar but slightly less aggressive weight based tPA strategy for submassive PE. The MOPPETT trial enrolled patients with slightly less severe criteria for inclusion and used a slightly less aggressive method of tPA delivery.

MOPPETT TPA delivery: 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. Warfarin was started at admission in all patients.

The MOPPETT trial noted no adverse bleeding and no significant difference was noted in the rate of individual outcomes of death and recurrent PE when assessed independently (same as PEITHO – PEITHO also included hemodynamic decompensation and looked at death and decompensation in aggregate).

In conclusion, the results from the MOPPETT trial suggests that “safe dose” thrombolysis is safe and effective in the treatment of moderate PE, with a significant immediate reduction in the pulmonary artery pressure that was maintained at 28 months. It was a more limited trial with fewer patients.

Discussion

Management of pulmonary embolism continues to evolve, and recently we have seen a number of studies informing management of the submassive PE category. Primary considerations in the decision to lyse or not-to-lyse include early benefit (mortality, incidence of arrest, etc), late benefit (mortality, incidence and symptom burden of chronic pulmonary hypertension), and risk of bleeding. MOPPETT showed no mortality benefit, but did suggest improved pulmonary artery pressures and symptoms at 22 months. These patients were defined as “moderate” PE, and overall seemed less ill than what we now consider sub-massive.

PEITHO, the biggest and most comprehensive study to date, looked at the submassive PE group in which we are interested, though patients with symptoms of up to 15 days were included (less acute, arguably less unstable). PEITHO shows early mortality benefits, but possibly offset by risk of severe hemorrhage; notably, it used a more aggressive large bolus thrombolytic plus heparin, while other available data suggest that lower dose alteplase, possibly with LMWH, maintains the benefits without the risk of hemorrhage. The long term follow-up to PEITHO now shows no benefits to the prevention of chronic pulmonary arterial hypertension, and in general indicates that chronic symptom burden is low.

In a certain sense this simplifies management of acute submassive PE, as now the primary considerations are acute benefit and risk of bleeding, but whether to lyse or not in individual circumstances will remain complicated. In a younger, healthier patient with large pulmonary embolism, and who shows concerning signs of possible decompensation, it is likely safe and beneficial to push lytics; whether this decreases their symptomatic burden down the road is unproven, but in a highly functioning individual may be a hoped-for benefit. In contrast, a 78-year-old with large PE with right heart strain, but risk factors suggesting a more friable neuro-vasculature, requires a careful risk-benefit consideration and may be a candidate for a catheter directed procedure. Future research on the optimal dose and timing of thrombolytic would be of further utility.

Consider the EMCRIT PE Risk-Benefit Continuum (Click here)

Co-authors: Dan Lautenbach, MD, Alexander Beyer, MD, Chris Hebert, MD.

Faculty Reviewer: Brendan Byrne, MD.

References:

  1. Kline JA, Nordenholz KE, Courtney DM, Kabrhel C, Jones AE, Rondina MT, 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;12(4):459-68.
  2. Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-11.
  3. Konstantinides SV, Vicaut E, Danays T, Becattini C, Bertoletti L, Beyer-Westendorf J, et al. Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. J Am Coll Cardiol. 2017;69(12):1536-44.
  4. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M. Moderate Pulmonary Embolism Treated With Thrombolysis (from the &#x201c;MOPETT&#x201d; Trial). American Journal of Cardiology;111(2):273-7.

 

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