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.
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
Meyer G, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. New Engl J Med. 2014 Apr 10. [early online release - NEJM abstract]
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 arm: Weight-based tenecteplase (range: 30 – 50 mg) given as an IV bolus + standard anticoagulation
- Control arm: Placebo + standard anticoagulation
- Death or hemodynamic decompensation within 7 days after randomization
- Extracranial major bleeding within 7 days after randomization
- Ischemic or hemorrhagic stroke within 7 days
- Serious adverse events within 30 days
|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|
- There is no mention of pulmonary pressures in the results
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.
- 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 . 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.
- Gregory EC. Fibrinolysis of Pulmonary Emboli — Steer Closer to Scylla. New Engl J Med. 2014. 370:15, 1457-1458.
Expert Peer Review
April 11, 2014
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 . 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 . 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 .
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.
- Sharifi M et al. Moderate pulmonary embolism treated with thrombolysis (from the “MOPPETT trial). J Cardiol 2013; 111: 273-7.
- Meyer G. Fibrinolysis for patients with intermediate-risk pulmonary embolism. NEJM 2014; 370(15): 1402-1411.
- 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.