Among patients with submassive PE, does low-dose tPA reduce the incidence of pulmonary hypertension or recurrent PE when compared to anticoagulation alone?
In this unblinded, single-center trial of patients with a particular definition of submassive PE, low-dose tPA plus anticoagulation reduced the incidence of pulmonary hypertension and of the composite outcome of pulmonary hypertension or recurrent PE compared to anticoagulation alone.
Thrombolysis with intravenous tPA is a standard treatment for acute massive PE. However, among patients with submassive PE, namely those who are hemodynamically stable but have signs of RV dysfunction, the selection of patients who may benefit from thrombolysis remains elusive. tPA has rarely been used in the latter population, where the benefit of thrombolysis has not clearly been demonstrated to outweigh the risk of major bleeding. The MAPPET-3 trial (2002) compared heparin therapy with either tPA or placebo in patients with submassive PE and found that tPA reduced a composite endpoint of in-hospital all-cause mortality or clinical decompensation requiring further intervention. However, no survival benefit was seen, an observation attributed in part to the excess in bleeding risk associated with tPA. Low-dose tPA may reduce this bleeding risk while retaining efficacy, although this hypothesis had not been formally tested.
The 2013 Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial randomized 121 patients at a single center with moderate PE to either low-dose tPA or control in an unblinded fashion. All patients received anticoagulation with LMWH or UFH as well as warfarin. Few patients had RV enlargement (21%) or RV dysfunction (6%), two criteria used in most definitions of "submassive PE". With a mean follow-up of 2.3 years, thrombolysis was associated with a reduction in pulmonary hypertension (16% vs. 57%) as well as the composite outcome of pulmonary hypertension or recurrent PE (16% vs. 63%), though there was no significant difference in rates of recurrent PE. tPA did not confer a survival benefit but there was a reduction in the composite endopoint of all-cause mortality or recurrent PE (1.6% vs. 10%).
The generalizability of this trial is limited by the unblinded, single-center design. Furthermore, the quality of data collection in this trial is questionable as no bleeding events were documented in either group despite the use of anticoagulants and thrombolytics.
Two other recent trials add to the evidence for the use of thrombolytics in pulmonary embolism. The 2014 PEITHO trial randomized patients with submassive PE to heparin with either the fibrinolytic tenecteplase or placebo. Initial results demonstrate reduction in all-cause mortality or hemodynamic collapse with fibrinolysis (2.6% vs. 5.6%) at the cost of increased major extracranial bleeding (6.3% vs. 1.2%) and hemorrhagic stroke (2.0% vs. 0.2%). The 2014 TOPCOAT trial randomized 83 patients with submassive PE to heparin plus tenecteplase or placebo. Fibrinolysis was associated with reduction in recurrent PE, poor functional capacity, or SF 36 score <30 at 90 days (15% vs. 37%). The study was closed well short of its goal enrollment of 200 patients due to relocation of the principal investigator.
As of April 2015, no guidelines have been published that reflect the results of this trial.
- Single-center, randomized, non-placebo-controlled, unblinded
- N=121 patients with submassive PE
- Low-dose thrombolysis (n=61)
- Control (n=60)
- Setting: One US center
- Enrollment: 2008-2010
- Mean follow-up: 2.3 years
- Analysis: Not explicitly stated
- Primary outcomes:
- Pulmonary hypertension
- Pulmonary hypertension or recurrent PE
- Adult patients
- Moderate PE, defined as:
- >70% involvement of thrombus in ≥2 lobar or either the left or right main pulmonary arteries
- High probability V/Q scan with V/Q mismatch in ≥2 lobes
- ≥2 signs or symptoms:
- Chest pain
- RR ≥22 breaths/minute
- Resting HR ?90 bpm
- SaO2 <95%
- JVP ≥12 cm H2O
- Onset >10 days prior
- >8 hours since initiation of parenteral anticoagulation
- SBP <95 mmHg or BP ≥200/100 mmHg
- Eligibility for full-dose thrombolytics
- Contraindication to UFH or LMWH
- Platelets <50,000/mm3
- Major bleeding requiring transfusion in prior 2 months
- Surgery or major trauma in prior 2 weeks
- Brain mass
- Neurologic surgery, ICH, or SDH in prior year
- End-stage illness and no plan for treatment of PE
- Inability to perform echocardiogram
From the low-dose thrombolytic group.
- Demographics: Male 46%, age 58 years
- Baseline health data: Weight 84 kg
- PMH: HTN 52%, DM 38%, any CVD 57%, HLD 33%, any pulmonary disease 36%, any renal disease 13%, current smoker 20%
- PE risk factors: Unprovoked 46%, active cancer 13%, prior cancer 5%, thombophilia 10%, prior VTE 21%, concurrent DVT 57%
- Randomization to either:
- Thrombolysis: tPA 0.5 mg/kg (max 50 mg), given as 10 mg bolus followed by remainder over 2 hours
- Control: no tPA given
- Echocardiogram within 2 hours and before administration of tPA
- Repeat echocardiogram at 24-48 hours and every 6 months
- All patients received LMWH (preferred) or UFH, as well as warfarin
Comparisons are thrombolysis vs. control.
- Pulmonary hypertension
- 16% vs. 57% (P<0.001; NNT 2)
- Pulmonary hypertension or 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 each group
- RV enlargement at enrollment
- 20% vs. 23% (P=NS)
- RV dysfunction at enrollment
- 5% vs. 7% (P=NS)
- BNP or troponin I elevation at enrollment
- 66% vs. 70% (P=NS)
- LMWH use
- 79% vs. 81% (P=NS)
- Open-label, single center
- Small sample size renders event rate small
- Questionable data collection. For example, this trial recorded no bleeding events; the published experience using LMWH and UFH in DVT/PE suggests major bleeding rates of 1.0% and 2.1%, respectively.
- The composite outcome of pulmonary hypertension or recurrent PE was reduced with low-dose tPA, but this was driven by a reduction in pulmonary hypertension without a statistically significant decline in rates of recurrent PE
- Surrogate endpoint of pulmonary hypertension is inferior to mortality
- Funding sources not disclosed
- Incomplete reporting of statistics in outcomes (eg, 95% CIs not provided)
- This does not help sort out the management of submassive PE, as that definition differs from the term "moderate PE" used in this trial
Not disclosed by authors.
- Jaff MR, et al. "Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: A scientific statement from the American Heart Association." Circulation. 2011;123(16):1788-1830.
- Konstantinides S, et al. "Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism." The New England Journal of Medicine. 2002; 347(15):1143-1150.
- Kline JA, et al. "Treatment of submassive pulmonary embolism with tenecteplase or placebo: Cardiopulmonary outcomes at three months (TOPCOAT): Multicenter double-blind, placebo-controlled randomized trial." Journal of Thrombosis and Haemostasis. 2014; epub.
- van Dongen CJ, et al. "Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism." Cochrane Database Syst Rev. 2004 Oct 18;(4):CD001100.