Do patients with submassive pulmonary embolism benefit from thrombolytic therapy?

TOPCOAT trial

The Tenecteplase or Placebo, Cardiopulmonary Outcomes at Three months (TOPCOAT) trial,³⁰ published in 2014, was a multicenter, double-blind, intention-to-treat, randomized trial carried out in eight centers in the United States. The authors evaluated a composite outcome (death, circulatory shock, intubation, major bleeding, recurrent pulmonary embolism, and functional capacity) with the use of tenecteplase in submassive pulmonary embolism.

A total of 83 patients received low-molecular-weight heparin and were randomized to also receive either tenecteplase or placebo. Submassive pulmonary embolism was defined as evidence of right ventricular strain based on echocardiographic findings and elevated cardiac markers (troponin, BNP, or NT-pro-BNP).

Results. Adverse outcomes occurred in 37% of the patients in the placebo group compared with 15% of those in the tenecteplase group (P = .017). The study was terminated early because the lead author relocated to another institution.

Wang et al

In a prospective, randomized, open-label, multicenter study³¹ conducted in China between 2002 and 2006, 118 patients received low-molecular-weight heparin plus alteplase in a dose of either 100 mg or 50 mg over 2 hours.

Results. There were significantly fewer bleeding episodes in patients receiving half-dose alteplase in the subgroups that weighed less than 65 kg (14.8% vs 41.2%, P = .049) or who had a body mass index less than 24 kg/m² (8.7% vs 42.9%, P = .014).

Meta-analysis

A subgroup analysis²⁵ of patients with submassive pulmonary embolism from a 2014 meta-analysis of randomized controlled trials of thrombolytic therapy in pulmonary embolism found that thrombolysis was associated with a lower mortality rate (OR 0.48; 95% CI 0.25–0.92) but a higher rate of major bleeding (OR 3.19, 95% CI 2.07–4.92).

Is there a role for low-dose thrombolytic therapy?

The MOPETT study, discussed above, evaluated the effect of thrombolysis in a low (“safe”) dose in reducing pulmonary artery pressure in moderate pulmonary embolism.²⁸ The primary end points were pulmonary hypertension and the composite end point of pulmonary hypertension and recurrent pulmonary embolism. In the thrombolysis group, the pulmonary arterial pressure fell immediately and was still lower at 28 months. As mentioned, although the incidence of pulmonary hypertension was lower with thrombolysis, no significant differences were noted in the rate of individual outcomes of death and recurrent pulmonary embolism when assessed independently. Furthermore, the definition of moderate pulmonary embolism used in this study is different from the submassive criteria.

Wang et al³¹ enrolled patients to receive low-molecular-weight heparin plus alteplase in a dose of either 50 or 100 mg. The rate of bleeding was lower with the 50-mg dose, but only in the subset of patients with lower weight and body mass index.

What is the role of catheter-guided therapy?

Catheter-directed therapy involves infusing thrombolytic agents directly into the pulmonary arteries where the clots are. The idea is to expose the patient to lower doses of systemic thrombolytics and thus decrease the risk of bleeding.

The ULTIMA study³² (Ultrasound-Assisted, Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism) evaluated whether this treatment would reverse right ventricular dilation in intermediate-risk patients, compared with anticoagulation. Intermediate-risk pulmonary embolism was defined as an embolus located in at least one main or proximal lower lobe pulmonary artery and an RV:LV ratio of at least 1.0 obtained from the echocardiographic apical four-chamber view.

The study showed hemodynamic improvement as evidenced by a lower RV:LV ratio. However, at 90 days the mortality rate was not significantly lower in the treatment group than in the control group. Of note, no major bleeding events were reported in the treatment group.

The SEATTLE II trial,³³ a nonrandomized study completed in April 2013, evaluated the efficacy and safety of ultrasonographically guided, catheter-based, low-dose fibrinolysis for patients with massive and submassive pulmonary embolism. Patients had CT evidence of proximal pulmonary embolism and a dilated right ventricle (RV:LV ratio ≥ 0.9). Patients received alteplase 24 mg, either as 1 mg/hour for 24 hours with a unilateral catheter or 1 mg/hour in each of two catheters for 12 hours.

At 48 hours after the procedure, the mean RV:LV ratio had decreased from 1.55 to 1.13, the mean pulmonary arterial systolic pressure had fallen, and the anatomical clot burden had decreased. A total of 15 patients (10%) experienced major bleeding but there were no reports of any fatal or intracranial bleeding. Patients with massive pulmonary embolism were more likely to experience major bleeding episodes than those with submassive pulmonary embolism (23% vs 7%, P = .02).

The weakness of this study is that it was a single-arm study and therefore limits comparisons with other therapies such as tissue plasminogen activator for massive pulmonary embolism or anticoagulation. Also, although there was an acute improvement in hemodynamics, it is unclear if that translates to improvement in mortality rate.

Based on the available literature,^29,31,33 patients presenting with submassive pulmonary embolism who are of low body weight (body mass index < 24 kg/m² or weight < 65 kg) or are over age 75 may benefit from low-dose catheter-guided thrombolysis therapy or low-dose systemic alteplase (50 mg). Further studies should be conducted comparing these two therapeutic strategies.

SURGICAL EMBOLECTOMY: STILL THE LAST RESORT

Surgery has been the last resort for patients with pulmonary embolism. Although recent reports show a decrease in mortality from advances in surgical embolectomy, the mortality rate is greater than 10%.³⁴

• Indications for surgical embolectomy are³⁵:
• Failure of or contraindications to thrombolytic therapy
• Continued hemodynamic instability despite maximal medical therapy
• Associated cardiac pathology such as patent foramen ovale, atrial septal defect, and free-floating right heart thrombi
• Inadequate time for systemic thrombolytics to take effect.

No large or randomized controlled trials of surgical embolectomy for submassive pulmonary embolism have been done. In one study, of 47 patients undergoing surgical embolectomy, 15 (32%) met the criteria for submassive pulmonary embolism based on right ventricular hemodynamic dysfunction. The report did not mention if biomarkers such as troponin and BNP were considered in the decision to operate.³⁶

At this time, surgical embolectomy remains a last resort for patients with acute massive pulmonary embolism who have contraindications to thrombolysis or for whom it has failed. Given the risk of death associated with surgical embolectomy, large randomized controlled trials need to be done to see if there is any benefit in the submassive pulmonary embolism population.

ONE TREATMENT DOES NOT FIT ALL

Given the evidence to date, we do not recommend thrombolytic therapy for all patients with submassive pulmonary embolism. The risk of complications (hemorrhage) is significant, and the benefit is unclear. A one-treatment-for-all approach cannot be applied in this situation.

Furthermore, each of the trials performed so far defined submassive pulmonary embolism slightly differently (Table 4), and many were underpowered to detect a difference in mortality rates between the treatment groups. Further studies are needed to determine the exact subset of patients with submassive pulmonary embolism that may truly benefit from thrombolytic therapy.

As such, patients with submassive pulmonary embolism should be managed by a multidisciplinary team to determine the need for thrombolytic therapy, especially in low doses, on a case-by-case basis according to the patient’s risk of further clinical deterioration.