Patients often are confused about the difference between thrombolytics and anticoagulants for treatment of pulmonary embolism (PE). If anticoagulants don’t break down clots and thrombolytics do, why don’t we give thrombolytics to more patients with acute PE? This is an excellent question with a rather complex answer.
Dr. Qiukui Hao and colleagues recently published an update of a 2015 systematic review of thrombolytic therapy for acute PE. They included 18 randomized trials enrolling 2,197 patients, comparing thrombolytic therapy followed by heparin with heparin alone or heparin plus placebo. Eleven of the 18 randomized controlled trials (RCTs) explicitly included submassive PE (PE with right heart dysfunction or elevated troponins but without systolic blood pressure < 90 mmHg). Outcome measures varied but the majority of trials reported overall mortality, recurrence of PE, and major bleeding. Thrombolytics used included alteplase, urokinase, streptokinase, recombinant tissue plasminogen activator, and tenecteplase. Risk of bias was high due to concerns about randomization, blinding, small sample sizes (range, 8 to 1,006 participants), and potential influence of pharmaceutical companies.
A meta-analysis of the studies with a lower risk of bias (n=2054) showed no mortality benefit for thrombolysis over heparin (OR, 0.66; 95% CI, 0.42-1.06; p=0.08). Furthermore, the risk of major bleeding was significantly higher in the thrombolytic group (OR, 2.90; 95% CI, 1.95-4.31; p<0.001, low quality of evidence). The results were not significantly different according to subgroup (massive PE/submassive PE/unknown types).
It is important to note that the mean age of participants in the meta-analysis was 60 years. Only one RCT (n=1,006) included a subgroup of participants older than 75 years.1 This subgroup showed a much higher risk of major extracranial bleeding with thrombolysis compared with heparin (OR, 20.4; 95% CI, 2.69-154.53) and an excessive number of intracranial bleeds (7 tenecteplase vs. 1 placebo).
The most current version of the American College of Chest Physicians Venous Thromboembolism Treatment guidelines (2016) recommends against thrombolysis in acute PE not associated with hypotension (Grade 1B).2 ASH guidelines addressing the same topic are awaited in 2019.
Most clinicians agree that thrombolysis is indicated in patients who present with PE and hemodynamic compromise. Within that context, the prognosis is so poor that the risk of major bleeding, including intracranial bleeding, is justified. The more challenging clinical scenario is when patients present with submassive PE without clear evidence of hemodynamic instability. The Cochrane Review article summarized here suggests there is no clear mortality benefit, though the upper limit of the 95 percent CI comes close to reaching significance.
My approach to symptomatic patients with submassive PE is to evaluate them on a case-by-case basis. If after 24 to 48 hours of anticoagulant therapy, there is no improvement in oxygen requirements, heart rate, and/or dyspnea with minimal exertion, I consider thrombolysis. I am much more reluctant to offer thrombolysis if the patient is 75 years or older, due to the increased risk of intracranial bleeding. For patients who do well with thrombolysis, the immediate improvement in vital signs and/or symptoms is very rewarding; however, when they experience intracranial bleeding, it is equally devastating.
Investigators are considering using lower doses of thrombolysis to offset the bleeding risk, especially in patients who are 75 years or older. Studies are needed to show whether this a safe and effective strategy.
Dr. Linkins indicated no relevant conflicts of interest.