Thrombolytics (tPA) improve intermediate risk PE outcomes, with a few head bleeds (PEITHO Trial)

The use of thrombolytics for pulmonary embolism is not controversial -- that is, if the PE is massive with hypotension (give thrombolytics) or mild, with normal blood pressure and right ventricular function (don't give them).

It's the patients with intermediate risk pulmonary emboli -- with normal blood pressure but with evidence of right ventricular dysfunction on echocardiogram, often with abnormal troponins -- who give their doctors fits. These patients' short-term mortality may be as high as 5-15%, but most of these patients will pull through just fine, and when thrombolytics can produce catastrophic intracranial bleeding 2-3% of the time, there is often no way to confidently recommend a treatment path.

Catheter-directed thrombolytics are a therapy under ongoing investigation, mostly in industry-funded device trials. The MOPPETT trial demonstrated that half-dose thrombolytics (50 mg tPA) might safely reduce the rate of recurrent PE and late-onset pulmonary hypertension in intermediate risk pulmonary embolism. This month, the multicenter, multinational PEITHO randomized trial reported in the New England Journal of Medicine takes the conversation a few steps forward.

Authors randomized 1,000 patients in 13 countries with intermediate-risk ("submassive") pulmonary embolism to receive a single bolus of 30-50 mg of tenecteplase (or TNKase -- a mutant form of tissue plasminogen activator / tPA, weight-dosed) or placebo, along with heparin infusion in all patients. Patients were normotensive, but had right ventricular dysfunction on echocardiogram and elevated troponin; half were >70 years old.

This dose should be considered a full dose of tPA: 50 mg of tenecteplase is the standard dose in the package insert. The half-dose in MOPPETT was 50 mg of alteplase, whose standard dose is 100 mg (in MOPPETT, the tPA was given as 10 mg in one minute, followed by 40 mg in 4 hours for patients >50 kg).

At 7 days, half as many patients receiving tenecteplase had death or shock as those treated with heparin alone (~3% vs. ~6%). Most of this difference was in the rate of shock, not death: only 15 patients died total (6 vs. 9) in the first week. Patients getting tenecteplase also had half the rate of mechanical ventilation.

After one month (a more pragmatic timeframe to consider outcomes), mortality was similar (2.4% vs 3.2%, nonsignificantly favoring tPA). Notably, almost 5% of placebo patients received salvage thrombolytic therapy after developing shock, as permitted in the trial design; usually this was after 7 days had passed.

About 1 in 50 patients receiving tenecteplase developed intracranial hemorrhage; most died or were disabled afterward.  About 1 in 15 patients getting tenecteplase had serious hemorrhages outside the brain. Only 1 placebo patient had an intracranial bleed.

Where does the PEITHO trial take us? Nowhere comfortable, but it might steer us toward sanity.

The 30-day mortality figures shouldn't be taken as a comparison between tenecteplase vs. heparin alone, because the sickest patients in the placebo arm got salvage thrombolytic therapy. Their mortality would likely have been higher otherwise, and the benefits of tPA more clear. Patients did very well overall, better than the higher mortality described in several previous trials among patients with intermediate-risk PE.

The trial can thus be seen pragmatically as comparing early tPA given to normotensive patients with intermediate risk pulmonary embolism, vs. observation on heparin, with late tPA reserved for those who deteriorate significantly. Interpreted this way, an early tPA strategy conferred a 0.8% absolute survival advantage at 30 days, or a number needed to treat of 125 to save a life. This came at a cost of causing 2-3 devastating intracranial hemorrhages and 8 serious non-cranial bleeds along the way. (All this at full dose tPA.)

Viewed like this, for me PEITHO provides one pathway for the treatment of patients with intermediate-risk pulmonary embolism: discuss all treatment options and their risks and benefits with a patient and her family, with a soft recommendation for close observation and conservative therapy with heparin alone initially, especially in older patients. For those who fail conservative therapy, tPA seems reasonable. "First, do no harm" is advice that was built to last.

Now, should that "late tPA" be full dose or half dose? Or is early low dose tPA (or catheter directed thrombolysis) for all intermediate risk PE actually the best strategy? Answering those questions is going to take another trial (or 3, or 4...).

Guy Meyer et al. Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism. N Engl J Med 2014; 370:1402-1411.