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A modified reperfusion protocol for intermediate-risk pulmonary embolism (PE) seemed to work without causing excessive bleeding in the small randomized CANARY trial.

Use of conventional catheter-directed thrombolysis (CDT) with alteplase led to 4.3% of patients showing right ventricular (RV) recovery at 3 months (in terms of echocardiographic RV/LV ratios >0.9), which was numerically, but not statistically, better than the 12.8% for the group randomized to anticoagulation alone (OR 0.31, 95% CI 0.06-1.69), reported Behnood Bikdeli, MD, MS, a vascular disease specialist at Brigham and Women's Hospital and Harvard Medical School in Boston, and colleagues.

"The current study suggests a more favorable durable effect for conventional CDT compared with anticoagulation monotherapy on several 3-month imaging indices," the authors wrote in . "Future [randomized clinical trials] should determine whether such hypothesis-generating imaging changes translate to relevant improvement in clinical outcomes."

Notably, the study was ultimately underpowered to assess the primary outcome, as it had been stopped prematurely due to COVID-19 when the investigators had only recruited 94 patients. Participants had intermediate- to-high-risk PE, a heterogeneous, difficult-to-treat population, for which reperfusion therapy is controversial because of the bleeding risk.

For , on the other hand, systemic thrombolysis is indicated in clinical practice unless contraindicated by high bleeding risk.

The CANARY investigators reported that there had been a significant advantage for intermediate-risk CDT recipients with respect to the primary RV recovery endpoint at 72 hours (27.0% vs 52.1%, OR 0.34, 95% CI 0.14-0.80).

As for safety, there was only one instance of nonfatal major gastrointestinal bleeding -- and no deaths -- in the 3 months after CDT delivering a lower-dose thrombolytic locally to the pulmonary arteries.

In contrast, there had been an excess of major bleeding in the older which studied full-dose tenecteplase in an intermediate-risk population with RV dysfunction, positive troponin, and normal blood pressure. In that trial, systemic thrombolytic therapy also showed a failure to improve long-term RV function, residual dyspnea, and mortality rates.

In an , Elaine Hylek, MD, MPH, an arterial and venous thromboembolism specialist at Boston University School of Medicine, pointed out that the mean age of PEITHO patients was 66 years, compared with 58 years in CANARY.

"The prevalence of cerebral vasculopathies like leukoaraiosis and amyloid angiopathy has been found to increase with age and comorbid illness and are associated with a higher risk of intracranial hemorrhage. These risk factors are also well established across the spectrum of thrombotic disease for anticoagulant-related extracranial hemorrhage," she wrote.

Therefore, it's unlikely that the low rate of major hemorrhage in the newer trial "is solely attributable to the locally delivered reduced dose of thrombolytic therapy, as the lower bleeding risk of the patients enrolled ... may also be a major factor," she noted.

Bikdeli and colleagues acknowledged that the majority of their study patients had low baseline bleeding risk.

The open-label phase III trial was conducted at two centers in Tehran, Iran, and randomized PE patients to CDT (consisting of fixed-dose alteplase for 24 hours) plus heparin or anticoagulation monotherapy.

Of the 94 patients enrolled (29% women), only 85 completed the 3-month echocardiographic follow-up.

Bikdeli's group cautioned that ultrasound-assisted CDT was not used in the study.

"Given the heightened risk of mortality among patients with submassive PE, well-designed trials are needed to guide clinical practice in patient selection, optimal dose, timing of intervention, and effective mode of delivery," Hylek urged.

Indeed, the ongoing HI-PEITHO, PEITHO-3, PE-TRACT, and mechanical thrombectomy trials are expected to provide more answers.

Better prediction models are also needed to identify PE patients at highest risk of decompensation who would benefit from an earlier aggressive approach, Hylek suggested.

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