Comparing different thrombolytic dosing regimens for treatment of acute pulmonary embolism

Background 
Optimal dosing of recombinant tissue-type plasminogen activator (rt-PA) is important in treating pulmonary thromboembolism (PTE). 
 
Methods 
Objective 
The aim of this study was to compare the efficacy and safety of a 50 mg/2 h rt-PA regimen with a 100 mg/2 h rt-PA regimen in patients with acute PTE. 
 
Design 
A prospective, randomized, open label trial. 
 
Setting 
A multicenter trial in China. 
 
Subjects 
118 patients with acute PTE and either hemodynamic instability or massive pulmonary artery obstruction. 
 
Intervention 
Patients were randomly assigned to receive a treatment regimen of either rt-PA at 50 mg/2 h (n = 65) or 100 mg/2 h (n = 53). 
 
Outcomes 
The efficacy was determined by observing the improvements of right ventricular dysfunctions (RVDs) on echocardiograms, lung perfusion defects on ventilation perfusion lung scans, and pulmonary artery obstructions on CT angiograms. The adverse events, including death, bleeding, and PTE recurrence, was also evaluated. 
 
Results 
Progressive improvements in RVDs, lung perfusion defects, and pulmonary artery obstructions were found to be similar in both treatment groups. This is true for patients with either hemodynamic instability or massive pulmonary artery obstruction. Three (6%) patients in the rt-PA 100 mg/2 h group and one (2%) in the rt-PA 50 mg/2 h group died as the result of either PTE or bleeding. Importantly, the 50 mg/2 h rt-PA regimen resulted in less bleeding tendency than the 100 mg/2 h regimen (3% vs. 10%), especially in patients with a body weight, 65 kg (14.8% vs. 41.2%, P = 0.049). No fatal recurrent PTE was found in either group. 
 
Conclusions 
Compared with the 100 mg/2 h regimen, the 50 mg/2 h rt-PA regimen exhibits similar efficacy and perhaps better safety in patients with acute PTE. These findings support the notion that optimizing rt-PA dosing is worthwhile when treating patients with PTE.


Background
Optimal dosing of recombinant tissue-type plasminogen activator (rt-PA) is important in treating pulmonary thromboembolism (PTE).

Methods
Objective: Th e aim of this study was to compare the effi cacy and safety of a 50 mg/2 h rt-PA regimen with a 100 mg/2 h rt-PA regimen in patients with acute PTE. Design: A prospective, randomized, open label trial. Setting: A multicenter trial in China. Subjects: 118 patients with acute PTE and either hemodynamic instability or massive pulmonary artery obstruction. Intervention: Patients were randomly assigned to receive a treatment regimen of either rt-PA at 50 mg/2 h (n= 65) or 100 mg/2 h (n= 53). Outcomes: Th e effi cacy was determined by observing the improvements of right ventricular dysfunctions (RVDs) on echocardiograms, lung perfusion defects on venti lation perfusion lung scans, and pulmonary artery obstructions on CT angiograms. Th e adverse events, including death, bleeding, and PTE recurrence, was also evaluated.

Results
Progressive improvements in RVDs, lung perfusion defects, and pulmonary artery obstructions were found to be similar in both treatment groups. Th is is true for patients with either hemodynamic instability or massive pulmonary artery obstruction. Th ree (6%) patients in the rt-PA 100 mg/2 h group and one (2%) in the rt-PA 50 mg/2 h group died as the result of either PTE or bleeding. Importantly, the 50 mg/2 h rt-PA regimen resulted in less bleeding tendency than the 100 mg/2 h regimen (3% vs. 10%), especially in patients with a body weight, 65 kg (14.8% vs. 41.2%, P = 0.049). No fatal recurrent PTE was found in either group.

Conclusions
Compared with the 100 mg/2 h regimen, the 50 mg/2 h rt-PA regimen exhibits similar effi cacy and perhaps better safety in patients with acute PTE. Th ese fi ndings support the notion that optimizing rt-PA dosing is worthwhile when treating patients with PTE.

Commentary
Acute pulmonary thromboembolism (PTE) is a disease with variable clinical severity that can range from no symptoms to severe hypoxia, hypotension, right heart failure and death. Th rombolytic therapy is known to improve physiologic parameters and right heart function in PTE. Th is therapy is routinely used in patients who have hemodynamic instability. However, its role in patients with large PTE in the absence of hemodynamic in stability, particularly in the subset with right ventricular strain, is controversial. Few large randomized clinical trials(RCTs) have been conducted to assess effi cacy of thrombolytic therapy for diff erent subgroups of patients with PTE and to compare diff erent dosing regimens, Current recommendations are largely based on results of observational studies or meta-analyses of small RCT [1-3].
Recombinant tissue-type plasminogen activator (rt-PA) is currently the most commonly used thrombolytic therapy for PTE. Similar to most thrombolytic agents, rt-PA carries a signifi cant dose-dependent risk of bleeding, and it is the most common adverse eff ect associated with thrombolytic therapy for PTE. In a retrospective analysis of 104 patients with PTE who receive rt-PA, 20 patients (19%) had major bleeding [4]. Th e most devastating complication is intracranial bleed and it occurs in up to 3% of patients. Th us, optimal dosing to maximize benefi ts and minimize bleeding complications is important.
Few studies had compared diff erent thrombolytic doses for PTE [5,6]. For example, Goldhaber and colleagues com pared 0.6 mg/kg over 15 min (maximum dose of 50 mg) and 100 mg over 2 hours in 90 patients. No signifi cant diff er ences were detected between both groups with regards to bleed ing complications and effi cacy, as measured by perfu sion lung scans, pulmonary angiograms and echo cardiograms.
With this background, Wang and colleagues conducted a randomized, multicenter study to compare low vs. high dose rt-PA in treatment of acute massive PTE [7]. Patients were included if they were 18 years or older and present with symptoms of acute PTE within 15 days of enrolment. Th is study enrolled patients with large PTE, as evidence by hemodynamic instability (systolic blood pressure [BP] <90 mmHg or drop in systolic BP of at least 40mmHg for at least 15 minutes), cardiogenic shock or those with anatomically massive PTE (CT scan showed occlusion of more than 2 lobar arteries, or V/Q scan showed occlusion >7 segments combined with right ventricular dysfunction on echocardiography). For sample size calculation, the authors calculated the number of patient needed to demonstrate a reduction in the CT obstruction score by 10 points. A total number of 118 patients were enrolled (65 in the low dose and 53 in the high dose group). Th e primary endpoints were effi cacy of thrombolysis, as measured by improvement in right ventricular function by echocardiogram, improve ment in perfusion by V/Q scan and improvement in CT obstruction score. No diff erences in effi cacy were ob served between the two groups. Secondary endpoints were safety endpoints, including bleeding risk. Bleeding events were categorized into major and minor events. Major events included bleeding leading to death, caused a drop in hemoglobin >2 g/dl, or required transfusion more than 400 cc blood and intra cranial hemorrhage. Minor events included bleeding that led to a drop of less than 2 g/dl in hemoglobin. Other secondary endpoints were recurrence of PTE and death. Although bleeding risk was no diff erent, in subgroup analysis stratifi ed by body weight, the risk of total number of bleeding episodes were less with the low dose regimen than in the high dose regimen, especially in patients with body weight <65 kg (14.8% in the low dose vs. 41.2% in the high dose group, P = 0.049) or BMI <24 (8.7% in the low dose vs. 42.9% in the high dose group, P = 0.014).
To date, this study is the largest one to compare diff erent dosing regimens of rt-PA for acute PTE. Th e subgroup analysis according to body weight suggests that using weight-based dosing may reduce bleeding complications. However the study has limitations. Th e authors chose a surrogate endpoint and its clinical signifi cance is unclear. For example, it is diffi cult to estimate the clinical signifi cance of a 1 point decrease in the CT obstruction score. Although mortality would be an important outcome measure, it was a secondary outcome in this study and there were only a few deaths.
Th is study highlights the importance of considering alternative study designs to compare diff erent dose regimens of thrombolytic therapy for PTE. For instance, lower dose may have similar effi cacy but lower bleeding complications, thus such studies should be designed as non-inferiority or equivalence trial, with the hypothesis that clinical effi cacy would be similar but bleeding risk would be lower.
In conclusion, this trial did not prove diff erences in effi cacy between low dose and high dose rt-PA regimens. Th e secondary analyses showing that lower dose of rt-PA may lower the risk of bleeding suggest a need for additional studies to use weight-based regimens to reduce risk of bleeding.