Catheter-Directed Thrombolysis for Risk Pulmonary Embolism
Catheter-Directed Thrombolysis for Risk Pulmonary Embolism
In the present study, fixed low-dose USAT for patients with high- and intermediate-risk PE improved right ventricular function based on invasive pulmonary artery pressure and CO measurements and was associated with low bleeding and mortality rates.
The goal of revascularization therapy is to facilitate right ventricular recovery, to increase systemic perfusion, to improve symptoms and survival, and to prevent chronic thrombo-embolic pulmonary hypertension. Previous studies reported a reduction of the pulmonary thrombus load following USAT. However, reduction in clot burden may not necessarily cause an improvement in right ventricular function and haemodynamic parameters. In a recent study by Kennedy et al. of 60 patients with PE, USAT using varying rt-PA dose and treatment duration improved pulmonary artery pressure at completion of treatment. The total rt-PA dose was nearly twice as high as in our study (35 vs. 20 mg). Cardiac risk stratification was not routinely performed, and several patients without right ventricular dilatation were treated. In addition, mean pulmonary artery pressure was lower than in the present study (27 vs. 37 mmHg). A novelty of our study is that a fixed low-dose thrombolysis regimen (total rt-PA dose 20 mg over 15 h) was used. Biomarker or imaging evidence of right ventricular dysfunction confirmed the presence of high- or intermediate-risk PE in all treated patients. In the present study, the reduction of pulmonary artery pressure was accompanied by an increase in cardiac index which suggests a reduction in pulmonary vascular resistance. In a randomized, controlled trial comparing a 2-h systemic infusion of rt-PA (total dose of 100 mg) to a double bolus of 10 units reteplase at an interval of 30 min in patients with high-risk PE, Tebbe et al. reported an increase of cardiac index of ~30% in both groups within 24 h. This corresponds well to the 33 and 42% increase in cardiac index after USAT in our patients with intermediate- and high-risk PE, respectively.
The long-term benefit of early haemodynamic improvement following catheter-based or systemic PE thrombolysis is less well established. Ribeiro et al. previously reported that after PE, pulmonary artery pressure progressively decreases during the first 30 days, followed by a stable phase. During 5 years of follow-up, only patients with persistent pulmonary hypertension during the stable phase required pulmonary thromboendarterectomy due to progressive right ventricular failure. In a randomized, controlled trial of systemic thrombolysis vs. anticoagulation alone, there was persistent improvement in echocardiographic parameters of right ventricular function throughout a 6-month follow-up in favour of the patients who underwent thrombolysis. In another randomized, controlled trial of systemic urokinase vs. heparin alone, pulmonary artery pressure and pulmonary vascular resistance at rest and during exercise at 7-year follow-up were lower in the thrombolysis group. Overall, it is reasonable to suggest that a revascularisation strategy with early improvement in haemodynamic parameters may potentially reduce the incidence of chronic pulmonary hypertension, the main long-term complication of PE.
An increased RV/LV ratio by echocardiography or CT angiography as a sign of right ventricular dysfunction predicts short-term mortality. Not surprisingly, changes in RV/LV ratio have been used as surrogate marker for clinical outcomes in the treatment of PE. A recent study found a significant reduction of the RV/LV ratio by CT angiography from 1.33 ± 0.24 to 1.00 ± 0.13 following USAT. No fixed-dose thrombolysis regimen was used in this study and the total mean rt-PA dose was higher (33.5 ± 15.5 mg) with longer infusion time (mean duration 19.7 ± 8.1 h) than in our study. A similar treatment effect for systemic thrombolysis was also observed in the randomized controlled Tenecteplase Italian Pulmonary Embolism trial, comparing weight-adjusted intravenous tenecteplase vs. standard therapy with unfractionated heparin without thrombolysis in patients with intermediate-risk PE. The RV/LV ratio decreased from 1.36 at baseline to 1.04 over 24 h in the tenecteplase group while, in the control group, no significant reduction of the RV/LV ratio was observed (1.32–1.22). Overall, a similar reduction in RV/LV ratio by ~0.3 was achieved after full-dose systemic thrombolysis and in our USAT subgroup of patients with serial echocardiographic imaging.
There is a great need for alternative revascularization strategies that are safer than systemic thrombolysis. The rate of major bleeding complications after systemic thrombolysis has been reported as high as 20%, with intracranial haemorrhage in up to 3%. The risk of bleeding complications with systemic thrombolysis has recently been confirmed in the large randomized controlled Pulmonary Embolism International Thrombolysis trial comparing a single, weight-adapted intravenous bolus of tenecteplase with standard anticoagulation alone in patients with intermediate-risk PE. Although a reduction in the combined primary endpoint of all-cause mortality and haemodynamic collapse was shown with tenecteplase, the rate of major bleeding was as high as 11.5%, with 2% haemorrhagic strokes. It is not surprising that potentially life-saving systemic thrombolysis was withheld in two thirds of patients with high-risk PE. According to a recent publication by Stein et al. the proportion of unstable PE patients receiving thrombolytic therapy decreased from 1999 to 2008 from 40 to 23%. Although the present study is relatively small, it is reassuring that no fatal bleeding complication and particularly no intracranial haemorrhage occurred. More research is needed to investigate the safety of fixed low-dose local thrombolysis.
It has been suggested that patients with the most severe presentation and the highest risk of dying might gain the most from thrombolysis. In our study, improvement in haemodynamic parameters after USAT was the greatest in patients with high-risk PE and in those with a symptom duration of <14 days.
Our study has several limitations. Although data collection was retrospective, we established a standardized catheter intervention procedure with a fixed low-dose thrombolysis regimen prior to the study. Although most patients with intermediate- and high-risk PE presenting to our institution were treated by USAT, selection bias may have contributed to the favourable outcome observed in our study. Baseline and 24-h echocardiography exams were not available for analysis in more than half of the patients. We were not able to assess the full spectrum of echocardiographic parameters of right ventricular dysfunction, including tricuspid annular systolic excursion, lateral annular tissue Doppler, or right ventricular strain. However, all patients had complete haemodynamic datasets pre- and post-USAT. We investigated invasive haemodynamic measurements at baseline and at 15 h but were unable to provide haemodynamic data during the first hours of treatment. Although our study confirmed haemodynamic improvement in patients with high-risk PE at completion of treatment, it remains unclear if USAT rapidly improves haemodynamic parameters in these patients. Local administration of a thrombolytic bolus at the time of catheter placement prior to the initiation of USAT may have contributed to the favourable haemodynamic response in our patients with high-risk PE. Both systemic thrombolysis and surgical embolectomy rapidly improve haemodynamic parameters in unstable patients, and therefore remain preferred treatment modalities in this setting. CO calculations were based on the Fick principle using assumed oxygen uptake, in addition, changes in fluid administration and inotropic support might have affected haemodynamic measurements. The classification of acute PE with symptom duration of <14 days is debatable, and symptom duration may be a poor indicator of PE onset. Of note, current consensus guidelines do not restrict the administration of thrombolytic therapy to patients with symptom duration of <14 days. We found somewhat greater haemodynamic improvement in patients with a symptom duration of <14 days when compared with patients with longer symptom duration; however, our study did not allow to assess the effect of symptom duration or delay in the initiation of treatment on haemodynamic parameters. The dose and duration of the used thrombolytic regimen (20 mg rt-PA during 15 h) was arbitrary. In a recent randomized trial of patients with intermediate-risk PE, this regimen significantly improved right ventricular enlargement at 24 h in comparison to treatment with heparin alone. Finally, the contribution of ultrasound to the CDT effect remains unclear. An ongoing randomized controlled trial in patients with ilio-femoral deep vein thrombosis aims to quantify the effect of adding ultrasound to fixed low-dose local thrombolysis by using the venographic reduction in thrombus burden from baseline to 15 h (NCT01482273).
In conclusion, our study results suggest that fixed low-dose USAT rapidly reverses haemodynamic impairment in patients with high- and intermediate-risk PE. Major bleedings, in particular intracranial haemorrhages, seem to be less frequent with this treatment regimen than with systemic thrombolysis. Future studies will further define the role of USAT in comparison to anticoagulation alone and to other revascularization strategies in the management of PE patients at increased risk.
Discussion
In the present study, fixed low-dose USAT for patients with high- and intermediate-risk PE improved right ventricular function based on invasive pulmonary artery pressure and CO measurements and was associated with low bleeding and mortality rates.
The goal of revascularization therapy is to facilitate right ventricular recovery, to increase systemic perfusion, to improve symptoms and survival, and to prevent chronic thrombo-embolic pulmonary hypertension. Previous studies reported a reduction of the pulmonary thrombus load following USAT. However, reduction in clot burden may not necessarily cause an improvement in right ventricular function and haemodynamic parameters. In a recent study by Kennedy et al. of 60 patients with PE, USAT using varying rt-PA dose and treatment duration improved pulmonary artery pressure at completion of treatment. The total rt-PA dose was nearly twice as high as in our study (35 vs. 20 mg). Cardiac risk stratification was not routinely performed, and several patients without right ventricular dilatation were treated. In addition, mean pulmonary artery pressure was lower than in the present study (27 vs. 37 mmHg). A novelty of our study is that a fixed low-dose thrombolysis regimen (total rt-PA dose 20 mg over 15 h) was used. Biomarker or imaging evidence of right ventricular dysfunction confirmed the presence of high- or intermediate-risk PE in all treated patients. In the present study, the reduction of pulmonary artery pressure was accompanied by an increase in cardiac index which suggests a reduction in pulmonary vascular resistance. In a randomized, controlled trial comparing a 2-h systemic infusion of rt-PA (total dose of 100 mg) to a double bolus of 10 units reteplase at an interval of 30 min in patients with high-risk PE, Tebbe et al. reported an increase of cardiac index of ~30% in both groups within 24 h. This corresponds well to the 33 and 42% increase in cardiac index after USAT in our patients with intermediate- and high-risk PE, respectively.
The long-term benefit of early haemodynamic improvement following catheter-based or systemic PE thrombolysis is less well established. Ribeiro et al. previously reported that after PE, pulmonary artery pressure progressively decreases during the first 30 days, followed by a stable phase. During 5 years of follow-up, only patients with persistent pulmonary hypertension during the stable phase required pulmonary thromboendarterectomy due to progressive right ventricular failure. In a randomized, controlled trial of systemic thrombolysis vs. anticoagulation alone, there was persistent improvement in echocardiographic parameters of right ventricular function throughout a 6-month follow-up in favour of the patients who underwent thrombolysis. In another randomized, controlled trial of systemic urokinase vs. heparin alone, pulmonary artery pressure and pulmonary vascular resistance at rest and during exercise at 7-year follow-up were lower in the thrombolysis group. Overall, it is reasonable to suggest that a revascularisation strategy with early improvement in haemodynamic parameters may potentially reduce the incidence of chronic pulmonary hypertension, the main long-term complication of PE.
An increased RV/LV ratio by echocardiography or CT angiography as a sign of right ventricular dysfunction predicts short-term mortality. Not surprisingly, changes in RV/LV ratio have been used as surrogate marker for clinical outcomes in the treatment of PE. A recent study found a significant reduction of the RV/LV ratio by CT angiography from 1.33 ± 0.24 to 1.00 ± 0.13 following USAT. No fixed-dose thrombolysis regimen was used in this study and the total mean rt-PA dose was higher (33.5 ± 15.5 mg) with longer infusion time (mean duration 19.7 ± 8.1 h) than in our study. A similar treatment effect for systemic thrombolysis was also observed in the randomized controlled Tenecteplase Italian Pulmonary Embolism trial, comparing weight-adjusted intravenous tenecteplase vs. standard therapy with unfractionated heparin without thrombolysis in patients with intermediate-risk PE. The RV/LV ratio decreased from 1.36 at baseline to 1.04 over 24 h in the tenecteplase group while, in the control group, no significant reduction of the RV/LV ratio was observed (1.32–1.22). Overall, a similar reduction in RV/LV ratio by ~0.3 was achieved after full-dose systemic thrombolysis and in our USAT subgroup of patients with serial echocardiographic imaging.
There is a great need for alternative revascularization strategies that are safer than systemic thrombolysis. The rate of major bleeding complications after systemic thrombolysis has been reported as high as 20%, with intracranial haemorrhage in up to 3%. The risk of bleeding complications with systemic thrombolysis has recently been confirmed in the large randomized controlled Pulmonary Embolism International Thrombolysis trial comparing a single, weight-adapted intravenous bolus of tenecteplase with standard anticoagulation alone in patients with intermediate-risk PE. Although a reduction in the combined primary endpoint of all-cause mortality and haemodynamic collapse was shown with tenecteplase, the rate of major bleeding was as high as 11.5%, with 2% haemorrhagic strokes. It is not surprising that potentially life-saving systemic thrombolysis was withheld in two thirds of patients with high-risk PE. According to a recent publication by Stein et al. the proportion of unstable PE patients receiving thrombolytic therapy decreased from 1999 to 2008 from 40 to 23%. Although the present study is relatively small, it is reassuring that no fatal bleeding complication and particularly no intracranial haemorrhage occurred. More research is needed to investigate the safety of fixed low-dose local thrombolysis.
It has been suggested that patients with the most severe presentation and the highest risk of dying might gain the most from thrombolysis. In our study, improvement in haemodynamic parameters after USAT was the greatest in patients with high-risk PE and in those with a symptom duration of <14 days.
Our study has several limitations. Although data collection was retrospective, we established a standardized catheter intervention procedure with a fixed low-dose thrombolysis regimen prior to the study. Although most patients with intermediate- and high-risk PE presenting to our institution were treated by USAT, selection bias may have contributed to the favourable outcome observed in our study. Baseline and 24-h echocardiography exams were not available for analysis in more than half of the patients. We were not able to assess the full spectrum of echocardiographic parameters of right ventricular dysfunction, including tricuspid annular systolic excursion, lateral annular tissue Doppler, or right ventricular strain. However, all patients had complete haemodynamic datasets pre- and post-USAT. We investigated invasive haemodynamic measurements at baseline and at 15 h but were unable to provide haemodynamic data during the first hours of treatment. Although our study confirmed haemodynamic improvement in patients with high-risk PE at completion of treatment, it remains unclear if USAT rapidly improves haemodynamic parameters in these patients. Local administration of a thrombolytic bolus at the time of catheter placement prior to the initiation of USAT may have contributed to the favourable haemodynamic response in our patients with high-risk PE. Both systemic thrombolysis and surgical embolectomy rapidly improve haemodynamic parameters in unstable patients, and therefore remain preferred treatment modalities in this setting. CO calculations were based on the Fick principle using assumed oxygen uptake, in addition, changes in fluid administration and inotropic support might have affected haemodynamic measurements. The classification of acute PE with symptom duration of <14 days is debatable, and symptom duration may be a poor indicator of PE onset. Of note, current consensus guidelines do not restrict the administration of thrombolytic therapy to patients with symptom duration of <14 days. We found somewhat greater haemodynamic improvement in patients with a symptom duration of <14 days when compared with patients with longer symptom duration; however, our study did not allow to assess the effect of symptom duration or delay in the initiation of treatment on haemodynamic parameters. The dose and duration of the used thrombolytic regimen (20 mg rt-PA during 15 h) was arbitrary. In a recent randomized trial of patients with intermediate-risk PE, this regimen significantly improved right ventricular enlargement at 24 h in comparison to treatment with heparin alone. Finally, the contribution of ultrasound to the CDT effect remains unclear. An ongoing randomized controlled trial in patients with ilio-femoral deep vein thrombosis aims to quantify the effect of adding ultrasound to fixed low-dose local thrombolysis by using the venographic reduction in thrombus burden from baseline to 15 h (NCT01482273).
In conclusion, our study results suggest that fixed low-dose USAT rapidly reverses haemodynamic impairment in patients with high- and intermediate-risk PE. Major bleedings, in particular intracranial haemorrhages, seem to be less frequent with this treatment regimen than with systemic thrombolysis. Future studies will further define the role of USAT in comparison to anticoagulation alone and to other revascularization strategies in the management of PE patients at increased risk.
