Abstract
Recombinant tissue plasminogen activator (rt-PA) is the most commonly used thrombolytic agent in patients with high risk and intermediate to high mortality risk acute pulmonary embolism (PE). Clinical trials have shown early efficacy and safety of low-dose rt-PA. This study investigated the effects of low-dose rt-PA treatment on acute PE in long-term prognosis, recurrence of pulmonary thromboembolism, or the development of late complications. In this study, 48 patients undergoing low-dose rt-PA for the relative contraindications of thrombolytic therapy and 48 patients undergoing standard-dose therapy were evaluated retrospectively. Long-term follow-up investigated the chronic PE, recurrence, and causes of morbidity and mortality.
In both treatment groups, embolism-induced mortality and overall mortality rates were similar in the first 30 days (p=1.000, p=0.714, respectively). Overall mortality rates in long-term follow-up were 41.7% in the low-dose treatment group and 16.7% in the standard-dose treatment group (p=0.013). The mortality rate at the first year was higher in the low-dose-treated group (p=0.011) and most of the deaths were due to accompanying comorbidities. There was no difference in PE recurrence and duration of recurrence between the groups (p=0.598, p=0.073, respectively). Intracranial hemorrhage due to therapy developed in one patient in both groups.
Low-dose thrombolytic therapy in acute PE reduces PE-related mortality in the early period. Long-term follow-up showed that thrombolytic therapy did not affect mortality rates independently of the dose and PE recurrence.
Significance of this study
What is already known about this subject?
Acute pulmonary embolism (PE) is a life-threatening disease, with approximately 25% of patients dying without a diagnosis because of sudden death.
Thrombolytic therapy is considered the most effective treatment for high-risk life-threatening PE.
The Food and Drug Administration approved recombinant tissue plasminogen activator regimen for PE is 100 mg as a 2-hour continuous infusion.
The most feared complication of thrombolysis is intracerebral hemorrhage.
What are the new findings?
To evaluate the efficacy and safety of low-dose thrombolytic therapy in patients with high and moderate- to high-risk PE compared with the standard therapy.
This study includes a 5 years follow-up data of these patients in terms of recurrence, morbidity, mortality, and causes of them.
It provides the data of the side effects of both therapeutic methods compared with each other.
How might these results change the focus of research or clinical practice?
The low-dose therapeutic method can be a choice in patients with bleeding risk or low body weight patients.
This will help reducing the treatment cost.
Introduction
Acute pulmonary embolism (PE) is a life-threatening disease. Despite improvements in diagnostic methods, mortality is still high, with approximately 25% of patients dying without a diagnosis because of sudden death.1 Right ventricular failure due to increased pressure in pulmonary arteries in severe PE is the main cause of death. The pulmonary artery pressure begins to increase when the thromboembolic pulmonary artery obstructs approximately 30%–50% of the total cross-sectional area of the bed. PE-induced vasoconstriction mediated by the release of thromboxane A2 and serotonin contributes to the increase in pulmonary vascular resistance after PE and can be reversed by these vasodilators.2
Thrombolytic agents are serine proteases that act by converting plasminogen to the natural fibrinolytic agent plasmin which allow the thrombosis to dissolve faster. Early resolution of pulmonary obstruction leads to a rapid fall in pulmonary artery pressure and resistance and to an improvement in right ventricular function.3 Thrombolytic therapy is considered the most effective treatment for high-risk life-threatening PE.4 It is also proposed as an effective treatment modality in patients with intermediate-risk to high-risk PE who have high markers of right ventricular dysfunction and/or myocardial damage without systemic hypotension.4 5
Recombinant tissue plasminogen activator (rt-PA) is the most commonly used thrombolytic agent for the treatment of acute PE. The Food and Drug Administration approved rt-PA regimen for PE is 100 mg as a 2-hour continuous infusion. The most feared complication of thrombolysis is intracerebral hemorrhage and occurs in 0.7%–6.4% of patients receiving thrombolytic agent.6 7 As dosages carry the risk of bleeding, studies are still on the optimal dose. Clinical trials have shown that low-dose rt-PA is safe and efficient, particularly in patients with low body weight (<65 kg), right ventricular dysfunction and high risk of bleeding.8–10 Applying a lower dose can be a life-saving in patients with high risk of bleeding, such as elderly patients (>75 years), cerebrovascular disease or those who have recently undergone surgery.
The impact of thrombolytic therapy on mortality and recurrent thromboembolism is controversial. In addition, long-term effects of thrombolytic therapy are not fully known. In this study, we aimed to evaluate the effect of low-dose rt-PA on long-term prognosis, safety, and the development of late complications in acute PE treatment.
Materials and methods
Patients selections
A total of 96 patients with high-risk and intermediate-risk to high-risk PE diagnosed with thrombolytic therapy were included in the study. The data were evaluated retrospectively. All cases were diagnosed by computed thorax pulmonary angiography (multislise 64–256 detector). Patients' age, gender, symptoms at admission, appendix disease, systemic arterial blood pressures, and oxygen saturation values measured by pulse oximeter were recorded. Significant risk factors for PE, such as recent surgery, immobilization, trauma, malignancy, deep vein thrombosis (DVT), were assessed. Wells scores and D-dimer levels were recorded. PE mortality risk classification was performed by evaluating echocardiographic (ECHO) findings (Philips iE33, İstanbul) of right ventricular overload, pulmonary arterial pressures, and myocardial damage biomarkers such as troponin T and N-terminal pro-brain natriuretic peptide.2 The patients who diagnosed with acute PE were treated by thrombolytic therapy within 14 days after the onset of symptoms. Patients with definite contraindications to thrombolytic therapy, pregnancies and patients under 18 years of age were not included in the study. This study was approved by the Ethics Committee of the Yildirim Beyazit University Faculty of Medicine (approval No: 26379996/213) and informed consent was obtained from all participants.
There are clinical studies investigating early efficacy and safety of low-dose administration of thrombolytic agents in PE treatment.8–10 To evaluate the long-term outcome of low-dose thrombolytic therapy, we included patients who were given a continuous infusion of 50 mg rt-PA over 1 hour, 23 patients were from our previous study in which we observed similar efficacy with standard-dose treatment and 25 patients with new PE who were treated the same way.10 Low doses of thrombolytic therapy were administered to a total of 48 patients with PE. Possible relative contraindications to thrombolytic therapy such as low body weight (<60 kg), recent surgery, bleeding story, invasive procedure, and ischemic stroke were also evaluated in these cases.4 In all, 48 patients without any contraindication to thrombolytic therapy received a standard dose of 100 mg/2-hour rt-PA. All patients received low-molecular-weight heparin (enoxaparin sodium, 1 mg/kg subcutaneously each 12 hours) after thrombolytic therapy.
Follow-up
Treatment with oral anticoagulant or low-molecular-weight heparin was completed in 6 or 12 months according to the recurrent PE risk of each patient. Right ventricular dysfunction and pulmonary arterial pressure values were recorded in patients with control ECHO at 6 months of treatment. Chronic PE assessed by computerized thorax pulmonary angiography at 6-month follow-up; controlled lower extremity Doppler ultrasound also assessed chronic DVT. The causes of PE recurrence and recurrence were evaluated. In the first month of treatment, in the first year and in the fifth year, death and the causes of death were recorded. The hospital records used for patients who died at our hospital and the national death notification system were used for other patients.
Statistical analysis
SPSS (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, V.21.0. Armonk, New York, USA) Statistics 21.0 program was used for statistical analysis and calculations. The distribution of continuous variables was examined by Sharipo-Wilk test and normality graphs, respectively. The groups were compared with Mann-Whitney U and χ2 tests, respectively, in terms of continuous and categorical variables. Statistical significance level was accepted as p<0.05.
Results
The data were obtained retrospectively from August 2009 to September 2014 from the medical records of 96 patients with high-risk and intermediate-risk to high-risk PE who were treated with thrombolytic therapy in our clinic. In all, 48 patients with a relative contraindication to thrombolytic therapy were given a low dose of 50 mg/1-hour rt-PA (table 1). In total, 48 patients received standard-dose (100 mg/2 hours) rt-PA. The mean age of the patients was 62.1±17.6 and 60.3±15.2, respectively. In both treatment groups, 28 (58.3%) patients were men and 20 (41.7%) were women. The demographic data and medical history of the patients were similar between the groups (table 2).
Comparison of the clinical findings and laboratory data in treatment groups showed troponin T value was higher in the half-dose-treated group (P=0.002). No statistically significant difference was observed between the other clinical findings and laboratory data (table 3).
Six-month control ECHO showed no difference between the groups in terms of systolic pulmonary artery pressure (sPAP) and right ventricular dysfunction (table 3). ECHO changes in sPAP at 6 months were similar in the low-dose and standard-dose rt-PA groups (p=0.271). However, there was a significant lack of ECHO control data in the low-dose treatment group at the sixth month. In the control computerized thorax pulmonary angiography, chronic PE findings in pulmonary arteries were detected in six patients in the 50 mg/1-hour rt-PA group and in 11 patients in the 100 mg/2-hour rt-PA group, the difference was not statistically significant (p=0.493). The rates of chronic DVT were also similar among the groups (table 4).
PE recurrence was detected in four cases of low-dose thrombolytic group; two at the eighth month and the other two in the 12th and 21st months and in seven cases of the standard-dose group in the third, 21st, 23rd ,24th, 36th, 40th and in the 70th months. There was no statistically significant difference between the groups in terms of PE recurrence and recurrence time (p=0.598, p=0.073, respectively). There was no difference between provoked and unprovoked PE groups (p=0.259). Recurrence is attributed to thrombophilia genetic causes in five of the patients who received standard dose, and one patient in each group, had suffered PE recurrence because of irregular oral anticoagulation use (table 5).
After long-term follow-up between the first day and the fifth year after thrombolytic therapy, all-cause mortality was 41.7% in the low-dose treatment group and 16.7% in the standard-dose treatment group (p=0.013). Mortality rates were similar between the groups in the first month as an early period and between first and fifth year in the long-term follow-up (p=0.714, p=0.205, respectively). The mortality rate at first year was higher in the low-dose thrombolytic therapy group and the difference was statistically significant (p=0.011) (table 4). Most of the late deaths that occurred during long-term follow-up (first and fifth years) were caused by cancer, chronic respiratory failure, heart failure, or other diseases. In the first month of treatment, embolus-induced death was observed in three (6.2%) patients who received low-dose rt-PA, two because of PE and one because of intracranial hemorrhage due to thrombolytic treatment. In the early and long-term follow-up, there was no difference between the groups in early mortality and in long-term PE-related mortality (p=1.000). PE recurrence-related deaths were observed in three patients, two in the low-dose treatment group and one patient in the standard-dose treatment group. Intracranial hemorrhage due to thrombolytic therapy observed in one patient (2.1%) in each group (table 5).
Discussion
Thrombolytic therapy in acute PE improves pulmonary capillary blood flow and effective gas exchange rapidly by reducing thromboembolic load, pulmonary vascular resistance, and right ventricular dysfunction. Therefore, thrombolytic therapy may reduce mortality during the early period in the patients with PE with high risk or middle risk with right ventricular dysfunction, and may prevent PE relapse by dissolving the remaining thrombus reservoir in the lower extremities or pelvis. Long-term anticipated effect is to prevent the development of chronic thromboembolic pulmonary hypertension and to maintain normal hemodynamic response to exercise.11
This study focuses on long-term efficacy and safety of low-dose rt-PA in acute PE treatment. There was no difference between the patients treated with 50 mg/ 1-hour rt-PA and the patients receiving standard-dose treatment in terms of early mortality and long-term PE-related mortality. Intracranial hemorrhage, the most serious complication related to thrombolytic treatment, was observed at a rate as low as 2.1%. Effective dose thrombolytic therapy is important for minimizing bleeding complications and achieving maximal benefit. There are very few studies in the literature comparing different thrombolytic regimens. Most of them show historical value and early effects of low-dose treatment.
Sors et al performed rapid-infusion of 0.6 mg/kg (maximum 50 mg) of alteplase for 15 min in 36 patients and infusion of 100 mg /2 hours for 17 patients of total 53 patients with acute massive PE. The change in total pulmonary resistance between the groups in the first hour was similar. There was no death or intracranial hemorrhage during the hospital stay.12
A similar study comparing bolus application of alteplase 0.6 mg / kg (maximum 50 mg) over 15 min to standard-dose therapy was prematurely terminated due to higher mortality (8% vs 2%;P=0.0035) when compared with the published data in the bolus group.13 The mortality rate was 23.5% in a retrospective study in which 21 patients with shock due to acute PE treated with 0.6 mg/kg (maximum 50 mg) of alteplase for 15 min infusion. The high incidence of major bleeding and mortality reported in older studies is not up to date or is not very consistent with experience. In our study, intracranial hemorrhage and death associated with it were observed in one patient in each treatment group.14
In a prospective randomized controlled trial by Wang et al, significant improvement was seen in right ventricular function, pulmonary perfusion, and pulmonary artery occlusion in patients with high-risk PE who treated with 50 mg rt-PA/2 hours compared with standard dose. There was no significant difference in mortality among the groups during the first 14 days of follow-up (p=0.472). Bleeding rates were lower in patients with low body mass index who received 50 mg dose.8
The first major study evaluating the efficacy of thrombolytic therapy in submassive PE is the Management Strategies and Prognosis of Pulmonary Embolism-3.15 In a prospective randomized double-blind trial, 118 patients received heparin with alteplase (100 mg over 2 hours) and 138 received heparin with placebo. In 30 days, 11% of the alteplase-heparin group and 24.6% of the placebo-heparin group (p=0.006) had died at the hospital or suffered clinical deterioration that required treatment change. In all, 32 patients of the 138 patients in the control group (23.2%) required secondary thrombolysis (p=0.001). The mortality rate was 3.4% in the alteplase-heparin group. In our study, there were PE with intermediate to high mortality risk in 30 (62.5%) of the patients receiving low-dose thrombolytic therapy and 18 (39.1%) of the patients received standard-dose treatment. In the first 30 days, embolism-induced death was observed in three (6.2%) of the low-dose-treated patients and in two of the standard-dose treated patients (4.2%). There was no difference between groups in terms of embolism-related and all-cause mortality.
In the Moderate Pulmonary Embolism Treated with Thrombolysis trial, it was investigated that effective and safe thrombolysis could be achieved with low- dose treatment considering the sensitivity of the lungs for thrombolysis.9 As a safe dose, a 50 mg of alteplase was applied as 10 mg intravenous bolus followed by 40 mg intravenous infusion for 2 hours for patients weighing ≥50 kg or 0.5 mg/kg intravenously (10 mg intravenous bolus followed by infusion of the remaining for 2 hours) for patients weighing <50 kg. Cardiac biomarkers were high in 60% of the patients and 20% of the cases had right ventricular dysfunction as an ECHO finding. sPAP was measured at 48 hours (34±7 vs 41±4 mm Hg; p<0.001), at the sixth month (31±6 vs 49±8 mm Hg; p<0.001) and at the 28±5 month (28±7 vs 43±6 mm Hg, p<0.001) which was significantly lower in the thrombolytic group comparing with the only anticoagulant group. There was no effect of alteplase on the recurrence of PE and mortality rates. In our study, right ventricular dysfunction was detected by ECHO in 89.6% of patients received standard-dose thrombolytic therapy and in 85.4% of patients received low-dose therapy. At the sixth month, the sPAP was similar between the groups (44.5±20.9, 36.4 ± 13.9, p=0.489, respectively). However, a big amount of data of the ECHO controls at the sixth month of patients received low-dose thrombolytic therapy was missed. The thrombolytic therapy dose had no effect on the development of PE recurrence (p=0.598). The role of thrombophilia genetic risk factor predisposition in PE relapse was high.
In the study carried by Mi et al, who evaluated the long-term effects of low-dose rt-PA (50 mg/2 hours) for submassive PE with right ventricular dysfunction, significant improvement was observed in the group receiving thrombolytic therapy at 24th hour and 12th month (p<0.001). In the first week and at 12th month, the thrombolytic group had significantly lower clot load than the anticoagulation group (p<0.001). There were no deaths due to major bleeding, minor bleeding was observed in the thrombolytic group (6.3%, p<0.05). The authors reported that low-dose thrombolysis has long-term safety and efficacy in treating submassive PE in patients at low risk of bleeding.16 In our study, sixth month control computerized pulmonary angiography showed marked reduction in clot load in both treatment groups. Six (16.7%) patients in the 50 mg rt-PA group and 11 (25.6%) patients in the standard-dose treatment group showed radiographic evidence of chronic PE. No statistical difference was found (p=0.493).
In a Pulmonary Embolism Thrombolysis (PEITHO) study, 1006 patients with submassive PE were randomized in two groups as tenecteplase plus heparin and placebo plus heparin. There was no significant difference in all-cause mortality between groups at 30 days (p=0.420). In the tenecteplase group, major intracranial hemorrhage and stroke were higher in 7 days (p<0.001, p=0.004, respectively).17 In a study evaluating the effect of thrombolytic therapy on long-term prognosis, symptoms and development of late complications, 709 of 1006 patients were randomized. Overall mortality rates were 20.3% and 18.0%, respectively (p=0.43). Chronic thromboembolic pulmonary hypertension was observed in six (3.2%) cases and in four (2.1%) cases (p=0.79).18 In our study, all-cause mortality rates were 41.7% in the low-dose treatment group and 16.7% in the standard-dose treatment group for the long-term follow-up between the first day and the fifth year (p=0.013). There was no difference between the groups in mortality rates in the first 30 days and long-term follow-up between the first and fifth years. In the low-dose treatment group, the mortality rate was high between 31st day and first year, which may explained by active cancer stories, additional comorbid diseases and older age of the patients of this group. It is not surprising that early thrombolysis has no ability to prevent these late deaths. In the early and long-term follow-up, there was no difference between the groups in embolism-related deaths (p=1.000).
In the meta-analyses conducted, thrombolytic therapy in patients with acute PE reduces total mortality, PE recurrence, and PE-related mortality. However, the overall decrease in mortality in hemodynamically stable patients is not significant. Thrombolytic therapy increases the incidence of major and minor hemorrhagic events.19 20 The risk of major bleeding and intracranial hemorrhage due to thrombolytic therapy increases especially in patients older than 65 years.21 In our study, intracranial hemorrhage rate was 2.1% in the low-dose rt-PA group, in spite of relative contraindications for thrombolytic therapy, advanced age, and comorbidities in some patients. Brandt et al also noted that low-dose rt-PA may be a safe and effective treatment option for acute PE, especially in patients at high risk of bleeding.22
The limitation
The major limitation of this study is the data which were obtained from a single center, small sample sizes and being a retrospective study. While it does not attain statistical significance, the proportion of high-risk PE was substantially higher in the high-dose group. There were lack of long-term follow-up due to insufficient post-discharge control applications and outpatient recordings from the hospital.
Conclusion
In this study, thrombolytic therapy in both treatment doses was found to have reduced PE-related mortality in the early period. It was observed that early thrombolytic therapy in acute PE did not affect long-term mortality and PE recurrence independent of the dose. Decrease in right ventricular dysfunction and decrease in sPAP values were similar in both treatment methods. Bleeding complications of rt-PA may be dose-dependent. In our study, low-dose thrombolytic therapy was administered to a group of patients with a high risk of bleeding with relative contraindications for thrombolytic therapy. As it is seen from our previous study results, reduced doses of thrombolytic therapy provided similar efficacy and lower risk of bleeding when compared with standard doses.10 PE is an acute, life-threatening condition. We think that prospective randomized study is not suitable for patients with high and intermediate to high mortality risk PE who should be given thrombolytic treatment. However, the results obtained from studies related to treatment dosing suggest that low-dose thrombolytic therapy is effective. Considering this fact, it can be said that rt-PA, which is an expensive treatment, is cost-effective at low dosage. More studies are needed to determine the optimal dose of rt-PA in patients with PE with high and intermediate to high mortality risk.
Footnotes
Contributors Only the authors are contributed in this work.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests HH, HK, OA, CH and AK declares that they have participated in the design, execution and analysis of the paper, and that they have approved the final version.
Provenance and peer review Not commissioned; externally peer reviewed.
Patient consent for publication Not required.