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Half-Dose Recombinant Tissue Plasminogen Activator Treatment in Venous Thromboembolism
  1. H. Canan Hasanoğlu, MD*,
  2. Habibe Hezer, MD,
  3. Ayşegül Karalezli, MD,
  4. Emine Argüder, MD,
  5. Hatice Kiliç, MD,
  6. Ayşegül Şentürk, MD,
  7. Mükremin Er, MD,
  8. Ayşe Nur Soytürk, MD
  1. From the *Department of Chest Diseases, Faculty of Medicine, Yıldırım Beyazit University, Ankara, Turkey; and †Department of Chest Diseases, Atatürk Training and Research Hospital, Ankara, Turkey.
  1. Received April 5, 2013, and in revised form June 12, 2008.
  2. Accepted for publication September 7, 2013.
  3. Reprints: Emine Argüder, MD, Department of Chest Diseases, Atatürk Training and Research Hospital, Bilkent Street Number 3, Postal code 06800, Ankara, Turkey. E-mail: drgullu2000{at}gmail.com.
  4. The study was presented orally at the 34th Turkish Respiratory Society National Congress (October 2012).
  5. The authors have no conflicts of interest.

Abstract

Introduction Pulmonary embolism (VTE) comes in different degrees of severity from massive pulmonary embolism to nonmassive pulmonary embolism with no symptoms or hypoxia. Thrombolytic therapy is a lifesaver especially for patients who are in the high-risk group. In this study, we aimed at evaluating symptoms and clinical and laboratory findings in patients who had a diagnosis of massive or submassive VTE and treated with 50-mg recombinant tissue plasminogen activator (rt-PA) per hour for various problems as opposed to the standard dose, which is 100 mg every 2 hours.

Materials and Methods Forty-six patients with a diagnosis of massive or submassive VTE who received thrombolytic therapy were evaluated retrospectively. Twenty-three patients who were treated with 50-mg rt-PA per hour were included in the study group. On the other hand, 23 patients who were treated with 100 mg of intravenous infusion of rt-PA every 2 hours were included in the control group. Echocardiographic assessment of the right ventricular size, systolic pulmonary artery pressure (sPAP), oxygen saturation, systemic arterial pressure, and heart rate before the thrombolytic therapy and in the first 24 hours after the administration of therapy were checked and noted in both of the groups.

Results No significant difference was found between the 2 groups with regard to demographic data, Wells scores, type of embolism, average symptom duration, sPAP, and oxygen saturation. Differences in recovery, as inferred from vital symptoms and sPAP measurements, were not significant between the 2 groups.

Conclusions Lower-dose thrombolytic therapy showed similar efficacy versus the standard dose in VTE. Thrombolytic therapy is a life-saving treatment in massive VTE. Furthermore, a harm/benefit analysis may lead to the administration of half-dose therapy in selected cases when it is contraindicated for various reasons.

Key Words
  • half dose rt-PA
  • massive pulmonary embolism
  • thrombolytic therapy

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Key Words

Venous thromboembolism (VTE) is a common disorder with significant morbidity and mortality. Epidemiological studies’ incidence of VTE was reported to be 1.0 per 1000 person-years.1Pulmonary embolism (VTE) severity varies from massive pulmonary embolism to nonmassive pulmonary embolism with no symptoms or hypoxia. It is a life-threatening, potentially reversible, and common cardiopulmonary disease, which is an emergency situation. It occurs when 90% of a deep vein thrombus comes off.2In the United States, VTE occurs approximately in 600,000 patients and may be accountable for more than 50,000 deaths annually.2,3Standard management with intravenous heparin was shown to reduce VTE-related mortality4; but still, between 10% and 17.5% of the cases will face mortality in the first 3 months,3and this rate is even higher in massive VTE cases.5,6In Europe, there are lower estimates for mortality: In the Registry of Patients with Venous Thromboembolism, of 6264 patients with VTE, overall mortality rate was found to be 8.6% at 3 months.7,8When VTE goes untreated, the mortality rate may go up approximately to 25% to 30%, which can be reduced to 2% to 8% by therapy. Most of the deaths due to VTE occur within the first 3 months after diagnosis has been established. Approximately 5% to 15% of all inhospital deaths and 20% to 30% of deaths due to pregnancy and childbirth were found to be associated with VTE.4,5

Unless there is an absolute contraindication, thrombolytic therapy is considered to be the most effective treatment for high- and moderate-risk VTE cases.5–9In massive VTE, the patient may experience acute right ventricular failure with hypotension, shock, and/or cardiopulmonary arrest. On the other hand, patients with submassive VTE have a stable hemodynamics but may show evidence of right ventricular dysfunction and/or myocardial damage.3,4,10

Clinical studies about thrombolytic therapy date back to the 1970s.11Thrombolytic drugs actively dissolve the thrombus, hence, providing rapid improvement in pulmonary perfusion, hemodynamics, gas exchange, and right ventricular functions.6,9

Thrombolytic therapy, which is administered within 48 hours after the occurrence of the symptoms, provides maximum benefit.12It is also reported to be effective when administered in the first 6 to 14 days.13

Resolution of the clot by thrombolytic therapy provides rapid improvement in pulmonary perfusion, hemodynamic findings, gas exchange, and right ventricular functions.14,15Recombinant tissue plasminogen activator (rt-PA) is a thrombolytic agent recommended by both the US Food and Drug Administration and the European Society of Cardiology. Its infusion time and half-life is short; besides, it is short acting. Recommended use of the agent is 50-mg/h infusion for 2 hours, hence, a total of 100 mg.10Recent history of surgery, cerebrovascular events, or gastrointestinal hemorrhage may be some of the contraindications for thrombolysis. Some studies recommend low-dose thrombolysis as an alternative to the standard dose in patients with VTE who have a high risk of bleeding.16Given that, low-dose thrombolytic therapy can be a lifesaver and prevent complications of bleeding. In this study, we aimed at evaluating symptoms, clinical and demographic characteristics, and effects of the therapy in patients with massive or submassive VTE who received 50-mg rt-PA per hour for various problems versus those who were given the standard dose, that is, 100 mg every 2 hours.

MATERIALS AND METHODS

Data were collected from medical records of 46 patients with confirmed VTE who were admitted to our department between August 2009 and May 2013. All of the patients, except for two, were diagnosed by thorax spiral computed tomographic pulmonary angiography (CTPA) with 64 detectors. The patients’ data were evaluated retrospectively. The patients’ age, sex, medical history, comorbidity states, physical examination findings, arterial blood gas values, oxygen saturation values measured by pulse oximetry, D-dimer and troponin levels, transthoracic echocardiographic results, lower-extremity venous Doppler ultrasonography results, and CTPA findings were noted.

First, patients who had major risk factors for VTE such as recent surgery, immobilization, trauma, malignancy, and deep vein thrombosis were identified. All the patients were evaluated by risk stratification besides clinic assessments (Table 1).17Wells scores upon admission were used for clinical assessment. Later on, the patients were divided into 3 groups as massive, submassive, and nonmassive according to the severity of the clinical picture, where the presence of hypotension indicated massive VTE and normal blood pressure, and echo finding of right-sided heart overload indicated submassive VTE and normal blood pressure and normal echo findings indicated non-massive VTE. More than 50% of the cases with pulmonary arterial occlusion were considered to have anatomically massive VTE due to excessive burden of thrombus.

TABLE 1

All Patients Were Evaluated According to the Risk Stratification*

In two patients with VTE, CTPA could not be performed due to acute/chronic kidney failure. These patients had a high clinical probability (Wells scores are 7, 7.5; respectively) of having VTE. In addition, their echocardiographic assessment demonstrated findings of right-sided heart failure (systolic pulmonary artery pressure [sPAP], 60 and 40, respectively) and their cardiac biomarkers were high (Troponin-t, 0.1 and 1, respectively; Pro-B-type natriuretic peptide, 6805, not applicable). Furthermore, their venous Doppler ultrasonography results were positive. In the light of these findings, we decided that these patients had VTE according to the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for VTE.18We performed CTPA to the second patient when his renal function tests were improved. We determined bilateral massive pulmonary embolism on his CTPA. We performed magnetic resonance angiograph without contrast to a new patient who had renal transplantation. Both anatomically and hemodynamically massive VTE cases were included in the study. Inclusion criteria were hemodynamic instability and cardiogenic shocks accompanied by vital signs and echocardiographic findings. Exclusion criteria were absolute contraindications for thrombolytic therapy or nonmassive VTE. After all the data of 39 patients with massive VTE and 7 patients with submassive VTE were evaluated and high and moderate risks of mortality were taken into consideration, a decision was made for the thrombolytic therapy.

Twenty-three patients without absolute contraindications for thrombolytic therapy who were given 50-mg intravenous rt-PA per hour owing to such reasons as very old age, poor clinical status, and adverse events such as bleeding and hypertension, which led to the discontinuation of the therapy, after 50-mg/h infusion of the standard regimen, were involved in the study group. In all of the patients, reasons of inapplicability of full-dose thrombolytic therapy were noted in detail. On the other hand, 23 patients who were given 100-mg intravenous infusion of rt-PA every 2 hours were included in the control group. Echocardiographic assessment of the right ventricular size, wall motion, pulmonary arterial pressure, oxygen saturation, systemic arterial pressure, and heart rate in the first 24 hours after the administration of thrombolytic therapy was noted for both of the groups. Thrombolytic therapy was given to each group in the first 14 days from the onset of the symptoms. As soon as the thrombolytic therapy was administered in both of the groups, weight-based dosing of flow molecular–weight heparin (enoxaparin sodium, 1 mg/kg per 12 hours subcutaneously) was initiated. Later on, oral anticoagulants (warfarin) were carried on for treatment.

This study was approved by the Ethics Committee of Ankara Ataturk Training and Research Hospital (Ankara, Turkey), and written informed consent was obtained from each participant.

Statistical Package for the Social Sciences was used for statistical evaluations in this study. Clinical end points are measured on a numerical scale and could be analyzed via the Student t test and shown in mean ± SD. Nonparametric values were shown “median (minimum-maximum)” and analyzed via the Mann-Whitney U test. The χ2 test, the Fisher exact test, the exact test, the Student t test, and the Mann-Whitney U test were used for comparison of all the parameters. P < 0.05 was considered statistically significant.

RESULTS

A total of 46 patients with massive or submassive VTE were included in this study. Twenty-three of these patients were treated with 50-mg rt-PA per hour, whereas 23 patients were treated with 100-mg rt-PA every 2 hours. The mean ± SD age of the 23 patients was 71.1 ± 13.3, whereas the mean ± SD age of the 23 patients was 67.8 ± 11.4. There was no significant difference between the 2 groups in demographic data, type of embolism, average symptom duration, initial sPAP, oxygen saturation, and D-dimer and troponin test results (Table 2).

TABLE 2

Demographics and General Characteristics of Patients

Significant differences between the 2 groups in major risk factors for VTE (recent surgical intervention, immobilization, trauma, malignity, and history of deep vein thrombosis, the presence of deep vein thrombosis and admission symptoms) were noted (Table 3). Wells scores calculated upon admission demonstrated no significant difference between the groups (P = 0.320; Table 4).

TABLE 3

Distribution of Major Risk Factors, Deep Vein Thrombosis, and Symptoms According to the Groups

TABLE 4

Wells Scores of Patients With VTE at Admission

General characteristics of the 23 patients who were given 50-mg rt-PA are shown in Table 5. As to the adverse effects of the treatment, none of the patients died of major bleeding or owing to the treatment. Minor bleeding occurred in 3 patients. In one of these patients, who received full-dose treatment, subconjunctival bleeding occurred. In the other one, bleeding occurred from surgical suture line in the form of leakage; and in the last one, cerebral hematoma occurred. Seven patients were given half-dose thrombolytic therapy owing to adverse effects such as minor bleeding, rise in blood pressure, or increase in dyspnea, which occurred during rt-PA administration. These findings rapidly improved when thrombolytic therapy was withdrawn. The patients who presented to the clinic with deteriorated general status were evaluated for the existence of comorbidities such as hypertension, diabetes mellitus, and congestive heart failure. The 3 patients with massive VTE who were both old (older than 75 years old) and hypertensive might have a higher risk of intracranial bleeding (Table 5). For this reason, these patients were given half-dose thrombolytic therapy. As to the comparison of patients who were given half-dose thrombolytic therapy versus those who were given a full dose, there was no statistically significant difference between these 2 with regard to recovery from vital symptoms, sPAP measurements, and right ventricular size (Table 6); (Figs. 1 and 2).

TABLE 5

General Characteristics of 18 Patients Treated With 50-mg rt-PA

TABLE 6

Symptoms Before and 24 Hours After the Thrombolytic Therapy

FIGURE 1.

Systolic pulmonary artery pressure before and 24 hours after the thrombolytic therapy. Full-dose, 100-mg rt-PA every 2 hours; Half-dose, 50-mg rt-PA per hour; Pret: prethrombolytic therapy; Postt: Post-thrombolytic therapy.

FIGURE 2.

Oxygen saturation before and 24 hours after the thrombolytic therapy. O2 saturation, oxygen saturation.

DISCUSSION

In this study, 50-mg rt-PA per hour and 100-mg rt-PA every 2 hours were administered to patients with right ventricular dysfunction or to hemodynamically unstable patients with massive pulmonary emboli. As a result, similar outcomes and fewer adverse effect profiles were observed in both groups.

Considering 7 patients who were given 50-mg rt-PA per hour and taking back effective positive results and so decreasing the effect of adverse effects to a minimum level are very important results.

The first-line treatment for high-risk patients with cardiogenic shock and/or persistent arterial hypotension is thrombolytic therapy. In selected patients with intermediate risk (patients with evidence of right ventricular dysfunction and/or myocardial damage), thrombolysis can be administered after a detailed review of the conditions that increase the risk of bleeding. However, thrombolytic therapy should not be used in patients with a low risk of VTE.18

Recombinant tissue plasminogen activator is a thrombolytic agent that is recommended by the Food and Drug Administration and the European Society of Cardiology, as its infusion time and half-life is quite short and it is short acting. Recommended dose is 50-mg/h with 2-hour infusion time.19As with the other thrombolytic agents, rt-PA has a dose-dependent risk of bleeding. The effective dose is very important to minimize bleeding complications and maximize benefits. There are few studies in the literature that compare different thrombolytic regimens. In a study that compared 0.6 mg/kg every 15 minutes (maximum) versus 100-mg rt-PA therapy every 2 hours in 90 patients, Goldhaber et al.20did not find any difference between the groups in efficacy of the regimens (lung perfusion scan, pulmonary angiography findings, and echocardiogram results) and bleeding complications. In a similar study, which was conducted in France, Sors et al.20also administered a bolus of 0.6-mg/kgVmaximum, 50-mg rt-PAVto 36 patients and 100-mg rt-PA to 17 patients in 2 hours. There was no significant difference between the groups with regard to total pulmonary resistance, findings of pulmonary perfusion scintigraphy, and risk of major bleeding.20These 2 studies were published in 1994.

These results indicate that the 50-mg rt-PA per-hour regimen is as effective as the 100-mg per 2-hour regimen. Seven patients who were given 50-mg rt-PA per hour demonstrated effective positive results with minimized adverse effects, which was a significant result.

There are several potential contraindications regarding thrombolytic therapy. For example, presence of active bleeding, stroke of hemorrhagic or unknown origin, ischemic stroke in the last 6 months, central nervous system tumors and major trauma, surgery, or head injury in the last 3 weeks and prior medication usage are absolute contraindications for thrombolytic therapy. On the other hand, relative contraindications include presence of active peptic ulcer, transient ischemic attack in the last 6 months, traumatic resuscitation, venture noncompressible sites, refractory hypertension (systolic blood pressure >180 mm Hg), advanced liver disease, pregnancy or the first week postpartum, and infective endocarditis.16Relative contraindications should be reviewed in each patient, taking into account risks and benefits. It is important to keep in mind the natural course and prognosis of high-, medium-, and low-risk VTE when comparing the potential clinical benefits of thrombolysis to the risk of bleeding. In the end, myocardial infarction, which is generally considered an absolute contraindication, may become a relative contraindication in patients with a life-threatening risk of VTE.18In this study, one of the patients who were given 50-mg rt-PA had a history of cardiopulmonary resuscitation in the emergency department and surgery, which was performed 20 days before admission. Another patient had a history of transient ischemic attack in the last 6 months.

A prospective randomized multicenter study in China divided the patients with acute VTE that were hemodynamically unstable or had massive pulmonary artery obstruction and right ventricular dysfunction into 2 groups to be administered either 50-mg rt-PA or 100-mg rt-PA every 2 hours. Both the regimens were similar in activity, but the 50-mg per 2-hour regimen was found to be safer than the 100-mg per 2-hour regimen. These findings support the idea that optimizing the dose of rt-PA when treating patients with VTE21is very important. In a Chinese study, hemodynamic parameters and echocardiographic findings were similar between the 2 study groups, namely, group A, which was given 50-mg rt-PA every 2 hours and group B, which was given 100 mg every 2 hours (baseline 24-hour PAP values [mm Hg] for groups A and B were 60–40 and 60–50, respectively; P = 0.00). In the present study, baseline 24-hour mean ± SD PAP values (mm Hg) for groups 1 and 2 were 59.1 ± 17.8 to 37.8 ± 19.5 and 58.6 ± 13.5 to 33.2 ± 6.8, respectively; P = 0.00).

Recombinant tissue plasminogen activator achieves 30% reduction in pulmonary artery pressure and 15% increase in cardiac index.22In general, 92% of the patients can be considered responders to thrombolysis owing to clinical and echocardiographic improvements that occur in the first 36 hours.23In this study, 50-mg rt-PA per-hour therapy was compared to 100-mg rt-PA per 2-hour therapy. In 24 hours after the administration of thrombolytic therapy, mean sPAP, oxygen saturation and vital values were similar in the 2 groups. Furthermore, to the best of our knowledge, this is the first study in English literature that compares these 2 regimens.

There are case studies in the literature about low-dose thrombolytic therapy. Biteker et al.24performed prolonged infusion of low-dose (25 mg) rt-PA in 3 hours in 35-week pregnant women who had right-sided heart thrombosis and massive VTE. Echocardiography was performed 6 hours after the administration of therapy, and a significant decrease was seen in the right ventricular size as well as a significant resolution in right ventricular thrombus.25

In stroke protocol, 0.9-mg/kg to 90-mg rt-PA is administered, 10% of which is given as a bolus and the remaining is given in 1 hour quickly and without heparin. Arsanjani et al.26indicated good results by means of stroke protocol with 10,000 units of heparin in a 68-year-old man who had a diagnosis of massive VTE who presented with cardiac arrest. In addition, 50-mg rt-PA per-hour treatment improved the condition of a 77-year-old female patient with colon cancer who presented with cardiac arrest 20 days after the surgery and was applied cardiopulmonary resuscitation.

Bulpa et al.26used low-dose urokinase treatment as opposed to the standard dose thrombolytic therapy in 2 different patients who had active duodenal ulcer bleeding and massive VTE in the first postoperative day notwithstanding the fact that they had absolute contraindications for the therapy. This therapy turned out to be a lifesaver for both patients, and the patients did not develop any major bleeding complications after the therapy.26In our study, 7 patients were selected for standard dose thrombolytic therapy, but after 50-mg rt-PA administration, such adverse effects as dyspnea, hypertension, subconjunctival hyperemia, hematuria, and rectal bleeding occurred in these patients, where the therapy had to be terminated. In addition, 3 patients who were given full-dose treatment experienced some minor adverse events.

There are several limitations in this study. First, the small sample size was both a common and important limitation. Second, one patient had a diagnosis of VTE not by CT angiography but by American College of Chest Physicians guideline.6Third, this is a retrospective study. Because application of half-dose rt-PA therapy has not been approved yet, a prospective randomized trial on low-dose thrombolytic therapy in massive/submassive VTE cases with a high risk of mortality does not seem to be ethical because it is not established in the guidelines.

In this study, 23 patients were given 50-mg rt-PA owing to relative contraindications and/or adverse effects that occurred during the course of treatment. Half-dose thrombolytic therapy showed similar efficacy versus standard dose. Therefore, thrombolytic therapy may be a lifesaver in massive VTE when it is contraindicated for various reasons. Thus, a harm/benefit analysis may lead to the administration of lower-dose therapy in selected cases when it is contraindicated for various reasons.

As a conclusion, this study suggests that half-dose rt-PA therapy can be administered efficiently with reduced risk of bleeding. Half-dose rt-PA therapy may carry more significant impact and less adverse events within the present finding of the study accompanied by biomedical literature. It was concluded that rt-PA protocols in the guideline may be changed from standard rt-PA therapy to half-dose rt-PA regimen after further expanded study results have been reviewed.

References

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