- Email: [email protected]
Systemic Thrombolytic Therapy and Catheter-Directed Fragmentation with Local Thrombolytic Therapy in Patients with Pulmonary Embolism
Accepted Manuscript Systemic Thrombolytic Therapy and Catheter-directed Fragmentation with Local Thrombolytic Therapy in Patients with Pulmonary Embolism Julia Klevanets, Vladimir Starodubtsev, Pavel Ignatenko, Olga Voroshilina, Pavel Ruzankin, Andrey Karpenko PII:
S0890-5096(17)30688-X
DOI:
10.1016/j.avsg.2017.05.003
Reference:
AVSG 3385
To appear in:
Annals of Vascular Surgery
Received Date: 22 March 2017 Revised Date:
2 May 2017
Accepted Date: 2 May 2017
Please cite this article as: Klevanets J, Starodubtsev V, Ignatenko P, Voroshilina O, Ruzankin P, Karpenko A, Systemic Thrombolytic Therapy and Catheter-directed Fragmentation with Local Thrombolytic Therapy in Patients with Pulmonary Embolism, Annals of Vascular Surgery (2017), doi: 10.1016/j.avsg.2017.05.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 2
Systemic Thrombolytic Therapy and Catheter-directed Fragmentation with Local
3
Thrombolytic Therapy in Patients with Pulmonary Embolism
4
Julia Klevanets, Vladimir Starodubtsev, Pavel Ignatenko,
6
Olga Voroshilina, Pavel Ruzankin*, Andrey Karpenko
7
Academician E.N. Meshalkin Novosibirsk State Budget Research Institute of Circulation Pathology”,
8
Ministry for Public Health Care Russian Federation Novosibirsk, Russian Federation
SC
9
RI PT
5
*The Sobolev Institute of Mathematics SB RAS, Novosibirsk State University
11
M AN U
10
Corresponding author:
13
Vladimir Starodubtsev, Academician E.N. Meshalkin Novosibirsk State Budget Research
14
Institute of Circulation Pathology”, Ministry for Public Health Care Russian Federation,
15
630055, Novosibirsk, Rechkunovsky str., 15
16
Email: [email protected]
17
Funding
18
This research received no specific grant from any funding agency in the public, commercial,
20 21
EP
or not-for-profit sectors.
AC C
19
TE D
12
Conflict of interest None declared.
22 23 24 1
ACCEPTED MANUSCRIPT Abstract
2
The objective was to compare immediate and long-term results of systemic thrombolytic therapy
3
(STT) and catheter-directed fragmentation (CDF) with local thrombolytic therapy (LTT) in patients
4
with massive pulmonary embolism (PE).
5
Methods:
6
209 patients with massive PE (the high risk of early death) were included in our study. From 2008 till
7
2010 in the first group (n=102) STT was performed. From 2011 till 2013 in the second group
8
(n=107) CDF with LTT was carried out. Echocardiography and pulmonary arteriography were
9
performed in all patients on admission to hospital and in 5 days after treatment. The patients of both
SC
RI PT
1
groups were re-examined in 6 months, 1, 2, 3 years after the operation.
11
Results:
12
In the first group there were 5 (4.9%) cases of in-hospital 30-day mortality. In the second group there
13
was 1 (0.9%) case of in-hospital 30-day mortality (p=0.08). In the first group a clinically significant
14
bleeding was noted in 4 (3.9 %) cases, but it caused mortality only in one case. In the second group
15
clinically significant bleeding was not found (p=0.038). Persistent postembolic pulmonary
16
hypertension (PPPH) in 9.8% cases of patients in the first group and 2.9% cases of patients in the
17
second group was determined (p=0.048).
18
Conclusions:
19
CDF combined with LTT is an effective minimal invasive treatment (helped us to reduce significantly the number of bleeding and PPPH cases), at least in the mid-term, in patients with massive PE.
22 23
TE D
EP
21
AC C
20
M AN U
10
24
Keywords
25 26
Pulmonary embolism, right ventricular dysfunction, heart failure, endovascular mechanical fragmentation, thrombolytic therapy
2
ACCEPTED MANUSCRIPT 1
Introduction
2
Acute pulmonary embolism (APE) is a frequent cause of death or severe disability1. About
3
10% of all patients with APE die within 3 months of being diagnosed2. Patients with a confirmed diagnosis of PE with persistent arterial hypotension and/or
5
cardiogenic shock, and hemodynamically stable patients manifesting echocardiographic signs of
6
Right Ventricle dysfunctions (RVD) have a high risk of early death and should undergo
7
pharmacological reperfusion therapy. An interventional approach combined with local thrombolytic
8
therapy (LTT) can be used as an alternative to systemic thrombolytic therapy (STT). 3
RI PT
4
Early recanalization of obstructed pulmonary arteries leads to a rapid reduction of resistance
10
and pressure in the pulmonary artery (PA) and the improvement of RV function4. Besides, survival
11
depends on effectiveness and rapid recanalization of the pulmonary arterial occlusion and the
12
reduction of the right ventricular afterload.5 At pulmonary artery pressure 40 -50 mm Hg the five-
13
year survival is 40%, at more expressed pulmonary hypertension it is only 10 %. 6
M AN U
SC
9
However, when choosing treatment tactics it is necessary to evaluate the risk of hemorrhagic
15
complications caused by the thrombolytic therapy, taking into account the high risk of early death in
16
these patients due to development of RV dysfunction, which is commonly accompanied by a drop in
17
systemic hemodynamics.7 A major issue with STT is associated with the risk of massive bleeds, as
18
well as intracranial hemorrhage. The frequency of intracranial hemorrhages ranges between 1.8% to
19
about 2.2 % 8,9 depending on choice of thrombolytic agents and dosing regiments and can reach up to
20
3% with increased age and presence of comorbidities10.
22
The objective of the study was to compare immediate and long-term results of STT and catheter directed fragmentation (CDF) with LTT in patients with massive PE.
EP
21
TE D
14
Methods
24
We prospectively enrolled consecutive 209 patients with APE and persistent arterial
AC C
23
25
hypotension and/or cardiogenic shock treated in the Division of vascular and Endovascular Surgery
26
at the Academician E.N. Meshalkin Novosibirsk State Budget Research Institute of Circulation
27
Pathology, Ministry for Public Health Care Russian Federation into a database. Our study was
28
approved by Local Ethics Committee of Academician E.N. Meshalkin Novosibirsk State Budget
29
Research Institute of Circulation Pathology, Ministry for Public Health Care of Russian Federation
30
and all patients entered the study after the procedure of informed consent.
3
ACCEPTED MANUSCRIPT Patients’
1
medical
history,
dynamic
clinical
status
assessment,
echocardiography,
angiopulmonography (APG) were performed upon admission and 5 days after treatment. Evaluation
3
of the functional state of the heart was done by transthoracic Echocardiography upon admission and 5
4
days and 6 months after treatment. We analyzed echocardiographic signs of RV dysfunction and the
5
systolic function of the right and left ventricles (RV, LV). All of the patients were monitored for measurements of heart rate; systolic, diastolic, and
6 7
RI PT
2
mean systemic blood pressures; and oxygen saturation with a pulse oximeter.
APG was performed in all patients with massive PE before treatment and 5 days after it. Then
9
systolic and average PA pressures were measured. Selective angiography was performed (flow rate
10
12–15 ml/s, injected volume 25–35 ml).
All patients underwent right heart catheterization with tensiometry of the pulmonary circuit
11
followed by APG (before treatment and 5 days after it).
M AN U
12
SC
8
The patients were subdivided into two groups. From 2008 till 2010 in the first group (n=102)
14
systemic thrombolytic therapy (STT) was performed. The recombinant tissue plasminogen activator
15
(rt-PA) was administered as a 10 mg bolus via central line and 90 mg continuous infusion over 2
16
hours (not to exceed 1.5 mg/kg if weight of patients was less than 65 kg). After systemic
17
thrombolytic therapy within the first 24 hrs all patients received heparin sodium at a dose 1,000 IU/h
18
to reach the increase of activated partial thromboplastin time to 1.5-2 times from the reference range.
19
The frequency of clinically significant bleeding in the first group (n=102) was high (4 cases (3.9%),
20
three of them - intracranial hemorrhages). We have decided to apply catheter directed fragmentation
21
(CDF) with LTT (reduce the dose of thrombolytic agents).
TE D
13
From 2011 till 2013 in the second group (n=107) CDF with LTT was performed. A 6-French
23
short sheath was inserted in the jugular vein. A guidewire and a conventional 6-French Pigtail
24
catheter for APG were advanced into PA. No patients were treated with systemic thrombolysis after
25
2011.
27 28
AC C
26
EP
22
After that patients underwent major-vessel pulmonary artery thromboembolic endovascular
mechanical fragmentation with a Pigtail catheter with LTT (Schmitz—Rode).11 During CDF with LTT the thrombolytic drug (rt-PA) was injected via the catheter deep into
29
the thrombus.12 The distal ends of the guidewire and the catheter were placed in the site of the
30
thrombus. The guidewire was remained in the peripheral PA, Pigtail catheter was advanced to a
31
central portion of PA. The catheter was spun quickly, so that the distal curve served as a rotor blade 4
ACCEPTED MANUSCRIPT 1
to fragment the thrombus. Our strategy was to fragment the largest central thrombi and restore
2
pulmonary flow without necessarily seeking to fragment thrombi located in segmental branches. During mechanical fragmentation, 50 mg of rt-PA was injected into embolus through catheter
4
(0.5-1 mg/kg by transcatheter intra-PA bolus infusion for 7-8 minutes, not to exceed 50 mg). Within
5
the first 24 hrs on embolus fragmentation completion all patients received heparin sodium at a dose
6
1,000 IU/h to reach the increase of activated partial thromboplastin time to 1.5-2 times from the
7
reference range.
RI PT
3
Low-molecular-weight heparins (nadroparin calcium or enoxaparin sodium) and, if there were
9
no contraindications, indirect acting anticoagulant (warfarin) were added to anticoagulation therapy
10
on the second postoperative day in both groups. The efficacy of the therapy in both groups was
11
estimated by APG with tensiometry in pulmonary circuit, as well as echocardiography.
SC
8
Inclusion and exclusion criteria
13
The inclusion criterion into the study was angiographic confirmation of massive PE with a
14
Miller score13 ≥ 22 (the patients with massive PE in the presence persistent arterial hypotension
15
and/or cardiogenic shock).
16
Exclusion
M AN U
12
criteria were hemodynamically stable condition
of
patients
(lack of
echocardiographic signs of RV dysfunction), chronic pulmonary thromboembolism, concomitant
18
broncho-pulmonary disease, renal failure (creatinine clearance < 30 ml/min), ischemic stroke which
19
took place less than 2 months before the study, open surgery up to 3 months earlier, anemia
20
(hemoglobin less than 90g/l) and gastro-duodenal ulcers less than 30 days prior to the study.
22 23 24
Diagnosis verification for all patients was based on APG. To determine the source of PE we used triplex ultrasound screening (TUS) of lower extremity and pelvic veins. The time from the onset of clinical symptoms to admission to the clinic ranged from 1 to 10
EP
21
TE D
17
days and, on average, was 5.0 ±4.2 days . All patients were admitted to the intensive care unit, due to presence of severe respiratory
26
disease and heart failure. Ten (9.8%) patients of the first group and 9 (8.4%) patients of the second
27
group (Fig.1) received mechanical ventilation and positive inotropic support before treatment
28
(p=0.73). The patients were kept on intensive care unit for at least 48 h. Systemic blood pressure,
29
heart rate were recorded pre- and post- (48 hours) CDF with LTT.
30
AC C
25
The immediate results of STT and CDF with LTT were analyzed from the point of view of
31
early 30-day mortality. In addition, we analyzed the changes in echocardiographic evidence of RV
32
dysfunction and its impact on prognosis and disease outcome in early observation periods (5 days).
5
ACCEPTED MANUSCRIPT 1
Efficiency criteria of STT and CDF with LTT were positive dynamics in clinical status
2
(stabilization of BP, relief of shortness of breath, chest pain, tachycardia, hemoptysis); the reduction
3
of PA pressure according to echocardiography and cardiac catheterization; perfusion obstruction
4
score reduction (Miller index); decrease or relief of the echocardiographic signs of RV dysfunction.
5
The patients of both groups were re-examined in 6 months, 1, 2, 3 years after the operation. Statistical analysis
7
In the paper the quantitative data are presented as a mean and standard deviation (SD). During
8
our investigation for testing the statistical hypothesis, the significance level of 0.05 was selected.
9
Pair-wise comparisons were made with application of Mann–Whitney U test. Qualitative characters
10
were compared with the usage of Pearson`s chi-squared test or Fisher’s Exact test. Outcome
11
probability (mortality) assessment during the study period was conducted by Kaplan – Meier
12
duplicate measurements. To perform calculations we used the statistical package MedCalc v15.2.2.
SC
Results Floating thrombi in the inferior vena cava (IVC) system were detected in 56 (27%) patients.
M AN U
13 14 15
RI PT
6
Before thrombolysis the implantation of a removable IVC filters was performed in 4 (1.9%) patients.
17
The patients’ demographic and clinical characteristics of both groups are shown in Table 1. Table 1 The patients’ demographic and clinical characteristics
18
Significant differences in demographic details, the time from the occurrence of clinical
16
symptoms to admission to hospital baseline, Miller score (MS) in groups were not found.
TE D
19
Analysis of immediate results of STT and CDF with LTT showed a positive trend in patient
21
clinical condition. So the decrease of clinical manifestations of acute respiratory failure in the early
22
period was observed in 97 (95%) patients of the first group and 107 (100%) patients of the second
23
group (Fig.2). Hemoptysis, chest pain, resting shortness of breath were eliminated in all patients of
24
both groups upon discharge. After STT and CDF with LTT a stabilization of systemic blood pressure
25
(BP) and a statistically significant decrease in heart rate were noted in the both groups.
EP
20
27
and in 5 days after CDF with LTT are presented table 2. Table 2 Dynamics of heart rate, systolic BP and oxygen saturation in patients with massive
28 29 30
AC C
Dynamics of heart rate, systolic BP and oxygen saturation in patients with massive PE before
26
PE
While
performing
transthoracic
echocardiography
we
evaluated
not
only
the
31
Echocardiographic criteria of RV dysfunction and RV systolic function (RV EF, TAPSE), but also
32
linear indicators of the right heart, average PA pressure, TAPSE at baseline and in 5 days after STT 6
ACCEPTED MANUSCRIPT and CDF with LTT (both groups). The data are presented in table 3. Table 3 shows a significant
2
decrease in right heart size during the early postoperative period compared to baseline EchoCG
3
measurements in both groups. Besides, Table 3 contains data demonstrating a significant
4
improvement in RV systolic function and an increase in tricuspid annular plane systolic excursion
5
(TAPSE) during the early postoperative period, as well as a significant decrease of average PA
6
pressure.
8 9 10
Table 3 EchoСG right heart parameters before and in 5 days after treatment
According to APG and pulmonary circuit tensiometry patients with massive PE had not only the massive thromboemboli in PAs, but also elevated PA average pressures in RA and RV. APG
SC
7
RI PT
1
parameters of the pulmonary circuit before and in 5 days after treatment are presented in table 4. Table 4 APG parameters before and in 5 days after treatment
12
Table 4 shows that in both groups there was not only an improvement of the pulmonary
13
circuit upon APG, but also a significant decrease of PA average pressure according to direct
14
tensiometry of RA and RV in the early postoperative period.
M AN U
11
Before treatment the strong correlation between the average PA pressure estimate obtained
16
noninvasively (EchoСG) versus invasively (APG) in the 1st group and second group was r=0.79,
17
r2=0.56, p=0.001 and r=0.85, r2=0.59, p=0.001, respectively.
TE D
15
In 5 days after treatment the strong correlation between the average PA pressure estimate
19
obtained noninvasively (EchoСG) versus invasively (APG) in the 1st group and second group was
20
r=0.81, r2=0.53, p=0.001 and r=0.84, r2=0.57, p=0.001, respectively.
22 23 24 25
During our investigation there were 6 (2.8%) cases in-hospital 30-day mortality (5 (4.9%)
AC C
21
EP
18
patients in the first group and 1 (0.9%) patient in the second group, p=0.08): -
five of them (four (3.9%) cases in the first group and one (0.9%) case in the second group) were patients who were admitted in critical condition with persistent hypotension and did not survive despite cardiotonic support. The reason of mortality in these cases was the
26
progression of cardiovascular and respiratory failure caused by the recurrence of
27
thromboembolism.
7
ACCEPTED MANUSCRIPT -
1
the last case of the mortality (the patient of the first group) was connected with clinically significant bleeding. The 79 year old patient with systemic hypotension died due to the
3
development of a subdural hematoma (the result of intracranial hemorrhage) in the left
4
frontotemporal region and an intracerebral hematoma of the left occipital lobe. Our
5
attempts to treat the intracranial hematomas were not successful.
RI PT
2
6
Summing up the data concerning the bleeding cases, except the above mentioned case that led
7
to the mortality, there were more 3 cases in the first group (two of them - intracranial hemorrhages) .
8
Conservative nootropic and antihypoxic therapy in the cases was effective.
So only in the first group (STT) a clinically significant bleeding was noted in 4 (3.9 %) cases,
10
but it caused mortality only in one case. In the second group clinically significant bleeding was not
11
found (p=0.038).
M AN U
SC
9
12
Performing STT and CDF with LTT promotes clinical stabilization of patients, restoration of
13
RV function and normalization of PA pressure in most patients, thereby, lowering the functional
14
class (FC) of Pulmonary Hypertension and increasing the survival rate in the early observation
15
period.
17
treatment and leads to RV systolic function disruption. The data are presented in table 5. Table 5 Dynamics of EchoCG signs of RV dysfunction in patients with massive PE after 6
18
months
EP
19
TE D
We analyzed EchoCG parameters which indicate RV dysfunction that persists 6 months after
16
Table 5 shows a significant decrease in the frequency of occurrence of the EchoCG signs of
21
RV dysfunction and average pressure in PA in the postoperative period (6 months) in groups,
22
indicating the regression of right ventricular failure due to massive PE.
23
AC C
20
In six months persistent postembolic pulmonary hypertension (PPPH) caused by chronic
24
obstruction of the main PA branches (average pressure in PA >25 mm Hg) was determined in 9
25
(9.8%) cases (92 patients observed) of the first group and in 3 (2.9%) cases (102 patients observed)
26
of the second group (p=0.048).
8
ACCEPTED MANUSCRIPT 1
During the follow-up (36 months), one patient of the first group (after 25 months) and two
2
patients of the second group (after 6 and 12 months) died. The cause of death in the groups is not
3
associated with PE (p=0.6). Kaplan- Meier curves showing survival function in the patients of both groups are represented
5
in Fig. 3. The survival function in the patients at 36 months was 92.5% in the first group and 98% in
6
the second group, respectively. No significant difference was found out in the groups (p=0.1).
7
Discussion The main purpose of using thrombolytic therapy in massive PE cases is to restore rapidly blood flow in branches of PA, normalize PA pressure in the right heart and improve RV function.14 Patients in shock and/or hypotension represent a distinct clinical problem, given a much higher early mortality rate that serves as the basis for immediate reperfusion therapy. Patients with massive PE should undergo emergency reperfusion in case of an early onset of hemodynamic decompensation. 15,16 Widespread use of thrombolytic agents is still limited due to the high risk of hemorrhagic complications in up to 13 % of cases, including fatal ones in 1.8% -2.2 %.17,18 Older age and presence of comorbidities are associated with a higher risk of bleeding complications.18 High risk of clinically significant bleeding and intracranial hemorrhages is the main limiting factor for use of thrombolytic therapy in patients with massive PE. In our study there were 4 cases clinically significant bleeding in the first group (three of them - intracranial hemorrhages). Persistent postembolic pulmonary hypertension (PPPH) which results from chronic obstruction of the main PA branches can reach up to 9.1 % and is a debilitating disease which often occurs in adults of working age.19 EchoCG signs of RV dysfunction (arterial hypotension and/or cardiogenic shock) were observed in all patients of our study. In the current study the use of STT and CDF with LTT improves RV function in the postoperative period (after 6 months RV dysfunction signs and PPPH were observed in 9 (9.8%) cases of the first group (STT) and in 3 (2.9%) cases of the second group (CDF with LTT), p=0.048. In 5 days STT and CDF with LTT leads to a significant decrease of average PA pressure according to data obtained by the noninvasive (EchoСG) and invasive (APG) methods. Besides, direct tensiometry (APG) shows the decrease of invasive pressure in RA and RV in both groups. It is important to underline that in the first group (STT) there were 5 (4.9%) cases of inhospital 30-day mortality and in the second group there was only one case (0.9%). The cause of mortality in five of them was the progression of cardiovascular and respiratory failure. The sixth case of death (first group) was connected with clinically significant bleeding. The clinically significant bleeding was noted in 4 (3.9%) cases in the first group, but it caused mortality only in one case in the
13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
SC
12
M AN U
11
TE D
10
EP
9
AC C
8
RI PT
4
9
ACCEPTED MANUSCRIPT
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
RI PT
6
SC
5
M AN U
4
TE D
3
EP
2
first group. The percentage datum in the second group is more lower (0 cases) than in other conducted studies (2.2%).18 However in six months PPPH in 9.8% of patients in the first group and 2.9% of patients in the second group (p=0.048) was determined. Before the treatment those patients of both groups had recurrent PE in anamnesis (the time from the onset of clinical symptoms to admission to the clinic ranged from 8 to 10 days), that might be one of reasons of PPPH. It is important to underline that CDF with LTT helped us to reduce significantly the number of PPPH cases. Reports from the literature20,21 demonstrate that catheter fragmentation facilitates at least partial recanalization of a central embolic occlusion. Moreover, the increased total surface area of the fragments may accelerate the efficacy of an accompanying thrombolysis. The rotational movement of the pigtail portion of the catheter acts directly on the clots in the pulmonary arteries, causing fragmentation and distal migration of the smaller fragments. The volume of the peripheral pulmonary arteries is approximately twice that of the central pulmonary arteries. Therefore, redistribution of a large central clot may acutely improve cardiopulmonary hemodynamics.21,22 Nowadays thrombolytic therapy still remains the gold standard in treatment of massive pulmonary embolism.23,24 The few reports25,26 of treatment of massive pulmonary thromboembolism using mechanical fragmentation combined with thrombolytic therapy have all indicated that the treatment results in rapid hemodynamic improvement. Moreover, an interventional approach combined with local thrombolytic therapy (LTT) can be used as an alternative to STT. Our technique CDF with LTT offers a possible synergistic effect with concurrent thrombolytic therapy because the resulting clot fragments have a greater surface area exposed to the thrombolytic agent, thus improving the results of lytic activity and allowing a reduction of dose and infusion time (the mean infusion time of rt-PA was 7-8 minutes). Besides, our technique allows reducing the frequency of hemorrhage complications (because of the reduction of thrombolytic agent dose). In our study it has been established that CDF with LTT is a safe and effective treatment for patients with massive PE (high risk of early death). This method helps not only to improve pulmonary circuit perfusion, to reduce pressure in PA and the right heart, but also to restore RV function in the postoperative period (to reduce significantly the number of PPPH cases). Our study has some important limitations. This was a prospective nonrandomized study in a referral center where many patients are from different regions of Russia; thus, consistent follow-up is difficult. Nevertheless, all patients who returned for follow-up in 1 year or later were examined to assess medium-term results and survival at 3 years. No doubt longer follow-up is ideal and may reveal data that could alter our current conclusions. Oxygen saturation was analyzed without taking into account the amount of the oxygen required to maintain it higher than 90%.
AC C
1
10
ACCEPTED MANUSCRIPT
2 3 4 5 6 7 8 9 10
The follow up average PA pressure estimate in 6 months was based on echo criteria and compared to preoperative criteria also obtained by echo. In 6 months the average PA pressure was not measured invasively (APG). Conclusion STT or CDF combined with LTT promote stabilization of the clinical state of patients and stops RV dysfunction while restoring patency of PA and reducing or normalizing pulmonary artery pressure in patients with massive PE. CDF combined with LTT is an effective minimal invasive treatment (helped us to reduce significantly the number of bleeding and PPPH cases), at least in the mid-term, in patients with massive PE.
RI PT
1
16
M AN U
15
TE D
14
EP
13
Funding This research received no specific grant from any funding agency in the public, commercial, or nonprofit sectors. Conflict of interest None declared.
AC C
12
SC
11
11
ACCEPTED MANUSCRIPT
TE D
M AN U
SC
RI PT
1. Acting Surgeon General Issues call to action to prevent deep vein thrombosis and pulmonary embolism. Press release of the Office of the Surgeon General, September 15, 2008. 2. Laporte S, Mismetti P, Decousus H, et al. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry. Circulation 2008; 117:1711-1716. 3. Torbicki A, Perrier A, Konstantinides SV. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008; 29:2276-2315. 4. Zhou WZ, Shi HB, Yang ZQ, Liu S, Zhou CG, Zhao LB, Xia JG, Feng YL, Li LS. Value of percutaneous catheter fragmentation in the management of massive pulmonary embolism. Chin Med J (Engl). 2009; 5: 122(15):1723-1727. 5. Victor F., Tapson M.D. Acute Pulmonary Embolism. N Engl J Med 2008; 358:1037-1052. 6. Lewсzuk J., Piszko P., Jacek J., Porada A.,Wojciak S., Sobkowiez B., Wrabec K. Prognostic factors in medically treated patients with chronic pulmonary embolism. Chest 2001;119:818-823. 7. Pollack C. V., Schreiber D., Goldhaber S. Z., Slattery D., Fanikos J., O’Neil B.J., Thompson J.R., Hiestand B., Briese B.A., Pendleton R.C., Miller C.D., Kline J.A. Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department: initial report of EMPEROR (Multicenter Emergency Medicine PulmonaryEmbolism in the RealWorld Registry). J AmColl Cardiol; 2011: 57( 6) :700–706. 8. Engelberger R. P., Kucher N. Ultrasound-assisted thrombolysis for acute pulmonary embolism: a systematic review. Eur Heart J;2014: 35(12): 758–764. 9. Jimenez D., Aujesky D., Moores L., Gomez V., Lobo J. L., Uresandi F., Otero R., Monreal M., Muriel A., Yusen R. D. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med; 2010: 170(15):1383–1389. 10. Mitchell J.D, Manasa S. M., Evan J. P. Bleeding risk with systemic thrombolytic therapy for pulmonary embolism: scope of the problem. Ther Adv Drug Saf. 2015 Apr; 6(2): 57–66. 11. Schmitz-Rode T, Janssens U., Duda S., et al. Massive pulmonary embolism: percutaneous emergency treatment by pigtail rotation catheter. JACC 2000; 2 (36):375-80. 12. Karpenko А., Klevanets J, Mironenko S, et al. Right vetricular myocardial function in acute pulmonary embolism patients before and after thrombolitic therapy. Cardiology 2014; 5: 29 – 32. 13. Miller GA, Sutton GC, Kerr IH, et al. Comparison of streptokinase and heparin in treatment of isolated acute massive pulmonary embolism. BMJ 1971; 2:681-684 14. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Prognostic role of echocardiography among patients with acute pulmonary embolism and a systolic arterial pressure of 90 mm Hg or higher. Arch Intern Med 2005; 165(15):1777–1781. 15. Avgerinos ED, Chaer RA. Catheter-directed interventions for acute pulmonary embolism Vasc. Surg. J 2015 Feb;61(2):559-605.
EP
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
References:
AC C
1
12
ACCEPTED MANUSCRIPT
35 36 37
RI PT
SC
M AN U
TE D
29 30 31 32 33 34
EP
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
16. Coutance G, Cauderlier E, Ehtisham J, et al. The prognostic value of markers of right ventricular dysfunction in pulmonary embolism: a meta-analysis. Crit Care 2011;15(2):103 17. Kanter DS, Mikkola KM, Patel SR, et al. Thrombolytic therapy for pulmonary embolism. Frequency of intracranial hemorrhage and associated risk factors. Chest 1997; 111(5):1241–1245. 18. Chatterjee S., Chakraborty A., Weinberg I., Kadakia M., Wilensky R., Sardar P., et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA 2014; 311: 2414–2421. 19. Lang IM, Pesavento R, Bonderman D, Yuan JX. Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding. Eur Respir J 2013;41(2):462– 468. 20. Kuo WT., Gould MK, Louie JD, et al. Catheter-directed Therapy for the Treatment of Massive Pulmonary Embolism: Systematic Review and Meta-analysis of Modern Techniques. J Vasc Interv Radiol 2010; 11(21):1774-1776 21. Kucher N, Goldhaber SZ. Mechanical catheter intervention in massive pulmonary embolism: proof of concept. Chest. 2008;134:2–4. 22. Kuo W.T., van den Bosch M.A., Hofmann L. V., Louie J. D., MD; Kothary N.,. Sze D.Y. Catheter-directed embolectomy, fragmentation, and thrombolysis for the treatment of massive pulmonary embolism after failure of systemic thrombolysis. Chest. 2008;134(2):250-254. 23. Marshall P.S., Matthews K.S., Siegel M.D. Diagnosis and Management of Life-Threatening Pulmonary Embolism. J Intensive Care Med. 2011; 26: 275-294. 24. Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ, Jenkins JS, Kline JA, Michaels AD, Thistlethwaite P, Vedantham S, White RJ, Zierler BK. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123:1788–1830. 25. Barbosa MA, Oliveira DC, Barbosa AT, Pavanello R, Kambara A, Egito ES, Romano ER, Pinto IM, Sousa JE, Piegas LS. Treatment of massive pulmonary embolism by percutaneous fragmentation of the thrombus. Arq Bras Cardiol. 2007;88:279–284. 26. Lin PH, Annambhotla S, Bechara CF, Athamneh H, Weakley SM, Kobayashi K, Kougias P Comparison of percutaneous ultrasound-accelerated thrombolysis versus catheter-directed thrombolysis in patients with acute massive pulmonary embolism. Vascular. 2009;17(suppl 3):S137–S147.
AC C
1 2 3 4 5 6 7
38 39 40 13
ACCEPTED MANUSCRIPT
Group 1
Group 2
(N=102)
(N=107)
52 (51%)/ 50 (49%)
58 (54%)/49 (46%)
0.64
Average age (years)
57±15.7
55±15.5
0.35
Admission to hospital (days)
4,7±4,4
RI PT
Table 1 The patients’ demographic and clinical characteristics Parameters
5,1±4,3
0.13
30 (28%)
0.68
2 (1.8%)
0.96
25,2±3,1
0.25
107 (100%)
NA
Gender (M/F)
Floating thrombi in IVC system
26 (25%)
The implantation of IVC filters
2 (1.9%)
Miller score
26,5±2,25
Signs of RV dysfunction
Group 1
Group 1
Before intervention (n=102)
Heart rate
99.9±12.7
Systolic BP
88.3±4.5
3
82.9±1.9
p
5 days after intervention (n=102)
Group 2
p
Group 2
Before 5 days after intervention intervention (n=107) (n=107)
79±2.9
0.001
100±13.1
78.7±3.9
0.001
121±7.9
0.001
89±4.8
122±8.9
0.001
0.001
81.9±1.8
99.7±0.5
0.001
TE D
Parameters
Oxygen saturation
99±0.7
Table 3 EchoСG right heart parameters before and in 5 days after treatment Group 1 5 days after intervention (n=102)
p
Group 2 before intervention (n=107)
Group 2 5 days after intervention (n=107)
p
4,7±0,6 3,64±0,63 40,7±11,6 1,3±0,4 40,9±14,1
3.8±0,5 2,8±0,4 50±10,4 2±0,1 24,5±8
0.01 0.01 0.01 0.01 0.001
4.6±0,62 3.5±0.7 41.1±10.7 1.4±0.34 39±12.6
3.7±0.5 2.7±0.4 51.6±8.7 2±0.3 23.5±8
0.01 0.01 0.01 0.01 0.001
102 (100%)
72 (70.6%)
0.001
107 (100%)
65 (61%)
0.001
EP
EchoСG parameters
Group 1 before intervention (n=102)
AC C
4
p
Table 2 Dynamics of heart rate, systolic BP and oxygen saturation in patients with massive PE
M AN U
2
102 (100%)
SC
1
RA, cm RV EDD, cm RV EF, % TAPSE, cm Average PA pressure, mmHg Signs of RV dysfunction
14
ACCEPTED MANUSCRIPT Table 4 APG parameters before and in 5 days after treatment Group 1
Before intervention (n=102)
5 days after intervention (n=102)
38,8±11,2
24,1±9
54,5±20,3
Average PA pressure, mmHg RV pressure, mmHg RA pressure, mmHg The Miller score, points
p
Group 2
Group 2
Before intervention (n=107)
5 days after intervention (n=107)
0.0001
37±10.3
21.5±8.6
0.0001
36,1±16,6
0.003
52.9±18.2
34±14.9
0.003
17,7±6,9
11,2±5,5
0.003
16.1±6.3
10.9±5.8
0.005
26,5±2,25
16,4±4,0
0.001
25,2±3,1
14.3±4.9
0.001
2
Signs of RV dysfunction Average pressure in PA > 25 mm Hg 5
Group 1 before intervention (n=102) 102 (100%)
M AN U
EchoCG signs of RV dysfunction
4
p
Table 5 Dynamics of EchoCG signs of RV dysfunction in patients with massive PE after 6 months Group 1 6 months after intervention (n=92) 9 (9.8%)
TE D
3
RI PT
Invasive parameter
Group 1
SC
1
102 (100%)
9 (9.8%)
p
Group 2 Group 2 before 6 months after intervention intervention (n=107) (n=102)
0.0001
107 (100%)
3 (2.9)%
0.0001
0.0001
107 (100%)
3 (2.9%)
0.0001
Fig.1 Patient C. APG before CDF with LTT. Massive PE (Miller score 31).
7
Fig.2. Patient C. APG in 5 days after CDF with LTT (Miller score 16).
8
Fig. 3. Kaplan- Meier curves showing survival function in the patients of both groups.
AC C
EP
6
9
p
15
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S0890-5096(17)30688-X
DOI:
10.1016/j.avsg.2017.05.003
Reference:
AVSG 3385
To appear in:
Annals of Vascular Surgery
Received Date: 22 March 2017 Revised Date:
2 May 2017
Accepted Date: 2 May 2017
Please cite this article as: Klevanets J, Starodubtsev V, Ignatenko P, Voroshilina O, Ruzankin P, Karpenko A, Systemic Thrombolytic Therapy and Catheter-directed Fragmentation with Local Thrombolytic Therapy in Patients with Pulmonary Embolism, Annals of Vascular Surgery (2017), doi: 10.1016/j.avsg.2017.05.003. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1 2
Systemic Thrombolytic Therapy and Catheter-directed Fragmentation with Local
3
Thrombolytic Therapy in Patients with Pulmonary Embolism
4
Julia Klevanets, Vladimir Starodubtsev, Pavel Ignatenko,
6
Olga Voroshilina, Pavel Ruzankin*, Andrey Karpenko
7
Academician E.N. Meshalkin Novosibirsk State Budget Research Institute of Circulation Pathology”,
8
Ministry for Public Health Care Russian Federation Novosibirsk, Russian Federation
SC
9
RI PT
5
*The Sobolev Institute of Mathematics SB RAS, Novosibirsk State University
11
M AN U
10
Corresponding author:
13
Vladimir Starodubtsev, Academician E.N. Meshalkin Novosibirsk State Budget Research
14
Institute of Circulation Pathology”, Ministry for Public Health Care Russian Federation,
15
630055, Novosibirsk, Rechkunovsky str., 15
16
Email: [email protected]
17
Funding
18
This research received no specific grant from any funding agency in the public, commercial,
20 21
EP
or not-for-profit sectors.
AC C
19
TE D
12
Conflict of interest None declared.
22 23 24 1
ACCEPTED MANUSCRIPT Abstract
2
The objective was to compare immediate and long-term results of systemic thrombolytic therapy
3
(STT) and catheter-directed fragmentation (CDF) with local thrombolytic therapy (LTT) in patients
4
with massive pulmonary embolism (PE).
5
Methods:
6
209 patients with massive PE (the high risk of early death) were included in our study. From 2008 till
7
2010 in the first group (n=102) STT was performed. From 2011 till 2013 in the second group
8
(n=107) CDF with LTT was carried out. Echocardiography and pulmonary arteriography were
9
performed in all patients on admission to hospital and in 5 days after treatment. The patients of both
SC
RI PT
1
groups were re-examined in 6 months, 1, 2, 3 years after the operation.
11
Results:
12
In the first group there were 5 (4.9%) cases of in-hospital 30-day mortality. In the second group there
13
was 1 (0.9%) case of in-hospital 30-day mortality (p=0.08). In the first group a clinically significant
14
bleeding was noted in 4 (3.9 %) cases, but it caused mortality only in one case. In the second group
15
clinically significant bleeding was not found (p=0.038). Persistent postembolic pulmonary
16
hypertension (PPPH) in 9.8% cases of patients in the first group and 2.9% cases of patients in the
17
second group was determined (p=0.048).
18
Conclusions:
19
CDF combined with LTT is an effective minimal invasive treatment (helped us to reduce significantly the number of bleeding and PPPH cases), at least in the mid-term, in patients with massive PE.
22 23
TE D
EP
21
AC C
20
M AN U
10
24
Keywords
25 26
Pulmonary embolism, right ventricular dysfunction, heart failure, endovascular mechanical fragmentation, thrombolytic therapy
2
ACCEPTED MANUSCRIPT 1
Introduction
2
Acute pulmonary embolism (APE) is a frequent cause of death or severe disability1. About
3
10% of all patients with APE die within 3 months of being diagnosed2. Patients with a confirmed diagnosis of PE with persistent arterial hypotension and/or
5
cardiogenic shock, and hemodynamically stable patients manifesting echocardiographic signs of
6
Right Ventricle dysfunctions (RVD) have a high risk of early death and should undergo
7
pharmacological reperfusion therapy. An interventional approach combined with local thrombolytic
8
therapy (LTT) can be used as an alternative to systemic thrombolytic therapy (STT). 3
RI PT
4
Early recanalization of obstructed pulmonary arteries leads to a rapid reduction of resistance
10
and pressure in the pulmonary artery (PA) and the improvement of RV function4. Besides, survival
11
depends on effectiveness and rapid recanalization of the pulmonary arterial occlusion and the
12
reduction of the right ventricular afterload.5 At pulmonary artery pressure 40 -50 mm Hg the five-
13
year survival is 40%, at more expressed pulmonary hypertension it is only 10 %. 6
M AN U
SC
9
However, when choosing treatment tactics it is necessary to evaluate the risk of hemorrhagic
15
complications caused by the thrombolytic therapy, taking into account the high risk of early death in
16
these patients due to development of RV dysfunction, which is commonly accompanied by a drop in
17
systemic hemodynamics.7 A major issue with STT is associated with the risk of massive bleeds, as
18
well as intracranial hemorrhage. The frequency of intracranial hemorrhages ranges between 1.8% to
19
about 2.2 % 8,9 depending on choice of thrombolytic agents and dosing regiments and can reach up to
20
3% with increased age and presence of comorbidities10.
22
The objective of the study was to compare immediate and long-term results of STT and catheter directed fragmentation (CDF) with LTT in patients with massive PE.
EP
21
TE D
14
Methods
24
We prospectively enrolled consecutive 209 patients with APE and persistent arterial
AC C
23
25
hypotension and/or cardiogenic shock treated in the Division of vascular and Endovascular Surgery
26
at the Academician E.N. Meshalkin Novosibirsk State Budget Research Institute of Circulation
27
Pathology, Ministry for Public Health Care Russian Federation into a database. Our study was
28
approved by Local Ethics Committee of Academician E.N. Meshalkin Novosibirsk State Budget
29
Research Institute of Circulation Pathology, Ministry for Public Health Care of Russian Federation
30
and all patients entered the study after the procedure of informed consent.
3
ACCEPTED MANUSCRIPT Patients’
1
medical
history,
dynamic
clinical
status
assessment,
echocardiography,
angiopulmonography (APG) were performed upon admission and 5 days after treatment. Evaluation
3
of the functional state of the heart was done by transthoracic Echocardiography upon admission and 5
4
days and 6 months after treatment. We analyzed echocardiographic signs of RV dysfunction and the
5
systolic function of the right and left ventricles (RV, LV). All of the patients were monitored for measurements of heart rate; systolic, diastolic, and
6 7
RI PT
2
mean systemic blood pressures; and oxygen saturation with a pulse oximeter.
APG was performed in all patients with massive PE before treatment and 5 days after it. Then
9
systolic and average PA pressures were measured. Selective angiography was performed (flow rate
10
12–15 ml/s, injected volume 25–35 ml).
All patients underwent right heart catheterization with tensiometry of the pulmonary circuit
11
followed by APG (before treatment and 5 days after it).
M AN U
12
SC
8
The patients were subdivided into two groups. From 2008 till 2010 in the first group (n=102)
14
systemic thrombolytic therapy (STT) was performed. The recombinant tissue plasminogen activator
15
(rt-PA) was administered as a 10 mg bolus via central line and 90 mg continuous infusion over 2
16
hours (not to exceed 1.5 mg/kg if weight of patients was less than 65 kg). After systemic
17
thrombolytic therapy within the first 24 hrs all patients received heparin sodium at a dose 1,000 IU/h
18
to reach the increase of activated partial thromboplastin time to 1.5-2 times from the reference range.
19
The frequency of clinically significant bleeding in the first group (n=102) was high (4 cases (3.9%),
20
three of them - intracranial hemorrhages). We have decided to apply catheter directed fragmentation
21
(CDF) with LTT (reduce the dose of thrombolytic agents).
TE D
13
From 2011 till 2013 in the second group (n=107) CDF with LTT was performed. A 6-French
23
short sheath was inserted in the jugular vein. A guidewire and a conventional 6-French Pigtail
24
catheter for APG were advanced into PA. No patients were treated with systemic thrombolysis after
25
2011.
27 28
AC C
26
EP
22
After that patients underwent major-vessel pulmonary artery thromboembolic endovascular
mechanical fragmentation with a Pigtail catheter with LTT (Schmitz—Rode).11 During CDF with LTT the thrombolytic drug (rt-PA) was injected via the catheter deep into
29
the thrombus.12 The distal ends of the guidewire and the catheter were placed in the site of the
30
thrombus. The guidewire was remained in the peripheral PA, Pigtail catheter was advanced to a
31
central portion of PA. The catheter was spun quickly, so that the distal curve served as a rotor blade 4
ACCEPTED MANUSCRIPT 1
to fragment the thrombus. Our strategy was to fragment the largest central thrombi and restore
2
pulmonary flow without necessarily seeking to fragment thrombi located in segmental branches. During mechanical fragmentation, 50 mg of rt-PA was injected into embolus through catheter
4
(0.5-1 mg/kg by transcatheter intra-PA bolus infusion for 7-8 minutes, not to exceed 50 mg). Within
5
the first 24 hrs on embolus fragmentation completion all patients received heparin sodium at a dose
6
1,000 IU/h to reach the increase of activated partial thromboplastin time to 1.5-2 times from the
7
reference range.
RI PT
3
Low-molecular-weight heparins (nadroparin calcium or enoxaparin sodium) and, if there were
9
no contraindications, indirect acting anticoagulant (warfarin) were added to anticoagulation therapy
10
on the second postoperative day in both groups. The efficacy of the therapy in both groups was
11
estimated by APG with tensiometry in pulmonary circuit, as well as echocardiography.
SC
8
Inclusion and exclusion criteria
13
The inclusion criterion into the study was angiographic confirmation of massive PE with a
14
Miller score13 ≥ 22 (the patients with massive PE in the presence persistent arterial hypotension
15
and/or cardiogenic shock).
16
Exclusion
M AN U
12
criteria were hemodynamically stable condition
of
patients
(lack of
echocardiographic signs of RV dysfunction), chronic pulmonary thromboembolism, concomitant
18
broncho-pulmonary disease, renal failure (creatinine clearance < 30 ml/min), ischemic stroke which
19
took place less than 2 months before the study, open surgery up to 3 months earlier, anemia
20
(hemoglobin less than 90g/l) and gastro-duodenal ulcers less than 30 days prior to the study.
22 23 24
Diagnosis verification for all patients was based on APG. To determine the source of PE we used triplex ultrasound screening (TUS) of lower extremity and pelvic veins. The time from the onset of clinical symptoms to admission to the clinic ranged from 1 to 10
EP
21
TE D
17
days and, on average, was 5.0 ±4.2 days . All patients were admitted to the intensive care unit, due to presence of severe respiratory
26
disease and heart failure. Ten (9.8%) patients of the first group and 9 (8.4%) patients of the second
27
group (Fig.1) received mechanical ventilation and positive inotropic support before treatment
28
(p=0.73). The patients were kept on intensive care unit for at least 48 h. Systemic blood pressure,
29
heart rate were recorded pre- and post- (48 hours) CDF with LTT.
30
AC C
25
The immediate results of STT and CDF with LTT were analyzed from the point of view of
31
early 30-day mortality. In addition, we analyzed the changes in echocardiographic evidence of RV
32
dysfunction and its impact on prognosis and disease outcome in early observation periods (5 days).
5
ACCEPTED MANUSCRIPT 1
Efficiency criteria of STT and CDF with LTT were positive dynamics in clinical status
2
(stabilization of BP, relief of shortness of breath, chest pain, tachycardia, hemoptysis); the reduction
3
of PA pressure according to echocardiography and cardiac catheterization; perfusion obstruction
4
score reduction (Miller index); decrease or relief of the echocardiographic signs of RV dysfunction.
5
The patients of both groups were re-examined in 6 months, 1, 2, 3 years after the operation. Statistical analysis
7
In the paper the quantitative data are presented as a mean and standard deviation (SD). During
8
our investigation for testing the statistical hypothesis, the significance level of 0.05 was selected.
9
Pair-wise comparisons were made with application of Mann–Whitney U test. Qualitative characters
10
were compared with the usage of Pearson`s chi-squared test or Fisher’s Exact test. Outcome
11
probability (mortality) assessment during the study period was conducted by Kaplan – Meier
12
duplicate measurements. To perform calculations we used the statistical package MedCalc v15.2.2.
SC
Results Floating thrombi in the inferior vena cava (IVC) system were detected in 56 (27%) patients.
M AN U
13 14 15
RI PT
6
Before thrombolysis the implantation of a removable IVC filters was performed in 4 (1.9%) patients.
17
The patients’ demographic and clinical characteristics of both groups are shown in Table 1. Table 1 The patients’ demographic and clinical characteristics
18
Significant differences in demographic details, the time from the occurrence of clinical
16
symptoms to admission to hospital baseline, Miller score (MS) in groups were not found.
TE D
19
Analysis of immediate results of STT and CDF with LTT showed a positive trend in patient
21
clinical condition. So the decrease of clinical manifestations of acute respiratory failure in the early
22
period was observed in 97 (95%) patients of the first group and 107 (100%) patients of the second
23
group (Fig.2). Hemoptysis, chest pain, resting shortness of breath were eliminated in all patients of
24
both groups upon discharge. After STT and CDF with LTT a stabilization of systemic blood pressure
25
(BP) and a statistically significant decrease in heart rate were noted in the both groups.
EP
20
27
and in 5 days after CDF with LTT are presented table 2. Table 2 Dynamics of heart rate, systolic BP and oxygen saturation in patients with massive
28 29 30
AC C
Dynamics of heart rate, systolic BP and oxygen saturation in patients with massive PE before
26
PE
While
performing
transthoracic
echocardiography
we
evaluated
not
only
the
31
Echocardiographic criteria of RV dysfunction and RV systolic function (RV EF, TAPSE), but also
32
linear indicators of the right heart, average PA pressure, TAPSE at baseline and in 5 days after STT 6
ACCEPTED MANUSCRIPT and CDF with LTT (both groups). The data are presented in table 3. Table 3 shows a significant
2
decrease in right heart size during the early postoperative period compared to baseline EchoCG
3
measurements in both groups. Besides, Table 3 contains data demonstrating a significant
4
improvement in RV systolic function and an increase in tricuspid annular plane systolic excursion
5
(TAPSE) during the early postoperative period, as well as a significant decrease of average PA
6
pressure.
8 9 10
Table 3 EchoСG right heart parameters before and in 5 days after treatment
According to APG and pulmonary circuit tensiometry patients with massive PE had not only the massive thromboemboli in PAs, but also elevated PA average pressures in RA and RV. APG
SC
7
RI PT
1
parameters of the pulmonary circuit before and in 5 days after treatment are presented in table 4. Table 4 APG parameters before and in 5 days after treatment
12
Table 4 shows that in both groups there was not only an improvement of the pulmonary
13
circuit upon APG, but also a significant decrease of PA average pressure according to direct
14
tensiometry of RA and RV in the early postoperative period.
M AN U
11
Before treatment the strong correlation between the average PA pressure estimate obtained
16
noninvasively (EchoСG) versus invasively (APG) in the 1st group and second group was r=0.79,
17
r2=0.56, p=0.001 and r=0.85, r2=0.59, p=0.001, respectively.
TE D
15
In 5 days after treatment the strong correlation between the average PA pressure estimate
19
obtained noninvasively (EchoСG) versus invasively (APG) in the 1st group and second group was
20
r=0.81, r2=0.53, p=0.001 and r=0.84, r2=0.57, p=0.001, respectively.
22 23 24 25
During our investigation there were 6 (2.8%) cases in-hospital 30-day mortality (5 (4.9%)
AC C
21
EP
18
patients in the first group and 1 (0.9%) patient in the second group, p=0.08): -
five of them (four (3.9%) cases in the first group and one (0.9%) case in the second group) were patients who were admitted in critical condition with persistent hypotension and did not survive despite cardiotonic support. The reason of mortality in these cases was the
26
progression of cardiovascular and respiratory failure caused by the recurrence of
27
thromboembolism.
7
ACCEPTED MANUSCRIPT -
1
the last case of the mortality (the patient of the first group) was connected with clinically significant bleeding. The 79 year old patient with systemic hypotension died due to the
3
development of a subdural hematoma (the result of intracranial hemorrhage) in the left
4
frontotemporal region and an intracerebral hematoma of the left occipital lobe. Our
5
attempts to treat the intracranial hematomas were not successful.
RI PT
2
6
Summing up the data concerning the bleeding cases, except the above mentioned case that led
7
to the mortality, there were more 3 cases in the first group (two of them - intracranial hemorrhages) .
8
Conservative nootropic and antihypoxic therapy in the cases was effective.
So only in the first group (STT) a clinically significant bleeding was noted in 4 (3.9 %) cases,
10
but it caused mortality only in one case. In the second group clinically significant bleeding was not
11
found (p=0.038).
M AN U
SC
9
12
Performing STT and CDF with LTT promotes clinical stabilization of patients, restoration of
13
RV function and normalization of PA pressure in most patients, thereby, lowering the functional
14
class (FC) of Pulmonary Hypertension and increasing the survival rate in the early observation
15
period.
17
treatment and leads to RV systolic function disruption. The data are presented in table 5. Table 5 Dynamics of EchoCG signs of RV dysfunction in patients with massive PE after 6
18
months
EP
19
TE D
We analyzed EchoCG parameters which indicate RV dysfunction that persists 6 months after
16
Table 5 shows a significant decrease in the frequency of occurrence of the EchoCG signs of
21
RV dysfunction and average pressure in PA in the postoperative period (6 months) in groups,
22
indicating the regression of right ventricular failure due to massive PE.
23
AC C
20
In six months persistent postembolic pulmonary hypertension (PPPH) caused by chronic
24
obstruction of the main PA branches (average pressure in PA >25 mm Hg) was determined in 9
25
(9.8%) cases (92 patients observed) of the first group and in 3 (2.9%) cases (102 patients observed)
26
of the second group (p=0.048).
8
ACCEPTED MANUSCRIPT 1
During the follow-up (36 months), one patient of the first group (after 25 months) and two
2
patients of the second group (after 6 and 12 months) died. The cause of death in the groups is not
3
associated with PE (p=0.6). Kaplan- Meier curves showing survival function in the patients of both groups are represented
5
in Fig. 3. The survival function in the patients at 36 months was 92.5% in the first group and 98% in
6
the second group, respectively. No significant difference was found out in the groups (p=0.1).
7
Discussion The main purpose of using thrombolytic therapy in massive PE cases is to restore rapidly blood flow in branches of PA, normalize PA pressure in the right heart and improve RV function.14 Patients in shock and/or hypotension represent a distinct clinical problem, given a much higher early mortality rate that serves as the basis for immediate reperfusion therapy. Patients with massive PE should undergo emergency reperfusion in case of an early onset of hemodynamic decompensation. 15,16 Widespread use of thrombolytic agents is still limited due to the high risk of hemorrhagic complications in up to 13 % of cases, including fatal ones in 1.8% -2.2 %.17,18 Older age and presence of comorbidities are associated with a higher risk of bleeding complications.18 High risk of clinically significant bleeding and intracranial hemorrhages is the main limiting factor for use of thrombolytic therapy in patients with massive PE. In our study there were 4 cases clinically significant bleeding in the first group (three of them - intracranial hemorrhages). Persistent postembolic pulmonary hypertension (PPPH) which results from chronic obstruction of the main PA branches can reach up to 9.1 % and is a debilitating disease which often occurs in adults of working age.19 EchoCG signs of RV dysfunction (arterial hypotension and/or cardiogenic shock) were observed in all patients of our study. In the current study the use of STT and CDF with LTT improves RV function in the postoperative period (after 6 months RV dysfunction signs and PPPH were observed in 9 (9.8%) cases of the first group (STT) and in 3 (2.9%) cases of the second group (CDF with LTT), p=0.048. In 5 days STT and CDF with LTT leads to a significant decrease of average PA pressure according to data obtained by the noninvasive (EchoСG) and invasive (APG) methods. Besides, direct tensiometry (APG) shows the decrease of invasive pressure in RA and RV in both groups. It is important to underline that in the first group (STT) there were 5 (4.9%) cases of inhospital 30-day mortality and in the second group there was only one case (0.9%). The cause of mortality in five of them was the progression of cardiovascular and respiratory failure. The sixth case of death (first group) was connected with clinically significant bleeding. The clinically significant bleeding was noted in 4 (3.9%) cases in the first group, but it caused mortality only in one case in the
13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
SC
12
M AN U
11
TE D
10
EP
9
AC C
8
RI PT
4
9
ACCEPTED MANUSCRIPT
7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
RI PT
6
SC
5
M AN U
4
TE D
3
EP
2
first group. The percentage datum in the second group is more lower (0 cases) than in other conducted studies (2.2%).18 However in six months PPPH in 9.8% of patients in the first group and 2.9% of patients in the second group (p=0.048) was determined. Before the treatment those patients of both groups had recurrent PE in anamnesis (the time from the onset of clinical symptoms to admission to the clinic ranged from 8 to 10 days), that might be one of reasons of PPPH. It is important to underline that CDF with LTT helped us to reduce significantly the number of PPPH cases. Reports from the literature20,21 demonstrate that catheter fragmentation facilitates at least partial recanalization of a central embolic occlusion. Moreover, the increased total surface area of the fragments may accelerate the efficacy of an accompanying thrombolysis. The rotational movement of the pigtail portion of the catheter acts directly on the clots in the pulmonary arteries, causing fragmentation and distal migration of the smaller fragments. The volume of the peripheral pulmonary arteries is approximately twice that of the central pulmonary arteries. Therefore, redistribution of a large central clot may acutely improve cardiopulmonary hemodynamics.21,22 Nowadays thrombolytic therapy still remains the gold standard in treatment of massive pulmonary embolism.23,24 The few reports25,26 of treatment of massive pulmonary thromboembolism using mechanical fragmentation combined with thrombolytic therapy have all indicated that the treatment results in rapid hemodynamic improvement. Moreover, an interventional approach combined with local thrombolytic therapy (LTT) can be used as an alternative to STT. Our technique CDF with LTT offers a possible synergistic effect with concurrent thrombolytic therapy because the resulting clot fragments have a greater surface area exposed to the thrombolytic agent, thus improving the results of lytic activity and allowing a reduction of dose and infusion time (the mean infusion time of rt-PA was 7-8 minutes). Besides, our technique allows reducing the frequency of hemorrhage complications (because of the reduction of thrombolytic agent dose). In our study it has been established that CDF with LTT is a safe and effective treatment for patients with massive PE (high risk of early death). This method helps not only to improve pulmonary circuit perfusion, to reduce pressure in PA and the right heart, but also to restore RV function in the postoperative period (to reduce significantly the number of PPPH cases). Our study has some important limitations. This was a prospective nonrandomized study in a referral center where many patients are from different regions of Russia; thus, consistent follow-up is difficult. Nevertheless, all patients who returned for follow-up in 1 year or later were examined to assess medium-term results and survival at 3 years. No doubt longer follow-up is ideal and may reveal data that could alter our current conclusions. Oxygen saturation was analyzed without taking into account the amount of the oxygen required to maintain it higher than 90%.
AC C
1
10
ACCEPTED MANUSCRIPT
2 3 4 5 6 7 8 9 10
The follow up average PA pressure estimate in 6 months was based on echo criteria and compared to preoperative criteria also obtained by echo. In 6 months the average PA pressure was not measured invasively (APG). Conclusion STT or CDF combined with LTT promote stabilization of the clinical state of patients and stops RV dysfunction while restoring patency of PA and reducing or normalizing pulmonary artery pressure in patients with massive PE. CDF combined with LTT is an effective minimal invasive treatment (helped us to reduce significantly the number of bleeding and PPPH cases), at least in the mid-term, in patients with massive PE.
RI PT
1
16
M AN U
15
TE D
14
EP
13
Funding This research received no specific grant from any funding agency in the public, commercial, or nonprofit sectors. Conflict of interest None declared.
AC C
12
SC
11
11
ACCEPTED MANUSCRIPT
TE D
M AN U
SC
RI PT
1. Acting Surgeon General Issues call to action to prevent deep vein thrombosis and pulmonary embolism. Press release of the Office of the Surgeon General, September 15, 2008. 2. Laporte S, Mismetti P, Decousus H, et al. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry. Circulation 2008; 117:1711-1716. 3. Torbicki A, Perrier A, Konstantinides SV. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008; 29:2276-2315. 4. Zhou WZ, Shi HB, Yang ZQ, Liu S, Zhou CG, Zhao LB, Xia JG, Feng YL, Li LS. Value of percutaneous catheter fragmentation in the management of massive pulmonary embolism. Chin Med J (Engl). 2009; 5: 122(15):1723-1727. 5. Victor F., Tapson M.D. Acute Pulmonary Embolism. N Engl J Med 2008; 358:1037-1052. 6. Lewсzuk J., Piszko P., Jacek J., Porada A.,Wojciak S., Sobkowiez B., Wrabec K. Prognostic factors in medically treated patients with chronic pulmonary embolism. Chest 2001;119:818-823. 7. Pollack C. V., Schreiber D., Goldhaber S. Z., Slattery D., Fanikos J., O’Neil B.J., Thompson J.R., Hiestand B., Briese B.A., Pendleton R.C., Miller C.D., Kline J.A. Clinical characteristics, management, and outcomes of patients diagnosed with acute pulmonary embolism in the emergency department: initial report of EMPEROR (Multicenter Emergency Medicine PulmonaryEmbolism in the RealWorld Registry). J AmColl Cardiol; 2011: 57( 6) :700–706. 8. Engelberger R. P., Kucher N. Ultrasound-assisted thrombolysis for acute pulmonary embolism: a systematic review. Eur Heart J;2014: 35(12): 758–764. 9. Jimenez D., Aujesky D., Moores L., Gomez V., Lobo J. L., Uresandi F., Otero R., Monreal M., Muriel A., Yusen R. D. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med; 2010: 170(15):1383–1389. 10. Mitchell J.D, Manasa S. M., Evan J. P. Bleeding risk with systemic thrombolytic therapy for pulmonary embolism: scope of the problem. Ther Adv Drug Saf. 2015 Apr; 6(2): 57–66. 11. Schmitz-Rode T, Janssens U., Duda S., et al. Massive pulmonary embolism: percutaneous emergency treatment by pigtail rotation catheter. JACC 2000; 2 (36):375-80. 12. Karpenko А., Klevanets J, Mironenko S, et al. Right vetricular myocardial function in acute pulmonary embolism patients before and after thrombolitic therapy. Cardiology 2014; 5: 29 – 32. 13. Miller GA, Sutton GC, Kerr IH, et al. Comparison of streptokinase and heparin in treatment of isolated acute massive pulmonary embolism. BMJ 1971; 2:681-684 14. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Prognostic role of echocardiography among patients with acute pulmonary embolism and a systolic arterial pressure of 90 mm Hg or higher. Arch Intern Med 2005; 165(15):1777–1781. 15. Avgerinos ED, Chaer RA. Catheter-directed interventions for acute pulmonary embolism Vasc. Surg. J 2015 Feb;61(2):559-605.
EP
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40
References:
AC C
1
12
ACCEPTED MANUSCRIPT
35 36 37
RI PT
SC
M AN U
TE D
29 30 31 32 33 34
EP
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
16. Coutance G, Cauderlier E, Ehtisham J, et al. The prognostic value of markers of right ventricular dysfunction in pulmonary embolism: a meta-analysis. Crit Care 2011;15(2):103 17. Kanter DS, Mikkola KM, Patel SR, et al. Thrombolytic therapy for pulmonary embolism. Frequency of intracranial hemorrhage and associated risk factors. Chest 1997; 111(5):1241–1245. 18. Chatterjee S., Chakraborty A., Weinberg I., Kadakia M., Wilensky R., Sardar P., et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA 2014; 311: 2414–2421. 19. Lang IM, Pesavento R, Bonderman D, Yuan JX. Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding. Eur Respir J 2013;41(2):462– 468. 20. Kuo WT., Gould MK, Louie JD, et al. Catheter-directed Therapy for the Treatment of Massive Pulmonary Embolism: Systematic Review and Meta-analysis of Modern Techniques. J Vasc Interv Radiol 2010; 11(21):1774-1776 21. Kucher N, Goldhaber SZ. Mechanical catheter intervention in massive pulmonary embolism: proof of concept. Chest. 2008;134:2–4. 22. Kuo W.T., van den Bosch M.A., Hofmann L. V., Louie J. D., MD; Kothary N.,. Sze D.Y. Catheter-directed embolectomy, fragmentation, and thrombolysis for the treatment of massive pulmonary embolism after failure of systemic thrombolysis. Chest. 2008;134(2):250-254. 23. Marshall P.S., Matthews K.S., Siegel M.D. Diagnosis and Management of Life-Threatening Pulmonary Embolism. J Intensive Care Med. 2011; 26: 275-294. 24. Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ, Jenkins JS, Kline JA, Michaels AD, Thistlethwaite P, Vedantham S, White RJ, Zierler BK. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123:1788–1830. 25. Barbosa MA, Oliveira DC, Barbosa AT, Pavanello R, Kambara A, Egito ES, Romano ER, Pinto IM, Sousa JE, Piegas LS. Treatment of massive pulmonary embolism by percutaneous fragmentation of the thrombus. Arq Bras Cardiol. 2007;88:279–284. 26. Lin PH, Annambhotla S, Bechara CF, Athamneh H, Weakley SM, Kobayashi K, Kougias P Comparison of percutaneous ultrasound-accelerated thrombolysis versus catheter-directed thrombolysis in patients with acute massive pulmonary embolism. Vascular. 2009;17(suppl 3):S137–S147.
AC C
1 2 3 4 5 6 7
38 39 40 13
ACCEPTED MANUSCRIPT
Group 1
Group 2
(N=102)
(N=107)
52 (51%)/ 50 (49%)
58 (54%)/49 (46%)
0.64
Average age (years)
57±15.7
55±15.5
0.35
Admission to hospital (days)
4,7±4,4
RI PT
Table 1 The patients’ demographic and clinical characteristics Parameters
5,1±4,3
0.13
30 (28%)
0.68
2 (1.8%)
0.96
25,2±3,1
0.25
107 (100%)
NA
Gender (M/F)
Floating thrombi in IVC system
26 (25%)
The implantation of IVC filters
2 (1.9%)
Miller score
26,5±2,25
Signs of RV dysfunction
Group 1
Group 1
Before intervention (n=102)
Heart rate
99.9±12.7
Systolic BP
88.3±4.5
3
82.9±1.9
p
5 days after intervention (n=102)
Group 2
p
Group 2
Before 5 days after intervention intervention (n=107) (n=107)
79±2.9
0.001
100±13.1
78.7±3.9
0.001
121±7.9
0.001
89±4.8
122±8.9
0.001
0.001
81.9±1.8
99.7±0.5
0.001
TE D
Parameters
Oxygen saturation
99±0.7
Table 3 EchoСG right heart parameters before and in 5 days after treatment Group 1 5 days after intervention (n=102)
p
Group 2 before intervention (n=107)
Group 2 5 days after intervention (n=107)
p
4,7±0,6 3,64±0,63 40,7±11,6 1,3±0,4 40,9±14,1
3.8±0,5 2,8±0,4 50±10,4 2±0,1 24,5±8
0.01 0.01 0.01 0.01 0.001
4.6±0,62 3.5±0.7 41.1±10.7 1.4±0.34 39±12.6
3.7±0.5 2.7±0.4 51.6±8.7 2±0.3 23.5±8
0.01 0.01 0.01 0.01 0.001
102 (100%)
72 (70.6%)
0.001
107 (100%)
65 (61%)
0.001
EP
EchoСG parameters
Group 1 before intervention (n=102)
AC C
4
p
Table 2 Dynamics of heart rate, systolic BP and oxygen saturation in patients with massive PE
M AN U
2
102 (100%)
SC
1
RA, cm RV EDD, cm RV EF, % TAPSE, cm Average PA pressure, mmHg Signs of RV dysfunction
14
ACCEPTED MANUSCRIPT Table 4 APG parameters before and in 5 days after treatment Group 1
Before intervention (n=102)
5 days after intervention (n=102)
38,8±11,2
24,1±9
54,5±20,3
Average PA pressure, mmHg RV pressure, mmHg RA pressure, mmHg The Miller score, points
p
Group 2
Group 2
Before intervention (n=107)
5 days after intervention (n=107)
0.0001
37±10.3
21.5±8.6
0.0001
36,1±16,6
0.003
52.9±18.2
34±14.9
0.003
17,7±6,9
11,2±5,5
0.003
16.1±6.3
10.9±5.8
0.005
26,5±2,25
16,4±4,0
0.001
25,2±3,1
14.3±4.9
0.001
2
Signs of RV dysfunction Average pressure in PA > 25 mm Hg 5
Group 1 before intervention (n=102) 102 (100%)
M AN U
EchoCG signs of RV dysfunction
4
p
Table 5 Dynamics of EchoCG signs of RV dysfunction in patients with massive PE after 6 months Group 1 6 months after intervention (n=92) 9 (9.8%)
TE D
3
RI PT
Invasive parameter
Group 1
SC
1
102 (100%)
9 (9.8%)
p
Group 2 Group 2 before 6 months after intervention intervention (n=107) (n=102)
0.0001
107 (100%)
3 (2.9)%
0.0001
0.0001
107 (100%)
3 (2.9%)
0.0001
Fig.1 Patient C. APG before CDF with LTT. Massive PE (Miller score 31).
7
Fig.2. Patient C. APG in 5 days after CDF with LTT (Miller score 16).
8
Fig. 3. Kaplan- Meier curves showing survival function in the patients of both groups.
AC C
EP
6
9
p
15
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT