Thrombolysis in acute pulmonary embolism

Tiago Spiazzi Bottega Marcele Gnata Vier Hugo Baldiaserotto Ellen Pierre de Oliveira Claudia Liliana Moreno Diaz Caio J. Fernandes About the authors

SUMMARY

OBJECTIVES

Acute pulmonary embolism (APE) is an important cause of cardiovascular mortality, due mainly to hemodynamic instability. In these cases, the recommendation is to perform some reperfusion procedure, with systemic thrombolysis being the main therapy used. However, national data evaluating the efficacy and safety of thrombolysis are scarce.

METHODS

Retrospective analysis of a case series. We included 13 patients diagnosed with high-risk APE and 4 patients with intermediate-high risk from a single-center, who were treated with alteplase 100mg.

RESULTS

The mean age of the patients was 55 years, most of them female (76.4%). Among the risk factors for VTE were immobilization (41.17%), contraceptive use (35.29%), cancer (17.63%), and previous history of DVT (11.76%). The most frequent clinical manifestations of APE were dyspnea (88.23%), hypoxia (82.35%), hypotension (82.35%), and tachycardia (64.70%). 82.35% of the patients had echocardiographic signs of right ventricular dysfunction, and 52.94% had increased troponin and BNP. Severe bleeding associated with thrombolysis occurred in 17.54% of cases. No patient died due to bleeding. There were 8 deaths from right ventricular failure (47%), 6 in the cases of patients presenting as high-risk APE (35.3%), and 2 in the cases of intermediate-high risk (11.8%).

CONCLUSION

Thrombolysis in patients with high-risk APE or intermediate-high risk had a severe bleeding rate of 17.6%. However, the high mortality of this population (47%) due to right ventricular failure justifies the use of this therapeutic modality.

Pulmonary embolism; Thrombolytic therapy; Tissue plasminogen activator; Ventricular dysfunction, right

RESUMO

OBJETIVOS

A embolia pulmonar aguda (EAP) é uma causa importante de mortalidade cardiovascular ao causar instabilidade hemodinâmica. Nesses casos, a recomendação é a realização de algum procedimento de reperfusão, sendo a trombólise sistêmica a principal terapia utilizada. No entanto, dados nacionais avaliando a eficácia e a segurança da trombólise são escassos.

MÉTODO

Análise retrospectiva de uma série de casos. Foram incluídos 13 pacientes com o diagnóstico de EAP de alto risco e quatro pacientes de risco intermediário-alto, de um único centro, e que foram tratados com alteplase 100 mg.

RESULTADOS

A média de idade dos pacientes foi 55 anos, sendo a maioria do gênero feminino (76,4%). Dos fatores de risco para TEV, estavam presentes a imobilização (41,17%), o uso de anticonceptivos (35,29%), câncer (17,63%) e história prévia de TVP (11,76%). As manifestações clínicas mais frequentes da EAP foram dispneia (88,23%), hipóxia (82,35%), hipotensão (82,35%) e taquicardia (64,70%); 82,35% dos pacientes apresentaram sinais ecocardiográficos de disfunção ventricular direita e 52,94% apresentaram aumento da troponina e BNP. Sangramento grave associado à trombólise ocorreu em 17,54% dos casos. Nenhum paciente faleceu em decorrência de sangramento. Houve oito mortes por insuficiência ventricular direita (47%): seis nos casos de paciente que se apresentaram como EAP de alto risco (35,3%) e duas nos casos de risco intermediário-alto (11,8%).

CONCLUSÃO

A trombólise nos pacientes com EAP de alto risco ou risco intermediário-alto apresentou uma taxa de sangramento grave de 17,6%. No entanto, a alta mortalidade dessa população (47%) por insuficiência ventricular direita justifica o uso desta modalidade terapêutica.

Embolia pulmonar; Terapia trombolítica; Ativador de plasminogênio tecidual; Disfunção ventricular direita

INTRODUCTION

Acute pulmonary embolism (APE) is the third leading cause of death from a cardiovascular cause, behind only acute myocardial infarction and cerebrovascular accidents11. Fernandes CJ, Alves Júnior JL, Gavilanes F, Prada LF, Morinaga LK, Souza R. New anticoagulants for the treatment of venous thromboembolism. J Bras Pneumol. 2016;42(2):146-54. {Fernandes, 2016, New anticoagulants for the treatment of venous thromboembolism}. Although it is an easily preventable and treatable disease, it is estimated that every year, more than 3 million people die as a result of venous thromboembolism (VTE) and its most severe clinical manifestation, APE22. Rocha AT, Paiva EF, Araújo DM, Cardoso DN, Pereira AC, Lopes AA, et al. Impact of a program for venous thromboembolism prophylaxis in hospitalized patients in four hospitals in Salvador. Rev Assoc Med Bras (1992). 2010;56(2):197-203.

3. Casella IB, Puech-Leão P. Generic versus branded enoxaparin in prophylaxis and treatment of vein thrombosis. Rev Assoc Med Bras (1992). 2015;61(1):44-50.
- 44. Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol. 2015;12(8):464-74. .

The main determinant of APE’s clinical outcome is the right ventricle (RV) response to the acute increase of its afterload due to the increased pulmonary vascular resistance induced by the presence of a clot and its induced vasoconstriction55. Fernandes CJCS, Jardim CVP, Alves Jr JL, Oleas FAG, Morinaga LTK, Souza R. Reperfusion in acute pulmonary thromboembolism. J Bras Pneumol. 2018: 44(3):237-43. , 66. Fernandes CJ, Luppino Assad AP, Alves-Jr JL, Jardim C, Souza R. Pulmonary embolism and gas exchange. Respiration. 2019:98(3):253-62. . When there is clear right-ventricular failure induced by APE with hemodynamic instability and hypotension, the recommendation, as a consensus, is some reperfusion procedure to reduce the afterload sharply and revert RV failure77. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-52.

8. Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med. 2012;125(5):465-70.
- 99. Miranda CH. Use of thrombolytic agents in the treatment of acute pulmonary thromboembolism: things are not as simple as you might think. J Bras Pneumol. 2019;45(1):e20180297. . As a rule, the therapy of choice in these cases is systemic thrombolysis. However, due to the risk of its main adverse event, i.e., bleeding, the use of thrombolytic drugs is still well below the actual clinical need of APE patients with hemodynamic instability1010. Xu Q, Huang K, Zhai Z, Yang Y, Wang J, Wang C. Initial thrombolysis treatment compared with anticoagulation for acute intermediate-risk pulmonary embolism: a meta-analysis. J Thorac Dis. 2015;7(5):810-21. . Another aggravating factor is that, in the medical literature, there is still scarce safety and efficacy data stating the role of this therapeutic strategy in the clinical management of APE patients at high risk of death, mainly in the national environment.

In certain situations, thrombolytic treatment is also an option for patients with medium-high risk APE. These patients are those who are able to maintain systemic perfusion with adequate systemic arterial pressure at the expense of RV stress. That stress is identified by the presence of abnormal biomarkers (BNP or troponin) RV imaging (via echo with pulmonary hypertension or RV dilation, or even an abnormal RV/LV ratio on a tomography)1111. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al.; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-69, 3069a-3069k. . The benefits of using a thrombolytic drug in this situation are more questionable, and there is also no data available in the literature on the clinical outcomes of thrombolysis in this population for our location1212. Fernandes CJCS, Jardim CVP, Alves-Jr JL, Oleas FAG, Morinaga LTK, Souza R. Reflections on the use of thrombolytic agents in acute pulmonary embolism. J Bras Pneumol. 2019;45(1):e20180297. .

In this study, we present a series of 17 cases from a secondary general hospital who were submitted to thrombolytic therapy with alteplase for the treatment of PTE. We evaluated its effectiveness and safety.

METHODS

This is a case-series study, analyzed retrospectively through the review of medical records. The study included 13 patients with a diagnosis of high-risk PTE and four patients of medium-high risk, according to the classification suggested by the consensus of the European Society of Cardiology/European Respiratory Society1111. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al.; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-69, 3069a-3069k. , from January 2014 to May 2016, in the General Hospital of Florianópolis - SC, and who were submitted to thrombolytic therapy with alteplase at a dose of 100 mg.

RESULTS

The mean age of patients was 55 years (23 to 84 years). Most patients were female (76.4%). Among the most prevalent risks for VTE, immobilization was present in 41.17%, followed by the use of oral contraception (35.29%). Three patients had a history of cancer (17.63%), demonstrating the relevance of this clinical condition, particularly in our area1313. Fernandes CJCS. Evolution in the management of non-small cell lung cancer in Brasil. J Bras Pneumol. 2017;43(6):403-4. , 1414. Fernandes CJ, Morinaga LTK, Alves JL Jr, Castro MA, Calderaro D, Jardim CVP, et al. Cancer-associated thrombosis: the when, how and why. Eur Respir Rev. 2019;28(151). pii: 180119. doi: 10.1183/16000617.0119-2018. . Two cases had a history of deep vein thrombosis (11.76%). The epidemiological data of patients with APE are expressed in Figure 1 .

FIGURE 1
RISK FACTORS IDENTIFIED IN PATIENTS WITH APE

The most frequent clinical manifestation of APE was sudden-onset dyspnea (88.23%), followed by O2 saturation lower than 90%, and systemic hypotension (defined as systolic blood pressure below 100 mmHg (82.35%). Tachycardia and lower levels of consciousness were observed in 11 patients (64.70%), while tachypnea and chest pain was observed in 52.94% ( Figure 2 ).

FIGURE 2
MAIN SIGNS AND SYMPTOMS PRESENTED BY APE PATIENTS.

Fourteen patients (82.35%) presented echocardiographic signs of right ventricular dysfunction, such as the RV hypokinesis, increased pulmonary artery systolic pressure (PASP), paradoxical septal movement, and dilatation of the right chambers. Electrocardiographic abnormalities were observed in 10 patients (58.82%), with a S1Q3T3 pattern in two cases, sinus tachycardia in one case, and atrial fibrillation in another. Nine cases had increased troponin and brain natriuretic peptide (BNP) values, corresponding to 52.94% ( Figure 3 )

FIGURE 3
MAIN PROPAEDEUTICS CHANGES PRESENTED BY APE PATIENTS.

Severe bleeding associated with thrombolytic therapy occurred in three cases (17.54%). The sites of the bleeding were retroperitoneal hematoma and hematoma associated with the puncture site of the central venous catheter. No patient died due to bleeding. There were, in total, eight deaths due to right ventricular failure (47%): six among the cases of patients who presented initially as high-risk APE (35.3%) and two among the cases of medium-high risk (11.8%). The data regarding the efficacy and safety of thrombolytic therapy are shown in Table 1

TABLE 1
EFFICACY AND SAFETY OF THROMBOLYTIC TREATMENT FOR APE

DISCUSSION

The most severe clinical presentation of venous thromboembolic disease is APE with hemodynamic instability. Our study highlights the seriousness of this situation in the national context (47% mortality) and demonstrates that the use of thrombolytic therapy is a viable alternative, with a quite acceptable rate of adverse events (greater bleeding in 17.6% of cases), considering the high lethality of the clinical situation. Data evaluating the efficacy and safety of thrombolytic treatment in Brasil are extremely rare. To our knowledge, this is the first time a series of cases reporting this treatment in the Brazilian context of APE is published.

Thrombolysis is the treatment of choice for high-risk APE, recommended by the most recent international consensuses1111. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al.; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-69, 3069a-3069k. . However, its main adverse event, i.e., severe bleeding, is an inhibiting factor to its use in patients with a clear indication88. Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med. 2012;125(5):465-70. . Our data demonstrate that, in the national context, although bleeding is, indeed, a condition associated with the use of thrombolytic therapy, its frequency is equivalent to half of the deaths induced by RV dysfunction associated with APE. Thus, the use of thrombolytic drugs in these more difficult situations, with hemodynamic instability and high risk of death, is justified.

For severe patients, considered as of medium-high risk, the role of thrombolysis is less clear. The Peitho study evaluated 1,006 patients in this situation and, despite having identified a benefit from thrombolysis performed with tenecteplase, which reduced the use of intubation or vasoactive drugs, could not identify benefits in terms of mortality. In addition, the use of thrombolytic drugs presented a rate of central nervous system bleeding ten times greater than the conventional treatment with conventional anticoagulation (2 vs. 0.2%, p=0.003)1515. Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-11. . Systemic thrombolysis also had no impact on the residual dyspnea or the incidence of chronic thromboembolic pulmonary hypertension (CTEPH) after two years1616. Konstantinides SV, Vicaut E, Danays T, Becattini C, Bertoletti L, Beyer-Westendorf J, et al. Impact of thrombolytic therapy on the long-term outcome of intermediate-risk pulmonary embolism. J Am Coll Cardiol. 2017;69(12):1536-44. . Full anticoagulation would be the main treatment for CTEPH prevention1717. Gavilanes-Oleas FA, Alves JL Jr, Fernandes CJC, Prada LFL, Salibe Filho W, Terra Filho M, et al. Use of direct oral anticoagulants for chronic thromboembolic pulmonary hypertension. Clinics (Sao Paulo). 2018;73:e216. . However, our data demonstrated that this population, in the national context, presents a high mortality rate and is not considered a candidate for thrombolytic treatment; thus, it must be monitored intensively for early identification of organic dysfunction and tissue hypoperfusion.

Recent national data evaluated different aspects of APE diagnosis and risk stratification in our context. The validation of the Pesi risk score1818. Soriano LA, Castro TT, Vilalva K, Borges MC, Pazin-Filho A, Miranda CH. Validation of the Pulmonary Embolism Severity Index for risk stratification after acute pulmonary embolism in a cohort of patients in Brasil. J Bras Pneumol. 2019;45(1):e20170251. , the lack of relevance of the Wells and Geneva scores for the APE diagnosis in patients with clinical comorbidities1919. Girardi AM, Bettiol RS, Garcia TS, Ribeiro GLH, Rodrigues ÉM, Gazzana MB, et al. Wells and Geneva Scores are not reliable predictors of pulmonary embolism in critically ill patients: a retrospective study. J Intensive Care Med. 2018:885066618816280. , and the use of magnetic resonance imaging to identify the severity of APE {Pasin, 2017 #7398}demonstrate the relevance of APE in the Brazilian medical literature. However, objective data on the treatment of more severe presentations of APE in the Brazilian context are still not available. Thus, our study aims to bridge part of this gap in science, contributing to the construction of epidemiological data on APE in Brasil.

Our study has a number of limitations. It is an uncontrolled case series from a single center. The indication for thrombolytic therapy was systematical, but at the discretion of the assistant physician. Moreover, we do not have data on APE patients with an indication to receive thrombolytic treatment, but who, for some reason, did not receive it. However, the considerable number of patients included and the scarcity of Brazilian data in the literature justify the analysis and interpretation of our data with due caution.

CONCLUSION

Thrombolytic therapy in this series of 17 cases from a single Brazilian center with high-risk or medium-high risk APE patients presented a rate of severe bleeding of 17.6%. However, the high mortality in this population (47%) due to right ventricular failure justifies the use of this therapy, despite the potential morbidity. No patient died due to bleeding in this series.

REFERENCES

  • 1
    Fernandes CJ, Alves Júnior JL, Gavilanes F, Prada LF, Morinaga LK, Souza R. New anticoagulants for the treatment of venous thromboembolism. J Bras Pneumol. 2016;42(2):146-54.
  • 2
    Rocha AT, Paiva EF, Araújo DM, Cardoso DN, Pereira AC, Lopes AA, et al. Impact of a program for venous thromboembolism prophylaxis in hospitalized patients in four hospitals in Salvador. Rev Assoc Med Bras (1992). 2010;56(2):197-203.
  • 3
    Casella IB, Puech-Leão P. Generic versus branded enoxaparin in prophylaxis and treatment of vein thrombosis. Rev Assoc Med Bras (1992). 2015;61(1):44-50.
  • 4
    Heit JA. Epidemiology of venous thromboembolism. Nat Rev Cardiol. 2015;12(8):464-74.
  • 5
    Fernandes CJCS, Jardim CVP, Alves Jr JL, Oleas FAG, Morinaga LTK, Souza R. Reperfusion in acute pulmonary thromboembolism. J Bras Pneumol. 2018: 44(3):237-43.
  • 6
    Fernandes CJ, Luppino Assad AP, Alves-Jr JL, Jardim C, Souza R. Pulmonary embolism and gas exchange. Respiration. 2019:98(3):253-62.
  • 7
    Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-52.
  • 8
    Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med. 2012;125(5):465-70.
  • 9
    Miranda CH. Use of thrombolytic agents in the treatment of acute pulmonary thromboembolism: things are not as simple as you might think. J Bras Pneumol. 2019;45(1):e20180297.
  • 10
    Xu Q, Huang K, Zhai Z, Yang Y, Wang J, Wang C. Initial thrombolysis treatment compared with anticoagulation for acute intermediate-risk pulmonary embolism: a meta-analysis. J Thorac Dis. 2015;7(5):810-21.
  • 11
    Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galiè N, et al.; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-69, 3069a-3069k.
  • 12
    Fernandes CJCS, Jardim CVP, Alves-Jr JL, Oleas FAG, Morinaga LTK, Souza R. Reflections on the use of thrombolytic agents in acute pulmonary embolism. J Bras Pneumol. 2019;45(1):e20180297.
  • 13
    Fernandes CJCS. Evolution in the management of non-small cell lung cancer in Brasil. J Bras Pneumol. 2017;43(6):403-4.
  • 14
    Fernandes CJ, Morinaga LTK, Alves JL Jr, Castro MA, Calderaro D, Jardim CVP, et al. Cancer-associated thrombosis: the when, how and why. Eur Respir Rev. 2019;28(151). pii: 180119. doi: 10.1183/16000617.0119-2018.
  • 15
    Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-11.
  • 16
    Konstantinides SV, Vicaut E, Danays T, Becattini C, Bertoletti L, Beyer-Westendorf J, et al. Impact of thrombolytic therapy on the long-term outcome of intermediate-risk pulmonary embolism. J Am Coll Cardiol. 2017;69(12):1536-44.
  • 17
    Gavilanes-Oleas FA, Alves JL Jr, Fernandes CJC, Prada LFL, Salibe Filho W, Terra Filho M, et al. Use of direct oral anticoagulants for chronic thromboembolic pulmonary hypertension. Clinics (Sao Paulo). 2018;73:e216.
  • 18
    Soriano LA, Castro TT, Vilalva K, Borges MC, Pazin-Filho A, Miranda CH. Validation of the Pulmonary Embolism Severity Index for risk stratification after acute pulmonary embolism in a cohort of patients in Brasil. J Bras Pneumol. 2019;45(1):e20170251.
  • 19
    Girardi AM, Bettiol RS, Garcia TS, Ribeiro GLH, Rodrigues ÉM, Gazzana MB, et al. Wells and Geneva Scores are not reliable predictors of pulmonary embolism in critically ill patients: a retrospective study. J Intensive Care Med. 2018:885066618816280.

Publication Dates

  • Publication in this collection
    03 June 2020
  • Date of issue
    Mar 2020

History

  • Received
    26 Aug 2019
  • Accepted
    31 Aug 2019
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