I congratulate Fernandes et al. on their review article entitled "Reperfusion in Acute Pulmonary Thromboembolism" (PTE) published in the JBP.(1)

I would like to make some practical comments on and comparisons with the use of thrombolytic agents in acute myocardial infarction (MI), initially with regard to high-risk group patients who present with hemodynamic instability-systolic blood pressure (SBP) < 90 mmHg or a sustained ≥ 40-mmHg decrease in SBP for 15 minutes in the absence of other reasons, such as new-onset arrhythmias, hypovolemia, or sepsis.(2) The use of thrombolytic agents in high-risk group patients has been reported to reduce the relative risk of death by 80%; however, according to one study, up to two thirds of such patients do not receive fibrinolytic agents.(3) This reduction in the relative risk of death is substantially larger than that observed in acute ST-segment elevation MI (STEMI), with ranges from 20-30%, according to one study.(4) Nevertheless, thrombolytic agents are widely used in acute STEMI, and not prescribing fibrinolytic therapy, especially when primary angioplasty is unavailable, is considered poor medical practice. I believe that the use of thrombolysis in high-risk PTE should be encouraged, provided that absolute contraindications are taken into account. Recently, a directive published in the Brazilian Official Federal Government Journal(5) mandated that the indication for alteplase in treating PTE be incorporated into the Brazilian Unified Health Care System. We should also be alert to the fact that several patients have borderline SBP (90-110 mmHg), and sometimes it is difficult to establish baseline blood pressure levels in order to determine whether there is a ≥ 40-mmHg decrease. In such cases, I recommend measuring serum lactate levels. Serum lactate levels > 2.0 mg/dL suggest that the observed blood pressure level is not adequate for tissue perfusion. If that is the case, the patient also meets the criteria for circulatory shock, since lactate levels are essential to detecting hemodynamic collapse. Some investigations have shown that lactate in this context is an independent predictor of mortality, being a better prognosticator than either troponin or N-terminal prohormone of brain natriuretic peptide (NT-proBNP). (6,7) Such a patient also meets criteria for thrombolysis.

With regard to the use of thrombolytic agents in intermediate-risk patients, I believe that the controversy continues, because a single randomized study does not provide enough evidence for a final verdict. We should consider that the markers used have a low positive predictive value for identifying patients at high risk for complications. Optimal cut-off values for troponin and NT-proBNP have not yet been established and may vary according to the method used for determining their levels. With regard to echocardiography, there is no methodological standardization for evaluating the right ventricle. Therefore, I consider it a great challenge to establish new parameters with adequate accuracy for selecting patients who are truly at risk, and perhaps these are the patients who can benefit from fibrinolytic therapy.

One study(8) that investigated thrombolysis with tenecteplase in intermediate-risk patients had numerous setbacks. First, the thrombolytic agent chosen. In this setting, the largest experience has been with alteplase. Tenecteplase's ease of administration as an i.v. bolus is a plus; however, the disadvantage is its duration of action (40 min), whereas alteplase's duration of action is 2 hours, which guarantees longer exposure time for thrombus dissolution, especially in patients with high thrombotic load. In a meta-analysis of the use of thrombolytic agents in PTE, alteplase did not increase the risk of bleeding (OR = 1.07; 95% CI: 0.43-2.62); however, this risk increased considerably with the use of tenecteplase (OR = 5.02; 95% CI: 2.72-9.26).(9) Therefore, I believe that alteplase should be considered the first choice for reperfusion in PTE. Second, the study by Meyer et al.(8) did not adjust the dose of tenecteplase for elderly patients, and although the use of tenecteplase was found to reduce the composite outcome of mortality and hemodynamic decompensation from 5.6% to 2.6% (p = 0.02), it caused a higher number of intracranial bleeds (2.0% vs. 0.2%; p = 0.003). In that study,(8) subgroup analysis demonstrated that the clinical benefit was limited to patients ≤ 75 years of age (OR = 0.33; 95% CI: 0.13-0.85). Of the 11 patients who had intracranial hemorrhage, 9 (82%) were ≥ 75 years of age.(8) Armstrong et al.(10) addressed thrombolysis with tenecteplase followed by angiography in the treatment of acute STEMI, initially demonstrating an increase in the rates of intracranial bleeding in patients ≥ 75 years of age who received tenecteplase (1.0% vs. 0.2%; p = 0.04); after an amendment to the study protocol, with the dose of tenecteplase being reduced by half in patients ≥ 75 years of age, the bleeding rate was equivalent between groups (0.5% vs. 0.3%; p = 0.45). Third, the recommended dose of unfractionated heparin for use with the thrombolytic agent in PTE is an i.v. bolus of 80 IU/kg, followed by 18 IU/kg per hour continuous infusion, with adjustment of the activated partial thromboplastin time (aPTT) to 2.0-2.5 × normal. One study on the use of fibrinolytic agents in acute STEMI showed a reduction in bleeding with the use of a lower-dose heparin regimen (60 IU/kg bolus; maximum, 4000 IU; followed by 12 IU/kg per hour continuous infusion; maximum, 1000 IU/h) with a target aPTT between 1.5 and 2.5.(11) After thrombolysis for PTE, it is not uncommon that patients are started on heparin therapy and that the first aPTTs reveal non-coagulability of blood, precisely at this stage when the risk of bleeding is more critical. In the study by Meyer et al.,(8) 30% of the patients had heparin levels above recommended levels. Why not start infusion more cautiously and gradually adjust it upward if necessary? And, finally, that study reported low mortality (2.4% in the tenecteplase group vs. 3.2% in the control group), which may be due to early diagnosis and treatment in European centers, from where the patients were recruited.(8) However, a sample of patients in Brazil had a higher mortality rate of approximately 20%, which may be due to delayed diagnosis because of difficulties within the Brazilian Unified Health Care System.(12) In this context, the role of fibrinolytic agents may be more prominent.

PTE is a neglected health problem, especially when compared with acute STEMI. With regard to treatment of low-risk patients, the institution of heparin therapy is sufficient. For high-risk group patients, we need to promote the use of thrombolysis. And, regarding intermediate-risk group patients, we still need to improve our scientific basis before establishing definitive approaches.

REFERENCES

1. Fernandes CJCDS, Jardim CVP, Alves JL Jr, Oleas FAG, Morinaga LTK, Souza R. Reperfusion in acute pulmonary thromboembolism. J Bras Pneumol. 2018;44(3):237-243. https://doi.org/10.1590/s1806-37562017000000204
2. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N, et al. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-69, 3069a-3069k.
3. 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. https://doi.org/10.1016/j.amjmed.2011.10.015
4. Verstraete M. Thrombolytic treatment in acute myocardial infarction. Circulation. 1990;82(3 Suppl):II96-109.
5. Brasil. Ministério da Saúde. Secretaria de Ciência, Tecnologia e Insumos Estratégicos. Portaria No. 37 (2018 Sep 11); Diário Oficial da União. 176(1):203.
6. Vanni S, Socci F, Pepe G, Nazerian P, Viviani G, Baioni M, et al. High plasma lactate levels are associated with increased risk of in-hospital mortality in patients with pulmonary embolism. Acad Emerg Med. 2011;18(8):830-5. https://doi.org/10.1111/j.1553-2712.2011.01128.x
7. Vanni S, Viviani G, Baioni M, Pepe G, Nazerian P, Socci F, et al. Prognostic value of plasma lactate levels among patients with acute pulmonary embolism: the thrombo-embolism lactate outcome study. Ann Emerg Med. 2013;61(3):330-8. https://doi.org/10.1016/j.annemergmed.2012.10.022
8. Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-11. https://doi.org/10.1056/NEJMoa1302097
9. Marti C, John G, Konstantinides S, Combescure C, Sanchez O, Lankeit M, et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J. 2015;36(10):605-14. https://doi.org/10.1093/eurheartj/ehu218
10. Armstrong PW, Gershlick AH, Goldstein P, Wilcox R, Danays T, Lambert Y, et al. Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction. N Engl J Med. 2013;368(15):1379-87. https://doi.org/10.1056/NEJMoa1301092
11. Giugliano RP, McCabe CH, Antman EM, Cannon CP, Van de Werf F, Wilcox RG, et al. Lower-dose heparin with fibrinolysis is associated with lower rates of intracranial hemorrhage. Am Heart J. 2001;141(5):742-50. https://doi.org/10.1067/mhj.2001.114975
12. Volschan A, Albuquerque DC, Tura BR, Knibel Mde F, Souza PC, Toscano ML. Pulmonary embolism: multicenter registry in tertiary hospitals. Rev Bras Ter Intensiva. 2009;21(3):237-46.