Intern Emerg Med DOI 10.1007/s11739-015-1194-8
DEBATE
Is there still a place for thrombolytic therapy in hemodynamically stable patients with acute pulmonary embolism? Yes Guy Meyer • Olivier Sanchez • Benjamin Planquette
Received: 22 December 2014 / Accepted: 8 January 2015 Ó SIMI 2015
Introduction Thrombolytic therapy is associated with faster hemodynamic, echocardiographic and angiographic improvements than heparin alone in patients with pulmonary embolism (PE) and right ventricular dysfunction, but this is obtained at the expense of an increased risk of bleeding. The use of thrombolytic therapy in patients with PE should therefore be decided on the estimation of the benefit-to-risk ratio depending both on the risk of death due to PE and to treatment-associated bleeding complications.
with heparin [1]. Alteplase produces an earlier reversal of right ventricular dysfunction than heparin [2]. Thrombolytic treatment also produces a faster decrease in vascular obstruction than heparin. Pulmonary vascular obstruction decreases significantly 2 h after the start of alteplase infusion, whereas no significant difference is observed with heparin alone [1]. Of note, translation of these hemodynamic and morphologic changes into clinical outcomes was missing until recently.
Risk stratification of patients with PE Thrombolytic therapy induces faster angiographic and hemodynamic improvements than heparin alone in patients with PE Thrombolytic treatment induces a rapid decline of pulmonary artery resistance in patients with acute PE and pulmonary hypertension. Alteplase significantly reduces mean pulmonary artery pressure and increases the cardiac index after 2 h, whereas no significant change is observed G. Meyer O. Sanchez B. Planquette Universite´ Paris Descartes, Sorbonne Paris Cite´, Paris, France G. Meyer O. Sanchez B. Planquette Division of Respiratory Diseases, Hoˆpital Europe´en Georges Pompidou, Assistance Publique Hoˆpitaux de Paris, Paris, France G. Meyer O. Sanchez B. Planquette INSERM UMRS 965, Paris, France G. Meyer (&) Service de Pneumologie-soins intensifs, Hoˆpital Europe´en Georges Pompidou, 20 rue Leblanc, 75015 Paris, France e-mail: [email protected]
Patients with PE are usually divided into two main groups regarding their prognosis: a small group of ‘‘high-risk’’ patients with systemic hypotension or cardiogenic shock, and a large group of clinically stable patients with normal blood pressure. Although the evidence is rather limited, the use of thrombolytic therapy is recommended by most guidelines in high-risk PE patients because these patients carry a high mortality risk when receiving anticoagulant treatment alone. In this setting, the hemodynamic effects of thrombolytic treatment far outweigh its bleeding risk. Conversely, normotensive patients with PE have a shortterm mortality risk of less than 5 % on average in the absence of major underlying illness. This group is, however, heterogeneous and clinical findings, right ventricular dilatation on echocardiography or spiral computed tomography and elevated cardiac biomarkers including troponin and brain natriuretic peptides are able to select a group with an intermediate risk of death or major complication [3].This has been exemplified in two recent publications showing that some normotensive patients carry a high risk of complications related to PE. In the first study, normotensive patients with a simplified PESI
123
Intern Emerg Med
score C1, right ventricular dilatation on spiral computed tomography, elevated brain natriuretic peptide and elevated troponin, have a risk of developing PE related adverse events of 20.4 % [4]. In the second study, normotensive patients with a simplified PESI score C1, an N terminal pro-BNP [600 pg/mL, and right ventricular dysfunction on echocardiography, have a risk of death or PE-related complications of 10.8 % [5]. Thus, modern multimodal risk stratification of normotensive patients with PE is able to select a subgroup of patients with a ‘‘high-intermediate risk’’ as defined by the recent guidelines issued by the European Society of Cardiology (ESC) [3]. What is the evidence for the use of thrombolytic therapy in these patients?
Thrombolytic therapy should not be used in low-risk PE patients Clearly, normotensive patients without signs of right ventricular dysfunction or damage carry a very low risk of mortality and PE-related complication, and do not require the use of thrombolytic treatment with its associated bleeding risk. In the two previous studies, such patients who either have a simplified PESI score \ 1 (i.e. low-risk patients) or who have neither right ventricular dilatation or elevated biomarkers (i.e. low-intermediate risk patients) have a risk of PE-related complication varying between 0 and 2.3 %, and between 0.9 and 6.1 % in the studies by Lankeit et al. and by Jimenez et al., respectively [4, 5]. These rates of PE-related complications are lower or about equal to the rate of major bleeding observed in recent trials assessing thrombolytic treatment in PE patients. Thus recent ESC guidelines advise not using thrombolytic treatment in these patients [3].
What about the use of thrombolytic therapy in patients with intermediate-risk or intermediate-high risk PE? In the most comprehensive meta-analysis published before 2014, studies were divided into those including unstable patients (i.e. high-risk patients according to ESC guidelines,) and those including clinically stable patients only (combining low-risk and intermediate-risk patients). According to this systematic analysis, thrombolytic therapy was associated with an odds ratio for death of 1.16 (95 % CI, 0.44–3.05,) and an odds ratio of the combined endpoint of death or recurrent PE of 1.07 (95 % CI, 0.50–2.30) [6]. Most trials included in this meta-analysis did not report right ventricular function data, and both low-risk and intermediate-risk PE patients were included. Only two studies reported echographic data, and only 36 and 31 % of
123
the patients had right ventricular dysfunction [2, 7]. Biomarker measurements were not performed in any study. Thus, most of the patients included in these trials had lowrisk PE, and the role of thrombolytic therapy for patients with intermediate-risk PE cannot be defined on this basis. In addition, fewer than 500 normotensive patients were included in this meta-analysis, limiting the power to identify a clinically significant reduction in death or recurrent PE [6]. The PEITHO study is the largest trial on thrombolytic therapy in PE reported to date. A total of 1,006 patients were randomized to receive either heparin and tenecteplase on a weight-adapted dosage or placebo and heparin [8]. All patients had normal blood pressure, and had both right ventricular dysfunction on echocardiography or spiral computed tomography, and right ventricular injury defined by an elevated troponin. The trial shows, for the first time, that the hemodynamic consequences of thrombolytic therapy translate into clinical events. The main clinical composite end-point of death from any cause or hemodynamic decompensation (or collapse) within 7 days after randomization occurred in 13 patients (2.6 %) in the tenecteplase group as compared with 28 patients (5.6 %) in the placebo group (odds ratio 0.44; 95 % CI 0.23–0.87; P = 0.02). Hemodynamic decompensation was defined as a need for cardiopulmonary resuscitation; or systolic blood pressure \90 mmHg for C15 min or drop by C40 mmHg for at least 15 min with end organ hypoperfusion: (cold extremities, urinary output \30 mL/h, mental confusion,) or a need for catecholamines to maintain adequate organ perfusion and a systolic blood pressure of C90 mmHg. This increase in efficacy was, however, obtained at the expense of an increase in major bleeding, and, most importantly, in intracranial bleedings. Major bleeding occurred between randomization and day 7 in 58 patients (11.5 %) in the tenecteplase group and 12 patients (2.4 %) in the placebo group. Overall, 12 patients (2.4 %) in the tenecteplase group had a stroke, and the stroke was hemorrhagic in 10; only 1 patient (0.2 %) in the placebo group had a hemorrhagic stroke (P = 0.003). Overall mortality was 1.2 % in the tenecteplase group and 1.8 % in the placebo group (P = 0.42) [8]. These results were combined with the other thrombolytic trials in a recent meta-analysis [9]. In patients with intermediate-risk PE, thrombolytic therapy was associated with an odds ratio for mortality of 0.42 (95 % CI 0.17–1.03), with an odds ratio for PE-related death of 0.17 (95 % CI 0.05–0.67) and an odds ratio for PE recurrence (which was not included in the main outcome of the PEITHO study), of 0.25 (95 % CI 0.06–1.03.) In the same meta-analysis, thrombolytic treatment was associated with a significantly increased risk of major bleeding (OR 2.91; 95 % CI 1.95–4.36,) and fatal or intracranial haemorrhage
Intern Emerg Med
(OR 3.18; 95 % CI 1.25–8.11) [9]. Thus, thrombolytic therapy is associated with a significant reduction in death due to PE, but with a significant increase of intracranial or fatal bleeding. In patients with intermediate-risk PE, the overall mortality is decreased by 60 % although this difference does not fulfil the criteria for statistical significance. This rather narrow benefit-to-risk ratio precludes the use of thrombolytic therapy in all patients with intermediate-risk PE. This is emphasized in the recent guidelines of the European Society of Cardiology suggesting that ‘‘thrombolytic therapy should be considered for patients with intermediate-high-risk PE and clinical signs of haemodynamic decompensation,’’ but that ‘‘routine use of primary systemic thrombolysis is not recommended in patients not suffering from shock or hypotension’’ [3].
How to increase the risk to benefit ratio of thrombolytic therapy in PE patients? First, all patients do not have the same risk of bleeding, and age is by far the most important risk factor for bleeding. This is exemplified by the PEITHO study where the increase in the risk of major extracranial bleeding associated with tenecteplase is much more pronounced in patients aged greater than 75 years than in younger patients, and where all but one intracranial bleeds occurred in patients aged over 70 years [8]. In the meta-analysis by Marti et al., the association between thrombolytic therapy and the risk of major bleeding was lower in studies using an upper age limit (OR 1.13; 95 % CI 0.47–2.71) than in studies including older patients (OR 3.71; 95 % CI 2.32–5.92) [9]. Second, the use of dose-reduced thrombolytic regimens is also associated with a lower risk of bleeding. This has been suggested with alteplase in patients with PE, and with tenecteplase in patients with acute coronary syndrome [10– 12].Third, thrombolytic treatment should only be given in the sickest patients belonging to the intermediate-high-risk PE category. Even in the PEITHO trial, only 5.8 % of patients died or experienced haemodynamic decompensation in the control group, which is far lower than in recent cohort studies [8]. The threshold for an abnormal troponin value in the PEITHO trial was left to the local laboratory, which is probably a limitation of the study whereas several recent cohort studies strongly suggest that the rate of PErelated complications increases with increasing blood levels of biomarkers [5, 13]. Thus, avoiding the use of thrombolytic therapy in patients aged more than 75 years, reducing the dosage, and reserving its use to the most severely ill patients among intermediate-risk PE patients might allow an increasing benefit to risk ratio of thrombolytic therapy in patients with PE.
In randomized controlled trials, thrombolytic therapy is associated with a significant decrease in death due to PE, and a non-significant reduction in overall mortality in patients with intermediate-risk PE, but this benefit is counterbalanced by a high risk of haemorrhagic stroke or major non-intracranial bleeding. Although cohort studies suggest that this benefit could be larger in intermediate high-risk patients, and indirect evidence based on subgroup analysis in PE trials and on trials performed in acute coronary syndrome suggest that avoiding the use of thrombolytic therapy in patients older than 75 years and the use of reduced dosage may allow increasing the benefit-to-risk ratio, this has not been confirmed in therapeutic trials to date. In summary, these findings support either the restricted use of thrombolytic treatment in young high-risk PE patients selected for their low bleeding risk, or close monitoring to permit early detection of haemodynamic decompensation and timely initiation of ‘rescue’ reperfusion therapy as suggested by the recent guidelines of the European Society of Cardiology [3]. Conflict of interest
None.
References 1. Dalla-Volta S, Palla A, Santolicandro A, Giuntini C, Pengo V, Visioli O, Zonzin P, Zanuttini D, Barbaresi F, Agnelli G et al (1992) PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. J Am Coll Cardiol 20:520–526 2. Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, Taveira da Silva AM, Come PC, Lee RT, Parker JA et al (1993) Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 341:507–511 3. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N, Gibbs JS, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M (2014) ESC 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) Endorsed by the European Respiratory Society (ERS). Eur Heart J 35(43):3033–3069 4. Jimenez D, Kopecna D, Tapson V, Briese B, Schreiber D, Lobo JL, Monreal M, Aujesky D, Sanchez O, Meyer G, Konstantinides S, Yusen RD, On Behalf of the Protect I (2014) Derivation and validation of multimarker prognostication for normotensive patients with acute symptomatic pulmonary embolism. Am J Respir Crit Care Med 189:718–726 5. Lankeit M, Jimenez D, Kostrubiec M, Dellas C, Kuhnert K, Hasenfuss G, Pruszczyk P, Konstantinides S (2014) Validation of N-terminal pro-brain natriuretic peptide cut-off values for risk stratification of pulmonary embolism. Eur Respir J 43:1669–1677 6. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW (2004) Thrombolysis compared with heparin for the initial treatment of
123
Intern Emerg Med pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 110:744–749 7. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W (2002) Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 347:1143–1150 8. Meyer GVE, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, Bluhmki E, Bouvaist H, Brenner B, Couturaud F, Dellas C, Empen K, Franca A, Galie` N, Geibel A, Goldhaber SZ, Jimenez D, Kozak M, Kupatt C, Kucher N, Lang IM, Lankeit M, Meneveau N, Pacouret G, Palazzini M, Petris A, Pruszczyk P, Rugolotto M, Salvi A, Schellong S, Sebbane M, Sobkowicz M, Stefanovic BS, Thiele H, Torbicki A, Verschuren F, Konstantinides SV, For the PEITHO Investigators (2014) Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 370:1402–1411 9. Marti C, John G, Konstantinides S, Combescure C, Sanchez O, Lankeit M, Meyer G, Perrier A (2014) Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J [Epub ahead of print]
123
10. Sors H, Pacouret G, Azarian R, Meyer G, Charbonnier B, Simonneau G (1994) Hemodynamic effects of bolus vs 2-h infusion of alteplase in acute massive pulmonary embolism. A randomized controlled multicenter trial. Chest 106:712–717 11. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M (2013) Moderate pulmonary embolism treated with thrombolysis (from the ‘‘MOPETT’’ Trial). Am J Cardiol 111:273–277 12. Armstrong PW, Gershlick AH, Goldstein P, Wilcox R, Danays T, Lambert Y, Sulimov V, Rosell Ortiz F, Ostojic M, Welsh RC, Carvalho AC, Nanas J, Arntz HR, Halvorsen S, Huber K, Grajek S, Fresco C, Bluhmki E, Regelin A, Vandenberghe K, Bogaerts K, Van de Werf F (2013) Fibrinolysis or primary PCI in STsegment elevation myocardial infarction. N Engl J Med 368:1379–1387 13. Sanchez O, Trinquart L, Caille V, Couturaud F, Pacouret G, Meneveau N, Verschuren F, Roy PM, Parent F, Righini M, Perrier A, Lorut C, Tardy B, Benoit MO, Chatellier G, Meyer G (2010) Prognostic factors for pulmonary embolism: the prep study, a prospective multicenter cohort study. Am J Respir Crit Care Med 181:168–173
DEBATE
Is there still a place for thrombolytic therapy in hemodynamically stable patients with acute pulmonary embolism? Yes Guy Meyer • Olivier Sanchez • Benjamin Planquette
Received: 22 December 2014 / Accepted: 8 January 2015 Ó SIMI 2015
Introduction Thrombolytic therapy is associated with faster hemodynamic, echocardiographic and angiographic improvements than heparin alone in patients with pulmonary embolism (PE) and right ventricular dysfunction, but this is obtained at the expense of an increased risk of bleeding. The use of thrombolytic therapy in patients with PE should therefore be decided on the estimation of the benefit-to-risk ratio depending both on the risk of death due to PE and to treatment-associated bleeding complications.
with heparin [1]. Alteplase produces an earlier reversal of right ventricular dysfunction than heparin [2]. Thrombolytic treatment also produces a faster decrease in vascular obstruction than heparin. Pulmonary vascular obstruction decreases significantly 2 h after the start of alteplase infusion, whereas no significant difference is observed with heparin alone [1]. Of note, translation of these hemodynamic and morphologic changes into clinical outcomes was missing until recently.
Risk stratification of patients with PE Thrombolytic therapy induces faster angiographic and hemodynamic improvements than heparin alone in patients with PE Thrombolytic treatment induces a rapid decline of pulmonary artery resistance in patients with acute PE and pulmonary hypertension. Alteplase significantly reduces mean pulmonary artery pressure and increases the cardiac index after 2 h, whereas no significant change is observed G. Meyer O. Sanchez B. Planquette Universite´ Paris Descartes, Sorbonne Paris Cite´, Paris, France G. Meyer O. Sanchez B. Planquette Division of Respiratory Diseases, Hoˆpital Europe´en Georges Pompidou, Assistance Publique Hoˆpitaux de Paris, Paris, France G. Meyer O. Sanchez B. Planquette INSERM UMRS 965, Paris, France G. Meyer (&) Service de Pneumologie-soins intensifs, Hoˆpital Europe´en Georges Pompidou, 20 rue Leblanc, 75015 Paris, France e-mail: [email protected]
Patients with PE are usually divided into two main groups regarding their prognosis: a small group of ‘‘high-risk’’ patients with systemic hypotension or cardiogenic shock, and a large group of clinically stable patients with normal blood pressure. Although the evidence is rather limited, the use of thrombolytic therapy is recommended by most guidelines in high-risk PE patients because these patients carry a high mortality risk when receiving anticoagulant treatment alone. In this setting, the hemodynamic effects of thrombolytic treatment far outweigh its bleeding risk. Conversely, normotensive patients with PE have a shortterm mortality risk of less than 5 % on average in the absence of major underlying illness. This group is, however, heterogeneous and clinical findings, right ventricular dilatation on echocardiography or spiral computed tomography and elevated cardiac biomarkers including troponin and brain natriuretic peptides are able to select a group with an intermediate risk of death or major complication [3].This has been exemplified in two recent publications showing that some normotensive patients carry a high risk of complications related to PE. In the first study, normotensive patients with a simplified PESI
123
Intern Emerg Med
score C1, right ventricular dilatation on spiral computed tomography, elevated brain natriuretic peptide and elevated troponin, have a risk of developing PE related adverse events of 20.4 % [4]. In the second study, normotensive patients with a simplified PESI score C1, an N terminal pro-BNP [600 pg/mL, and right ventricular dysfunction on echocardiography, have a risk of death or PE-related complications of 10.8 % [5]. Thus, modern multimodal risk stratification of normotensive patients with PE is able to select a subgroup of patients with a ‘‘high-intermediate risk’’ as defined by the recent guidelines issued by the European Society of Cardiology (ESC) [3]. What is the evidence for the use of thrombolytic therapy in these patients?
Thrombolytic therapy should not be used in low-risk PE patients Clearly, normotensive patients without signs of right ventricular dysfunction or damage carry a very low risk of mortality and PE-related complication, and do not require the use of thrombolytic treatment with its associated bleeding risk. In the two previous studies, such patients who either have a simplified PESI score \ 1 (i.e. low-risk patients) or who have neither right ventricular dilatation or elevated biomarkers (i.e. low-intermediate risk patients) have a risk of PE-related complication varying between 0 and 2.3 %, and between 0.9 and 6.1 % in the studies by Lankeit et al. and by Jimenez et al., respectively [4, 5]. These rates of PE-related complications are lower or about equal to the rate of major bleeding observed in recent trials assessing thrombolytic treatment in PE patients. Thus recent ESC guidelines advise not using thrombolytic treatment in these patients [3].
What about the use of thrombolytic therapy in patients with intermediate-risk or intermediate-high risk PE? In the most comprehensive meta-analysis published before 2014, studies were divided into those including unstable patients (i.e. high-risk patients according to ESC guidelines,) and those including clinically stable patients only (combining low-risk and intermediate-risk patients). According to this systematic analysis, thrombolytic therapy was associated with an odds ratio for death of 1.16 (95 % CI, 0.44–3.05,) and an odds ratio of the combined endpoint of death or recurrent PE of 1.07 (95 % CI, 0.50–2.30) [6]. Most trials included in this meta-analysis did not report right ventricular function data, and both low-risk and intermediate-risk PE patients were included. Only two studies reported echographic data, and only 36 and 31 % of
123
the patients had right ventricular dysfunction [2, 7]. Biomarker measurements were not performed in any study. Thus, most of the patients included in these trials had lowrisk PE, and the role of thrombolytic therapy for patients with intermediate-risk PE cannot be defined on this basis. In addition, fewer than 500 normotensive patients were included in this meta-analysis, limiting the power to identify a clinically significant reduction in death or recurrent PE [6]. The PEITHO study is the largest trial on thrombolytic therapy in PE reported to date. A total of 1,006 patients were randomized to receive either heparin and tenecteplase on a weight-adapted dosage or placebo and heparin [8]. All patients had normal blood pressure, and had both right ventricular dysfunction on echocardiography or spiral computed tomography, and right ventricular injury defined by an elevated troponin. The trial shows, for the first time, that the hemodynamic consequences of thrombolytic therapy translate into clinical events. The main clinical composite end-point of death from any cause or hemodynamic decompensation (or collapse) within 7 days after randomization occurred in 13 patients (2.6 %) in the tenecteplase group as compared with 28 patients (5.6 %) in the placebo group (odds ratio 0.44; 95 % CI 0.23–0.87; P = 0.02). Hemodynamic decompensation was defined as a need for cardiopulmonary resuscitation; or systolic blood pressure \90 mmHg for C15 min or drop by C40 mmHg for at least 15 min with end organ hypoperfusion: (cold extremities, urinary output \30 mL/h, mental confusion,) or a need for catecholamines to maintain adequate organ perfusion and a systolic blood pressure of C90 mmHg. This increase in efficacy was, however, obtained at the expense of an increase in major bleeding, and, most importantly, in intracranial bleedings. Major bleeding occurred between randomization and day 7 in 58 patients (11.5 %) in the tenecteplase group and 12 patients (2.4 %) in the placebo group. Overall, 12 patients (2.4 %) in the tenecteplase group had a stroke, and the stroke was hemorrhagic in 10; only 1 patient (0.2 %) in the placebo group had a hemorrhagic stroke (P = 0.003). Overall mortality was 1.2 % in the tenecteplase group and 1.8 % in the placebo group (P = 0.42) [8]. These results were combined with the other thrombolytic trials in a recent meta-analysis [9]. In patients with intermediate-risk PE, thrombolytic therapy was associated with an odds ratio for mortality of 0.42 (95 % CI 0.17–1.03), with an odds ratio for PE-related death of 0.17 (95 % CI 0.05–0.67) and an odds ratio for PE recurrence (which was not included in the main outcome of the PEITHO study), of 0.25 (95 % CI 0.06–1.03.) In the same meta-analysis, thrombolytic treatment was associated with a significantly increased risk of major bleeding (OR 2.91; 95 % CI 1.95–4.36,) and fatal or intracranial haemorrhage
Intern Emerg Med
(OR 3.18; 95 % CI 1.25–8.11) [9]. Thus, thrombolytic therapy is associated with a significant reduction in death due to PE, but with a significant increase of intracranial or fatal bleeding. In patients with intermediate-risk PE, the overall mortality is decreased by 60 % although this difference does not fulfil the criteria for statistical significance. This rather narrow benefit-to-risk ratio precludes the use of thrombolytic therapy in all patients with intermediate-risk PE. This is emphasized in the recent guidelines of the European Society of Cardiology suggesting that ‘‘thrombolytic therapy should be considered for patients with intermediate-high-risk PE and clinical signs of haemodynamic decompensation,’’ but that ‘‘routine use of primary systemic thrombolysis is not recommended in patients not suffering from shock or hypotension’’ [3].
How to increase the risk to benefit ratio of thrombolytic therapy in PE patients? First, all patients do not have the same risk of bleeding, and age is by far the most important risk factor for bleeding. This is exemplified by the PEITHO study where the increase in the risk of major extracranial bleeding associated with tenecteplase is much more pronounced in patients aged greater than 75 years than in younger patients, and where all but one intracranial bleeds occurred in patients aged over 70 years [8]. In the meta-analysis by Marti et al., the association between thrombolytic therapy and the risk of major bleeding was lower in studies using an upper age limit (OR 1.13; 95 % CI 0.47–2.71) than in studies including older patients (OR 3.71; 95 % CI 2.32–5.92) [9]. Second, the use of dose-reduced thrombolytic regimens is also associated with a lower risk of bleeding. This has been suggested with alteplase in patients with PE, and with tenecteplase in patients with acute coronary syndrome [10– 12].Third, thrombolytic treatment should only be given in the sickest patients belonging to the intermediate-high-risk PE category. Even in the PEITHO trial, only 5.8 % of patients died or experienced haemodynamic decompensation in the control group, which is far lower than in recent cohort studies [8]. The threshold for an abnormal troponin value in the PEITHO trial was left to the local laboratory, which is probably a limitation of the study whereas several recent cohort studies strongly suggest that the rate of PErelated complications increases with increasing blood levels of biomarkers [5, 13]. Thus, avoiding the use of thrombolytic therapy in patients aged more than 75 years, reducing the dosage, and reserving its use to the most severely ill patients among intermediate-risk PE patients might allow an increasing benefit to risk ratio of thrombolytic therapy in patients with PE.
In randomized controlled trials, thrombolytic therapy is associated with a significant decrease in death due to PE, and a non-significant reduction in overall mortality in patients with intermediate-risk PE, but this benefit is counterbalanced by a high risk of haemorrhagic stroke or major non-intracranial bleeding. Although cohort studies suggest that this benefit could be larger in intermediate high-risk patients, and indirect evidence based on subgroup analysis in PE trials and on trials performed in acute coronary syndrome suggest that avoiding the use of thrombolytic therapy in patients older than 75 years and the use of reduced dosage may allow increasing the benefit-to-risk ratio, this has not been confirmed in therapeutic trials to date. In summary, these findings support either the restricted use of thrombolytic treatment in young high-risk PE patients selected for their low bleeding risk, or close monitoring to permit early detection of haemodynamic decompensation and timely initiation of ‘rescue’ reperfusion therapy as suggested by the recent guidelines of the European Society of Cardiology [3]. Conflict of interest
None.
References 1. Dalla-Volta S, Palla A, Santolicandro A, Giuntini C, Pengo V, Visioli O, Zonzin P, Zanuttini D, Barbaresi F, Agnelli G et al (1992) PAIMS 2: alteplase combined with heparin versus heparin in the treatment of acute pulmonary embolism. Plasminogen activator Italian multicenter study 2. J Am Coll Cardiol 20:520–526 2. Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, Taveira da Silva AM, Come PC, Lee RT, Parker JA et al (1993) Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 341:507–511 3. Konstantinides SV, Torbicki A, Agnelli G, Danchin N, Fitzmaurice D, Galie N, Gibbs JS, Huisman MV, Humbert M, Kucher N, Lang I, Lankeit M, Lekakis J, Maack C, Mayer E, Meneveau N, Perrier A, Pruszczyk P, Rasmussen LH, Schindler TH, Svitil P, Vonk Noordegraaf A, Zamorano JL, Zompatori M (2014) ESC 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) Endorsed by the European Respiratory Society (ERS). Eur Heart J 35(43):3033–3069 4. Jimenez D, Kopecna D, Tapson V, Briese B, Schreiber D, Lobo JL, Monreal M, Aujesky D, Sanchez O, Meyer G, Konstantinides S, Yusen RD, On Behalf of the Protect I (2014) Derivation and validation of multimarker prognostication for normotensive patients with acute symptomatic pulmonary embolism. Am J Respir Crit Care Med 189:718–726 5. Lankeit M, Jimenez D, Kostrubiec M, Dellas C, Kuhnert K, Hasenfuss G, Pruszczyk P, Konstantinides S (2014) Validation of N-terminal pro-brain natriuretic peptide cut-off values for risk stratification of pulmonary embolism. Eur Respir J 43:1669–1677 6. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW (2004) Thrombolysis compared with heparin for the initial treatment of
123
Intern Emerg Med pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation 110:744–749 7. Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W (2002) Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 347:1143–1150 8. Meyer GVE, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, Bluhmki E, Bouvaist H, Brenner B, Couturaud F, Dellas C, Empen K, Franca A, Galie` N, Geibel A, Goldhaber SZ, Jimenez D, Kozak M, Kupatt C, Kucher N, Lang IM, Lankeit M, Meneveau N, Pacouret G, Palazzini M, Petris A, Pruszczyk P, Rugolotto M, Salvi A, Schellong S, Sebbane M, Sobkowicz M, Stefanovic BS, Thiele H, Torbicki A, Verschuren F, Konstantinides SV, For the PEITHO Investigators (2014) Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 370:1402–1411 9. Marti C, John G, Konstantinides S, Combescure C, Sanchez O, Lankeit M, Meyer G, Perrier A (2014) Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J [Epub ahead of print]
123
10. Sors H, Pacouret G, Azarian R, Meyer G, Charbonnier B, Simonneau G (1994) Hemodynamic effects of bolus vs 2-h infusion of alteplase in acute massive pulmonary embolism. A randomized controlled multicenter trial. Chest 106:712–717 11. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M (2013) Moderate pulmonary embolism treated with thrombolysis (from the ‘‘MOPETT’’ Trial). Am J Cardiol 111:273–277 12. Armstrong PW, Gershlick AH, Goldstein P, Wilcox R, Danays T, Lambert Y, Sulimov V, Rosell Ortiz F, Ostojic M, Welsh RC, Carvalho AC, Nanas J, Arntz HR, Halvorsen S, Huber K, Grajek S, Fresco C, Bluhmki E, Regelin A, Vandenberghe K, Bogaerts K, Van de Werf F (2013) Fibrinolysis or primary PCI in STsegment elevation myocardial infarction. N Engl J Med 368:1379–1387 13. Sanchez O, Trinquart L, Caille V, Couturaud F, Pacouret G, Meneveau N, Verschuren F, Roy PM, Parent F, Righini M, Perrier A, Lorut C, Tardy B, Benoit MO, Chatellier G, Meyer G (2010) Prognostic factors for pulmonary embolism: the prep study, a prospective multicenter cohort study. Am J Respir Crit Care Med 181:168–173
