International Journal of Cardiology 187 (2015) 645–647
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Are direct oral anticoagulants equally effective in reducing deep vein thrombosis and pulmonary embolism? Nicola Mumoli a, Marco Cei a, Raffaele Pesavento b, Mauro Campanini c, Francesco Dentali d,⁎ a
Department of Internal Medicine, Ospedale Civile di Livorno, Italy Department of Medicine, Internal Medicine 3, Vascular Unit, University of Padua, Padua, Italy Department of Internal Medicine, AOU Maggiore della Carità, Novara, Italy d Department of Clinical Medicine, Insubria University, Varese, Italy b c
a r t i c l e
i n f o
Article history: Received 27 January 2015 Accepted 25 March 2015 Available online 27 March 2015 Keywords: Direct oral anticoagulants Deep vein thrombosis Pulmonarty embolism Venous thromboembolism
Dear Sirs, Venous thromboembolism (VTE) is the third cause of morbidity and mortality in western countries with an incidence rate of 1–3 per 1000 individuals/year [1]. In recent years, new direct oral anticoagulants (DOAC) have been developed, including factor IIa and FXa inhibitors, and a number of randomized controlled trials (RCTs) in patients with acute VTE showed a comparable efficacy and a superior safety of DOAC compared to vitamin K antagonist (VKA) [2,3]. Moreover, data of two recent meta-analyses have further confirmed that these compounds are at least as effective in reducing the VTE recurrences compared to VKAs [4,5]. However, VTE encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE) and the clinical implications of these two expressions of the same disease may be dramatically different. Unfortunately, none of the RCTs has enough power to assess potential differences in the efficacy of these compounds in DVT and PE prevention and published meta-analyses did not assess in particular this aspect. Thus, we performed a systematic review and metaanalysis of the literature in order to overcome this limitation. A protocol detailing objectives, study selection criteria, outcomes evaluation and statistical methods were prospectively developed and ⁎ Corresponding author at: U.O. Medicina Interna, Ospedale di Circolo, Viale Borri 57, 21100 Varese, Italy. E-mail address: [email protected] (F. Dentali).
http://dx.doi.org/10.1016/j.ijcard.2015.03.370 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
this systematic review was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Medline and Embase databases were searched in duplicate by two reviewers up to December 2014 without any language restriction. The search strategy was conducted using medical subject headings and text words and supplemented searching for unpublished trials on the www.clinicaltrials.gov web site. Only RCTs comparing the efficacy and safety of DOACs and VKAs in patients with acute VTE were included in our systematic review. For each selected study, incidence of PE (either fatal or non-fatal with or without an associated DVT) and of isolated DVT (without a concomitant symptomatic PE) in patients randomized to DOACs and to VKAs were separately collected. Differences among groups in the efficacy outcomes were expressed as Risk Ratio (RR) with pertinent 95% confidence intervals (95% CI). The overall effect was tested using Z scores and significance was set at p b 0.05. The random-effect method was used to take into account the variability among included studies. Statistical heterogeneity among the results of single studies and between different outcomes was assessed with chi square Cochran’s Q test. Heterogeneity was considered significant when p b 0.10. Statistical analysis was carried out using Review Manager [Version 5.2, The Cochrane Collaboration, Copenhagen, Denmark]. Publication bias was graphically represented by funnel plots of the effect size versus the standard error. After abstracts and full texts evaluation, six studies for a total of 27,023 patients were included in our systematic review [2,3,6–9]. No additional unpublished studies were identified by searching on www. clinicaltrials.gov (results of search strategy are available upon request). General characteristics of included studies were summarized in Table 1. Four studies compared factor Xa inhibitors (2 rivaroxaban, 1 apixaban and 1 edoxaban), and two a factor IIa inhibitor (dabigatran) to VKA. The primary outcome for efficacy was VTE recurrence and VTE related death. Patients included in the selected studies were treated for a period ranging from 3 to 12 months. Overall, the primary outcome occurred in 271 of 13,512 patients treated with a DOAC, and in 301 of 13,511 patients assigned to VKA treatment (RR 0.91; 95% CI, 0.79, 1.06) thus confirming non-inferiority of DOAC in respect to VKA, in the absence of heterogeneity among studies (I2 = 0%). Funnel plot of effect size versus standard error was symmetrical, suggesting the absence of publication bias (plot available upon request). Considering isolated DVT as endpoint, there were 150 events (1.11%) in patients treated with DOAC and 176 events (1.30%) in patients treated with
646
N. Mumoli et al. / International Journal of Cardiology 187 (2015) 645–647
Table 1 General characteristics of included studies. Study
Drug
DOAC treatment
Duration
Age (mean)
Males
Study population
RECOVER I 2009
Dabigatran
Heparin ≥5 days followed by DAB 150 mg/BID
6 months
55 years
58%
EINSTEIN-DVT 2010
Rivaroxaban
3–6 — 12 months
56 years
57%
EINSTEIN-PE 2012
Rivaroxaban
3–6 — 12 months
58 years
53%
AMPLIFY 2013
Apixaban
6 months
57 years
59%
HOKUSAI 2013
Edoxaban
15 mg/BID (3 weeks) +20 mg/OD 15 mg/BID (3 weeks) +20 mg/OD 10 mg/BID (1 week) +5 mg/BID Heparin ≥5 days followed by EDO 60 mg/OD
3–12 months
56 years
57%
RECOVER II 2014
Dabigatran
Heparin ≥5 days followed by DAB 150 mg/BID
6 months
55 years
61%
DOAC group: 1274 VKA group: 1265 DOAC group: 1731 VKA group: 1718 DOAC group: 2419 VKA group: 2413 DOAC group: 2691 VKA group: 2704 DOAC group: 4118 VKA group: 4122 DOAC group: 1279 VKA group: 1289
BID: twice daily; OD: once daily; DOAC: direct oral anticoagulant; VKA: vitamin K antagonist; DAB: Dabigatran; EDO: Edoxaban
VKA resulting in a similar efficacy of the two treatments (RR 0.85; 95% CI 0.64, 1.13), with a non-significant heterogeneity among the studies (I2 = 36%, p = 0.16), Fig. 1a. Again, when we consider fatal and nonfatal PE as endpoint, there were 193 events (1.43%) in patients treated with DOAC and 176 events (1.30%) in patients treated with VKA for a resulting similar efficacy of the two treatments (RR 0.99; 95% CI 0.81, 1.21), with no heterogeneity among the studies (I2 = 0%; p = 0.46), Fig. 1b. The efficacy of DOACs compared to VKA appeared similar in reducing the incidence of isolated DVT and the incidence of PE (heterogeneity among the two endpoints: I2 = 0%, p = 0.40). All the six selected studies and two recent meta-analyses pooling data of these studies demonstrated a similar efficacy of DOACs compared to VKAs in reducing the composite end point of VTE recurrence and VTE related death in patients treated for an acute episode of VTE. As a further step, in our meta-analysis, we demonstrated a similar efficacy of these compounds compared to VKAs in reducing both isolated DVT and PE. Our results may have some important clinical implications since a number of prospective cohort studies and large registries have clearly shown that patients presenting with PE had a worse short and long term prognosis in comparison to patients presenting with DVT [10,11]. Opposite to DVT, clinical presentation as acute PE deserves hospitalization in the majority of patients. Furthermore, PE patients
have a higher short and long-term risk of death and the incidence of chronic thromboembolic pulmonary hypertension is not negligible in this group of patients. Thus, the evidence of a similar efficacy of DOACs compared to VKAs in reducing also the incidence of PE further supports their use in the management of patients presenting with acute VTE. Our meta-analysis has some potential limitations. This is a retrospective study, therefore results should be considered hypothesis generating only. Furthermore, patients enrolled in the RCTs included in our metaanalysis may be highly selected and not representative of general patients with VTE. Thus, our results should be interpreted with caution. In conclusion, DOACs appeared equally effective in comparison to VKAs in reducing both isolated DVT and fatal and non-fatal PE further supporting their use in patients with an acute episode of VTE. Other properly designed studies are warranted to confirm our preliminary findings.
Conflict of interest The authors report no relationships that could be construed as a conflict of interest.
Fig. 1. Efficacy of DOACs in comparison to VKAs in preventing DVT (1a) and PE (1b).
N. Mumoli et al. / International Journal of Cardiology 187 (2015) 645–647
References [1] S.Z. Goldhaber, Venous thromboembolism: epidemiology and magnitude of the problem, Best Pract. Res. Clin. Haematol. 235–242 (2012). [2] EINSTEIN Investigators, R. Bauersachs, S.D. Berkowitz, B. Brenner, H.R. Buller, H. Decousus, A.S. Gallus, A.W. Lensing, F. Misselwitz, M.H. Prins, G.E. Raskob, A. Segers, P. Verhamme, P. Wells, G. Agnelli, H. Bounameaux, A. Cohen, B.L. Davidson, F. Piovella, S. Schellong, Oral rivaroxaban for symptomatic venous thromboembolism, N. Engl. J. Med. 363 (26) (2010) 2499–2510. [3] G. Agnelli, H.R. Buller, A. Cohen, M. Curto, A.S. Gallus, M. Johnson, U. Masiukiewicz, R. Pak, J. Thompson, G.E. Raskob, J.I. Weitz, AMPLIFY Investigators, Oral apixaban for the treatment of acute venous thromboembolism, N. Engl. J. Med. 369 (9) (2013) 799–808. [4] N. van Es, M. Coppens, S. Schulman, S. Middeldorp, H.R. Büller, Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials, Blood 124 (12) (2014) 1968–1975. [5] T. van der Hulle, J. Kooiman, P.L. den Exter, O.M. Dekkers, F.A. Klok, M.V. Huisman, Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis, J. Thromb. Haemost. 12 (3) (2014) 320–328. [6] S. Schulman, C. Kearon, A.K. Kakkar, P. Mismetti, S. Schellong, H. Eriksson, D. Baanstra, J. Schnee, S.Z. Goldhaber, RE-COVER Study Group, Dabigatran versus warfarin in the treatment of acute venous thromboembolism, N. Engl. J. Med. 361 (24) (2009) 2342–2352.
647
[7] EINSTEIN–PE Investigators, H.R. Büller, M.H. Prins, A.W. Lensin, H. Decousus, B.F. Jacobson, E. Minar, J. Chlumsky, P. Verhamme, P. Wells, G. Agnelli, A. Cohen, S.D. Berkowitz, H. Bounameaux, B.L. Davidson, F. Misselwitz, A.S. Gallus, G.E. Raskob, S. Schellong, A. Segers, Oral rivaroxaban for the treatment of symptomatic pulmonary embolism, N. Engl. J. Med. 366 (14) (2012) 1287–1297. [8] Hokusai-VTE Investigators, H.R. Büller, H. Décousus, M.A. Grosso, M. Mercuri, S. Middeldorp, M.H. Prins, G.E. Raskob, S.M. Schellong, L. Schwocho, A. Segers, M. Shi, P. Verhamme, P. Wells, Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism, N. Engl. J. Med. 369 (15) (2013) 1406–1415. [9] S. Schulman, A.K. Kakkar, S.Z. Goldhaber, S. Schellong, H. Eriksson, P. Mismetti, A.V. Christiansen, J. Friedman, F. Le Maulf, N. Peter, C. Kearon, RE-COVER II Trial Investigators, Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis, Circulation 129 (7) (2014) 764–772. [10] S. Laporte, P. Mismetti, H. Décousus, F. Uresandi, R. Otero, J.L. Lobo, M. Monreal, RIETE Investigators, 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 117 (13) (2008) 1711–1716. [11] V. Pengo, A.W. Lensing, M.H. Prins, A. Marchiori, B.L. Davidson, F. Tiozzo, P. Albanese, A. Biasiolo, C. Pegoraro, S. Iliceto, P. Prandoni, Thromboembolic Pulmonary Hypertension Study Group, Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism, N. Engl. J. Med. 350 (22) (2004) 2257–2264.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Are direct oral anticoagulants equally effective in reducing deep vein thrombosis and pulmonary embolism? Nicola Mumoli a, Marco Cei a, Raffaele Pesavento b, Mauro Campanini c, Francesco Dentali d,⁎ a
Department of Internal Medicine, Ospedale Civile di Livorno, Italy Department of Medicine, Internal Medicine 3, Vascular Unit, University of Padua, Padua, Italy Department of Internal Medicine, AOU Maggiore della Carità, Novara, Italy d Department of Clinical Medicine, Insubria University, Varese, Italy b c
a r t i c l e
i n f o
Article history: Received 27 January 2015 Accepted 25 March 2015 Available online 27 March 2015 Keywords: Direct oral anticoagulants Deep vein thrombosis Pulmonarty embolism Venous thromboembolism
Dear Sirs, Venous thromboembolism (VTE) is the third cause of morbidity and mortality in western countries with an incidence rate of 1–3 per 1000 individuals/year [1]. In recent years, new direct oral anticoagulants (DOAC) have been developed, including factor IIa and FXa inhibitors, and a number of randomized controlled trials (RCTs) in patients with acute VTE showed a comparable efficacy and a superior safety of DOAC compared to vitamin K antagonist (VKA) [2,3]. Moreover, data of two recent meta-analyses have further confirmed that these compounds are at least as effective in reducing the VTE recurrences compared to VKAs [4,5]. However, VTE encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE) and the clinical implications of these two expressions of the same disease may be dramatically different. Unfortunately, none of the RCTs has enough power to assess potential differences in the efficacy of these compounds in DVT and PE prevention and published meta-analyses did not assess in particular this aspect. Thus, we performed a systematic review and metaanalysis of the literature in order to overcome this limitation. A protocol detailing objectives, study selection criteria, outcomes evaluation and statistical methods were prospectively developed and ⁎ Corresponding author at: U.O. Medicina Interna, Ospedale di Circolo, Viale Borri 57, 21100 Varese, Italy. E-mail address: [email protected] (F. Dentali).
http://dx.doi.org/10.1016/j.ijcard.2015.03.370 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
this systematic review was conducted according to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Medline and Embase databases were searched in duplicate by two reviewers up to December 2014 without any language restriction. The search strategy was conducted using medical subject headings and text words and supplemented searching for unpublished trials on the www.clinicaltrials.gov web site. Only RCTs comparing the efficacy and safety of DOACs and VKAs in patients with acute VTE were included in our systematic review. For each selected study, incidence of PE (either fatal or non-fatal with or without an associated DVT) and of isolated DVT (without a concomitant symptomatic PE) in patients randomized to DOACs and to VKAs were separately collected. Differences among groups in the efficacy outcomes were expressed as Risk Ratio (RR) with pertinent 95% confidence intervals (95% CI). The overall effect was tested using Z scores and significance was set at p b 0.05. The random-effect method was used to take into account the variability among included studies. Statistical heterogeneity among the results of single studies and between different outcomes was assessed with chi square Cochran’s Q test. Heterogeneity was considered significant when p b 0.10. Statistical analysis was carried out using Review Manager [Version 5.2, The Cochrane Collaboration, Copenhagen, Denmark]. Publication bias was graphically represented by funnel plots of the effect size versus the standard error. After abstracts and full texts evaluation, six studies for a total of 27,023 patients were included in our systematic review [2,3,6–9]. No additional unpublished studies were identified by searching on www. clinicaltrials.gov (results of search strategy are available upon request). General characteristics of included studies were summarized in Table 1. Four studies compared factor Xa inhibitors (2 rivaroxaban, 1 apixaban and 1 edoxaban), and two a factor IIa inhibitor (dabigatran) to VKA. The primary outcome for efficacy was VTE recurrence and VTE related death. Patients included in the selected studies were treated for a period ranging from 3 to 12 months. Overall, the primary outcome occurred in 271 of 13,512 patients treated with a DOAC, and in 301 of 13,511 patients assigned to VKA treatment (RR 0.91; 95% CI, 0.79, 1.06) thus confirming non-inferiority of DOAC in respect to VKA, in the absence of heterogeneity among studies (I2 = 0%). Funnel plot of effect size versus standard error was symmetrical, suggesting the absence of publication bias (plot available upon request). Considering isolated DVT as endpoint, there were 150 events (1.11%) in patients treated with DOAC and 176 events (1.30%) in patients treated with
646
N. Mumoli et al. / International Journal of Cardiology 187 (2015) 645–647
Table 1 General characteristics of included studies. Study
Drug
DOAC treatment
Duration
Age (mean)
Males
Study population
RECOVER I 2009
Dabigatran
Heparin ≥5 days followed by DAB 150 mg/BID
6 months
55 years
58%
EINSTEIN-DVT 2010
Rivaroxaban
3–6 — 12 months
56 years
57%
EINSTEIN-PE 2012
Rivaroxaban
3–6 — 12 months
58 years
53%
AMPLIFY 2013
Apixaban
6 months
57 years
59%
HOKUSAI 2013
Edoxaban
15 mg/BID (3 weeks) +20 mg/OD 15 mg/BID (3 weeks) +20 mg/OD 10 mg/BID (1 week) +5 mg/BID Heparin ≥5 days followed by EDO 60 mg/OD
3–12 months
56 years
57%
RECOVER II 2014
Dabigatran
Heparin ≥5 days followed by DAB 150 mg/BID
6 months
55 years
61%
DOAC group: 1274 VKA group: 1265 DOAC group: 1731 VKA group: 1718 DOAC group: 2419 VKA group: 2413 DOAC group: 2691 VKA group: 2704 DOAC group: 4118 VKA group: 4122 DOAC group: 1279 VKA group: 1289
BID: twice daily; OD: once daily; DOAC: direct oral anticoagulant; VKA: vitamin K antagonist; DAB: Dabigatran; EDO: Edoxaban
VKA resulting in a similar efficacy of the two treatments (RR 0.85; 95% CI 0.64, 1.13), with a non-significant heterogeneity among the studies (I2 = 36%, p = 0.16), Fig. 1a. Again, when we consider fatal and nonfatal PE as endpoint, there were 193 events (1.43%) in patients treated with DOAC and 176 events (1.30%) in patients treated with VKA for a resulting similar efficacy of the two treatments (RR 0.99; 95% CI 0.81, 1.21), with no heterogeneity among the studies (I2 = 0%; p = 0.46), Fig. 1b. The efficacy of DOACs compared to VKA appeared similar in reducing the incidence of isolated DVT and the incidence of PE (heterogeneity among the two endpoints: I2 = 0%, p = 0.40). All the six selected studies and two recent meta-analyses pooling data of these studies demonstrated a similar efficacy of DOACs compared to VKAs in reducing the composite end point of VTE recurrence and VTE related death in patients treated for an acute episode of VTE. As a further step, in our meta-analysis, we demonstrated a similar efficacy of these compounds compared to VKAs in reducing both isolated DVT and PE. Our results may have some important clinical implications since a number of prospective cohort studies and large registries have clearly shown that patients presenting with PE had a worse short and long term prognosis in comparison to patients presenting with DVT [10,11]. Opposite to DVT, clinical presentation as acute PE deserves hospitalization in the majority of patients. Furthermore, PE patients
have a higher short and long-term risk of death and the incidence of chronic thromboembolic pulmonary hypertension is not negligible in this group of patients. Thus, the evidence of a similar efficacy of DOACs compared to VKAs in reducing also the incidence of PE further supports their use in the management of patients presenting with acute VTE. Our meta-analysis has some potential limitations. This is a retrospective study, therefore results should be considered hypothesis generating only. Furthermore, patients enrolled in the RCTs included in our metaanalysis may be highly selected and not representative of general patients with VTE. Thus, our results should be interpreted with caution. In conclusion, DOACs appeared equally effective in comparison to VKAs in reducing both isolated DVT and fatal and non-fatal PE further supporting their use in patients with an acute episode of VTE. Other properly designed studies are warranted to confirm our preliminary findings.
Conflict of interest The authors report no relationships that could be construed as a conflict of interest.
Fig. 1. Efficacy of DOACs in comparison to VKAs in preventing DVT (1a) and PE (1b).
N. Mumoli et al. / International Journal of Cardiology 187 (2015) 645–647
References [1] S.Z. Goldhaber, Venous thromboembolism: epidemiology and magnitude of the problem, Best Pract. Res. Clin. Haematol. 235–242 (2012). [2] EINSTEIN Investigators, R. Bauersachs, S.D. Berkowitz, B. Brenner, H.R. Buller, H. Decousus, A.S. Gallus, A.W. Lensing, F. Misselwitz, M.H. Prins, G.E. Raskob, A. Segers, P. Verhamme, P. Wells, G. Agnelli, H. Bounameaux, A. Cohen, B.L. Davidson, F. Piovella, S. Schellong, Oral rivaroxaban for symptomatic venous thromboembolism, N. Engl. J. Med. 363 (26) (2010) 2499–2510. [3] G. Agnelli, H.R. Buller, A. Cohen, M. Curto, A.S. Gallus, M. Johnson, U. Masiukiewicz, R. Pak, J. Thompson, G.E. Raskob, J.I. Weitz, AMPLIFY Investigators, Oral apixaban for the treatment of acute venous thromboembolism, N. Engl. J. Med. 369 (9) (2013) 799–808. [4] N. van Es, M. Coppens, S. Schulman, S. Middeldorp, H.R. Büller, Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials, Blood 124 (12) (2014) 1968–1975. [5] T. van der Hulle, J. Kooiman, P.L. den Exter, O.M. Dekkers, F.A. Klok, M.V. Huisman, Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis, J. Thromb. Haemost. 12 (3) (2014) 320–328. [6] S. Schulman, C. Kearon, A.K. Kakkar, P. Mismetti, S. Schellong, H. Eriksson, D. Baanstra, J. Schnee, S.Z. Goldhaber, RE-COVER Study Group, Dabigatran versus warfarin in the treatment of acute venous thromboembolism, N. Engl. J. Med. 361 (24) (2009) 2342–2352.
647
[7] EINSTEIN–PE Investigators, H.R. Büller, M.H. Prins, A.W. Lensin, H. Decousus, B.F. Jacobson, E. Minar, J. Chlumsky, P. Verhamme, P. Wells, G. Agnelli, A. Cohen, S.D. Berkowitz, H. Bounameaux, B.L. Davidson, F. Misselwitz, A.S. Gallus, G.E. Raskob, S. Schellong, A. Segers, Oral rivaroxaban for the treatment of symptomatic pulmonary embolism, N. Engl. J. Med. 366 (14) (2012) 1287–1297. [8] Hokusai-VTE Investigators, H.R. Büller, H. Décousus, M.A. Grosso, M. Mercuri, S. Middeldorp, M.H. Prins, G.E. Raskob, S.M. Schellong, L. Schwocho, A. Segers, M. Shi, P. Verhamme, P. Wells, Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism, N. Engl. J. Med. 369 (15) (2013) 1406–1415. [9] S. Schulman, A.K. Kakkar, S.Z. Goldhaber, S. Schellong, H. Eriksson, P. Mismetti, A.V. Christiansen, J. Friedman, F. Le Maulf, N. Peter, C. Kearon, RE-COVER II Trial Investigators, Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis, Circulation 129 (7) (2014) 764–772. [10] S. Laporte, P. Mismetti, H. Décousus, F. Uresandi, R. Otero, J.L. Lobo, M. Monreal, RIETE Investigators, 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 117 (13) (2008) 1711–1716. [11] V. Pengo, A.W. Lensing, M.H. Prins, A. Marchiori, B.L. Davidson, F. Tiozzo, P. Albanese, A. Biasiolo, C. Pegoraro, S. Iliceto, P. Prandoni, Thromboembolic Pulmonary Hypertension Study Group, Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism, N. Engl. J. Med. 350 (22) (2004) 2257–2264.
