European Heart Journal Advance Access originally published online on September 7, 2007
European Heart Journal 2007 28(20):2430-2431; doi:10.1093/eurheartj/ehm366
Functional limitation and right ventricular dysfunction at 6-month follow-up in patients with non-massive pulmonary embolism: useful outcomes for testing therapy of acute submassive pulmonary embolism?
Unit of Cardiology, ‘Ospedale dei Pellegrini’, ASL NA1, Naples, Italy
* Corresponding author. Tel: +39 081 2543536; fax: +39 081 2543536. E-mail address: vpalmier{at}med.cornell.edu
This editorial refers to ‘Echocardiographic and functional cardiopulmonary problems 6 months after first-time pulmonary embolism in previously healthy patients’ by B.G. Stevinson et al., on page 2517
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
Acute pulmonary embolism (PE) is a syndrome with a significant annual incidence, potentially associated with an elevated morality rate.1 Patients presenting with acute PE and persistent systemic hypotension, cardiogenic shock, or cardiac arrest are classified as having massive PE; in the absence of haemodynamic instability, PE is defined generically as non-massive. The latter, however, is classified as submassive acute PE in the presence of right ventricular (RV) dysfunction,1 to indicate that patients with normotensive acute PE and RV dysfunction may suddenly need escalation of therapy (vasopressor and/or inotropic support, rescue fibrinolysis, cardiopulmonary resuscitation).2–4
While clinical manifestation of acute PE may vary widely and significantly between patients, acute RV dysfunction is more quantifiable and uniform objective information in PE with relation to the severity of pulmonary vascular impairment.5 RV failure is the prominent cause of death in acute PE. This is further supported by the fact that in the setting of non-massive acute PE, RV dysfunction correlates with brain natriuretic peptide and troponins, which are in turn biomarkers of the severity of RV overload,6 providing additional information for risk stratification of the heterogeneous group of patients with normotensive PE.7–11 However, whether aggressive treatment (i.e. fibrinolysis or catheter-based pulmonary embolectomy) should be employed in acute submassive PE in addition to anticoagulation is controversial.1 In fact, while fibrinolysis or thromboembolectomy are associated with partial recovery of RV dysfunction,12 there is non-conclusive evidence of the superiority of fibrinolysis over anticoagulation alone. The only randomized controlled study available in acute submassive PE found that alteplase was associated with a reduction in the need for rescue fibrinolysis, which, however, did not impact significantly on the 30 day mortality rate.13 The impact of fibrinolysis in submassive PE on long-term prevention of persistent RV dysfunction, pulmonary hypertension, and quality of life is less well established. To this extent, it appears a logical approach to assess long-term outcome related to RV dysfunction for assessment of the global impact of acute management of submassive PE.
Stevinson et al.14 showed that at 6-month follow-up, a significant proportion (41%) of previously healthy patients with first-time non-massive PE (50% with submassive PE) had functional limitation [i.e. a 6-min walk test (6MWT) < 330 m or NYHA class > 2] or echocardiographic RV dysfunction.14 Therefore, functional limitation and/or RV dysfunction at 6-month follow-up are proposed as additive end-points to be accounted for in treatment studies of PE.
Does this study provide useful information for better understanding of the natural history of non-massive PE? No doubt. Is the information provided by this study14 really useful to re-think studies on treatment of submassive PE? Hardly.
First, all patients evaluated by Stevinson et al.14 were previously healthy. While such a peculiarity of the study is used to reinforce the relevance of the outcome at 6-month follow-up, it also represents an intrinsic limitation of the study, because the study sample does not fully represent the population of patients with PE, who most often are affected by co-morbidity; thus, the results of the study cannot be generalized. However, and importantly, the truth is that RV dysfunction and functional limitation may be even more incident in unselected patients surviving to acute submassive PE, with a potentially significant impact of the disability on public heath and general welfare.
Secondly, in the study by Stevinson et al.,14 echocardiographic RV dysfunction at baseline performed poorly in predicting the composite outcome at 6 months. The authors stressed that for identification of the outcome at 6-month follow-up (abnormal functional capacity and/or RV dysfunction) accuracy was higher with RV hypokinesis at baseline than with RV dilatation or estimated pulmonary pressure above 40 mmHg. Notwithstanding this, the positive predictive value associated with acute RV hypokinesis for identification of ‘pulmonary problems’ at 6-month follow-up was only 26%. Only nine patients (33%) had functional limitation among the 27 with RV dysfunction at 6-month follow-up, whereas functional limitation was reported in 18 patients among those without RV dysfunction at 6 months (18/82, 22%); therefore, there was no clinically significant concordance between RV dysfunction and functional limitation at 6-month follow-up. Therefore, in a clinical scenario in single patients, RV hypokinesis or RV dilatation at rest at the diagnosis of non-massive PE does not appear to be a reliable indicator of outcome at 6 months. Conversely, the data of Stevinson et al. showed that the absence of RV dysfunction may really predict a benign clinical course with a specificity of 80%, reinforcing previous data.15 On the other hand, the study by Stevinson et al. may be affected by the survival effect. The authors only evaluated survivors to acute submassive PE, and recorded four deaths during the observation period, all in patients with RV dysfunction at baseline. Thus, whether 6-month follow-up RV dysfunction or functional disability are useful end-points for assessment of treatment studies of acute submassive PE remains elusive. Patients with vascular obstruction of < 50% of the pulmonary vascular bed are more likely to present with non-massive PE, and tend to show a bimodal temporal trend of the mortality rate, with a first significant peak within 10 days from presentation, and a second relevant peak between the third and the fourth week following the acute PE event.16 Later, mortality tended to reach a plateau after the third month from the acute event, while co-morbidity tended to emerge as the most important determinant of the prognosis.16 Interestingly, patients with persistent RV dysfunction at discharge after acute PE have a higher rate of recurrent venous thromboembolism and death.17 However, the extent to which fibrinolysis or catheter-based embolectomy in the setting of submassive PE may impact on long-term mortality remains an unresolved issue.
While 41% of patients had ‘cardiopulmonary problems’ at 6-month follow-up, only 20% of the study sample actually expressed some index of poor quality of life;14 "feeling unable to do the shopping" most often identified poor quality of life, whereas only 8% of the patients evaluated in the study had both RV dysfunction and functional limitation. Whether "feeling unable to do the shopping" may be considered as a reliable index of functional limitation is unclear; on the other hand, in the study population, 87% reported improved heath status after the hospitalization for PE.
Therefore, treatment strategies having resolution of acute RV dysfunction as the therapeutic target in acute PE should be evaluated against short-term end-points. In this regard, assessment of troponins11,15,18,19 and of brain natriuretic peptide9 may be useful to refine prognostic stratification of submassive acute PE by contributing to the identification of patients in whom the short- and long-term benefit of fibrinolysis or catheter-based embolectomy20 may be superior to risks of treatment. Nevertheless, the pathophysiological relationship between acute management of submassive PE vs. long-term persistent RV dysfunction and functional disability in submassive PE remains to be clarified in large randomized controlled trials.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehm295 
References
- European Society of Cardiology Task Force on Pulmonary Embolism. Guidelines on diagnosis and management of acute pulmonary embolism. Eur Heart J (2000) 21:1301–1336.
[Free Full Text] - 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) 165:1777–1781.
[Abstract/Free Full Text] - Grifoni S, Olivotto I, Cecchini P, Pieralli F, Camaiti A, Santoro G, Conti A, Agnelli G, Berni G. Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure, and echocardiographic right ventricular dysfunction. Circulation (2000) 101:2817–2822.
[Abstract/Free Full Text] - Quiroz R, Kucher N, Schoepf UJ, Kipfmueller F, Solomon SD, Costello P, Goldhaber SZ. Right ventricular enlargement on chest computed tomography: prognostic role in acute pulmonary embolism. Circulation (2004) 109:2401–2404.
[Abstract/Free Full Text] - Miniati M, Monti S, Pratali L, Di Ricco G, Marini C, Formichi B, Prediletto R, Michelassi C, Di Lorenzo M, Tonelli L, Pistolesi M. Value of transthoracic echocardiography in the diagnosis of pulmonary embolism: results of a prospective study in unselected patients. Am J Med (2001) 110:528–535.[CrossRef][Web of Science][Medline]
- Kucher N, Goldhaber SZ. Cardiac biomarkers for risk stratification of patients with acute pulmonary embolism. Circulation (2003) 108:2191–2194.
[Free Full Text] - Giannitsis E, Muller-Bardorff M, Kurowski V, Weidtmann B, Wiegand U, Kampmann M, Katus HA. Independent prognostic value of cardiac troponin T in patients with confirmed pulmonary embolism. Circulation (2000) 102:211–217.
[Abstract/Free Full Text] - Konstantinides S, Geibel A, Olschewski M, Kasper W, Hruska N, Jackle S, Binder L. Importance of cardiac troponins I and T in risk stratification of patients with acute pulmonary embolism. Circulation (2002) 106:1263–1268.
[Abstract/Free Full Text] - Binder L, Pieske B, Olschewski M, Geibel A, Klostermann B, Reiner C, Konstantinides S. N-terminal pro-brain natriuretic peptide or troponin testing followed by echocardiography for risk stratification of acute pulmonary embolism. Circulation (2005) 112:1573–1579.
[Abstract/Free Full Text] - Kline JA, Hernandez-Nino J, Rose GA, Norton HJ, Camargo CA Jr. Surrogate markers for adverse outcomes in normotensive patients with pulmonary embolism. Crit Care Med (2006) 34:2773–2780.[CrossRef][Web of Science][Medline]
- Gallotta G, Palmieri V, Piedimonte V, Rendina D, De Bonis S, Russo V, Celentano A, Di Minno MN, Postiglione A, Di Minno G. Increased troponin I predicts in-hospital occurrence of hemodynamic instability in patients with sub-massive or non-massive pulmonary embolism independent to clinical, echocardiographic and laboratory information. Int J Cardiol (2007) (E-pub ahead of print, March 23).
- Kipfmueller F, Quiroz R, Goldhaber SZ, Schoepf UJ, Costello P, Kucher N. Chest CT assessment following thrombolysis or surgical embolectomy for acute pulmonary embolism. Vasc Med (2005) 10:85–89.
[Abstract/Free Full Text] - Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med (2002) 347:1143–1150.
[Abstract/Free Full Text] - Stevinson BG, Hernandez-Nino J, Rose G, Kline JA. Echocardiographic and functional cardiopulmonary problems 6 months after first-time pulmonary embolism in previously healthy patients. Eur Heart J. doi:10.1093/eurheartj/ehm295.
- Kucher N, Wallmann D, Carone A, Windecker S, Meier B, Hess OM. Incremental prognostic value of troponin I and echocardiography in patients with acute pulmonary embolism. Eur Heart J (2003) 24:1651–1656.
[Abstract/Free Full Text] - Miniati M, Monti S, Bottai M, Scoscia E, Bauleo C, Tonelli L, Dainelli A, Giuntini C. Survival and restoration of pulmonary perfusion in a long-term follow-up of patients after acute pulmonary embolism. Medicine (Baltimore) (2006) 85:253–262.[CrossRef][Medline]
- Grifoni S, Vanni S, Magazzini S, Olivotto I, Conti A, Zanobetti M, Polidori G, Pieralli F, Peiman N, Becattini C, Agnelli G. Association of persistent right ventricular dysfunction at hospital discharge after acute pulmonary embolism with recurrent thromboembolic events. Arch Intern Med (2006) 166:2151–2156.
[Abstract/Free Full Text] - Zhu L, Yang YH, Wu YF, Zhai ZG, Wang C. Value of transthoracic echocardiography combined with cardiac troponin I in risk stratification in acute pulmonary thromboembolism. Chin Med J (2007) 120:17–21.[Web of Science][Medline]
- Logeart D, Lecuyer L, Thabut G, Tabet JY, Tartiere JM, Chavelas C, Bonnin F, Stievenart JL, Solal AC. Biomarker-based strategy for screening right ventricular dysfunction in patients with non-massive pulmonary embolism. Intensive Care Med (2007) 33:286–292.[CrossRef][Web of Science][Medline]
- Kucher N, Windecker S, Banz Y, Schmitz-Rode T, Mettler D, Meier B, Hess OM. Percutaneous catheter thrombectomy device for acute pulmonary embolism: in vitro and in vivo testing. Radiology (2005) 236:852–858.
[Abstract/Free Full Text]
CiteULike 
Connotea 
Del.icio.us What's this?
Related articles in EHJ:
- Echocardiographic and functional cardiopulmonary problems 6 months after first-time pulmonary embolism in previously healthy patients
- Brad G. Stevinson, Jackeline Hernandez-Nino, Geoffrey Rose, and Jeffrey A. Kline
EHJ 2007 28: 2517-2524.[Abstract] [FREE Full Text]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||