Prognostic Significance of Deep Vein Thrombosis in Patients Presenting with Acute Symptomatic Pulmonary Embolism David Jime´nez1, Drahomir Aujesky2, Gema Dı´az3, Manuel Monreal4, Remedios Otero5, David Martı´6, Elena Marı´n7, Enrique Aracil7, Antonio Sueiro1, Roger D. Yusen8, and the RIETE Investigators* Am J Respir Crit Care Med Vol 181. pp 983–991, 2010 R3 채정민

INTRODUCTION In patients with acute pulmonary embolism –mortality rates during the first 3 months of treatment: 1.4 ~ 17.4%, but heterogenous among studies PE-associated complications (acute PAH and right HF) or PE recurrence –Most commonly cause early deaths after PE The aim of the initial management of PE with DVT –prevent fatal and nonfatal recurrent VTE and PAH –prevention of the postthrombotic syndrome –At high risk of early death → more intensive surveillance or aggressive therapy –At low risk of early complications (death, recurrent VTE, and major bleeding) → partial or complete outpatient treatment of their PE

INTRODUCTION acute PE is related to a high prevalence (up to 61%) of concomitant DVT the association between concomitant DVT at the time of PE diagnosis and VTE recurrence rates ?? This study aimed to assess the association between the presence of concomitant DVT and the risk of death in patients with a first, objectively confirmed episode of acute symptomatic PE To achieve this aim, we conducted a prospective cohort study, and we externally and retrospectively validated our findings in a large independent cohort of patients

methods Prostectively screened from January 2003 through October 2007 Emergency Department of Ramo´n y Cajal Hospital Patients who underwent evaluation for possible acute PE (e.g., new or worsening dyspnea or chest pain) Eligibility criteria –patients with a first episode of objectively confirmed acute symptomatic PE Exclusion criteria –those with a history of previous VTE –not successfully complete the protocol-required bilateral lower extremity compression ultrasonography (CCUS)

methods Considered as PE –by high-probability ventilation–perfusion (V/Q) scintigraphy –contrast-enhanced, PE-protocol, helical chest CT - positive –inconclusive ventilation–perfusion scans or negative CT scans that also had a lower limb venous compression ultrasonography positive for proximal DVT assessed signs and symptoms of DVT before CCUS testing bilateral proximal and distal lower extremity CCUS was done within 48 hours of the diagnosis of PE Vein incompressibility was the sole diagnostic criterion for DVT

methods Outcomes were assessed during the 3 months after the diagnosis of acute PE The primary outcome –all-cause mortality secondary outcomes –PE-specific mortality and recurrent symptomatic VTE definite fatal PE –confirmed by autopsy, or if death followed a clinically severe PE possible fatal PE –death of a patient who died suddenly or unexpectedly

methods Recurrent symptomatic VTE –a recurrent PE, or as a new or a recurrent distal or proximal lower extremity DVT, within 3 months A diagnosis of recurrent PE –presence of a new perfusion defect involving 75% or more of a lung segment on V/Q scintigraphy –new intraluminal filling defect or an extension of a previous filling defect on PE-protocol chest CT New or recurrent DVT –the appearance of a new noncompressible vein segment –4-mm or more increase in the diameter of a thrombus on CCUS

methods therapeutic doses of IV unfractionated heparin or SC low molecular weight heparin + oral vitamin K antagonist therapy initiated within 24 to 48 hours of diagnosis Heparin was discontinued after a minimal duration of 5 days initially closely monitored until the INR was stable and between 2 ~ 3 the INR was checked approximately twice per month The quality of oral anticoagulation was considered suboptimal –30% or more of all measured INR values were less than 2.0 Thrombolytic treatment of acute PE was considered in patients with cardiogenic shock In patients with a contraindication to anticoagulant treatment –an inferior vena cava (IVC) filter was inserted

methods Before hospital discharge, patients were instructed to contact the investigators telephonically if symptoms of recurrent PE or new or recurrent DVT occurred Patients with suspected VTE –undergo diagnostic testing without delay patients were seen in the investigators’ outpatient clinic at the end of the 3-month follow-up period

methods chi-square or Fisher’s exact tests –compare categorical data Mann-Whitney U test –Continuous data between the groups Kaplan-Meier probabilities –outcomes of time to death and time to VTE recurrence log-rank test –differences between the groups Cox proportional hazards regression –association between concomitant DVT at the time of presentation with PE and the outcome measures

results

Confounding factor at multivariate analysis

Independent predictor

Independent predictor of recurrent VTE at multivariate analysis

In the RIETE registry : after adjusting for cancer and immobilization concomitant DVT : a significantly higher all-cause mortality (HR: 1.66) independently significant association with PE-specific mortality (HR: 2.01)

discussion patients with acute symptomatic PE and concomitant DVT : had a higher short-term risk for all-cause death, PE-related death, and recurrent VTE The risk of death among patients with concomitant DVT : about two times higher the risk of recurrent VTE and PE-specific death : about four times higher than in patients without DVT The large RIETE validation cohort confirmed the prognostic significance

discussion The prevalence of ultrasound (CCUS)-detectable DVT in the study cohort : 51% V/Q scan-proven PE had concurrent DVT : 45% (similar) venographically detected DVT in patients with angiography- proven PE : 82% (lower) This discrepancy may be explained –the lower sensitivity of CCUS compared with lower limb venography –CCUS diagnoses DVT in only about half of the patients who have symptoms or clinical signs of DVT

discussion conflicting data regarding the association between concomitant DVT at the time of PE diagnosis and the risk of VTE recurrence Predicting adverse outcome in patients with acute pulmonary embolism: a risk score Wicki J, Perrier A, Perneger TV, Bounameaux H, Junod AF Thromb Haemost 2000;84:548–552 Acute pulmonary embolism: clinical outcomes in the international cooperative pulmonary embolism Registry (ICOPER) Goldhaber SZ, Visani L, De Rosa M Lancet 1999;353:24–27 Evaulation du Scanner Spirale´ dans l’Embolie Pulmonaire Study Group. Deep venous thrombosis in patients with acute pulmonary embolism: prevalence, risk factors, and clinical significance Girard P, Sanchez O, Leroyer C, Musset D, Meyer G, Stern JB, Parent F Chest 2005;128:1593–1600

discussion not originally designed to evaluate the impact of concomitant DVT on patient prognosis a large number of exclusion criteria –Pregnancy –major PE –life expectancy of less than 3 months –CT negative for the diagnosis of PE –Anticoagulant treatment for more than 48 hours before entry into the study → led to the selective enrollment of less severely ill patients and strikingly low 3-month mortality rate of 4% strong evidence supporting the concept of this study –large sample size –the adjustment for potential confounders –the robustness of the findings, –the validation of our initial findings in another large cohort

discussion First, because patients with PE who have concomitant DVT have an increased risk of recurrent VTE and PE-related death → they may potentially benefit from more intensive surveillance and treatment such as thrombolysis Second, because patients without concomitant DVT have a relative low rate of VTE recurrence and mortality → these patients may be more optimal candidates for partial or full outpatient PE therapy

discussion suboptimal quality of oral anticoagulation –not associated with a higher risk of overall mortality, PE-related mortality, or recurrent symptomatic VTE Conflicting data exist –the association between poor-quality oral anticoagulation and the risk of VTE recurrence insertion of an inferior vena cava filter –improve outcomes placement of an IVC filter –associated with increased mortality in this study –Maybe associated with disease severity Interventional studies should address the efficacy of placing an IVC filter in patients with PE and concomitant DVT

conclusion In patients with a first episode of acute symptomatic PE the presence of concomitant DVT : an independent predictor of death in the ensuing 3 months after diagnosis Assessment of the thrombotic burden should assist with risk stratification of patients with acute PE