Abstract
Rationale: Concomitant deep vein thrombosis (DVT) in patients with acute pulmonary embolism (PE) has an uncertain prognostic significance.
Objectives: In a cohort of patients with PE, this study compared the risk of death in those with and those without concomitant DVT.
Methods: We conducted a prospective cohort study of outpatients diagnosed with a first episode of acute symptomatic PE. Patients underwent bilateral lower extremity venous compression ultrasonography to assess for concomitant DVT.
Measurements and Main Results: The primary study outcome, all-cause mortality, and the secondary outcome of PE-specific mortality were assessed during the 3 months of follow-up after PE diagnosis. Multivariate Cox proportional hazards regression was done to adjust for significant covariates. Of 707 patients diagnosed with PE, 51.2% (362 of 707) had concomitant DVT and 10.9% (77 of 707) died during follow-up. Patients with concomitant DVT had an increased all-cause mortality (adjusted hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.24 to 3.38; P = 0.005) and PE-specific mortality (adjusted HR, 4.25; 95% CI, 1.61 to 11.25; P = 0.04) compared with those without concomitant DVT. In an external validation cohort of 4,476 patients with acute PE enrolled in the international multicenter RIETE Registry, concomitant DVT remained a significant predictor of all-cause (adjusted HR, 1.66; 95% CI, 1.28 to 2.15; P < 0.001) and PE-specific mortality (adjusted HR, 2.01; 95% CI, 1.18 to 3.44; P = 0.01).
Conclusions: In patients with a first episode of acute symptomatic PE, the presence of concomitant DVT is 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.
Risk stratification of patients with pulmonary embolism may identify patients at high risk of early death who may benefit from more intensive surveillance or aggressive therapy. Alternatively, patients deemed low risk for early complications might be considered for partial or complete outpatient treatment of their pulmonary embolism.
In patients with a first episode of acute symptomatic pulmonary embolism, the presence of concomitant deep vein thrombosis is an independent predictor of death in the ensuing 3 months after diagnosis. This study validates the use of the lower extremity venous compression ultrasonography for prognostication and risk stratification of patients with acute symptomatic pulmonary embolism.
The initial management of PE aims to prevent fatal and nonfatal recurrent venous thromboembolism (VTE), and pulmonary arterial hypertension from PE, while it aims to minimize treatment-related complications such as bleeding. For patients with concomitant deep vein thrombosis (DVT), treatment objectives also include the prevention of the postthrombotic syndrome. Risk stratification of patients with PE may identify patients at high risk of early death who may benefit from more intensive surveillance or aggressive therapy (6, 7). Alternatively, patients deemed low risk for early complications (i.e., death, recurrent VTE, and major bleeding) might be considered for partial or complete outpatient treatment of their PE (8, 9).
Studies of patients with proven acute PE have reported a high prevalence (i.e., up to 61%) of concomitant DVT (10). However, studies have shown conflicting data regarding the association between concomitant DVT at the time of PE diagnosis and VTE recurrence rates (1, 11, 12). Although one study found the presence of proximal DVT on compression ultrasonography to be an independent predictor of adverse patient outcomes (i.e., death, recurrent thromboembolism, and major bleeding) (11), two other studies did not confirm these findings (1, 12).
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. Some of the results of this study have been previously reported in the form of an abstract (13).
The Institutional Review Board of Ramón y Cajal Hospital (Madrid, Spain) approved the study. The study methods and results are reported in accordance with the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines (14).
We prospectively screened consecutive adult outpatients from the Emergency Department of Ramón y Cajal Hospital who underwent evaluation for possible acute PE (e.g., new or worsening dyspnea or chest pain) from January 2003 through October 2007 (Figure 1). Patients with a first episode of objectively confirmed acute symptomatic PE were potentially eligible, whereas those with a history of previous VTE were excluded. We also excluded patients who did not successfully complete the protocol-required bilateral lower extremity compression ultrasonography (CCUS). The statistics section provides information regarding the external validation cohort.
Figure 1. Patient flow diagram. CCUS = complete compression ultrasonography; DVT = deep vein thrombosis; PE = pulmonary embolism.
[More] [Minimize]The diagnosis of PE was established by high-probability ventilation–perfusion (V̇/Q̇) scintigraphy (15) or positive contrast-enhanced, PE-protocol, helical chest computerized tomography (CT) (16). Single-detector and multidetector CT were used during the study. The study also considered PE present in patients with inconclusive ventilation–perfusion scans or negative CT scans that also had a lower limb venous compression ultrasonography positive for proximal DVT (17). Ventilation–perfusion scans and CT scans were interpreted by a board-certified radiologist. Other than conducting the clinically indicated lung study and the CCUS, the study did not enforce a diagnostic algorithm.
Investigators assessed patients for signs and symptoms of DVT before CCUS testing. Patients underwent bilateral proximal and distal lower extremity CCUS of the veins within 48 hours of the diagnosis of PE. Trained and certified vascular surgeons, who were unaware of patients' clinical details, used a standardized CCUS protocol and Toshiba Nemio (linear 4- to 7-MHz transducer) ultrasound equipment to evaluate for DVT (18). Vein incompressibility was the sole diagnostic criterion for DVT. Clinicians were made aware of the CCUS results.
Outcomes were assessed during the 3 months after the diagnosis of acute PE. The primary outcome of the study was all-cause mortality. We assessed mortality using patient or proxy interviews, and/or hospital chart review. PE-specific mortality and recurrent symptomatic VTE were secondary outcomes. Two independent experts (authors D.J. and D.M.), blinded to initial CCUS results, adjudicated all causes of death as definite PE, fatal PE, possible fatal PE, or death from other causes. Death was adjudicated as a definite fatal PE if it was confirmed by autopsy, or if death followed a clinically severe PE, either initially or after an objectively confirmed recurrent event. Death of a patient who died suddenly or unexpectedly was classified as possible fatal PE.
Recurrent symptomatic VTE (see the next section) was defined as a recurrent PE, or as a new or a recurrent distal or proximal lower extremity DVT, within 3 months of study entry with acute PE. A diagnosis of recurrent PE was established by the presence of a new perfusion defect involving 75% or more of a lung segment on V̇/Q̇ scintigraphy, or a new intraluminal filling defect or an extension of a previous filling defect on PE-protocol chest CT (16). New or recurrent DVT was diagnosed by the appearance of a new noncompressible vein segment, or a 4-mm or more increase in the diameter of a thrombus on CCUS (19). Cases of VTE recurrence were adjudicated by an independent committee of two clinicians (authors D.J. and D.M.) and two radiologists (authors E.M and E.A.) who were blinded regarding each patient's clinical data. In the case of suspected PE recurrence, the committee members were blinded to previous CCUS findings.
Patients were treated in a similar fashion, although the study did not require strict adherence to a standardized protocol. The study did monitor the adequacy of anticoagulation. Typically, patients initially received therapeutic doses of intravenous unfractionated heparin or subcutaneous low molecular weight heparin, combined with oral vitamin K antagonist therapy that was initiated within 24 to 48 hours of diagnosis. Heparin treatment was discontinued after a minimal duration of 5 days and after two consecutive international normalized ratio (INR) values achieved a value at or exceeding the therapeutic threshold (INR of 2.0). The intensity of oral anticoagulant therapy was initially closely monitored until the INR was stable and between 2.0 and 3.0. Thereafter, the INR was checked approximately twice per month. The quality of oral anticoagulation was considered suboptimal if 30% or more of all measured INR values were less than 2.0 (20).
Thrombolytic treatment of acute PE was considered for use in all patients with cardiogenic shock, which was defined as a persistent systolic arterial pressure of less than 100 mm Hg in the setting of clinical signs of organ hypoperfusion (clouded sensorium, oliguria, cold and clammy skin, or lactic acidosis). In patients with a contraindication to anticoagulant treatment, an inferior vena cava (IVC) filter was inserted. Anticoagulation was later used if the contraindication resolved.
Before hospital discharge, patients were instructed to contact the investigators (blinded to the initial CCUS results) telephonically if symptoms of recurrent PE (e.g., dyspnea, chest pain, tachycardia) or new or recurrent DVT (e.g., unilateral lower extremity edema, redness, tenderness, pain, swelling) occurred. Patients with suspected VTE were instructed to undergo diagnostic testing (see Study Outcome Measures) without delay. Otherwise, patients were seen in the investigators' outpatient clinic at the end of the 3-month follow-up period.
The analyses used chi-square or Fisher's exact tests to compare categorical data between those with and those without concomitant DVT. Variables that used continuous data were tested for a normal distribution with the Kolmogorov-Smirnov test. Continuous data between the groups were compared with the Mann-Whitney U test. To estimate the outcomes of time to death and time to VTE recurrence, Kaplan-Meier probabilities were computed (21), and differences between the groups were assessed with the log-rank test. Cox proportional hazards regression was done to evaluate the association between concomitant DVT at the time of presentation with PE and the outcome measures. Survival analyses censored for loss to follow-up (none) and end of study. In addition, the VTE recurrence models censored for death. A manual backward stepwise approach was used to develop the multivariable models. In the full model, variables with imbalance between the groups at baseline were considered for inclusion. Variables that showed evidence of confounding (i.e., the coefficient of the variable group changed by more than 10% when removing that variable from the full model) for the effect of concomitant DVT on the outcome undergoing analysis were not removed from the model. Statistical significance was defined as a two-tailed P value less than 0.05 for all analyses. Regression diagnostics were performed to assess model assumptions and the effects of outliers and influential cases. Specific candidate variables were forced, one at a time, into the full model to assess their effects. To test the robustness of the models, the effects of excluding patients who received therapy with an IVC filter, thrombolytics, or both, as initial treatment of their PE, were assessed. In addition, we assessed the effects of the removal of patients with nondiagnostic V̇/Q̇ scans or negative contrast-enhanced helical chest CT scans from the models. Analyses were performed with SPSS, version 14.0 for the PC (SPSS, Inc., Chicago, IL).
To externally and retrospectively validate the regression models, patient data from the Registro Informatizado de la Enfermedad Tromboembólica (RIETE) were used. RIETE is an ongoing, international multicenter, observational registry of consecutively enrolled patients, designed to collect and analyze data on treatment patterns and clinical outcomes in patients with acute symptomatic VTE. Study design and patient eligibility criteria of RIETE have been described elsewhere (22). The validation cohort for this study consisted of a subgroup of 4,476 (63%) of the first 7,106 patients enrolled in the RIETE Registry that had acute symptomatic PE, had undergone bilateral lower extremity venous CCUS, had complete CCUS and follow-up data, and had not been included in this study. The final regression models developed in this study were applied to the RIETE data, and the model characteristics were assessed.
Of the 2,845 patients with a clinical suspicion of a first PE screened for the study, 27.0% (768 of 2,845 patients) had an objective diagnosis of PE. Of these, 7.9% (61 of 768 patients) were excluded because they did not have a technically adequate CCUS (n = 28), were unavailable for follow-up (n = 17), or refused to give informed consent (n = 16) (Figure 1). The eligible study cohort of 707 patients included 316 men and 391 women. In the vast majority of patients, PE was diagnosed by a high-probability V̇/Q̇ scan (62%; 439 of 707 patients) or a positive PE-protocol CT (41%; 293 of 707 patients) (Table 1). Diagnosis was based on CCUS results in 28 of the 707 patients (4.0%; 95% confidence interval [CI], 2.5 to 5.4%) Of these 28 patients, 10 had a nondiagnostic V̇/Q̇ scan, 4 had a negative single-row detector contrast-enhanced helical chest CT, and 14 had a nondiagnostic V̇/Q̇ scan and a negative single-row detector contrast-enhanced helical chest CT. CCUS detected DVT in 51.2% of patients (362 of 707 patients); DVT was solely proximal in 351 of 362 (97.0%) of patients, solely distal in 7 of 362 (1.9%) of patients, and proximal and distal in 4 of 362 (1.1%) of patients. Signs or symptoms of DVT were present in 174 of 362 (48%) of the patients with an objective diagnosis of DVT.
Pulmonary embolism confirmed (n = 707) |
| High-probability V̇/Q̇ scan (n = 386) |
| Low clinical probability plus a positive D-dimer test result (n = 122) |
| Intermediate or high clinical probability (n = 264) |
| Positive contrast-enhanced helical chest CT scan (n = 240*) |
| Low clinical probability plus a positive D-dimer test result (n = 43) |
| Intermediate or high clinical probability (n = 197) |
| High-probability V̇/Q̇ scan and positive contrast-enhanced helical chest CT scan (n = 53) |
| Nondiagnostic V̇/Q̇ scan plus deep vein thrombosis on CCUS (n = 10) |
| †Negative contrast-enhanced helical chest CT scan plus deep vein thrombosis on CCUS (n = 4) |
| ‡Negative contrast–enhanced helical chest CT scan, nondiagnostic V̇/Q̇ scan, and deep vein thrombosis on CCUS (n = 14) |
Compared with patients without concomitant DVT, patients with concomitant DVT had a significantly higher prevalence of male sex, cancer, and symptoms or signs of DVT at the time of presentation (Table 2). Patients without concomitant DVT had a higher prevalence of syncope and a history of chest pain.
All Patients (n = 707) | DVT Group (n = 362) | DVT-free Group (n = 345) | P Value | |||||
|---|---|---|---|---|---|---|---|---|
| Clinical characteristics | ||||||||
| Age, yr (mean ± SD) | 68.2 ± 15.9 | 69.0 ± 15.7 | 67.5 ± 16.1 | 0.08 | ||||
| Age >65 yr | 466 (66%) | 246 (68%) | 220 (64%) | 0.27 | ||||
| Male sex | 316 (45%) | 180 (50%) | 136 (39%) | 0.006 | ||||
| Risk factors for VTE | ||||||||
| Cancer* | 162 (23%) | 103 (28%) | 59 (17%) | <0.001 | ||||
| Recent surgery† | 73 (10%) | 31 (9%) | 42 (12%) | 0.14 | ||||
| Immobilization‡ | 124 (17%) | 74 (20%) | 50 (14%) | 0.07 | ||||
| Comorbid diseases | ||||||||
| COPD | 50 (7%) | 19 (5%) | 31 (9%) | 0.06 | ||||
| Congestive heart failure | 45 (6%) | 22 (6%) | 23 (7%) | 0.77 | ||||
| Clinical symptoms and signs at presentation | ||||||||
| Syncope | 88 (12%) | 36 (10%) | 52 (15%) | 0.04 | ||||
| Chest pain | 327 (46%) | 131 (36%) | 196 (57%) | <0.001 | ||||
| Dyspnea | 507 (72%) | 249 (69%) | 258 (75%) | 0.08 | ||||
| Heart rate >100/min | 169 (24%) | 83 (23%) | 86 (25%) | 0.60 | ||||
| Arterial PaO2 <60 mm Hg | 263 (37%) | 123 (34%) | 140 (41%) | 0.67 | ||||
| SBP <100 mm Hg | 54 (8%) | 21 (6%) | 33 (10%) | 0.09 | ||||
| DVT signs or symptoms§ | 186 (26%) | 174 (48%) | 12 (3%) | <0.001 | ||||
| Treatment | ||||||||
| Thrombolytic therapy | 19 (3%) | 10 (3%) | 9 (3%) | 1 | ||||
| Insertion of an IVC filter | 13 (2%) | 12 (3%) | 1 (0.3%) | 0.003 | ||||
| Suboptimal quality of oral anticoagulation‖ | 265 (37%) | 140 (39%) | 125 (36%) | 0.53 | ||||
Patients with concomitant DVT received significantly more inferior vena cava filters than those without concomitant DVT, although the overall number of patients treated with inferior vena cava filters was small (1.8%; 13 of 707 patients). Three percent of patients (19 of 707) in both groups were treated with thrombolytic therapy. The two groups had similar proportions of patients with suboptimal oral anticoagulation (Table 2).
Mortality data were available for all patients at the conclusion of the study. Overall, 77 of 707 patients died (10.9%; 95% confidence interval [CI], 8.9 to 13.4%) during the 3 months of follow-up. Twenty-nine patients (29 of 707 patients; 4.1%; 95% CI, 2.8 to 5.8%) died of definite (n = 8) or possible PE (n = 21), whereas other deaths were caused by cancer (3.5%; 25 of 707 patients), infection (1.1%; 8 of 707 patients), major bleeding (0.6%; 4 of 707 patients), other diseases (1.3%; 9 of 707 patients), and unknown causes (0.3%; 2 of 707 patients). Fifty-five deaths (55 of 362 patients; 15.2%; 95% CI, 11.6 to 19.3%) occurred in the group of patients entering the study with acute PE and concomitant DVT, whereas 22 deaths (22 of 345 patients; 6.4%; 95% CI, 4.0 to 9.5%) occurred in the group without concomitant DVT (absolute difference, 8.8%; 95% CI of the absolute difference, 4.3 to 13.3%; P < 0.001); 24 and 5 deaths were due to definite or possible PE in the two respective groups. Patients with acute PE and concomitant DVT had a significantly higher cumulative mortality than the patients with acute PE and no concomitant DVT (P < 0.001, log-rank test; Figure 2). Separation between survival curves occurred soon after the diagnosis of PE, and the most common cause of death was deterioration due to the initial PE or recurrent PE.
Figure 2. Mortality of patients with acute symptomatic pulmonary embolism, stratified by the presence or absence of concomitant deep vein thrombosis at the time of pulmonary embolism diagnosis. DVT = deep vein thrombosis; PE = pulmonary embolism. Log-rank P < 0.001.
[More] [Minimize]In univariate analyses, patients with objectively confirmed concomitant DVT (hazard ratio [HR], 2.48; 95% CI, 1.51 to 4.07; P < 0.001), DVT signs or symptoms (HR, 1.74; 95% CI, 1.10 to 2.76; P = 0.02), cancer (HR, 3.70; 95% CI, 2.37 to 5.78; P < 0.001), and insertion of an inferior vena cava filter (HR, 3.20; 95% CI, 1.17 to 8.74; P = 0.02) at the time of acute PE diagnosis were significantly more likely to die during follow-up (Table 3). In the multivariate analysis, cancer (HR, 3.69; 95% CI, 2.32 to 5.85; P < 0.001) and immobilization (HR, 1.96; 95% CI, 1.20 to 3.20; P = 0.007) were confounding variables for the association between concomitant DVT and all-cause mortality during follow-up (adjusted HR, 2.05; 95% CI, 1.24 to 3.38; P = 0.005) (Table 3). Using the same model variables, concomitant DVT remained an independent predictor of all-cause mortality when patients who had an IVC filter inserted or were treated with thrombolytic therapy were excluded from the analysis (concomitant DVT, adjusted HR, 2.19; 95% CI, 1.30 to 3.69; P = 0.003). Concomitant DVT remained an independent predictor of all-cause mortality when patients with nondiagnostic V̇/Q̇ scans or negative contrast-enhanced helical chest CT scans (n = 28) were excluded from the analysis (adjusted HR, 2.15; 95% CI, 1.29 to 3.58; P = 0.03). After adjustment, concomitant DVT at the time of presentation was also independently significantly associated with PE-related death (adjusted HR, 4.25; 95% CI, 1.61 to 11.25; P = 0.004) (Table 4).
Risk Factor | Unadjusted HR (95% CI) | P Value | Adjusted HR (95% CI) | P Value |
|---|---|---|---|---|
| Age, per year | 1.01 (0.99–1.02) | 0.22 | — | — |
| Male sex | 1.43 (0.91–2.24) | 0.12 | — | — |
| COPD | 0.93 (0.38–2.31) | 0.88 | — | — |
| Presence of DVT | 2.48 (1.51–4.07) | <0.001 | 2.05 (1.24–3.38) | 0.005 |
| SBP <100 mm Hg | 1.25 (0.57–2.71) | 0.58 | — | — |
| Dyspnea | 0.99 (0.61–1.63) | 0.98 | — | — |
| Chest pain | 0.86 (0.55–1.36) | 0.53 | — | — |
| Syncope | 0.58 (0.25–1.34) | 0.20 | — | — |
| Cancer* | 3.70 (2.37–5.78) | <0.001 | 3.69 (2.32–5.85) | <0.001 |
| Immobilization† | 1.58 (0.99–2.53) | 0.06 | 1.96 (1.20–3.20) | 0.007 |
| DVT signs or symptoms | 1.74 (1.10–2.76) | 0.02 | — | — |
| Insertion of an IVC filter | 3.20 (1.17–8.74) | 0.02 | — | — |
| Suboptimal quality of oral anticoagulation‡ | — | — |
Risk Factor | Unadjusted HR (95% CI) | P Value | Adjusted HR (95% CI) | P Value |
|---|---|---|---|---|
| Age, per year | 1.02 (0.99–1.05) | 0.12 | — | — |
| Male sex | 0.77 (0.36–1.62) | 0.49 | — | — |
| COPD | 1.0 (0.24–4.20) | 1 | — | — |
| Presence of DVT | 4.75 (1.81–12.46) | 0.002 | 4.25 (1.61–11.25) | 0.004 |
| SBP <100 mm Hg | 1.97 (0.69–5.66) | 0.21 | — | — |
| Dyspnea | 0.65 (0.31–1.38) | 0.27 | — | — |
| Chest pain | 0.71 (0.33–1.49) | 0.36 | — | — |
| Syncope | 1.10 (0.38–3.17) | 0.86 | — | — |
| Cancer* | 2.51 (1.20–5.27) | 0.01 | 3.69 (2.32–5.85) | 0.01 |
| Immobilization† | 2.94 (1.66–5.18) | <0.001 | 3.74 (1.94–7.20) | <0.001 |
| DVT signs or symptoms | 1.52 (0.71–3.27) | 0.28 | — | — |
| Insertion of an IVC filter | 2.06 (0.28–15.15) | 0.48 | — | — |
| Suboptimal quality of oral anticoagulation‡ | 1.53 (0.94–2.51) | 0.09 | — | — |
All surviving patients returned for follow-up. Fifty (7.1%) of the 707 patients had clinically suspected recurrent VTE during follow up, and symptomatic VTE was objectively confirmed in 32 patients in the cohort (32 of 707 patients; 4.5%; 95% CI, 3.1 to 6.3%). Twenty-four (3.4%; 95% CI, 2.2 to 5.0%) of 707 patients had recurrent symptomatic PE and 8 (1.1%; 95% CI, 0.5 to 2.2%) of 707 patients had symptomatic DVT (7 proximal and 1 distal).
Of the patients with concomitant DVT at the time of initial PE diagnosis, 26 (26 of 362 patients; 7.2%; 95% CI, 4.7 to 10.3%) had a symptomatic VTE recurrence during follow-up, whereas only 6 (6 of 345 patients; 1.7%; 95% CI, 0.6 to 3.7%) of the patients without concomitant DVT experienced a symptomatic VTE recurrence (absolute difference, 5.5%; 95% CI of the absolute difference, 2.5 to 8.5%; P < 0.001) The cumulative incidence of symptomatic VTE recurrence was significantly higher in patients with concomitant DVT compared with those without concomitant DVT (P < 0.001, log-rank test; Figure 3). Separation between symptomatic VTE recurrence curves occurred soon after the diagnosis of PE at study entry.
Figure 3. Recurrent symptomatic venous thromboembolism in patients with acute symptomatic pulmonary embolism, stratified by the presence or absence of concomitant deep vein thrombosis at the time of pulmonary embolism diagnosis. DVT = deep vein thrombosis; PE = pulmonary embolism. Log-rank P < 0.001.
[More] [Minimize]In univariate Cox regression analyses, patients with concomitant DVT at the time of study entry with acute PE diagnosis (HR, 4.23; 95% CI, 1.74 to 10.27; P = 0.001) and patients with cancer (HR, 2.06; 95% CI, 1.01 to 4.21; P = 0.048) were significantly more likely to have recurrent VTE (Table 5). In the multivariate analysis, only concomitant DVT at the time of PE was an independent predictor of recurrent VTE (model chi square = 12.04; P = 0.001). Concomitant DVT at the time of study entry with acute PE diagnosis was still a significant predictor of recurrent VTE when patients who had an IVC filter inserted or were treated with thrombolytic therapy were excluded from the analysis (concomitant DVT, adjusted HR, 4.19; 95% CI, 1.72 to 10.23; P = 0.002). Concomitant DVT remained an independent predictor of recurrent VTE when patients with nondiagnostic V̇/Q̇ scans or negative contrast-enhanced helical chest CT scans (n = 28) were excluded from the analysis (adjusted HR, 4.93; 95% CI, 1.89 to 12.89; P = 0.001).
Risk Factor | Unadjusted HR (95% CI) | P Value | Adjusted HR (95% CI) | P Value |
|---|---|---|---|---|
| Age, per year | 0.99 (0.97–1.01) | 0.42 | — | — |
| Male sex | 1.56 (0.75–3.24) | 0.23 | — | — |
| COPD | 0.04 (0–16.575) | 0.30 | — | — |
| Concomitant DVT | 4.23 (1.74–10.27) | 0.001 | 4.23 (1.74–10.27) | 0.001 |
| SBP <100 mm Hg | 0.04 (0–12.17) | 0.28 | — | — |
| Dyspnea | 0.87 (0.41–1.85) | 0.73 | — | — |
| Chest pain | 0.90 (0.45–1.82) | 0.78 | — | — |
| Syncope | 1.0 (0.35–2.85) | 1 | — | — |
| Cancer* | 2.06 (1.01–4.21) | 0.05 | — | — |
| Immobilization† | 1.48 (0.70–3.13) | 0.31 | — | — |
| DVT signs or symptoms | 0.05 (0–617.97) | 0.53 | — | — |
| Insertion of an IVC filter | 1.79 (0.24–13.13) | 0.56 | — | — |
| Suboptimal quality of oral anticoagulation‡ | 1.91 (0.86–4.26) | 0.11 | — | — |
Compared with the 707 patients in the original study cohort, the 4,476 eligible patients from the RIETE validation cohort were significantly more likely to have immobilization for 4 days or more, chronic pulmonary disease, and symptoms or signs of DVT and PE at the time of presentation (Table 6). Hypoxemia was significantly more prevalent among patients in the RIETE cohort compared with the study cohort. However, patients in the RIETE cohort had a lower prevalence of cancer compared with patients in the study cohort. In the RIETE cohort, concomitant DVT was detected in 62.6% of patients (2,803 of 4,476 patients; 62.6%; 95% CI, 61.2 to 64.0%), compared with the 51.2% of patients in the study cohort (362 of 707 patients; 51.2%; 95% CI, 47.5 to 54.9%; absolute risk difference, 11.4%; 95% CI, 7.5 to 15.4%).
Original Cohort (n = 707) | RIETE Registry (n = 4,476) | P Value | ||||
|---|---|---|---|---|---|---|
| Clinical characteristics | ||||||
| Age, yr (mean ± SD) | 68.2 ± 15.9 | 67.4 ± 16.3 | 0.22 | |||
| Age >65 yr | 466 (66%) | 2949 (66%) | 0.97 | |||
| Male sex | 316 (45%) | 2135 (48%) | 0.16 | |||
| BMI >30 kg/m2 | 120 (17%) | 916 (20%) | 0.07 | |||
| Risk factors for VTE | ||||||
| History of VTE | 0 (0%) | 701 (16%) | <0.001 | |||
| Cancer* | 162 (23%) | 806 (18%) | 0.002 | |||
| Recent surgery | 73 (10%)† | 458 (10%)‡ | 0.95 | |||
| Immobilization for ≥4 d | 124 (17%)† | 1012 (23%)‡ | <0.001 | |||
| Comorbid diseases | ||||||
| COPD | 50 (7%) | 560 (12%)§ | <0.001 | |||
| Congestive heart failure | 45 (6%) | 280 (6%) | 0.94 | |||
| Clinical symptoms and signs at presentation | ||||||
| Syncope | 88 (12%) | 688 (15%) | 0.04 | |||
| Chest pain | 327 (46%) | 2273 (51%) | 0.02 | |||
| Dyspnea | 507 (72%) | 3626 (81%) | <0.001 | |||
| Heart rate >100/min | 169 (24%) | 1235 (27%) | 0.10 | |||
| Arterial PaO2 <60 mm Hg | 263 (37%) | 1378 (40%) | 0.002 | |||
| SBP <100 mm Hg | 54 (8%) | 274 (6%) | 0.05 | |||
| DVT signs or symptoms‖ | 186 (26%) | 2196 (49%) | <0.001 | |||
| Treatment | ||||||
| Thrombolytic therapy | 19 (3%) | 81 (2%) | 0.12 | |||
| Insertion of an IVC filter | 13 (2%) | 138 (3.1%) | 0.15 | |||
| Suboptimal quality of oral anticoagulation¶ | 265 (37%) | Not available | — | |||
Of the 4,476 patients included in the RIETE validation cohort, 697 (697 of 4,476 patients; 15.6%; 95% CI, 14.5 to 16.7%) patients died, compared with 10.9% (77 of 707 patients; 95% CI, 8.9 to 13.4%) in the original study cohort (absolute risk difference, 4.7%; 95% CI, 2.1 to 7.2%) during the 3 months of follow-up. In RIETE, 3.7% of patients had recurrent VTE (167 of 4,476 patients; 3.7%; 95% CI, 3.2 to 4.3%), compared with 4.5% (32 of 707 patients; 95% CI, 3.1 to 6.3%) in the study cohort (absolute risk difference, −0.8%; 95% CI, −2.4 to 0.8%) during the 3 months of follow-up.
In RIETE, after adjusting for cancer and immobilization at the time of acute PE diagnosis, patients with concomitant DVT at the time of diagnosis of PE had a significantly higher all-cause mortality compared with those without concomitant DVT (adjusted HR, 1.66; 95% CI, 1.28 to 2.15; P < 0.001). After adjustment, concomitant DVT at the time of presentation had an independently significant association with PE-specific mortality (adjusted HR, 2.01; 95% CI, 1.18 to 3.44; P = 0.01). The presence of concomitant DVT at the time of diagnosis of acute PE was also significantly associated with VTE recurrence (unadjusted HR, 1.56, 95% CI: 1.02 to 2.37; P = 0.04).
This study showed that patients with acute symptomatic PE and concomitant DVT had a higher short-term risk for all-cause death, PE-related death, and recurrent VTE than patients diagnosed solely with PE (i.e., without DVT), after adjusting for potential confounders. The risk of death among patients with concomitant DVT was about two times higher and 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 of concomitant DVT in patients with acute symptomatic PE.
The prevalence of ultrasound (CCUS)-detectable DVT in the study cohort (51%) was similar to that in a previous meta-analysis in which 45% of patients with V̇/Q̇ scan-proven PE had concurrent DVT (23), and lower than in a previous study in which the prevalence of venographically detected DVT in patients with angiography-proven PE was 82% (24). Interestingly, DVT was distal in only 3% of patients. The study by Girard and colleagues found a prevalence of 40% of distal DVT in 213 patients with an objective diagnosis of PE. This discrepancy between the studies may be explained at least in part by the lower sensitivity of CCUS compared with lower limb venography (24). Also, this study suggests that CCUS diagnoses DVT in only about half of the patients who have symptoms or clinical signs of DVT (12, 25).
Prior evidence suggests that the risk of recurrent VTE during the ensuing months of anticoagulant treatment is greatly increased among patients with ongoing risk factors that include active cancer (20), antiphospholipid antibody syndrome (26), or immobilization resulting from chronic medical diseases (27). However, studies have shown conflicting data regarding the association between concomitant DVT at the time of PE diagnosis and the risk of VTE recurrence (1, 11, 12). In a smaller study of 296 patients from the emergency center of the university hospital of Geneva that had confirmed symptomatic acute PE, Wicki and colleagues found that patients with concomitant DVT had a higher risk of recurrent VTE and death compared with patients without concomitant DVT (11). In contrast, a larger study of 2,442 patients in the International Cooperative Pulmonary Embolism Registry (ICOPER) that had acute PE and underwent baseline ultrasound evaluation did not detect an association between concomitant DVT and all-cause mortality (1). ICOPER included patients who had a subjective diagnosis of PE made by the attending physician, despite a lack of objective confirmation. In a study that enrolled 281 patients with acute PE, Girard and colleagues did not find a significant association between DVT and prognosis (12). However, the study by Girard was a post hoc analysis of a multicenter outcome study; it was not originally designed to evaluate the impact of concomitant DVT on patient prognosis. Moreover, the study had a large number of exclusion criteria, such as pregnancy, major PE, life expectancy of less than 3 months, CT negative for the diagnosis of PE, and anticoagulant treatment for more than 48 hours before entry into the study, that potentially led to the selective enrollment of less severely ill patients and a strikingly low 3-month mortality rate of 4%. Also, the lack of association between DVT and prognosis may have been due to a lack of statistical power. Our study's large sample size, the adjustment for potential confounders (i.e., intensity of anticoagulation treatment, therapy with an IVC filter, thrombolytics, or both), the robustness of the findings, and the validation of our initial findings in another large cohort provide strong evidence supporting the concept that concomitant DVT at the time of acute PE diagnosis is a predictor of all-cause death, PE-related death, and recurrent VTE.
The findings from this study have at least two practical implications. First, because patients with PE who have concomitant DVT have an increased risk of recurrent VTE and PE-related death compared with those without concomitant DVT, they may potentially benefit from more intensive surveillance and treatment such as thrombolysis. A previous clinical trial did not demonstrate any significant mortality reduction in hemodynamically stable patients with acute PE and right ventricular dysfunction who received thrombolytic therapy (28). In patients with massive PE, the thrombus burden and cardiopulmonary status interact to produce hemodynamic instability (29). Whether the administration of thrombolysis has the potential to improve outcomes in patients with acute PE who have right ventricular dysfunction and concomitant DVT, should be further examined. 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 compared with those with concomitant DVT. Prospective studies should further address the safety and efficacy of treating hemodynamically stable patients with PE who do not have concomitant DVT in an outpatient setting.
In our study, suboptimal quality of oral anticoagulation was not associated with a higher risk of overall mortality, PE-related mortality, or recurrent symptomatic VTE. Conflicting data exist regarding the association between poor-quality oral anticoagulation and the risk of VTE recurrence (30). In view of our results, it seems plausible that the insertion of an inferior vena cava filter might improve outcomes. However, placement of an IVC filter was associated with increased mortality in this study. The IVC filter may have been a marker of disease severity. Interventional studies should address the efficacy of placing an IVC filter in patients with PE and concomitant DVT.
There are multiple potential reasons why the magnitude of association between the presence of concomitant DVT and VTE recurrence and death in the study cohort was less extreme in the RIETE validation cohort. First, the RIETE Registry does not require testing for DVT, and lower limb ultrasonography was not available for 37% of patients screened for validation cohort eligibility. Thus, we cannot entirely exclude the possibility that the weaker relationship between concomitant DVT and VTE recurrence and death in the RIETE Registry was a consequence of selection bias. Second, because the RIETE Registry does not consistently collect data on the quality of anticoagulation (i.e., serial INR measurements) during follow-up, we cannot say whether the weaker association between DVT and outcomes in the RIETE Registry may have been due to differences in anticoagulation quality. Finally, other important nonmeasured factors may have differed between the study and the validation cohorts.
In conclusion, the results of this study of patients with acute symptomatic PE suggest that patients with concomitant DVT, compared with those without DVT, have an increased risk of all-cause death, PE-related death, and recurrent VTE over 3 months of follow-up. Therefore, assessment of thrombotic burden should assist with risk stratification in patients with acute symptomatic PE.
The authorsthank Sanofi-Aventis Spain for supporting this registry with an unrestricted educational grant, and the Registry Coordinating Center, S & H Medical Science Service, for their quality control, logistic, and administrative support.
RIETE Registry: Dr. Manuel Monreal (Spain). RIETE Steering Committee members: Dr. Hervè Decousus (France), Dr. Paolo Prandoni (Italy), Dr. Benjamin Brenner (Israel). RIETE national coordinators: Dr. Raquel Barba (Spain), Dr. Pierpaolo Di Micco (Italy), Dr. Karine Rivron-Guillot (France). RIETE Registry Coordinating Center: S & H Medical Science Service. Members of the RIETE group: Spain—Arcelus JI, Barba R, Blanco A, Barrón M, Casado I, Cañas I, Cisneros E, Conget F, Falgá C, Fernández-Capitán C, Gabriel F, Gallego P, García-Bragado F, Grau E, Guijarro R, Guil M, Gutiérrez J, Hernández L, Herrera S, Jiménez D, León JM, Lecumberri R, Lobo JL, López L, López I, Lorenzo A, Luque JM, Madridano O, Marchena PJ, Martín-Villasclaras JJ, Monreal M, Montes J, Muñóz FJ, Naufall MD, Nieto JA, Otero R, Orue MT, Penadés G, Perelló JI, Portillo J, Riera A, Roldán V, Rosa V, Ruiz-Gamietea A, Ruiz-Giménez N, Ruiz-Ribó MD, Sahuquillo JC, Sánchez JF, Sánchez R, Sandoval R, Soler S, Tiberio G, Tirado R, Todolí JA, Tolosa C, Trujillo J, Uresandi F, Valdés V, Valle R; France—Mismetti P, Rivron-Guillot K, Boccalon H, Le Corvoisier P, Quere I, Szwebel TA; Israel—Brenner B; Italy—Dalla Valle F, Di Micco P, Duce R, Iannuzzo MT, Poggio R, Prandoni P, Quintavalla R, Schenone A, Surico T, Tiraferri E, Visonà A.
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