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Thrombosis Research xxx (2010) xxx–xxx
TR-04076; No of Pages 5
Contents lists available at ScienceDirect
Thrombosis Research
j ourna l homepage: www.e lsev ie r.com/ locate / th romres
Regular Article
Clinical outcomes in patients with isolated subsegmental pulmonary embolidiagnosed by multidetector CT pulmonary angiography☆
Anthony A. Donato a,⁎,1, Swapnil Khoche b, Joseph Santora c, Brent Wagner b
a Jefferson Medical College, The Reading Hospital and Medical Center, Reading, PA USAb The Reading Hospital and Medical Center, USAc Philadelphia College of Osteopathic Medicine, USA
Abbreviations: PE, Pulmonary Embolism; VTE, VenouQ, Ventilation/Perfusion; CTPA, CT Pulmonary Angiogrmental Pulmonary Emboli; IVC, Inferior Vena Cava; ELsorbent Assay.☆ Research carried out at The Reading Hospital and MPA, 19612.⁎ Corresponding author. Department of Internal Medi
Medical Center, Sixth and Spruce Streets, West Reading8133; fax: +1 610 988 9003.
E-mail address: [email protected] (A.A. D1 Dr. Anthony Donato had full access to the data in the
for the integrity of the data and the accuracy of the analyno conflicts of interest with regards to this manuscript.
0049-3848/$ – see front matter © 2010 Published by Edoi:10.1016/j.thromres.2010.07.001
Please cite this article as: Donato AA, etmultidetector CT pulmonary angiography,
a b s t r a c t
a r t i c l e i n f o21
Article history:22
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Received 25 November 2009Received in revised form 5 April 2010Accepted 9 July 2010Available online xxxx
Keywords:Pulmonary embolism/therapyThromboembolism/therapy
Introduction: CT Pulmonary Angiography has been shown to be equivalent to Ventilation/ Perfusion scanningin 3-month outcome studies, but it detects more pulmonary emboli. Isolated subsegmental pulmonaryemboli are thought to account for some of the increase in diagnosis, but it is not known whether theseemboli represent a harbinger for future thromboembolic events. The objective of this study was to determinethe 3-month clinical outcomes of a cohort of patients diagnosed with isolated subsegmental pulmonaryemboli.Materials and Methods: Review of 10,453 consecutive CTPA radiology reports over 74-month period since theimplementation of Multidetector CT Pulmonary Angiography identified a cohort of 93 patients found to have
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acute pulmonary embolism isolated to subsegmental pulmonary arteries without other evidence of deepvenous thrombosis at one institution. The study measured 3-month clinical outcomes (anticoagulation use,recurrence, death, hemorrhage) determined by review of records and telephone interviews with physicians.Results: Seventy-one patients (76%) were treated with anticoagulation and/or IVC filter, while 22 (24%) wereobserved without therapy. One patient (1/93, 1.05%; 95% CI: 0-6.6%) who was treated with anticoagulantsand a vena caval filter had a recurrent subsegmental pulmonary embolus. No patients died of pulmonaryembolism. There were 8 hemorrhages, including 5 (5.3%) major hemorrhages without any hemorrhage-related mortality.Conclusions: Patients diagnosed with isolated subsegmental pulmonary emboli have favorable 3-monthoutcomes. Short-term prognosis for recurrent thromboembolism may be lower than the risk of adverseevents with anticoagulation in patients at high risk of hemorrhage.
© 2010 Published by Elsevier Ltd.
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Acute Pulmonary Embolism (PE) has been estimated to occur in630,000 patients per year, and is the cause of death in 100,000 [1].Mortality in pooled studies is reduced 10-fold by treatment withanticoagulants, with a 7-fold reduction in recurrence rate [2], lendingsupport to the widespread adoption of anticoagulation therapy for
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s Thromboembolic Disease; V/aphy; ISSPE, Isolated Subseg-ISA, Enzyme-Linked Immuno-
edical Center, West Reading,
cine, The Reading Hospital and, PA 19611. Tel.: +1 610 988
onato).study and takes responsibilitysis. He and his co-authors have
lsevier Ltd.
al, Clinical outcomes in patiThromb Res (2010), doi:10.1
venous thromboembolic disease (VTE) despite its inherent bleedingrisks.
The PIOPED study[3] firmly established the Ventilation/Perfusion(V/Q) scan as the test of choice for diagnosis of pulmonary emboliuntil innovations in multidetector CT Pulmonary Angiography (CTPA)technology made imaging to the level of subsegmental vessel bothfeasible and accurate [4]. Studies have demonstrated CTPA's excellentnegative predictive value in 3-month outcome studies [5] and morerecently its noninferiority to V/Q [6]. However, in a head-to-headstudy with V/Q, the diagnosis of PE was made significantly more often(14 vs. 19%) without statistically significant improvement in 3-monthoutcomes [6].Whether the increase in pulmonary embolism diagnosisby CTPA represented false positive results, a subset of more benigndisease, or accurate detection of a natural, benign “clearing” process ofthe lungs was not clear, but the question of isolated subsegmentalpulmonary emboli (ISSPE), which is reported 4- 7% of all CTPA studiesin recent reports [6–8] seemed to be central to this debate [9].
In order to ascertain the natural outcomes of these subsegmentalpulmonary emboli, we retrospectively reviewed the 3-month out-comes of patients diagnosed with ISSPE in one facility without other
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detected venous thromboembolic disease to determine whether theirdisease progression followed the course of typical thromboembolicdisease or whether its prognosis was more benign.
Materials and methods
Patient selection
This study was performed in a 754-bed community hospital with aLevel 2 Trauma Center and 110,000 emergency department visits peryear. A retrospective analysis of the dictated reports of 10,453 CTChest studies performed with contrast from the start of use ofmultidetector CT scanning (October 19, 2001) until December 31,2007 was undertaken. Records were identified by computerizedidentification of all Current Procedural Terminology (CPT) codes forCT chest with contrast (CPT codes 71260 and 71275). Identifieddictated reports were then reviewed and validated manually. Allpatients with a final dictated report describing pulmonary emboluswere included. The positive reports were then characterized by thehighest order branch affected. Those found to have emboli isolated tothe subsegmental (5th order) artery were selected for further study.All CT Chest films with isolated subsegmental emboli described wereexternally re-reviewed by a board-certified radiologist (B.W.) toconfirm the diagnosis and the highest order affected, if available. Forpatients without imaging studies available for external review, twoexaminers reviewed the report to confirm highest order affected andabsence of higher order emboli. Patients with subsegmental pulmo-nary emboli and concomitant venous thromboembolic diseasedetected during that admission had another compelling reason foranticoagulation and were excluded from further review. Two patientswith no available hospital records to review at the time of theirimagingwere also excluded. Ninety-three patients were subsequentlyidentified. Charts were retrospectively reviewed to determine 3-month outcomes of recurrence or bleeding, other diagnostic testingperformed (lower extremity duplex ultrasound, Pulmonary angiog-raphy, V/Q scanning, and D-dimer testing), pharmacologic or surgical(IVC filter) intervention.
Ct protocol
All patients included in the study were evaluated by the standardCT imaging protocol for pulmonary embolism detection used by TheReading Hospital and Medical Center. Helical CT scans wereperformed on one of two GE HighSpeed CT/I scanners or on a GELightSpeed Plus scanner, which included two 16-detector and one 64-detector capability. All interpreting radiologists were board certifiedand had extensive CT experience at this institution, which performsover 60,000 CT scans each year. The interpreting radiologists werecommunity radiologists and not full-time academic thoracic imagingspecialists.
D-Dimer
D-Dimer by ELISA was measured with the Vidas D-Dimer(bioMérieux-Marcy l'Etoile, France). D-Dimer levels were considerednormal according to the hospital reference standards if the measuredvalue was less than 500 ng/mL.
Solicitation of outcomes
To determine 3-month outcomes, inpatient admission historiesand physicals were sought that occurred at least 3 months after theindex study. For patients with unavailable inpatient data, phonecontact was made to the physicians charged with managing thepatient's anticoagulation to determine if the patient had had arecurrence of venous thromboembolic disease. Recurrence was
Please cite this article as: Donato AA, et al, Clinical outcomes in patimultidetector CT pulmonary angiography, Thromb Res (2010), doi:10.1
defined as a radiologically documented venous thrombolic event(deep venous thrombosis or pulmonary embolism) within 3 monthsof the index diagnosis. Patients who died or could not be found in the3-month period had death records requested from the state and fromlocal cancer registries as appropriate.
Data on hemorrhage was also collected. Major bleeding wasdefined as fatal or clinically overt bleeding resulting in fall ofhemoglobin by 2 g/L or more or bleeding into critical anatomicalsites (subdural hematoma, intraspinal hemorrhage, retroperitoneal,intraocular, pericardial, atraumatic intraarticular) or leading totransfusion of≥2 U of blood or red cells. Minor bleeding was definedas bleeding requiring intervention but not qualifying as a major bleedincluding bleeding precipitating treatment cessation [10].
All deaths and potential recurrences were reviewed by anindependent adjudication committee. Death certificates, autopsyreports and clinical information were reviewed as available, anddeaths were classified as “Death likely due to recurrent pulmonaryembolism” or “Death unlikely due to pulmonary embolism”.
The study design and request towaive authorizationwas approvedby the hospital's Institutional Review Board.
Treatment decisions
The hospital does not have a protocol for management of venousthromboembolism, so treatment decisions for isolated subsegmentalpulmonary emboli were made by doctors at their discretion at thetime of the positive study, weighing the patient's risks of bleedingagainst the risk of further thrombosis.
Statistical methods
Confidence intervals were calculated using the method of RobertNewcombe accessed at http://faculty.vassar.edu/lowry/prop1.html[11] T-tests were used to compare D-dimer results in treated anduntreated groups (STATA 8.0, College Station, TX).
Results
During the 74-month review period, 10,453 patients underwentCT chest scanning with contrast, of which pulmonary emboli werediagnosed in 1,463 (14%) (Fig. 1). One hundred fifteen of those (7.9%of total) were isolated to one or more subsegmental branches withoutmore proximal thrombus and were considered for further study. Onehundred and seven patients had images and reports externally re-reviewed to confirm diagnosis and absence of other emboli, whileeight had dictated reports re-reviewed only as their images were nolonger available. Review of records found five reports that were lateramended as negative, and they were eliminated from furtherconsideration. Fifteen patients who were found to have concomitantdeep vein thrombosis during that admission, and therefore hadanother compelling reason to receive anticoagulation, were alsoexcluded. Two patients had no inpatient records at the time of studyto determine course of therapy chosen, and they were excluded.
Ninety-three patients were selected for further study. All of the 93patients had their study performed utilizing the current PulmonaryEmbolism protocol in place during the time of their examination.Treatment decisions were made by individual physicians based ontheir judgment. Seventy-one (76%) of the patients in the study groupreceived treatment for pulmonary embolus (58 received Warfarin, 10received Warfarin and an IVC filter, 1 received low molecular weightheparin, and 2 received an IVC filter only) (Fig. 1). Twenty-two(23.6%) were observed without mechanical or anticoagulationtherapy.
Forty were inpatients (43%), 44 (47%) were emergency depart-ment patients, and 9 were outpatients (10%). The patient populationconsisted of 41 men and 52 women had an average age of 63.5 years.
ents with isolated subsegmental pulmonary emboli diagnosed by016/j.thromres.2010.07.001
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Fig. 1. Recruitment and Outcomes of Patients.
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Duplex ultrasound of lower extremities was negative in 63 (68%), andwas not performed in 30 (32%). Twenty of 22 untreated patients hadvenous ultrasound (one was done serially), all of which werenegative. Pulmonary arteriogram was performed in 5 (5.3%) andwas negative in all cases. Concomitant V/Q scanningwas obtained in 7patients during the index admission, with 1 high probability, 3indeterminate and 3 low probability scan results. D-dimer wasobtained in 41 cases. Average d-dimer result was 1617 ng/ml, with4/41 (9.7%) results in the normal range (b500 ng/ml); there was nostatistical difference between treated and untreated groups(p=0.36).
Three-month outcomes were determined for 92 of the 93 patients.Sixty-eight patients (68/93, 73%) had inpatient admission documentsthat determined clinical outcome, while 24 (24/93, 25%) neededcontact with the outpatient primary care physician or outpatientcardiologist managing their anticoagulation to determine outcomes.
Please cite this article as: Donato AA, et al, Clinical outcomes in patimultidetector CT pulmonary angiography, Thromb Res (2010), doi:10.1
One patient in the group not receiving anticoagulation had a negativefollow-up CT angiogram at day 55, but no further clinical data could befound. There was one recurrent pulmonary embolus (1/93, 1.05%, 95%CI: 0.06- 6.6%), found in a new subsegmental vessel 15 days after theoriginal study despite adequate anticoagulation and placement of anIVC filter following the initial diagnosis. Two patients (2.1%) died inthe 3-month study window, both on a home hospice program. Onedied at day 15 of widely metastatic breast cancer, the other on day 30of pneumonia. Review of the available clinical data by the adjudicationcommittee determined that neither deaths were likely due torecurrent pulmonary embolism, however autopsy data was notavailable.
Bleeding events occurred in 8 (8.5%, 95% CI: 5.3-21%), including 3minor and 5 major hemorrhage within the 3-month study period, allin anticoagulated patients. Major hemorrhage events included 1subdural, 1 retroperitoneal, 2 gastrointestinal and 1 urologic
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hemorrhage; 3 of the 5 required transfusions of 2 or more units ofpacked red cells.
Discussion
This study found that three-month outcomes in patients diagnosedwith ISSPE (1.05% recurrence, 0% VTE-related mortality) weresignificantly more favorable than the outcomes in the literature ofanticoagulated patients with typical pulmonary emboli (8% recur-rence, 1.7% mortality) [12]. Our results are similar to other authors’findings who followed 3-month outcomes of patients with ISSPE(Table 1), which suggest, in aggregate, a recurrence rate of 1/192(0.5%; 95% CI: 0-2.9%) with no PE- attributed deaths [8,13,14]. Ourdata also demonstrate that ISSPE may have a more subtle clinicalpresentation than typical patients with pulmonary embolism. Wefound relatively low concomitant DVT rates (14%), similar to LeGal etal's series where DVT diagnosis (17%) was lower in patients withISSPE than it was in patients with larger branch pulmonary emboli(43%) [13]. We also found D-dimer testing to be relatively lesssensitive (37/41, 90%) for ISSPE as was similarly reported by Sijens,where sensitivity for subsegmental PE was 76% for ISSPE versus 98%for segmental and higher order emboli [15].
Our primary outcome, recurrence of venous thromboembolicevents, was determined retrospectively by review of the existinginpatient records, calls to outpatient physicians, death records andcancer registries. Studieswith retrospective designsmay be limited byreporting and ascertainment biases, as it is possible that outcomeevents may be omitted by medical records or ignored by the patient(reporting bias), or possibly may be over-interpreted by the studyexaminers (ascertainment bias). However, hard outcome events suchas a recurrent thromboembolism or death are unlikely to go unnoticedby patients and providers, and generally result in the patient seekinginpatient medical attention, especially in patients who were recentlyinformed they had a pulmonary embolism. Furthermore, patientsreceiving anticoagulation require close laboratory monitoring, facil-itating closer contact with the medical system and healthcareproviders. Finally, the outcome of ‘newly diagnosed VTE event’ limitsthe ascertainment bias of the study researchers. Similar clinicalendpoints obtained by retrospective medical record review andphysician contact have been used to document the 3-month outcomesof negative CTPA studies in prior research [16–23]. Although thisstudy and similarly designed retrospective studies may have missedclinically “silent” recurrences of pulmonary emboli, those recurrencesare by definition clinically insignificant and were not the intendedprevention targets of therapy with anticoagulation.
Our study used full-time clinical radiologists using multidetectorCT scanners and followed outcomes of patients without DVT, so itclosely represents the real- world scenarios of physicians managingISSPE without DVT in a typical clinical environment. However, ourstudy was limited by a lack of “gold standard” to validate the emboliidentified in the reviewed radiology reports. Although conventionalarteriogram had previously been considered that standard, recentevidence suggests that interrater reliability is better for multidetectorCTPA (0.73 vs. 0.45) [4,24]. Although we did re-review the available
Table 1Three-month outcomes of isolated Subsegmental Pulmonary Emboli in the literature.
Author n Lost to follow-up Died(non-PE cause)
Donato et al. 93 1 2Eyer et al.7 77 10 7LeGal et al.15 22 0 0Schultz et al.16 17 7 0TOTALS 209 18 9/192 (4.7%)
All patients : recurrence rate, 1/192 (0.52%); 95% CI: 0- 2.9%.13
Please cite this article as: Donato AA, et al, Clinical outcomes in patimultidetector CT pulmonary angiography, Thromb Res (2010), doi:10.1
images available, this was done by one general radiologist studyexaminer at the same facility, so that the selected patient populationmay have been dependent on the quality of CT interpretation here. Ifour cohort had included normal patients with false positive results,the outcomes seen may have underrepresented the true risk of ISSPE.However, this institution's ISSPE detection rate among all studiespositive for PEwas 7.9%, a rate that is concordant with other reports inthe literature, where subsegmental PE represented 7-24% of allpositive studies[6,7,24,25], suggesting that overdiagnosis in ourcohort is not likely. Our cohort was intended to exclude patientswho had no DVT diagnosed by ultrasound. Thirty patients did nothave any ultrasound performed, and it is possible that DVT could havegone undiagnosed in this subset. If DVT's were missed, it may havecaused us to actually underestimate the risk of future thromboembolicevents. Given we had so few VTE recurrences, this scenario seems lesslikely. Although our study is the largest series of ISSPE outcomesreported to date, our relatively low number of subjects still leaves awide confidence interval for recurrence rate (0-6.6%), suggesting theneed for larger, multicenter databases to definitively answer thisquestion.
Could ISSPE represent a more benign subset of disease? Our cohortappears to be at significantly lower risk for recurrence and death thanpooled patients with recognized pulmonary emboli from theliterature, where recurrence and mortality has been reported in 39%and 26% of untreated [2] and 8% and 1.7% of anticoagulated patients[12]. If we assumed that our cohort had a similar disease process, wewould predict that more than 6 patients would have died and nearly14 patients should have suffered recurrences among our 93 treatedand untreated subjects. In fact, our cohort has a rate of PE recurrenceand death that is quite similar to that of a meta-analysis of negativeCTPA studies (recurrence, 1.4%, and fatal PE 0.5%) [5], which leadsthese authors to conclude that ISSPE may have a more benignoutcome than typical pulmonary emboli.
What has never been in question is the relative hazards ofanticoagulation. Three-months of anticoagulation therapy carrieswith it a 2-3% risk of major hemorrhage and 0.4% risk of fatalbleeding, a risk that may be higher outside of carefully controlledstudies[2]. Although not powered to detect hemorrhage rates as anoutcome, the fact that our cohort had a higher rate of major bleedingthan PE recurrence highlights the dangers of anticoagulant use inpatient populations in which the likelihood of recurrence ofthromboembolic disease may fall below the likelihood of harm fromanticoagulation.
Unfortunately, this leaves physicians the uncomfortable choice ofnot treating a “positive” result on CT pulmonary angiography. Hull etal. [26] showed that in patients with good cardiopulmonary reserveand indeterminate V/Q scans, a strategy including serial ultrasoundexaminations had an acceptably low 3-month recurrence rate (1.9%).Wells et al. [27] similarly found an acceptable 0.5% 3-monthrecurrence rate in patients without high clinical suspicion, indeter-minate V/Q and serial negative ultrasound examinations. We arguethat our data supports the recommendations of Goodman [28] thatISSPE may be the equivalent of these indeterminate V/Q scans. Inpatients diagnosedwith ISSPEwithout high pre-test clinical suspicion,
No anticoagulation Anticoagulated/treated
n 3-month outcome:PE n 3-month outcome:PE
22 0/22 71 1/7125 0/25 42 0/428 0/8 14 0/14
10 0/1065 0/65 (0%) (none) 127 1/127 (0.7%) (none fatal)
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good cardiopulmonary reserve, no thrombus burden in the lowerextremities, and especially in patients with an increased risk ofbleeding complications, a strategy including serial ultrasound exam-inations may be a safer option than standard anticoagulation. Amulticenter prospective trial of this strategy is indicated to bestdetermine patients most suited for observation.
Conflict of interest statement
Drs. Donato, Khoche, Wagner and Mr. Santora have no financialinterests or personal relationships with people or organizations todisclose that pertain to this manuscript. The authors have no fundingsources or sponsors to disclose.
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