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The diagnosis and prognosis of venous thromboembolism : variations on a
theme
Gibson, N.S.
Publication date
2008
Link to publication
Citation for published version (APA):
Gibson, N. S. (2008). The diagnosis and prognosis of venous thromboembolism : variations
on a theme.
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Isscreeningforchronicthromboembolic
pulmonaryhypertensioninpatientswitha
previouspulmonaryembolismindicated?
NADINES.GIBSON,SULAIMANSURIE,VICTORE.A.GERDES,BERTOJ.BOUMA, BERTHEL.F.VANECK–SMIT,HARRYR.BÜLLER,PAULBRESSER
SUBMITTED
138
A
BSTRACT
Background
With the refinement of pulmonary endarterectomy in chronic thromboembolic pulmonaryhypertension(CTEPH)theprognosishasimproved.Thepresentstudy wasperformedtodeterminewhethersystematicscreeningforCTEPHinpatients withpulmonaryembolism(PE)isindicated.
Methods
Systematic screening was performed through a questionnaire in consecutive patientswithPE,toexaminetheextentofdyspnoeaonexertion.Incaseofnewor
increased complaints of dyspnoea, patients were evaluated with
echocardiography,perfusionlungscanningandpulmonaryangiography.
Results
We screened 110 consecutive patients with PE for CTEPH. The overall mortality rate after a median followup of three years was 30% (33 patients). A total of 66 questionnaires (response rate 75%) were returned, of whom 27 patients had complaintsofdyspnoeaonexertion.InonepatientCTEPHwasdiagnosedbefore initiation of the study. None of the remaining patients met the criteria for the diagnosisof CTEPH.Theincidenceof0.9%(95%CI0.02%4.96%)isinagreement withearlierreportedincidences.
Conclusion
The findings of our study do not support an active and systematic search for CTEPHinpatientswithahistoryofrecentPE.However,alowthresholdapproach inthosepatientswithcomplaintsofdyspnoeaonexertioniswarranted.
139 C HAPTER 10
I
NTRODUCTION
Theincidenceofchronicthromboembolicpulmonaryhypertension(CTEPH)asalate complication of acute pulmonary embolism was originally believed to be very low (0.1%0.5%),butarecentcohortstudyin223consecutivepatientswithafirstepisodeof PE revealed a cumulative incidence of 3.8% after two years1,2. Until recently this
disorderhadaninfaustprognosiswithanoverall5yearssurvivaloflessthan50%3. Patientswithacutepulmonaryembolismaretraditionallytreatedwithanticoagulants for6to12monthsandcurrentguidelinesdonotaddresstheneedtoperformactive followupinordertodetectCTEPH4. Withtheintroductionandrefinementofpulmonaryendarterectomyinpatientswith CTEPHtheprognosishasimproveddramatically,in particularwhenoperatedprior
to reaching end stage disease5. The question therefore arises whether systematic
screeningofpatientswithpulmonaryembolismisindicated.
We,therefore,performedaretrospectivestudyinconsecutivepatientswithconfirmed acute pulmonary embolism and evaluated the effectiveness of screening for complaints on exertion, followed by echocardiography and perfusion lung scanning inthosewithneworwithincreasingpulmonarysymptoms.
M
ETHODS
BetweenNovember2002andAugust2004,alargediagnosticmanagementstudywas performed that included patients with clinically suspected pulmonary embolism in twelveDutchhospitals.Thatstudy,describedindetailelsewhere,demonstratedthat a diagnostic management strategy with a clinical decision rule, a Ddimer test and spiral CT, is safe in the workup of patients with clinically suspected pulmonary
embolism6.
Forthepresentanalysisallpatientswithobjectivelyconfirmedpulmonaryembolism withinoneoftheparticipatingstudycenters(AcademicMedicalCenter,Amsterdam, TheNetherlands)wereincluded.Patientsweretreatedinitiallyfor510dayswithlow molecular weight heparin followed by vitamin Kantagonists therapy for at least six months. To reach the appropriate intensity of the vitamin Kantagonists, the International Normalized Ratio (INR) was monitored by specialized anticoagulation
clinics7. The Institutional Review Board approved the study protocol and informed
140
Table 1. Questionnaire for complaints on exertion.
A for the purpose of the study designed questionnaire to determine the degree of shortness of breath on exertion was used, which was based on the New York Heart Association (NYHA) classification for heart failure (Table 1). It contained seven questionswithagradualaspecttoassestheseverityofshortnessofbreathassociated with daily activities. The questionnaire was sent to all consecutive patients that had not died two to four years after they were diagnosed with pulmonary embolism. In caseofnoresponseasecondquestionnairewassentandsubsequentlythepatientor the family physician was contacted. If a patient had died, the family physician, the hospitalchargesand/orthefamilywerecontactedtoretracethecauseofdeath. Ifpatientsdidnotexperiencecomplaintsofdyspnoeaonexertion,oriftheydidnot experienceanyincreaseinpreviouslyexistingsymptoms,nofurtheractionwastaken. Incaseofneworworseningcomplaintsofdyspnoeapatientswereinvitedtocometo theoutpatientclinic.Inallthesepatientsamedicalhistorywastaken,andaphysical examination, a transthoracic echocardiography and perfusion lung scanning were
performed8,9.
ThepresenceofCOPD,chronicheartfailureandinterstitiallungdiseasesweresorted outbycarefulmedicalhistorytakingandthephysicalexaminationwasperformedto identify the potential causes of dyspnoea. With echocardiography the systolic pulmonary artery pressure, was measured. The perfusion lung scan was a sixview
perfusion lung scintigraphy using 7288MBq of 99mTechnetiumlabeled macro
aggregates of albumin. CTEPH was considered if the systolic pulmonaryartery pressure exceeded 40 mmHg on echocardiography and if a perfusion defect was
shownonthelobarorsegmentallevelsofthelungs1.Ifthesefindingswerepresent,
Questions True Untrue
I have to walk slower than others, or I have to stop to rest.
Small jobs like household tasks take a lot of time, or I have to stop to rest. I have to take the stairs slowly or stop in between.
When I have to hurry, I have to stop or walk more slowly.
Due to my breathing it is difficult for me to walk up a hill, or a bridge, to do easy things in the garden (weed), or carry things up the stairs, dance, bowling, or play golf.
Due to my breathing it is difficult for me to carry heavy things, work in the garden, jog, walk fast, play tennis or swim.
Due to my breathing it is difficult to do really heavy work, run a race, cycle race, swim fast or heavy sports.
141
C
HAPTER
10
Table 2. Baseline clinical characteristics of the 110 consecutive patients with PE.
Characteristics n (%)
Age, mean (SD), y 56 (18)
Female 50 (46%)
Outpatients 76 (69%)
Duration of symptoms in days, median (IQR) 3 (1 to 7)
Immobilization or recent surgery 49 (45%)
Previous venous thromboembolism 17 (16%)
COPD with treatment 8 (7.3%)
Heart failure with treatment 11 (10%)
Malignancy 27 (25%)
Estrogen use, women 8 (16%)
Clinical symptoms of deep venous thrombosis 6 (6%)
Heart rate > 100 43 (39%)
Hemoptysis 16 (15%)
SD: standard deviation IQR: interquartile range
COPD: chronic obstructive pulmonary disease
patients underwent further diagnostic workup with pulmonary angiography with direct measurement of the pulmonaryartery pressure, to confirm or refute the diagnosis of CTEPH. CTEPH was diagnosed when the pulmonary capillary wedge pressure was normal, the mean pulmonary artery pressure exceeded 25 mmHg and
thereweretypicalangiographicsignsofCTEPH10.
R
ESULTS
Atotalof110consecutivepatientswereeligibleforthestudybasedonprovenacute pulmonaryembolismonmultislicecomputedtomographywithinthestudyperiodof the original multi center study. The baseline clinical characteristics are detailed in Table2.Themeanagewas56yearsand46%wasfemale.Twothirdswereoutpatients and patients underwent diagnostic testing after a median duration of symptoms of threedays.Onequarteroftheeligiblepatientswereknowntosufferfrommalignancy at the time of enrolment. Twenty two patients were known to have died within 24 months of enrolment in the original study, before initiation of the present study. Therefore, we could only sent out questionnaires to 88 patients (Figure 1). Based on data received by sending the questionnaire we discovered that an additional 11
142
Figure 1. Consecutive series of patients with confirmed PE.
patientshaddied,hencetheoverallmortalityrateoveramedianfollowupperiodof three years was 30% (33 patients). The causes of death were cancer (15 patients), cardiovascular disease (5 patients), sepsis (5 patients), fatal recurrent pulmonary embolism(3patients),massivehemoptysis(1patient)andunknownintheremaining 4patients.
In two of the five patients that died of cardiovascular disease were already known withpulmonaryhypertension;inthefirstpatientitwasinthecontextofsarcoidosis and the other patient was known with a history of atrial switch procedure due to transposition of the great arteries which is a common risk factor for pulmonary hypertension.
The patient that died of massive hemoptysis recurrent pulmonary embolism was
recognizedwhichwastreatedwithacenocoumarol11.Twomonthspriortothisacute
episode an echocardiography was performed because of complaints of dyspnoea, which showed a mean systolic pressure exceeding 65 mmHg and a dilated right ventricle the diagnosis CTEPH was likely. An additional contrastenhanced helical multidetector CT scan demonstrated abnormalities consistent with chronic
110 with pulmonary embolism
88 questionnaire
66 returned questionnaire (75%)
40 patients with complaints
27 patients invited
3 additional testing prior to study 3 end stage malignant disease 1 refused additional testing 20 echocardiography + perfusion scan
11 patients † 9 lost to follow-up
2 did not return questionnaire
No CTEPH 1 CTEPH
143 C HAPTER 10 thromboembolism,however,apulmonaryangiographywasnotyetperformed.None oftheremainingpatientsthatdied,hadahistorysuggestiveforCTEPH. Elevenpatientsdidnotreturnthequestionnaire:ninepatientswerelosttofollowup of whom three had moved abroad and two patients were contacted by telephone; bothhadnosymptomssuggestiveforcomplaintsonexertion.
A total of 66 questionnaires were returned (response rate 75%): 26 patients did not have any pulmonary complaints. Forty patients reported shortness of breath upon exertion. Eighteen patients responded positively to all seven items of the questionnaire (Table 1). Six patients answered true to six questions, whereas the remaining16patientswereequallydividedwithpositiveanswersrangingfrom1to5. Of these 40 patients, 13 experienced already complaints of dyspnoea on exertion beforetheepisodeofacutepulmonaryembolismandthesesymptomshadremained constant over time. Seven patients reported an increase of preexisting symptoms following the acute pulmonary embolism and twenty patients developed new symptoms.
Allofthese27patients,witheithernewcomplaintsonexertion,oranincreaseoftheir symptoms after the acute episode of pulmonary embolism, were invited to undergo
echocardiographyandperfusionlungscanning.
Prior to initiation of this present study three patients had already undergone perfusion lung scanning, echocardiography and angiography due to shortness of breathonexertion.CTEPHwasconfirmedinoneofthesepatients,andinonepatient chronic thromboembolism without pulmonary hypertension was diagnosed. In the third patient CTEPH was ruled out. One patient refused additional testing as complaints dissolved, and three patients were not able to visit the outpatient departmentduetotendstagemalignantdisease.
In12ofthe20studiedstudypatientsneithertheechocardiographynortheperfusion lung scan showed abnormalities. Two patients had a systolic pulmonary artery pressure that exceeded 40 mmHg, but without any perfusion defects on lung scanning. Six patients had a normal echocardiography with subsegmental perfusion defectsonthelungperfusionscan.Noneofthe20patientswhounderwentperfusion lung scanning and echocardiography met the predefined criteria for further investigationwithpulmonaryangiographyforthedefiniteconfirmationofCTEPH.
144
D
ISCUSSION
ThisstudyshowsanincidenceofCTEPHof0.9%(1/110;95%CI0.025.0%),whichisin agreement with previously reported incidences. If the patient that died before an angiographic diagnosis could be made, indeed suffered from CTEPH, the incidence wouldhavebeen1.8%(2/110;95%CI0.26.4%).Bothpatientswerealreadydiagnosed with(probable)CTEPHbeforethestudyquestionnairewassent.Thissuggeststhatit is not worthwhile to actively screen for CTEPH in patients with a documented episodeofacutepulmonaryembolism.
It is remarkable that 27 of the 66 patients who returned their questionnaire experiencednewcomplaintsofshortnessofbreathonexertionoranincreaseintheir symptomsaftertheiracutepulmonaryembolism.Nineteenofthesepatientsevenhad severe complaints, with functional impairment during walking or doing small household tasks. This might suggest a correlation with the pulmonary embolism. However, the origin of these complaints could not be determined with echocardiography or perfusion lung scanning; more detailed investigations were beyondthescopeofthecurrentstudy.
Some methodological aspects require comment. First, our study has a moderate sample size, and therefore the incidence figure of CTEPH has a wide confidence interval0.9%(95%CI0.02%4.96%).Wecannotexcludethepossibilitythatamongthe ninepatientsthatdidnotreturntheirquestionnaireorcouldnotbetracedanymore, one or more may have had undiagnosed CTEPH. In general however, patients with complaints of dyspnoea will tend to respond more easily than those without complaints.
A second limitation of the study concerns the retrospective character. A threeyear survivalof70%isinagreementwiththepublishedliterature,butitalsoindicatesthat
aconsiderableproportionofpatientshaddied12.Inthepatientsinwhomthecauseof
deadwasknownfromhospitalchartsoraftercontactingthefamilyphysicianorthe family, there was no suspicion for CTEPH, but we can not exclude this with full certainty.
Third, there is no generally accepted diagnostic strategy for diagnosing CTEPH. We employedastrategywithaquestionnaire,echocardiography,lungperfusionscanning and if indicated a pulmonary angiography. Since a validated questionnaire for CTEPH is not available we designed one and it remains unclear what the precise sensitivityandspecificityis.Wethereforeinvitedallpatientswithneworworsening complaintsofdyspnoeatoincreasethelikelihoodofdetectingCTEPH.
145
C
HAPTER
10
Finally, none of our patients qualified for a confirmatory pulmonary angiography. Given the fact that CTEPH is considered to develop within 2 years after the acute episode of pulmonary embolism, we assume that those patients that did not have
complaintsofdyspnoeadonothaveCTEPH,oratleastnotclinicallysignificant2,3.
In conclusion, the findings of our study do not support an active and systematic search for CTEPH in patients with a history of a recent pulmonary embolism. However,itseemsthatalowthresholdapproachinthosepatientswithcomplaintsof shortness of breath on exertion is warranted, given the improved surgical and therapeuticaloptionsforCTEPH.
146
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