Chronic thromboembolic pulmonary. Prognostic and aetiological factors in chronic thromboembolic pulmonary hypertension

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1 Eur Respir J 2009; 33: DOI: / CopyrightßERS Journas Ltd 2009 Prognostic and aetioogica factors in chronic thromboemboic pumonary hypertension R. Condiffe*,#, D.G. Kiey #, J.S.R. Gibbs ", P.A. Corris +,1, A.J. Peacock e, D.P. Jenkins*, K. Godsmith*, J.G. Coghan** and J. Pepke-Zaba* ABSTRACT: Severa prognostic variabes have previousy been identified in patients with chronic thromboemboic pumonary hypertension (CTEPH). Specific medica conditions have aso been associated with the deveopment and prognosis of CTEPH. Using a nationa registry, the current authors have assessed the prognostic vaue of a arger number of variabes and have aso attempted to vaidate the cinica importance of previousy identified aetioogica factors. Baseine information for a 469 CTEPH patients diagnosed in the UK pumonary hypertension service between January 2001 and June 2006 was coected from hospita records. Athough univariate anaysis confirmed the prognostic importance of pumonary resistance, in mutivariate anaysis gas transfer and exercise capacity predicted pumonary endarterectomy perioperative mortaity. Cardiac index and exercise capacity independenty predicted outcome in patients with nonoperabe disease. Previous spenectomy was noted in 6.7% of patients, being significanty more common in patients with nonoperabe than operabe disease (13.7 versus 3.6%). Medica risk factors were not found to predict mortaity. In a arge nationa cohort, predictors of outcome in patients with both operabe and nonoperabe chronic thromboemboic pumonary hypertension have been identified. These may be usefu in panning treatment. The aetioogica importance of previousy identified medica risk factors has been confirmed, athough the current authors were unabe to vaidate their prognostic strength. KEYWORDS: Endarterectomy, prognosis, pumonary hypertension, thromboemboism AFFILIATIONS *Pumonary Vascuar Disease Unit, Papworth Hospita, Cambridge, # Pumonary Vascuar Disease Unit, Roya Haamshire Hospita, Sheffied, " Dept of Cardioogy, Hammersmith Hospita, **Dept of Cardioogy, Roya Free Hospita, London, + Northern Vascuar Unit, Freeman Hospita, 1 Institute of Ceuar Medicine, Newcaste University, Newcasteupon-Tyne, and e Scottish Pumonary Vascuar Unit, Western Infirmary, Gasgow, UK. CORRESPONDENCE J. Pepke-Zaba Pumonary Vascuar Disease Unit, Papworth Hospita, Cambridge, CB23 3RE, UK. Fax: E-mai: joanna.pepkezaba@ papworth.nhs.uk Chronic thromboemboic pumonary hypertension (CTEPH) is thought to resut primariy from incompete ysis of acute pumonary emboism with subsequent organisation of the obstructing materia into vesse was and obstruction of pumonary vascuar bood fow [1]. The definitive treatment for CTEPH is pumonary endarterectomy (PEA) which has proven symptomatic and surviva benefit [2]. In a proportion of patients, the pumonary vascuar resistance (PVR) is disproportionate to the degree of obar and segmenta arteria obstruction reveaed by imaging. The risk of post-operative mortaity reated to dista vascuopathy may therefore outweigh the potentia benefits and these cases are therefore cassified as being nonoperabe. Treatment in this group of patients has increasingy invoved the disease-modifying therapies used in other forms of pumonary hypertension (PH). Surviva before effective treatments became avaiabe was poor, with 2-yr surviva of 10% in patients with a mean pumonary arteria pressure (P pa).50 mmhg [3]. Surviva in patients with both surgica and nonsurgica disease has, however, recenty been shown to have improved [2]. In view of the increasing use of surgica and medica therapy in patients with CTEPH, reiabe prognostic markers are important to hep guide appropriate management. In surgica patients, PVR has previousy been identified as an important predictor of perioperative mortaity [4 7]. Various medica risk factors for the deveopment of CTEPH have been identified, which have subsequenty been highighted as potentia predictors of poor outcome in both surgica and nonsurgica disease [8 11]. Since 2001, the diagnosis and management of a cases of CTEPH in the UK has been centraised to six PH centres, one of which is aso the nationa surgica referra centre for PEA. This has provided the opportunity to study prognostic factors in patients with both surgicay treated and Received: June Accepted after revision: September SUPPORT STATEMENT Statistica support was provided by the Nationa Institute for Heath Research (London, UK) Biomedica Research Centre Award to the Cambridge University NHS Trusts (Cambridge, UK). STATEMENT OF INTEREST Statements of interest for R. Condiffe, D.G. Kiey, J.S.R. Gibbs, P.A. Corris, A.J. Peacock, J.G. Coghan and J. Pepke-Zaba, and the study itsef, can be found at statements.shtm European Respiratory Journa Print ISSN Onine ISSN VOLUME 33 NUMBER 2 EUROPEAN RESPIRATORY JOURNAL

2 R. CONDLIFFE ET AL. PROGNOSTIC AND AETIOLOGICAL FACTORS IN CTEPH nonsurgica CTEPH within a arge cohort comprising a of the diagnosed patients within a singe country. It has aso been possibe to vaidate the various risk factors for deveoping CTEPH that have been identified in smaer series. METHODS Detais of patients in the nationa registry have been described esewhere [2]. Briefy, demographic detais of a patients diagnosed with CTEPH at a UK PH centre between January 1, 2001 and June 31, 2006 were entered prospectivey into oca databases. Suppementary data regarding diagnosis, baseine characteristics and risk factors were then obtained retrospectivey from oca hospita medica records by a singe investigator (R. Condiffe). In the vast majority (87%) of cases, disease distribution was assigned foowing review of cinica detais and radioogica investigations by the mutidiscipinary meeting (consisting of PEA surgeons, pumonary vascuar physicians and pumonary vascuar radioogists) at the nationa surgica referra centre (Pumonary Vascuar Disease Unit, Papworth Hospita, Cambridge, UK). The diagnosis assigned at this meeting was used in the registry. In a minority of cases, where referra was either not deemed appropriate or was refused by the patient, it was assigned by experienced pumonary vascuar physicians and radioogists at one of the five other nationa pumonary hypertension centres. Disease was cassified as operabe on the basis of whether abnormaities in pumonary haemodynamics, especiay pumonary resistance, were deemed to be proportiona to the degree of surgicay accessibe thromboemboic obstruction demonstrated using mutipe radioogica modaities. Mortaity status was ascertained at the censoring date of January 27, A sma proportion of patients was ost to foow-up (n54) or underwent ung transpantation (n53); in these patients, the date of ast contact or transpantation was taken as the censoring date. Percentage of predicted gas transfer of the ung for carbon monoxide (TL,CO) was assessed by the singe breath technique according to British Thoracic Society/Association of Respiratory Technoogists and Physioogists guideines [12]. The nationa registry was designed to define current care and so forma ethics approva was not required. The nationa Patient Information Advisory Group was, however, fuy informed regarding the use of patient data. Statistica anaysis Quantitative data were described using the mean SD or confidence interva. Comparison of continuous data was performed using the t-test (unpaired) and of categorica data using the Chi-squared test. Predictors of surviva in patients with nonsurgica disease were investigated using mutipevariabe Cox regression anaysis and factors associated with perioperative mortaity using mutipe-variabe ogistic regression anaysis. Haemodynamic variabes were coded into twoeve variabes by spitting the variabes at their median vaue. Variabes with.10% of vaues missing had a missing category added. Two different exercise tests are presenty used to assess patients with PH in the UK. Wak distances were therefore standardised into a singe variabe by conversion into a z-score, which corresponded to the number of standard deviations from the mean. Exercise toerance coud thus be incorporated into mutipe-variabe anaysis, which was performed using manua forward stepwise regression. Variabes with p-vaues f0.2 in univariate regression anaysis were considered for mutipe regression anayses. The ikeihood ratio test p-vaue was used at each iteration to decide which variabe woud enter the mode. The variabe with the smaest ikeihood ratio test p-vaue was entered into the mode and this was repeated unti a variabes with p-vaues,0.05 had been entered. Limiting this anaysis to subjects with non-missing data in the regression anaysis of perioperative mortaity meant modeing was done using approximatey haf of the patients, so the base mode from the stepwise regression was then tested with each remaining variabe in turn in the subset of patients for whom there was data for the variabes in question. Surviva was estimated using the Kapan Meier method, with comparisons performed using the og-rank test. A p-vaue,0.05 was regarded as statisticay significant throughout. RESULTS Study popuation During the study period, 469 patients were diagnosed with CTEPH, out of whom 236 underwent PEA and 148 patients had dista, nonoperabe disease. A patients had been investigated with computed tomography pumonary angiography, with a arge proportion aso having undergone isotope perfusion scanning and pumonary or magnetic resonance angiography. Right heart catheter detais were ocated for 97% of cases, whie a cases had cear evidence of significant PH with no evidence of significant eft ventricuar systoic or diastoic function on echocardiography. PH was defined as P pa o25 mmhg and a PVR o240 dyn?s?cm -5. In 19% of cases, the pumonary capiary wedge pressure was found to be.15 mmhg. As this measurement can be more difficut to obtain in this group of patients, due to an organised cot within the arteria umen, patients with a high wedge pressure were incuded in the registry and tota pumonary resistance (TPR) rather than PVR was used in the anaysis. Two forms of exercise test are in use within the UK PH service. The distance waked in the 6-min waking test (6MWT) was ocated for 69% of patients and in the incrementa shutte waking test (ISWT) for 20% of patients. Predictors of surviva in surgicay treated disease The median time to surgery from diagnostic catheter was 210 days (interquartie range 190 days). The resuts of both the univariate and mutipe-variabe anayses of predictors of perioperative mortaity are shown in tabe 1. In univariate anaysis, non-white patients had a greater risk of not surviving to hospita discharge (perioperative death) than those of white ethnicity. Higher TPR was associated with increased perioperative death and higher cardiac index (CI), wak distance and TL,CO with better perioperative surviva. In mutipevariabe anaysis, TL,CO and wak distance were independent predictors of perioperative mortaity. The outcome in surgicay treated patients improved from the third year onwards (data not shown) which is ikey to be due, in part, to the earning effect that has been seen in other PEA programmes [6]. Perioperative mortaity in patients diagnosed from 2003 onwards, according to both the independent predictors of exercise toerance (6MWT distance) and TL,CO, as we as TPR, are shown in figure 1. Mean 6MWT distance was m and mean ISWT distance was m. c EUROPEAN RESPIRATORY JOURNAL VOLUME 33 NUMBER 2 333

3 PROGNOSTIC AND AETIOLOGICAL FACTORS IN CTEPH R. CONDLIFFE ET AL. TABLE 1 Predictors of perioperative mortaity Variabe (reference) Univariate OR p-vaue Mutipe OR p-vaue Age (fmedian (58.9 yrs)) 1.00 ( ).0.99 Sex (femae) ( ) 0.84 Ethnicity (white) 4.69 ( ) Symptom duration, 24 months 1.85 ( ) months Reference WHO cass (I/II) 1.15 ( ) 0.81 P ra (fmedian (8.5 mmhg)) 1.71 ( ) 0.15 P pa (fmedian (48.0 mmhg)) 1.12 ( ) 0.76 CI (fmedian (1.90 L?min -1?m -2 )) 0.37 ( ) TPR (fmedian (1000 dyn?s?cm -5 )) 2.42 ( ) SV,O2 (fmedian (62.0%)) 0.40 ( ) Wak z-score (fmedian (-0.02)) 0.26 ( ) ( ) TL,CO %pred(fmedian (71.0%)) 0.25 ( ) ( ) 0.03 Missing 1.62 ( ) 1.51 ( ) FEV1/FVC (fmedian (71.7%)) 0.74 ( ) 0.45 Associated medica condition ( ) 0.96 Odds ratios (OR) are presented with 95% confidence intervas. WHO: Word Heath Organization; P ra: mean right atria pressure; P pa: mean pumonary artery pressure; CI: cardiac index; TPR: tota pumonary resistance; SV,O 2: mixed venous oxygen saturation; TL,CO: transfer coefficient of the ung for carbon monoxide; % pred: % predicted; FEV1: forced expiratory voume in one second; FVC: forced vita capacity. Predictors of surviva in nonoperabe disease In univariate anaysis, patients in Word Heath Organization (WHO) functiona cass III or IV had more than three times the mortaity of patients in WHO cass I or II. Mean right atria pressure, P pa and TPR above the median were associated with an increased risk of death, athough this did not reach significance for P pa. Conversey, CI, mixed venous oxygen saturation, wak distance, TL,CO and forced expiratory voume in one second/ forced vita capacity (FEV1/FVC) ratio above the median were associated with better surviva. In mutivariate anaysis, CI and wak distance were independent predictors of surviva. The resuts of the Cox anaysis are shown in tabe 2 and surviva based on the median vaue of the independent predictor of CI is shown in figure 2a. Mean pre-operative 6MWT distance was m and mean ISWT distance was m. Surviva based on the 6MWT distance (228 m) corresponding to the median z-score (-0.08) is shown in figure 2b. Medica risk factors for deveoping CTEPH Data regarding medica risk factors was present for 96% of cases and are shown in tabe 3. A previousy documented venous thromboemboic event (VTE) was significanty more common in patients with operabe disease, whereas a previous spenectomy was significanty more common in those with nonoperabe disease. The underying reason for spenectomy was haemoytic anaemia in 42%, myeoproiferative disease in a) 30 b) c) Perioperative mortaity % < < >400 < TL,CO % pred 6MWD TPR dynes cm -5 >1500 FIGURE 1. Perioperative mortaity according to a) 6-min wak distance (6MWD), b) transfer coefficient of the ung for carbon monoxide (TL,CO) and c) tota pumonary resistance (TPR). % pred: % predicted. 334 VOLUME 33 NUMBER 2 EUROPEAN RESPIRATORY JOURNAL

4 R. CONDLIFFE ET AL. PROGNOSTIC AND AETIOLOGICAL FACTORS IN CTEPH TABLE 2 Predictors of mortaity in patients with nonoperabe chronic thromboemboic pumonary hypertension Variabe (reference) Univariate HR p-vaue Mutipe HR p-vaue Age yrs ( ) ( ) o60 Reference Sex (femae) 1.19 ( ) 0.59 WHO cass I/II Reference 0.04 III/IV 3.52 ( ) P ra (fmedian (10.0 mmhg)) 2.19 ( ) P pa (fmedian (49.0 mmhg)) 1.80 ( ) CI (fmedian (2.00 L?min -1?m -2 )) 0.26 ( ) ( ) TPR (fmedian ( dyn?s?cm -5 ) 4.60 ( ),0.001 SV,O 2 (fmedian (60%)) 0.34 ( ) Wak z-score (fmedian (-0.08)) 0.30 ( ) ( ) TL,CO %pred(fmedian (67.5%)) 0.52 ( ) Missing 1.61 ( ) FEV1/FVC (fmedian (71.9%)) 0.43 ( ) Treatment regime Singe Reference Combination 1.10 ( ) 0.87 No prescription 1.75 ( ) 0.17 Associated medica conditions 1.17 ( ) 0.68 Hazard ratios (HR) are presented with 95% confidence intervas. WHO: Word Heath Organization; P ra: mean right atria pressure; P pa: mean pumonary artery pressure; CI: cardiac index; TPR: tota pumonary resistance; SV,O 2: mixed venous oxygen saturation; TL,CO: transfer factor of the ung for carbon monoxide; % pred: % predicted; FEV1: forced expiratory voume in one second; FVC: forced vita capacity. 29% and road traffic accident in 29% of cases. The presence or absence of the associated medica conditions of previous spenectomy, ventricuo-atria shunt, pacemaker ead and infammatory bowe disease did not affect surviva in either operabe or nonoperabe disease (p50.7), athough the tota number of patients with these conditions was reativey sma. There was, however, a nonsignificant trend towards these associated medica conditions being more common in surgicay treated patients who had persistent PH 3 months after surgery (12.9 versus 5.4%; p50.096). DISCUSSION Using the first nationa registry of a CTEPH patients diagnosed and treated within a singe country, the present authors have been abe to study in detai prognostic markers for both surgicay treated and nonoperabe disease. It was demonstrated that exercise capacity and TL,CO independenty predicted perioperative mortaity in surgica patients, whie exercise capacity and CI independenty predicted outcome in patients with nonoperabe disease. In a series of 34 patients undergoing PEA, HARTZ et a. [4] reported in 1996 that the perioperative mortaity of patients with apvr.1,100 dyn?s?cm -5 was six times greater than that of patients with a PVR beow this figure. TSCHOLL et a. [5] reviewed 69 patients treated with PEA and found that in univariate anaysis age, right atria pressure, functiona cass, cardiac output and creatinine predicted outcome [5]. In the present study, PVR did not significanty predict surviva. However, in a subsequent, arger series of 275 PEA cases, DARTEVELLE et a. [7] did observe a prognostic significance of PVR, with mortaity increasing when the baseine PVR exceeded 900 dyn?s?cm -5 and a further increase in mortaity at resistances.1,200 dyn?s?cm -5 [7]. In the present study, it was found that in surgicay treated patients, pumonary resistance was a significant prognostic factor in univariate, but not in mutivariabe anaysis. As there was ikey coinearity between variabes such as TPR and exercise capacity, prognostic importance can sti be assigned to pumonary resistance. Patients with a TPR.1,000 dyn?s?cm -5 had 2.4 times the risk of dying in the perioperative period as patients with a TPR beow this figure. Pumonary resistance shoud, therefore, continue to be centra to the decision-making process regarding suitabiity for surgery. The current authors have aso, however, identified TL,CO and exercise capacity as being independent prognostic markers in patients undergoing PEA. A reduction in TL,CO in patients with CTEPH has previousy been described, due primariy to a reduction in pumonary membrane diffusing capacity (DM)with a esser reduction in pumonary capiary bood voume (Vc)[13]. SUNTHARALINGAM et a. [14] observed that TL,CO was ower in patients with idiopathic pumonary arteria hypertension or dista CTEPH than in patients with proxima CTEPH [14]. They postuated that this may have been due to DM being more affected in patients with dista disease. It is therefore possibe that the increased perioperative mortaity observed by the present authors in patients with ower TL,CO was due to a higher degree of dista vascuopathy. STEENHUIS et a. [15] were, however, unabe to demonstrate a difference in DM or Vc in patients with idiopathic pumonary arteria hypertension and c EUROPEAN RESPIRATORY JOURNAL VOLUME 33 NUMBER 2 335

5 PROGNOSTIC AND AETIOLOGICAL FACTORS IN CTEPH R. CONDLIFFE ET AL. a) Cumuative surviva b) Cumuative surviva Time from diagnosis yrs FIGURE 2. Surviva from diagnosis of nonoperabe patients, grouped by a) baseine cardiac index (CI) and b) 6-min wak distance (6MWD) above or beow the median.??????: CI.2 L?min -1?m -2 ; : CI,2 L?min -1?m -2 ; : 6MWD.228 m;???? : 6MWD,228 m; ***: p,0.001; # :p CTEPH [15]. Furthermore, there was no significant difference in the TL,CO of patients in the present study with either operabe or nonoperabe disease (69.1 versus 68.4%; p50.72) [2]. Athough a ow FEV1/FVC ratio suggestive of airfow obstruction did not increase perioperative mortaity, it is possibe that the prognostic significance of a ow TL,CO may, in part, aso be due to coexisting respiratory disease. The prognostic significance of exercise toerance in surgicay treated patients has not been extensivey studied. *** # SUNTHARALINGAM et a. [14] found that a 6MWT distance f345 m predicted perioperative mortaity with a sensitivity of 100%, athough specificity was ony 36% [16]. The resuts of the present study demonstrated that a 6MWT distance o250 m was associated with a perioperative mortaity of,5%, whie a 6MWT distance,250 m was associated with a perioperative mortaity of o10%. The current study has aso provided important insight into prognostic factors in patients with nonoperabe disease. LEWCZUK et a. [17] studied 49 patients with conservativey treated CTEPH and found that an exercise capacity of,2 metaboic equivaents, a P pa.30 mmhg or the presence of significant chronic obstructive pumonary disease were predictive of poorer surviva [17]. In the present study, mutipevariabe anaysis demonstrated that exercise capacity as we as CI were independent predictors of surviva. BONDERMAN et a. [11] studied 181 CTEPH patients and found that CI did not independenty predict surviva; however, this anaysis aso incuded 105 patients who had undergone PEA, which may have introduced a therapeutic bias to the resuts [11]. Patients with nonoperabe disease who did not receive diseasemodifying therapy were not significanty more ikey to die during foow-up. However, ony 15% of patients received no such therapy, and the majority of those had mid symptoms and/or pumonary haemodynamics. It is therefore unikey that this anaysis woud demonstrate a surviva benefit from disease-modifying therapy even if such a benefit does exist. As we as investigating prognostic factors the current authors have aso been abe to assess the previousy described cinica risk factors for the deveopment of CTEPH. It is interesting to note that in the present study a significant proportion (42%) of patients did not have a history of a previousy documented VTE. In their study of 109 patients BONDERMAN et a. [8] found no history of VTE in 52% of cases whie LANG [18] reported that 63% of 142 consecutive patients had no previousy documented VTE. It is possibe that a proportion of patients, especiay those with a history of sudden-onset symptoms, had a previous VTE which at the time was undiagnosed. It is interesting to note that the ack of a previousy documented VTE in the current cohort was significanty more common in those with dista disease. This fact coud end credence to a hypothesis that in a proportion of patients a process of in situ thrombosis may occur [19]. A history of previous spenectomy was present in amost 7% of a cases, and in 13.7% of patients with nonoperabe disease. The TABLE 3 Cinica risk factors for deveoping chronic thromboemboic pumonary hypertension A patients Surgicay accessibe Nonsurgica disease p-vaue Patients n Previous VTE Spenectomy ,0.001 Ventricuo-atria shunt or pacemaker ead IBD AMC Data are presented as %, uness otherwise stated. VTE: venous thromboemboic event; IBD: infammatory bowe disease; AMC: associated medica conditions (spenectomy, ventricuo-atria shunt or pacemaker ead and IBD). 336 VOLUME 33 NUMBER 2 EUROPEAN RESPIRATORY JOURNAL

6 R. CONDLIFFE ET AL. PROGNOSTIC AND AETIOLOGICAL FACTORS IN CTEPH association of spenectomy and CTEPH, especiay in nonoperabe disease, has previousy been described [8, 9, 20]. Severa potentia mechanisms for this phenomenon have been postuated, incuding oss of spenic function eading to the circuation of pateet-derived mediators, which, when acting in conjunction with abnorma erythrocytes, promote thrombus formation in the pumonary circuation [9]. Athough in the present study ventricuo-atria shunts and pacemaker eads were found in under haf of the proportion that was noted by BONDERMAN et a. [8], the present figures were sti higher than those observed in the contro patients in that study. In a subsequent study, the same group found that the associated medica conditions of spenectomy, centra i.v. ines and chronic infammatory conditions were strong predictors of mortaity in both surgicay and nonsurgicay treated patients [11]. The present authors have been unabe to reproduce this observation, athough a trend was seen towards persistent PH foowing PEA being more common in patients with these conditions. The main imitation of the present study is the retrospective nature of much of the data coection. Retrieva bias may therefore have been introduced because information was gathered from notes which had different eves of competeness. The effects of having missing haemodynamic and functiona data were accounted for somewhat by incuding missing categories variabes in the regression modes. Furthermore, the number of patients with missing data concerning previous thromboemboic events and associated medica conditions was ow. It is unikey that important features such as previous spenectomy, ventricuo-atria shunt, pacemaker ead or infammatory bowe disease woud have been missed when reviewing patient notes and etters. Data regarding thrombophiias has not been presented, as such data was incompete and invoved mutipe centres with different assays, and in many cases patients were aready receiving treatment with warfarin, which made interpretation difficut. The associated medica conditions highighted in the previous studies discussed above aso incuded osteomyeitis [11]. Athough the present study did not coect data regarding this condition, it is unikey that doing so woud have significanty affected the findings regarding their prognostic strength. The present study, the first to invove a nationa registry of chronic thromboemboic pumonary hypertension patients, has found the independent predictors of surviva in patients undergoing pumonary endarterectomy to be transfer factor of the ung for carbon monoxide and exercise capacity, and in patients with nonoperabe disease to be cardiac index and exercise capacity. 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