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TIMI Risk Index as a Predictor of 30-Day Outcomes in Patients With Acute Pulmonary Embolism
Accepted Manuscript Title: TIMI Risk Index as a Predictor of 30-Day Outcomes in Patients with Acute Pulmonary EmbolismTIMI Risk Index in Acute Pulmonary Embolism–> Authors: Marco Zuin MD, Luca Conte MD, Claudio Picariello MD, Gianni Pastore MD, Dobrin Vassiliev MD, PhD, Daniela Lanza MD, Pietro Zonzin MD, Giovanni Zuliani MD, Gianluca Rigatelli MD, PhD, EBIR, Loris Roncon MD PII: DOI: Reference:
S1443-9506(17)30319-0 http://dx.doi.org/doi:10.1016/j.hlc.2017.02.035 HLC 2355
To appear in: Received date: Revised date: Accepted date:
13-3-2016 10-2-2017 27-2-2017
Please cite this article as: Zuin Marco, Conte Luca, Picariello Claudio, Pastore Gianni, Vassiliev Dobrin, Lanza Daniela, Zonzin Pietro, Zuliani Giovanni, Rigatelli Gianluca, Roncon Loris.TIMI Risk Index as a Predictor of 30-Day Outcomes in Patients with Acute Pulmonary Embolism.Heart, Lung and Circulation http://dx.doi.org/10.1016/j.hlc.2017.02.035 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
TIMI Risk Index as a Predictor of 30-Day Outcomes in Patients with Acute Pulmonary Embolism
Running Title: TIMI Risk Index in Acute Pulmonary Embolism
Marco Zuin 1 , MD, Luca Cont e 1 , MD, Claudio Picar iello 1 , MD, Gianni Past ore 2 , MD, Dobr in Vassiliev
3
, MD, PhD, Daniela Lanza
1
, MD, Piet ro Zonzin
1
, MD,
Giovanni Zuliani 4 , MD, Gianluca Rigat elli 5 , MD, PhD, EBIR, Loris Roncon 1 , MD
1
2
Cardi ol ogy Departm ent, Sant a Mari a Dell a Mi seri cordi a Hospit al, Rov igo, It aly. Arrhyt hmi a and El ect rophysi ol ogy Uni t, Cardi ol ogy Departm ent , Sant a Mari a Dell a
Mi seri cordi a Hospit al, Rov igo, It aly. 3
4
Cardi ol ogy Cli nic, Al ex androska Univ ersit y Hospi t al , Sof i a, Bul gari a Secti on of I nt ernal and Cardi opulm onary Medi ci ne, Departm ent of Medi cal Sci ence,
Univ ersi ty of F errara, F errara, I t al y 5
Secti on of Adul t Congenit al and Adult Heart Di sease, Cardi ov ascul ar Di agnosi s and
Endol umi nal I nt erv enti ons, Rov i go G eneral Hospi t al , It aly
Corresponding author: Loris Roncon, MD Department of Cardiology, Santa Maria della Misericordia Hospital Viale Tre Martiri 140, 45100 Rovigo, Italy Phone: +39 0425393286 Fax: +39 0425393597 E-mail: [email protected]; [email protected]
1
Abstract Background: Available st udies have already ident ified age, heart rat e (HR) and syst olic blood pressure (SBP) as st rong predict ors of ear ly mort alit y in acut e PE.
Material and Methods: One-hundred-sevent y pat ient s, wit h acut e PE confir med on comput ed
tomography
Myocardial Infarct ion
angiography
(CTA)
were
enrolled.
Thrombolys is
In
(TIMI) risk index (TRI) was calculat ed using t he formula
[HR x (AGE/10 2 )/SBP]. St udy out comes were 30-day mort alit y and/or clinica l det eriorat ion.
Results: Receiver operat ing charact erist ics (ROC) curve revealed t hat a TRI ≥ 45 was highly specific for bot h out comes (AUC 0.91, 95 % CI 0.83–0.98, p<0.0001) wit h a posit ive predict ive value (PPV) and negat ive predict ive value (NPV) of 8.3 and 96 % for 30-day mort alit y while PP V and NPV for 30-day mort alit y and/or clinical det eriorat ion were 21.1 and 98.2 %, respect ively. Mult ivar iat e regressio n analysis showed t hat TRI≥45 was an independent predict or of 30-day mort alit y (O.R. 22.24, 95% CI 2.54–194.10, p=0.005) independent ly from posit ive cTnI and RVD (O.R. 9.57, 95% CI 1.88–48.78, p=0.007; OR 24.99, 95% CI 2.84–219.48, p=0.004). Similar ly, 30-day mort alit y and/or clinical det eriorat ion was predict ed by TRI ≥45 (O.R. 11.57, 95 % CI 2.36–56.63, p=0.003) and t hrombo lysis (3.83, 95% CI 1.04–14.09, p=0.043), independent ly fro m age, RVD and posit ive cTnI. Cox regression analysis confir med t he role of TRI as independent predictor for bot h out comes. Mant el-Cox analysis showed that aft er 30-day fo llow-up t here was a st at ist ically significant difference in t he dist r ibut ion of survival bet ween pat ient s wit h and wit hout TRI ≥ 45 [log rank (Mant el-Cox) chi- square 17.04, p<0.0001].
Conclusions: TIMI risk index predict ed bot h 30-days mort alit y (all-causes) and/or clinical det er iorat ion in pat ient s wit h acut e PE.
K eywords: Pulmo nar y embo lis m; Risk st rat ificat ion; TIMI risk index.
Introduction
2
Risk st rat ificat ion is an int egral part of clinical prognost icat ion, especially in pot ent ially life-t hreat ening cardiovascular diseases, such as acut e pulmonar y embo lism (PE) [1]. The out comes of an acut e episode of PE are strongly connect ed to bot h haemodynamic st at us and to t he possible cardio vascular adapt at ions t hat may have t aken place [2, 3]. Pat ient s wit h ST-elevat ion myocardial infarct io n (STEMI) need a simple r isk st rat ificat ion algor it hm t o quickly assess mort alit y risk. The Thrombo lysis I n Myocardial Infarct ion (TIMI) risk index (TRI) is a valid clinical tool for r isk assessment of pat ient s wit h STEMI, which co mbines age, heart rat e (HR) and syst olic blood pressure (SBP), which are independent predictors of deat h in STEMI [4]. Similar ly, recent analyses fro m clinical t rials, regist ry and single st udies in pat ient s wit h PE have also est ablished t hat age, HR and SBP are st rong independent predictors of early mo rt alit y; in part icular, age and HR have a posit ive, while SBP has an inverse associat ion, respect ively [5-9]. Different algorit hms and scores are current ly availa ble for t he risk st rat ificat ion of acut e PE, but in most cases, t hey are too complex for use in daily clinical pract ice, because t hey require imaging t echniques such as t ranst horacic echocardiography (TTE) (not always
immediat ely
available
in
all
emergency
depart ment s),
comput ed
angiography t omography (CTA), cardiac bio markers, medical hist ory et c. [10-14]. Alt hough PE pat ient s at “high-r isk” have well-est ablished t reat ment s using t hrombo lysis or percut aneous t echniques [9], t he ident ificat ion of pat ient s at int er mediat e-risk and t heir opt imal t reatment remains one of t he most debat ed topics, in part icular in t he use of t hrombolysis [9, 14]. We sought to evaluat e t he ut ilit y o f TRI for t he predict ion of 30-day mort alit y and/or clinical det er iorat ion in an It alian populat ion-based cohort wit h confir med acut e PE.
Material and Methods 3
Study Design This was a ret rospect ive, single-cent re analysis o f prospect ively co llect ed dat a. The inclusio n per iod was from Januar y 2010 to August 2014. The local Et hics Commit t ee approved t he st udy and all procedures were in accordance wit h t he Declarat ion of Helsinki and wit h Inst it ut ional Guidelines. All enro lled pat ient s gave infor med consent . Inclusion cr it er ia were: object ively confir med diagnosis o f acut e sympt omat ic PE at CTA; all diagnost ic invest igat ion per formed in our hospit al; age ≥18 years old ; TTE performed wit hin 24-hours from admissio n; and ult rasonography (US) limb assessment for deep vein t hrombosis execut ed wit hin 24 hours fro m PE diagnosis. Conversely, exclusio n cr it eria were: subject s wit hout confir med diagnosis o f PE at CTA; absence of TTE wit hin 24 hours fro m admission; absence of lower limb US wit hin 24-hours from PE diagnosis; cont inuat ion o f t reat ment in ot her regional ho spit als; age < 18 years o ld ; and denia l of consent for part icipat ion in t he st udy. During t he st udy per iod, 170 pat ient s (70 men and 100 women) fulfilled t he st udy crit er ia; 28 pat ient s were excluded for absence of at least one of t he inclusion crit er ia. In part icular, 16 pat ient s did not have TTE performed dur ing t he 24-hours aft er admission; 4 pat ient s, aft er diagnosis, were t ransferred to a secondar y regional hospit al to cont inue t he treat ment ; and 8 subject s received PE diagnosis t hrough vent ilat ion-per fusio n scan. No pat ient s were lost during t he fo llow -up; indeed, of 170 pat ient s, 150 were evaluat ed wit h clinical examinat ion 30 days aft er discharge and 10 pat ient s received t he fo llow-up during furt her hospit alisat ion (t hey were hospit alised again, but not in our depart ment and for reasons not attribut able to PE). Ten subject s died aft er discharge; in t his case, mort alit y for all-causes was assessed t hrough t he hospit al dat abase.
The ent ire populat ion was st rat ified at admissio n wit h sPESI
score [11], as recommended by t he lat est European guidelines [9]. Personal medical 4
hist ory was t aken at admissio n and always confir med by previous hospit al records. All enro lled subject s underwent a post-discharge clinical evaluat ion aft er 30 days; 30-day fo llow-up was performed in person for all pat ient s. If t he pat ient died during t he period bet ween discharge and fo llow-up evaluat ion, 30-day mort alit y was regist ered using t he local hospit al database. For t his reason, due to a limit at ion of t he dat abase, we could evaluat e only all-cause mort alit y.
Data Collection and Definitions S yst olic (SBP) and diast olic (DBP) blood pressure were t aken at admissio n using a mercur y sphygmo mano met er (diast olic Korotkoff phase 5); heart rat e (HR) was measured at t he same t ime. For t he analys is we used t he measurement performed at t he t ime o f confir mat ion o f PE. Art erial hypot ensio n was defined as (SBP) ≤90 mmHg.
Shock
index
(SI)
was
calculat ed
as
t he
rat io
of
HR
and
SBP.
Haemodynamic inst abilit y at admissio n was defined as SBP < 90 mmHg or drop of t he same by ≥40 mmHg for ≥15 minut es, need for cat echolamine infusio n or cardiopulmo nar y resuscit at ion (CPR) or SI great er t han one. Respirat ory rat e was det ermined by count ing how many t imes t he chest expanded per minut e wit h t he pat ient in a supine posit ion. The presence of dyspnoea was also evaluat ed. Body mass index (BMI) was calculat ed (in kg/ m2) as t he rat io of weight to squared height . Subject s were considered as obese if BMI was ≥30 kg/m 2 . A venous blood sample for cardiac markers was obt ained before st art ing any t reat ment : t he levels of cardiac t roponin I (cTnI) were measured by immunoassay using Dimensio n®RxL analyzer (Dade Behr ing, Newark, DE) in t he hospit al cent ral laboratory. This syst em was able t o det ect a minimum cTnI level of 0.04 ng/ ml, which was 5
considered t he upper limit for normal pat ient s. Right vent ricular dysfunct ion (RVD) was det ect ed by echocardiography ( iE33, Philips Ult rasound, Bot hell, WA) or Vivid 9, (GE Vingmed Ult rasound AS, Hort en, Norway), performed w it hin 24 hours from admission. Right vent ricular dysfunct ion was defined in t he presence of at least one of t he fo llowing: (1) right -to-left vent ricular/end diast olic diamet er rat io > 1 in apical four-chamber view; (2) r ight -to-left vent ricular/end diast olic rat io > 0.6 in parast ernal long-axis or subcost al four-chamber view; and (3) right vent ricular-to right at rial pressure gradient > 30 mm Hg [15]. Right vent ricular dysfunct ion was not considered to be of acut e onset in t he presence of a right vent ricular wall t hickness of >7 mm or previous document at ion of right vent ricular overload. Clinical det eriorat ion was defined as a clinically worsening condit ion t hat required at least one of t he fo llowing: (1) IV cat echolamine infusio n; (2) endotrachea l int ubat ion; or (3) CPR.
Therapeutic Management During t he acut e phase unfract ionat ed hepar in (UFH), adjust ed for t he act ivat ed part ial t hromboplast in t ime (aPTT) or low- mo lecular weight hepar in (LMWH) (enoxapar in 1.0 mg/kg, ever y 12 hours) were administ ered over t he first 5 to 10 days [9, 16]. Ant icoagulat ion was cont inued unt il t he int ernat ional nor malised rat io (INR) was bet ween 2.0 and 3.0 for t wo consecut ive days and t hen adjust ed wit h vit amin K ant agonist (VKA). Recombinant t issue plasminoge n act ivat or (r-Tpa) was used if indicat ed, wit h a dose of 100 mg over 2 hours or 0.6 mg/kg over 15 minut es, wit h a maximum dose of 50 mg [9]. In pat ient s wit h abso lut e cont raindicat ions
to
t hrombo lysis,
Percut aneous
cat het er-direct ed
Treat ment
(PCDT) was performed using t he AngioJet ® 6F PE® (Bayer, Germany) in conjunct ion wit h recombinant t issue plasminogen act ivat or (r-t PA) [17]. 6
Clinical Outcomes The main out comes were 30-day mort alit y (all-causes) and/or clinical det eriorat ion.
Statistical Analysis In t he fir st st ep, we evaluat ed t he relat ions bet ween age, HR and SBP. Age showed a non- linear but unifor mly increasing relat ion wit h t he endpoint s of t he st udy and so it was t herefore modelled using a quadrat ic t erm. Guided by t he obser ved relat ion (Figure 1) we applied t he TRI as:
[HR X (Age/10) 2 ]
[4]
SBP
The enrolled populat ion was t hen st rat ified across t he quart iles of TRI. Cat egorica l var iables were expressed as percent age rat es and compared wit h t he Pearson’s χ 2 t est . Cont inuous var iables were expressed as mean and st andard deviat ion and t he difference values were evaluat ed by analysis of var iance. The null hypot hesis was reject ed for p<0.05. To ident ify t he opt imal t hresho ld value for TRI a ROC curve analysis was per formed. Unadjust ed and adjust ed OR were assessed for t he TRI as a predict or of 30-day mort alit y and/or clinical det eriorat ion using mult ivar iat e regression analysis. Risk for 30-day mort alit y and/or clinical det er iorat ion were calculat ed wit h a Cox proport ional hazard model. The abilit y o f t he TIMI to classify t he pat ient s wit h a TRI value great er t han t he t hresho ld was assessed by 7
t he C st at ist ics [18]. Posit ive predict ive value (PPV) and negat ive predict ive value (NPV) are also descr ibed. Follow-up was perfor med to assess t he overall mort alit y for 30 days aft er discharge. Kaplan-Meier survival analysis was per formed and surviving pat ient s wit h a TRI great er t han t he opt imal t hresho ld were compared wit h t hose wit h a TRI <45 using log-rank (Mant el-Cox) analysis. St at ist ica l analyses were perfor med using SPSS package versio n 19.0 for Windows (SPSS, Chicago, IL, USA).
Results The st udy populat ion co mpr ised 170 consecut ive pat ient s (70 men and 100 wo men, mean age 71.05±13.70 years). The general charact er ist ics of t he subject s are summar ised in Table 1, also showing t he current ESC st rat ificat ion for acut e PE. Haemodynamic inst abilit y became more evident wit h t he increase in r isk group (p<0.0001). No significant differences were found in t he prevalence of gender, risks fact ors for PE, posit ive cT nI, and cardiac arrest across t he risk cat egories. Deat h occurred in 5.8% of t he pat ient s enro lled, wit h an incidence t hat became higher wit h increasing sever it y of PE (0, 2. 6, 38.8% p=0.04). In cont rast , clinica l det eriorat ion was observed in 2.9 % of cases. Thirt y-day mort alit y ( for all-causes) and/or clinical det eriorat ion occurred in 8.8 % of pat ient s (1.4, 2.0, 15.1, 38.8%, p<0.0001). The TRI and t he composit e out come were significant ly higher in upper vs lower r isk cat egories (p<0.0001). The t herapeut ic st rat egies adopt ed are shown in Table 2. Thrombo lysis was per for med mainly in t he int er mediat e- and high-r isk groups. Five pat ient s (2.9%) were treat ed wit h PCDT, due to t he absolut e cont raindicat ion
for
t hrombolys is.
There
were
no
deat hs
associat ed
wit h 8
complicat ions of t herapy; however, in t wo pat ient s a t ransit ory anaemia occurred aft er t he t hrombo lysis. The prevalence of pulmo nar y hypert ensio n at discharge was equally in int er mediat e-low and high-r isk pat ient s (16.0% vs 16.7%, p=ns). As shown in Table 3, age, SBP, DBP, HR, respirat ory rat e and SI were significant ly higher in upper vs lower TRI quart iles (p<0.0001). Mort alit y rat e (0, 0, 2.3 and 18%, p=0.020) and t he composit e out come of t he st udy (0, 2.3, 2.3, 25%, p=0.001) were increasingly dist ribut ed in t he quart iles of TRI, while clinical det er iorat ion was not different bet ween t hem. The TRI mean value bet ween survivors and no nsurvivors is showed in Figure 2. A receiver operat ing charact er ist ics cur ve (Figure 3) was used to find t he opt imal cut -off value of TRI for 30-day mort alit y (allcauses) and/or clinical det er iorat ion. The TRI ≥ 45 appeared to be highly specific for bot h out comes (AUC 0.91, 95 % CI 0.83–0.98, p<0.0001). Posit ive predict ive value for 30-day mort alit y was 8.3%, while NPV was 96 %. Conversely, for 30-day mort alit y and/or clinical det eriorat ion, PPV and NPV were 21.1 and 98.2%, respect ively. Unadjust ed regression analys is showed t hat pat ient s wit h TRI ≥45 had a higher risk of 30-day mort alit y t han t hose wit h a TRI less t han 45, (OR 23.18, 95% CI 2.87–189.48, p=0.003). This result was also confir med for t he combined endpo int (OR 11.25, 95% CI 2.37–53.31, p=0.002). Mult ivar iat e regression analys is showed t hat TRI≥45 was an independent predict or of 30-day all-cause mort alit y (OR 22.24, 95% CI 2.54–194.10, p=0.005) independent ly fro m posit ive cTnI and RVD (OR 9.57, 95% CI 1.88–48.78, p=0.007; OR 24.99, 95% CI 2.84–219.48, p=0.004). Adding gender, t he model similar ly predict s t he out come (OR 37.25, 95 % CI 3.79–366.06, p=0.002; OR 12.32, 95 % CI 2.19–69.18, p=0.004 and OR 25.59, 95% CI 2.91–224.48, p=0.003, for TRI, cTnI and RVD, respect ively). Taking int o account t he composit e out come as dependent var iables, 30-day mort alit y and/or clinical det er iorat ion was predict ed by TRI ≥45 (OR 11.57, 95% CI 2.36– 9
56.63, p=0.003) and t hrombo lysis (OR 3.83, 95% CI 1.04–14.09, p=0.043), independent ly fro m age, RVD and posit ive cTnI; adding gender did not modify t he model. Cox regression analysis showed that pat ient s wit h a TRI ≥45 had a higher risk for 30-day mort alit y t han t hose with a TRI <45 (HR 24.09, 95% CI 2.44– 237,97, p=0.006), independent ly fro m posit ive cTnI, and RVD (HR, 25.27, 95% CI 2.16–295.02, p=0.010; HR 10.38, 95 % CI 1.76–61.25, p=0.010, respect ively). The higher risk for t he composit e out come was also confir med at Cox analysis, t aking int o account 30-day mort alit y and/or clinical det eriorat ion as dependent var iable s (HR 8.68, 95% CI 1.78–41.95, p=0.007 – adjust ed for t he same confounders used in t he mult ivar iat e analys is). The C st atist ic showed an improvement of t he discr iminatory power of TRI fo r t he 30-day mort alit y vs t he ESC st rat ificat ion (0.91, 95% CI 0.85–0.97, p<0.0001 vs 0.90, 95% CI 0.79 to -1.00, p<0.0001, respect ively) and also for t he composit e out come (0.84, 95% CI 0.74–0.94, p<0.0001 vs 0.82, 95% CI 0.69–0.95, p<0.0001, respect ively). S imilar result s were obt ained analysing t he discr iminat ory power of SI for t he same out comes (0.91, 95% CI 0.89–0.97, p<0.0001 and 0.88, 95% CI 0.81–0.96, p<0.0001). Taking int o account t he pat ient s at int ermediat e-risk (low and high) t he TRI nicely predict s t he 30-day mort alit y and t he composit e out comes (0.81, 95% CI 0.69–0.93, p=0.001 and 0.79, 95% CI 0.67–0.91, p<0.0001, respect ively). However, a furt her subanalysis revealed t hat t he discr iminat ory power was high only in int er mediat e-high risk subject s (0.82, 95% CI 0.70–0.93, p=0.001 vs 0.18, 95% CI 0.06–0.29, p=0.001, for high and low int er mediat e risk, respect ively).
Mant el-Cox analysis
showed t hat aft er 30-day fo llow-up t here was a st at ist ically significant difference in t he dist ribut ion o f survival bet ween pat ient s wit h and wit hout TRI ≥ 45 [log rank (Mant el-Cox) chi- square 17.04, p<0.0001] (Figure 4).
10
Discussion Our st udy clear ly suggest s t hat t he TRI predict ed bot h 30-day mort alit y and /or clinical det er iorat ion. Age is t he one of t he most import ant det erminant s of PE sever it y; indeed, it was recent ly confir med in several st udies [5, 7, 8, 19]. It is well known t hat t achycardia and hypot ension are signs of haemodynamic inst abilit y and, moreover, it has already been est ablished t hat t he lat t er predict s a poor out come in PE. In effect , HR has been recent ly described as an import ant paramet er to t ake int o considerat ion during acut e PE, being st rongly correlat ed wit h worse out come [7, 10, 20]. Moreover, when t achycardia is present , a seven- fo ld higher r isk of inhospit al deat h has been report ed [5]. Inst ead, blood pressure and in part icular hypot ension, is one o f t he d iscr iminat ory paramet ers used for recognising pat ient s wit h high-r isk PE [9]. These aspect s are, as is known, not new. Inst ead, what ma y be new is t he use of a clinical score, generally applied in pat ient s wit h STEMI, in t he sett ing of acut e PE. In clinical pract ice, rapid and effect ive risk st rat ificat ion is mandat ory in t hese pat ient s. The aim is obviously t o ident ify pat ient s at high r isk of ear ly mort alit y or complicat ions in order to int ervene wit hout delay. As evidenced by our result s, TRI could be able t o reclassify pat ient s, t aking int o account t he ESC risk st rat ificat ion as a reference. It would be unrealist ic to t hink t hat a clinical score, consist ing of BP and HR can be an alt ernat ive in t he evaluat ion of t he right vent ricular funct ion in acut e PE. Indeed, t he import ance of t he latt er paramet er has been est ablished by several st udies in t he last 30 years. Moreover, we have demo nst rat ed t hat TRI has a major discr iminat ory power in t he assessment of 30-day mort alit y and/or clinical det er iorat ion wit h respect to t he ESC model. Int erest ing result s have been present ed also in t he evaluat ion of t he aforement ioned out comes especially in pat ient s at int ermediat e-high r isk. The low
11
C st at ist ic value, for t he previous endpo int s, in pat ient s at int ermed iat e- low risk is probably due t o t he ver y low rat e event s in t his group. As a mat t er of fact , in our st udy, one of t he most import ant limit at ions is t he small sample size and t he low rat e of mort alit y and clinical det er iorat ion; as a result , t he TRI PPV result s are low. Moreover, t he clinical det eriorat ion rat e, which was one of t he out comes, is low, wit h only five pat ient s regist ered. However, we believe t hat t his out come is import ant and wort hy of being considered, despit e it s value. No cases o f clinical det eriorat ion were regist ered in t he high-r isk group but , as is known, t hese pat ient s, as per definit ion, are haemodynamically unst able and oft en t hey die wit hout going t hrough a phase of det eriorat ion or t hey are already in a ser ious medical co ndit ion, where a furt her and rapid det eriorat ion may precede deat h wit hout t ime for furt her medical int er vent io n. To t he best of our knowledge, t his is t he sit uat ion in which to use TRI in pat ient s wit h PE. The TRI formula could be considered as t he int egrat ion of SI wit h the var iable age. Indeed, t he formula it is explained as:
HR x (AGE/10) 2 SI x (AGE/10) 2
TRI= SBP
Shock index has been already defined as an independent predict or of 30-day mort alit y in pat ient s wit h acut e PE. Indeed, it has been used to accelerat e t he triage of pat ient s and to rapidly assess t he haemodynamic inst abilit y [21, 22]. Since TRI is a modificat ion of SI we assessed the addit ional value t hat it adds to SI, demonst rat ing an equivalent result wit h respect to t he 30-day mort alit y. Different 12
st udies have suggest ed a strong associat ion among elevat ed cTnI, RVD and short t erm mort alit y, consider ing t hem individually or as component s of prognost ic models [9, 12, 23, 24, 25]. Unfortunat ely, some of t he exist ing scoring models are ver y oft en quit e unreliable in daily clinical pract ice while ot hers, such as sPESI, are
relat ively
simple.
Moreover,
a
furt her
limit at ion
of
t he
current
ESC
st rat ificat ion st rat egy is t hat , alt hough examinat ion of cardiac bio markers are available 24 hours a day, t he assessment of r ight vent ricular funct ion (RVF) wit h echocardiography is not always possible in an emergency. In t his regard, evaluat ion of RVD t hrough t he CTA [26, 27] could be an alt ernat ive st rat egy to eliminat e any delay in wait ing for TTE. This approach allow s a fast er pat ient assessment but some major limit at ions in t he use of CTA st ill remain, such as possible t echnical problems or t he impossibilit y o f t ransferring haemo dynamically unst able pat ient s. In our research, RVD was not evaluat ed wit h CTA, due t he design of t he st udy; indeed, for several pat ient s we could not ret rospect ively evaluat e t hese findings. The TRI calculat ed fro m simple var iables seems t o have an increment al prognost ic value in pat ient s wit h acut e PE. These result s must be conclusively demonst rat ed in a larger cohort ; however, a simplificat ion in pat ient risk assessment could be ver y useful in daily clinical pract ice.
Limitations of the Study Our invest igat ion present s different limit at ions. First of all, t he number of t he pat ient s enrolled and, consequent ly, t he low mort alit y and clinical det eriorat ion rat es, wit h respect to ot her st udies, could be a limit at ion. Moreover, we have evaluat ed only t he mort alit y rat e for all-causes, during t he 30-days aft er discharge; a longer fo llow-up is needed, t aking int o considerat ion also PE-relat ed mort alit y, t o confir m t he result s. Right vent ricular dysfunct ion was not evaluat ed t hrough CTA 13
but only wit h TTE. However, ESC guidelines also recommended t his last t echnique for t he assessment of r ight vent ricular funct ion. Despit e t hese limit at ions, t he result s sat isfied t he purposes of t he st udy.
Conclusions
Alt hough a number of limit at ions are recognisable in our st udy, such as it was an observat ional single cent re st udy, and t he discret ion left to t he t reat ing physicia n about t he t herapeut ic st rat egy, it is clear t hat t he combinat ion of t hree alread y recognised clinical predict ors of short -t erm mort alit y, considered in a single for mula, can cont ribut e to t he reclassificat ion of pat ient s wit h acut e PE, using t he ESC risk classificat ion as a reference.
Financial/nonfinancial Disclosu res No pot ent ial conflict s.
Funding Supports No funding was received for t his st udy. Other Contributions None
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18
Figure Legends:
Figure 1. causes).
Relat ionship bet ween heart rat e and age wit h 30-day mort alit y (all
19
Figure 2. Mean and st andard deviat ion of TRI across survivors and non-sur vivors in t he enrolled populat ion (p<0.0001)
20
Figure 3. ROC curve for opt imal t hreshold value of TRI.
21
Figure 4. Kaplan–Meier overall sur vival curves co mpar ing t he out comes o f pat ient s wit h PE and TRI ≥ or < 45.
22
Table 1. General charact er ist ics of t he populat ion across PE risk classes.
Items
N=67 (%)
Intermedi ate lo w ris k N=50 (%)
Intermedi ate high ris k N=33 (%)
71.05 13.70
68.27 14.71
69.16 15.29
73.45 12.01
SBP ( m mH g)
128.97 26.67
138.90 14.71
69.16 15.29
DBP ( m mHg)
74.02 17.06
78.45 16.96
74.49 10.16
Hea rt ra t e ( bp m)
95. 6320.89
89. 4515.96
R e sp i r a t o r y r a t e ( m i n )
11 . 2 5 1 1 . 4 0
BMI ( Kg/ m2 )
A g e ( y e a r s)
Al l
Lo w ris k
N=170 (%)
High ris k
p
N=18 (%) 7 6 . 1 1 8 . 1 3
NS
73.45 12.01
7 6 . 1 1 8 . 1 3
<0.0001
78.48 14.78
49.68 16.77
<0.0001
91. 7620.69
113.85 22.25
113.44 21.20
<0.0001
7.4010.40
1 1 . 9 2 1 0 . 5 2
14.52 12.16
16.26 12.60
0.003
27. 305.20
27. 235.06
27. 155.38
27.55 5.31
27.25 5.39
NS
0.78.32 58. 8
0.660.15 52. 2
0.710.21 64. 0
0.800.19 54.5
1.40.39 61.1
<0.0001
41. 9725.42
31. 4013.29
35. 3317.27
44.52 18.32
87.33 36.93
NS <0.0001
5.8 [10] 2.9 [5] 8.8 [15]
0 [0] 1.4 [1] 1.4 [1]
2 [1] 2[1] 4.0 [2]
6 [2] 9 [3] 15.1 [5]
38.8 [7] 0 [0] 38.8 [7]
0.04 NS <0.0001
17.5 24.1 35.9
17.7 24.2 40.3
17.3 25.0 36.0
18.2 24.2 33.3
15.8 21.1 22.2
NS NS NS
I m m o b i l i s a t i o n (% ) H e a r t f a i l u re (% ) C o ro n a r y a r t e r y d i s e a s e (% ) S u rg e r y < 4 we e k s (% ) O b e s i t y (% )
18.7 6.0 11.4 17.5 24.1
19.4 6.5 9.7 17.7 17.9
9.6 7.7 15.4 17.3 22.0
27.3 6.1 15.2 15.2 30.3
26.3 0 0 21.1 33.3
NS NS NS NS NS
Clinic al fea tures RVD ( % ) P o si t i v e t r o p o n i n ( % )
41.2 41.2
0 1.5
25 50
100 100
66.7 55.6
0.002 NS
SI Fe ma l e ( %) TRI M ortality 3 0 -d a y s m o r t a l i t y ( a l l c a u s e s) ( % ) Cli nical d et eri orati on ( %) C o m p o si t e o u t c o m e ( % ) Ris k F actors P r e v i o u s VT E ( % ) C a n c e r (% ) D V T (% )
23
Sh ock ( %) Syncope ( %) C a r d i a c a r r e st ( % ) D y sp n o e a ( % ) T h r o m b o l y si s ( % ) PH at di scharg e ( %)
10.0 21.8 1.8 80.1 13.9 12.9
0 13.4 0 66.1 1.5 1.5
0 20.0 0 86.5 12.0 16.0
0 24.2 0 93.9 24.2 30.3
94.4 50.0 16.7 84.2 50.0 16.7
<0.0001 0.012 NS 0.002 0.002 NS
Legend: In Mort alit y sect ion, squar e bracket s indicat e t he number of pat ient s and percent ages are referred to each cat egory ’s risk. Abbreviat ions: SBP: syst olic blood pressure; DBP: diast olic blood pressure; BMI: body mass index; TRI: TIMI risk index; Composit e out come: in hospit al deat h and/ or clinical det er iorat ion; VTE: venous t hromboembo lis m; DVT : deep vein t hrombosis; RVD: right vent ricular dysfunct ion; PH: pulmo na r y hypert ensio n.
24
Table 2. Treat ment strat egies
Tr e a t m e n t
Al l
Intermedi ate -lo w risk N=50 (%)
Intermedi ate high ris k N=33 (%)
High risk N=18 (%)
p
N=170 (%)
Lo w risk N=67 (%)
UFH
56.6
56.8
53.5
45.5
72.1
NS
LMWH r -t PA
62.4 14.5
63.6 6.8
76.7 7.0
68.2 11.4
39.5 32.6
<0.0001 NS
PCDT
2.9
0
2
3.0
16.6
NS
VKA
78. 0
90. 9
79. 1
77.3
65.1
<0.0001
Abbreviat ions: UFH: Unfr act ionat ed hepar in; LMWH: Low mo lecular weight hepar in; PCDT: Percut aneous c at het er-direct ed treat ment ; VKA: Vit amin K ant agonist .
25
Table 3. General charact er ist ics of t he populat ion across t he TRI quart iles
I t e ms
1 s t q ua rt il e ( 1 6. 8 7 5. 6 6)
2 n d qu a rti le ( 3 0. 7 1 3. 7 0)
Age ( ye a r s)
5 3 .3 1 1 4. 5 6
6 9 .6 3 8 .8 9
7 8 .9 1 6 .6 6
7 8 .8 6 7 .5 7
<0 . 0 00 1
S BP ( mmHg)
1 4 1. 4 3 2 3. 0 9
1 3 4. 0 2 1 7. 2 5
1 3 7. 7 4 2 0. 9 7
1 0 2. 3 6 2 5. 5 4
<0 . 0 00 1
DBP ( mmHg)
7 7 .9 0 1 7. 0 0
7 9 .1 3 11. 59
7 7 .9 3 1 3. 8 1
6 0 .3 8 1 8. 4 4
<0 . 0 00 1
He a rt ra te ( b p m)
8 5 . 1 7 1 9. 42
8 7 . 0 7 1 9. 17
9 5 .9 3 1 5. 1 9
11 2. 95 17 .6 3
<0 . 0 00 1
8 . 5 9 9. 5 0
9 . 56 1. 42
1 2 .5 8 1 2. 7 8
1 6 .4 8 11. 85
0 . 00 1
2 9 . 3 5 5. 6 2
2 9 . 1 3 5. 3 3
2 4 .5 2 3 .7 9
2 6 .0 0 4 .4 6
0 . 00 1
0 . 6 1 0. 1 6 38.1
0 . 6 5 0. 1 5 60.5
0 . 70 0. 13 6 5 .1
1 . 17 0. 38 6 4 .3
<0 . 0 00 1
0 0
0 2.3
2.3 2.3
1 8 .0 7.1
0 . 02 0 NS
0
2.3
2.3
2 5 .0
0 . 00 1
2 8 .6 1 4 .6 4 2 .9 4.9 2.4 1 2 .5
1 3 .3 2 2 .2 3 9 .5 24 .4 6.7 11. 1
1 7 .5 3 2 .5 3 9 .5 2 0 .0 1 0 .0 1 2 .5
1 2 .5 2 7 .5 2 1 .4 2 5 .0 1 5 .0 1 0 .0
NS NS NS NS NS NS
9.8 31.
1 7 .8 2 9 .9
2 2 .5 1 4 .0
2 0 .0 2 3 .8
NS NS
3 8 .1 31
2 5 .6 4 4 .2
2 7 .9 4 1 .9
7 3 .8 2 6 .2
0 . 00 2 NS
Re s pi ra t or y r at e ( mi n) BM I ( Kg/ m2 ) SI F e ma le (% ) M or t al it y 3 0 -da y mor t a l it y ( %) Cli ni ca l de te ri or at i on
3 r d q ua rt il e ( 4 3. 0 6 2. 9 8)
4 t h q u ar til e ( 7 3.11 2 8. 6 3)
p
NS
( %) Comp os i te ou t come ( %) Ri s k F ac t or s P r e vi ou s VTE (% ) Ca n c er (%) DVT (%) I mmo bi li sa ti on (%) Hea r t Fa il ure Co ron ar y a rt er y d i s eas e S u rg er y < 4 week s Ob es i ty (%) Cl i ni ca l f e at u re s RVD ( %) P os i ti ve t r op on i n ( %)
26
S h ock (% ) S yn c op e (%) Ca r di a c a rr es t ( %) D ys p n oe a ( %) Th r omb ol ys i s (%) P H at d is ch a rge (%)
0 7.1 0 6 6 .7 7. 1 1 4 .3
0 2 0 .9 0 7 2 .1 7.0 1 4 .0
0 1 8 .5 0 8 5 .4 9.3 7.0
4 0 .5 4 0 .5 7.1 8 3 .3 3 3 .3 1 6 .7
NS 0 . 01 2 NS NS 0 . 00 2 NS
Abbreviat ions: SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index; Co mposit e out come: in hospit al deat h and/or clinical det eriorat ion; VTE: venous t hromboembolis m; DVT: deep vein t hrombosis; RVD: r ight vent ricular dysfunct ion; PH: pulmo nar y hypert ension.
27
S1443-9506(17)30319-0 http://dx.doi.org/doi:10.1016/j.hlc.2017.02.035 HLC 2355
To appear in: Received date: Revised date: Accepted date:
13-3-2016 10-2-2017 27-2-2017
Please cite this article as: Zuin Marco, Conte Luca, Picariello Claudio, Pastore Gianni, Vassiliev Dobrin, Lanza Daniela, Zonzin Pietro, Zuliani Giovanni, Rigatelli Gianluca, Roncon Loris.TIMI Risk Index as a Predictor of 30-Day Outcomes in Patients with Acute Pulmonary Embolism.Heart, Lung and Circulation http://dx.doi.org/10.1016/j.hlc.2017.02.035 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
TIMI Risk Index as a Predictor of 30-Day Outcomes in Patients with Acute Pulmonary Embolism
Running Title: TIMI Risk Index in Acute Pulmonary Embolism
Marco Zuin 1 , MD, Luca Cont e 1 , MD, Claudio Picar iello 1 , MD, Gianni Past ore 2 , MD, Dobr in Vassiliev
3
, MD, PhD, Daniela Lanza
1
, MD, Piet ro Zonzin
1
, MD,
Giovanni Zuliani 4 , MD, Gianluca Rigat elli 5 , MD, PhD, EBIR, Loris Roncon 1 , MD
1
2
Cardi ol ogy Departm ent, Sant a Mari a Dell a Mi seri cordi a Hospit al, Rov igo, It aly. Arrhyt hmi a and El ect rophysi ol ogy Uni t, Cardi ol ogy Departm ent , Sant a Mari a Dell a
Mi seri cordi a Hospit al, Rov igo, It aly. 3
4
Cardi ol ogy Cli nic, Al ex androska Univ ersit y Hospi t al , Sof i a, Bul gari a Secti on of I nt ernal and Cardi opulm onary Medi ci ne, Departm ent of Medi cal Sci ence,
Univ ersi ty of F errara, F errara, I t al y 5
Secti on of Adul t Congenit al and Adult Heart Di sease, Cardi ov ascul ar Di agnosi s and
Endol umi nal I nt erv enti ons, Rov i go G eneral Hospi t al , It aly
Corresponding author: Loris Roncon, MD Department of Cardiology, Santa Maria della Misericordia Hospital Viale Tre Martiri 140, 45100 Rovigo, Italy Phone: +39 0425393286 Fax: +39 0425393597 E-mail: [email protected]; [email protected]
1
Abstract Background: Available st udies have already ident ified age, heart rat e (HR) and syst olic blood pressure (SBP) as st rong predict ors of ear ly mort alit y in acut e PE.
Material and Methods: One-hundred-sevent y pat ient s, wit h acut e PE confir med on comput ed
tomography
Myocardial Infarct ion
angiography
(CTA)
were
enrolled.
Thrombolys is
In
(TIMI) risk index (TRI) was calculat ed using t he formula
[HR x (AGE/10 2 )/SBP]. St udy out comes were 30-day mort alit y and/or clinica l det eriorat ion.
Results: Receiver operat ing charact erist ics (ROC) curve revealed t hat a TRI ≥ 45 was highly specific for bot h out comes (AUC 0.91, 95 % CI 0.83–0.98, p<0.0001) wit h a posit ive predict ive value (PPV) and negat ive predict ive value (NPV) of 8.3 and 96 % for 30-day mort alit y while PP V and NPV for 30-day mort alit y and/or clinical det eriorat ion were 21.1 and 98.2 %, respect ively. Mult ivar iat e regressio n analysis showed t hat TRI≥45 was an independent predict or of 30-day mort alit y (O.R. 22.24, 95% CI 2.54–194.10, p=0.005) independent ly from posit ive cTnI and RVD (O.R. 9.57, 95% CI 1.88–48.78, p=0.007; OR 24.99, 95% CI 2.84–219.48, p=0.004). Similar ly, 30-day mort alit y and/or clinical det eriorat ion was predict ed by TRI ≥45 (O.R. 11.57, 95 % CI 2.36–56.63, p=0.003) and t hrombo lysis (3.83, 95% CI 1.04–14.09, p=0.043), independent ly fro m age, RVD and posit ive cTnI. Cox regression analysis confir med t he role of TRI as independent predictor for bot h out comes. Mant el-Cox analysis showed that aft er 30-day fo llow-up t here was a st at ist ically significant difference in t he dist r ibut ion of survival bet ween pat ient s wit h and wit hout TRI ≥ 45 [log rank (Mant el-Cox) chi- square 17.04, p<0.0001].
Conclusions: TIMI risk index predict ed bot h 30-days mort alit y (all-causes) and/or clinical det er iorat ion in pat ient s wit h acut e PE.
K eywords: Pulmo nar y embo lis m; Risk st rat ificat ion; TIMI risk index.
Introduction
2
Risk st rat ificat ion is an int egral part of clinical prognost icat ion, especially in pot ent ially life-t hreat ening cardiovascular diseases, such as acut e pulmonar y embo lism (PE) [1]. The out comes of an acut e episode of PE are strongly connect ed to bot h haemodynamic st at us and to t he possible cardio vascular adapt at ions t hat may have t aken place [2, 3]. Pat ient s wit h ST-elevat ion myocardial infarct io n (STEMI) need a simple r isk st rat ificat ion algor it hm t o quickly assess mort alit y risk. The Thrombo lysis I n Myocardial Infarct ion (TIMI) risk index (TRI) is a valid clinical tool for r isk assessment of pat ient s wit h STEMI, which co mbines age, heart rat e (HR) and syst olic blood pressure (SBP), which are independent predictors of deat h in STEMI [4]. Similar ly, recent analyses fro m clinical t rials, regist ry and single st udies in pat ient s wit h PE have also est ablished t hat age, HR and SBP are st rong independent predictors of early mo rt alit y; in part icular, age and HR have a posit ive, while SBP has an inverse associat ion, respect ively [5-9]. Different algorit hms and scores are current ly availa ble for t he risk st rat ificat ion of acut e PE, but in most cases, t hey are too complex for use in daily clinical pract ice, because t hey require imaging t echniques such as t ranst horacic echocardiography (TTE) (not always
immediat ely
available
in
all
emergency
depart ment s),
comput ed
angiography t omography (CTA), cardiac bio markers, medical hist ory et c. [10-14]. Alt hough PE pat ient s at “high-r isk” have well-est ablished t reat ment s using t hrombo lysis or percut aneous t echniques [9], t he ident ificat ion of pat ient s at int er mediat e-risk and t heir opt imal t reatment remains one of t he most debat ed topics, in part icular in t he use of t hrombolysis [9, 14]. We sought to evaluat e t he ut ilit y o f TRI for t he predict ion of 30-day mort alit y and/or clinical det er iorat ion in an It alian populat ion-based cohort wit h confir med acut e PE.
Material and Methods 3
Study Design This was a ret rospect ive, single-cent re analysis o f prospect ively co llect ed dat a. The inclusio n per iod was from Januar y 2010 to August 2014. The local Et hics Commit t ee approved t he st udy and all procedures were in accordance wit h t he Declarat ion of Helsinki and wit h Inst it ut ional Guidelines. All enro lled pat ient s gave infor med consent . Inclusion cr it er ia were: object ively confir med diagnosis o f acut e sympt omat ic PE at CTA; all diagnost ic invest igat ion per formed in our hospit al; age ≥18 years old ; TTE performed wit hin 24-hours from admissio n; and ult rasonography (US) limb assessment for deep vein t hrombosis execut ed wit hin 24 hours fro m PE diagnosis. Conversely, exclusio n cr it eria were: subject s wit hout confir med diagnosis o f PE at CTA; absence of TTE wit hin 24 hours fro m admission; absence of lower limb US wit hin 24-hours from PE diagnosis; cont inuat ion o f t reat ment in ot her regional ho spit als; age < 18 years o ld ; and denia l of consent for part icipat ion in t he st udy. During t he st udy per iod, 170 pat ient s (70 men and 100 women) fulfilled t he st udy crit er ia; 28 pat ient s were excluded for absence of at least one of t he inclusion crit er ia. In part icular, 16 pat ient s did not have TTE performed dur ing t he 24-hours aft er admission; 4 pat ient s, aft er diagnosis, were t ransferred to a secondar y regional hospit al to cont inue t he treat ment ; and 8 subject s received PE diagnosis t hrough vent ilat ion-per fusio n scan. No pat ient s were lost during t he fo llow -up; indeed, of 170 pat ient s, 150 were evaluat ed wit h clinical examinat ion 30 days aft er discharge and 10 pat ient s received t he fo llow-up during furt her hospit alisat ion (t hey were hospit alised again, but not in our depart ment and for reasons not attribut able to PE). Ten subject s died aft er discharge; in t his case, mort alit y for all-causes was assessed t hrough t he hospit al dat abase.
The ent ire populat ion was st rat ified at admissio n wit h sPESI
score [11], as recommended by t he lat est European guidelines [9]. Personal medical 4
hist ory was t aken at admissio n and always confir med by previous hospit al records. All enro lled subject s underwent a post-discharge clinical evaluat ion aft er 30 days; 30-day fo llow-up was performed in person for all pat ient s. If t he pat ient died during t he period bet ween discharge and fo llow-up evaluat ion, 30-day mort alit y was regist ered using t he local hospit al database. For t his reason, due to a limit at ion of t he dat abase, we could evaluat e only all-cause mort alit y.
Data Collection and Definitions S yst olic (SBP) and diast olic (DBP) blood pressure were t aken at admissio n using a mercur y sphygmo mano met er (diast olic Korotkoff phase 5); heart rat e (HR) was measured at t he same t ime. For t he analys is we used t he measurement performed at t he t ime o f confir mat ion o f PE. Art erial hypot ensio n was defined as (SBP) ≤90 mmHg.
Shock
index
(SI)
was
calculat ed
as
t he
rat io
of
HR
and
SBP.
Haemodynamic inst abilit y at admissio n was defined as SBP < 90 mmHg or drop of t he same by ≥40 mmHg for ≥15 minut es, need for cat echolamine infusio n or cardiopulmo nar y resuscit at ion (CPR) or SI great er t han one. Respirat ory rat e was det ermined by count ing how many t imes t he chest expanded per minut e wit h t he pat ient in a supine posit ion. The presence of dyspnoea was also evaluat ed. Body mass index (BMI) was calculat ed (in kg/ m2) as t he rat io of weight to squared height . Subject s were considered as obese if BMI was ≥30 kg/m 2 . A venous blood sample for cardiac markers was obt ained before st art ing any t reat ment : t he levels of cardiac t roponin I (cTnI) were measured by immunoassay using Dimensio n®RxL analyzer (Dade Behr ing, Newark, DE) in t he hospit al cent ral laboratory. This syst em was able t o det ect a minimum cTnI level of 0.04 ng/ ml, which was 5
considered t he upper limit for normal pat ient s. Right vent ricular dysfunct ion (RVD) was det ect ed by echocardiography ( iE33, Philips Ult rasound, Bot hell, WA) or Vivid 9, (GE Vingmed Ult rasound AS, Hort en, Norway), performed w it hin 24 hours from admission. Right vent ricular dysfunct ion was defined in t he presence of at least one of t he fo llowing: (1) right -to-left vent ricular/end diast olic diamet er rat io > 1 in apical four-chamber view; (2) r ight -to-left vent ricular/end diast olic rat io > 0.6 in parast ernal long-axis or subcost al four-chamber view; and (3) right vent ricular-to right at rial pressure gradient > 30 mm Hg [15]. Right vent ricular dysfunct ion was not considered to be of acut e onset in t he presence of a right vent ricular wall t hickness of >7 mm or previous document at ion of right vent ricular overload. Clinical det eriorat ion was defined as a clinically worsening condit ion t hat required at least one of t he fo llowing: (1) IV cat echolamine infusio n; (2) endotrachea l int ubat ion; or (3) CPR.
Therapeutic Management During t he acut e phase unfract ionat ed hepar in (UFH), adjust ed for t he act ivat ed part ial t hromboplast in t ime (aPTT) or low- mo lecular weight hepar in (LMWH) (enoxapar in 1.0 mg/kg, ever y 12 hours) were administ ered over t he first 5 to 10 days [9, 16]. Ant icoagulat ion was cont inued unt il t he int ernat ional nor malised rat io (INR) was bet ween 2.0 and 3.0 for t wo consecut ive days and t hen adjust ed wit h vit amin K ant agonist (VKA). Recombinant t issue plasminoge n act ivat or (r-Tpa) was used if indicat ed, wit h a dose of 100 mg over 2 hours or 0.6 mg/kg over 15 minut es, wit h a maximum dose of 50 mg [9]. In pat ient s wit h abso lut e cont raindicat ions
to
t hrombo lysis,
Percut aneous
cat het er-direct ed
Treat ment
(PCDT) was performed using t he AngioJet ® 6F PE® (Bayer, Germany) in conjunct ion wit h recombinant t issue plasminogen act ivat or (r-t PA) [17]. 6
Clinical Outcomes The main out comes were 30-day mort alit y (all-causes) and/or clinical det eriorat ion.
Statistical Analysis In t he fir st st ep, we evaluat ed t he relat ions bet ween age, HR and SBP. Age showed a non- linear but unifor mly increasing relat ion wit h t he endpoint s of t he st udy and so it was t herefore modelled using a quadrat ic t erm. Guided by t he obser ved relat ion (Figure 1) we applied t he TRI as:
[HR X (Age/10) 2 ]
[4]
SBP
The enrolled populat ion was t hen st rat ified across t he quart iles of TRI. Cat egorica l var iables were expressed as percent age rat es and compared wit h t he Pearson’s χ 2 t est . Cont inuous var iables were expressed as mean and st andard deviat ion and t he difference values were evaluat ed by analysis of var iance. The null hypot hesis was reject ed for p<0.05. To ident ify t he opt imal t hresho ld value for TRI a ROC curve analysis was per formed. Unadjust ed and adjust ed OR were assessed for t he TRI as a predict or of 30-day mort alit y and/or clinical det eriorat ion using mult ivar iat e regression analysis. Risk for 30-day mort alit y and/or clinical det er iorat ion were calculat ed wit h a Cox proport ional hazard model. The abilit y o f t he TIMI to classify t he pat ient s wit h a TRI value great er t han t he t hresho ld was assessed by 7
t he C st at ist ics [18]. Posit ive predict ive value (PPV) and negat ive predict ive value (NPV) are also descr ibed. Follow-up was perfor med to assess t he overall mort alit y for 30 days aft er discharge. Kaplan-Meier survival analysis was per formed and surviving pat ient s wit h a TRI great er t han t he opt imal t hresho ld were compared wit h t hose wit h a TRI <45 using log-rank (Mant el-Cox) analysis. St at ist ica l analyses were perfor med using SPSS package versio n 19.0 for Windows (SPSS, Chicago, IL, USA).
Results The st udy populat ion co mpr ised 170 consecut ive pat ient s (70 men and 100 wo men, mean age 71.05±13.70 years). The general charact er ist ics of t he subject s are summar ised in Table 1, also showing t he current ESC st rat ificat ion for acut e PE. Haemodynamic inst abilit y became more evident wit h t he increase in r isk group (p<0.0001). No significant differences were found in t he prevalence of gender, risks fact ors for PE, posit ive cT nI, and cardiac arrest across t he risk cat egories. Deat h occurred in 5.8% of t he pat ient s enro lled, wit h an incidence t hat became higher wit h increasing sever it y of PE (0, 2. 6, 38.8% p=0.04). In cont rast , clinica l det eriorat ion was observed in 2.9 % of cases. Thirt y-day mort alit y ( for all-causes) and/or clinical det eriorat ion occurred in 8.8 % of pat ient s (1.4, 2.0, 15.1, 38.8%, p<0.0001). The TRI and t he composit e out come were significant ly higher in upper vs lower r isk cat egories (p<0.0001). The t herapeut ic st rat egies adopt ed are shown in Table 2. Thrombo lysis was per for med mainly in t he int er mediat e- and high-r isk groups. Five pat ient s (2.9%) were treat ed wit h PCDT, due to t he absolut e cont raindicat ion
for
t hrombolys is.
There
were
no
deat hs
associat ed
wit h 8
complicat ions of t herapy; however, in t wo pat ient s a t ransit ory anaemia occurred aft er t he t hrombo lysis. The prevalence of pulmo nar y hypert ensio n at discharge was equally in int er mediat e-low and high-r isk pat ient s (16.0% vs 16.7%, p=ns). As shown in Table 3, age, SBP, DBP, HR, respirat ory rat e and SI were significant ly higher in upper vs lower TRI quart iles (p<0.0001). Mort alit y rat e (0, 0, 2.3 and 18%, p=0.020) and t he composit e out come of t he st udy (0, 2.3, 2.3, 25%, p=0.001) were increasingly dist ribut ed in t he quart iles of TRI, while clinical det er iorat ion was not different bet ween t hem. The TRI mean value bet ween survivors and no nsurvivors is showed in Figure 2. A receiver operat ing charact er ist ics cur ve (Figure 3) was used to find t he opt imal cut -off value of TRI for 30-day mort alit y (allcauses) and/or clinical det er iorat ion. The TRI ≥ 45 appeared to be highly specific for bot h out comes (AUC 0.91, 95 % CI 0.83–0.98, p<0.0001). Posit ive predict ive value for 30-day mort alit y was 8.3%, while NPV was 96 %. Conversely, for 30-day mort alit y and/or clinical det eriorat ion, PPV and NPV were 21.1 and 98.2%, respect ively. Unadjust ed regression analys is showed t hat pat ient s wit h TRI ≥45 had a higher risk of 30-day mort alit y t han t hose wit h a TRI less t han 45, (OR 23.18, 95% CI 2.87–189.48, p=0.003). This result was also confir med for t he combined endpo int (OR 11.25, 95% CI 2.37–53.31, p=0.002). Mult ivar iat e regression analys is showed t hat TRI≥45 was an independent predict or of 30-day all-cause mort alit y (OR 22.24, 95% CI 2.54–194.10, p=0.005) independent ly fro m posit ive cTnI and RVD (OR 9.57, 95% CI 1.88–48.78, p=0.007; OR 24.99, 95% CI 2.84–219.48, p=0.004). Adding gender, t he model similar ly predict s t he out come (OR 37.25, 95 % CI 3.79–366.06, p=0.002; OR 12.32, 95 % CI 2.19–69.18, p=0.004 and OR 25.59, 95% CI 2.91–224.48, p=0.003, for TRI, cTnI and RVD, respect ively). Taking int o account t he composit e out come as dependent var iables, 30-day mort alit y and/or clinical det er iorat ion was predict ed by TRI ≥45 (OR 11.57, 95% CI 2.36– 9
56.63, p=0.003) and t hrombo lysis (OR 3.83, 95% CI 1.04–14.09, p=0.043), independent ly fro m age, RVD and posit ive cTnI; adding gender did not modify t he model. Cox regression analysis showed that pat ient s wit h a TRI ≥45 had a higher risk for 30-day mort alit y t han t hose with a TRI <45 (HR 24.09, 95% CI 2.44– 237,97, p=0.006), independent ly fro m posit ive cTnI, and RVD (HR, 25.27, 95% CI 2.16–295.02, p=0.010; HR 10.38, 95 % CI 1.76–61.25, p=0.010, respect ively). The higher risk for t he composit e out come was also confir med at Cox analysis, t aking int o account 30-day mort alit y and/or clinical det eriorat ion as dependent var iable s (HR 8.68, 95% CI 1.78–41.95, p=0.007 – adjust ed for t he same confounders used in t he mult ivar iat e analys is). The C st atist ic showed an improvement of t he discr iminatory power of TRI fo r t he 30-day mort alit y vs t he ESC st rat ificat ion (0.91, 95% CI 0.85–0.97, p<0.0001 vs 0.90, 95% CI 0.79 to -1.00, p<0.0001, respect ively) and also for t he composit e out come (0.84, 95% CI 0.74–0.94, p<0.0001 vs 0.82, 95% CI 0.69–0.95, p<0.0001, respect ively). S imilar result s were obt ained analysing t he discr iminat ory power of SI for t he same out comes (0.91, 95% CI 0.89–0.97, p<0.0001 and 0.88, 95% CI 0.81–0.96, p<0.0001). Taking int o account t he pat ient s at int ermediat e-risk (low and high) t he TRI nicely predict s t he 30-day mort alit y and t he composit e out comes (0.81, 95% CI 0.69–0.93, p=0.001 and 0.79, 95% CI 0.67–0.91, p<0.0001, respect ively). However, a furt her subanalysis revealed t hat t he discr iminat ory power was high only in int er mediat e-high risk subject s (0.82, 95% CI 0.70–0.93, p=0.001 vs 0.18, 95% CI 0.06–0.29, p=0.001, for high and low int er mediat e risk, respect ively).
Mant el-Cox analysis
showed t hat aft er 30-day fo llow-up t here was a st at ist ically significant difference in t he dist ribut ion o f survival bet ween pat ient s wit h and wit hout TRI ≥ 45 [log rank (Mant el-Cox) chi- square 17.04, p<0.0001] (Figure 4).
10
Discussion Our st udy clear ly suggest s t hat t he TRI predict ed bot h 30-day mort alit y and /or clinical det er iorat ion. Age is t he one of t he most import ant det erminant s of PE sever it y; indeed, it was recent ly confir med in several st udies [5, 7, 8, 19]. It is well known t hat t achycardia and hypot ension are signs of haemodynamic inst abilit y and, moreover, it has already been est ablished t hat t he lat t er predict s a poor out come in PE. In effect , HR has been recent ly described as an import ant paramet er to t ake int o considerat ion during acut e PE, being st rongly correlat ed wit h worse out come [7, 10, 20]. Moreover, when t achycardia is present , a seven- fo ld higher r isk of inhospit al deat h has been report ed [5]. Inst ead, blood pressure and in part icular hypot ension, is one o f t he d iscr iminat ory paramet ers used for recognising pat ient s wit h high-r isk PE [9]. These aspect s are, as is known, not new. Inst ead, what ma y be new is t he use of a clinical score, generally applied in pat ient s wit h STEMI, in t he sett ing of acut e PE. In clinical pract ice, rapid and effect ive risk st rat ificat ion is mandat ory in t hese pat ient s. The aim is obviously t o ident ify pat ient s at high r isk of ear ly mort alit y or complicat ions in order to int ervene wit hout delay. As evidenced by our result s, TRI could be able t o reclassify pat ient s, t aking int o account t he ESC risk st rat ificat ion as a reference. It would be unrealist ic to t hink t hat a clinical score, consist ing of BP and HR can be an alt ernat ive in t he evaluat ion of t he right vent ricular funct ion in acut e PE. Indeed, t he import ance of t he latt er paramet er has been est ablished by several st udies in t he last 30 years. Moreover, we have demo nst rat ed t hat TRI has a major discr iminat ory power in t he assessment of 30-day mort alit y and/or clinical det er iorat ion wit h respect to t he ESC model. Int erest ing result s have been present ed also in t he evaluat ion of t he aforement ioned out comes especially in pat ient s at int ermediat e-high r isk. The low
11
C st at ist ic value, for t he previous endpo int s, in pat ient s at int ermed iat e- low risk is probably due t o t he ver y low rat e event s in t his group. As a mat t er of fact , in our st udy, one of t he most import ant limit at ions is t he small sample size and t he low rat e of mort alit y and clinical det er iorat ion; as a result , t he TRI PPV result s are low. Moreover, t he clinical det eriorat ion rat e, which was one of t he out comes, is low, wit h only five pat ient s regist ered. However, we believe t hat t his out come is import ant and wort hy of being considered, despit e it s value. No cases o f clinical det eriorat ion were regist ered in t he high-r isk group but , as is known, t hese pat ient s, as per definit ion, are haemodynamically unst able and oft en t hey die wit hout going t hrough a phase of det eriorat ion or t hey are already in a ser ious medical co ndit ion, where a furt her and rapid det eriorat ion may precede deat h wit hout t ime for furt her medical int er vent io n. To t he best of our knowledge, t his is t he sit uat ion in which to use TRI in pat ient s wit h PE. The TRI formula could be considered as t he int egrat ion of SI wit h the var iable age. Indeed, t he formula it is explained as:
HR x (AGE/10) 2 SI x (AGE/10) 2
TRI= SBP
Shock index has been already defined as an independent predict or of 30-day mort alit y in pat ient s wit h acut e PE. Indeed, it has been used to accelerat e t he triage of pat ient s and to rapidly assess t he haemodynamic inst abilit y [21, 22]. Since TRI is a modificat ion of SI we assessed the addit ional value t hat it adds to SI, demonst rat ing an equivalent result wit h respect to t he 30-day mort alit y. Different 12
st udies have suggest ed a strong associat ion among elevat ed cTnI, RVD and short t erm mort alit y, consider ing t hem individually or as component s of prognost ic models [9, 12, 23, 24, 25]. Unfortunat ely, some of t he exist ing scoring models are ver y oft en quit e unreliable in daily clinical pract ice while ot hers, such as sPESI, are
relat ively
simple.
Moreover,
a
furt her
limit at ion
of
t he
current
ESC
st rat ificat ion st rat egy is t hat , alt hough examinat ion of cardiac bio markers are available 24 hours a day, t he assessment of r ight vent ricular funct ion (RVF) wit h echocardiography is not always possible in an emergency. In t his regard, evaluat ion of RVD t hrough t he CTA [26, 27] could be an alt ernat ive st rat egy to eliminat e any delay in wait ing for TTE. This approach allow s a fast er pat ient assessment but some major limit at ions in t he use of CTA st ill remain, such as possible t echnical problems or t he impossibilit y o f t ransferring haemo dynamically unst able pat ient s. In our research, RVD was not evaluat ed wit h CTA, due t he design of t he st udy; indeed, for several pat ient s we could not ret rospect ively evaluat e t hese findings. The TRI calculat ed fro m simple var iables seems t o have an increment al prognost ic value in pat ient s wit h acut e PE. These result s must be conclusively demonst rat ed in a larger cohort ; however, a simplificat ion in pat ient risk assessment could be ver y useful in daily clinical pract ice.
Limitations of the Study Our invest igat ion present s different limit at ions. First of all, t he number of t he pat ient s enrolled and, consequent ly, t he low mort alit y and clinical det eriorat ion rat es, wit h respect to ot her st udies, could be a limit at ion. Moreover, we have evaluat ed only t he mort alit y rat e for all-causes, during t he 30-days aft er discharge; a longer fo llow-up is needed, t aking int o considerat ion also PE-relat ed mort alit y, t o confir m t he result s. Right vent ricular dysfunct ion was not evaluat ed t hrough CTA 13
but only wit h TTE. However, ESC guidelines also recommended t his last t echnique for t he assessment of r ight vent ricular funct ion. Despit e t hese limit at ions, t he result s sat isfied t he purposes of t he st udy.
Conclusions
Alt hough a number of limit at ions are recognisable in our st udy, such as it was an observat ional single cent re st udy, and t he discret ion left to t he t reat ing physicia n about t he t herapeut ic st rat egy, it is clear t hat t he combinat ion of t hree alread y recognised clinical predict ors of short -t erm mort alit y, considered in a single for mula, can cont ribut e to t he reclassificat ion of pat ient s wit h acut e PE, using t he ESC risk classificat ion as a reference.
Financial/nonfinancial Disclosu res No pot ent ial conflict s.
Funding Supports No funding was received for t his st udy. Other Contributions None
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Gr ifoni S, Olivot to I, Cecchini P, P ieralli F, Camait i A, Sant oro G, et al.
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al. Haemodynamically unst able pulmonar y embo lism in t he RIETE Regist ry: syst olic blood pressure or shock index? Eur Respir J. 2007;30(6):1111-6. 22.
Kucher N, Luder CM, Dörnhö fer T, Windecker S, Meier B, Hess OM. Nove l
management st rat egy for pat ient s wit h suspect ed pulmo nar y embo lism. Eur Heart J. 2003;24(4):366-76. 23.
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Jiménez D, Uresandi F, Ot ero R, Lobo JL, Monreal M, Mart í D, et al.
Troponin- based r isk st rat ificat ion of pat ient s wit h acut e nonmassive pulmo nar y embo lism: syst emat ic review and met aanalysis. Chest . 2009;136(4):974-82. 25.
Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Prognost ic role o f
echocardiography amo ng pat ient s wit h acut e pulmo nar y embo lism and a syst olic art erial pressure of 90 mm Hg or higher. Arch Int ern Med. 2005;165(15):1777-81.
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Figure Legends:
Figure 1. causes).
Relat ionship bet ween heart rat e and age wit h 30-day mort alit y (all
19
Figure 2. Mean and st andard deviat ion of TRI across survivors and non-sur vivors in t he enrolled populat ion (p<0.0001)
20
Figure 3. ROC curve for opt imal t hreshold value of TRI.
21
Figure 4. Kaplan–Meier overall sur vival curves co mpar ing t he out comes o f pat ient s wit h PE and TRI ≥ or < 45.
22
Table 1. General charact er ist ics of t he populat ion across PE risk classes.
Items
N=67 (%)
Intermedi ate lo w ris k N=50 (%)
Intermedi ate high ris k N=33 (%)
71.05 13.70
68.27 14.71
69.16 15.29
73.45 12.01
SBP ( m mH g)
128.97 26.67
138.90 14.71
69.16 15.29
DBP ( m mHg)
74.02 17.06
78.45 16.96
74.49 10.16
Hea rt ra t e ( bp m)
95. 6320.89
89. 4515.96
R e sp i r a t o r y r a t e ( m i n )
11 . 2 5 1 1 . 4 0
BMI ( Kg/ m2 )
A g e ( y e a r s)
Al l
Lo w ris k
N=170 (%)
High ris k
p
N=18 (%) 7 6 . 1 1 8 . 1 3
NS
73.45 12.01
7 6 . 1 1 8 . 1 3
<0.0001
78.48 14.78
49.68 16.77
<0.0001
91. 7620.69
113.85 22.25
113.44 21.20
<0.0001
7.4010.40
1 1 . 9 2 1 0 . 5 2
14.52 12.16
16.26 12.60
0.003
27. 305.20
27. 235.06
27. 155.38
27.55 5.31
27.25 5.39
NS
0.78.32 58. 8
0.660.15 52. 2
0.710.21 64. 0
0.800.19 54.5
1.40.39 61.1
<0.0001
41. 9725.42
31. 4013.29
35. 3317.27
44.52 18.32
87.33 36.93
NS <0.0001
5.8 [10] 2.9 [5] 8.8 [15]
0 [0] 1.4 [1] 1.4 [1]
2 [1] 2[1] 4.0 [2]
6 [2] 9 [3] 15.1 [5]
38.8 [7] 0 [0] 38.8 [7]
0.04 NS <0.0001
17.5 24.1 35.9
17.7 24.2 40.3
17.3 25.0 36.0
18.2 24.2 33.3
15.8 21.1 22.2
NS NS NS
I m m o b i l i s a t i o n (% ) H e a r t f a i l u re (% ) C o ro n a r y a r t e r y d i s e a s e (% ) S u rg e r y < 4 we e k s (% ) O b e s i t y (% )
18.7 6.0 11.4 17.5 24.1
19.4 6.5 9.7 17.7 17.9
9.6 7.7 15.4 17.3 22.0
27.3 6.1 15.2 15.2 30.3
26.3 0 0 21.1 33.3
NS NS NS NS NS
Clinic al fea tures RVD ( % ) P o si t i v e t r o p o n i n ( % )
41.2 41.2
0 1.5
25 50
100 100
66.7 55.6
0.002 NS
SI Fe ma l e ( %) TRI M ortality 3 0 -d a y s m o r t a l i t y ( a l l c a u s e s) ( % ) Cli nical d et eri orati on ( %) C o m p o si t e o u t c o m e ( % ) Ris k F actors P r e v i o u s VT E ( % ) C a n c e r (% ) D V T (% )
23
Sh ock ( %) Syncope ( %) C a r d i a c a r r e st ( % ) D y sp n o e a ( % ) T h r o m b o l y si s ( % ) PH at di scharg e ( %)
10.0 21.8 1.8 80.1 13.9 12.9
0 13.4 0 66.1 1.5 1.5
0 20.0 0 86.5 12.0 16.0
0 24.2 0 93.9 24.2 30.3
94.4 50.0 16.7 84.2 50.0 16.7
<0.0001 0.012 NS 0.002 0.002 NS
Legend: In Mort alit y sect ion, squar e bracket s indicat e t he number of pat ient s and percent ages are referred to each cat egory ’s risk. Abbreviat ions: SBP: syst olic blood pressure; DBP: diast olic blood pressure; BMI: body mass index; TRI: TIMI risk index; Composit e out come: in hospit al deat h and/ or clinical det er iorat ion; VTE: venous t hromboembo lis m; DVT : deep vein t hrombosis; RVD: right vent ricular dysfunct ion; PH: pulmo na r y hypert ensio n.
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Table 2. Treat ment strat egies
Tr e a t m e n t
Al l
Intermedi ate -lo w risk N=50 (%)
Intermedi ate high ris k N=33 (%)
High risk N=18 (%)
p
N=170 (%)
Lo w risk N=67 (%)
UFH
56.6
56.8
53.5
45.5
72.1
NS
LMWH r -t PA
62.4 14.5
63.6 6.8
76.7 7.0
68.2 11.4
39.5 32.6
<0.0001 NS
PCDT
2.9
0
2
3.0
16.6
NS
VKA
78. 0
90. 9
79. 1
77.3
65.1
<0.0001
Abbreviat ions: UFH: Unfr act ionat ed hepar in; LMWH: Low mo lecular weight hepar in; PCDT: Percut aneous c at het er-direct ed treat ment ; VKA: Vit amin K ant agonist .
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Table 3. General charact er ist ics of t he populat ion across t he TRI quart iles
I t e ms
1 s t q ua rt il e ( 1 6. 8 7 5. 6 6)
2 n d qu a rti le ( 3 0. 7 1 3. 7 0)
Age ( ye a r s)
5 3 .3 1 1 4. 5 6
6 9 .6 3 8 .8 9
7 8 .9 1 6 .6 6
7 8 .8 6 7 .5 7
<0 . 0 00 1
S BP ( mmHg)
1 4 1. 4 3 2 3. 0 9
1 3 4. 0 2 1 7. 2 5
1 3 7. 7 4 2 0. 9 7
1 0 2. 3 6 2 5. 5 4
<0 . 0 00 1
DBP ( mmHg)
7 7 .9 0 1 7. 0 0
7 9 .1 3 11. 59
7 7 .9 3 1 3. 8 1
6 0 .3 8 1 8. 4 4
<0 . 0 00 1
He a rt ra te ( b p m)
8 5 . 1 7 1 9. 42
8 7 . 0 7 1 9. 17
9 5 .9 3 1 5. 1 9
11 2. 95 17 .6 3
<0 . 0 00 1
8 . 5 9 9. 5 0
9 . 56 1. 42
1 2 .5 8 1 2. 7 8
1 6 .4 8 11. 85
0 . 00 1
2 9 . 3 5 5. 6 2
2 9 . 1 3 5. 3 3
2 4 .5 2 3 .7 9
2 6 .0 0 4 .4 6
0 . 00 1
0 . 6 1 0. 1 6 38.1
0 . 6 5 0. 1 5 60.5
0 . 70 0. 13 6 5 .1
1 . 17 0. 38 6 4 .3
<0 . 0 00 1
0 0
0 2.3
2.3 2.3
1 8 .0 7.1
0 . 02 0 NS
0
2.3
2.3
2 5 .0
0 . 00 1
2 8 .6 1 4 .6 4 2 .9 4.9 2.4 1 2 .5
1 3 .3 2 2 .2 3 9 .5 24 .4 6.7 11. 1
1 7 .5 3 2 .5 3 9 .5 2 0 .0 1 0 .0 1 2 .5
1 2 .5 2 7 .5 2 1 .4 2 5 .0 1 5 .0 1 0 .0
NS NS NS NS NS NS
9.8 31.
1 7 .8 2 9 .9
2 2 .5 1 4 .0
2 0 .0 2 3 .8
NS NS
3 8 .1 31
2 5 .6 4 4 .2
2 7 .9 4 1 .9
7 3 .8 2 6 .2
0 . 00 2 NS
Re s pi ra t or y r at e ( mi n) BM I ( Kg/ m2 ) SI F e ma le (% ) M or t al it y 3 0 -da y mor t a l it y ( %) Cli ni ca l de te ri or at i on
3 r d q ua rt il e ( 4 3. 0 6 2. 9 8)
4 t h q u ar til e ( 7 3.11 2 8. 6 3)
p
NS
( %) Comp os i te ou t come ( %) Ri s k F ac t or s P r e vi ou s VTE (% ) Ca n c er (%) DVT (%) I mmo bi li sa ti on (%) Hea r t Fa il ure Co ron ar y a rt er y d i s eas e S u rg er y < 4 week s Ob es i ty (%) Cl i ni ca l f e at u re s RVD ( %) P os i ti ve t r op on i n ( %)
26
S h ock (% ) S yn c op e (%) Ca r di a c a rr es t ( %) D ys p n oe a ( %) Th r omb ol ys i s (%) P H at d is ch a rge (%)
0 7.1 0 6 6 .7 7. 1 1 4 .3
0 2 0 .9 0 7 2 .1 7.0 1 4 .0
0 1 8 .5 0 8 5 .4 9.3 7.0
4 0 .5 4 0 .5 7.1 8 3 .3 3 3 .3 1 6 .7
NS 0 . 01 2 NS NS 0 . 00 2 NS
Abbreviat ions: SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index; Co mposit e out come: in hospit al deat h and/or clinical det eriorat ion; VTE: venous t hromboembolis m; DVT: deep vein t hrombosis; RVD: r ight vent ricular dysfunct ion; PH: pulmo nar y hypert ension.
27