How Does Pulmonary Embolism Increase Troponin

Astute pulmonary embolism has a wide spectrum of clinical presentations. The curt-term clinical outcome of patients with pulmonary embolism varies from an early recovery of symptoms to hemodynamic deterioration and death. Prognostic stratification of patients with acute pulmonary embolism is crucial to tailor in-infirmary management and to potentially ameliorate clinical outcome.^1,ii Currently, prognostic stratification is based primarily on blood pressure at admission. Systemic hypotension is associated with high in-hospital bloodshed, which increases up to ≈l% in patients with daze.² Among patients with normal blood force per unit area at admission, correct ventricular dysfunction at echocardiography identifies those at high take a chance for in-hospital bloodshed.^3–six In these patients, elevated levels of troponin have been shown to be associated with right ventricular dysfunction at echocardiography. The relationship between serum levels of troponin and clinical result in patients with pulmonary embolism has been assessed in a number of pocket-sized studies just remains undefined.

Clinical Perspective p 433

We performed a meta-analysis aimed at assessing the prognostic value of troponin for both short-term mortality and agin consequence events in patients with astute pulmonary embolism.

Methods

The methods for this meta-analysis are in accordance with "Meta-Analysis of Observational Studies in Epidemiology: A Proposal for Reporting."⁷

Written report Objectives

The primary objective of this analysis was to appraise whether elevated serum troponins are associated with short-term mortality in patients with acute pulmonary embolism. The secondary objectives were to appraise whether elevated serum troponins are associated with brusque-term bloodshed resulting from pulmonary embolism or adverse effect events.

Study Outcomes

Death was adjudicated as the result of pulmonary embolism by the authors of the private studies. In the large bulk of the analyzed studies, death was adjudicated as the event of pulmonary embolism in case of irreversible right ventricular failure or recurrent pulmonary embolism.

For the purpose of this assay, agin outcome events were the composite of death and any of the following: daze, demand for thrombolysis, endotracheal intubation, catecholamine infusion for sustained hypotension, cardiopulmonary resuscitation, or recurrent pulmonary embolism.

Study Selection

Studies were included in this analysis if they had reported on patients with an objective diagnosis of pulmonary embolism, troponin sampling in the initial in-infirmary phase, and brusk-term death or adverse outcome events.

Report authors were contacted when their studies did not report data, allowing the creation of a two×ii tabular array based on troponin levels (normal and elevated) and outcome (decease and survival, adverse outcome events, and no adverse event events).

Finding Relevant Studies

We searched MEDLINE and EMBASE betwixt January 1, 1998, and November 2006. Furthermore, reference lists of retrieved manufactures and review manufactures were reviewed manually to implement our search. Search criteria included the terms "pulmonary embolism" and "troponin." The search was not express to the English language; just total articles were considered for assay.

One writer (C.B.) performed the electronic search and listed the trials that were eligible for inclusion in the report. Report option was initially performed by review of title. Candidate abstracts were then reviewed and selected for information retrieval. Two authors (C.B. and C.V.) independently reviewed each study for quality assessment and extracted data on studies and patient characteristics, also as outcomes, using standardized extraction forms. Because no standardized quality scoring system exists for quality assessment of observational studies, the components of the quality review were derived largely from the Egger'south quality checklist for prognostic studies.^eight Studies were assessed for the presence of 8 features: description of patient sample characteristics, description of inclusion and exclusion criteria, potential choice bias, completeness of follow-upwardly, a priori definition of study outcomes, objectivity of outcomes, and definition and measurement of prognostic variables and handling. Disagreements were resolved through revision past an boosted reviewer (G.A.) and by give-and-take.

For each study, the post-obit individual data were extracted: general data (study design), patients (number of included patients, mean historic period, gender, methods for diagnosis of pulmonary embolism, hemodynamic status at inclusion in the study, and treatment for pulmonary embolism), troponin assays (name of the assay, blazon of examined troponin [I or T], cutoff level, timing of determination, and overall troponin-positive patients), and cease points (number of patients with the primary stop point among troponin-positive or -negative patients and number of patients with secondary end points among troponin-positive and -negative patients).

Statistical Analysis

Meta-analyses of all outcomes are reported using random-furnishings models because stock-still- and random-effects results were similar. Cochran'south χ² test and the I² test for heterogeneity were used to assess betwixt-report heterogeneity. Statistically meaning heterogeneity was considered present at P<0.10 and I^two >l%.^viii Pooled odds ratios (ORs) were reported with 95% conviction intervals (CIs). Publication bias was assessed visually by the utilise of funnel plots.^nine

For studies evaluating >1 troponin assay, data on troponin I were considered for the pooled assay. Split up analyses were performed on retrospective and prospective studies, studies including hemodynamically unstable or hemodynamically stable patients only, and studies assessing troponin I or T. Meta-regression was used to assess the relationship between death and different cutoff levels separately for the three troponin assays. Analyses were performed with Review Manager 4.ii.8 (The Cochrane Collaboration, Oxford, England).

The authors had full access to and accept full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.

Results

Overall, 96 articles were found searching by "pulmonary embolism" and "troponin" from January 1, 1998, to November 2006. Manufactures were excluded by review of title if they were review articles (northward=28), editorials or letters (n=6), or case reports (north=half dozen) or if they reported on studies on differential diagnosis of elevated troponins (n=xiv), comparison of other biomarkers (n=v), evaluation of troponin assays (northward=three), or animals (n=1) (Figure 1).

**Figure 1.** Flow diagram for written report selection.

Twenty-four studies were found in which patients with acute pulmonary embolism had blood sampling for troponin at admission.^10–33 3 studies were excluded^thirty–32 considering they appeared to report on the aforementioned patients included in other analyzed studies.^16–23 In 6 studies,^{sixteen,xviii,23,24,29,33} the numbers of patients who had died or had experienced an agin issue consequence were non reported. For 5 of these studies, the numbers of patients who had died or had experienced an adverse result event were obtained by contacting the authors.^{xvi,18,23,24,29} One of these studies was excluded afterwards the authors were contacted because data were confirmed to be unavailable.³³

Selected Studies

Overall, 20 studies were selected for this assay,^x–29 and iv were retrospective.^19,20,27,28 The main features of the selected studies are reported in Table 1. Demographic features of written report populations (historic period, gender) were similar beyond the studies, and almost all the included patients had an objective diagnosis of pulmonary embolism. Vii studies included hemodynamically stable patients only.^{12,xiii,21,22,24,26,29} Ane report reported information on both troponin T and I.²³

**TABLE 1. Characteristics of Selected Studies**
Author	Year	Study Blueprint	Patients, n	Confirmed Diagnosis, n	Hemodynamic Instability^*	Timing of Troponin Sampling	Report Upshot		Thrombolysis, n	Historic period	Male, %	Follow-Upwardly
Author	Year	Study Blueprint	Patients, n	Confirmed Diagnosis, n	Hemodynamic Instability^*	Timing of Troponin Sampling	Chief	Secondary	Thrombolysis, n	Historic period	Male, %	Follow-Upwardly
Prosp indicates prospective; hosp, hospital; PE, pulmonary embolism; BNP, brain natriuretic peptide; Tn, troponin; A, in-hospital death, need for cardiopulmonary resuscitation, mechanical ventilation, pressors, thrombolysis, catheter fragmentation, or surgical embolectomy; B, in-infirmary decease, cardiogenic shock; C, in-hospital death, cardiogenic shock and respiratory failure; D, in-hospital decease, right ventricle chronic hypertension; Due east, recurrent venous thromboembolism; F, in-hospital death, demand for thrombolytic treatment, catecholamine administration, endotracheal intubation, or cardiopulmonary resuscitation; and G, in-infirmary death, demand for thrombolytic treatment, catecholamine administration, or cardiopulmonary resuscitation. Values are mean±SD when appropriate.
*Hemodynamic instability eligible for the study.
Meyer et al¹⁰	2000	Prosp	36	36	Aye	Admission	B	NA	NA	63±16	36	In hosp
Giannitsis et al¹¹	2000	Prosp	56	forty	Yes	Access, 12 h	Decease	NA	16	69±2	50	In hosp
Pruszczyk et al¹²	2003	Prosp	64	64	No	Admission, 6, 12, 18 h	Death	G	8	61±17	53	In hosp
Douketis et al¹³	2002	Prosp	24	22	No	viii, 12 h	NA	NA	2	NA	NA	In hosp
Mehta et al¹⁴	2003	Prosp	38	38	Yep	NA	Expiry	C	Na	64±17	34	In hosp
Kucher et al¹⁵	2003	Prosp	91	91	Yes	NA	A	Death	13	61±17	45	In hosp
Janata et al¹⁶	2003	Prosp	106	106	Yes	NA	Death	NA	Na	60	50	In hosp
La Vecchia et al¹⁷	2004	Prosp	48	46	Aye	Admission, 8 h	Decease	NA	32	64±15	48	In hosp
Enea et al¹⁸	2004	Prosp	26	26	Yeah	Admission, 24 h	Tn, BNP, eco	NA	17	68±xiv	31	In hosp
Bova et al²¹	2005	Prosp	lx	sixty	No	NA	F	Death	0	65	35	In hosp
Kostrubiec et al²²	2005	Prosp	100	100	No	Access	PE death	Decease, Thou	7	62±xviii	35	40 d
Binder et al²³	2005	Prosp	124	120	Aye	Admission, iv, 8 and 24 h	F	Death	12	lx±18	40	In hosp
Douketis et al²⁴	2005	Prosp	458	458	No	24 h	Death	E	0	62.2	43	three mo
Kaczynska et al²⁵	2006	Prosp	77	77	Yes	Access	Death	G	6	65±16	20	30 d
Tulevski et al²⁶	2006	Prosp	28	28	No	Admission	Decease	D	NA	53±xviii	43	3 mo
Kline et al²⁹	2006	Prosp	193	193	No	NA	A	Death	NA	53±17	41	In hosp
Yalamanchili et al¹⁹	2004	Retro	147	147	Na	Admission	Expiry	NA	NA	58±sixteen	50	In hosp
Scridon et al²⁰	2005	Retro	141	89	Yes	72 h	Death	NA	14	61±sixteen	45	30 d
Amorim et al²⁷	2006	Retro	threescore	36	Yes	Access	Death	NA	19	sixty±15	47	In hosp
Hsu et al²⁸	2006	Retro	110	110	Yes	Admission, 24 h	Expiry	NA	7	66±fourteen	50	100 d

Overall mortality was reported in all studies, troponin T in 8 studies, and troponin I in 12 studies (Table ii). Two studies reported on the composite cease point and not on mortality.^23,29

**TABLE 2. Characteristics of Troponin Assays**
Author	Troponin	Assay	Manufacturer and Location	Kind of Assay	Cutoff, μg/L	Elevated Troponin, %*	Cut Betoken for Normal, μg/50
ACS:10 indicates Automated Chemiluminescence System; AxSym, Automated Immunoassay Musical instrument System; ADVIA, Avant-garde Immunoassay; ECLIA, Enhanced Chemiluminescence Immunoassay; Elecsys, Electroluminescence Organization; and NA, not applicative.
Meyer et al¹⁰	I	ACS:180	Bayer	Quantitative	>0.fifteen	39	<0.15
Douketis et al¹³	I	AxSYM	Abbott	Quantitative	>0.twoscore	21	<0.40
Mehta et al¹⁴	I	AxSYM	Abbott	Quantitative	>0.forty	47	<0.40
Kucher et al^xv	I	NA	Abbott	NA	≥0.06	31	<0.40
La Vecchia et al¹⁷	I	RXL	Dade Behring	Quantitative	>0.60	29	<0.07
Yalamanchili et al¹⁹	I	AxSYM	Abbott	Quantitative	≥2.00	16	<2.00
Scridon et al^xx	I	NA	Baxter	NA	>0.10	52	<0.x
Enea et al¹⁸	I	Opus	Dade Behring	Quantitative	≥0.10	77	<0.10
Binder et al²³	I	ADVIA	Bayer	Quantitative	≥0.07	46	<0.07
Douketis et al²⁴	I	AxSYM	Abbott	Quantitative	>0.fifty	14	<0.fifty
Amorim et al²⁷	I	NA	NA	NA	≥0.10	70	<0.10
Hsu et al²⁸	I	NA	NA	NA	≥0.40	56	NA
Pruszczyk et al¹²	T	ECLIA	Roche	Quantitative	>0.01	fifty	<0.01
Giannitsis et al¹¹	T	TropT or ES 300	Roche	Qualitative, quantitative	≥0.x	32	<0.10
Janata et al^xvi	T	Elecsys	Roche	Quantitative	>0.09	39	<0.10
Bova et al²¹	T	NA	NA	NA	>0.01	43	NA
Kostrubiec et al²²	T	ECLIA	Roche	Quantitative	>0.01	39	<0.01
Binder et al²³	T	Elecsys	Roche	Quantitative	≥0.04	33	<0.04
Kaczynska et al²⁵	T	ECLIA	Roche	Quantitative	>0.03	32	<0.03
Tulevski et al²⁶	T	NA	NA	Qualitative	>0.01	21	<0.01
Kline et al²⁹	T	Elecsys	Roche	Quantitative	>0.x	x	<0.08

Fourth dimension to study end indicate was different among the studies, varying from the in-hospital stay up to 100 days. For the purpose of this analysis, nosotros considered death and adverse outcome events occurring in the short-term follow-upward (in-infirmary or 30 days). In 2 studies, mortality was available just at ninety days^24,26; in a 3rd study, mortality was available just at 100 days.²⁸

Troponin Assays

As reported in Table 2, iii different assays for troponin T were used throughout the studies, with dissimilar cutoff points for abnormal levels. For the troponin I studies, investigators used 5 unlike manufacturers' assays and different cutoff points.

In virtually of the studies, the cutting points for troponin assays were divers according to standard criteria that were values exceeding the 99% percentile of healthy subjects with a coefficient of variation of 10%.

Death

Data on death were reported in xx studies (1985 patients). Four studies were retrospective (all evaluating troponin I). The hateful age and the prevalence of middle or respiratory diseases in patients with elevated and normal troponin levels (when these data were available) were similar.

Overall, 122 of 618 patients with elevated troponin levels died (xix.seven%; 95% CI, 16.6 to 22.eight) compared with 51 of 1367 with normal troponin levels (3.7%; 95% CI, 2.7 to 4.7). High levels of troponins, both I and T, were associated with a high risk of short-term death (OR, 5.24; 95% CI, three.28 to 8.38), with no evidence for overall heterogeneity (Effigy 2). The upshot was consequent for either troponin I (OR, 4.01; 95% CI, 2.23 to 7.23) or troponin T (OR, seven.95; 95% CI, 3.79 to sixteen.65).

**Effigy 2.** OR for death based on elevated or normal serum troponin I and T.

The analysis of the iv retrospective studies revealed heterogeneity (I², 60.9%). The predictive value of elevated troponin levels with respect to short-term decease was confirmed when the assay was limited to sixteen studies (1527 patients) using a prospective design (OR, 6.33; 95% CI, iii.38 to 10.34), with no show for heterogeneity. The association between elevated serum troponins and decease likewise was confirmed after substituting 0.5 for 0 in the random-effects calculation (OR, 5.70; 95% CI, 3.62 to viii.95) for prospective studies.

Seven studies (915 patients), all with a prospective pattern, included only patients with normal blood pressure at infirmary admission. The incidence of decease was 17.9% (34 of 190; 95% CI, 12.4 to 23.3) in patients with elevated troponin levels and two.3% (17 of 725; 95% CI, i.2 to three.iv) in patients with normal troponin levels. The pooled analysis of these studies showed an association between loftier levels of serum troponins and mortality (OR, five.90; 95% CI, ii.68 to 12.95), with no evidence for heterogeneity. The results were confirmed after substituting 0.five for 0 in the random-effects calculation (OR, 4.98; 95% CI, 2.64 to 9.39).

The clan betwixt high levels of serum troponins and mortality was institute individually for the three more commonly used troponin assays (Enhanced Chemiluminescence Immunoassay [ECLIA], Automatic Immunoassay Musical instrument Organization [AxSYM], and Electroluminescence Arrangement [Elecsys]). Among studies using the same troponin analysis, ORs for mortality were higher in studies using college troponin cutoffs (encounter Figure III of the online Information Supplement). However, meta-regression did not show any significant difference in the risk of death for studies using different cutoffs of the aforementioned troponin assay.

Eight prospective studies (645 patients) reported on deaths resulting from pulmonary embolism. Overall, 40 events were observed: 34 in 207 patients with elevated troponin (sixteen.iv%; 95% CI, 11.four to 21.4) and 6 in 438 with normal troponin levels (1.4%; 95% CI, 0.8 to 1.9).^{10,12,15,18,21,22,24,28} Elevated troponin levels were associated with a high take a chance of death resulting from pulmonary embolism (OR, 9.44; 95% CI, 4.xiv to 21.49) (Figure 3).

**Effigy 3.** OR for death resulting from pulmonary embolism based on elevated or normal serum troponin I and T.

The analysis of 6 studies showed that right ventricular dysfunction is more common in patients with elevated troponin compared with patients with normal troponin levels (P<0.05). Analysis of 3 of these studies^x,xx,28 showed an independent prognostic value for elevated troponin levels (P=0.01) and right ventricular dysfunction at echocardiography (P=0.005), with no evidence for interaction (P=0.29).

Adverse Consequence Events

Nine studies (530 patients), all with a prospective design, evaluated the occurrence of brusk-term adverse outcome events.^{10,12,14,fifteen,21,22,24,25} The incidence of agin result was 43.half dozen% (92 of 211 patients; 95% CI, 36.nine to 50.iii) and 14.7% (47 of 319 patients; 95% CI, 10.eight to 18.half dozen) in patients with and without elevated troponin levels, respectively. To minimize the effect of heterogeneity amidst studies (χ², 31.xiv; P=0.0001; I², 74.3%), a random-furnishings model was used for analysis. Elevated troponin levels were associated with a high risk of agin events during the in-hospital stage (OR, 7.03; 95% CI, two.42 to 20.43) (Effigy 4). Heterogeneity was due mainly to the v studies evaluating troponin T (χ², xix.58; P=0.0006; I², 79.6%) compared with studies on troponin I (χ², 3.46; P=0.33; I², thirteen.2%).

**Figure 4.** OR for short-term adverse outcome events based on elevated or normal serum troponin I and T.

Four studies (252 patients) reported the incidence of adverse result events in patients with normal blood pressure level at hospital admission.^12,21,22,25 Adverse consequence events were seen in 38 of 103 patients with elevated troponin levels (36.9%) compared with 32 of 149 patients with normal troponin levels (21.5%). Analysis of these studies showed an clan between elevated serum troponins and adverse upshot events in hemodynamically stable patients (OR, iv.12; 95% CI, 0.71 to 23.86).

Discussion

This meta-analysis shows that elevated serum troponins are associated with short-term death and adverse outcome events in patients with acute pulmonary embolism. Elevated troponin levels likewise are associated with expiry related to pulmonary embolism.

In patients with pulmonary embolism, shock or sustained hypotension is associated with increased short-term bloodshed. In patients with acute pulmonary embolism and normal claret pressure level, prognostic stratification remains an unsolved clinical issue. Short-term mortality in these patients has been shown to range from 0% to 10%. Grifoni et al⁵ have shown that acute right ventricular overload, equally assessed by echocardiography, tin exist used to stratify patients with normal blood pressure for the risk of death. Nevertheless, echocardiography requires around-the-clock defended personnel and suffers from some disagreement about criteria for correct ventricular dysfunction.

Serum troponins are currently used widely for the diagnosis of astute coronary syndromes and are rapidly available in the urgent setting. Nosotros showed that elevated levels of troponin were predictors of short-term death in the overall population of patients with acute pulmonary embolism and in patients with acute pulmonary embolism and normal blood pressure level. According to our assay, troponin and echocardiography are independent prognostic factors with addictive prognostic value in risk stratification.

In addition to death, nosotros showed the prognostic value of troponin on adverse outcome events. This cumulative terminate signal was defined differently in the private studies. However, our results should be of clinical value considering all the definitions of agin event events were aimed at identifying those patients who experienced in-hospital clinical deterioration.

The prognostic value of troponin was consistent among the studies, regardless of the specific assay and the relative cutoff point. The results were consequent for both troponin I and T. The association between high levels of serum troponins and bloodshed is confirmed individually for the 3 more commonly used troponin assays. Thus, information technology is conceivable that any the assay, troponin levels tin be used to stratify patients with acute pulmonary embolism.

Private studies reported a correlation between different levels of elevated troponins and clinical outcome in patients with pulmonary embolism.^fifteen,17 Our analysis does non permit the conclusion of such a correlation.

We included retrospective studies in this meta-analysis. However, the results of the analysis are consistent subsequently these studies are excluded.

It is unclear whether thrombolysis has a role in the treatment of hemodynamically stable patients, and if so, it is unclear which among these patients should receive this treatment. The results of this meta-analysis suggest a role for troponin in the choice of hemodynamically stable patients with a worse outcome who could potentially do good from a more aggressive treatment.

Conclusions

Elevated serum troponins identify a subgroup of patients with acute pulmonary embolism at loftier take a chance of in-hospital expiry and adverse outcome events. These findings identify troponin every bit a promising tool for rapid risk stratification of patients with pulmonary embolism. Prospective randomized studies are needed to evaluate the clinical benefits of more aggressive treatments in patients with pulmonary embolisms and elevated troponin levels.

We thank Karin Janata, Iolanda Enea, Jeffrey Kline, James Douketis, and Stavros Konstantinides for their unpublished data that were included in this analysis. We also thank Sandra Maria Amorim for providing her commodity.

Disclosures

None.

Footnotes

Correspondence to Dr Cecilia Becattini, Medicina Interna east Cardiovascolare, Dipartimento di Medicina Interna, Academy of Perugia, Via One thousand. Dottori one, 06129 Perugia, Italy. Eastward-mail [email protected]

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