postoperative troponin screening: a cardiac cassandra?
TRANSCRIPT
DOI: 10.1161/CIRCULATIONAHA.113.003195
1
Postoperative Troponin Screening: a Cardiac Cassandra?
Running title: Beckman; Troponin: Barometer or Weathervane?
Joshua A. Beckman, MD, MS
Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA
Address for Correspondence:
Joshua A. Beckman, MD, MS
Cardiovascular Division
Brigham and Women’s Hospital
75 Francis Street
Boston, MA 02115
Tel: 617-525-7053
Fax: 617-232-2749
E-mail: [email protected]
Journal Subject Codes: Diagnostic testing:[33] Other diagnostic testing
Key words: surgery, surveillance, troponin T, myocardial infarction, Editorial
Cardiovascular Division, Brigham and Women’s Hospital, Boston, MAMAA
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The cardiovascular management of the patient undergoing non-cardiac surgery has been in
evolution for the last 35 years. Over this time frame, two secular trends have advanced in parallel
but provided contrary practice implications for the care of the surgical patient. First,
cardiovascular event rates have been dropping significantly over time. In 1977, Goldman and
colleagues created a risk evaluation system that predicted a 22% rate of “life-threatening”
cardiovascular events and more than 50% mortality in the highest risk group 1 in 1001 patients
undergoing surgery. These rates of events have dropped each decade since significantly. Finks
and colleagues reported 2 years ago a mere 2.8% national mortality rate for open abdominal
aortic aneurysm repair; the exemplar of routine, high-risk surgery 2. These numbers were
recapitulated world-wide for high-risk patients undergoing noncardiac surgery in the
PeriOperative ISchemic Evaluation (POISE) trial 3. Improvements in surgical and anesthetic
techniques, perioperative medical therapy, and intensive care have each participated in the
significant improvement in outcomes.
Second, the sensitivity of testing to detect evidence of cardiovascular disease or ischemia
has increased dramatically. In this same time frame, risk assessment has evolved from stress
testing, to nuclear – vasodilator testing, inotropic echocardiographic assessment, cardiac
magnetic resonance imaging, and positron emission tomographic (PET) scanning.
Counterintuitively, the ability to accurately detect smaller and smaller amounts of disease has not
improved post-operative cardiovascular event prognostication. Indeed, the positive predictive
value for each of these modalities in predicting a cardiovascular event remains below 20% 4. The
poor performance may be attributed to two components. First, improvements in disease detection
fosters inclusion of patients previously deemed healthy by less sensitive modalities. Indeed, it is
the specific coronary heart disease detection improvement that undermines its prognostic value
ecapitulated world-wide for high-risk patients undergoing noncardiac surgery iinn n thhhee
PeriOperative ISchemic Evaluation (POISE) trial 3. Improvements in surgical and anesthetic
eechchhnininiqququesess,, peperiopopopeererative medical therapy, and ininntetennsive care havevee eacach h h ppparticipated in the
iiignnnifi icant immprprovovovememeenent tt ininin oooutututcocomememes.s.
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has increased d drdrdramammatata iciccalala lylyy.. InInIn tthihihiss s sasasamememe tttimimime e e frfrframamme,e,e rrisiskk k asasassesesessssssmemm ntntnt hhhasasas eeevovovolvlvvededd fffrororom mm stress
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in the stable patient by diminishing the risk of the group with a “positive study.” Second, ever-
dropping event rates largely render the prognostic value of these tests moot. A three-fold hazard
ratio in the setting of a 1-3% surgical mortality provides little insight into patient selection for
higher level therapies beyond medical therapy. Because of the overall low mortality and the
limited value of noninvasive testing to clarify outcome and need for preoperative coronary artery
revascularization 5, there has been an increase in effort to find patients at heightened risk post-
operatively to stave off severe adverse events. Over the last decade, much of this effort has
focused on biomarkers of myocardial injury, the cardiac troponins.
The troponin complex is co-located with tropomyosin on the actin filament and
participates in cardiac muscle contraction. The complex consists of three peptide components, T,
I, and C. The first two have been used in the measurement of myocardial injury whereas troponin
C, the calcium binding site, is not because of its shared location in skeletal muscle. Measurement
of troponin T was approved by the Food and Drug Administration in 1996 and its uptake into the
medical practice was rapid. Just 4 years later, the cardiology community made troponin the
preferred biomarker to diagnose myocardial infarction 6 as part of the guideline process. By
2007, troponin measurement became the de facto global standard when the first Universal
Definition of Myocardial Infarction was published 7. Over the last decade, the troponin use has
skyrocketed beyond the limited use for determining the presence or absence of an acute coronary
syndrome and become a nonspecific marker of illness. Indeed, the value of troponin in the
diagnosis of myocardial infarction may have reached its apex in 2001 with the publication of the
Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative
Strategy (TACTICS) study. The investigators showed that early invasive therapy was superior to
a conservative approach in patients presenting to the hospital with chest pain with a troponin T of
participates in cardiac muscle contraction. The complex consists of three peptidde e cooompmpponnonenenentstst ,, T,
, and C. The first two have been used in the measurement of myocardial injury whereas troponin
C,C, ttthehehe ccc lalalciciciumumum bbininindidid ng site, is not because of itss shshs aaared location ininn skeelelelettatal muscle. Measurement
off ttrroroponin T wawaas appprpprovovovededed bbbyyy ththe ee FoFoF ododd anddd DDDruggg AdAdmimim ninissts rraratitioonon iin n 1911 99696 aaandndnd iitstss uuptptp akaka eee iininttot the
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preferred biomommarara kekeker r r totoo dddiaagngngnosoo e e e mymymyocoo ararardididialalal iiinfnfnfararrctctctioioonn 666 aaass s papapartrtrt ooof thththeee guguguidididelele ininne e prprprocococesee s. By
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> 0.01 ng/ml but not without this troponin T elevation 8. This led to the wide adoption of
troponin in the standard evaluation of patients with chest pain or thought to be at risk of
myocardial infarction.
Subsequently, troponin has been measured in a wide variety of settings to provide
prognostic information in diseases that do not originate in the coronary arteries. Prognostic
information has been generated for diseases that originate with the heart, affect the heart, are
remote from the heart, and have extended to patients who aren’t acutely ill. Elevations in
troponin associate with worse outcomes in patients with myocarditis 9, congestive heart failure 10,
11, and cardiac contusions 12 showing the value of this biomarker in a broad range of cardiac
disease. Troponin release provides significant prognostic information for pulmonary disease,
presumably because of its direct vascular coupling with the right ventricle. For example, many
studies have shown that troponin release during pulmonary embolism is a marker of severity and
adverse prognosis 13-15. Similarly, elevations in troponin during chronic obstructive pulmonary
disease exacerbation are associated with a greater need for ventilator support and worse long-
term survival 16. The release of troponin is thought to result from a direct increase in right
ventricular overload and right heart strain.
Perhaps more impressively, release of cardiac troponin has become sensitive enough to
act a barometer of the severity of illness unrelated to the heart. Patients with septicemia who
have measurable troponin levels suffer worse outcomes than those who do not, even after
adjustment for other prognostic markers 17. Similarly, the release of troponin predicts poorer
outcomes in patients admitted with subarachnoid hemorrhage 18-20. More recently, investigators
have shown that troponin release may occur in the absence of overt illness and provide
prognostic data for outcomes in the non-hospitalized person. Using a high-sensitivity troponin T
disease. Troponin release provides significant prognostic information for pulmonnnaryryy dddisisiseaeaeasesese,,
presumably because of its direct vascular coupling with the right ventricle. For example, many
ttududdieieiesss hahahaveveve ssshoownwnwn that troponin release during pppulullmonary embolollisi m m isisis aa marker of severity and
addvveverse prognonosisis s 13-3-15151 . SiSiSimimimilalalarlrly,y, eelelel vvvatttionsss iinn troooppponiniinn n duduuriinng g chchrooniniicc oobobstststruruuctctivivvee pupup lmlmmononaararyyy
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erm survivaal l 161616.. ThThThee e rerer lelel asasse e e ofofo tttrororopopoponiiin nn isisis ttthohohougugughththt tttooo reeesususultltlt fffroroom m m a a dididirererectctct ininncrcreaeaeasesese iiin n n rir ght
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assay, investigators in the Dallas Heart Study have shown that among 3546 individuals aged 30
to 65 years enrolled between 2000 and 2002, 25% of the cohort had detectable troponin T 21.
Moreover, when the troponin level was greater than 0.0014 ng/ml, the hazard ratio for all-cause
death over the 6.4 years of follow up was nearly 5 five fold higher despite adjusting for age,
race/ethnicity, sex, diabetes, hypertension, hypercholesterolemia, low high-density lipoprotein
cholesterol level, current smoking, log-transformed values of high-sensitivity C-reactive protein,
and chronic kidney disease categories. Moreover, the troponin elevation across the range
predicted all-cause mortality and cardiovascular mortality similarly. And, therein, lies the
problem. Although certainly originating in the heart, when used to provide prognostic data
beyond cardiac-in-origin diseases, troponin elevation no longer provides cardiovascular
outcome-specific information. It becomes a nonspecific test of illness that requires interpretation
by setting. Indeed, the screening measurement of troponin post-operatively most resembles the
use of troponin in the Dallas Heart Study as a screening tool.
In this issue of Circulation, Van Waes and colleagues are to be commended for reporting
the largest single-center study of post-operative troponins yet published. The investigators
studied 2,232 consecutive intermediate to high risk noncardiac surgery patients aged >60 years
who underwent surgery in 2011 22. Of the total surgical population, all-cause mortality was 3%,
troponin T release was detected in 19%, and elevations predicted death in a dose-related manner,
consistent with past work. Also consistent with past work and similar to the Dallas Heart Study
was a stronger association with all-cause mortality than myocardial infarction. In this cohort,
myocardial infarction (based on the universal definition) was diagnosed in 10 subjects or 0.6% of
the total.
Other studies have demonstrated both a similar relationship between troponin elevation
beyond cardiac-in-origin diseases, troponin elevation no longer provides cardiovvaaascucuc lalalar r
outcome-specific information. It becomes a nonspecific test of illness that requires interpretation
byy sssetetettititingngg.. InInInddeededd,, tht e screening measurement ofofof trrooponin post-oopepp raatitiivevevelyl most resembles the
uuse ofo troponiin n inini tthehe DDalalallalalass HHHeaeartrtrt SSStutuuddyy as a screeeeenninnnggg totooool.
InIn ttthihihiss isissususue e e ofoff CCiCircrculullatatioioion,n,n, VaVaVann WaWaWaeses aaandndd cccololleleagagaguueuesss arara eee tototo bbeee cocoommmmmenene dedeedd d foorrr rrerepopoorrtiining
he largest siingngnglelel -c-ccenenenteteter r r sttudududy yy ofofof pppososost-t opopoperereratatativiviveee trtrtropopoponono ininns s yeyeyet t pupupublbb isisishehehed.d.d TTTheheh iiinvnvnvesesestititigagag tors
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and mortality after surgery and the relative infrequency of myocardial infarction by the universal
definition in this setting 23, however, it is the Vascular Events In Noncardiac Surgery Patients
Cohort Evaluation (VISION) Study that puts the whole picture in perspective 24. The VISION
investigators measured troponin T levels 6 to 12 hours after surgery and on days 1, 2, and 3 after
surgery in patients older than 45 years who required at least a one-night stay in the hospital.
Overall, the 30-day mortality rate was 1.9% and troponin T was measurable in 11.6% of the
patients. Across a narrow range of troponin T elevation, the hazard for mortality rose quickly,
with a 10-fold mortality risk noted in patients with troponin elevations 0.30 ng/ml. Despite the
fact that the vascular death category included nontraditional elements like pulmonary embolism,
hemorrhage, and death from unknown causes, the number of vascular deaths remained smaller
than non-vascular deaths. The VISION investigators reported that increases in troponin T
predicted cardiovascular and non-vascular death equivalently. Thus, post-operative troponin
elevation has become a non-specific marker of hazard.
In this author’s opinion, practitioners underappreciate this lack of specificity of post-
operative troponin testing. For example, the authors of the Third Universal Definition of
Myocardial Infarction 25 recommend “routine monitoring of cardiac biomarkers in high-risk
patients, both prior to and 48–72 h after major surgery” because “most patients who have a
perioperative MI will not experience ischemic symptoms. Nevertheless, asymptomatic
perioperative MI is as strongly associated with 30-day mortality, as is symptomatic MI.” They
then go on to recommend close clinical scrutiny, but without any specific recommendation for
care. I favor an approach to testing as advocated by Laine 26 in posing certain questions prior to
ordering a test. First, will the test change the care of my patient? In the asymptomatic patient
without ECG changes, a troponin elevation does not predict any specific kind of death, thus the
hemorrhage, and death from unknown causes, the number of vascular deaths remmmaininnededd ssmamamallllllerer
han non-vascular deaths. The VISION investigators reported that increases in troponin T
prrededdicicicteteteddd cacacardrdrdioovavavascscular and non-vascular death hh eqeqequuivalently. Thhusuu , popooststst-operative troponin
ellevvvaation has bebecococomeme a nnnononon-s-s-sppepecicififif ccc mmamarrkerr oof haaazaaard.. .
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test provides no direction for care and clinicians should continue to treat patients individually.
Second, what are the probability and potential adverse consequences of a false positive result?
For this, I would refer to the vanishingly small number of type 1 myocardial infarctions
diagnosed and worry that management for plaque rupture events (antiplatelet therapy,
anticoagulation, and possibly catheterization) would be provided for patients with hemodynamic
(type 2 myocardial infarction) events. None of these interventions is likely beneficial for the vast
majority of patients, particularly early after major surgery when the troponin is likely to be
elevated. As noted by Van Waes and the VISION investigators, the majority of troponin T
release occurs by the end of post-operative day 1, a high-risk period for bleeding. Third, is the
patient in potential danger over the short term if I do not perform this test? Although it is
certainly true that an elevation in troponin portends adverse outcome, the lack of specificity
concerning the mechanism of adverse outcome suggests that the test will not foster a change or
modification of therapy. In a small study of patients over aged 60 years undergoing emergency
orthopedic surgery, the addition of cardiovascular care to troponin positive patients did not affect
in-hospital cardiovascular complications or 1 year mortality 27. Most telling, however, is that the
cardiologists did little to alter care. No coronary angiography was performed and only 1 in 6
patients seen by cardiologists had the addition of aspirin, beta blockers, or both.
It is the author’s opinion that improvements in troponin T assay sensitivity have created a
condition in which the biomarker is so easily measured that it now culls out patients at higher
risk for any adverse event more than diagnoses cardiac-specific events. Indeed, one may suggest
that the results are similar to the Dallas Heart Study, but instead of free-living individuals, the
perioperative patient population represents an asymptomatic group exposed to surgical stress,
and the elevation in troponin similarly indicates a high-risk group for all-cause death. In the
patient in potential danger over the short term if I do not perform this test? Althoougugughh h iitit iiisss
certainly true that an elevation in troponin portends adverse outcome, the lack of specificity
cooncncncererernininingngng ttthehh mmmeecechah nism of adverse outcome sususuggggests that the ttesee t wiwiwillllll not foster a change or
mmoddidification oof ff thtt eererapappy... IIInnn aa a ssmsmalallll l sststuuddyyy off paaatiennnttss oveveverr agagageeded 6600 yeyeararss uunundedederrgrgoioinngng eememmerrgrgenennccyy
orrthththopopopedede icic sssuururgegeeryyy,,, ththhee adada diditititiononn ooof f f ccacarrddioioovavavascccululu ararr ccacareree tttooo trtrtroppponononininn ppposossiitiivivee papap titit enenntststs dididd nnnotot aaafffffece t
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absence of any demonstrated beneficial treatment strategy, the possibility of harm in applying the
standard treatment for type 1 myocardial infarction, and the potential to divert attention from a
true cause of adverse event (non-vascular morbidity) to a false one (myocardial infarction), the
author believes that routine measurement of troponin is more likely to cause harm than provide
benefit and should not be used as a screening modality.
Currently, low rates of overall perioperative mortality in the setting of guidelines based
care 28 have made risk prediction difficult and largely limited the task of risk assessment to
ferreting out patients with active cardiac conditions, severe pulmonary disease, or severe
underlying medical illness. These factors may or may not be related to the features seemingly
most predictive of troponin release, such as intra-operative hypotension, pre-operative
hypertension, and the presence of atherosclerosis 29-31. Studies are ongoing to determine response
strategies to elevations of troponin post-operatively, but until a specific strategy or treatment is
identified, the ontogeny of troponin testing makes unlikely patient benefit from its routine
measurement after noncardiac surgery.
Conflict of Interest Disclosures: Consulting: Ferring Pharmaceutical, Novartis Pharmaceutical, Merck Pharmaceutical, Astra Zeneca, and Boston Scientific. Board Membership: VIVA Physicians. Research Grants: Bristol-Myers Squibb References 1. Goldman L, Caldera DL, Nussbaum SR, Southwick FS, Krogstad D, Murray B, Burke DS, O'Malley TA, Goroll AH, Caplan CH, Nolan J, Carabello B, Slater EE. Multifactorial index of cardiac risk in noncardiac surgical procedures. N Engl J Med. 1977;297:845-850. 2. Finks JF, Osborne NH, Birkmeyer JD. Trends in hospital volume and operative mortality for high-risk surgery. N Engl J Med. 2011;364:2128-2137. 3. Devereaux PJ, Yang H, Yusuf S, Guyatt G, Leslie K, Villar JC, Xavier D, Chrolavicius S, Greenspan L, Pogue J, Pais P, Liu L, Xu S, Malaga G, Avezum A, Chan M, Montori VM, Jacka M, Choi P. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (poise trial): A randomised controlled trial. Lancet. 2008;371:1839-1847.
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ttraraatetetegigigieses ttto o o eeelevvvatatatioions of troponin post-operativvveelelyyy, but until a spppece ifficicc ssstrt ategy or treatment is
dddennntit fied, the e ononntooogegenynny oofff trtrtropoppononnininin tteessttiing mmmaaakesss uuunliiikekeelylyy patatieieentt bbennefefitit fffrororomm ititts ss rororouututinnnee
memeeasasa urururememenenenttt afaftteerr r nononncncarardid aacac sssurururgegegeryry..
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Joshua A. BeckmanPostoperative Troponin Screening: A Cardiac Cassandra?
Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2013 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation published online May 10, 2013;Circulation.
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