Novel&Assays&for&Cardiac&Troponin:&& Diagnosis,&Risk ...Novel&Assays&for&Cardiac&Troponin:&&...

Novel Assays for Cardiac Troponin: Diagnosis, Risk Prediction, and Treatment

Brendan M. Evere,, MD, MPH, FACC, FAHA Director, General Inpa<ent Cardiology Service

Brigham and Women’s Hospital Assistant Professor of Medicine, Harvard Medical

School

Disclosures

•  Inves<gator-‐ini<ated grant awards from Novar<s Pharmaceu<cals, Roche Diagnos<cs, and the NIH

•  Consul<ng/Advisory Board: Roche Diagnos<cs

Outline

•  Development and defini<on of high-‐sensi<vity cardiac troponin assays

•  The use of these assays for the evalua<on of suspected myocardial infarc<on

•  Cardiac troponin as a popula<on screening tool

What is cardiac troponin? What is a high-‐sensitivity assay

for cardiac troponin?

Diagnostic Criteria for MI

Slide courtesy of James de Lemos

ESC/ACCF/AHA/WHF Expert Consensus Document

Third Universal Definition of Myocardial InfarctionKristian Thygesen, Joseph S. Alpert, Allan S. Jaffe, Maarten L. Simoons, Bernard R. Chaitman, and

Harvey D. White: the Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for theUniversal Definition of Myocardial Infarction

AUTHORS/TASK FORCE MEMBERS CHAIRPERSONSKristian Thygesen (Denmark),* Joseph S. Alpert (USA),* Harvey D. White (New Zealand),* Biomarker Subcommittee:

Allan S. Jaffe (USA), Hugo A. Katus (Germany), Fred S. Apple (USA), Bertil Lindahl (Sweden), David A. Morrow (USA),ECG Subcommittee: Bernard R. Chaitman (USA), Peter M. Clemmensen (Denmark), Per Johanson (Sweden),

Hanoch Hod (Israel), Imaging Subcommittee: Richard Underwood (UK), Jeroen J. Bax (The Netherlands),Robert O. Bonow (USA), Fausto Pinto (Portugal), Raymond J. Gibbons (USA), Classification Subcommittee:

Keith A. Fox (UK), Dan Atar (Norway), L. Kristin Newby (USA), Marcello Galvani (Italy),Christian W. Hamm (Germany), Intervention Subcommittee: Barry F. Uretsky (USA), Ph. Gabriel Steg (France),William Wijns (Belgium), Jean-Pierre Bassand (France), Phillippe Menasché (France), Jan Ravkilde (Denmark),

Trials & Registries Subcommittee: E. Magnus Ohman (USA), Elliott M. Antman (USA), Lars C. Wallentin (Sweden),Paul W. Armstrong (Canada), Maarten L. Simoons (The Netherlands), Heart Failure Subcommittee:

James L. Januzzi (USA), Markku S. Nieminen (Finland), Mihai Gheorghiade (USA), Gerasimos Filippatos (Greece),Epidemiology Subcommittee: Russell V. Luepker (USA), Stephen P. Fortmann (USA), Wayne D. Rosamond (USA),Dan Levy (USA), David Wood (UK), Global Perspective Subcommittee: Sidney C. Smith (USA), Dayi Hu (China),José-Luis Lopez-Sendon (Spain), Rose Marie Robertson (USA), Douglas Weaver (USA), Michal Tendera (Poland),

Alfred A. Bove (USA), Alexander N. Parkhomenko (Ukraine), Elena J. Vasilieva (Russia), Shanti Mendis (Switzerland)

ESC COMMITTEE FOR PRACTICE GUIDELINES (CPG)Jeroen J. Bax (CPG Chairperson) (Netherlands), Helmut Baumgartner (Germany), Claudio Ceconi (Italy),

Veronica Dean (France), Christi Deaton (UK), Robert Fagard (Belgium), Christian Funck-Brentano (France),David Hasdai (Israel), Arno Hoes (Netherlands), Paulus Kirchhof (Germany/UK), Juhani Knuuti (Finland),

Philippe Kolh (Belgium), Theresa McDonagh (UK), Cyril Moulin (France), Bogdan A. Popescu (Romania),Željko Reiner (Croatia), Udo Sechtem (Germany), Per Anton Sirnes (Norway), Michal Tendera (Poland),

Adam Torbicki (Poland), Alec Vahanian (France), Stephan Windecker (Switzerland)

*Corresponding authors/co-chairpersons: Professor Kristian Thygesen, Department of Cardiology, Aarhus University Hospital, Tage-Hansens Gade 2,DK-8000 Aarhus C, Denmark. Tel: !45 7846-7614; fax: !45 7846-7619: E-mail: [email protected]. Professor Joseph S. Alpert, Department of Medicine,Univ. of Arizona College of Medicine, 1501 N. Campbell Ave., P.O. Box 245037, Tucson AZ 85724, USA, Tel: !1 520 626 2763, Fax: !1 520 6260967, E-mail: [email protected]. Professor Harvey D. White, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92024,1030 Auckland, New Zealand. Tel: !64 9 630 9992, Fax: !64 9 630 9915, E-mail: [email protected].

The European Society of Cardiology, American College of Cardiology Foundation, American Heart Association, and the World Heart Federation makeevery effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or businessinterest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaireshowing all such relationships that might be perceived as real or potential conflicts of interest.

This document was approved by the European Society of Cardiology, American College of Cardiology Foundation, American Heart Association, andWorld Heart Federation in July 2012.

The American Heart Association requests that this document be cited as follows: Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, WhiteHD; the Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction. Third universaldefinition of myocardial infarction. Circulation. 2012;126:2020–2035.

This article has been copublished in the European Heart Journal, Journal of the American College of Cardiology, and Global Heart.Copies: This document is available on the World Wide Web sites of the European Society of Cardiology (www.escardio.org.), American College of

Cardiology (www.cardiosource.org), American Heart Association (my.americanheart.org), ), and the World Heart Federation (www.world-heart-federation.org). A copy of the document is available at http://my.americanheart.org/statements by selecting either the “By Topic” link or the “By Publication Date”link. To purchase additional reprints, call 843-216-2533 or e-mail [email protected].

The disclosure forms of the authors and reviewers are available as a Data Supplement on the Circulation Web site.The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIR.0b013e31826e1058/-/DC1.Expert peer review of AHA Scientific Statements is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines

development, visit http://my.americanheart.org/statements and select the “Policies and Development” link.Permissions: Multiple copies, modification, alteration, enhancement, and/or distribution of this document are not permitted without the express

permission of the American Heart Association. Instructions for obtaining permission are located at http://www.heart.org/HEARTORG/General/Copyright-Permission-Guidelines_UCM_300404_Article.jsp. A link to the “Copyright Permissions Request Form” appears on the right side of the page.

(Circulation. 2012;126:2020-2035.)© 2012 by The European Society of Cardiology, American College of Cardiology Foundation, American Heart Association, Inc., and the World Heart Federation.

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0b013e31826e1058

2020 by BRENDAN EVERETT on April 10, 2014http://circ.ahajournals.org/Downloaded from

Detec<on of a rise and/or fall of cardiac markers (preferably troponin) with at least one value >99th percen<le* of the upper reference limit (URL) together with evidence of myocardial ischemia *The assay should have a coefficient of varia<on (CV) is ≤︎ 10% at the 99th percen<le URL

Thygesen K, et al. Third universal defini<on of myocardial infarc<on. 2012. p. 2020–2035.

Diagnostic Criteria for MI

Novel high-‐sensitivity troponin assays

99% of a healthy popula<on 1% of a healthy popula<on

New LOD URL (upper reference limit)

Current Limit of detec<on (LOD)

Circula(ng cardiac troponin concentra(on

Freq

uency

Myocardial injury No myocardial injury

10% CV

High Sensitivity Troponins for MI Diagnosis T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 361;9 nejm.org august 27, 2009866

says. We hypothesize that our findings can be generalized to other cardiac troponin assays that have similar sensitivity and precision. However, additional large, multicenter studies are needed to confirm this hypothesis. Second, since this was a prospective, observational study, we cannot quantify the clinical effect associated with the in-crease in early diagnostic accuracy. Intervention

studies are warranted to provide this important additional information. Third, our study showed a high diagnostic accuracy of sensitive cardiac troponin assays among patients with impaired renal function; however, we cannot comment on the accuracy among patients with terminal kid-ney failure requiring dialysis, since such patients were excluded from our study. Fourth, some of the patients with positive results of sensitive car-diac troponin assays whose final diagnosis was classified as a condition other than an acute myo-cardial infarction might have had small acute myocardial infarctions that were below the limit of detection of the conventional assays, a result that might have led to an underestimate of the specificity of the sensitive assays.

In conclusion, sensitive cardiac troponin as-says have an excellent diagnostic performance as early as at the time of a patient’s presentation in the emergency department and may thereby sub-stantially improve the early diagnosis of acute myocardial infarction, particularly in patients with a recent onset of chest pain.

Supported by grants from the Swiss National Science Founda-tion (PP00B-102853), the Swiss Heart Foundation, Abbott, Roche, Siemens, and the Department of Internal Medicine, University Hospital Basel.

Dr. Mueller reports receiving research grant support from Ab-bott, Brahms, Nanosphere, Roche, and Siemens, consulting fees from Abbott, and lecture fees from Abbott, Biosite, Brahms, Roche, and Siemens. No other potential conflict of interest was reported.

We thank the patients who participated in the study, the staff of the emergency department and the laboratory technicians for their most valuable efforts, and Dr. C. Schindler for expert sta-tistical advice.

22p3

1.000

0.900

0.950

0.850

0.800

0.700

0.750

0.000≤2 ≤4 ≤6 ≤10

AUTHOR:

FIGURE:

JOB:

4-CH/T

RETAKEICM

CASE

EMail LineH/TCombo

Revised

REG F

Enon

1st2nd3rd

Reichlin

3 of 3

08-27-09

ARTIST: ts

36109 ISSUE:

Abbott–ArchitectTroponin I

Roche High-SensitiveTroponin T

Roche Troponin I

SiemensTroponin IUltra

Standardassay

Figure 3. Diagnostic Accuracy of Cardiac Troponin Assays at Presentation According to Time since Onset of Chest Pain.

The area under the receiver-operating-characteristic curve (AUC) is shown, according to the time since the onset of chest pain, for the four sensitive cardiac troponin assays and the standard assay performed on blood samples obtained at presentation for the diagnosis of acute myocardial infarction.

References

Nawar EW, Niska RW, Xu J. National 1. Hospital Ambulatory Medical Care Survey: 2005 emergency department summary. Advance data from vital and health statis-tics. No. 386. Hyattsville, MD: National Center for Health Statistics, 2007.

Anderson JL, Adams CD, Antman EM, 2. et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-elevation myocardial in-farction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writ-ing Committee to Revise the 2002 Guide-lines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction): developed in col-laboration with the American College of Emergency Physicians, the Society for Car-diovascular Angiography and Interven-tions, and the Society of Thoracic Sur-geons: endorsed by the American Associ-ation of Cardiovascular and Pulmonary

Rehabilitation and the Society for Aca-demic Emergency Medicine. Circulation 2007;116(7):e148-e304.

Bassand JP, Hamm CW, Ardissino D, 3. et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1598-660.

Thygesen K, Alpert JS, White HD, et 4. al. Universal definition of myocardial in-farction. Circulation 2007;116:2634-53.

Pope JH, Aufderheide TP, Ruthazer R, 5. et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N Engl J Med 2000;342:1163-70.

Wang K, Asinger RW, Marriott HJ. ST-6. segment elevation in conditions other than acute myocardial infarction. N Engl J Med 2003;349:2128-35.

Morrow DA, Cannon CP, Rifai N, et al. 7. Ability of minor elevations of troponins I and T to predict benefit from an early in-vasive strategy in patients with unstable

angina and non-ST elevation myocardial infarction: results from a randomized trial. JAMA 2001;286:2405-12.

Morrow DA, Antman EM, Tanasijevic 8. M, et al. Cardiac troponin I for stratifica-tion of early outcomes and the efficacy of enoxaparin in unstable angina: a TIMI-11B substudy. J Am Coll Cardiol 2000;36: 1812-7.

Mueller C, Neumann FJ, Perruchoud 9. AP, Zeller T, Buettner HJ. Prognostic value of quantitative troponin T measurements in unstable angina/non-ST-segment eleva-tion acute myocardial infarction treated early and predominantly with percutane-ous coronary intervention. Am J Med 2004; 117:897-902.

Hochholzer W, Buettner HJ, Trenk D, 10. et al. New definition of myocardial in-farction: impact on long-term mortality. Am J Med 2008;121:399-405.

Hamm CW, Heeschen C, Goldmann 11. B, et al. Benefit of abciximab in patients

The New England Journal of Medicine as published by New England Journal of Medicine.Downloaded from www.nejm.org at HARVARD UNIVERSITY on August 19, 2010. For personal use only. No other uses without permission.

Copyright © 2009 Massachusetts Medical Society. All rights reserved.

Reichlin T, et al. N Engl J Med. 2009;361:858–867.

Parameter cTnT hs-‐cTnT

Sens 83 95

Spec 95 80

NPV 97 99

PPV 72 50

Slide courtesy of James de Lemos

Accelerated Diagnostic Protocols •  ADAPT Score: Low risk

chest pain –  TIMI risk score = 0 or 1 –  ECG without ischemic

changes –  Hs-‐cTnI at 0-‐ and 2-‐

hours < (26.2 ng/L)

Acute Chest Pain N=1635

ADAPT Low risk TIMI = 0

N=320 (20%)

30-‐day MACE N=0 (0%)

No 30-‐day MACE N=320 (100%)

ADAPT Low risk TIMI ≤ 1

N=678 (42%)

Sens: 100% NPV: 100%

30-‐day MACE N=2 (0.3%)

Cullen L, et al. JACC. 2013;62:1242–1249 and Than M, et al. JACC. 2012;59:2091–2098.

No 30-‐day MACE N=676 (99.7%)

Sens: 99.2% NPV: 99.7%

Also works with contemporary cTnI

Myocardial Infarction in 2016 Myocardial Injury

Adapted from de Lemos JA.. JAMA. 2013;309:2262–2269.

Acute Rise in cTn

Plaque Rupture?

Supply/Demand Mismatch?

Non ischemic Injury?

Chronic Eleva<on in cTn

Renal disease LVH Chronic CAD Advanced Age Diabetes

Type 1 MI

Follow ACS guidelines

Type 2 MI

Correct Underlying

Cause

PE, HF, myocardi<s, subarachnoid hemorrhage, etc.

High-‐Sensitivity Troponin Assays in the ED

•  The key advantage appears to be the high sensi<vity, and the high nega<ve predic<ve value

•  Very low values may be adequate to ROMI within a short <me period

•  There will be a high prevalence of false posi<ve results

•  Unclear whether hs-‐Tn lead to improved ACS outcomes

Troponin Determines BeneMit from an Early Invasive Strategy in ACS

Morrow DA. JAMA. 2001;286:2405–2412. TACTICS TIMI 18

Troponin in the General Population

Prevalence of a Detectable hs-‐cTnT in the General Population

25

75

DHS 30

70

WHS

66

34

CHS

67

33

ARIC

Age ≥ 65

Age 30-‐65 Age 51-‐63

Age 54-‐74

Evere, BM, et al. Circula2on. 2011;123:2811–2818. Saunders JT, et al. Circula2on. 2011;123:1367–1376.

de Lemos JA, et al. JAMA. 2010;304:2503–2512. Defilippi CR, et al. JAMA. 2010;304:2494–2502.

% Detectable

% Undetectable

Cardiac Troponin I Concentration in Men and Women Enrolled in JUPITER

0

2

4

6

8

10

12

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Freq

uency (%

)

High-‐Sensi(vity Troponin I Concentra(on (ng/L)

Men

Women

Median (IQR) 3.6 (2.7-‐5.3) Median (IQR) 3.1 (2.3-‐4.5)

91.9%

P<0.0001

Key Determinants of Circulating Troponin Concentrations

•  Age •  Male sex •  Black race •  LVH •  Hypertension •  Renal dysfunc<on •  Diabetes •  Exis<ng coronary artery disease •  Conges<ve heart failure

hsTnT: Primary Prevention in the Elderly

demonstrate subsequent changes incTnT at the follow-up measurement(eTable 4). The rate of new-onset HFand cardiovascular death based on thepresence or absence of a detectablecTnT on follow-up testing, stratified byinitial cTnT category, are shown ineFigure 1 and eFigure 2. The risks ofHF and cardiovascular death were

higher among those participants withdetectable compared with undetect-able levels at follow-up, irrespective ofthe baseline level.

Differentiation of risk for both endpoints could be further refined bycategorizing participants within eachcategory by a more than 50% increaseor decrease from baseline level

(FIGURE 3). Within each category, riskof HF and cardiovascular death washighest for those with an increase incTnT level of more than 50% and low-est for those with a more than 50% de-crease in cTnT level on follow-up test-ing compared with participants with achange of 50% or less. For partici-pants with measurable baseline cTnT

Figure 2. Kaplan-Meier Curves Reflecting Cumulative Proportion of Older Adults Free of Heart Failure and Without Cardiovascular Death byBaseline Cardiac Troponin T Concentration

1.0

0.8

0.4

0.6

0.2

0

No. at risk

0 3 6 9 12 15 18

Category 1 1427 1380 1281 1131 956 763 461Category 2 697 658 586 508 401 291 169Category 3 700 642 550 435 333 231 131Category 4 697 628 505 377 272 176 99Category 5 700 532 357 213 119 77 36

Follow-up Time, y

Heart failure

Pro

porti

on F

ree

of H

eart

Failu

re

Cardiac troponin T

Category 2

Category 5Category 4Category 3

Category 1

1.0

0.8

0.4

0.6

0.2Log-rank P<.001 Log-rank P<.001

0

No. at risk

0 3 6 9 12 15 18


Follow-up Time, y

Cardiovascular deathP

ropo

rtion

With

out

Car

diov

ascu

lar D

eath

Categories of cardiac troponin T concentrations were divided into category 1 (!3.00 pg/mL), category 2 (3.00-5.44 pg/mL), category 3 (5.45-8.16 pg/mL),category 4 (8.17-12.94 pg/mL), and category 5 ("12.94 pg/mL).

Table 2. Association of Baseline cTnT Concentration With Incident Heart Failure and Cardiovascular DeathcTnT Concentration, pg/mL

!3.00(n = 1427)

3.00-5.44(n = 697)

5.45-8.16(n = 700)

8.17-12.94(n = 697)

"12.94(n = 700)

Heart failure (n = 311) (n = 180) (n = 235) (n = 237) (n = 316)Incidence rate (95% CI), per 100 person-years 1.6 (1.4-1.8) 2.1 (1.8-2.4) 3.0 (2.6-3.4) 3.4 (3.0-3.8) 6.4 (5.8-7.2)Hazard ratio (95% CI)

Unadjusted 1 [Reference] 1.33 (1.11-1.60) 1.96 (1.65-2.31) 2.27 (1.91-2.69) 4.83 (4.12-5.66)Adjusted for demographic factorsa 1 [Reference] 1.21 (1.01-1.46) 1.71 (1.44-2.03) 1.79 (1.50-2.14) 3.52 (2.95-4.21)Adjusted for demographic and traditional risk factorsb 1 [Reference] 1.13 (0.93-1.36) 1.41 (1.18-1.69) 1.47 (1.22-1.77) 2.48 (2.04-3.00)Adjusted for demographic factors, traditional risk factors,

and NT-proBNP and CRP1 [Reference] 1.09 (0.90-1.32) 1.27 (1.06-1.52) 1.24 (1.03-1.50) 1.84 (1.51-2.24)

Cardiovascular death (n = 222) (n = 153) (n = 204) (n = 239) (n = 285)Incidence rate (95% CI), per 100 person-years 1.1 (0.9-1.2) 1.6 (1.4-1.9) 2.3 (2.0-2.7) 3.0 (2.6-3.4) 4.8 (4.3-5.4)Hazard ratio (95% CI)

Unadjusted 1 [Reference] 1.59 (1.30-1.96) 2.34 (1.93-2.82) 3.14 (2.61-3.77) 5.93 (4.96-7.08)Adjusted for demographic factorsa 1 [Reference] 1.41 (1.14-1.73) 1.92 (1.58-2.33) 2.24 (1.84-2.71) 3.80 (3.12-4.64)Adjusted for demographic and traditional risk factorsc 1 [Reference] 1.35 (1.10-1.67) 1.66 (1.36-2.02) 1.91 (1.57-2.33) 2.91 (2.37-3.58)Adjusted for demographic factors, traditional risk factors,


Abbreviations: CI, confidence interval; CRP, C-reactive protein; cTnT, cardiac troponin T; NT-proBNP, N-terminal pro-type B natriuretic peptide.aAdjusted for age, sex, and race (black vs other).bAdjusted for demographic factors and systolic blood pressure, serum glucose, coronary heart disease, smoking status (never, current, former), creatinine, albumin, heart rate, and left

ventricle hypertrophy by electrocardiogram.cAdjusted for demographic factors and systolic and diastolic blood pressure, antihypertensive medications, coronary heart disease, smoking status (never, current, former), diabetes, and

total and high-density lipoprotein cholesterol.

SENSITIVE CARDIAC TROPONIN T IN OLDER ADULTS

©2010 American Medical Association. All rights reserved. (Reprinted) JAMA, Published online November 15, 2010 E5

by guest on November 16, 2010 www.jama.comDownloaded from

demonstrate subsequent changes incTnT at the follow-up measurement(eTable 4). The rate of new-onset HFand cardiovascular death based on thepresence or absence of a detectablecTnT on follow-up testing, stratified byinitial cTnT category, are shown ineFigure 1 and eFigure 2. The risks ofHF and cardiovascular death were

higher among those participants withdetectable compared with undetect-able levels at follow-up, irrespective ofthe baseline level.

Differentiation of risk for both endpoints could be further refined bycategorizing participants within eachcategory by a more than 50% increaseor decrease from baseline level

(FIGURE 3). Within each category, riskof HF and cardiovascular death washighest for those with an increase incTnT level of more than 50% and low-est for those with a more than 50% de-crease in cTnT level on follow-up test-ing compared with participants with achange of 50% or less. For partici-pants with measurable baseline cTnT

Figure 2. Kaplan-Meier Curves Reflecting Cumulative Proportion of Older Adults Free of Heart Failure and Without Cardiovascular Death byBaseline Cardiac Troponin T Concentration

1.0

0.8

0.4

0.6

0.2

0

No. at risk

0 3 6 9 12 15 18


Follow-up Time, y

Heart failureP

ropo

rtion

Fre

e of

Hea

rt Fa

ilure

Cardiac troponin T

Category 2

Category 5Category 4Category 3

Category 1

1.0

0.8

0.4

0.6

0.2Log-rank P<.001 Log-rank P<.001

0

No. at risk

0 3 6 9 12 15 18


Follow-up Time, y

Cardiovascular death

Pro

porti

on W

ithou

tC

ardi

ovas

cula

r Dea

th

Categories of cardiac troponin T concentrations were divided into category 1 (!3.00 pg/mL), category 2 (3.00-5.44 pg/mL), category 3 (5.45-8.16 pg/mL),category 4 (8.17-12.94 pg/mL), and category 5 ("12.94 pg/mL).

Table 2. Association of Baseline cTnT Concentration With Incident Heart Failure and Cardiovascular DeathcTnT Concentration, pg/mL

!3.00(n = 1427)

3.00-5.44(n = 697)

5.45-8.16(n = 700)

8.17-12.94(n = 697)

"12.94(n = 700)

Heart failure (n = 311) (n = 180) (n = 235) (n = 237) (n = 316)Incidence rate (95% CI), per 100 person-years 1.6 (1.4-1.8) 2.1 (1.8-2.4) 3.0 (2.6-3.4) 3.4 (3.0-3.8) 6.4 (5.8-7.2)Hazard ratio (95% CI)

Unadjusted 1 [Reference] 1.33 (1.11-1.60) 1.96 (1.65-2.31) 2.27 (1.91-2.69) 4.83 (4.12-5.66)Adjusted for demographic factorsa 1 [Reference] 1.21 (1.01-1.46) 1.71 (1.44-2.03) 1.79 (1.50-2.14) 3.52 (2.95-4.21)Adjusted for demographic and traditional risk factorsb 1 [Reference] 1.13 (0.93-1.36) 1.41 (1.18-1.69) 1.47 (1.22-1.77) 2.48 (2.04-3.00)Adjusted for demographic factors, traditional risk factors,


Cardiovascular death (n = 222) (n = 153) (n = 204) (n = 239) (n = 285)Incidence rate (95% CI), per 100 person-years 1.1 (0.9-1.2) 1.6 (1.4-1.9) 2.3 (2.0-2.7) 3.0 (2.6-3.4) 4.8 (4.3-5.4)Hazard ratio (95% CI)

Unadjusted 1 [Reference] 1.59 (1.30-1.96) 2.34 (1.93-2.82) 3.14 (2.61-3.77) 5.93 (4.96-7.08)Adjusted for demographic factorsa 1 [Reference] 1.41 (1.14-1.73) 1.92 (1.58-2.33) 2.24 (1.84-2.71) 3.80 (3.12-4.64)Adjusted for demographic and traditional risk factorsc 1 [Reference] 1.35 (1.10-1.67) 1.66 (1.36-2.02) 1.91 (1.57-2.33) 2.91 (2.37-3.58)Adjusted for demographic factors, traditional risk factors,


Abbreviations: CI, confidence interval; CRP, C-reactive protein; cTnT, cardiac troponin T; NT-proBNP, N-terminal pro-type B natriuretic peptide.aAdjusted for age, sex, and race (black vs other).bAdjusted for demographic factors and systolic blood pressure, serum glucose, coronary heart disease, smoking status (never, current, former), creatinine, albumin, heart rate, and left

ventricle hypertrophy by electrocardiogram.cAdjusted for demographic factors and systolic and diastolic blood pressure, antihypertensive medications, coronary heart disease, smoking status (never, current, former), diabetes, and

total and high-density lipoprotein cholesterol.

SENSITIVE CARDIAC TROPONIN T IN OLDER ADULTS

©2010 American Medical Association. All rights reserved. (Reprinted) JAMA, Published online November 15, 2010 E5

by guest on November 16, 2010 www.jama.comDownloaded from

<3 ng/L

>13 ng/L

Defilippi CR, et al. JAMA. 2010;304:2494–2502.

High-‐Sensitivity cTnT and the Risk of CHD: ARIC

Prediction of Fatal CHD + MI: NRI 10%, IDI 0.032, AUC 0.014 (All significantly improved)

Saunders JT, et al. Circula2on. 2011;123:1367–1376.

population and in women; in men, all parameters except forNRI for all CHD were significantly improved (Table 3).Improvements in statistical parameters for hard CHD predic-tion were generally better than for all CHD. Calibration of the

models assessed by the Grønnesby-Borgan test indicatedimproved model fit with the addition of cTnT for hard CHDin the overall group and for all CHD in women. For mortalityand HF hospitalization, adding cTnT to the base model

Figure 2. Age-, race-, and gender-adjusted survival curves assessing the time to incident CHD (A), death (B), and HF hospitalization (C)across cardiac troponin T (cTnT) categories. CHD indicates coronary heart disease; hs-cTnT, highly sensitive cTnT assay; and HF, heart failure.

Saunders et al High-Sensitivity Troponin T Predicts Risk in ARIC 1371

at Harvard University on March 28, 2011 circ.ahajournals.orgDownloaded from

0.0 0.5 1.0 1.5 2.0 2.5

0.00

0.01

0.02

0.03

0.04

Years

Cum

ulat

ive

Inci

denc

ehsTnI tertile 1hsTnI tertile 2hsTnI tertile 3

First Major Cardiovascular Event

Log-rank P<0.0001

First major cardiovascular event according to baseline tertile of high-‐sensitivity cardiac troponin I: JUPITER

Evere, BM et al. Circula2on. 2015;131:1851

Adjusted HR for T3 vs. T1: 2.19 (1.56–3.06) P<0.0001

1.00

0.90

Adjusted Risk of a Mirst cardiovascular event according to baseline hsTnI: subgroups

SubgroupAge 70+Age <70 MenWomen WhiteNon white Current smokersNon smokers HypertensionNo hypertension BMI <25BMI 25 to <30BMI 30+ Metabolic syndromeNo metabolic syndrome HDL lowHDL normal LDL 100+LDL <100 hsCRP 5+hsCRP<5 Triglycerides 150+Triglyderides <150 Summary BNP Age 70+Age <70 MenWomen WhiteNon white Current smokersNon smokers HypertensionNo hypertension BMI <25BMI 25 to <30BMI 30+ Metabolic syndromeNo metabolic syndrome HDL lowHDL normal LDL 100+LDL <100 hsCRP 5+hsCRP <5 Triglycerides 150+Triglyderides <150 Summary hsTnI

Participants34317626

70214036

90082049

16889364

61964855

244044654123

44256527

32357821

74983557

42416816

34937563

11057

40858871

82604696

105942362

195210999

72085742

283752204869

52197626

38429113

88064148

50927864

41528803

12956

Events121115

16868

20630

48188

15581

6110668

91143

70166

15482

103133

79157

236

150154

22183

26440

63241

198106

7813194

127175

99205

199105

137167

113191

304

Tertile 10.940.58

0.750.38

0.670.52

0.850.61

0.720.58

0.660.820.48

0.790.55

0.670.64

0.640.66

0.70.62

0.940.47

0.65

0.870.49

0.610.47

0.560.59

0.880.5

0.70.46

0.740.6

0.41

0.710.48

0.760.48

0.450.76

0.530.58

0.930.39

0.56

Tertile 21.420.58

1.110.63

0.940.47

1.210.81

1.190.46

1.010.910.73

0.740.96

1.040.79

0.90.77

0.890.85

0.890.85

0.86

1.260.72

1.070.6

0.940.64

1.310.85

0.950.85

1.141.040.64

0.721.03

0.870.92

0.861

1.030.83

1.030.84

0.9

Tertile 32.231.26

1.831.55

1.751.63

2.791.58

1.891.48

1.981.861.38

1.541.82

1.741.73

1.592

2.111.48

1.541.8

1.73

2.271.32

1.91.42

1.751.66

2.811.58

1.921.38

2.11.8

1.48

1.771.72

1.851.69

1.681.86

2.051.51

1.651.78

1.74

0.5 1.0 2.0 4.0 8.0

Figure 2

Adjusted Hazard Ratio for Tertile 3 vs. Tertile 1 of hsTnI

Incidence Rate*

Subgroup Participants Events Tertile 1 Tertile 2 Tertile 3

1.00

0.50

0.60

0.70

0.60 1.90

2.10 1.80

0.90


Summary HR 2.19 (1.56–3.06)

Improvements in Risk Prediction: ARIC Base model Base model + hsTnT Base model + hsCRP

CHD death and nonfatal MI*

AUC 0.710 0.724 0.714

NRI 10.1% 3.0%

All-‐cause mortality†

AUC 0.719 0.740 0.723

NRI 10.7% 2.5%

Heart failure†

AUC 0.749 0.777 0.752

NRI 15.4% 2.9%

Saunders JT, et al. Circula2on. 2011;123:1367–1376. Slide courtesy of James de Lemos

* CHD base model: ARIC coronary risk score †Base model for total mortality and heart failure: ARIC Coronary Risk Score + BMI + LVH + crea<nine -‐ Results from BiomarCaRE, a study of >90,000 pa<ents without preexis<ng CVD are in submission

Hammers, nails, and personalized medicine

Risk factors

Sta<n Algorithm

Yes Sta<n No Sta<n

•  Are troponins (or other biomarkers) only useful if they improve the performance of exis<ng algorithms?

•  Or, are there specific therapies that should be u<lized in pa<ents with abnormal troponin?

Absolute and Relative Risk Reductions in the JUPITER Primary Endpoint by hsTnI Category at Baseline

0.42

0.68

1.17

0.71

1.13

2.29

0.0

0.5

1.0

1.5

2.0

2.5

Ter<le 1 Ter<le 2 Ter<le 3

Incide

nce Ra

te per 100 person years

Rosuvasta<n

Placebo

RRR 0.6 (0.3-‐1.0) RRR 0.6 (0.4-‐0.9) RRR 0.5 (0.4-‐0.7)

NNT 5yrs = 18 NNT 5yrs = 45 NNT 5 yrs = 67


Sex-‐specific High-‐Sensi(vity Cardiac Troponin I Ter(le

P for interac<on between rosuvasta<n and hsTnI ter<le = 0.53

Absolute and Relative Risk Reductions in the JUPITER Primary Endpoint by Framingham Risk Score at Baseline


0.30

0.60

1.05

0.49

0.94

2.05

0.0

0.5

1.0

1.5

2.0

2.5

≤5% >5 to ≤10% >10%

Incide

nce Ra

te per 100 person years

Rosuvasta<n

Placebo

RRR 0.6 (0.3-‐1.4) RRR 0.7 (0.4-‐1.1) RRR 0.5 (0.4-‐0.7)

Framingham Risk Score 10-‐year Risk of CHD

P for interac<on between rosuvasta<n and FRS = 0.40

NNT 5yrs = 20 NNT 5yrs = 59 NNT 5 yrs = 103

Troponin in the General Population

•  Troponin is a strong marker of increased risk for major cardiovascular events and mortality

•  Troponin is a non-‐specific marker of myocardial injury

•  Troponin could be used to iden<fy a high risk group for higher risk or more expensive therapy

Troponin and SpeciMic Therapies

•  Troponins iden<fy pa<ents with acute coronary syndromes who benefit from coronary revasculariza<on

•  Could troponin also iden<fy a group of pa<ents with stable ischemic heart disease who would benefit coronary revasculariza<on?

Stable Ischemic Heart Disease

Stable Ischemic Heart Disease •  Pa<ents with stable ischemic heart disease and diabetes frequently have abnormal cardiac troponin levels

•  Elevated cardiac troponin concentra<ons are a strong predictor of major CV events and death

•  Could these markers be used to iden<fy pa<ents who would benefit from coronary revasculariza<on, just as they have in pa<ents with ACS?

Troponin Determines BeneMit from an Early Invasive Strategy in ACS

Morrow DA. JAMA. 2001;286:2405–2412. TACTICS TIMI 18

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 373;7 nejm.org August 13, 2015610

From the Divisions of Cardiovascular Medicine (B.M.E., D.L.B.) and Preventive Medicine (B.M.E.), Brigham and Women’s Hospital and Harvard Medical School, Boston; the Department of Epidemiology and Graduate School of Public Health, Uni-versity of Pittsburgh, Pittsburgh (M.M.B., H.E.A.V.); Center for Cardiovascular Care, Saint Louis University School of Medi-cine, St. Louis (B.R.C.); and the Depart-ment of Medicine, Division of Cardiovas-cular Diseases, Mayo Clinic, Rochester, MN (R.L.F.). Address reprint requests to Dr. Everett at Brigham and Women’s Hos-pital, 75 Francis St., Boston, MA 02115, or at beverett@ partners . org.

* A complete list of investigators in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) Study Group is provided in the Supplementary Appendix, available at NEJM.org.

N Engl J Med 2015;373:610-20.DOI: 10.1056/NEJMoa1415921Copyright © 2015 Massachusetts Medical Society.

BACKGROUNDCardiac troponin concentrations are used to identify patients who would benefit from urgent revascularization for acute coronary syndromes. We hypothesized that they might be used in patients with stable ischemic heart disease to identify those at high risk for cardiovascular events who might also benefit from prompt coro-nary revascularization.

METHODSWe measured the cardiac troponin T concentration at baseline with a high-sensi-tivity assay in 2285 patients who had both type 2 diabetes and stable ischemic heart disease and were enrolled in the Bypass Angioplasty Revascularization In-vestigation in Type 2 Diabetes trial. We tested for an association between the troponin T concentration and a composite end point of death from cardiovascular causes, myocardial infarction, or stroke; we then evaluated whether random as-signment to prompt revascularization reduced the rate of the composite end point in patients with an abnormal troponin T concentration (≥14 ng per liter) as com-pared with those with a normal troponin T concentration (<14 ng per liter).

RESULTSOf the 2285 patients, 2277 (99.6%) had detectable (≥3 ng per liter) troponin T con-centrations and 897 (39.3%) had abnormal troponin T concentrations at baseline. The 5-year rate of the composite end point was 27.1% among the patients who had had abnormal troponin T concentrations at baseline, as compared with 12.9% among those who had had normal baseline troponin T concentrations. In models that were adjusted for cardiovascular risk factors, severity of diabetes, electrocar-diographic abnormalities, and coronary anatomy, the hazard ratio for the compos-ite end point among patients with abnormal troponin T concentrations was 1.85 (95% confidence interval [CI], 1.48 to 2.32; P<0.001). Among patients with abnor-mal troponin T concentrations, random assignment to prompt revascularization, as compared with medical therapy alone, did not result in a significant reduction in the rate of the composite end point (hazard ratio, 0.96; 95% CI, 0.74 to 1.25).

CONCLUSIONSThe cardiac troponin T concentration was an independent predictor of death from cardiovascular causes, myocardial infarction, or stroke in patients who had both type 2 diabetes and stable ischemic heart disease. An abnormal troponin T value of 14 ng per liter or higher did not identify a subgroup of patients who benefited from random assignment to prompt coronary revascularization. (Funded by the National Institutes of Health and Roche Diagnostics; BARI 2D ClinicalTrials.gov number, NCT00006305.)

A BS TR AC T

Troponin and Cardiac Events in Stable Ischemic Heart Disease and Diabetes

Brendan M. Everett, M.D., M.P.H., Maria Mori Brooks, Ph.D., Helen E.A. Vlachos, M.S., Bernard R. Chaitman, M.D., Robert L. Frye, M.D.,

and Deepak L. Bhatt, M.D., M.P.H., for the BARI 2D Study Group*

Original Article

The New England Journal of Medicine Downloaded from nejm.org at Harvard Library on August 12, 2015. For personal use only. No other uses without permission.


Evere, BM. N Engl J Med. 2015;373:610

BARI 2D: Trial Schema Type 2 diabetes and stable ischemic heart

disease

PCI most appropriate N=1605

CABG most appropriate N=763

Prompt revasculariza<on plus intensive medical therapy

N=1176

Intensive medical therapy Alone N=1192

Randomiza<on

BARI 2D Study Group, Frye RL. NEJM 2009;360:2503

MI, stroke, CV death: HR 0.98 (0.80 to 1.19)

0.0

2.0

9.0

14.8 14.8

11.7

8.5

7.1

4.4

3.5 3.0 3.0

2.1 1.7 1.6

1.1 1.1 0.7 0.9 0.5 0.7 0.5

7.3

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

[0-2) [4-6) [8-10) [12-14) [16-18) [20-22) [24-26) [28-30) [32-34) [36-38) [40-42) >=44

Perc

ent

Baseline Cardiac Troponin Concentration (ng/L) - BARI 2D

2277/2285 (99.6%) ≥ 3 ng/L hsTnT 95th percentile: 60.6 ng/L hsTnT 99th percentile: 309.4 ng/L hsTnT maximum: 3308.0 ng/L

Abnormal (hsTnT ≥ 14) N = 897 (39.3%)

Normal (hsTnT<14) N = 1388 (60.7%)

High Sensitivity Cardiac Troponin T (ng/L)

Five-‐Year Rate of Myocardial Infarction, Stroke, or Cardiovascular Death StratiMied by Baseline Cardiac Troponin T




cause, myocardial infarction, stroke, or heart failure (Fig. 3B) was significantly higher in those who had an increase of more than 25% in tro-ponin T concentration from baseline to 1 year, as compared with those who had an increase or

decrease of 25% or less and with those who had a decrease of more than 25%. In adjusted mod-els, in which an increase or decrease in troponin T concentration of 25% or less was considered the reference category, both baseline troponin T concentration and an increase of more than 25% in troponin T concentration were independent predictors of the primary composite end point and the secondary composite end point (Table S11 in the Supplementary Appendix).

Discussion

In this study involving patients with both type 2 diabetes and stable ischemic heart disease, base-line cardiac troponin T concentrations above the upper limit of normal were associated with ap-proximately a doubling of the risks of myocar-dial infarction, stroke, heart failure, death from cardiovascular causes, and death from any cause. Nearly 40% of the patients in our study had a high-sensitivity cardiac troponin T concentra-tion at baseline that was above the upper refer-ence limit used to define myocardial injury. The incidence of the primary composite end point of death from cardiovascular causes, myocardial infarction, or stroke at 5 years in this group was 27%, which was double the rate in the group with normal baseline troponin T concentrations. Similar results were seen with respect to other important outcomes, such as the secondary composite outcome of death from any cause, myocardial infarction, stroke, or heart failure. The addition of prompt coronary revasculariza-tion to intensive medical therapy did not im-prove the outcome in these patients. Despite aggressive medical therapy for type 2 diabetes and stable ischemic heart disease, the median troponin T concentration increased over 1 year of follow-up, and no significant reductions in troponin T concentrations were observed in pa-tients who underwent coronary revasculariza-tion. Finally, the patients in the BARI 2D trial who had an increase of more than 25% in tro-ponin T concentration from baseline to the 1-year follow-up had a worse outcome than those who had a stable or decreasing troponin T concentration.

The strength of the relationship between tro-ponin T concentration and the subsequent risk

Figure 1. Unadjusted Kaplan–Meier Estimates of Adverse Outcomes over 5 Years.

The primary end point (Panel A) was a composite of death from cardiovascu-lar causes, myocardial infarction, or stroke. Death from any cause (Panel B) was a secondary end point. Data are shown for patients with an abnormal high-sensitivity cardiac troponin T level (≥14 ng per liter) at baseline, as compared with those with a normal level (<14 ng per liter) at baseline, who were enrolled in the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2D) trial.

Even

t Rat

e (%

)

100

80

60

40

20

00 12 24 36 48 60

Months since Randomization

A 5-Yr Rate of Primary Composite End Point

P<0.001

No. at RiskTroponin T

≥14 ng/literTroponin T

<14 ng/liter

897

1388

737

1281

684

1229

620

1124

455

892

255

529

Troponin T ≥14 ng/liter

Troponin T <14 ng/liter

27.1

12.9

Even

t Rat

e (%

)

100

80

60

40

20

00 12 24 36 48 60

Months since Randomization

B 5-Yr Rate of Death from Any Cause

P<0.001

No. at RiskTroponin T

≥14 ng/literTroponin T

<14 ng/liter

897

1388

847

1370

813

1355

787

1334

665

1160

406

739

Troponin T ≥14 ng/liter

Troponin T <14 ng/liter

19.6

7.1



Five-‐Year Rate of Myocardial Infarction, Stroke, Heart Failure, or Death StratiMied by Baseline Cardiac Troponin T


! 21

!Figure S6. Unadjusted Kaplan-Meier estimates of 5-year death/myocardial infarction (MI)/stroke/congestive heart failure (CHF) rates for BARI 2D subjects with an abnormal high sensitivity cardiac troponin T (hsTnT≥ 14 ng/L) at baseline compared to those with a normal hsTnT (<14 ng/L) at baseline. !! !

0

0.2

0.4

0.6

0.8

1

0 12 24 36 48 60

Eve

nt R

ate

Months from randomization

hsTnT ≥14 hsTnT <14

Figure S6- Five year Death/MI/Stroke/CHF Rates for BARI 2D Patients Stratified by Baseline hsTnT

45.0% 22.2%

P-value=0.0001

No. at Risk

hsTnT ≥14 895 718 646 588 473 269

hsTnT <14 1388 1272 1221 1160 989 605

Random Allocation to Prompt Coronary Revascularization Does Not BeneMit Patients with Abnormal Troponin T




known coronary anatomy, stable coronary heart disease, diabetes, and abnormal troponin T con-centration did not benefit from percutaneous coronary intervention, and the potential benefit of coronary-artery bypass grafting was the same regardless of baseline troponin T concentration. These results, when viewed in the context of other trials involving patients with chronic sta-ble angina, emphasize the importance of taking a detailed history in distinguishing stable from unstable coronary heart disease and support initial medical therapy as a reasonable first ap-proach in patients who do not have unstable coronary artery disease.11,19,20 The high preva-lence of abnormal troponin T concentration, at least according to the established threshold of 14 ng per liter, raises the possibility that the

widespread use of this assay in populations similar to the population enrolled in the BARI 2D trial could lead to an increase in the use of revascularization procedures that, on the basis of our findings, appear to offer little benefit with respect to the reduction of key outcomes, including a composite of death from any cause, myocardial infarction, stroke, or heart failure. However, increasing the threshold at which troponin T concentration would be considered abnormal ignores the risk of adverse cardiovas-cular outcomes in patients with troponin T concentrations between 14 and 23 ng per liter, for whom there was also no evident benefit of revascularization.

Revascularization did not appear to reduce the proportion of patients who had an abnormal

Figure 2. Hazard Ratios for the Primary Composite End Point and Selected Secondary End Points.

Data are shown for the patients who were randomly assigned to either prompt revascularization plus intensive medical therapy (revascu-larization group) or intensive medical therapy alone (medical-therapy group), stratified according to a normal (<14 ng per liter) or an ab-normal (≥14 ng per liter) high-sensitivity cardiac troponin T concentration at baseline. The size of the boxes is proportional to the size of the subgroups.

0.50 1.00 2.00 4.00

Medical TherapyBetter

RevascularizationBetter

Death from cardiovascular causes,myocardial infarction, or stroke

Troponin T <14 ng/literTroponin T ≥14 ng/liter

Death from cardiovascular causesTroponin T <14 ng/literTroponin T ≥14 ng/liter

Myocardial infarctionTroponin T <14 ng/literTroponin T ≥14 ng/liter

StrokeTroponin T <14 ng/literTroponin T ≥14 ng/liter

Death from any causeTroponin T <14 ng/literTroponin T ≥14 ng/liter

Heart failureTroponin T <14 ng/literTroponin T ≥14 ng/liter

Death from any cause, myocardialinfarction, stroke, or heart failure


RevascularizationGroup Hazard Ratio (95% CI)

Medical-TherapyGroupSubgroup

1.03 (0.83–1.29)0.87 (0.71–1.05)

0.87 (0.67–1.13)1.07 (0.78–1.47)

1.06 (0.80–1.39)0.77 (0.53–1.14)

1.03 (0.51–2.05)0.87 (0.43–1.77)

0.94 (0.66–1.35)0.72 (0.52–1.00)

1.27 (0.85–1.91)0.63 (0.34–1.14)

0.96 (0.71–1.30)

0.25

0.96 (0.74–1.25)

P Value forHeterogeneity

11.826.5

2.611.7

8.215.6

2.14.6

6.419.4

11.523.8

22.342.2

14.027.6

4.410.1

10.121.7

2.54.2

7.719.8

10.727.6

22.247.8

0.99

0.05

0.28

0.75

0.20

0.32

0.24

5-yr event rate (%)





known coronary anatomy, stable coronary heart disease, diabetes, and abnormal troponin T con-centration did not benefit from percutaneous coronary intervention, and the potential benefit of coronary-artery bypass grafting was the same regardless of baseline troponin T concentration. These results, when viewed in the context of other trials involving patients with chronic sta-ble angina, emphasize the importance of taking a detailed history in distinguishing stable from unstable coronary heart disease and support initial medical therapy as a reasonable first ap-proach in patients who do not have unstable coronary artery disease.11,19,20 The high preva-lence of abnormal troponin T concentration, at least according to the established threshold of 14 ng per liter, raises the possibility that the

widespread use of this assay in populations similar to the population enrolled in the BARI 2D trial could lead to an increase in the use of revascularization procedures that, on the basis of our findings, appear to offer little benefit with respect to the reduction of key outcomes, including a composite of death from any cause, myocardial infarction, stroke, or heart failure. However, increasing the threshold at which troponin T concentration would be considered abnormal ignores the risk of adverse cardiovas-cular outcomes in patients with troponin T concentrations between 14 and 23 ng per liter, for whom there was also no evident benefit of revascularization.

Revascularization did not appear to reduce the proportion of patients who had an abnormal

Figure 2. Hazard Ratios for the Primary Composite End Point and Selected Secondary End Points.

Data are shown for the patients who were randomly assigned to either prompt revascularization plus intensive medical therapy (revascu-larization group) or intensive medical therapy alone (medical-therapy group), stratified according to a normal (<14 ng per liter) or an ab-normal (≥14 ng per liter) high-sensitivity cardiac troponin T concentration at baseline. The size of the boxes is proportional to the size of the subgroups.

0.50 1.00 2.00 4.00

Medical TherapyBetter

RevascularizationBetter

Death from cardiovascular causes,myocardial infarction, or stroke


Death from cardiovascular causesTroponin T <14 ng/literTroponin T ≥14 ng/liter

Myocardial infarctionTroponin T <14 ng/literTroponin T ≥14 ng/liter

StrokeTroponin T <14 ng/literTroponin T ≥14 ng/liter

Death from any causeTroponin T <14 ng/literTroponin T ≥14 ng/liter

Heart failureTroponin T <14 ng/literTroponin T ≥14 ng/liter

Death from any cause, myocardialinfarction, stroke, or heart failure


RevascularizationGroup Hazard Ratio (95% CI)

Medical-TherapyGroupSubgroup

1.03 (0.83–1.29)0.87 (0.71–1.05)

0.87 (0.67–1.13)1.07 (0.78–1.47)

1.06 (0.80–1.39)0.77 (0.53–1.14)

1.03 (0.51–2.05)0.87 (0.43–1.77)

0.94 (0.66–1.35)0.72 (0.52–1.00)

1.27 (0.85–1.91)0.63 (0.34–1.14)

0.96 (0.71–1.30)

0.25

0.96 (0.74–1.25)

P Value forHeterogeneity

11.826.5

2.611.7

8.215.6

2.14.6

6.419.4

11.523.8

22.342.2

14.027.6

4.410.1

10.121.7

2.54.2

7.719.8

10.727.6

22.247.8

0.99

0.05

0.28

0.75

0.20

0.32

0.24

5-yr event rate (%)



Summary: Troponin in Stable Heart Disease

•  Troponin is a strong predictor of major cardiovascular events and mortality

•  A substan<al propor<on of pa<ents with stable heart disease and diabetes have values that are high enough to meet the “MI threshold”

•  Revasculariza<on does not appear to mi<gate the CV risk associated with an elevated troponin

Summary and Conclusions (1)

•  High sensi<vity assays for cardiac troponin are in rou<ne clinical use in Europe and Asia, and are likely to be approved for use in the US soon

•  These assays can oxen detect circula<ng cardiac troponin even in healthy adults

•  Cardiac troponin is a non-‐specific marker of myocardial injury and adverse prognosis

Summary and Conclusions (2)

•  Hs-‐cTn assays may shorten the <me required to rule out MI, but may have serious downstream consequences in increased tes<ng and cardiology consulta<on

•  Cardiac troponin is a marker of adverse prognosis regardless of the e<ology of its release

Summary and Conclusions (2) •  Cardiac troponin assays are promising for risk

assessment in the ambulatory seyng – Modest improvement in risk predic<on in primary preven<on

–  Iden<fy pa<ents at high risk in secondary preven<on

•  Troponin may provide a novel means of monitoring disease ac<vity

•  Iden<fied popula<ons may be amenable to preven<ve interven<on

Summary and Conclusions (3) •  Outside of ACS, no interven<on that specifically benefits pa<ents with abnormal troponin has been iden<fied

•  Sta<ns and revasculariza<on do not appear to directly target troponin-‐associated risk

•  Troponin’s lack of pathophysiologic specificity may actually make it a be,er marker of general cardiovascular risk

Acknowledgements BWH Paul Ridker Peter Libby Pat O’Gara Deepak Bha, Calum MacRae Aruna Pradhan Samia Mora Nina Paynter Nancy Cook Bob Glynn David Conen

UT Southwestern James de Lemos Univ of Hamburg-‐Eppendorf Stefan Blankenberg Tanja Zeller BARI 2D Maria Brooks Bernard Chaitman Helen Vlachos Robert Frye

Thank you! Brendan M. Evere,, MD, MPH Director, General Cardiology Inpa2ent Service Assistant Professor of Medicine, Harvard Medical School

www.brighamandwomens.org/heart

Cardiac Troponin and Treatment for Conservatively Managed ACS: PLATO Trial

296 Circulation January 21, 2014

congestive heart failure, peripheral arterial disease, previous MI, pre-vious PCI, previous CABG, ST depression in ECG at entry, and the declaration of planned invasive or noninvasive treatment at random-ization were included. The results from the models were presented as estimated hazard ratios, with 95% confidence intervals, of the treat-ment effect of ticagrelor using clopidogrel as reference. The treatment hazard ratios were reported for each level of the biomarker, regardless of the significance of interaction. The proportional hazards assump-tion, with respect to the cardiac biomarkers, was assessed by visual inspection of log-cumulative hazard plots. Kaplan-Meier curves were estimated for the time to event for each cutoff range of the biomarker and the log-rank test was calculated. All analyses were performed by using SAS version 9.2. A P value of 0.05 was used as a critical value determining statistical significance, and there were no adjustments for multiple comparisons.

ResultsIn the PLATO trial, 9946 patients had an entry diagnosis of NSTE-ACS and provided plasma samples for analyses of all biomarkers, allowing inclusion in the present study. Baseline characteristics by randomized treatment and management strategy are shown in the Table. The randomized treat-ment groups were balanced within the respective in-hospital

invasively and noninvasively managed patients, with the exception that there were somewhat more smokers in the clop-idogrel group in the in-hospital noninvasive arm. As expected, there were differences in characteristics in relation to the in-hospital invasive or noninvasive treatment. Patients treated invasively were more often male and habitual smokers, and reported less hypertension, diabetes mellitus, previous angina pectoris, MI, heart failure and stroke, but more often previous PCI. At entry, the invasively managed patients less often had ST-segment depression but more often had troponin elevation and higher Thrombolysis in Myocardial Infarction NSTE-ACS risk score.

Biomarkers and Effects of Ticagrelor in the In-Hospital Noninvasive GroupIn patients managed without revascularization, hs-TnT levels were significantly related to the rate of the primary composite end point of CV death, MI, and stroke (log-rank P<0.001), driven by associations both with CV death and spontaneous MI (Figures 1 and 2) corresponding mainly to type 1 to 3 MI

Figure 1. Efficacy of ticagrelor relative clopidogrel on CV death, MI, and stroke in relation to predefined levels of biomarkers at baseline in the in-hospital noninvasive group. Cox proportional hazards model with biomarker level, treatment, interaction between treatment and biomarker level and established risk factors as covariates. Established risk factors in the model are sex, diabetes mellitus, smoking status, hypertension, congestive heart failure, peripheral arterial disease, previous MI, previous PCI, previous CABG, ST-depression in ECG at entry, and the declaration of planned invasive or noninvasive treatment at randomization. CABG indicates coronary artery bypass grafting; CI, confidence interval; CV, cardiovascular; GDF-15, growth differentiation factor-15; HR, hazard ratio; hs-TnT, high-sensitivity troponin T; MI, myocardial infarction; NT-proBNP, N-terminal pro-brain natriuretic peptide; and PCI, percutaneous coronary intervention.

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Packer et al Angiotensin Neprilysin Inhibition in Heart Failure 59

have primarily reported improvements in exercise tolerance or functional class or decreases in the risk of hospitaliza-tion for heart failure.28–30 In the few trials that have reported worsening of symptoms, quality of life, or functional class, active treatments produced a meaningful reduction in the risk of clinical worsening only when missing data were imputed or when patients who died were included in the analysis and assigned the worst possible score.29,31–33 In contrast, the PARADIGM-HF study is among the first trials to demon-strate a reduction of clinical worsening of surviving patients, which is not only of paramount importance to those afflicted with the disease and their families, but also to the physicians

who care for them and the insurers who pay for the intensifi-cation of treatments. The advantage of LCZ696 over enalapril in preventing clinical deterioration was apparent early in the trial and persisted for the duration of double-blind therapy.

Our clinical findings are supported by the effects on biomarkers measured in surviving patients in the trial. As expected from neprilysin inhibition,34 levels of both urinary cyclic GMP and plasma BNP were higher during treatment with LCZ696 than with enalapril; the increases in cyclic GMP reflect the fact that the peptides whose levels are enhanced by neprilysin inhibition act through enhancement of cyclic GMP.35–37 In contrast, in comparison with enalapril, patients receiving LCZ696 had consistently lower levels of NTproBNP (reflecting reduced cardiac wall stress) and tro-ponin (reflecting reduced cardiac injury) throughout the trial. The contrasting effects of LCZ696 on the 2 types of natri-uretic peptides represents an important finding, because the levels of the 2 peptides characteristically parallel each other during the course of heart failure.38 However, because BNP (but not NTproBNP) is a substrate for neprilysin,39 levels of BNP will reflect the action of the drug, whereas levels of NTproBNP will reflect the effects of the drug on the heart. Furthermore, although differences in the levels of troponin between the 2 treatment groups were small, even very low levels of troponin release are believed to reflect ongoing myo-cardial injury (possibly related to increased wall stress),40 and even small increases in the levels of troponin reflect a higher risk of disease progression in heart failure.41,42

In conclusion, in comparison with guideline-recommended doses of an ACE inhibitor, combined inhibition of both the angiotensin receptor and neprilysin was more effective not only in reducing all-cause and cardiovascular mortality,12 but also in reducing the risks and rates of multiple manifestations of clinical deterioration of surviving patients with heart fail-ure. The effect of LCZ696 to stabilize the course of heart fail-ure is likely to have important ramifications for both quality of life and resource utilization in this disorder.

Sources of Funding The study was funded by Novartis.

DisclosuresAll authors have consulted for or received research support from Novartis, sponsor of the PARADIGM-HF trial. Dr Packer has con-sulted for Novartis, Pfizer, Sanofi, Cytokinetics, Cardiokinetix, BioControl, Janssen, Amgen, CardioMEMS, and Cardiorentis. Prof McMurray’s employer, University of Glasgow, was paid by Novartis for Prof McMurray’s time spent as cochairman of the PARADIGM-HF trial. Dr Desai consulted for Novartis, Relypsa, and St. Jude Medical. Drs Gong, Lefkowitz, Rizkala, and Shi are employees of Novartis. Drs Böhm, Hagege, Swedberg, and Zile have received honoraria from Novartis for sponsored lectures. Drs Chen and Martinez are on the speaker’s bureau of Novartis. Dr Bĕlohlávek received honoraria from AstraZeneca for sponsored lectures and consulted for AstraZeneca and Servier. Dr Erglis is on the speakers’ bureau of Pfizer, Abbott Laboratories, Merck, and Sanofi. Dr Gomez consulted for Biotoscana. Drs Mosterd and Squire received honoraria from Novartis for partici-pating in various activities. Dr Vinereanu received research support and honoraria from and consulted for Novartis and honoraria from Servier, Pfizer, BMS, and AstraZenica. An immediate family mem-ber of Dr Negrusz-Kawecka received research support from Novartis, and her institution received institutional fees from Novartis.

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Figure 3. A, Median values for N-terminal pro-BNP and troponin T at entry and during single-blind run-in and double-blind periods. Medians are shown in circles, and 25%/75% interquartile ranges are shown in bars, where patients in the LCZ696 group are shown in white circles and white bars and patients in the enalapril group are shown in black circles and gray bars. P values designate the significance of difference between the 2 treatment groups. Troponin T was not measured at the end of the enalapril phase of the run-in period. B, Median values for B-type natriuretic peptide and urinary cyclic GMP at entry and during single-blind run-in and double-blind periods. Medians are shown in circles, and 25%/75% interquartile ranges are shown in bars, where patients in the LCZ696 group are shown in white circles and white bars and patients in the enalapril group are shown in black circles and gray bars. P values designate the significance of the difference between the 2 treatment groups. Urinary cyclic GMP was not measured at the end of the enalapril phase of the run-in period. BNP indicates B-type natriuretic peptide; ENL, end of the enalapril phase of the run-in period; and LCZ, end of the LCZ696 phase of the run-in period.

Valsartan-‐Sacubitril vs. Enalapril in HF

Packer et al., Circula<on 2015:131;54

Enalapril

Sacubitril/ valsartan

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