Improving the detection of myocardial infarction in women

Transcription

1 Improving the detection of myocardial infarction in women British Cardiac Society Listening to the Female Voice 4 th June 2014 anoopsshah@gmail.com Dr Anoop Shah BHF Centre for Cardiovascular Sciences The University of Edinburgh Royal Infirmary of Edinburgh Scotland UK

2 Declaration of interests Funding: Sponsorship: Interests: British Heart Foundation Special Project Grant (SP/12/10/29922 ) Abbott Diagnostics (reagent only) University of Edinburgh NHS Lothian Speaker fees (Abbott Diagnostics)

3 atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting intraluminal thrombus in one or more of the coronary arteries What is a heart attack?

4 Disparities in mortality by gender in randomised control studies 2.5 TIMI-II Relative risk Increased risk in women Decreased risk in women TAMI ITSM GUSTO-1 ISIS-3 TIMI-II TAMI ITSM GUSTO-1 ISIS-3 Crude RR Age-adjusted RR

5 Women at higher risk of 30-day death following myocardial infarction Unadjusted RR Adjusted RR N= 138,956 (49% female) Relative risk (95% CI) Gan,et al NEJM, 343(1), 8 15.

6 Women at higher risk of in-hospital death following myocardial infarction N= 384,878 (40% female) Vaccarino et al NEJM 1999 vol. 341 (4) pp

7 Age, years Women at higher risk of in-hospital death following myocardial infarction Decreased risk in women Increased risk in women < ³75 N= 1,143,513 (42% female) Canto et al JAMA (8), Relative risk (95% CI) Adjusted for comorbidity, treatment provision and hospital characteristics

8 The diagnosis of myocardial infarction Defined on histology as area of focal necrosis

9 Universal Definition of Myocardial Infarction ESC/ACC UNIVERSAL 1st WHO 2nd WHO MONICA THIRD UNIVERSAL AST CK CK-MB Troponin T Troponin I Detection of a rise and/or fall of cardiac troponin with at least one value above the 99 th percentile as upper reference limit Eur Heart J Oct;33(20): nick.mills@ed.ac.uk

10 What is cardiac troponin? Myocardium Cardiac myocyte Sarcomere Myofibrril Actin (thin filament) Myosin (thick filament) Actin monomer Tropomyosin Myosin Troponin

11 Frequency High-sensitivity cardiac troponin assays 99 th centile Can detect troponin in the blood in majority of healthy individuals The guidelines define an abnormal level as one that is above the 99 th centile of the normal population Troponin concentration, ng/l

12 Determining the reference range B Abbott ARCHITECT high-sensitive troponin I assay 99 th percentile Men 34 ng/l Women 16 ng/l All 26 ng/l Distribution of troponin and 99 th percentile upper reference limits in 4,590 samples from healthy men and women

13 Gender differences in reference range with high-sensitivity troponin assays 100 All Females Males 80 Troponin, ng/l Roche Cobas e691, hsctnt Abbott Architect STAT, hstni Singulex Erena, hstni Beckman Access 2, hstni Siemens Dimension Vista, hstni 99 th percentile for troponin differs between men and woman when determined by high-sensitivity assays

14 RANDOMISATION High-Sensitive Troponin in the Evaluation of patients with Acute Coronary Syndrome (High-STEACS): A randomised controlled trial Stepped-wedge cluster randomised trial months 5 sites Standard care High-sensitivity assay Follow up Early Implementation 5 sites Standard care Standard care High-sensitivity assay Follow up Validation Late Implementation Aim: to determine whether lowering the diagnostic threshold for myocardial infarction using a high-sensitivity cardiac troponin I assay will improve outcomes in patients with suspected acute coronary syndromes number: NCT nick.mills@ed.ac.uk

15 Participating sites NHS GG&C Dr Nicholas Mills Clinical Lecturer and Specialist Registrar in Cardiology Royal Infirmary Edinburgh NHS Lothian Western Infirmary Vale of Leven Inverclyde Royal Royal Alexandra, Paisley Glasgow Royal Victoria Infirmary Southern General Royal Infirmary Western General St Johns Ten hospitals (clusters) across NHS Lothian and Greater Glasgow & Clyde Health Boards

16 Should we use different criteria for diagnosing heart attacks in men and women? Inequalities exist in the treatment and outcome of men and women with acute coronary syndromes with an increase in early and late deaths in women 1-2 High-sensitivity troponin assays have identified differences in the reference range between men and women with 99 th percentiles two-fold higher in men 3 Whether use of a single diagnostic threshold has contributed to the under diagnosis of myocardial infarction in women is unknown We evaluate the impact of sex-specific diagnostic thresholds for myocardial infarction in consecutive men and women with suspected acute coronary syndrome 1 N Engl J Med. 2000:343; Ann Intern Med. 2001:134; Clin Chem. 2012:58;

17 Study population Suspected acute coronary syndrome (n=1,126) MEN n=622 (55%) WOMEN n=504 (45%) Adjudication of diagnosis Contemporary assay (single threshold) = 50 ng/l High-sensitivity assay (single threshold) = 26 ng/l High-sensitivity assay (sex-specific) = 34 (men)/16 (women) ng/l

18 Percentage Diagnosis of myocardial infarction Contemporary assay High-sensitivity assay 30 single single sex-specific Men 23% 26% 24% Women 13% 17% 24% Men Women FREQUENCY

19 Type 2 myocardial infarction Thygesen et al, EHJ 2012

20 Percentage Diagnosis of type 2 myocardial infarction Contemporary assay High-sensitivity assay 30 single single sex-specific Men 4% Women 4% 5% 5% 5% 6% Men Women FREQUENCY

21 C Sensitivity Specificity Negative predictive Sensitivity Specificity value Negative predictive value and specificity value for value myocardial infarction Women in women Women Positive predictive Positive predictive Percentage, 95% CI 80 Percentage, 95% CI Sensitivity Specificity Negative predictive Positive predictive Sensitivity Specificity value Negative predictive value Positive predictive value value Contemporary troponin I assay (single threshold, 50 ng/l) Contemporary troponin I assay (single threshold, 50 ng/l) High-sensitivity troponin I assay (single threshold, 26 ng/l) High-sensitivity troponin I assay (single threshold, 26 ng/l) High-sensitivity troponin I assay, (sex-specific thresholds, men 34 ng/l; women 16ng/L) High-sensitivity troponin I assay, (sex-specific thresholds, men 34 ng/l; women 16ng/L) nick.mills@ed.ac.uk

22 A Sensitivity Specificity Negative predictive value Positive predictive value Sensitivity and specificity for myocardial Women infarction in men C Percentage, 95% CI 80 Percentage, 95% CI Conventiona threshold High sensitiv (generic thres High sensitiv (gender speci Sensitivity Specificity Negative predictive Positive predictive Sensitivity Specifcity value value Negative predictive Positive predictive value value Contemporary troponin I assay (single threshold, 50 ng/l) High-sensitivity troponin I assay (single threshold, 26 ng/l) High-sensitivity troponin I assay, (sex-specific thresholds, men 34 ng/l; women 16ng/L) nick.mills@ed.ac.uk

23 Baseline characteristics Suspected acute coronary syndrome Myocardial infarction * Men (n=622) Women (n=504) Men (n=152) Women (n=117) Age, years 63 (15) 69 (16) 67 (14) 75 (13) Chest pain 529 (85%) 407 (81%) 139 (91%) 96 (82%) Risk factors Smoker 198 (34%) 79 (17%) 47 (33%) 20 (19%) Hypertension 325 (52%) 271 (54%) 83 (55%) 71 (61%) Hyperlipidemia 293 (47%) 210 (42%) 80 (53%) 53 (45%) Diabetes mellitus 112 (18%) 72 (14%) 33 (22%) 22 (19%) Medical history Ischemic heart disease 273 (44%) 193 (38%) 81 (54%) 56 (48%) Previous myocardial infarction 187 (30%) 105 (21%) 55 (36%) 37 (32%) Previous PCI 116 (19%) 50 (10%) 33 (22%) 14 (12%) Previous CABG 65 (11%) 21 (4%) 22 (15%) 7 (6%) Cerebrovascular accident 54 (9%) 30 (8%) 13 (9%) 13 (11%) Clinical chemistry Creatinine, mmol/l 93 (64) 79 (34) 103 (78) 92 (43) Troponin I, ng/l 2,860 (10,000) 1,300 (6,560) 11,300 (17,800) 5,450 (12,800) Electrocardiography ST elevation 83 (14%) 35 (7%) 47 (31%) 22 (19%) ST depression 47 (8%) 59 (12%) 32 (21%) 24 (21%) T-wave inversion 121 (20%) 100 (21%) 40 (26%) 28 (24%) * Defined using high-sensitivity assay sex-specific thresholds nick.mills@ed.ac.uk

24 Management of men and women with myocardial infarction C1 Men (n=152) Women (n=117) P-value Cardiology referral 132 (87%) 60 (52%) <0.001 Investigation Exercise tolerance test 5 (3%) 2 (2%) Echocardiography 40 (26%) 31 (27%) Coronary angiography 102 (67%) 33 (28%) <0.001 Revascularization PCI 88 (58%) 21 (18%) <0.001 CABG 5 (3%) 0 (0%) Medication on discharge Aspirin 126 (86%) 79 (72%) Clopidogrel 112 (76%) 53 (49%) <0.001 B-blockers 84 (57%) 52 (48%) ACE inhibitors 92 (63%) 54 (50%) Statins 123 (84%) 66 (61%) <0.001 Myocardial infarction defined using high-sensitivity assay sex-specific thresholds nick.mills@ed.ac.uk

25 Management of women with suspected acute coronary syndrome C1 Troponin concentration <16 ng/l ng/l >50 ng/l Cardiology referral 51 (15%) 11 (20%) 43 (80%) Investigation Exercise tolerance test 6 (2%) 1 (2%) 0 (0%) Echocardiography 16 (5%) 5 (9%) 25 (46%) Coronary angiography 10 (3%) 1 (2%) 26 (47%) Revascularization PCI 5 (2%) 0 (0%) 16 (29%) CABG 0 (0%) 0 (0%) 0 (0%) Medication on discharge Aspirin 117 (35%) 29 (57%) 44 (85%) Clopidogrel 41 (12%) 9 (18%) 39 (75%) B-blockers 81 (24%) 23 (45%) 25 (48%) ACE inhibitors 90 (27%) 19 (37%) 31 (60%) Statins 130 (39%) 30 (59%) 31 (60%) Women with suspected acute coronary syndrome stratified by peak high-sensitivity troponin concentration nick.mills@ed.ac.uk

26 Outcome of women with suspected acute coronary syndrome Survival free from death or recurrent myocardial infarction, % Survival free from death or recurrent MI, % C1 nick.mills@ed.ac.uk Troponin I concentration ³ 50 ng/l Log rank test P< Days Days

27 Summary and conclusions High-sensitivity assays with different criteria for diagnosis in men and women would increase the diagnosis of heart attacks in women (from 13% to 23%) with little effect in men (from 23% to 24%) Even patients with small heart attacks only identified using the highsensitivity assay are at increased risk of poor outcomes We believe that women may have been under diagnosed as a result of the less sensitive tests previously used to assess patients with suspected heart attacks Our trial will determine whether the use of a high sensitive assay and different criteria for diagnosing heart attacks in men and women will lead to better care and better outcomes. nick.mills@ed.ac.uk

28 Acknowledgments Funders British Heart Foundation Special Project Grant (SP/12/10/29922 ) Abbott Diagnostics (reagent only) High-STEACS Steering Committee Professor Ian Ford (Chair) Dr Nicholas Mills Dr Shannon Amoiles (funder) Professor Fred Apple Professor Paul Collinson Dr Simon Walker Professor Colin Berry Professor Keith Fox Professor David Newby Professor Alasdair Gray Dr Colin Fischbacher Professor John Norrie Dr Chris Weir Trial Management Team & Edinburgh Clinical Trials Unit Dr Anoop Shah Dr Fiona Strachan Dr Mary Stoddart Allan Walker Dr Chris Weir University of Glasgow Dr Iain Findlay Dr Anne Cruikshank Dr Alan Reid University of Edinburgh Megan Griffiths Dr Kuan Ken Lee Dr Amanda Hunter Dr David McAllister nick.mills@ed.ac.uk