risk stratification in acute coronary syndromes

RISK STRATIFICATION IN

ACUTE CORONARY SYNDROMES

ADAM OSTER PGY-2JANUARY 9, 2002RESIDENT ORAL PRESENTATION

RISK STRATIFICATION IN ACS

• Objectives– Discuss the major risk stratification

models– Examine strategies to define the very

low risk group– The future of risk stratification

The Undifferentiated Chest Pain Patient

• Risk of ACI• Risk of short-term mortality,

cardiac events or complications• Risk of long-term mortality, events

or complications

How Predictive are Routine Historic Features?

• Goodacre et al. How Useful are Clinical Features in the Diagnosis of Acute, Undifferentiated Chest Pain? Academic Emergency Medicine, vol. 9, no. 3, 2002.– Prospectively evaluated 893 CPOU (normal ECG, no CHF

or arrhythmia)– ST seg monitoring, troponin T >6hrs, +/-EST or thallium– F/U at 3d and 6mo, 12mo– Endpoints: AMI at presentation and ACS (AMI at any

time, pos. EST cardiac death, arrhythmia, revascularisation procedure)

– Assessed predictive power of routine historic features

Goodacre et al. How Useful are Clinical Features in the Diagnosis of Acute,

Undifferentiated Chest Pain? Academic Emergency Medicine, vol. 9, no. 3, 2002.

Feature OR CI pRadiation to Shoulder 5.7 1.5-21.4 sig

Radiation to Both Arms 4.9 1.3-19.4 sigBurning/Indigestion 3.4 0.4-31.0 NSNausea/Vomiting 1.3 0.5-3.3 NSExertional Pain 3.3 1.3-8.4 sig

Tender Chest Wall 0.2 0.05-0.97 sig

Features Predictive of AMI:

Multivariate analysis table

Didn’t make it to MV analysis

Radiation to L arm

radiation to throat

radiation to back

heavy pressure

diaphoresis

relief after nitro

Goodacre et al. How Useful are Clinical Features in the Diagnosis of Acute,

Undifferentiated Chest Pain? Academic Emergency Medicine, vol. 9, no. 3, 2002.

Feature OR CI pRadiation to shoulder 5.2 2.0-13.4 sigRadiation to left arm 2.1 1.0-4.4 sig

Radiation to both arms 4.8 1.8-13.2 sigExertional pain 2.4 1.3-4.5 sigPleuritic pain 0.6 0.2-1.7 NS

Tender chest wall 0.6 0.3-1.2 NS

Features Predictive of ACS:

These features do not have the sensitivities or

specificities to rule in or rule out the diagnoses on their own

Many commonly used clinical features were not independent predictors or AMI/ACS

maybe underpowered to detect

failure of N/V/D may reflect that these features are typically present in larger inf AMI with ECG changes

Pope et al. Missed Diagnoses of Acute Cardiac Ischemia in the Emergency Department. New England Journal of Medicine vol. 342, no. 16,

2000. • 10 689 patients • Data collected for 30d

(hospitalised patients) or at 24 to 72hrs for non-hospitalised patients

• Outcomes assigned by physicians at study sites using pre-defined criteria


2000.• Final Diagnosis

– 1866 (17%) ACI– 894 (8.5%) AMI– 972 (9%) unstable angina– 21% non-ischemic cardiac problem– 55% non-cardiac


2000.• 22 missed unstable angina (2.26%)

– MC diagnosis;• stable angina, atypical chest pain


2000.• 19 missed AMIs (2.1% of 894)

– MC diagnosis; • non-cardiac chest pain, pulmonary

conditions and stable angina


2000.• Factors associated with non-hospitalisation

for patients with missed ACI– female– <55– non-white– chief complaint of SOB – normal ECG– 30d adjusted risk of mortality 1.7 times

higher if not hospitalised (95% CI 0.7 to 5.2)

Low rate of missed ACI/AMI diagnosis

but associated with a poor outcome

ACI Prediction• Pozen et al. The Usefulness of a Predictive

Instrument to Reduce Inappropriate Admission to the Coronary Care Unit. Annals of Internal Medicine, Vol. 92, 1980. – Original predictive instrument derived from

2801 patient encounters, 1979-1980.• Designed to predict unstable angina and AMI• Of 59 candidate clinical variables, 7 found to be

predictive of ACI• estimate (0-100%) provides patients likelihood of

having ACI

Pozen et al. The Usefulness of a Predictive Instrument to Reduce Inappropriate Admission to

the Coronary Care Unit. Annals of Internal Medicine, Vol. 92, 1980.

Chest Pain or Pressure

or left arm pain?Chief Complaint Yes but not

Chief ComplaintNo

No Previous MIPrev. MI or nitro use

Both MI and Nitro use





ST and T analysis ST and T analysis ST and T analysis

Pozen et al. The Usefulness of a Predictive Instrument to Reduce Inappropriate Admission to

the Coronary Care Unit. Annals of Internal Medicine, Vol. 92, 1980.

Original was programmed onto a handheld calculator.

This is the Table Version

Selker et al. A Tool for Judging Coronary Care Unit Admission Appropriateness,Valid for Both Real Time and

Retrospective Use: A Time-Insensitive Predictive Instrument (TIPI) for Acute Cardiac Ischemia: A Multicentre

Study. Medical Care. Vol. 29.1991.• Prospectively tested OPI (N=2320)

– Intervention vs Control• proven ACI; no change in admission patterns• proven no ACI; sig. lower CCU admission rates

(24% to 17%, p=0.03)• ED d/c home; 51% vs 44%• patients with <50% prob ACI;

– 22% reduction in FP diagnosis (p=0.002)• patients with >50% prob ACI;

– no stat sig. diagnostic benefit

Instrument most helpful in making a correct diagnosis

in patients with atypical or less definitive symptoms

In higher probability patients, physician judgement alone suffices

Selker et al. A Tool for Judging Coronary Care Unit Admission Appropriateness,Valid for Both Real Time and

Retrospective Use: A Time-Insensitive Predictive Instrument (TIPI) for Acute Cardiac Ischemia: A Multicentre

Study. Medical Care. Vol. 29.1991.• patients proved not to have ACI

– ave. predicted probability 24%• patients proved to have ACI

– ave. predicted probability 62%

Original ACI Predictive Instrument

• Critique of Selker Study– Although prospective and controlled,

randomisation method was different among the 3 study hospitals

– Blinding of predicted probability to clinicians determining ultimate diagnosis questionable

– Gold Standard poorly defined– Outcome of those discharged home not published– Generalisability to different settings (e.g

Telemetry Units)

OPI should be used in conjunction with EP judgement

No specific cutoff point was determined

ACI-TIPI• Acute Coronary Ischemia, Time-

Insensitive Predictive Instrument– next generation of ACI predictive tools

• modified the clinical variables• computerised interpretation of ECG• designed for prospective and retrospective use (time-

insensitive)• prediction printed onto ECG• change in performance

– designed to predict AMI > unstable angina in order to produce less false negatives for AMI

By giving more weight to greater ST deviation

ACI-TIPI

ACI-TIPI• Age, sex • chest pain or pressure or left arm

pain as primary complaint• pathologic Q waves• presence and degree of ST

segment elevation or depression• T wave elevation or inversion

ACI-TIPI• original predictive instrument and

ACI-TIPI had virtually identical area under ROC curve (0.89) when tested prospectively and simultaneously with OPI (N=2320)

• higher sensitivity for AMI than OPI

Selker et al. Annals of Internal Medicine. Vol 129. No. 11, 1998.

– N=10 689 with chest pain or Sx c/w ischemia– ACI-TIPI prediction either printed or not printed

on ECG; 7 alternating months of intervention and control

– outcomes: triage to CCU, telemetry,ward or home, patient diagnosis and patient outcomes

– diagnosis assigned by blinded site physician on basis of all available information after 30d period

– also looked at triage decisions relative to capacity of CCU vs telemetry unit and level of training of EP


• Patients with ACI (unstable angina or AMI)– intervention not associated with a

change in admission– mean predicted probability of ACI

59%


• Patients with Stable Angina– intervention associated with reduction

in CCU admission of 50% (26% to 13%) • 95% CI -70% to -17%

– increase in discharge home from 20% to 22% (RRI 10%)• 95% CI -29 to 70%, p=0.02


• Patients without ACI– intervention associated with reduction in CCU

admission of 16% (15% to 12%, – 95% CI -30% to 0%

– increased in ED discharge to home from 49% to 52%, RRI of 6%

– 0-14%, p=0.09– reductions in admission were greatest in low

(<10%) probability group (OR 0.51) – CI 0.28-0.91

– mean predicted probability of ACI, 21%


• 30 day mortality– patients discharged home

• control 0.2%• intervention 0.5%, p=0.2

ACI-TIPI• Summary

– 0-100% probability of ACI– tested in ED and found to be accurate

for ACI and non-ACI– incorporated into the conventional

12-lead ECG– time-insensitive

ACI-TIPI• Future Studies

– prospective trial in various types of EDs – effect on time to disposition decision– increase in discharge home and

decreased utilisation of in-hospital resources and personnel for cardiac work-up

– pre-hospital use– applicability to population subgroups

Goldman Chest Pain Protocol

• Goldman et al. Prediction of the Need for Intensive Care in Patients Who Come to the Emergency Departments With Acute Chest Pain. New England Journal of Medicine. Vol 334. 1996.– Designed to predict the risk of major complications

in patients presenting to the ED with chest pain– an aid to triaging to ICU/CCU setting– derivation of decision rule N=10 682 [1982-1984]– validation of CDR N=4676 [1990-1994]– validation at other sites N=1033 [1997-1999]

Goldman: lots of research in this area.

Decided to focus not on prediction of AMI

but on prediction of complication in ACS patients

Goldman et al. Prediction of the Need for Intensive Care in Patients Who Come to the

Emergency Departments With Acute Chest Pain. New England Journal of Medicine. Vol 334. 1996.• Outcomes (defined apriori)

– Major events (requiring ICU/CCU care)• VF, CA, 3rd degree block, pacemaker insertion,

emergent cardioversion, cardiogenic shock, IABP, intubation, recurrent chest pain requiring PCI< CABG within 72hrs

– Intermediate Events (no ICU/CCU)• A. flutt., Mobitz Type I or II (no pacemaker), sinus

brad., pulmonary edema, infarct extension


Emergency Departments With Acute Chest Pain. New England Journal of Medicine. Vol 334. 1996.• Risk of major event within 72hrs

(derivation phase)– age >60 – male– pain same as prior infarction or worse than previous

angina– SBP<100– Crackles above the bases bilaterally– abnormality on ECG

• STE or Q waves not known to be old• STD or T wave inversion not known to be old


Emergency Departments With Acute Chest Pain. New England Journal of Medicine. Vol 334. 1996.• Grouped into 4

risk groups based on risk of major event at 24hrs– very low– low – moderate – high


Emergency Departments With Acute Chest Pain. New England Journal of Medicine. Vol 334. 1996.

Risk Category Derivation Validation

High 21.5 16.1Moderate 8.1 7.8

Low 3.6 3.9Very Low 0.8 0.6

Rate of events by risk group at 72hrs


Emergency Departments With Acute Chest Pain. New England Journal of Medicine. Vol 334. 1996.• After initial 12hrs the risk of a

major event depended more on the occurrence of an event than the initial risk category


Emergency Departments With Acute Chest Pain. New England Journal of Medicine. Vol 334. 1996.• Critique

– ECG and cardiac enzymes at discretion of physician

– derivation set • 28% of eligible patients not enrolled or

ultimately did not contribute to results in• of discharged patients 35% did not follow-up

– validation set• 17% of discharged patients followed-up


Emergency Departments With Acute Chest Pain. New England Journal of Medicine. Vol 334. 1996.• Critique

– validation set event rate > derivation set (2.8 vs 1.8, p<0.01)

– revascularisation procedures more common in validation set than derivation set

Application of Goldman Clinical Decision Rule

• Reily et al. Impact of A Clinical Decision Rule on Hospital Triage of Patients With Suspected Acute Cardiac Ischemia in the Emergency Department. JAMA, no.288. Vol.3, 2002.– Pre-intervention and intervention cohort– Outcomes assessed; Safety and Efficiency

• Safety -- percent of patients triaged to CCU/telemetry who had cardiac events within 72hrs

• Efficiency -- proportion of patients who did not experience a cardiac event triaged to non-monitored ward or ED CPOU

Reily et al. Impact of A Clinical Decision Rule on Hospital Triage of Patients With Suspected Acute Cardiac Ischemia in the Emergency Department.

JAMA, 288, vol.3, 2002.• Included patients without chest pain• Excluded patients discharged home

– but studied a separate cohort of patients discharged home directly from ED for complications within 72hrs to monitor the safety of the discharge decision

• added LBBB (not known to be old) to ECG evidence of acute ischemia

• Intention-to-treat analysis

Adam Oster:

Eps responsible for admitting patients but cardiology consult and permission required for CCU/telemetry admissions


JAMA, 288, vol.3, 2002.


JAMA, 288, vol.3, 2002.• 98.6% follow-up• groups similar • 35 major complications

in intervention group

• Safety Outcome– 94% vs 89%, NS.

• Efficiency Outcome– 36% vs 21% (RRI 15%,

CI 8%-21%, p<0.001)

largest change in triaging patterns between

pre-intervention and intervention group occurred

in very low risk patients. No sig. Different

changes in higher risk groups

Much larger sample sizes would be needed to narrower

confidence intervals for the decisions rules safety (around 15000)


JAMA, 288, vol.3, 2002.• Patients

discharged home (subgroup analysis) N=326 – no complications

in 300– 26 LTFU

• no recorded deaths

Adam Oster:

follow-up would miss small, uncomplicated MIs

Braunwald Risk Stratification

• Braunwald E. Unstable Angina: A Classification. Circulation. 1989; vol. 2 no. 7– Derived scoring system in 1989 for unstable

angina– designed to aid in clinical decision making

and clinical trials

Braunwald E. Unstable Angina: A Classification. Circulation. 1989; vol. 2 no. 7.

Prospective Validation of the Braunwald Classification• Calvin et al. Risk Stratification in

Unstable Angina. JAMA. 1995. Vol 273, no. 2– determined elements of the Braunwald RS

that predict risk of complications– Consecutive patients admitted to CCU with

UA, N=393 – Outcomes:

• in-hospital death, MI, CHF, VT or VF– all patients treated at discretion of physician

eligibility criteria:

ischemic type chest pain either responsive to NO or assoc with STD

lasting >20mins at rest

or exertional chest pain increasing in frequency

MI ruled out

Calvin et al. Risk Stratification in Unstable Angina. JAMA. 1995. Vol. 273, no. 2

• 4 clinical factors associated with development of the composite endpoint (n=30)– MI <14d prior to presentation (OR 5.72,

1.92-16.97)– need to IV nitro (OR 2.33, 1.31-4.17)– lack of bBlocker or CCB use prior to

presentation (OR 3.83, 1.55-9.42)– baseline STD (OR 2.81, 1.45-5.47)

Example of calculation

male with previous <14d MI and no use of bblocker

5.72x3.82=21.8 (CI 2.5-159)

not prospectively validated

wide confidence intevals

likely underpowered

novel in that uses intensity of therapy

as an element to classify

Thrombolysis in Myocardial Infarction (TIMI) Risk

Stratification• Antman et al. JAMA. 2000. Vol. 284,

No.7.– TIMI RS based on data from TIMI 11b

(N=3910) and ESSENCE (N=3171)– Test cohort (TIMI UFH)– Validation cohort (TIMI and ESSENCE

enoxaparin groups and ESSENCE UFH)– TIMI RS derived in test cohort

TIMI Risk StratificationAntman et al. JAMA. 2000. Vol. 284,

No.7.• Endpoints

– all-cause death, new or recurrent MI or UR at 14d post-randomisation

• Eligibility (1 of following)– admitted patients who presented within 24hrs

with symptoms of unstable angina/NSTEMI– transient STE or STD or 0.05mV (TIMI) or

0.01mV (ESSENCE)– known CAD*– increased Troponin

TIMI Risk StratificationAntman et al. JAMA. 2000. Vol. 284, No.7

• All patients received ASA• randomised to enoxaparin or UFH• Derivation cohort;

– tested 12 candidate variablesage ST deviationat least 3 CAD risk factors>2 anginal events in 24hrssignificant coronary stenosis use of ASA in last 7dprior MI elevated cardiac markersprior CABG prior history of CHFprior PTCA


• Derivation cohort– 7 variables remained statistically significant

after multivariate analysis• Age >65• at least 3 CAD RF• STD• severe anginal symptoms• prior stenosis >50%• use of ASA over previous 7d• elevated serum cardiac markers

*paraneter estimates (odds ratios) for each variable of similar magnitude


• Small numbers of patients in extreme risk scores required combining

• criteria of known stenosis >50%, insensitive to missing data and remained a significant predictor

derivation of RS


• Validation Phase– different rate of

increase for rate of composite endpoint in UFH vs enoxaparin

– merged the databases– TIMI RS and treatment

were both significant predictors of risk of the composite endpoint


• Predicting the individual components of the composite endpoint

• all statistically sig.


• Caveats and Critique– tested on admitted patients with unstable angina/NSTEMI– Validation Phase not prospective– cohort who qualified for enrolment in a phase III study; ?

generalisabilty to all-comers with chest pain – enrolment criteria for TIMI 11b changed during the trial – duration of treatment different between UFH (3-8d) and

enoxaparin (8d or hospital discharge)– elevated CKMB was both a predictor of an endpoint as well

as part of the definition of an endpoint– CKMB was the marker in TIMI but now use Troponin without

study to prove similarly predictive

Initially used history of CAD as entry criteria but then switched to STD or pos. CKMB


• Support– consider using on chest pain patients to be

admitted– simple to use and to communicate to

consultants– cannot use to determine who is at low risk – cannot use to determine who is safe for

discharge

DEFINING THE LOW RISK GROUP

• Previous studies not designed to define the low risk group (or group safe to discharge home)

• Many studies evaluating Troponin to define low risk group

• Only one which uses combination of RS criteria and serum marker in an attempt to define

Combining Goldman and Troponin

• Limkakeng et al. Combination of Goldman Risk and Initial Cardiac Troponin I for Emergency Department Chest Pain Patient Risk Stratification. Academic Emergency Medicine, Vol. 8, No. 7, 2001. – Prospective cohort study of consecutive

ED chest pain patients– Goldman RS score calculated and

presentation TnI determined– followed those with Goldman RS <4% and

single negative TnI

Testing the hypothesis that low Goldman RS and neg TnI would confer a risk of death, MI or UR of <1%

Limkakeng et al. Combination of Goldman Risk and Initial Cardiac Troponin I for Emergency

Department Chest Pain Patient Risk Stratification. Academic Emergency Medicine,

Vol. 8, No. 7, 2001.• >24 yrs• c/o chest pain• had an ECG• patients followed

daily for complications and interventions

• 30d follow-up for 91% of participants

• ECG classified by treating EP

• TnI collected• EPs blinded to Goldman

• Final data set included those with Goldman <4% and negative TnI

• Primary endpoints– death, AMI, UR



Vol. 8, No. 7, 2001.• Of 2322 pts 1657 had low Goldman RS• 998 had low Goldman and initially negative TnI

(<0.3ng/ml)

• 49 patients experienced an endpoint (4.9%)• AMI N=23 (2.3%)• Death N=10 (1.0%)• PCI/stent/CABG N= 23 (2.3%)• 4 patients initially discharged home experienced a cardiac

event

some patients experienced more than 1 endpoint



Vol. 8, No. 7, 2001.• Sensitivity and NPV to detect a 30d

endpoint better with combined predictors than either alone

• neither criteria alone or in combination achieved <1% likelihood of a 30d endpoint

variable times to TnI determination

Summary• 4 major RS models

– ACI-TIPI probability of ACI in undiff. CP– Goldman Risk of Complications in Chest Pain– Braunwald Death, MI, UR in UA patients– TIMI Death, MI, UR within 14d in admitted CP

• None able to identify the low risk chest pain patient or the patient safe to discharge Home

The Future of Risk Stratification

• Combination of ACI-TIPI with Troponin

• Prospectively validate TIMI

risk stratification in acute coronary syndromes

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