UvA-DARE (Digital Academic Repository) Early risk ...Chapterr4 Robbertt J. de Winte r Radhaa Bholasingh Annee B. Nieuwenhuijs Rudolph.. W . Koster Ronn J. G. Peters Gerard.. T. Sanders

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Early risk stratification in patients with chest pain

Bholasingh, R.

Publication date2004

Link to publication

Citation for published version (APA):Bholasingh, R. (2004). Early risk stratification in patients with chest pain.

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Chapterr 4

Robbertt J. de Winter Radhaa Bholasingh

Annee B. Nieuwenhuijs Rudolph.. W. Koster

Ronn J. G. Peters Gerard.. T. Sanders

Rulingg out acute myocardial infarctionn early with two seriall creatine-kinase MBmass determinations s

EurEur Heart J 1999;20:967-972

RulingRuling out myocardial infarction

ABSTRACT T

Objective e

Wee studied the diagnostic value for acute myocardial infarction of serial creatine kinase-

MBnasss measurements on admission and at 7 hours after the onset of symptoms.

Methodss and results

Patientss presenting to our chest pain unit with symptoms of < 5 hours duration were eligible.

Patientss were kept under observation at least untill 12 hours after onset of symptoms.

Bloodsampless were drawn on admission, 7 and 10 hours after onset of symptoms. Creatine

kinase-MBnuBss >7.0 ug/1 (upper reference limit for acute myocardial infarction), or an increase

>> 2.0 ug/1 (reference change value) between admission and at 7 hours was considered

abnormal.. Of a total of 470 patients, 248 patients had acute myocardial infarction: 100/248

patientss had a single creatine kinase-MB,̂ >7.0 ug/1 on admission (sensitivity 40%, 95%

C.I.:34-36),, 234/248 patients at 7 hours (sensitivity 94%, 95% CI.:91-97), and 240/248 at 10

hourss (sensitivity 97%, 95% C.L:94-99). At 7 hours, 246/248 patients either had a single

creatinee kinase-MBmass >7.0ug/l or a significant increase between admission and 7 hours

(sensitivityy 99%* 95% C.I.: 98-100). Of 222 patients without acute myocardial infarction, 214

hadd a normal serial creatine kinase-MBn,̂ (specificity 96%, 95% CI. :93-98).

Conclusion n

Inpatientss with symptoms of < 5 hours duration, acute myocardial infarction can be ruled-out

inn 99% using serial creatine kinase-MB,,̂ taken on admission and at 7 hours.

50 0

ChapterChapter 4

INTRODUCTION N

Earlyy diagnosis of acute myocardial infarction may improve treatment and reduce

complications.. Conversely, identification of low-risk patiënte without myocardial infarction

mayy allow for early triage and the rational use of intensive care facilities. Goldman et al.(30),

evaluatingg the need for intensive care in patients with acute chest pain, snowed that the risk of

majorr complications could be estimated on the basis of clinical presentation (symptoms,

physicall examination, electrocardiogram) and an additional 12-hours observation period.

However,, others have demonstrated that 4-8% of patients with myocardial infarction may be

missed(107).. Patients in whom the diagnosis of myocardial infarction is missed and who are

inadvertentlyy discharged from the emergency department, have increased short-term mortality

comparedd with admitted patients(4). New rapid assays for creatine lanase-MBmas, with

excellentt precision in the normal concentration range are now available for early and more

accuratee diagnosis of myocardial infarction(29;83;108;109). We(29;86) and others(110;Ul),

havee shown that, with me high precision of creatine kinase-MBmass assays, a so-called

referencee Change value (or critical difference) can be calculated A significant increase in

seriall creatine kinase-MBnBB» which can occur within the reference limit, is defined as a

differencee larger than the reference change-Value, and such an increase signifies myocardial

damage(90).. Using mis definition in the interpretation of serial creatine kinase-MB

measurementss could increase sensitivity for the early detection of myocardial damage. We

havee shown previously that sensitivity of a single value does not reach 100% untill 12-16

hourss after the onset of symptoms(29;44). In the present study, we assessed the diagnostic

valuee of two creatine kinase-MBmagg samples taken on admission and at 7 hours, and the

additionall value of a third sample at 10 hours. The study question was whether myocardial

infarctionn could already be recognized or ruled out with high sensitivity on the basis of an

abnormall serial creatine kmase-MBaass measured on admission and at 7 hours

METHODS S

Fromm the 1996 database of the "cardiac emergency room" or chest pain unit of the Academic

Medicall Center (The Netherlands), all patients were reviewed with admission diagnosis of

typicall chest pain. Patients were included when the onset of symptoms was


fromfrom admission, 7 and 10 hours after die onset of symptoms according to our routine protocol.

Hospitall records were reviewed to assess patients' characteristics, in-hospital clinical course

andd discharge diagnosis.

Acutee myocardial infarction was prospectively defined according to World Health

Organizationn criteria(87), using a typical history, definite electrocardiogram changes and an

increasee in creatine kinase-MBn̂ levels. A final diagnosis of acute myocardial infarction was

retrospectivelyy established by one of the investigators (R.B.) combining discharge diagnosis

fromfrom hospital records, electrocardiogram findings and creatine kinase-MBnass results from all

timee points. The upper reference limit for myocardial infarction was 7.0 ug/1.

Creatinee kinase-MBnass was measured with the IMMUNO-1 analyzer (Bayer, Leverkusen,

Germany);; the coefficient of variation was 2.5% at 5.0 ug/1, me turn-around time of the assay

wass 1 hour.

InIn all patients, creatine kinase-MBnass was measured on admission and at 7 and 10 hours.

Whenn creatine kinase-MB,,̂ at any of these three time point was >7.0 ug/1 or when a

significantt increase between two samples (>2.0 ug/I) was present, patients were admitted to

thee coronary care unit and additional creatine kinase-MBnass measurements were made at 12

hourss and at 4-hour intervals thereafter untill a peak value was reached. Patients who had

recurrentt symptoms with concommittant electrocardiographic changes while under

observationn in the cardiac emergency room were diagnosed as severely unstable angina and

admittedd to die coronary care unit irrespective of creatine kinase-MBnass results, as were aU

otherr patients in whom the attending cardiologist decided that coronary care unit monitoring

wass necessary. Patients without evidence of myocardial damage and without recurrent

symptomss while under observation until 12 hours after the onset of symptoms, were usually

discharged.. Symptom limited exercise tests, echocardiograms or other diagnostic procedures

beforee discharge from the cardiac emergency room were ordered at the discretion of the

attendingg cardiologist.

Interpretationn of serial creatine kinase-MBmass samples was as follows: creatine kinase-MÊ

>7.00 ug/1 were considered indicative of myocardial infarction. A difference between

admissionn and 7 hours >2.0 ug/1 (significant increase), was considered abnormal (figure 1). A

creatinee kinase-MBnass 7.0 ug/1 on admission, 7 hours, 10 hours, or any time point

52 2

ChapterChapter 4

thereafter)) was calculated for a single creatine kinase-MBmas, at time points admission, 7

hours,, and for the serial creatine kinase-MBnass combining these two time points. Confidence

intervalss for sensitivity and specificity were calculated with the formula for a binomial

distributionn x s.e., where s.e.=V[p(l-p)/n]. The investigation conformed with the

principless outlined in the Declaration of Helsinki

RESULTS S

Théé database included 1179 patients coded for "presenting with chest pain". A total of 680

patientss were excluded owing to admission later than 5 hours after the onset of symptoms

(2355 patients), or because of atypical chest fain, arrhythmias, congestive heart failure or non-

cardiacc disease where creatine kinase-MBnass samples were not drawn according to protocol

(4388 patients). In 7 patients, creatine lunase-MB,̂ samples were missing due to cardiogenic

shockk or large myocardial infarction, where urgent treatment interfered with marker

measurements.. The remaining 499 patients were presenting within 5 hours after the onset of

symptomss and had complete series of creatine kinase-MBmass samples taken on admission, 7

andd 10 hours. Because of incomplete, equivocal or missing hospital records, another 29

patientss were excluded and therefore 470 patients comprised the study group. Table 1 shows

thee patients* characteristics which were representative of those of chest pain patients admitted

too the cardiac emergency room. Myocardial infarction was diagnosed in 248 patients (table 2):

1000 patients with a creatine kmase-MBâ >7.0 ug/1 on admission (sensitivity: 40%, 95%C.I.:

34-46),, 234 patients with a creatine kmase-MB,̂ >7.0 ug/1 at 7 hours (sensitivity: 94%,

95%C.L:: 91-97), and 240 patients with a creatine kinase-MB̂ >7.0 ug/1 at 10 hours

(sensitivity:: 97%, 95% C.L: 94-99). A total of 254 patients had an abnormal serial creatine

kmase-MBnro;; 237 patients with a creatine kinase-MBmass >7.0 ug/1 either on admission

and/orr 7 hours, and 17 patients with a significant increase between admission and 7 hours but

noo creatine kinase-MB̂ >7.0 ug/1 at either time point. Qf these 17 patients, 9 were

diagnosedd as myocardial infarction with a creatine kmase-MBmass release curve that continued

too increase above 7.0ug/l at 10 h (table 3, patients 1-9; figure 1). The other 8 patients had a

significantt increase between admission and 7 hours but a creatine kinase-MBnass at 10 hours

beloww 7.0 ug/1 (table 3, patients 10-17; figure 1). Of 216 patients with a normal serial creatine

kinase-MBmasgg on admission and at 7 hours, 214 patients had a creatine kinase-MB̂ below

7.00 ug/1 at 10 hours. Two patients had a creatine kinase-MBraB» at 10 hours above 7.0ug/L, one

53 3


off these patients (who was diagnosed as myocardial infarction) was resuscitated outside the

hospitall and admitted to the emergency room in cardiogenic shock, the other patient was

admittedd with severe unstable angina with repetitive episodes of recurrent angina after

admissionn and later diagnosed as myocardial infarction (table 3, patients a and b). There were

1377 patients with ST-elevation on the admission electrocardiogram, 131 with myocardial

infarctionn and 6 without myocardial infarction. ST-depression or T-wave changes was present

inn 167 patients, 67 with myocardial infarction and 100 without myocardial infarction. Of the

remainingg 166 patients with either a non-diagnostic or a normal electrocardiogram, 50 had

myocardiall infarction and 116 did not have myocardial infarction. The sensitivity and

specificityy of an abnormal serial creatine kinase-MBmagj according to admission

electrocardiogramm is depicted in figure 2, demonstrating no significant differences between

groups. .

Inn summary, of 248 patients diagnosed as myocardial infarction, 246 were identified with

seriall creatine lunase-MB,̂ on admission and at 7 hours (sensitivity 99%, 95% CI.: 98-100).

Off 222 patients not diagnosed as myocardial infarction, 214 had normal serial creatine kinase-

MBmasss (specificity 96%, 95% CI.: 93-99).

DISCUSSION N

Inn the present study we analyzed the value of serial samples taken on admission (before 5

hours)) and at 7 hours after the onset of symptoms, and compared this with a single

measurementt taken on admission, at 7 hours and at 10 hours. The combined information from

thee creatine kinase-MBmasg measurement on admission and at 7 hours had a sensitivity of 99%,

higherr than for a single measurement at each of these three time points. Of 216 patients with a

normall serial creatine Jonase-MB,̂ in only two patients did creatine kinase-MBmass at 10

hourss increase (unexpectedly) above 7.0 ug/1. One patient was resuscitated outside the

hospitall but the onset of symptoms was thought to have occurred prior to the time of cardiac

arrest;; the other was admitted with severe unstable angina and may have had another episode

off severe ischemia after admission mat caused a late increase of creatine kinase-ME^a,». Both

thesee patients had a clinical presentation that made admission to the coronary care unit

necessary,, irrespective of the creatine kinase-MBroass results. The specificity of the presented

algorithmm was only 96%: eight patients had an increase between admission and 7 hours >2.0

ug/11 but no diagnosis of myocardial infarction, thus lowering specificity (although it could be

54 4

ChapterChapter 4

arguedd that these patients had indeed signs of myocardial damage). The sensitivity of this

algorilhmm was similarly high in patients with ST-elevation, ST-depression or non-diagnostic

orr normal electrocardiograms on admission. Specificity was 83% (5 of 6) in the small group

off patients with ST-elevation but without infarction.

Thee upper reference limit of the creatine kinase-MÊ assay was established using the 95m

percentilee of the distribution of healthy donors (7.0 ug/1 for the IMMUNO-1 assay in our

institution).. However, the distribution of healthy donors is heavily skewed to the right, and for

mostt healthy individuals, the normal creatine kinase-MBasss is around 1.5-2.5 ug/L For these

individualss a creatine kmase-MBn̂ of e.g. 5.0 ug/1 can be abnormal, although it is still within

thee reference limits. Using serial sampling with carefully timed bloodsamples, the difference

betweenn samples detects abnormal creatine kinase-MB̂ changes within the reference limits.

Neww assays for creatine kmase-MBmasa have very good precision in the normal concentration

range,, the assay used in mis study had a coefficient of variation of 2.5% in the range of 5.0

ug/LL Moreover, biological variation of creatine kinase-MBmass is small(29;86;ni), therefore

thee reference change-value or me maximum change in creatine kinase-MBmass due to

analyticall and biological variation is only 2.0 ug/1 for values within me reference limits. The

analyticall variation for creatine kmase-MB̂ 2.5% at 5.0 ug/I with the IMMUNO-1 assay in

ourr laboratory, which is somewhat better man the 6.8% recently reported by Ross et al. tor the

OBA


withinn 24 hours(29;86), whereas others have demonstrated that a significant increase in

creatinee kinase-MBmass has prognostic implication̂ 110;111).

Theree are some limitations to the study. Including only those patients in the study presenting

withinn 5 hours after onset of symptoms and with a complete series of creatine kinase-MBjnass

sampless may have preferentially selected patiënte with myocardial infarction and patients with

aa clear time of onset of symptoms. However, in many patients which were coded 'presenting

withh chest pain' in the database, creatine kinase-MBma» measurements were not performed

owingg to a low suspicion of ischemic myocardial injury. Therefore, patients in whom creatine

kinase-MBmasss measurements were considered relevant were included in thee study. Secondly,

ourr study was a retrospective study, and whether a sampling protocol with two serial creatine

kinase-MBaasss measurements on admission and at 7 hours will allow safe discharge at that

timee point of patients with normal results (both creatine kinase-MBmass results ^7.0 ug/1,

differencee

ChapterChapter 4

RCV V

Admission n «« *

100 15 20

Timee after onset of symptoms 2.0ug/l,

whichh may signify minor myocardial damage (patient nr. 13, table 3).

57 7


#f f >J»--

o o i i «ft t > >

—

> > m m

100 0

80 0

60 0

40 0

20 0 & &

0 0 ST-elevatt ion ST-deprcwssion / Non-diagnostic /

T-wavoo changes normal ECG

n=137 7 ami=131 1

n=167 7 ami=67 7

n=166 6 amm i=50

Figuree 2.

Sensitivityy (shaded columns) and specificity (solid columns) of the algorithm for an abnormal serial creatine kinase-

MBmaa,, (>7.0ug/l on admission or at 7 h or a rise between admission and 7 h >2.0ug/l) for the diagnosis of acute

myocardiall infarction (ami). Patients are grouped according to the admission electrocardiogram: the presence of ST-

elevation,, ST-depression or T-wave changes, or non-diagnostic or normal. There were no significant differences in

sensitivityy and specificity between groups.

58 8

ChapterChapter 4

Tablee 1, Characteristics of 470 study patients with chest pain suggestive of myocardial

ischemiaa presenting within 5 hours after the onset of symptoms

Characteristic c

Males s

Females s

Agee (years; median» range)

Historyy of:

Acutee myocardial infarction

CABG G

PTCA A

Angina a

Riskk factors;

Smoking g

Hypertension n

Diabetess Mellitus

Hyperiipidemia a

Positivee family history

Medication: :

Aspirin n

B-blockers s

Nitrates s

Ca-antagonists s

Noo medication

Admissionn ECG: ST-elevation n

ST-depressionn / T-wave changes

Non-diagnosticc /normal

Number r

328 8 142 2

64(31-93) )

157 7 80 0 90 0

251 1

153 3 156 6 73 3

100 0 127 7

188 8

160 0 191 1

167 7 175 5

153 3

125 5 192 2

(%) ) 70 0 30 0

33 3 17 7 19 9 53 3

33 3

33 3 16 6 21 1 27 7

40 0 34 4 41 1

36 6

37 7

32 2

27 7 41 1

CABG== coronary artery bypass grafting; ECG, electrocardiogram; PTCA=percutaneous transluminal coronary

59 9


Tablee 2. Number of patients with and without acute myocardial infarction diagnosed with a

creatinee kinase-MBmass >7.0ug/l at admission or 7 hours after the onset of symptoms and

additionall patients identified with a significant increase between these time points

Acutee No acute Myocardiall myocardial infarctionn infarction

(n=248)) (n=222)

Creatinee kinase-MB̂ >7.0 ug/1 Ta and/or T7

Significantt increase Ta-T7 and creatinee Jonase-MB̂ > 7.0 ug/1 at T10

Noo significant increase Ta-T7 and creatinee tanase-MB̂ > 7.0 ug/1 at T10

Significantt increase Ta-T7 and creatinee kinase-MBmass ̂ 7.0 ug/1 at T10

Noo significant increase Ta-T7 and creatinee kJnase-MBn̂

ChapterChapter 4

Tablee 3. Creatine kinase M B ^ results in individual patients

Patientt no.

1 1

2 2

3 3

4 4

5 5

6 6

7 7

8 8

9 9

10 0

11 1

12 2

13 3

14 4

15 5

16 6

17 7

a a

b b

Ta a

2.7 7

1.0 0

1.6 6

1.6 6

1.2 2

3.6 6

2.6 6

2.6 6

1.8 8

2.5 5

1.8 8

2.3 3

3.2 2

1.1 1

2.8 8

2.3 3

22 22

2.9 9

3.2 2

T7 7

6.9 9

3.1 1

4.6 6

5.6 6

6.3 3

6.6 6

4.8 8

7.0 0

6.5 5

5.0 0

5.3 3

5.3 3

6.0 0

4.6 6

5.4 4

6.4 4

6.7 7

1.8 8

2.5 5

A C K - M B ^ C H - T a) )

4.2 2

2.1 1

3.0 0

4.0 0

5.1 1

3.0 0

2.2 2

4.4 4

4.7 7

2.5 5

3.5 5

2.8 8

2.8 8

3.5 5

2.6 6

4.1 1

4.5 5

-1.1 1

-0.7 7

T10 0

499 9

7.9 9

13.1 1

7.2 2

7.2 2

8.3 3

12.0 0

7.3 3

10.1 1

5.7 7

5.6 6

3.8 8

6.7 7

6.0 0

4.3 3

6.9 9

6.8 8

14.2 2

9.6 6

CK-MB,»,, results in 9 patients (patients 1-9) with a significant increase (>2.0ug/l) between admission and 7 hours

afterr the onset of symptoms and with a CK-MB ^ above 7.0 u/l at 10 hours. There were 8 patients (patients 10-17)

withh a significant increase between admission and at 7 hou» after the onset of symptoms but with a CK-MB ^ at T10

beloww 7.0 ug/1. An additional 2 patients did not have a significant increase between admission and at 7 hours after the

onsett of symptoms but with a CK-MB™,, at T10 above 7.0 ug/1 (patients a and b).

CK-MBBB ^^ creatine kinase MBaa»; Ta*= time of admission; T7= seven hours after the onset of symptoms; T10= ten

hourss after the onset of symptoms.

61 1

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UvA-DARE (Digital Academic Repository) Early risk ...Chapterr4 Robbertt J. de Winte r Radhaa Bholasingh Annee B. Nieuwenhuijs Rudolph.. W . Koster Ronn J. G. Peters Gerard.. T. Sanders