S.M.N.A. Nadeem ( Cardiology Section, Department of Medicine, The Aga Khan University )
K. Kazmi ( Cardiology Section, Department of Medicine, The Aga Khan University )
I. Chandna ( Cardiology Section, Department of Medicine, The Aga Khan University )
N. Basir ( Cardiology Section, Department of Medicine, The Aga Khan University )
A. Pathan ( Cardiology Section, Department of Medicine, The Aga Khan University )
Acute coronary syndrome is a useful operational term, referring to clinical situations with symptoms suggestive of acute myocardial ischemia. It encompasses acute myocardial infarction including ST-segment elevation myocardial infarction, non-ST-segment elevation myocardial infarction (NSTEMI), unstable angina (UA) and sudden ischemic death. Patients with acute ST-elevation myocardial infarction constitute a distinct group with distinct management strategies including immediate reperfusion therapy either by fibronolytic agents or by catheter based interventional procedures, as dictated by patient's hemodynamic state, availability of treatment modalities and other logistic considerations.
Several studies have shown that patients with UA and NSTEMI are a heterogeneous group with a variable subsequent adverse outcome. At the time of presentation, patients with UA and NSTEMI may be indistinguishable and are managed on similar lines. Early risk stratification is therefore important to identify high-risk patients requiring aggressive management strategies including early revascularization procedures. Recent prognostic studies have shown that both short and long term mortality and risk of subsequent reinfarction are largely determined by myocardial damage at initial presentation. Cardiac specific Troponin-T (TnT) and Troponin-I assays are highly sensitive in detecting myocardial damage.1 Recent clinical data has suggested TnT as an independent predictor for short and long term adverse cardiac events.2
Most of the prognostic studies done on TnT have been reported from west.3-9 Reports from the developing world addressing the role of TnT in patients with acute coronary syndrome are scarce.10-12 To our knowledge none of the report from developing world has so far discussed long-term prognostic significance of TnT.
The purpose of this study was to validate the prognostic significance of this novel marker of myocardial injury in a cohort from Pakistan, a developing county. We also sought to test the independent prognostic significance of other early available clinical risk indicators after adjustment for Troponin Status.
This was a single center, prospective, observational, follow-up study conducted at The Aga Khan University Hospital, a tertiary care referral center. All consecutive patients admitted to coronary care and step down units between November 1, 1997 and October 31, 1998 with the diagnosis of acute coronary syndrome (ACS) without ST-segment elevations were screened for eligibility. ACS was defined as typical resting chest pain symptoms or sudden acute respiratory distress suggestive of coronary insufficiency. A dynamic ST deviation on electrocardiogram was considered supportive but not mandatory for inclusion. Diagnosis of NSTEMI was later confirmed by total creatinine kinase (CK) greater than twice-upper limits of normal or an elevated CK-MB fraction.
During the study period 350 consecutive patients with acute coronary syndrome without ST-Segment elevations were screened for eligibility. Exclusion criteria included significant renal impairment defined as serum creatinine greater than 2.0 mg/dl (n=36), left bundle branch block (n=24), cardiogenic shock (n=3), revascularization either percutaneous or surgical in last six months (n=5), recent myocardial infarction in last two months (n=4), acute coronary syndrome precipitated by secondary causes like anemia (n=8) and Non cardiac chest pain on subsequent evaluation during hospital stay (n=15). After exclusion, 255 patients were found eligible for inclusion.
Troponin-T Assay: All patients had a baseline TnT estimation at presentation and repeated, in case of an initial negative result, at least 12 hours from onset of symptoms. Strips manufactured by Roche for specific detection of cardiac TnT through quantitative immunological tests were used. This test contains two monoclonal antibodies specific for cardiac TnT: one gold-labeled, the other biotinylated. Test strips were analyzed by using optical system of cardiac reader provided by Roche. The quantitative range for cardiac TnT detection extends from 0.1ng/ml to 2ng/ml. The reader interprets TnT concentration below or above this range qualitatively (low or high respectively). The cutoff used in our study for positive TnT assay was 0.1ng/ml.
Follow-up information was collected by telephone contact and review of medical records, with a mean follow-up of 13 + 6 months (33 days to 30 months). The prospectively determined primary end point was a composite of all cause mortality and non-fatal Myocardial Infarction at long-term follow-up .
Data was analyzed using Statistical software SPSS Version 10.0. Descriptive data will be expressed as mean+SD for variables with normal distribution and median with range for all other variables. Chi-square test was done for categorical variables to assess differences among baseline clinical features, while student's t test for continuous variables. Overall survival and event free survival were computed according to the Kaplan-Meier method. Comparison of survival between subgroups was performed by the log-rank test. Independent determinants of prognosis were identified by multivariate Cox-regression proportional hazard model using all-important biological variables and variables with a p value less than 0.2 by univariate analysis. A difference in log likelihood was used to test significance of added variables. Statistical significance would be inferred at a two-tailed p value <0.05.
From the initial 255 patients selected for study, follow-up was available in 233 (91.4%). Follow up was available in 92.7% of patients with positive Troponin-T assay and 90.3% of patients with negative Troponin-T test, signifying no differential loss to follow up. There were more males (p=0.03) and smokers (p=0.002) among patients with positive TnT as compared to those with negative TnT (Table 1). Rest of the baseline characteristics were equally distributed between the two groups. Significantly higher proportions of patients with negative
TnT were talking either beta-blockers or Calcium antagonists at the time of index cardiac event (Table 1).
|Table 1. Baseline characteristics according to Troponin-T status.
||Positive troponin-T (n=102)
||Neagative tronion_T (n=131)
|Current smokers 2
|Ever Smoked 3
|Family History of CAD
History of :
|Medications at presentation
Data are expressed as mean + SD or number (%) of patients. NS > 0.05.
MI=Myocardial Infarction, PTCA=percutaneous transluminal coronary angioplasty.
CABG = Coronary artery bypass grafting, CHF=Congestive Heart Failure, CAD = Coronary artery disease.
ACE-I = Angiotensin converting enzyme inhibitor.
1. Diabetes is defined as history of diabetes, need for oral hypoglycemic agents or insulin or fasting blood glucose of greater than 126 mg/dl.
2. Current smoker is defined as smoking within one month of presentation. 3. Ever smoked means any prior history of smoking. Patients with positive TnT had significantly higher pulse rate at presentation (p=0.004) higher proportion had dynamic ST depressions (p < 0.01) and comparatively lower left ventricular ejection fraction (p<0.001). Patient with positive TnT also required longer stay at Coronary Care or step down units (p < 0.001) and more frequent need for repeat visits to Coronary Care or step down units during same hospitalization (Table 2).
Patients with positive TnT had significantly higher incidence of heart failure (p < 0.001) during hospital stay, a trend toward higher incidence of recurrent angina (p=0.09) and arrhythmia requiring treatment (p=0.05). Three patients died during hospital stay, all with evidence of Troponin leak (Table 2). Among patients with negative TnT, 13 had evidence of NSTEMI based on conventional criteria of two-fold or greater rise of total CK or CK-MB greater than upper limits of normal (Table-II). However none of these patients had any adverse outcome, including death, myocardial infarction or need for revascularization, on long-term follow-up (data not shown).
In the 30-day follow-up no patient with negative TnT died. Higher incidence of heart failure and recurrent angina was observed among patients with positive TnT
(Table 3) along with higher need for repeat hospitalization for cardiac reasons.
Table 3. Short term (30-day) clinical outcome.
* P value according to Fisher's exact test. NS > 0.05
PTCA = percutaneous transluminal coronary angioplasty
CABG = Coronary artery bypass grafting
CHF = Congestive heart failure.
Overall survival was significantly reduced in patients with positive TnT. By Kaplan-Meier analysis with negative TnT was 93.6% vs. 75.1% for those with positive TnT (p=0.001). The incidence of composite end point of death and non-fatal MI (Figure-2) was significantly low in patients with negative TnT 7.2% vs. 33.1% among those with positive TnT (p< 0.001).
Table 4. Cox regression by univariate analysis for predictors of Death or Non-Fatal Myocardial Infarction on Long Term Follow-up.
NS > 0.05
* Continuous variables, Hazard ratios are for per unit increase.
CHF=Congestive Heart Failure, SBP=Systolic blood pressure.
w Use during hospital stay and / or at discharge.
y Dynamic ST depression of greater than 0.5 mm.
= Medication in use by patients at presentation.
p LVEF=Left ventricular ejection fraction (%), data available for 115 patients.
f Troponin - T > 0.1ng/ml
Table 5. Multivariate Cox-Regression Proportional hazard analysis for predictors of long-term mortality and non-fatal myocardial infarction.
* Hazard ratio's are for per unit increase.
= Troponin - T > 0.1ng/ml
Age, previous history of CHF, pulse rate at presentation, positive TnT, peak CK and a low LVEF had strong positive association with primary composite outcome
by univariate analysis (Table 4). Prior MI, systolic blood pressure at presentation and ST-depression were also positively associated with subsequent death and non-fatal MI, whereas elevated cholesterol and use of lipid lowering therapy (mostly statins) showed negative association. High association was observed between elevated cholesterol and subsequent use of lipid lowering therapy (p<0.001) explaining the probable cause of observed protective effect of elevated cholesterol on univariate analysis. Similar associations were observed between history of CHF and use of Angiotensin converting enzyme Inhibitors (p<0.001). Strong linear correlation was observed between pulse rate at presentation and systolic blood pressure at presentation (p = 0.005). All variables with p<0.2 and gender being clinically important, were entered into multivariate analysis by Cox regression proportional hazard analysis using time to death or non-fatal MI as dependant variable. Independent predictors for primary outcome by multivariate analysis are listed in Table 5. Low LVEF, although strongly associated with primary outcome on univariate testing was not used for multivariate analysis because information was missing in significant proportion of patients.
This study confirms that the presence of myocardial damage identified by elevation of TnT is a strong prognostic indicator in patients with unstable acute coronary syndromes. Elevation of TnT >0.1mg/ml was associated with a 3.5 fold increase in the relative risk of death and non-fatal MI at one year (Figure 2). The curve starts to diverge very early in first 30 days, with no death observed among patients with negative TnT, however the difference was not statistically significant due to small number of events (Table 3). The curves continue to separate with time, with relative risk increasing to 4.5 fold at 18 months between the groups (Figure 2). These results are in accordance with the previously reported cohorts.3-9 Similar results have recently been reported from India showing significantly worse in hospital outcome among those patients with an initial TnT leak at admission.11
Troponin-T has been used in emergency rooms for triage of patient with acute chest pain.13 It has also been shown to have independent prognostic value in patients without ischemic electrocardiographic changes, a subset otherwise believed to have low-prevalence of coronary artery disease and good prognosis.14 In our study ischemic ST-depression, were not identified as an independent predictor. Previous reports have shown that ST segment depression in patients with acute myocardial infarction was associated with increased short-term mortality15, however reports on long-term survival are conflicting.15-17 The multi-center Diltiazem post infarction trial research group showed approximately double one-year mortality in patients with ST segment depression with or without Q waves17 and ST segment depression as an independent predictor of mortality over 4-years of follow-up period17, whereas others have failed to demonstrate such effects on long term survival.15
CHF (HR 6.17; 95% CI 2.4-15.8, <0.001) and age (HR 1.05; 95% CI 1.02-1.08; p = 0.002) were identified as an independent risk predictor (Table 5) in our group. These findings are consistent with most of the previously reported studies.18,19 The excess relative mortality associated with CHF has previously been reported to be associated with every age strata and absolute excess mortality most pronounced in the elderly than in young.18 LVEF was found to be a powerful predictor of subsequent adverse outcome in our study on univariate analysis, however due to substantial amount of missing data on LVEF, we were not able to test in multivariate analysis, one of the major limitation of our study. Previous reports have clearly shown LVEF to be a strong independent predictor, and its interaction with transient or persistent CHF has also been reported.19
Positive TnT was an independent predictor in our study (Table 5). It is estimated that approximately 30% of patients who present with rest pain without ST-segment elevation and would otherwise be diagnosed as having unstable angina because of a lack of CK-MB elevation actually have non-ST-elevation myocardial infarction when assessed with cardiac specific Troponin assay.20, 21 Case reports exists that confirm histological evidence of focal myocyte necrosis or micro infarction in patient with elevated cardiac Troponin levels and normal CK-MB or CK values indicating that myocardial necrosis can be recognized with increased sensitivity.22,23 Myocardial infarction has recently been redefined, incorporating rise of Troponin as one of the diagnostic criteria for acute MI.24
Peak CK was also an independent predictor in our study (Table 5). Both early and late peak CK has been described as a marker of successful reperfusion with myocardial salvage in patients with acute ST segment elevation myocardial infarction receiving thrombolytic therapy25,26, predicting favorable long-term clinical outcome. However, prognostic value of peak-CK in patients with NSTEMI has not been frequently studied. Peak CK has also been reported as predictor of in hospital CHF with subsequent increased adverse cardiac events on late follow-up.27
Gender was not identified to be associated with subsequent clinical outcome. Based on previous studies, estimates of the relative risk of woman as opposed to men have varied from unity to as high as 1.5.28-31 Since the disease occurs average 10 years later in women and because women have a higher incidence of other risk factors and co-morbid features-particularly hypertension, diabetes and obesity - it is difficult to assess the effect of female gender per se.32 A report from China has suggested higher short-term mortality in women after myocardial infarction even after adjustment for age, hypertension and other associated co-morbid, however 10-year cumulative mortality was not significantly different between both genders.33
Pulse rate at presentation was significantly associated with subsequent death and myocardial infarction on univariate analysis. Pulse rate was also highly correlated with age (p=0.001) and associated with prior history of CHF (p< 0.001). When entered with model containing age and CHF, pulse rate was not identified as independent predictor of subsequent adverse events.
It has been recognized for several decades that diabetic patients have a two to three fold increased risk for cardiovascular disease compared with their non-diabetic counterparts. Prevalence of diabetes mellitus in cohorts with acute coronary syndrome reported from west, ranges from 11-27%34-36, whereas the proportion of diabetes in our cohort was 51.9%, further raising the concerns of alarming epidemic of diabetes in Asia.37,38 In our study diabetes was not identified as predictor of death or MI at long-term follow-up. This is in contrast to most previous reports suggesting diabetes as an independent predictor of subsequent mortality after unstable angina and non-Q-wave myocardial infarction.39,40 However a report from Sweden suggest that although overall one year mortality rate was higher among diabetes with MI, adjusted multivariate analysis failed to show diabetes as predictor of death or reinfarction.41
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We would like to acknowledge the help of Dr. Waris Qidwai in designing the questions, Dr. Abdul Hafeez for his help in conducting the questionnaire and Mr. Kareem Keshwani for his help with the manuscript. We would also like to acknowledge the help of the Bioethics Group of the Aga Khan University in funding the project.
A poster based on this data was presented at UAE international Conference on Healthcare Ethics, Abu Dhabi 10-13 March 2002.
Objectives: Troponin T (TnT) is an independent predictor for short and long-term adverse cardiac event. We evaluated the prognostic significance of TnT in our patients and also tested the prognostic significance of other early available clinical risk indicators, after adjustment for TnT.
Methods: We studied 255 consecutive patients admitted with the diagnosis of Unstable Angina (UA) and Non- ST-Segment elevation myocardial infarction (NSTEMI). All patients had a baseline TnT estimation at presentation and repeated twelve hours later, in case of an initial negative result. Follow-up was available in 233 patients (91%) with a mean duration of 13 + 6 months.
Results: By Kaplan Meier estimates; survival free of myocardial infarction was 92.8% in TnT- vs. 66.9% in TnT+ group (p = 0.001) at 18 months. By multivariate Cox- regression analysis, independent predictors of death and myocardial infarction (MI) were positive TnT (HR 2.96, 95% CI 1.34-6.56), increasing age (HR for one year increase 1.05, 95% CI 1.02-1.08), history of congestive heart failure (CHF) (HR 6.17, 95% CI 2.40 - 15.87) and peak CK (HR for one IU/L rise 1.00, 95% CI 1.00-1.001).
Conclusion: Positive Troponin T in patients with UA/NSTEMI is a strong, independent risk predictor of future death and MI. In addition, history of CHF, peak CK and age were also associated with increased risk of death and MI. Conventional risk predictors like pulse rate, ST depression, gender and diabetes were not identified as independent risk predictors (JPMA 53:280;2003).