Acute Coronary Syndrome in Patients with Prior Coronary Artery Bypass Surgery: Observations from a 20-Year Registry in a Middle-Eastern Country

Objectives Clinical characteristics and trends in the outcome of acute coronary syndrome (ACS) in patients with prior coronary artery bypass graft surgery (CABG) are unclear. The aim of this study was to evaluate clinical characteristics, in-hospital treatment, and outcomes in patients presented with ACS with or without a history of prior CABG over 2 decades. Methods Data were derived from hospital-based study for collected data from 1991 through 2010 of patients hospitalized with ACS in Doha, Qatar. Data were analyzed according to their history of prior CABG. Baseline clinical characteristics, in-hospital treatment, and outcome were compared. Results A total 16,750 consecutive patients with ACS were studied, of which 693 (4.1%) had prior CABG. Patients with prior CABG were older (mean 60.5±11 vs. 53±12 years; P = 0.001), more likely to be females and have more cardiovascular risk factors than the non-CABG group. Prior CABG patients had larger infarct size, were less likely to receive reperfusion therapy, early invasive therapy and more likely to receive evidence-based therapies when compared to non-CABG patients. In-hospital mortality and stroke rates were comparable between the 2 groups. Over 2 decades, there was reduction in the in-hospital mortality rates and stroke rates in both groups (CABG, death; 13.2% to 4%, stroke; 1.9% to 0.0%, non-CABG, death; 10% to 3.2%, stroke 1.0% to 0.1%; all, p = 0.001). Conclusion Significant reduction in-hospital morbidity and mortality among ACS patients with prior CABG over a 20-year period.


Introduction
There is a growing global attention concerning the short and long term prognosis of acute coronary syndrome (ACS) in patients with prior coronary artery bypass grafting (CABG). Despite the indisputable benefit of CABG surgery in reducing morbidity and mortality [1], acute myocardial infarction (MI) still reported with an incidence of 3% to 8% annually following bypass graft surgery [2]. In patients with ACS, some of the previous reports suggested prior CABG as an independent risk factor for mortality [3,4], while others reported equal or even more favorable prognosis when compared to non-BABG patients [5][6][7][8][9]. A recent global rising in the number of ACS was observed in patients with prior CABG [10], as a result of the worldwide increasing numbers of bypass surgeries performed annually [11,12] and in the consequences of the angiographically recognized loss of vein graft after surgery (50% become diseased and 25% occluded) by 5 years [2].
In general, patients with prior CABG have often been underrepresented in ACS clinical trials. Furthermore, trend in the outcome of ACS patients with prior CABG patients is lacking. We hypothesize that the clinical characteristics, treatment and outcome of ACS patients with prior CABG to be different than patients without prior CABG. Our second hypothesis is that the improvement in the surgical techniques of CABG and increase use of evidence-based therapy over the past two decades resulted in significant reduction in morbidity and mortality of ACS patients with prior CABG.

Study Setting
This study is based at Hamad General Hospital, Doha, Qatar. This hospital provides inpatient and outpatient medical and surgical care for all population of Qatar, including nationals and expatriates. More than 95% of cardiac patients are being treated in this hospital, making it an ideal center for population-based studies. The vast majority of acute coronary syndrome patients (.95%) are admitted at this hospital. In the last decade of the 20 th century, cardiovascular diseases are the leading causes of morbidity and mortality in Qatar. Qatar is a small country with a population of around 600,000 (2001 Census) and 1,6 million (2010 Census), consisting of Qatari and other Middle Eastern Arabs (less than 40%) and non-Middle Eastern Arabs of which the vast majority are South Asians mainly from India, Pakistan, Nepal and Bangladesh.
The Cardiology and Cardiovascular Surgery Database at Hamad General Hospital was used for this study. A case report form with a specific registration identification number for each patient admitted to Hamad General Hospital with cardiac illnesses was filled out by the assigned physician who followed the patient throughout hospital stay using standard definitions, and completed before the patient's hospital discharge. Data were collected from the clinical records according to predefined criteria for each variable. These records have been coded and registered at the cardiology department since January 1991 [13]. With the described database, all patients presenting with ACS whom hospitalized in the 20-year period between January 1991 and end of 2010 were retrospectively identified. We categorized our study cohort (n = 16,750) on the basis of prior bypass surgery into two groups, with or without prior CABG. Accordingly data were analyzed and compared for clinical characteristics, treatment and in-hospital outcomes. Ethical approval from Research Committee of Hamad Medical Corporation was obtained before starting collection of data for the study. The ethics committee waived the need of informed consent because of its retrospective analysis and the fact that the data was analyzed anonymously.

Definitions
Standard definitions were used to diagnose ACS. Formerly acute MI was defined for this study according to the World Heart Organization criteria for Q-wave and non Q-wave MI. Then, STEMI and NSTEMI were defined by a positive serial troponin-T blood test result ($0.1 ng/ml) in the setting of symptoms and electrocardiographic changes consistent with MI [14]. Unstable angina was diagnosed if the patient had a negative cardiac biomarker and any one of the following characteristics: new-onset angina (,2 months) of at least class III according to the Canadian Cardiovascular Society, prolonged (.20 minutes) angina at rest, recent (,2 months) worsening of angina pectoris, or angina that occurred within two weeks of an acute MI [15].
The presence of hypertension was determined by any documentation in the medical record of hypertension or if the patient was on treatment by the patient's physician. The presence of diabetes mellitus was determined by the documentation in the patient's previous or current medical record of a documented diagnosis of diabetes mellitus that had been treated with medications or insulin. Smoking history: Patients were divided into current cigarette smokers, past smokers defined as more than 6 months abstinence from smoking, and those who never smoked. Chronic renal impairment was defined as creatinine .1.5 upper normal range. The presence of hyperlipidemia was determined by the demonstration of a fasting cholesterol .5.2 mmol/L in the patient's medical record, or any history of treatment of hyperlipdemia by the patient's physician. Congestive heart failure (CHF) was defined using the Framingham criteria. The simultaneous presence of at least two major criteria or one major criterion in conjunction with two minor criteria was required to establish a diagnosis of CHF. Major criteria included paroxysmal nocturnal dyspnea or orthopnea, jugular venous distension, pulmonary rales, radiographic cardiomegaly, acute pulmonary edema, a third heart sound, central venous pressure above 16 cm of water, hepatojugular reflux, and weight loss of at least 4.5 kg in 5 days in response to treatment of heart failure. Minor criteria included bilateral ankle edema, nocturnal cough, dyspnea on ordinary exertion, hepatomegaly, pleural effusion, and a heart rate of at least 120 beats per minute. Minor criteria were acceptable only if they could not be attributed to any other medical condition (such as chronic lung disease, cirrhosis, ascites, or the nephrotic syndrome) [16].

Statistical Analysis
Patients' characteristics are presented in frequency and percentages for categorical variables and in mean 6 SD for Table 2. Medication received before, during admission and at discharge in acute coronary syndrome patients with or without prior coronary artery bypass surgery.

Study Population
Overall, from January, 1991 to the end of year 2010, a total of 41,438 patients hospitalized with acute cardiac disease were scrutinized 16,750 of these patients were admitted with ACS, of them 693 patients (4.1%) were with prior CABG and 16,057 patients without previous CABG. Table 1 shows the baseline clinical characteristics of the patients. Those patient with prior CABG were older than patients without prior CABG (mean 60.5611 vs 53612 years; P = 0.001).

Baseline Clinical Characteristics
Females constituted 17.7% of the CABG group and were significantly more in numbers than the non-CABG group 14.7% (P = 0.03). The body mass index mean values showed no significant variation between the two groups (27.565 vs 28614; P = 0.61). Study of different population ethnicity showed Middle Eastern Arabs were significantly more common to have a prior bypass surgery than patient without bypass (55.4% vs 41.9%; P = 0.001). While South Asian population were less commonly had prior CABG (35.4% vs 45.1%; P = 0.001). Sub-analysis of age revealed patients with prior CABG were significantly older than their counterparts in all ethnicities (p = 0.001).
During hospitalization, the comparison of coronary care unit days of stay showed a significant longer stay in CABG patients as compared to patients without prior CABG (4.6265.6 vs 3.4663.2; p = 0.006). Likewise, total days of stay including step-down ward stay was longer in CABG patients (6.6967 vs 5.4965.54; p = 0.001). Patients with no prior bypass graft surgery reported higher mean values of peak ceatine kinase-MB when presented with ACS (231.26757 vs 87.46288; p = 0.001). Similarly, higher positive results of troponin-T during hospitalization (43.3 vs 36.2; p = 0.001). Table 2 shows medication use before, during admission and at discharge in ACS patients without prior CABG.

Medications Prescribed
Before admission. Primarily ACS patients with prior CABG were more commonly prescribed previous treatment with aspirin, clopidogrel, beta blockers, calcium channel blockers (CCB) and angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARB) than patients with no prior CABG (P = 0.001).
Trend of outcomes. Table 3 shows the trend of outcomes in term of mortality and stroke in ACS patients with or without prior CABG. Over the 20-year period, there was significant increasing number of CABG operations (p = 0.001). The in-hospital mortality rate significantly reduced from peak 13.2% to 4.0% (p = 0.001) for patients with prior CABG and from 10% to 3.2% (p = 0.001) for patients without prior CABG (figure 1). Stroke rates also, reduced from peak 1.9% to 0.0% (p = 0.001) for patients with prior CABG and from peak 1.0% to 0.1% (p = 0.001) for patients without prior CABG.
Ten years comparison of outcomes. Table 5 reveals morbidities and mortality comparison in periods, 1991-2000 and 2001-2010 according to history of prior CABG. There was significant reduction in mortality and the majority of morbidities measured (reinfarction, cardiogenic shock and advanced heart block) in the latter when compared to the earlier time periods regardless of prior CABG history, with the exception of stroke and ventricular arrhythmia rates which were comparable in the two time periods among patients with prior CABG only.

Discussion
The current study reports the clinical characteristics, treatment and outcome of Middle-eastern ACS patients according to their    history of prior CABG. Patients with prior CABG were older, constitutes more females and carrying more cardiovascular risk factors including diabetes mellitus and hypertension than non-CABG group. Prior CABG patients were more likely to have larger infarct size and less likely to receive reperfusion therapy and early invasive therapy when compared to non-CABG patients. Despite having worse clinical profile, prior CABG patients had comparable morbidity and mortality to non-CABG patients. Over 20-years period, the current study reports for the first time significant reduction in mortality and stroke rates among ACS patients with prior CABG, which may be attributed to improvement in surgical CABG techniques and more use of evidence therapies.
The prevalence of prior CABG in ACS patients is variable. This study demonstrates a lower proportion of patients with prior CABG (4.2%) in our ACS cohort as compared to previous reports from Western countries (7%-27%), [8][9][10][17][18][19][20][21][22]. However, similar data were reported in other series [5,23,24]. We reported an increasing number of CABG patients hospitalized with ACS matching the significant increase in the population of Qatar which nearly tripled since 2001 (600,000 population in 2001 and 1.6 million population in 2010).

Clinical Characteristics
The reported older ages in CABG patients is consistent with previous studies when compared to patients without prior CABG [9,18,21,[25][26][27]. Likewise, the predominance of men in both groups. Females were significantly more prevalent in our population with prior CABG, a similar finding was reported in previous studies conducted on same Middle-eastern population [28,29]. This female preponderance with prior CABG was not reported in Western population. In comparison to patients without prior CABG and consistent with the earlier reports, CABG patients clearly had more adverse baseline characteristics and burden of co-morbidities when presenting with ACS. They more often had a history of cardiovascular risk factors such as hypertension, diabetes and dyslipidemia, as well as, higher prevalence of chronic renal impairment. In addition, they had a greater likelihood of prior MI and treated heart failure [9,18,22,23,[25][26][27]30].

In-hospital Management
Evidence-based therapies among ACS patients with prior CABG are very limited to post-hoc analysis of limited number of trials and registries, which suggested underuse of evidence-based therapies in this high-risk group as aspirin, beta-blocker, or thrombolytic therapy in the VALIANT trial [10], or evidencebased medications and PCI in the expanded-GRACE analysis in NSTEMI [3]. Our observations demonstrate increased use of aspirin, clopidogrel, b-blockers, ACE/ARB among ACS patients with prior CABG. The significant greater likelihood of evidencebased medications used before and during admission in our cohort with prior CABG reflect the unprejudiced utilization of evidence based medication in previous CABG patients by our physicians as well as this results may emphasize on the protective value accomplished by these medications as have been well established in different studies to reduce mortality in patients with coronary artery disease [31][32][33][34][35]. We observed an overall very low use of invasive procedures including coronary angiography and percutaneous coronary revascularization when compared to reports from Western countries, however it is consistent with recent study (2006)(2007) conducted in 6 Middle -eastern countries and reported overall 20% use of coronary angiography among ACS patients [36]. The Effect of Prior CABG on Outcomes In-hospital mortality. The effect of prior CABG on mortality after ACS remains controversial (Table 7). Observational studies based on selected clinical trial populations have demonstrated a worse clinical outcomes and reported higher likelihood of adverse events of patients with ACS and prior CABG compared to those without prior CABG [10,18,19,22,[37][38][39]. Prior CABG is an independent risk factor for in-hospital mortality [10] and at both 30 days and 1 year after MI [40,41]. In GUSTO-1 (Global Utilization of Streptokinase and TPA for Occluded Arteries I) trial, patients with prior CABG had shown an increased 30-day mortality of 10.7% vs 6.7% (P = 0.001). In the GRACE registry prior CABG was associated with increased both inhospital mortality and early mortality [7,30]. All these older studies showed poor prognosis in patients with prior CABG presenting with ACS.
On the other hand, more recently several studies have showed no significant differences in in-hospital and long term prognosis in patients with or without prior CABG presenting with ACS. Teixeira et al, reported no significant influence of prior CABG on short or medium term outcomes, such as all-cause mortality and adverse cardiac events in patient presenting with ACS [5]. As well as, Kim et al [4] concluded that, in-hospital mortality did not differ significantly from non-CABG patients who had NSTEMI (adjusted ORs 1.00, 95% CI 0.92-1.11 and 0.99, 95% CI 0.87-1.11, respectively). In addition, Elbarasi et al, demonstrated less in-hospital mortality in NSTE-ACS patient with prior CABG (1.7%) and prior CABG with PCI (0.9%) than in patients without prior CABG (2.3%) (P = 0.001) [3]. Wisemann et al, reported similar 1-and 5-year mortality rates in patients with and without prior CABG [42]. Furthermore, Mathew et al, reported a weak association of prior CABG with adjusted in-hospital mortality in patients who had STE/LBBB (OR 1.11, 95% CI 1.00-1.23), but not in patients had NSTE/ LBBB (OR 0.99, 95% CI 0.92-1.07), [9]. These reports may point toward a possible protective role might be played by CABG against death in patients who have history of severe coronary artery disease enough to merit revascularization presented currently with ACS. In addition, the better prognosis observed in the recent studies may be a sign toward the role of the guideline recommended evidence based therapies in the management of coronary artery disease patients.
In this study it was found that although patients who had previously undergone CABG presented with significantly adverse baseline characteristics and had larger infarct size, they demonstrate no significant difference in in-hospital mortality when compared to patients without prior CABG. It remains somewhat intriguing, why high risk background did not translate into worse mortality. Advanced age is an important risk factor for mortality, however our CABG patients demonstrated to be younger than other reported cohorts. This along with less recurrence of ischemia or infarction together with the higher prevalence of previous and in-hospital treatment with evidence-based medications may explain to some extent their favorable outcome.

The Effect on Stroke and other Morbidities
Most of studies revealed a higher prevalence of prior stroke in prior CABG patient when presented with ACS. However, the occurrence of stroke as a new complication in those patients is still controversial.The observed non-significant difference of stroke between post-CABG patients and those who had not undergone a previous CABG, was a similar finding observed by texiera et al [5] and others [18]. In contrary brikalis et al reported those with previous CABG were approximately 2 times as likely as to develop stroke than those without prior CABG [19]. Likewise, Berry et al, showed CABG patients were more likely to experience the composite outcome of cardiovascular death, MI, HF, resuscitated cardiac arrest, or stroke; 3 year Kaplan-Meier rate, 64 vs. 39% (adjusted hazard ratio 1.29, 95% CI 1.17-1.43; P, 0.0001), [10].

The Trends
Mortality rates from coronary heart disease and from acute MI, in particular, have been declining steadily since the 1970s in several Western populations. In the United States, Krumholz et al, reported significant decrease in the risk-standardized hospital mortality rate for patients discharged with Acute MI between 1995 and 2006 [43]. We observed for the first time, over 20 year period, there was a significant reduction in mortality and stroke rates among our population with or without prior CABG who presented with ACS.
It is worth mentioning that, although, the results were generalized and including all patients admitted to CCU and no case exempted for registration in the registry. The result of this study should be interpreted in the context that, the data presented were intended to provide a fairly general representation of the practice and trends over the last 2 decades; as such, these data are largely descriptive without adjustment for case mix, so conclusions based on observed associations should be made with caution.

Conclusion
The current study on the clinical characteristics, treatment and outcome of Middle-eastern ACS patients according to the history of prior CABG reports significant reduction in-hospital morbidity and mortality among ACS patients with or without prior CABG over 20-years period.

Study Limitations
First, as in all registry studies spanning long time intervals, admission policies to the CCU and management of ACS would have changed considerably during this study period. Second, our data were collected retrospectively from records registration over 20 years, which is another limitation. The fundamental limitations of retrospective observational studies cannot be eliminated because of the nonrandomized nature and unmeasured confounding factors. However, well-designed retrospective observational studies may provide valid results without systematic overestimation, bias or predilection. Finally, detailed surgical data was not available on prior CABG patients such as the number of bypass grafts and the use arterial grafts.