Surviving a Decade or More After Coronary Revascularization in a Middle Eastern Population: The Impact of Diabetes Mellitus.

Introduction and aims There is scarcity of studies that evaluate cardiovascular events and repeat revascularization among Middle Eastern patients who have long-term survival after coronary artery revascularization. In this study, patients who survived at least 10 years after percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) were assessed for the evolution of cardiovascular risk factors, occurrence of acute cardiovascular events and the need for further coronary revascularization procedures after the index coronary revascularization. Patients were classied according to the presence or absence of diabetes mellitus (DM) at baseline. Methods


Introduction
Coronary artery disease (CAD) is the leading cause of death in the Middle East (1-3) and many patients require coronary artery revascularization by either coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI).
Diabetes mellitus (DM) is a major risk factor for the development and progression of CAD and adverse cardiovascular outcomes. The prevalence of DM is high and rapidly increasing among Middle Eastern region (4)(5)(6)(7). There is scarcity of studies that addressed the impact of DM on the evolution of risk factors and the need for further coronary revascularization after the initial revascularization procedure in the Middle East.
The current study enrolled Middle Eastern patients who had undergone coronary revascularization at least one decade earlier to determine the impact of DM on the prevalence and evolution of cardiovascular risk factors, the occurrence of cardiovascular events, and the need for further coronary revascularizations.

Methods
We enrolled consecutive Middle Eastern patients who had coronary revascularization by either PCI or CABG at least 10 years prior to enrollment. Patients were included if they were ≥ 18 years old at the time of the index coronary revascularization with available medical records and adequate documentation of patients' events.
Patients were enrollment during routine out-patient evaluation or in-patient settings when they sought medical care for cardiovascular or non-cardiovascular health issues. A case report form for each patient was lled out by the physician assigned by the study steering committee in each participating center.
Data were collected from patients, relatives and from medical records according to prede ned criteria for each variable. Patients were categorized at the time of the index coronary revascularization as having DM or not having DM. Data were analyzed and compared accordingly for clinical characteristics at baseline, evolution of cardiovascular risk factors, cardiovascular events and further coronary revascularization from the time of the index procedure until the time of enrollment. Cardiovascular risk factors were de ned according to standard de nitions published by the American College of Cardiology/American Heart Association (8). Hypertension was de ned as having either systolic blood pressure elevated above 140 mm Hg and/or diastolic blood pressure above 90 mm Hg on several occasions during hospital stay, being diagnosed to have hypertension or prescribed anti hypertension medications by a treating physician. DM was de ned according to the standard criteria set by the American Diabetes Association, i.e., fasting serum glucose ≥ 126 mg/dl, 2-hour glucose level ≥ 200 mg/dl, or glycosylated hemoglobin (HbA1c) value ≥ 6.5%. DM was also diagnosed in patients who had unequivocal hyperglycemia and classical symptoms of DM (polyuria, polydipsia, and unexplained weight loss) and casual plasma glucose ≥ 200 mg/dL, and those with a prior diagnosis of DM or who were prescribed anti-diabetic medications by a treating physician. Patients who were cigarette smokers at enrollment were considered current smokers. Patients who never smoked, and past smokers who quit at least one month prior to enrollment were considered non-smokers. Family history of premature CVD was de ned as MI, coronary revascularization, or sudden death before 55 years of age in father or other male rst degree relative, or before 65 years of age in mother or other female rst-degree relative. Hypercholesterolemia was determined by a diagnosis by a physician or/and a lipid lowering agent prescription, serum cholesterol ≥ 240 mg/dL, or low-density lipoprotein cholesterol level ≥ 100 mg/dL. Cardiovascular events that occurred since the index coronary revascularization included (a) acute coronary syndrome diagnosed by documented typical chest pain, electrocardiographic changes of STsegment elevation or depression, T-wave inversion, with or without elevated cardiac enzymes, (b) heart failure, diagnosed by a physician based on clinical, radiological and echocardiographic features of left ventricular systolic dysfunction (ejection fraction < 40%), (c) stroke, diagnosed by a neurologist, (d) chronic renal impairment, de ned as the presence of kidney damage or an estimated glomerular ltration rate (eGFR) Less than 60 ml/min/1.73 m 2 persisting for 3 months or more, irrespective of the cause.
Further coronary revascularization included all documented repeat PCI or CABG after the index procedure.
The study was approved by the Internal Review Board in all participating centers and an informed consent was obtained from all patients.
Statistical Analysis: Patients' characteristics were described using frequency and percentages for categorical variables and in mean ± SD for continuous variables. The differences in percentages between DM and no DM groups were analyzed using the Chi-square test and the differences in the means between the two groups were analyzed using the two-tailed Student's t test. A p value of less than 0.05 was considered statistically signi cant. All p values were the results of two-tailed tests.
Availability of data and materials: The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Table 1 shows baseline clinical characteristics at the time of the index coronary revascularization according to DM status. Patients in the DM group were more likely to have hypertension and dyslipidemia and were less likely to be smokers compared with patients with no DM group. The no DM group had longer time elapsed since the index revascularization to enrollment compared with DM group and that mainly driven by more patients in the no DM who had over 20 years elapsed since the index procedure. There were no signi cant differences in the other characteristics between the two groups.  Table 2 demonstrates the evolution of major risk factors and the development of major adverse events among the two groups from the index procedure till enrollment. The no MD group were more likely to develop hypertension compared to DM group. There were no signi cant differences in the evolution of other risk factors of clinical events among the two groups.  Table 3 summarizes the need for further coronary revascularization after the index procedure till enrollment. The DM group was more likely to require PCI procedures compared to no DM group. CABG was required similarly in the two groups. Table 3 Repeat coronary revascularization after the index procedure  Table 4 shows cardiometabolic medications used in diabetic vs non diabetic patients at the time of enrollment. Generally, there was a high utilization of guideline-directed secondary preventive therapies with no signi cant difference between the two groups except higher utilization of clopidogrel in the DM group compared to no DM.

Discussion
This is the rst report, up to our knowledge, that addressed the impact of DM on the prevalence and evolution of cardiovascular risk factors, the occurrence of cardiovascular events, the need for further coronary revascularizations among long-term survivors of coronary revascularization in a Middle Eastern population. Almost 40% of the study population had DM at baseline with close to additional 30% developed DM during the elapsed time between the index procedure and enrollment. This nding speaks to the alarming high prevalence of DM in our region. With the addition of high smoking rate among our population, it is not surprising to see the baseline index revascularization was performed at a very young age compared to western population.
The DM group required more repeat PCI compared to the no DM group; however, CABG and adverse cardiovascular outcomes were similar among the two groups. This may be related to the retrospective nature of the current study and longer time elapsed after the index revascularization in no DM group.
Retrospective nature of this study may had downplayed or missed more serious adverse events in the DM group like mortality or major disability that prevents enrollment of such patients. This is partially supported by the longer time elapsed after the index revascularization in the no DM group, thus many adverse events and repeat revascularizations are related to time factor diminishing the impact of DM. Furthermore, extended survival in this report after the index revascularization could be related to a relatively young age of patients at the time of index procedure, adoption of contemporary percutaneous and surgical coronary revascularization strategies, and the high utilization of secondary cardiovascular prevention medications.
The global burden of DM has more than doubled over the last three decades (5) with a greater escalation over the same time span was seen in the Middle East (4-6). The ascending trends of DM prevalence in our region leads to more premature heart disease, stroke and other vascular disorders (9, 10). The cardiovascular diseases (CVD) had become the leading cause of death in the Middle East (1-3, 10), with almost one to two thirds of patients admitted with acute coronary syndrome (ACS) are diabetics (11)(12)(13).
These alarming trends in the prevalence of DM and premature CVD in the region should be addressed and overturned through national and regional preventive health policies.
Coronary atherosclerosis in patients with DM is usually diffuse and rapidly progressive disease (R).
Revascularization is these patients is usually faced with augmented risk related to DM itself, type of treatment and the angiographic complexity of CAD. Thus, it is not surprising to nd that revascularization in DM patients is associated with higher rates of major cardiac adverse events (MACE) compared to no DM (14-16).

Limitations
The major limitation of the study is inherited in its retrospective design. Enrollment was limited to patients encountered after at least 10 years after coronary revascularization. The information may be biased by random selection and lack of prospective controlled data collection.

Conclusions
In this retrospective observation of Middle Eastern patients who survived at least a decade after coronary revascularization, the initial revascularization procedure was performed at a younger age compared to western population mostly related to abundance of risk factors. Almost 40% of the population had DM at baseline and an additional 30% acquired DM during the elapsed time. During follow up, DM group required more PCI revascularization compared with no DM group. Preventive strategies targeting Middle East populations are essential to minimize the burden of the disease and its consequences.

Declarations
Competing interests: The authors declare that they have no competing interests.