Analysis of Bleeding Complications in Acute Coronary Syndrome: Comparison of Effect of Tirofiban in Diabetic and Non-Diabetic Patients

Background: Coronary artery disease (CAD) is the most prevalent manifestation of cardiovascular diseases and is associated with high mortality and morbidity. The clinical presentations of CAD include silent ischemia, stable angina pectoris, unstable angina, myocardial infarction (MI), heart failure, and sudden death. Objective: This study was designed to define the frequency of hemorrhagic complications and to identify clinical variables associated with increased risk of bleeding complications in diabetic versus non-diabetic patients presented with acute coronary syndrome whom received aspirin, clopidogrel and heparin only or in combination with GPIIb/IIIa receptors blockade (Tirofiban) and to detect any bleeding complications in all patients during the period of admission in the hospital. Patients and Methods: 150 patients with ACS were divided into two groups, 82 diabetic patients and 68 nondiabetic patients. 40 patients out of total sample received tirofiban. Assessment of in hospital TIMI bleeding, GRACE and CRUSADE risk scores was estimated for all of them. Results: We observed that, there is no statistically significant difference in TIMI bleeding in both heparin and tirofiban group in diabetic versus non-diabetic patients. Cardiac catheterization access site was the most frequent location of bleeding most likely secondary to the high rate of coronary angiography performed in the study. Tirofiban added to heparin did not increase the risk of bleeding at the vascular access site. Conclusion: There was no statistically significant increase in all TIMI bleeding, thrombocytopenia or blood transfusions with the combination of tirofiban with heparin in both diabetic and non-diabetic patients.


Introduction
Acute coronary syndrome (ACS) is the umbrella term for the clinical signs and symptoms of myocardial ischemia: unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI), and STsegment elevation myocardial infarction (STEMI). Coronary artery disease can lead to ACS, which describes any condition characterized by signs and symptoms of sudden myocardial ischemia. The term ACS was adopted as it believed to reflect more clearly the disease progression associated with myocardial ischemia. Unstable angina and NSTEMI normally result from a partially or intermittently occluded coronary artery, whereas STEMI results from a fully occluded coronary artery.
Atherosclerotic plaque rupture with luminal thrombosis is the most common mechanism responsible for the majority of acute coronary syndromes and sudden coronary death. Despite continuous advances in medical interventional and surgical therapies for the treatment of atherosclerotic coronary disease the latter remains the principal killer in the Western and the developing world [1]. In addition to being a dominant risk factor for the development of coronary disease, diabetes mellitus is associated with early and late mortality after presentation with an ACS [2]. This risk was approximately equal to other major determinants of mortality following ACS. Additional robust evidence is derived by the TIMI group. An analysis of more than 60,000 ACS patients, 10,613 (17%) of whom had diabetes pooled from 11 trials during 1997 to 2006 demonstrated a nearly two-fold increase in the risk of short-term (30 days) and long-term (1-year) mortality associated with diabetes, independent of all other risk factors [3]. Diabetic patients who present with an ACS have an increased risk of future atherothrombotic adverse events, largely attributable to increased platelet reactivity and higher burden of disease severity at baseline. These patients also derive a greater benefit from established therapies, particularly more intensive platelet-inhibiting therapies, including clopidogrel "pretreatment" and GPIIb/IIIa inhibitor use, particularly during PCI. Since platelet aggregation is an important consequence and initiative factor of the formation of thrombus, antiplatelet therapy has of particular importance. Therefore, we discussed the bleeding complications in diabetic and non-diabetic patients with ACS treated by aspirin, clopidogrel and heparin alone or in combination with glycoprotein IIb/IIIa inhibitors (Tirofiban).

Subjects and Methods
The study included 150 patients with ACS; according to clinical presentation, cardiac enzymes, and Electrocardiography (ECG) admitted to Alexandria university hospital and International cardiac center starting from May 2015 till December 2015 divided into two main groups.

Group I
It included 82 diabetic patients (defined as fasting blood glucose ≥ 126 mg/dl or on treatment).

Group II
It included 68 non-diabetic patients.
All patients randomly assigned to one of the treatment groups: 65 diabetic patients received aspirin, clopidogrel and heparin only, 17 diabetic patients received aspirin, clopidogrel, heparin and GPIIb/IIIa (Tirofiban), 45 non diabetic patients received aspirin, clopidogrel and heparin only and 23 non-diabetic patients received aspirin, clopidogrel, heparin and GPIIb/IIIa (Tirofiban).
All patients underwent general, cardiac examination, laboratory tests as (CK-MB, troponin, CBC, Liver function tests, Renal function tests PT, PTT, INR), ECG, Echocardiography, risk stratification using GRACE and CRUSADE risk scores, assessment of in hospital bleeding according to TIMI classification.
Exclusion criteria: Advanced liver diseases, and coagulopathy.

Statistical analysis
Data were fed to the computer and analyzed using IBM SPSS software package version 20.0. Qualitative data were described using number and percent. Quantitative data were described using minimum and maximum, mean, standard deviation and median. Comparison between different groups regarding the categorical variables was tested using Chi-square test. Significance of the obtained results was judged at the 5% level.

Results
This study included 150 patients, 114 males and 36 females. Their mean age was 58.79 ± 11.77 yrs, 57.3% are having hypertension and 54.7% were diabetics. 11.60 ± 14.75 7.29 ± 6.86 Median 6.0 4.5 Table 1: Comparison between the two studied groups according to GRACE score and death (%). Table 1 shows comparison between diabetic and non-diabetic patients according to GRACE score and death (%), there is statistically significant difference in both GRACE and in hospital death percentage in both groups. Table 2 shows comparison between diabetic and non-diabetic patients according to crusade and in hospital major bleeding. There is statistically significant difference in crusade and in hospital major bleeding in both groups.  Table 2: Comparison between the two studied groups according to crusade and in hospital major bleeding. Table 3 describes the details of TIMI bleeding and blood transfusion in both groups TIMI major bleeding were infrequent in both groups, without statistically significant difference in all TIMI bleeding in both groups.  Table 3: Comparison between the two studied groups according to TIMI bleeding and blood transfusion.   Figure 2 shows that the catheterization site was the commonest site for bleeding in both groups followed by hematuria, GIT bleeding was more frequent in non-diabetic, without statistically significant difference in the site of bleeding in both groups.    Table 5 and Figure 3 describe the details of TIMI bleeding and blood transfusion in heparin alone and Heparin+tirofiban group in total sample. TIMI major bleeding was infrequent in both groups, without statistically significant difference in all TIMI bleeding in both groups.     Table 6: Locations of all TIMI bleedings in heparin alone and heparin +tirofiban groups. Table 7 describes the details of TIMI bleeding and blood transfusion in all studied groups. TIMI major bleeding was infrequent in all groups, without statistically significant difference in all TIMI bleeding in all groups. There is only one patients had TIMI major bleeding (in the Heparin arm of the diabetic group).

Discussion
Thrombus formation caused by unstable coronary plaque rupture, platelet activation, aggregation and adhesion was the pathological basis of acute myocardial infarction (AMI) [4]. After restoration of blood flow of infarct-related artery by PCI, slow blood flow or no-reflow was one of the major complications of emergency PCI. Acute or sub-acute thrombosis was the most serious complications and cardiovascular events (major adverse cardiac events, MACE) in emergency PCI for AMI [5]. The incidence of slow flow or no-reflow and thrombotic event for diabetic patients after emergency PCI was significantly higher than that of general population [6], dual anti-platelet therapy of thromboxane (TXA2) inhibitor (aspirin) and P2Y12 receptor inhibitors was the main therapeutic measures to prevent thrombosis.
However, there were still serious complications due to thrombosis in some patients, IIb/IIIa receptor inhibitors plus dual anti-platelet therapy can effectively reduce the incidence of slow flow or no-reflow, reduce acute and sub-acute thrombosis, reduce AMI complications and the occurrence of MACE [7], but the occurrence probability of the bleeding in the triple combination treatment of anti-platelet drugs significantly increased. How to weigh the risks of thrombotic events and bleeding complications was a serious problem that we must face [8].

In hospital bleeding
All bleeding events and blood transfusion: There was an elevated incidence of bleeding and only 2 patients required blood transfusion on both groups. Neither incidence of bleeding nor blood transfusion was statistically significant. The power to detect a statistically significant difference in these endpoints was limited by the small number of events. Our results are in agreement with Vaduganathan [9], Huynh et al. [10] and Liu et al. [11] as they did not find significant difference in major bleeding events when tirofiban and other glycoprotein IIb/IIIa inhibitors were added to heparin. Cardiac catheterization access site was the most frequent location of bleeding most likely secondary to the high rate of coronary angiography performed in the study. Tirofiban added to heparin did not increase the risk of bleeding at the vascular access site.
Bleeding and gender: In our study, male patients representing (75%) of TIMI bleeding group compared to females (25%). This risk increase was independent of age and body weight, this is matching with Tsung-Hsien et al. [12] as there were 38 males in the TIMI bleeding group (71.7%) out of 53 patients While in Alexander et al. [13], women experience more bleeding than men in the course of routine care for NSTE ACS. This higher relative risk in women is apparent with or without treatment with GPIIb/IIIa inhibitors. In addition, treatment with appropriately dosed GPIIb/IIIa inhibitors is associated with a greater bleeding risk than no treatment, and excess dosing is associated with further elevation in this risk among women and men alike. This difference may be due to small number of females in our study and more men were hypertensive with more risk of bleeding in Huynh et al. [10] and our study.
Hypertension and bleeding: In our study, 72% and 39.7% had hypertension in both diabetic and non-diabetic group respectively, 18 patients (64.3%) out of 28 patients included in all TIMI bleeding group were hypertensive (put the P value was 0.41), which is similar with Pierre et al. [14]. In the study of Lin and Tsung-Hsien et al. [12], 35 patients had hypertension in TIMI bleeding group (66.04%) with P value <0.01. In Huynh et al. [10], Tsung-Hsien et al. [12] and our study, elevated blood pressure was associated with increased risk of bleeding. The small number of major bleeding events also limits our power to detect statistically significant differences in this measure. The explanation for elevated blood pressure as a risk factor for increased risk of bleeding is not clear, and may be due to fragility of the small vessel beds in patients with prolonged uncontrolled hypertension.
Diabetes and bleeding: In our study, 28 patients (18.66%) have TIMI bleeding out of 150 patients (50%) in both diabetic and non-diabetic group, 14 patients out of 82 diabetic patients (17.07%) and 14 patients out of 68 non-diabetic patients (20.58%) which is in agreement with Tsung-Hsien et al. [12]. In the study of Pierre et al. [14] 12 patients (21.8%) out of 55 patients had DM in TIMI major bleeding.
In our study of diabetic patients, 1.5% had TIMI major bleeding in heparin group, and all TIMI bleeding represented 12.3% and 35.2% in heparin and tirofiban group respectively, while in non-diabetic patients no one had TIMI major bleeding, 20% and 21.7% had all TIMI bleeding in heparin and tirofiban group respectively, this is similar with Kleiman et al. [15] and Pierre et al. [14]. There was a modest though not statistically significant incremental risk of nonmajor TIMI bleeding with the combination of tirofiban plus heparin.

Conclusion
Finally it may be concluded that there is no statistically significant increase in all TIMI bleeding, thrombocytopenia or blood transfusions with the combination of tirofiban plus heparin in both diabetic and non-diabetic patients. The power to detect a statistically significant difference in these endpoints was limited by the small number of events.