Management of acute UGIB and endoscopic examination in poor cardiac function patients are complex. To our knowledge, this study was the first multicenter RCT to evaluate the efficacy and safety of urgent endoscopy for management of acute UGIB in ACS patients. We have found that EE had higher rate of hemorrhage control, lower 3-day rebleeding rate, and lower needs for blood transfusion than PPI therapy alone. Additionally, early intervention with endoscopy did not increase risk of complications as compared with medical treatment. However, EE should be carefully considered for male patients with recent ACS, while there might be higher complication rate than female patients by logistic regression analysis in our study.
Acute UGIB remains challenging with significant morbidity, particularly composite ischemia (HR 1.94 at 30-day, p<0.05, and 1.9 at 1-year, p<0.001), mortality from all-cause (HR 4.87 at 30-day, p<0.05, and 3.97 at 1-year, p<0.05) and cardiac events (HR 5.35 at 30-day, p<0.05, and 3.77 at 1-year, p<0.05).1,22−25 Despite of many benefits from EE, no study has been able to demonstrate that EE leads to a reduction in mortality of acute UGIB. One of the most important reasons is probably due to that mortality of patients with acute UGIB is mainly determined by co-morbidity rather than the success of hemorrhage control.1,2,26 Moreover, endoscopy carries certain potential risk for complications, including cardiopulmonary events, infectious and thromboembolic events, bleeding, instrumental (perforation, penetration and impaction), and drug reaction from premedication.5,6 Thus, whether to perform EE in ACS patients presenting acute UGIB is always questionable.
Among ACS patients, DAPT remains cornerstone for the management, especially after coronary artery stenting.7 Aspirin interferes platelet aggregation activity and has been demonstrated to reduce the risk of cardio-and cerebro-vascular events by as much as 30%, and 18% of all-cause mortality in the secondary prevention of cardiovascular diseases.13,27,28 However, aspirin increased the risk for GI adverse effects because of inhibition of cyclooxygenase-mediated prostaglandin synthesis. Up to 60% of aspirin users develop GI mucosal lesions under endoscopic examination, especially stomach and duodenum.29 Clopidogrel, another antiplatelet agent, inhibits platelet function by blocking the adenosine diphosphate receptor on platelets and the CAPRIE trial has shown that long-term clopidogrel monotherapy was more effective and better tolerated than aspirin in reducing combined risk of ischaemic stroke, MI, or vascular death.30 Clopidogrel seems to be associated with fewer GI adverse effects compared with aspirin.30 Nonetheless, an animal study revealed that clopidogrel impair the healing of gastric ulcers by suppressing the release of platelet-derived growth factors which are crucial for repair of mucosal defects.9 Clinical studies have also disclosed that 8-12% of clopidogrel users with a history of PUD bleeding develop recurrent GI bleeding within 12 months.31,32 A nationwide population-based study demonstrated that the use of clopidogrel increased the risk of UGIB with HR of 3.66 (95% CI 2.96-4.51), especially in elderly, CKD, past history of PUD, and concomitant use of aspirin and NSAIDs.12 Therefore, how to deal with acute UGIB in the setting of recent ACS is still challenging to gastroenterologists and cardiologists.
In patients with recent ACS, the safety and timing of endoscopy is not well known. Dynamic changes in infarct size may occur since the loss of viable myocardium is progressive after coronary artery occlusion during several hours to days. The infarcted region which itself is a critical determinant of remodeling, incidence of arrhythmias, sudden cardiac death and thus prognosis of ACS, may further expand or contract. Therefore, endoscopy within the first week after MI seems to be associated with higher risk for cardiovascular events. Nonetheless, in several observational cohort and retrospective studies, endoscopy for post-ACS patients has been described as relatively acceptable with complication rates ranging from 7.5–48.4%, depending on the definition of complications, timing of endoscopy, and clinical condition of enrolled patients.34–39 A systemic review of literature has shown that overall complication rate of esophagogastroduodenoscopy after MI was about 1–8%, with a large predominance of minor complications.40 Women seem to experience more periprocedural MI than men (31% vs. 11%, p=.058),37 and ACS patients who are very ill (APACHE-II score ≧ 16) are more likely to develop endoscopic complications than those with relatively stable condition (21% vs. 2%).36 Another retrospective study has also revealed that patients with APACHE II scores >16 experienced more minor complications (chest pain, abnormal vital signs, or minor arrhythmias) than those with scores ≦15 (54.5% vs. 24.2%, p=.02).38 From the result of a nationwide database involving 1,281,749 ACS patients, endoscopy after coronary arterial catherization was not associated with a difference in mortality compared with pre-angiogram endoscopy (OR = 0.84, 95%CI 0.60-1.19).41 However, design of these studies is mostly retrospective or observational. Given the lack of guidelines and RCTs, gastroenterologists are always reluctant to perform endoscopy for UGIB in ACS patients due to potential risk of complications. In our RCT, we have demonstrated that complication rates were not increased by EE as compared with PPI therapy alone, but higher risk in male patients.
Theoretically, the drug-drug interaction between PPI and clopidogrel reduces the antiplatelet effects and increases the major composite ischemia events. However, several clinical studies and recommendations from international societies suggested prophylactic PPI use for ACS patients taking antiplatelet or antithrombotic agents, particularly those at high risk of UGIB.42,43 A register-based RCT to examine the effect of screening for risk of UGIB and prophylactic PPI treatment in DAPT patients did not show a reduced incidence of UGIB (1.3% vs. 0.8%, p=0.38) but a higher compliance with DAPT and reduced risk of recurrent cardiovascular events.41 In our study, about one-third of patients discontinued DAPT in both groups which was associated with higher risk of coronary artery stent re-thrombosis (Table 1&4). Given that EE could provide initial higher rate of bleeding control, resuming DAPT as early as possible might be achieved to reduce recurrent cardiac ischemic events after coronary artery stenting. According to our results, patients in EE group resumed any antiplatelet agent earlier than those in non-EE group (mean 5.13 vs. 8.63 days), although statistically insignificant (Table 1). Additionally, lower needs for blood transfusion after EE may attenuates complications from over-transfusion of component therapy, particularly in ACS patients who had heart failure and pulmonary edema.
There were some limitations in this study. First, because of more than half ACS patients receiving prophylactic PPI therapy in our institute, the acute UGIB rate was lower than our expectation. Therefore, the number of patients enrolled were smaller than estimated sample size. However, the primary endpoint has been achieved with statistically significance. Secondly, the discontinuing and resuming DAPT was at the discretion of cardiologists rather than a standardized protocol. It was difficult to suggest the strategy in adjusting DAPT during acute UGIB in ACS patients from our result. Finally, we only identify male gender as the significant risk factor for complications from EE in ACS patients. This is probably due to the small sample size and we need further enrollment of eligible patients.
In conclusion, EE for acute UGIB in recent ACS patients has been demonstrated as an efficient and safe procedure for hemorrhage control with lower needs for blood transfusion in this multicenter RCT. Enrollment of more patients and longer study period are warranted to identify risk factors for complications from EE.