Gastrointestinal Bleeding in Cardiovascular Patients
Rosemary Nustas, MD, Khaled AbdelJawad, MD, Zaid Ammari, MD, Julia Masaad, MD
Introduction
Cardiac patients are a fast emerging population vulnerable to gastrointestinal bleeding (GIB) [1,2,3,4,5]. As the American population ages, it is anticipated that there will be an increased incidence of upper and lower GIB related to age-specific disease, higher burden of comorbidity and increased use of anti-thrombotic drugs to treat cardiac diseases [3,4,5,6].
The United States Preventive Services Task Force (USPSTF) released updated guidelines in 2009 recommending aspirin to prevent myocardial infarction among at-risk men and stroke among at-risk women [2,5]. Unfortunately, the GI side effects associated with aspirin therapy continue to be a major complication in both symptomatic and asymptomatic patients. These safety concerns should be important considerations in the decision making to use aspirin and warrant further education. The medical community needs to continue to improve awareness of aspirin-induced GIB to better equip physicians and improve care for patients requiring aspirin therapy [2].
Another concern is clopidogrel, which is a widely used antiplatelet agent for the secondary prevention of cardiovascular events in patients with stable coronary heart disease, acute coronary syndromes and ischemic stroke [7].
Etiologies of GIB in cardiac patients
Anti-thrombotic drugs
These include aspirin, NSAIDs, anti-platelet and anti-coagulation drugs, especially if used in combination [2,3,4,6,7].
Even though clopidogrel is safer than aspirin in terms of risk for GIB, that risk is not negligible in patients treated with this agent [7].
Studies of patients with atrial fibrillation show no evidence of marked excess of overall bleeding events when comparing dabigatran with warfarin users [8]. However, dabigatran was associated with increased risk of major gastrointestinal hemorrhage compared with warfarin in elderly patients with non-valvular atrial fibrillation. These associations were most pronounced in patients treated with dabigatran 150 mg twice daily. On the other hand, it had a reduced risk of ischemic stroke, intracranial hemorrhage, and death [9].
Rivaroxaban and warfarin have a similar risk for major and non-major clinically relevant bleeding. Older age, male sex, baseline diastolic blood pressure >90, prior GIB and/or Helicobacter infection, prior acetylsalicylic acid use and anemia were associated with risk of major bleeding [10].
Stress ulcers bleeding
Most commonly seen in critically-ill patients [11], after cardiac surgery [12] and left ventricular assist device (LVAD) implantation [13,14].
Acquired Von Willebrand (VW) disease
It arises from a deficiency in the quality or quantity of von Willebrand factor (vWF), a multimeric protein that is required for platelet adhesion, thus leading to increased bleeding tendencies [15].
This condition is described in hypertrophic obstructive cardiomyopathy (HOCM) [16], aortic stenosis (AS) [17], mitral regurgitation (MR) [18], LVAD implantation [13,14].
Heyde’s syndrome
Described as angiodysplasia associated with AS, causing lower GIB [17,19]. Also, Heyde’s syndrome is associated with acquired VW disease [17,19].
AV malformations
AV malformations are a frequent cause of lower GIB in cardiac patients [14].
Ischemic enteritis
Risk factors for this condition include old age, Diabetes Mellitus, cardiovascular disease and cardiac surgery [12].
Clinical Presentation
Patients with cardiac disease who have GIB can have a variety of presentations ranging from occult iron deficiency anemia to massive overt bleeding. Therefore, a high index of suspension is important for detection of such cases [12].
It is important to take a good history and perform a full physical examination. This is essential to assess the severity of the bleed, identify potential sources of bleeding and guide resuscitation, diagnosis and treatment approaches. Obtaining detailed medication history (like aspirin, antiplatelet and anticoagulation drugs) and information about previous GIB are valuable parts of the initial evaluation. Assessing the stool color can add information about the location of the bleeding. Hematemesis and coffee-ground emesis suggest bleeding proximal to the ligament of Treitz. Hematochezia usually indicates a lower GIB and melena indicates an upper GI source. However, those are not always reliable indicators to the location of the bleeding, and they should be used as part of the full evaluation [20,21].
Other symptoms and signs can be related to either the GIB itself or the resultant anemia, hypotension at presentation, indicating acute and large volume blood loss, has been associated with increased mortality [22].
Workup
As in any patient with GIB, initial laboratory tests should include a complete blood count (CBC), serum chemistries, liver tests and coagulation studies [23]. When evaluating the CBC, it is important to look at the MCV as acute bleeding has normocytic red blood cells and chronic bleeding or iron deficiency anemia usually have microcytic red blood cells. In addition, serial electrocardiograms and cardiac enzymes may be needed in patients at risk of myocardial infarction, such as patients with a history of coronary artery disease, older adults or patients with symptoms such as chest pain or dyspnea.
Some studies support the use of immunochemical fecal occult blood test to predict dual antiplatelet therapy (DAPT) discontinuation following coronary stenting [24]. GI related bleeding is the main cause of DAPT discontinuation in patients after coronary stenting. One study suggested screening patients who are undergoing coronary stenting for potential GI related bleeding. They used iFOBT as the screening method. They demonstrated that a positive iFOBT had the strongest predictive value for GI-related discontinuation of DAPT. Therefore, they propose iFOBT as a screening method that cardiologist can use to assess the risk of DAPT discontinuation in patients undergoing percutaneous coronary intervention [24].
Further work up may include endoscopy and/or colonoscopy [25,26], and in some cases, angiography for localization followed by transcatheter arterial embolization (TAE) for treatment of the site of bleeding [27,28].
The term “obscure GIB” after the introduction of video capsule endoscopy (VCE) in the U.S. in 2001 and deep enteroscopy in 2004, should be reserved for patients with no source of bleeding found on standard upper and lower endoscopic examinations in addition to full small bowel evaluation with VCE and/or enteroscopy, and radiographic testing including cross-sectional imaging (computed tomography or magnetic resonance) enterography, angiography, and scintigraphy. The diagnostic yield included any causes of bleeding detected distal to the ampulla of Vater or proximal to the ileocecal valve by any testing modality [29,30].
Risk factors and high risk population
The American College of Gastroenterology (ACG) offers a set of recommendations to prevent NSAID related ulcers, based upon CV and GI risk stratification. Risk factors that have been shown consistently to increase incidence of NSAID-related GI injury include old age, co-morbidities, concurrent medications, prior medical history, and H. pylori infection [39]. The ACG recommends testing for and treating H. pylori in all patients regardless of risk status who are about to start long-term traditional NSAID therapy.
Patients at moderate GI risk (presence of one or two risk factors) who also are at a high CV risk (i.e., prior history of a cardiovascular event, diabetes, hypertension, hyperlipidemia, and obesity) should be treated with naproxen plus misoprostol or a proton pump inhibitor (PPI), because the combination of naproxen and low-dose aspirin markedly increases the risk of GIB. Naproxen may be the agent of choice as it appears to have the least cardiotoxic effects [40,41,42,43].
Despite being associated with a significantly lower incidence of gastric and duodenal ulcers when compared to traditional NSAIDs, COX2 inhibitors’ usefulness is negated when the patient is taking concomitant low-dose aspirin. In addition, their association with myocardial infarction and other thrombotic CV events has outweighed their benefits [42,43].
Patients at high GI risk (multiple risk factors, a history of ulcer complications, or concomitant use of corticosteroids or anticoagulants) and high CV risk should avoid using NSAIDs or COX2 Inhibitors. Alternative therapy should be prescribed [39,40].
Management
Clinical decision making should take place on an individual basis [44]. Resuscitation is an immediate priority in unstable patients, using fluids and blood transfusions with a goal to keep Hemoglobin >10 g/dl [25,45]. Apply appropriate efforts to identify and correct any coagulopathy and stop any drugs that could be causing the bleeding. Endoscopic interventions provide diagnostic and therapeutic options and might be done urgently in the ICU setting after stabilizing the patient [24,25]. Other procedural approaches include transcatheter srterial embolization (TAE) which is a safe and effective choice if endoscopy fails [26]. Surgery is usually a last resort if the other options fail [26]. Surgical options include; correction of acquired vWB with aortic valve replacement in Heyde’s syndrome [16,18], HOCM septal reduction [15] and correction of the MR [17]. In LVAD patients, after failure of conventional methods, one case showed successful GI bleeding control after transfusions of a purified von Willebrand factor (VWF) concentrate, almost devoid of Factor VIII (Wilfactin, LFB) [13]. Other complex management options may be warranted based on the individual case.
Percutaneous closure of left atrium appendage may be the only therapeutic option for patients with atrial fibrillation and esophageal varices carrying a high risk of GIB thus eliminating the need for oral anticoagulants in this population which is intrinsically at high risk for major GIB [46].
Medical management includes PPI. Restart the anti-thrombotic as soon as the cardiovascular risk outweighs the bleeding risk [44,47]. A second endoscopic exam might be helpful to detect asymptomatic GIB before restarting the anti-thrombotic [47].
In cases of small bowel bleeding, small bowel angiodysplastic lesions remain the most common cause, and despite endoscopic therapy, demonstrate high recurrence rates. Supportive care with iron given orally or intravenously is a mainstay of treatment for mild small intestinal bleeding. Medical therapy with somatostatin analogs, such as octreotide, or antiangiogenic agents, such as thalidomide, may be an option for refractory patients. Surgical therapy should be reserved for patients requiring lysis of adhesions for successful deep enteroscopy.
Special Considerations in Cardiac Patients
What is the target Hemoglobin?
For patients with coronary heart disease, the target hemoglobin should be above 8 g/dl. This is based on two trials. The first one, the FOCUS trial (Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair), which compared a restrictive transfusion strategy (transfusion threshold of 8 g/dL or for symptomatic anemia) to transfusion threshold of 10 g/dL and found that the former strategy was not associated with worse outcomes. In the TRICC trial (Transfusion Requirements in Critical Care), it was found that patients with coronary artery disease had lower mortality when they received transfusion with a restrictive strategy (transfusion at a threshold of 7 g/dL) compared to a threshold of 10 g/dL [11,20,48,49,50,51].
In patients with heart failure, there is limited data for the target hemoglobin for transfusion. A meta-analysis of patients with anemia and heart disease found that higher transfusion thresholds did not improve mortality rates. It also found conflicting results regarding safety of this approach in patients with decompensated heart failure. Therefore, it is generally recommended to follow a transfusion threshold of hemoglobin of 7 to 8 g/dl with caution to volume status [48,49,50,51].
Endoscopy in patients with Implanted Cardiac Devices (ICDs)? [52]
Patients with implanted cardiac devices (ICDs) who suffer from GIB might need to undergo endoscopy which might require the use of electrocautery. Special caution should be applied in that situation, as the electrical signal may be interpreted as physiologic or pathophysiologic, temporarily inhibiting or triggering output from the ICD. Also, the electrical current can damage the device and the surrounding tissue. It is always important to determine the type of cardiac device and its indication and to use continuous electrocardiographic rhythm monitoring during the endoscopy while applying the lowest effective power output of the electrocautery device and minimizing exposure time as much as possible.
Despite the limited data regarding precautions when dealing with patients with pacemakers or/and ICD, it is recommended that patients undergo routine uses of electrocautery unless they are pacemaker dependent and in whom prolonged electrocautery is anticipated. In those cases, consultation with cardiology is recommended for possible deactivation of ICD or reprogramming of the pacemaker to an asynchronous mode via application of a magnet over the pulse generator during the use of electrocautery. Continuous rhythm monitoring should be used while the ICD is deactivated. If deactivated, the ICD should be reprogrammed as soon as possible after the procedure [52].
Another consideration is the use of bipolar cautery or a device with no electromagnetic field in patients with an ICD who are pacemaker dependent and the ICD cannot be reprogrammed to an asynchronous mode and prolonged cautery application may be required [12,52].
Prognosis
It is well known that GIB in cardiovascular patients carries a worse prognosis, with increased morbidity and mortality and is one of the leading causes of readmission after LVAD implantation [53]. In patients with CAD, GIB was associated with increased all-cause mortality and the composite of death, myocardial infarction or stroke. In patients with stable CAD (i.e., >1 year, with no acute events), major GIB events are rare, but are an independent predictor of death, particularly in those receiving both vitamin K antagonist and antiplatelet therapy [45].
In patients with atrial fibrillation, GI hemorrhages on warfarin are certainly no worse and may be less life threatening than those occurring off warfarin, in contrast to the deleterious effect of warfarin on mortality from intracranial hemorrhage, favoring anticoagulation in clinical decision making for patients with atrial fibrillation [54].
After long-term follow-up of patients on dual anti-platelet drugs with PPI co-therapy, lower GIB appears to be more common than upper GIB [55].
Prevention
Starting with careful evaluation of the benefit to risk ratio, especially when prescribing anti-thrombotic drugs. Several subjective methods have been proposed, such as CHADS2 score which predicts the rate of stroke in atrial fibrillation [56], the Modified Outpatient Bleeding Risk Index ( mOBRI ) which predicts the risk of major bleeding [56], The Aspirin Cardiovascular/GI risk calculator [57] and the CRUSADE score which can be used to predict the likelihood of subsequent GIB [58]. The relative risk of upper GIB in patients taking low-dose aspirin is higher when used for primary than for secondary cardiovascular disease prevention, but this difference is more than compensated by the lower baseline risk in the primary prevention population. Such estimates are important for an assessment of the net clinical benefit in primary prevention [59].
In patients with atrial fibrillation who suffered a major GIB on warfarin therapy, decision to restart warfarin has been associated with improved survival and decreased thromboembolism without increased risk of GIB after 7 days of interruption [60].
In general, clinicians should practice bleeding avoidance strategies during PCI irrespective of the access site used [31]. Risk-minimization efforts include using the lowest safest dose of aspirin and other antithrombotic drugs, using gastro-protective medications (PPI, H2 receptor blockers, prostaglandin analogues), treatment of H.pylori infection, close monitoring of INR in patients taking warfarin and improving education and awareness among patients and physicians [2,7,61,62]. Oral PPI is effective and economical prophylaxis against GI complications following cardiac surgery [63]. Although PPIs are the preferred drugs for GI protection, they have their own adverse effects and there needs to be effective communication between patients and their care providers [64].
The appropriate use of bivalirudin monotherapy is an acceptable alternative to heparin and glycoprotein IIb/IIIa inhibitors in patients with chronic kidney disease [33,34].
Emerging benefit of octreotide in reducing the frequency of admissions, blood transfusions, and endoscopic procedures in patients supported with continuous LVAD who have recurrent GIB. Further prospective studies are needed to clarify its benefits in this population [53]. Colonoscopy can help with early detection of common lower GIB in patients after VADs implantation [14].
Other measures have been employed in different situations, such intragastric pH-metry in cardio-surgical patients at risk of gastrointestinal hemorrhage [65].
Percutaneous occlusion of the left atrial appendage may be considered as an alternative to anticoagulation therapy for stroke prevention therapy in atrial fibrillation patients with a high bleeding risk [66].
Future approaches/strategies
New therapeutic agents include nitric oxide- and hydrogen sulfide-releasing NSAIDs which are anticipated to minimize the risk of GI ulcerations and bleeding. These novel manufacturing technologies enhance dissolution and absorption of NSAID products, which allows for administration at lowest dose possible. New NSAIDs formulations targeted directly to the site of inflammation are expected to reduce systemic drug exposure and side effects [67].
Important Drug Interactions
Clopidogrel and Omeprazole/Esomeprazole
The lack of power analysis in terms of the cardiovascular endpoint does not allow definite conclusions regarding the cardiovascular safety of clopidogrel/omeprazole combination [7,61,62]. Other proton pump inhibitors do not appear to interact with clopidogrel [7,61]. Among patients at high risk of upper GIB, those on concomitant PPI and clopidogrel were at a decreased risk of mortality, and possibly also a decreased risk of recurrence of cardiovascular disease [62]. In one study of patients with carotid artery stenting, there was no apparent interaction between clopidogrel and omeprazole [68]. Nevertheless, the decision to administer proton pump inhibitors to patients treated with clopidogrel should be individualized based on the patient’s bleeding and cardiovascular risk [7,61].
It is thought that omeprazole and esomeprazole attenuate the effect of clopidogrel, by inhibiting CYP2C19 leading to increased cardiovascular events. Although a meaningful prospective study failed to prove these retrospective findings, the FDA warns against the use of such combinations and recommends the use of other PPIs (pantoprazole) [7,61,68].
Prescribers should also be aware of the multiple drug interactions with warfarin, including supplements and dietary products [69].
Cardiac patients are a fast emerging population vulnerable to gastrointestinal bleeding (GIB) [1,2,3,4,5]. As the American population ages, it is anticipated that there will be an increased incidence of upper and lower GIB related to age-specific disease, higher burden of comorbidity and increased use of anti-thrombotic drugs to treat cardiac diseases [3,4,5,6].
The United States Preventive Services Task Force (USPSTF) released updated guidelines in 2009 recommending aspirin to prevent myocardial infarction among at-risk men and stroke among at-risk women [2,5]. Unfortunately, the GI side effects associated with aspirin therapy continue to be a major complication in both symptomatic and asymptomatic patients. These safety concerns should be important considerations in the decision making to use aspirin and warrant further education. The medical community needs to continue to improve awareness of aspirin-induced GIB to better equip physicians and improve care for patients requiring aspirin therapy [2].
Another concern is clopidogrel, which is a widely used antiplatelet agent for the secondary prevention of cardiovascular events in patients with stable coronary heart disease, acute coronary syndromes and ischemic stroke [7].
Etiologies of GIB in cardiac patients
Anti-thrombotic drugs
These include aspirin, NSAIDs, anti-platelet and anti-coagulation drugs, especially if used in combination [2,3,4,6,7].
Even though clopidogrel is safer than aspirin in terms of risk for GIB, that risk is not negligible in patients treated with this agent [7].
Studies of patients with atrial fibrillation show no evidence of marked excess of overall bleeding events when comparing dabigatran with warfarin users [8]. However, dabigatran was associated with increased risk of major gastrointestinal hemorrhage compared with warfarin in elderly patients with non-valvular atrial fibrillation. These associations were most pronounced in patients treated with dabigatran 150 mg twice daily. On the other hand, it had a reduced risk of ischemic stroke, intracranial hemorrhage, and death [9].
Rivaroxaban and warfarin have a similar risk for major and non-major clinically relevant bleeding. Older age, male sex, baseline diastolic blood pressure >90, prior GIB and/or Helicobacter infection, prior acetylsalicylic acid use and anemia were associated with risk of major bleeding [10].
Stress ulcers bleeding
Most commonly seen in critically-ill patients [11], after cardiac surgery [12] and left ventricular assist device (LVAD) implantation [13,14].
Acquired Von Willebrand (VW) disease
It arises from a deficiency in the quality or quantity of von Willebrand factor (vWF), a multimeric protein that is required for platelet adhesion, thus leading to increased bleeding tendencies [15].
This condition is described in hypertrophic obstructive cardiomyopathy (HOCM) [16], aortic stenosis (AS) [17], mitral regurgitation (MR) [18], LVAD implantation [13,14].
Heyde’s syndrome
Described as angiodysplasia associated with AS, causing lower GIB [17,19]. Also, Heyde’s syndrome is associated with acquired VW disease [17,19].
AV malformations
AV malformations are a frequent cause of lower GIB in cardiac patients [14].
Ischemic enteritis
Risk factors for this condition include old age, Diabetes Mellitus, cardiovascular disease and cardiac surgery [12].
Clinical Presentation
Patients with cardiac disease who have GIB can have a variety of presentations ranging from occult iron deficiency anemia to massive overt bleeding. Therefore, a high index of suspension is important for detection of such cases [12].
It is important to take a good history and perform a full physical examination. This is essential to assess the severity of the bleed, identify potential sources of bleeding and guide resuscitation, diagnosis and treatment approaches. Obtaining detailed medication history (like aspirin, antiplatelet and anticoagulation drugs) and information about previous GIB are valuable parts of the initial evaluation. Assessing the stool color can add information about the location of the bleeding. Hematemesis and coffee-ground emesis suggest bleeding proximal to the ligament of Treitz. Hematochezia usually indicates a lower GIB and melena indicates an upper GI source. However, those are not always reliable indicators to the location of the bleeding, and they should be used as part of the full evaluation [20,21].
Other symptoms and signs can be related to either the GIB itself or the resultant anemia, hypotension at presentation, indicating acute and large volume blood loss, has been associated with increased mortality [22].
Workup
As in any patient with GIB, initial laboratory tests should include a complete blood count (CBC), serum chemistries, liver tests and coagulation studies [23]. When evaluating the CBC, it is important to look at the MCV as acute bleeding has normocytic red blood cells and chronic bleeding or iron deficiency anemia usually have microcytic red blood cells. In addition, serial electrocardiograms and cardiac enzymes may be needed in patients at risk of myocardial infarction, such as patients with a history of coronary artery disease, older adults or patients with symptoms such as chest pain or dyspnea.
Some studies support the use of immunochemical fecal occult blood test to predict dual antiplatelet therapy (DAPT) discontinuation following coronary stenting [24]. GI related bleeding is the main cause of DAPT discontinuation in patients after coronary stenting. One study suggested screening patients who are undergoing coronary stenting for potential GI related bleeding. They used iFOBT as the screening method. They demonstrated that a positive iFOBT had the strongest predictive value for GI-related discontinuation of DAPT. Therefore, they propose iFOBT as a screening method that cardiologist can use to assess the risk of DAPT discontinuation in patients undergoing percutaneous coronary intervention [24].
Further work up may include endoscopy and/or colonoscopy [25,26], and in some cases, angiography for localization followed by transcatheter arterial embolization (TAE) for treatment of the site of bleeding [27,28].
The term “obscure GIB” after the introduction of video capsule endoscopy (VCE) in the U.S. in 2001 and deep enteroscopy in 2004, should be reserved for patients with no source of bleeding found on standard upper and lower endoscopic examinations in addition to full small bowel evaluation with VCE and/or enteroscopy, and radiographic testing including cross-sectional imaging (computed tomography or magnetic resonance) enterography, angiography, and scintigraphy. The diagnostic yield included any causes of bleeding detected distal to the ampulla of Vater or proximal to the ileocecal valve by any testing modality [29,30].
Risk factors and high risk population
- GIB is one of the most common causes of non-access site-related bleeding after PCI, even months after the procedure, bearing worse prognosis than access site bleeding [31]. Predictors include older patient age, particularly over 70 years of age, active smoking, history of GIB or malignancy and triple antithrombotic therapy i.e. combination of oral anticoagulation and dual antiplatelet therapy [32]. Also, the risk of bleeding after PCI increases with worsening chronic kidney disease [33]. Studies have shown that bivalirudin was associated with reduced risk of GIB across all categories of renal dysfunction [33]. However, the dose of bivalirudin has to be decreased in renal failure patients as compared to normal kidney function patients [34].
- GIB following cardiac surgery is uncommon but may be life-threatening [12,35]. The overall hospital mortality among patients with GI complications was 63% compared with a mortality rate of 2.9% in patients without postoperative GI complications. There are several factors that put these patients at risk of GI complications including age greater than 65 years, low left ventricular ejection fraction (EF<30%), preoperative creatinine>1.5 mg/dL, on pump operation, prolonged time of cardiopulmonary bypass (CPB), prolonged time of aortic cross clamp, congenital heart disease, aortic dissection, use of intra-aortic balloon pump (IABP), blood transfusion, hypotension, sodium bicarbonate use, increased duration of mechanical ventilation, elevation of international normalized ratio and Clostridium difficile colitis [12,35].
- After trans-catheter aortic valve replacement (TAVR), patients are at risk of major late bleeding complications. GIB is the most common source of bleeding in this population. Independent predictors of this are the presence of low hemoglobin at baseline, atrial fibrillation or flutter at baseline or within 30 days of procedure, the presence of moderate or severe para-valvular leak at 30 days and greater left ventricular mass at 30 days [36].
- Patients after LVAD placement were at higher risk of GIB in the absence of aortic valve movement after the procedure [37]. This relates to the observation of the aortic valve after placement of continuous flow LVAD. Continuous flow (CF) circulation causes nonphysiological events in human body circulation. Decreased pulse pressure and low pulsatility are the most significant risk factors for complication. GIB has recently become one of the reported complications after continuous flow LVAD placement. This study demonstrated a relationship between GIB and aortic valve movement in patients who underwent continuous flow LVAD placement. They observed that all the patients who had GIB following the procedure, had absent aortic valve movement.
The American College of Gastroenterology (ACG) offers a set of recommendations to prevent NSAID related ulcers, based upon CV and GI risk stratification. Risk factors that have been shown consistently to increase incidence of NSAID-related GI injury include old age, co-morbidities, concurrent medications, prior medical history, and H. pylori infection [39]. The ACG recommends testing for and treating H. pylori in all patients regardless of risk status who are about to start long-term traditional NSAID therapy.
Patients at moderate GI risk (presence of one or two risk factors) who also are at a high CV risk (i.e., prior history of a cardiovascular event, diabetes, hypertension, hyperlipidemia, and obesity) should be treated with naproxen plus misoprostol or a proton pump inhibitor (PPI), because the combination of naproxen and low-dose aspirin markedly increases the risk of GIB. Naproxen may be the agent of choice as it appears to have the least cardiotoxic effects [40,41,42,43].
Despite being associated with a significantly lower incidence of gastric and duodenal ulcers when compared to traditional NSAIDs, COX2 inhibitors’ usefulness is negated when the patient is taking concomitant low-dose aspirin. In addition, their association with myocardial infarction and other thrombotic CV events has outweighed their benefits [42,43].
Patients at high GI risk (multiple risk factors, a history of ulcer complications, or concomitant use of corticosteroids or anticoagulants) and high CV risk should avoid using NSAIDs or COX2 Inhibitors. Alternative therapy should be prescribed [39,40].
Management
Clinical decision making should take place on an individual basis [44]. Resuscitation is an immediate priority in unstable patients, using fluids and blood transfusions with a goal to keep Hemoglobin >10 g/dl [25,45]. Apply appropriate efforts to identify and correct any coagulopathy and stop any drugs that could be causing the bleeding. Endoscopic interventions provide diagnostic and therapeutic options and might be done urgently in the ICU setting after stabilizing the patient [24,25]. Other procedural approaches include transcatheter srterial embolization (TAE) which is a safe and effective choice if endoscopy fails [26]. Surgery is usually a last resort if the other options fail [26]. Surgical options include; correction of acquired vWB with aortic valve replacement in Heyde’s syndrome [16,18], HOCM septal reduction [15] and correction of the MR [17]. In LVAD patients, after failure of conventional methods, one case showed successful GI bleeding control after transfusions of a purified von Willebrand factor (VWF) concentrate, almost devoid of Factor VIII (Wilfactin, LFB) [13]. Other complex management options may be warranted based on the individual case.
Percutaneous closure of left atrium appendage may be the only therapeutic option for patients with atrial fibrillation and esophageal varices carrying a high risk of GIB thus eliminating the need for oral anticoagulants in this population which is intrinsically at high risk for major GIB [46].
Medical management includes PPI. Restart the anti-thrombotic as soon as the cardiovascular risk outweighs the bleeding risk [44,47]. A second endoscopic exam might be helpful to detect asymptomatic GIB before restarting the anti-thrombotic [47].
In cases of small bowel bleeding, small bowel angiodysplastic lesions remain the most common cause, and despite endoscopic therapy, demonstrate high recurrence rates. Supportive care with iron given orally or intravenously is a mainstay of treatment for mild small intestinal bleeding. Medical therapy with somatostatin analogs, such as octreotide, or antiangiogenic agents, such as thalidomide, may be an option for refractory patients. Surgical therapy should be reserved for patients requiring lysis of adhesions for successful deep enteroscopy.
Special Considerations in Cardiac Patients
What is the target Hemoglobin?
For patients with coronary heart disease, the target hemoglobin should be above 8 g/dl. This is based on two trials. The first one, the FOCUS trial (Transfusion Trigger Trial for Functional Outcomes in Cardiovascular Patients Undergoing Surgical Hip Fracture Repair), which compared a restrictive transfusion strategy (transfusion threshold of 8 g/dL or for symptomatic anemia) to transfusion threshold of 10 g/dL and found that the former strategy was not associated with worse outcomes. In the TRICC trial (Transfusion Requirements in Critical Care), it was found that patients with coronary artery disease had lower mortality when they received transfusion with a restrictive strategy (transfusion at a threshold of 7 g/dL) compared to a threshold of 10 g/dL [11,20,48,49,50,51].
In patients with heart failure, there is limited data for the target hemoglobin for transfusion. A meta-analysis of patients with anemia and heart disease found that higher transfusion thresholds did not improve mortality rates. It also found conflicting results regarding safety of this approach in patients with decompensated heart failure. Therefore, it is generally recommended to follow a transfusion threshold of hemoglobin of 7 to 8 g/dl with caution to volume status [48,49,50,51].
Endoscopy in patients with Implanted Cardiac Devices (ICDs)? [52]
Patients with implanted cardiac devices (ICDs) who suffer from GIB might need to undergo endoscopy which might require the use of electrocautery. Special caution should be applied in that situation, as the electrical signal may be interpreted as physiologic or pathophysiologic, temporarily inhibiting or triggering output from the ICD. Also, the electrical current can damage the device and the surrounding tissue. It is always important to determine the type of cardiac device and its indication and to use continuous electrocardiographic rhythm monitoring during the endoscopy while applying the lowest effective power output of the electrocautery device and minimizing exposure time as much as possible.
Despite the limited data regarding precautions when dealing with patients with pacemakers or/and ICD, it is recommended that patients undergo routine uses of electrocautery unless they are pacemaker dependent and in whom prolonged electrocautery is anticipated. In those cases, consultation with cardiology is recommended for possible deactivation of ICD or reprogramming of the pacemaker to an asynchronous mode via application of a magnet over the pulse generator during the use of electrocautery. Continuous rhythm monitoring should be used while the ICD is deactivated. If deactivated, the ICD should be reprogrammed as soon as possible after the procedure [52].
Another consideration is the use of bipolar cautery or a device with no electromagnetic field in patients with an ICD who are pacemaker dependent and the ICD cannot be reprogrammed to an asynchronous mode and prolonged cautery application may be required [12,52].
Prognosis
It is well known that GIB in cardiovascular patients carries a worse prognosis, with increased morbidity and mortality and is one of the leading causes of readmission after LVAD implantation [53]. In patients with CAD, GIB was associated with increased all-cause mortality and the composite of death, myocardial infarction or stroke. In patients with stable CAD (i.e., >1 year, with no acute events), major GIB events are rare, but are an independent predictor of death, particularly in those receiving both vitamin K antagonist and antiplatelet therapy [45].
In patients with atrial fibrillation, GI hemorrhages on warfarin are certainly no worse and may be less life threatening than those occurring off warfarin, in contrast to the deleterious effect of warfarin on mortality from intracranial hemorrhage, favoring anticoagulation in clinical decision making for patients with atrial fibrillation [54].
After long-term follow-up of patients on dual anti-platelet drugs with PPI co-therapy, lower GIB appears to be more common than upper GIB [55].
Prevention
Starting with careful evaluation of the benefit to risk ratio, especially when prescribing anti-thrombotic drugs. Several subjective methods have been proposed, such as CHADS2 score which predicts the rate of stroke in atrial fibrillation [56], the Modified Outpatient Bleeding Risk Index ( mOBRI ) which predicts the risk of major bleeding [56], The Aspirin Cardiovascular/GI risk calculator [57] and the CRUSADE score which can be used to predict the likelihood of subsequent GIB [58]. The relative risk of upper GIB in patients taking low-dose aspirin is higher when used for primary than for secondary cardiovascular disease prevention, but this difference is more than compensated by the lower baseline risk in the primary prevention population. Such estimates are important for an assessment of the net clinical benefit in primary prevention [59].
In patients with atrial fibrillation who suffered a major GIB on warfarin therapy, decision to restart warfarin has been associated with improved survival and decreased thromboembolism without increased risk of GIB after 7 days of interruption [60].
In general, clinicians should practice bleeding avoidance strategies during PCI irrespective of the access site used [31]. Risk-minimization efforts include using the lowest safest dose of aspirin and other antithrombotic drugs, using gastro-protective medications (PPI, H2 receptor blockers, prostaglandin analogues), treatment of H.pylori infection, close monitoring of INR in patients taking warfarin and improving education and awareness among patients and physicians [2,7,61,62]. Oral PPI is effective and economical prophylaxis against GI complications following cardiac surgery [63]. Although PPIs are the preferred drugs for GI protection, they have their own adverse effects and there needs to be effective communication between patients and their care providers [64].
The appropriate use of bivalirudin monotherapy is an acceptable alternative to heparin and glycoprotein IIb/IIIa inhibitors in patients with chronic kidney disease [33,34].
Emerging benefit of octreotide in reducing the frequency of admissions, blood transfusions, and endoscopic procedures in patients supported with continuous LVAD who have recurrent GIB. Further prospective studies are needed to clarify its benefits in this population [53]. Colonoscopy can help with early detection of common lower GIB in patients after VADs implantation [14].
Other measures have been employed in different situations, such intragastric pH-metry in cardio-surgical patients at risk of gastrointestinal hemorrhage [65].
Percutaneous occlusion of the left atrial appendage may be considered as an alternative to anticoagulation therapy for stroke prevention therapy in atrial fibrillation patients with a high bleeding risk [66].
Future approaches/strategies
New therapeutic agents include nitric oxide- and hydrogen sulfide-releasing NSAIDs which are anticipated to minimize the risk of GI ulcerations and bleeding. These novel manufacturing technologies enhance dissolution and absorption of NSAID products, which allows for administration at lowest dose possible. New NSAIDs formulations targeted directly to the site of inflammation are expected to reduce systemic drug exposure and side effects [67].
Important Drug Interactions
Clopidogrel and Omeprazole/Esomeprazole
The lack of power analysis in terms of the cardiovascular endpoint does not allow definite conclusions regarding the cardiovascular safety of clopidogrel/omeprazole combination [7,61,62]. Other proton pump inhibitors do not appear to interact with clopidogrel [7,61]. Among patients at high risk of upper GIB, those on concomitant PPI and clopidogrel were at a decreased risk of mortality, and possibly also a decreased risk of recurrence of cardiovascular disease [62]. In one study of patients with carotid artery stenting, there was no apparent interaction between clopidogrel and omeprazole [68]. Nevertheless, the decision to administer proton pump inhibitors to patients treated with clopidogrel should be individualized based on the patient’s bleeding and cardiovascular risk [7,61].
It is thought that omeprazole and esomeprazole attenuate the effect of clopidogrel, by inhibiting CYP2C19 leading to increased cardiovascular events. Although a meaningful prospective study failed to prove these retrospective findings, the FDA warns against the use of such combinations and recommends the use of other PPIs (pantoprazole) [7,61,68].
Prescribers should also be aware of the multiple drug interactions with warfarin, including supplements and dietary products [69].
References
1- Hamon M, Lemesle G, Tricot O, et al. Incidence, source, determinants, and prognostic impact of major bleeding in outpatients with stable coronary artery disease. J Am Coll Cardiol. 2014 Oct 7;64(14):1430-6
2- Peura DA, Wilcox CM. Aspirin and proton pump inhibitor combination therapy for prevention of cardiovascular disease and Barrett's esophagus. Postgrad Med. 2014 Jan;126(1):87-96
3- DiNicolantonio JJ, D'Ascenzo F, Tomek A, et al. Clopidogrel is safer than ticagrelor in regard to bleeds: a closer look at the PLATO trial. Int J Cardiol. 2013 Oct 3;168(3):1739-44
4- Inaba T, Ishikawa S, Miyoshi M, et al. Present status of gastrointestinal damage due to non-steroidal anti-inflammatory drugs (NSAIDs). Nihon Rinsho. 2013 Jun;71(6):1109-15
5- Patrono C. Low-dose aspirin in primary prevention: cardioprotection, chemoprevention, both, or neither? Eur Heart J. 2013 Nov;34(44):3403-11
6- Takahashi Y, Nishida Y, Nakayama T. Comparative effect of clopidogrel and aspirin versus aspirin alone on laboratory parameters: a retrospective, observational, cohort study. Cardiovasc Diabetol. 2013 Jun 14;12:87
7- Bouziana SD, Tziomalos K . Clinical relevance of clopidogrel-proton pump inhibitors interaction. World J Gastrointest Pharmacol Ther. 2015 May 6;6(2):17-21
8- Larsen TB, Gorst-Rasmussen A, Rasmussen LH, et al. Bleeding events among new starters and switchers to dabigatran compared with warfarin in atrial fibrillation. Am J Med. 2014 Jul;127(7):650-656.e5
9- Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation. 2015 Jan 13;131(2):157-64
10- Goodman SG, Wojdyla DM, Piccini JP, et al. ROCKET AF Investigators. Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol. 2014 Mar 11;63(9):891-900
11- Ali T, Harty RF. Stress-induced ulcer bleeding in critically ill patients. Gastroenterol Clin North Am. 2009 Jun;38(2):245-65
12- Hashemzadeh K, Hashemzadeh S. Predictors and outcome of gastrointestinal complications after cardiac surgery. Minerva Chir. 2012 Aug;67(4):327-35
13- Fischer Q, Huisse MG, Voiriot G, et al. Von Willebrand factor, a versatile player in gastrointestinal bleeding in left ventricular assist device recipients? Transfusion. 2015 Jan;55(1):51-4
14- Singh G, Albeldawi M, Kalra SS, et al. Features of patients with gastrointestinal bleeding after implantation of ventricular assist devices. Clin Gastroenterol Hepatol. 2015 Jan;13(1):107-14
15- "Von Willebrand disease: MedlinePlus Medical Encyclopedia". www.nlm.nih.gov
16- Blackshear JL, Stark ME, Agnew RC, et al. Remission of recurrent gastrointestinal bleeding after septal reduction therapy in patients with hypertrophic obstructive cardiomyopathy-associated acquired von Willebrand syndrome. J Thromb Haemost. 2015 Feb;13(2):191-6
17- Godino C, Lauretta L, Pavon AG, et al. Heyde's syndrome incidence and outcome in patients undergoing transcatheter aortic valve implantation. J Am Coll Cardiol. 2013 Feb 12;61(6):687-9
18- Blackshear JL, Wysokinska EM, Safford RE, et al. Shear stress-associated acquired von Willebrand syndrome in patients with mitral regurgitation. J Thromb Haemost. 2014 Dec;12(12):1966-74
19- Thompson JL, Schaff HV, Dearani JA, et al. Risk of recurrent gastrointestinal bleeding after aortic valve replacement in patients with Heyde syndrome. J Thorac Cardiovasc Surg. 2012 Jul;144(1):112-6
20- Cappell MS, Friedel D. Initial management of acute upper gastrointestinal bleeding: from initial evaluation up to gastrointestinal endoscopy. Med Clin North Am 2008; 92:491
21- Jensen DM, Machicado GA. Diagnosis and treatment of severe hematochezia. The role of urgent colonoscopy after purge. Gastroenterology 1988; 95:1569
22- Yachimski PS, Friedman LS. Gastrointestinal bleeding in the elderly. Nature Clinical Practice Gastroenterology & Hepatology (2008) 5,80-93
23- Fatemi O1, Torguson R, Chen F, et al. Red cell distribution width as a bleeding predictor after percutaneous coronary intervention. Am Heart J. 2013 Jul;166(1):104-9
24- Ikeda K, Koyama T, Ishida M, et al. Immunochemical fecal occult blood tests predict dual antiplatelet therapy discontinuation after coronary stenting. Intern Med. 2014;53(5):375-81
25- Katsinelos P, Lazaraki G, Gkagkalis A, et al. The role of capsule endoscopy in the evaluation and treatment of obscure-overt gastrointestinal bleeding during daily clinical practice: a prospective multicenter study. Scand J Gastroenterol. 2014 Jul;49(7):862-70
26- Cena M, Gomez J, Alyousef T, et al. Safety of endoscopic procedures after acute myocardial infarction: a systematic review. Cardiol J. 2012;19(5):447-52
27- Lee L, Iqbal S, Najmeh S, et al. Mesenteric angiography for acute gastrointestinal bleed: predictors of active extravasation and outcomes. Can J Surg. 2012 Dec;55(6):382-8.
28- Katano T, Mizoshita T, Senoo K, et al. The efficacy of transcatheter arterial embolization as the first-choice treatment after failure of endoscopic hemostasis and endoscopic treatment resistance factors. Dig Endosc. 2012 Sep;24(5):364-9
29- Gerson LB, Fidler JL, Cave DR, et al. ACG Clinical Guideline: Diagnosis and Management of Small Bowel Bleeding. Am J Gastroenterol 2015; 110:1265–1287
30- Pasha SF, Leighton JA, Das A, et al. Double-balloon enteroscopy and capsule endoscopy have comparable diagnostic yield in small-bowel disease: a meta-analysis. Clin Gastroenterol Hepatol 2008;6:671–6
31- Kwok CS, Khan MA, Rao SV, et al. Access and non-access site bleeding after percutaneous coronary intervention and risk of subsequent mortality and major adverse cardiovascular events: systematic review and meta-analysis. Circ Cardiovasc Interv. 2015 Apr;8(4
32- Koskinas KC, Räber L, Zanchin T, et al. Clinical impact of gastrointestinal bleeding in patients undergoing percutaneous coronary interventions. Circ Cardiovasc Interv. 2015 May;8(5)
33- Perdoncin E, Zhang M, Riba A, et al. Impact of worsening renal dysfunction on the comparative efficacy of bivalirudin and platelet glycoprotein IIb/IIIa inhibitors: insights from Blue Cross Blue Shield of Michigan Cardiovascular Consortium. Circ Cardiovasc Interv. 2013 Dec;6(6):688-93
34- Ann Pharmacother. Bivalirudin dosing adjustments for reduced renal function with or without hemodialysis in the management of heparin-induced thrombocytopenia. 2011 Oct;45(10):1185-92
35- Bhat M, Larocque M, Amorim M, et al. Prediction and prevention of upper gastrointestinal bleeding after cardiac surgery: a case control study. Can J Gastroenterol. 2012 Jun;26(6):340-4
36- Généreux P, Cohen DJ, Mack M, et al. Incidence, predictors, and prognostic impact of late bleeding complications after transcatheter aortic valve replacement. J Am Coll Cardiol. 2014 Dec 23;64(24):2605-15
37- Balcioglu O, Engin C, Yagdi T, et al. Effect of aortic valve movements on gastrointestinal bleeding that occured in continuous flow left ventricular assist device patients. Transplant Proc. 2013 Apr;45(3):1020-1
38- Lanza F, Chan F, Quigley E, and the Practice Parameters Committee of the American College of Gastroenterology. Guidelines for Prevention of NSAID-Related Ulcer Complications. Am J Gastroenterol 2009; 104:728–738
39- Graham DY, Chan FK. NSAIDs, risks, and gastroprotective strategies: current status and future. Gastroenterology 2008;134:1240-6
40- Lanas A, Garcia-Rodriguez LA, Arroyo MT, et al. Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. Am J Gastroenterol 2007;102:507-15
41- Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomized controlled trial. Lancet 2004;364:665-74
42- McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006;296:1633-44
43- Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-infl ammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomized trials. BMJ 2006;332:1302-8
44- Feagins LA, Iqbal R, Harford WV, et al. Low rate of postpolypectomy bleeding among patients who continue thienopyridine therapy during colonoscopy. Clin Gastroenterol Hepatol. 2013 Oct;11(10):1325-32
45- Yachimski P, Hur C. Upper endoscopy in patients with acute myocardial infarction and upper gastrointestinal bleeding: Results of a decision analysis. Digestive Diseases Scien, 2009; 54: 701–711
46- Grosset-Janin D, Barth E, Bertrand B, et al. Percutaneous left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation and contraindication for anticoagulation. Rev Neurol (Paris). 2015 May;171(5):426-32
47- Lee JK, Kang HW, Kim SG, et al. Risks related with withholding and resuming anticoagulation in patients with non-variceal upper gastrointestinal bleeding while on warfarin therapy. Int J Clin Pract. 2012 Jan;66(1):64-8
48- Carson JL, Terrin ML, Magaziner J, et al; FOCUS Investigators. Transfusion triggers trial for functional outcomes in cardiovascular patients undergoing surgical hip fracture repair (FOCUS). Transfusion. 2006 Dec;46(12):2192-206
49- Hébert PC, Wells G, et al. A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care. N Engl J Med 1999; 340:409-417
50- Carson JL1, Grossman BJ, Kleinman S, Tinmouth AT, et al. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2012 Jul 3;157(1):49-58
51- Kansagara D, Dyer E, Englander H, et al. Treatment of anemia in patients with heart disease: a systematic review. Ann Intern Med 2013; 159:746
52- American Society of Gastroinstestinal Endoscopy. Endoscopy in patients with implanted electronic devices. Gastrointest Endosc 2007;65:563-70
53- Loyaga-Rendon RY, Hashim T, Tallaj JA, et al. Octreotide in the management of recurrent gastrointestinal bleed in patients supported by continuous flow left ventricular assist devices. ASAIO J. 2015 Jan-Feb;61(1):107-9
54- Ashburner JM, Go AS, Reynolds K, et al. Comparison of frequency and outcome of major gastrointestinal hemorrhage in patients with atrial fibrillation on versus not receiving warfarin therapy (from the ATRIA and ATRIA-CVRN cohorts). Am J Cardiol. 2015 Jan 1;115(1):40-6
55- Casado Arroyo R, Polo-Tomas M, Roncalés MP, et al. Lower GI bleeding is more common than upper among patients on dual antiplatelet therapy: long-term follow-up of a cohort of patients commonly using PPI co-therapy. Heart. 2012 May;98(9):718-23
56- Sood M, Larkina M, Thumma JR, et al. Major bleeding events and risk stratification of antithrombotic agents in hemodialysis: Results from the DOPPS. Kidney Int. 2013 Sep;84(3):600-8
57- Lanas A, Polo-Tomás M, Casado-Arroyo R. The aspirin cardiovascular/gastrointestinal risk calculator-a tool to aid clinicians in practice. Aliment Pharmacol Ther. 2013 Apr;37(7):738-48
58- Thomas MR, Storey RF. Optimal management of antiplatelet therapy and proton pump inhibition following percutaneous coronary intervention. Curr Treat Options Cardiovasc Med. 2012 Feb;14(1):24-38
59- Lin KJ, De Caterina R, García Rodríguez LA. Low-dose aspirin and upper gastrointestinal bleeding in primary versus secondary cardiovascular prevention: a population-based, nested case-control study. Circ Cardiovasc Qual Outcomes. 2014 Jan;7(1):70-7
60- Qureshi W, Mittal C, Patsias I, et al. Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation. Am J Cardiol. 2014 Feb 15;113(4):662-8
61- Johnson DA, Chilton R, Liker HR. Proton-pump inhibitors in patients requiring antiplatelet therapy: new FDA labeling. Postgrad Med. 2014 May;126(3):239-45
62- Wang Q, Ljung R, Lagergren J, et al. Prognosis of concomitant users of clopidogrel and proton-pump inhibitors in a high-risk population for upper gastrointestinal bleeding. BMC Pharmacol Toxicol. 2014 Apr 15;15:22
63- Fujita K, Hata M, Sezai A, et al. Is prophylactic intravenous administration of a proton pump inhibitor necessary for perioperative management of cardiac surgery? Heart Surg Forum. 2012 Oct;15(5):E277-9
64- Chen J, Yuan YC, Leontiadis GI, et al. Recent safety concerns with proton pump inhibitors. J Clin Gastroenterol. 2012 Feb;46(2):93-114
65- Mandel' IA, Sukhodolo IV, Pleshko RI, et al. Gastrointestinal hemorrhage in cardiosurgery in patients with endothelial dysfunction. Klin Med (Mosk). 2014;92(3):63-8
66- Lewalter T, Kanagaratnam P, Schmidt B, et al. Ischaemic stroke prevention in patients with atrial fibrillation and high bleeding risk: opportunities and challenges for percutaneous left atrial appendage occlusion. Europace. 2014 May;16(5):626-30
67- McCarberg BH, Cryer B. Evolving Therapeutic Strategies to Improve Nonsteroidal Anti-inflammatory Drug Safety. Am J Ther. 2015 Nov-Dec;22(6):e167-78
68- Ma B, Hang L, Chen G, et al. Effect of clopidogrel with or without omeprazole in patients with carotid artery stenting. West Indian Med J. 2013 Feb;62(2):135-9
69- Hines LE, Ceron-Cabrera D, Romero K, et al. Evaluation of warfarin drug interaction listings in US product information for warfarin and interacting drugs. Clin Ther. 2011 Jan;33(1):36-45
1- Hamon M, Lemesle G, Tricot O, et al. Incidence, source, determinants, and prognostic impact of major bleeding in outpatients with stable coronary artery disease. J Am Coll Cardiol. 2014 Oct 7;64(14):1430-6
2- Peura DA, Wilcox CM. Aspirin and proton pump inhibitor combination therapy for prevention of cardiovascular disease and Barrett's esophagus. Postgrad Med. 2014 Jan;126(1):87-96
3- DiNicolantonio JJ, D'Ascenzo F, Tomek A, et al. Clopidogrel is safer than ticagrelor in regard to bleeds: a closer look at the PLATO trial. Int J Cardiol. 2013 Oct 3;168(3):1739-44
4- Inaba T, Ishikawa S, Miyoshi M, et al. Present status of gastrointestinal damage due to non-steroidal anti-inflammatory drugs (NSAIDs). Nihon Rinsho. 2013 Jun;71(6):1109-15
5- Patrono C. Low-dose aspirin in primary prevention: cardioprotection, chemoprevention, both, or neither? Eur Heart J. 2013 Nov;34(44):3403-11
6- Takahashi Y, Nishida Y, Nakayama T. Comparative effect of clopidogrel and aspirin versus aspirin alone on laboratory parameters: a retrospective, observational, cohort study. Cardiovasc Diabetol. 2013 Jun 14;12:87
7- Bouziana SD, Tziomalos K . Clinical relevance of clopidogrel-proton pump inhibitors interaction. World J Gastrointest Pharmacol Ther. 2015 May 6;6(2):17-21
8- Larsen TB, Gorst-Rasmussen A, Rasmussen LH, et al. Bleeding events among new starters and switchers to dabigatran compared with warfarin in atrial fibrillation. Am J Med. 2014 Jul;127(7):650-656.e5
9- Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation. 2015 Jan 13;131(2):157-64
10- Goodman SG, Wojdyla DM, Piccini JP, et al. ROCKET AF Investigators. Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol. 2014 Mar 11;63(9):891-900
11- Ali T, Harty RF. Stress-induced ulcer bleeding in critically ill patients. Gastroenterol Clin North Am. 2009 Jun;38(2):245-65
12- Hashemzadeh K, Hashemzadeh S. Predictors and outcome of gastrointestinal complications after cardiac surgery. Minerva Chir. 2012 Aug;67(4):327-35
13- Fischer Q, Huisse MG, Voiriot G, et al. Von Willebrand factor, a versatile player in gastrointestinal bleeding in left ventricular assist device recipients? Transfusion. 2015 Jan;55(1):51-4
14- Singh G, Albeldawi M, Kalra SS, et al. Features of patients with gastrointestinal bleeding after implantation of ventricular assist devices. Clin Gastroenterol Hepatol. 2015 Jan;13(1):107-14
15- "Von Willebrand disease: MedlinePlus Medical Encyclopedia". www.nlm.nih.gov
16- Blackshear JL, Stark ME, Agnew RC, et al. Remission of recurrent gastrointestinal bleeding after septal reduction therapy in patients with hypertrophic obstructive cardiomyopathy-associated acquired von Willebrand syndrome. J Thromb Haemost. 2015 Feb;13(2):191-6
17- Godino C, Lauretta L, Pavon AG, et al. Heyde's syndrome incidence and outcome in patients undergoing transcatheter aortic valve implantation. J Am Coll Cardiol. 2013 Feb 12;61(6):687-9
18- Blackshear JL, Wysokinska EM, Safford RE, et al. Shear stress-associated acquired von Willebrand syndrome in patients with mitral regurgitation. J Thromb Haemost. 2014 Dec;12(12):1966-74
19- Thompson JL, Schaff HV, Dearani JA, et al. Risk of recurrent gastrointestinal bleeding after aortic valve replacement in patients with Heyde syndrome. J Thorac Cardiovasc Surg. 2012 Jul;144(1):112-6
20- Cappell MS, Friedel D. Initial management of acute upper gastrointestinal bleeding: from initial evaluation up to gastrointestinal endoscopy. Med Clin North Am 2008; 92:491
21- Jensen DM, Machicado GA. Diagnosis and treatment of severe hematochezia. The role of urgent colonoscopy after purge. Gastroenterology 1988; 95:1569
22- Yachimski PS, Friedman LS. Gastrointestinal bleeding in the elderly. Nature Clinical Practice Gastroenterology & Hepatology (2008) 5,80-93
23- Fatemi O1, Torguson R, Chen F, et al. Red cell distribution width as a bleeding predictor after percutaneous coronary intervention. Am Heart J. 2013 Jul;166(1):104-9
24- Ikeda K, Koyama T, Ishida M, et al. Immunochemical fecal occult blood tests predict dual antiplatelet therapy discontinuation after coronary stenting. Intern Med. 2014;53(5):375-81
25- Katsinelos P, Lazaraki G, Gkagkalis A, et al. The role of capsule endoscopy in the evaluation and treatment of obscure-overt gastrointestinal bleeding during daily clinical practice: a prospective multicenter study. Scand J Gastroenterol. 2014 Jul;49(7):862-70
26- Cena M, Gomez J, Alyousef T, et al. Safety of endoscopic procedures after acute myocardial infarction: a systematic review. Cardiol J. 2012;19(5):447-52
27- Lee L, Iqbal S, Najmeh S, et al. Mesenteric angiography for acute gastrointestinal bleed: predictors of active extravasation and outcomes. Can J Surg. 2012 Dec;55(6):382-8.
28- Katano T, Mizoshita T, Senoo K, et al. The efficacy of transcatheter arterial embolization as the first-choice treatment after failure of endoscopic hemostasis and endoscopic treatment resistance factors. Dig Endosc. 2012 Sep;24(5):364-9
29- Gerson LB, Fidler JL, Cave DR, et al. ACG Clinical Guideline: Diagnosis and Management of Small Bowel Bleeding. Am J Gastroenterol 2015; 110:1265–1287
30- Pasha SF, Leighton JA, Das A, et al. Double-balloon enteroscopy and capsule endoscopy have comparable diagnostic yield in small-bowel disease: a meta-analysis. Clin Gastroenterol Hepatol 2008;6:671–6
31- Kwok CS, Khan MA, Rao SV, et al. Access and non-access site bleeding after percutaneous coronary intervention and risk of subsequent mortality and major adverse cardiovascular events: systematic review and meta-analysis. Circ Cardiovasc Interv. 2015 Apr;8(4
32- Koskinas KC, Räber L, Zanchin T, et al. Clinical impact of gastrointestinal bleeding in patients undergoing percutaneous coronary interventions. Circ Cardiovasc Interv. 2015 May;8(5)
33- Perdoncin E, Zhang M, Riba A, et al. Impact of worsening renal dysfunction on the comparative efficacy of bivalirudin and platelet glycoprotein IIb/IIIa inhibitors: insights from Blue Cross Blue Shield of Michigan Cardiovascular Consortium. Circ Cardiovasc Interv. 2013 Dec;6(6):688-93
34- Ann Pharmacother. Bivalirudin dosing adjustments for reduced renal function with or without hemodialysis in the management of heparin-induced thrombocytopenia. 2011 Oct;45(10):1185-92
35- Bhat M, Larocque M, Amorim M, et al. Prediction and prevention of upper gastrointestinal bleeding after cardiac surgery: a case control study. Can J Gastroenterol. 2012 Jun;26(6):340-4
36- Généreux P, Cohen DJ, Mack M, et al. Incidence, predictors, and prognostic impact of late bleeding complications after transcatheter aortic valve replacement. J Am Coll Cardiol. 2014 Dec 23;64(24):2605-15
37- Balcioglu O, Engin C, Yagdi T, et al. Effect of aortic valve movements on gastrointestinal bleeding that occured in continuous flow left ventricular assist device patients. Transplant Proc. 2013 Apr;45(3):1020-1
38- Lanza F, Chan F, Quigley E, and the Practice Parameters Committee of the American College of Gastroenterology. Guidelines for Prevention of NSAID-Related Ulcer Complications. Am J Gastroenterol 2009; 104:728–738
39- Graham DY, Chan FK. NSAIDs, risks, and gastroprotective strategies: current status and future. Gastroenterology 2008;134:1240-6
40- Lanas A, Garcia-Rodriguez LA, Arroyo MT, et al. Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. Am J Gastroenterol 2007;102:507-15
41- Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomized controlled trial. Lancet 2004;364:665-74
42- McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006;296:1633-44
43- Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-infl ammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomized trials. BMJ 2006;332:1302-8
44- Feagins LA, Iqbal R, Harford WV, et al. Low rate of postpolypectomy bleeding among patients who continue thienopyridine therapy during colonoscopy. Clin Gastroenterol Hepatol. 2013 Oct;11(10):1325-32
45- Yachimski P, Hur C. Upper endoscopy in patients with acute myocardial infarction and upper gastrointestinal bleeding: Results of a decision analysis. Digestive Diseases Scien, 2009; 54: 701–711
46- Grosset-Janin D, Barth E, Bertrand B, et al. Percutaneous left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation and contraindication for anticoagulation. Rev Neurol (Paris). 2015 May;171(5):426-32
47- Lee JK, Kang HW, Kim SG, et al. Risks related with withholding and resuming anticoagulation in patients with non-variceal upper gastrointestinal bleeding while on warfarin therapy. Int J Clin Pract. 2012 Jan;66(1):64-8
48- Carson JL, Terrin ML, Magaziner J, et al; FOCUS Investigators. Transfusion triggers trial for functional outcomes in cardiovascular patients undergoing surgical hip fracture repair (FOCUS). Transfusion. 2006 Dec;46(12):2192-206
49- Hébert PC, Wells G, et al. A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care. N Engl J Med 1999; 340:409-417
50- Carson JL1, Grossman BJ, Kleinman S, Tinmouth AT, et al. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2012 Jul 3;157(1):49-58
51- Kansagara D, Dyer E, Englander H, et al. Treatment of anemia in patients with heart disease: a systematic review. Ann Intern Med 2013; 159:746
52- American Society of Gastroinstestinal Endoscopy. Endoscopy in patients with implanted electronic devices. Gastrointest Endosc 2007;65:563-70
53- Loyaga-Rendon RY, Hashim T, Tallaj JA, et al. Octreotide in the management of recurrent gastrointestinal bleed in patients supported by continuous flow left ventricular assist devices. ASAIO J. 2015 Jan-Feb;61(1):107-9
54- Ashburner JM, Go AS, Reynolds K, et al. Comparison of frequency and outcome of major gastrointestinal hemorrhage in patients with atrial fibrillation on versus not receiving warfarin therapy (from the ATRIA and ATRIA-CVRN cohorts). Am J Cardiol. 2015 Jan 1;115(1):40-6
55- Casado Arroyo R, Polo-Tomas M, Roncalés MP, et al. Lower GI bleeding is more common than upper among patients on dual antiplatelet therapy: long-term follow-up of a cohort of patients commonly using PPI co-therapy. Heart. 2012 May;98(9):718-23
56- Sood M, Larkina M, Thumma JR, et al. Major bleeding events and risk stratification of antithrombotic agents in hemodialysis: Results from the DOPPS. Kidney Int. 2013 Sep;84(3):600-8
57- Lanas A, Polo-Tomás M, Casado-Arroyo R. The aspirin cardiovascular/gastrointestinal risk calculator-a tool to aid clinicians in practice. Aliment Pharmacol Ther. 2013 Apr;37(7):738-48
58- Thomas MR, Storey RF. Optimal management of antiplatelet therapy and proton pump inhibition following percutaneous coronary intervention. Curr Treat Options Cardiovasc Med. 2012 Feb;14(1):24-38
59- Lin KJ, De Caterina R, García Rodríguez LA. Low-dose aspirin and upper gastrointestinal bleeding in primary versus secondary cardiovascular prevention: a population-based, nested case-control study. Circ Cardiovasc Qual Outcomes. 2014 Jan;7(1):70-7
60- Qureshi W, Mittal C, Patsias I, et al. Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation. Am J Cardiol. 2014 Feb 15;113(4):662-8
61- Johnson DA, Chilton R, Liker HR. Proton-pump inhibitors in patients requiring antiplatelet therapy: new FDA labeling. Postgrad Med. 2014 May;126(3):239-45
62- Wang Q, Ljung R, Lagergren J, et al. Prognosis of concomitant users of clopidogrel and proton-pump inhibitors in a high-risk population for upper gastrointestinal bleeding. BMC Pharmacol Toxicol. 2014 Apr 15;15:22
63- Fujita K, Hata M, Sezai A, et al. Is prophylactic intravenous administration of a proton pump inhibitor necessary for perioperative management of cardiac surgery? Heart Surg Forum. 2012 Oct;15(5):E277-9
64- Chen J, Yuan YC, Leontiadis GI, et al. Recent safety concerns with proton pump inhibitors. J Clin Gastroenterol. 2012 Feb;46(2):93-114
65- Mandel' IA, Sukhodolo IV, Pleshko RI, et al. Gastrointestinal hemorrhage in cardiosurgery in patients with endothelial dysfunction. Klin Med (Mosk). 2014;92(3):63-8
66- Lewalter T, Kanagaratnam P, Schmidt B, et al. Ischaemic stroke prevention in patients with atrial fibrillation and high bleeding risk: opportunities and challenges for percutaneous left atrial appendage occlusion. Europace. 2014 May;16(5):626-30
67- McCarberg BH, Cryer B. Evolving Therapeutic Strategies to Improve Nonsteroidal Anti-inflammatory Drug Safety. Am J Ther. 2015 Nov-Dec;22(6):e167-78
68- Ma B, Hang L, Chen G, et al. Effect of clopidogrel with or without omeprazole in patients with carotid artery stenting. West Indian Med J. 2013 Feb;62(2):135-9
69- Hines LE, Ceron-Cabrera D, Romero K, et al. Evaluation of warfarin drug interaction listings in US product information for warfarin and interacting drugs. Clin Ther. 2011 Jan;33(1):36-45