Acute GI Bleeding After Percutaneous Coronary Intervention
Acute GI Bleeding After Percutaneous Coronary Intervention
Given the possible adverse outcomes for those that suffer a GI bleed after PCI, strategies that could reduce its incidence need consideration.
Very few of the pre-PCI risk factors for GI bleeding are able to be modified, other than baseline anemia and shock. There is no evidence to suggest that the correction of these risk factors pre-PCI will reduce rates of GI bleeding after PCI. However, attempting to correct shock is mandatory and a well-established part of managing ACS.
Baseline anemia is a common finding among those with ACS, and in those presenting for elective PCI. Rates of between 12 and 40% have been reported. The effect of a blood transfusion in those with ACS or undergoing PCI is not fully understood and results from observational studies have been conflicting. However, most of the evidence suggests that those who receive a blood transfusion in this setting have poorer outcomes, and recommendations have been made to avoid the use of blood transfusions to achieve an arbitrary hemoglobin level in an otherwise stable patient. A proposed mechanism underlying this apparent relationship between transfusion and poor outcomes is an increased risk of stent thrombosis due to an inflammatory cascade stimulated by transfusion. Except for symptomatic anemia, including when anemia is the likely precipitant for ACS, the correction of baseline anemia to some arbitrary figure prior to PCI cannot be recommended.
It is important for the cardiologist to consider the GI bleeding risk for each patient receiving PCI. For those considered high risk for bleeding, such as the elderly, those with a history of GI bleeding or those with significant comorbidities, the cardiologist may wish to modify the management that patient receives. Recent reviews highlight the different PCI, antiplatelet and anticoagulant strategies that may be used in those with varying degrees of risk for bleeding.
For example, choosing a bare-metal stent over a drug-eluting stent will reduce the requirement for dual antiplatelet therapy from at least 12 months to 3 months or potentially even less. In some patients, avoiding stent implantation with the use of balloon angioplasty alone may be an option to reduce the need for dual antiplatelet therapy. Similar strategies should be considered for patients receiving warfarin for atrial fibrillation, recurrent deep vein thrombosis or a mechanical heart valve, as the addition of dual antiplatelet therapy to warfarin increases bleeding risk by threefold compared with warfarin alone, and also for patients awaiting noncardiac surgery where dual antiplatelet therapy is considered a relative contraindication.
There are no comparative data measuring outcomes that validate the selective use of balloon angioplasty, bare-metal stents and drug-eluting stents to offset GI bleeding risk. It appears unlikely that prospective trials with bleeding rates as a primary outcome with differing PCI strategies will occur. Despite this, we recommend each patient be examined prospectively for their GI bleeding risk against the potential benefit an intensive PCI strategy may bring.
The use of a proton-pump inhibitor (PPI) with clopidogrel is a controversial issue and has been summarized accurately elsewhere. In 2008, the use of PPIs to attenuate the risk with, and for the management of, dual antiplatelet therapy-induced GI bleeding was recommended by the American College of Cardiology Foundation, the American College of Gastroenterologists and the American Heart Foundation. A number of retrospective case series together with pharmacokinetic data have resulted in conflicting views as to whether the addition of a PPI to clopidogrel increases the rate of major cardiac events. It is postulated that PPIs competitively inhibit the CYP450 enzyme responsible for generating the active metabolite of clopidogrel, thereby reducing its clinical efficacy and increasing the rate of major cardiac events. The only prospective trial examining the use of a PPI with dual antiplatelet therapy confirmed the ability of a PPI to reduce the rate of GI bleeding in these patients (1.1 vs 2.9%; hazard ratio [HR]: 0.34; p < 0.001). More importantly, it did not show an increase in major cardiac events with the addition of a PPI, in this case omeprazole 20-mg daily. It should be noted that this trial was stopped before the planned number of patients were enrolled owing to financial issues. The authors conceded that consequently its power was limited, as the anticipated number of GI events did not occur. Updated guidelines from 2010 recommend the prophylactic use of a PPI with dual antiplatelet therapy in those that are at significant risk for a GI bleed, although they still stated that a clinically important interaction cannot be excluded. Identifying those patients at risk requires the clinician to appreciate the risk factors that have been previously discussed.
Accordingly, we recommend a PPI for patients who are due to undergo PCI and are at high risk for a GI bleed, and for it to continue for the duration of dual antiplatelet therapy. Specific high-risk groups include the elderly, those with a history of a GI bleed, any patient who undergoes primary PCI, those that present with cardiogenic shock or require inotropic support, and those with renal failure. There are no conclusive data to recommend one PPI over another.
A recent retrospective case–control study of patients presenting with a first-time MI has suggested that those treated with a PPI concomitantly with aspirin have worse outcomes than those treated with aspirin alone. While the authors present a number of theories to explain this apparent interaction, there is no obvious mechanistic link and it is unclear if this is simply an epiphenomenon or a true clinically meaningful association. This area will require further prospective investigation.
NSAIDs, including the selective COX-2 inhibitors, are ulcerogenic; their effect on GI mucosal integrity is synergistic to that of aspirin monotherapy. Their use is a risk factor for late onset GI bleeding post PCI and accordingly their use, in addition to aspirin after PCI, should be strongly discouraged.
Famotidine, an H2-receptor antagonist, has been shown to reduce the rate of gastric and duodenal ulcer formation in those on low-dose aspirin. However, H2-receptor antagonists are not currently recommended for use in upper GI hemorrhage. To the best of our knowledge there is no evidence to suggest famotidine is effective in reducing GI bleeding with dual antiplatelet therapy.
Prasugrel is a newer thienopyridine that is approved for use in the USA, Europe, the UK and, more recently, Australia for similar indications to clopidogrel. It has been shown to result in fewer ischemic events than clopidogrel post PCI but is associated with significantly more bleeding episodes. It does not appear to interact with PPIs. The nonthienopyridine ticagrelor has also been associated with improved cardiovascular efficacy after PCI, but increased non-procedure-related bleeding when compared with clopidogrel.
In a recent series, a significant proportion of patients undergoing PCI have serological Helicobacter pylori positivity, up to 37%. The presence of H. pylori is mechanistically linked with peptic ulceration, and the addition of antiplatelet agents can result in bleeding of these lesions. While the presence of serological H. pylori positivity has not been linked with increased risk of GI bleeding post PCI, it seems reasonable to recommend eradication of H. pylori prior to elective PCI and after emergent PCI, particularly in patients with identifiable risk factors for GI bleeding. Eradication of H. pylori is becoming more complex as resistant strains emerge, therefore post-treatment confirmation of eradication, for example with a urea breath test, is mandatory.
Preventative Strategies
Given the possible adverse outcomes for those that suffer a GI bleed after PCI, strategies that could reduce its incidence need consideration.
Modifying Pre-PCI Risk Factors for GI Bleeding
Very few of the pre-PCI risk factors for GI bleeding are able to be modified, other than baseline anemia and shock. There is no evidence to suggest that the correction of these risk factors pre-PCI will reduce rates of GI bleeding after PCI. However, attempting to correct shock is mandatory and a well-established part of managing ACS.
Baseline anemia is a common finding among those with ACS, and in those presenting for elective PCI. Rates of between 12 and 40% have been reported. The effect of a blood transfusion in those with ACS or undergoing PCI is not fully understood and results from observational studies have been conflicting. However, most of the evidence suggests that those who receive a blood transfusion in this setting have poorer outcomes, and recommendations have been made to avoid the use of blood transfusions to achieve an arbitrary hemoglobin level in an otherwise stable patient. A proposed mechanism underlying this apparent relationship between transfusion and poor outcomes is an increased risk of stent thrombosis due to an inflammatory cascade stimulated by transfusion. Except for symptomatic anemia, including when anemia is the likely precipitant for ACS, the correction of baseline anemia to some arbitrary figure prior to PCI cannot be recommended.
PCI Treatment Strategy
It is important for the cardiologist to consider the GI bleeding risk for each patient receiving PCI. For those considered high risk for bleeding, such as the elderly, those with a history of GI bleeding or those with significant comorbidities, the cardiologist may wish to modify the management that patient receives. Recent reviews highlight the different PCI, antiplatelet and anticoagulant strategies that may be used in those with varying degrees of risk for bleeding.
For example, choosing a bare-metal stent over a drug-eluting stent will reduce the requirement for dual antiplatelet therapy from at least 12 months to 3 months or potentially even less. In some patients, avoiding stent implantation with the use of balloon angioplasty alone may be an option to reduce the need for dual antiplatelet therapy. Similar strategies should be considered for patients receiving warfarin for atrial fibrillation, recurrent deep vein thrombosis or a mechanical heart valve, as the addition of dual antiplatelet therapy to warfarin increases bleeding risk by threefold compared with warfarin alone, and also for patients awaiting noncardiac surgery where dual antiplatelet therapy is considered a relative contraindication.
There are no comparative data measuring outcomes that validate the selective use of balloon angioplasty, bare-metal stents and drug-eluting stents to offset GI bleeding risk. It appears unlikely that prospective trials with bleeding rates as a primary outcome with differing PCI strategies will occur. Despite this, we recommend each patient be examined prospectively for their GI bleeding risk against the potential benefit an intensive PCI strategy may bring.
Use of Proton-pump Inhibitors
The use of a proton-pump inhibitor (PPI) with clopidogrel is a controversial issue and has been summarized accurately elsewhere. In 2008, the use of PPIs to attenuate the risk with, and for the management of, dual antiplatelet therapy-induced GI bleeding was recommended by the American College of Cardiology Foundation, the American College of Gastroenterologists and the American Heart Foundation. A number of retrospective case series together with pharmacokinetic data have resulted in conflicting views as to whether the addition of a PPI to clopidogrel increases the rate of major cardiac events. It is postulated that PPIs competitively inhibit the CYP450 enzyme responsible for generating the active metabolite of clopidogrel, thereby reducing its clinical efficacy and increasing the rate of major cardiac events. The only prospective trial examining the use of a PPI with dual antiplatelet therapy confirmed the ability of a PPI to reduce the rate of GI bleeding in these patients (1.1 vs 2.9%; hazard ratio [HR]: 0.34; p < 0.001). More importantly, it did not show an increase in major cardiac events with the addition of a PPI, in this case omeprazole 20-mg daily. It should be noted that this trial was stopped before the planned number of patients were enrolled owing to financial issues. The authors conceded that consequently its power was limited, as the anticipated number of GI events did not occur. Updated guidelines from 2010 recommend the prophylactic use of a PPI with dual antiplatelet therapy in those that are at significant risk for a GI bleed, although they still stated that a clinically important interaction cannot be excluded. Identifying those patients at risk requires the clinician to appreciate the risk factors that have been previously discussed.
Accordingly, we recommend a PPI for patients who are due to undergo PCI and are at high risk for a GI bleed, and for it to continue for the duration of dual antiplatelet therapy. Specific high-risk groups include the elderly, those with a history of a GI bleed, any patient who undergoes primary PCI, those that present with cardiogenic shock or require inotropic support, and those with renal failure. There are no conclusive data to recommend one PPI over another.
A recent retrospective case–control study of patients presenting with a first-time MI has suggested that those treated with a PPI concomitantly with aspirin have worse outcomes than those treated with aspirin alone. While the authors present a number of theories to explain this apparent interaction, there is no obvious mechanistic link and it is unclear if this is simply an epiphenomenon or a true clinically meaningful association. This area will require further prospective investigation.
Other Medications
NSAIDs, including the selective COX-2 inhibitors, are ulcerogenic; their effect on GI mucosal integrity is synergistic to that of aspirin monotherapy. Their use is a risk factor for late onset GI bleeding post PCI and accordingly their use, in addition to aspirin after PCI, should be strongly discouraged.
Famotidine, an H2-receptor antagonist, has been shown to reduce the rate of gastric and duodenal ulcer formation in those on low-dose aspirin. However, H2-receptor antagonists are not currently recommended for use in upper GI hemorrhage. To the best of our knowledge there is no evidence to suggest famotidine is effective in reducing GI bleeding with dual antiplatelet therapy.
Prasugrel is a newer thienopyridine that is approved for use in the USA, Europe, the UK and, more recently, Australia for similar indications to clopidogrel. It has been shown to result in fewer ischemic events than clopidogrel post PCI but is associated with significantly more bleeding episodes. It does not appear to interact with PPIs. The nonthienopyridine ticagrelor has also been associated with improved cardiovascular efficacy after PCI, but increased non-procedure-related bleeding when compared with clopidogrel.
Helicobacter Pylori
In a recent series, a significant proportion of patients undergoing PCI have serological Helicobacter pylori positivity, up to 37%. The presence of H. pylori is mechanistically linked with peptic ulceration, and the addition of antiplatelet agents can result in bleeding of these lesions. While the presence of serological H. pylori positivity has not been linked with increased risk of GI bleeding post PCI, it seems reasonable to recommend eradication of H. pylori prior to elective PCI and after emergent PCI, particularly in patients with identifiable risk factors for GI bleeding. Eradication of H. pylori is becoming more complex as resistant strains emerge, therefore post-treatment confirmation of eradication, for example with a urea breath test, is mandatory.