Case introduction
The patient, male, 60 years old, was admitted to our hospital on May 10, 2013 due to 2 months of coronary artery disease and tarry, unformed and dilute stools 3 times with about 200 ml each time after the use of antiplatelet drugs. The patient was diagnosed with coronary artery disease 2 months ago and implanted one coronary drug-coated stent, and was taking enteric aspirin 100mg/d, Polivyte 75mg/d, simvastatin 20mg/d and other medications consistently. After admission, he was given an examination: erythrocytes 3.1×1012/L, hemoglobin 78g/L, platelets 79×109/L, blood pressure 90/60 mm Hg, gastroscopy showed: duodenal bulb ulcer, chronic gastritis, and the diagnosis was duodenal bulb ulcer with bleeding. The patient was immediately stopped from taking aspirin and poliovirus, advised to abstain from food and water, given cardiac monitoring, oxygen, rehydration, intravenous omeprazole, aminoglutethimide 0.3 g + phenolsulfonamide 3.0 g + 10% potassium chloride 1.0 g + 5% glucose solution 500 ml intravenous drip treatment to stop bleeding once a day. At 9:00 on the third day, the patient’s condition worsened, with a tarry stool of about 300 ml, shortness of breath, ECG monitoring showed a heart rate of 120 beats/min, blood pressure of 80/50mmHg, respiration of 27 breaths/min, oxygen saturation of 90% to 93%, considering that there was still continued gastrointestinal bleeding, urgent investigation of hemoglobin 60 g/L, red blood cells 2.6×1012/L, continued expansion of blood volume After 4 d, the patient’s gastrointestinal bleeding gradually stopped and continued to be observed. The patient’s condition was stable, no further blood in the stool and negative fecal occult blood. The patient was discharged from the hospital after 20 d. At follow-up 1 month later, the patient continued to take Bolivir without aspirin and did not have any further gastrointestinal bleeding.
Numerous clinical studies have demonstrated the benefit of antiplatelet therapy for the primary and secondary prevention of thromboembolic disease. Small doses of aspirin (75-150 mg/d) are now widely used in the treatment of coronary atherosclerotic heart disease (CHD), cerebrovascular disease, and peripheral arterial disease. Aspirin inhibits platelet activation and thrombosis by inhibiting cyclo-oxygenase on the one hand, and damages the mucosa of the GI tract on the other hand, leading to ulcer formation and bleeding, which can cause death in severe cases; other antiplatelet drugs such as clopidogrel can also aggravate GI tract damage, and the damage is more serious when combined with the drug. The damage is even more serious when combined. This article introduces the prevention and treatment of GI injury with antiplatelet drugs.
The mechanism of GI injury caused by aspirin includes both local and systemic effects, while the ADP receptor antagonist clopidogrel can prevent the healing of damaged GI mucosa. Adverse GI reactions caused by aspirin range from mild dyspepsia to fatal peptic ulcer bleeding and perforation. Studies have shown that aspirin can increase the risk of GI injury by 2 to 4 times. Clopidogrel (75 mg/d) has a similar risk of causing GI bleeding to aspirin (100 mg/d). When clopidogrel was combined, the incidence of GI bleeding was significantly higher than when one antiplatelet drug was used alone, with a 2- to 3-fold increased risk.
Anti-thrombotic drugs are widely used in the prevention and treatment of cardiovascular diseases. Even small doses of aspirin may increase the risk of GI injury, and clopidogrel may aggravate GI injury, and the risk is higher when aspirin is combined with clopidogrel.
A. Clinical manifestations and characteristics of GI tract injury caused by antiplatelet drugs
(A) Clinical manifestations
The adverse reactions of aspirin are mainly in the digestive system, of which the above gastrointestinal injury is more common. In recent years, it has been found that patients receiving dual antiplatelet therapy and mostly combined with PPI (proton pump inhibitors, such as omeprazole, etc.) are more likely to suffer from gastrointestinal tract injury.
Such as omeprazole, etc.), the incidence of lower GI bleeding is significantly higher than that of upper GI bleeding.
1. Common symptoms: nausea, vomiting, epigastric discomfort or pain, diarrhea, vomiting blood, black stool, etc. 2.
2. Common lesions: GI mucosal erosion, ulcers, life-threatening GI bleeding and perforation, and less commonly, intestinal stricture. Clinical features of aspirin-induced ulcers include: more common in elderly women, mostly painless, more common in gastric ulcers than duodenal ulcers, and prone to bleeding and perforation.
(B) Anti-platelet drugs and gastrointestinal injury
1. Time of occurrence: 12 months after taking the drug is the most frequent stage of gastrointestinal tract injury, reaching a peak at 3 months.
2. Relationship with dose: The antithrombotic effect of aspirin does not increase with dose in a certain range, but the risk of GI injury increases significantly with dose. Patients taking aspirin doses >200 mg/d had a 3-fold increase in total bleeding events compared with patients taking <100 mg< font="">/d. Therefore, it is recommended that the lowest effective dose (75-100 mg/d) should be selected for long-term aspirin use.
3. Relationship with dosage form: Mechanistically, aspirin enteric tablets have less direct damage to the gastric mucosa than non-enteric tablets, but there is no clinical evidence that effervescent or enteric tablets significantly reduce the risk of gastrointestinal damage from aspirin compared to flat tablets.
4. Relationship with age: Elderly patients are at high risk for GI injury from antiplatelet agents, and the risk increases with age. The risk of upper GI bleeding associated with low-dose aspirin increases with age (2.3% increase in the incidence of GI bleeding for every 1-year increase in age). The incidence of peptic ulcer perforation in patients on low-dose aspirin (75 mg/d) was 0.1 per 1,000 for those aged ≤65 years; 1.07 per 1,000 for those aged >65 years. The antiplatelet drug therapy is mostly used in the elderly and the efficacy is certain, so the advantages and disadvantages should be weighed when using it.
5. Relationship with Helicobacter pylori (Hp) infection: Hp infection can aggravate the GI damage effect of aspirin, and Hp eradication can reduce the risk of ulcer recurrence in patients with a history of ulcer bleeding. Therefore, before starting long-term antiplatelet therapy, it is recommended that Hp be tested and eradicated in patients who are eligible.
6. Combination of drugs: The combination of antiplatelet drugs or the combination of antiplatelet drugs and anticoagulants increases the risk of upper gastrointestinal bleeding by 2 to 7 times. Patients with acute coronary syndrome (ACS) often require the combination of multiple antiplatelet and/or anticoagulant drugs, and particular attention should be paid to the assessment and prevention of the risk of GI injury at this time.
Core tip: The initial symptoms of aspirin-induced GI injury are easily overlooked, so once the risk of bleeding is high, any changes in symptoms and signs should not be ignored in patients with a history of drug use. The risk of aspirin-induced GI injury increases significantly with patient age and drug dose, and co-infection with Hp and combination medications also increase its risk.
Screening and prevention of GI injury in patients on long-term antiplatelet therapy
1. Standardize the indications for antiplatelet therapy: antiplatelet drugs are difficult to avoid completely when bleeding adverse reactions occur while reducing thrombotic events, so they are recommended only when the benefit is greater than the risk of bleeding. The benefits of aspirin in the secondary prevention of cardiovascular disease far outweigh the risks, i.e., aspirin reduces cardiovascular deaths significantly more than serious bleeding events. However, there is controversy regarding the place of aspirin in the primary prevention of cardiovascular disease. Currently, national and international guidelines consistently recommend that aspirin should be given to selected patients at moderate to high risk according to their cardiovascular disease risk stratification. For example, European guidelines recommend that aspirin should not be used for primary prevention in the following patients: patients with hypertension who have neither cardiovascular disease nor renal insufficiency or risk factors for cardiovascular disease; and patients with diabetes mellitus who do not have atherosclerotic disease.
In secondary prevention of cardiovascular disease, the duration of the combination of antithrombotic drugs should be reasonably controlled to reduce the risk of bleeding, and the long-term combination of antithrombotic drugs should be minimized, including the combination of different antiplatelet drugs and the combination of antiplatelet and anticoagulant drugs.
2. People at risk for GI injury: Studies have shown that people over 65 years of age benefit more from antiplatelet therapy than those under 65 years of age, but advanced age is also an independent risk factor for GI injury. Patients with a history of gastrointestinal disease have a significantly increased risk of gastrointestinal injury, with a 13-fold increased risk in patients who have had peptic ulcer bleeding.
3. Reasonable combination of antithrombotic drugs: The combination of aspirin and other antiplatelet or anticoagulant drugs significantly increases the risk of serious bleeding, mainly in the gastrointestinal tract. Therefore, combined antithrombotic therapy should be avoided for people at high risk of gastrointestinal injury. Anticoagulant therapy (warfarin or heparin) does not directly cause GI injury, but it can increase the risk of GI bleeding. For long-term combined application of oral anticoagulant warfarin and antiplatelet agents, the drug dose should be adjusted to the lowest effective dose, i.e. 75-100 mg/d for aspirin and 75 mg/d for clopidogrel, and the warfarin dose should be set at the International Normalized Ratio (INR) target value of 2.0-2.5, but for mechanical valve replacement the latter may require more intense anticoagulation.
4. Screening and eradication of Hp: In patients on long-term low-dose aspirin, Hp infection is an independent risk factor for GI bleeding, and eradication of Hp may reduce recurrence of ulcers and bleeding. It is recommended to test for Hp before long-term antiplatelet therapy, and those who are positive should be referred to a gastroenterologist for eradication.
5. Application of H2 receptor antagonist (H2RA) to prevent gastrointestinal injury: for patients taking aspirin (75-325 mg/d), famotidine can prevent gastroduodenal ulcer and erosive esophagitis, but it is worse than PPI. The advantage is that it is less expensive, and it can be considered for patients who cannot use PPI. There is no drug interaction between famotidine and clopidogrel, and it also has the effect of protecting the gastric mucosa. Cimetidine should be avoided because it is a potent inhibitor of CYP2C19 and can affect the activation of clopidogrel.
6. Application of PPI to prevent GI injury: PPI significantly reduces the incidence of GI injury in patients taking aspirin and/or clopidogrel. In a randomized controlled clinical trial, PPI reduced GI bleeding by 87% in patients on dual antiplatelet therapy. PPI is the drug of choice for preventing antiplatelet drug-related GI injury, and it is recommended that the timing of PPI combination application be determined on a patient-by-patient basis. high-risk patients can be treated with PPI combination for the first 6 months of antiplatelet drug therapy, and then switched to H2RA or intermittent PPI after 6 months. PPI.
Core tips: (1) to reduce the GI damage of antiplatelet drugs, the use of antithrombotic drugs should be standardized and high-risk patients should be evaluated and screened according to the process; (2) the indications for long-term co-application of antithrombotic drugs should be strictly controlled and adjusted to the lowest effective dose; (3) it is recommended to screen and eradicate Hp in patients taking long-term antiplatelet drugs and to give effective acid-suppressing drugs to high-risk patients at the same time. PPI is preferred, and H2RA can be given to those who cannot tolerate PPI.
The combined application of PPI and clopidogrel
1. Pharmacologically, there are differences in the interactions between different PPIs and clopidogrel.
2. Clopidogrel combined with PPI can significantly reduce gastrointestinal adverse effects, clinical studies did not find significant differences in cardiovascular events, but laboratory studies have shown that some PPIs can affect the antiplatelet effect of clopidogrel.
3. If the combination of PPI is needed along with antiplatelet drug therapy, omeprazole or esomeprazole should be avoided as much as possible.
IV. Treatment of antiplatelet drug gastrointestinal injury
1. Discontinuation of antiplatelet drugs: Whether to discontinue antiplatelet drugs when gastrointestinal injury occurs should be evaluated individually according to the risk of gastrointestinal injury and the risk of cardiovascular disease. If the patient only shows symptoms of dyspepsia, anti-platelet drugs can be discontinued and acid suppressants can be given; if the patient has active bleeding, anti-platelet drugs often need to be discontinued until the bleeding situation is stable. However, some patients are at increased risk of thrombotic events due to discontinuation of antiplatelet agents, especially patients with ACS, within 1 month of implantation of bare metal stents, and within 6 months of drug-coated stents, and it is recommended to avoid complete discontinuation of antiplatelet agents. Patients on a combination of multiple antiplatelet and anticoagulant drugs should consider reducing the drug class and dose if bleeding occurs. When severe GI bleeding is life-threatening, it may be necessary to discontinue all anticoagulant and antiplatelet agents and restart aspirin or clopidogrel after 3 to 5 d of discontinuation if the bleeding is stable, especially in patients at high risk for cardiovascular disease.
Gastrointestinal bleeding due to aspirin may be restarted with antiplatelet therapy after PPI treatment and/or endoscopic hemostasis, under close monitoring for at least 24 h. If no rebleeding occurs, antiplatelet therapy may be restarted, but in combination with PPI, while closely monitoring the patient for possible recurrence of bleeding.
2. Regarding substitution therapy: The American College of Cardiology (ACC) guidelines downgrade the level of evidence that clopidogrel can be substituted in patients with coronary artery disease who are unable to tolerate aspirin due to gastrointestinal injury. In patients with a high risk of recurrent ulcer bleeding, clopidogrel is not recommended as a substitute for aspirin, and a combination of aspirin and PPI should be given instead.
3. Treatment of GI injury: PPI, H2RA and mucosal protective agents should be chosen, with PPI being the drug of choice for the prevention and treatment of aspirin-related GI injury. Blood transfusion or endoscopic hemostasis if necessary. Patients with acute, severe bleeding need to temporarily discontinue antiplatelet drugs and strictly grasp the indications for transfusion. Patients with hemodynamic stability and hematocrit >25% or Hb >80g/L can be temporarily excluded from transfusion. If severe bleeding cannot be controlled after active treatment, platelet transfusion can be given if necessary.
4. Hp eradication therapy: all patients who need to take anti-platelet drugs for a long time are recommended to detect and eradicate Hp. Currently, a quadruple therapy of PPI, clarithromycin, amoxicillin plus bismuth is recommended for a course of 10~14d.
Core tips: (1) whether to discontinue antiplatelet drugs after the occurrence of GI injury needs to be weighed against the patient’s risk of thrombosis and bleeding; (2) for patients with peptic ulcers and bleeding caused by aspirin, clopidogrel is not recommended to replace aspirin, and aspirin combined with PPI is recommended; (3) for patients with ulcers and bleeding, acid suppressants and gastric mucosal protectors should be actively given, PPI is preferred, and Hp eradication and blood transfusion if necessary.
Conclusion
○Aspirin is the cornerstone of long-term antithrombotic therapy in patients with cardiovascular disease, including primary and secondary prevention. The rate of fatal GI injury due to aspirin is low, with an average of 1 case of hematemesis per 5000 patients treated with aspirin and a reduction of 19 serious cardiovascular events per year per 1000 patients treated with aspirin. Therefore, long-term antiplatelet therapy should be adhered to in patients with indications, while taking appropriate measures to avoid and reduce the occurrence of gastrointestinal injury.
The optimal dose of aspirin for long-term use is 75-100 mg/d. Small doses of aspirin can also lead to GI injury, and there is no significant difference in the risk of peptic ulcer and GI bleeding caused by different doses of aspirin.
○ADP receptor antagonists (such as clopidogrel) can aggravate GI injury.
○Patients at high risk for GI bleeding: ≥65 years old, history of peptic ulcer or bleeding, combined Hp infection, combined antiplatelet therapy or anticoagulation, combined treatment with NSAIDs, glucocorticoid-like drugs.
○For the high-risk group who take antiplatelet drugs for a long time should be screened and a eradicated Hp, can be combined with PPI or H2RA for prevention and treatment, PPI is preferred.
○Whether to discontinue antiplatelet agents after the occurrence of GI injury needs to balance the thrombotic and bleeding risks of patients. Resume antiplatelet therapy as soon as possible after hemorrhage stabilization.
○For patients with aspirin-induced ulcers and bleeding, clopidogrel is not recommended to replace aspirin therapy, and aspirin combined with PPI therapy is recommended.
○When patients taking clopidogrel need to use PPI in combination, try to avoid omeprazole and esomeprazole.
○When combining PPI with dual antiplatelet therapy, it is recommended to use it continuously for no more than 6 months, after which it can be replaced with H2RA or intermittent PPI.
○Clinicians and patients should pay attention to monitoring the gastrointestinal tract injury during long-term antiplatelet therapy, pay attention to the presence of black stools, and perform regular fecal occult blood and routine blood tests.