Acetylsalicylic acid

Mechanism

Ketorolac is the most potent oral and parenteral NSAID. Aspirin irreversibly blocks platelet cyclooxygenase. Co-administration of two NSAIDs adds up the risks: gastrointestinal bleeding, acute kidney injury, sodium and fluid retention. FDA Toradol Section 4.3 specifically lists aspirin and other NSAIDs as contraindications.

Symptoms

Black or tarry stools (melena), vomiting blood or coffee-ground material, epigastric pain. Acute kidney injury and a rise in blood pressure are also possible. Risk of bleeding multiplies in patients over 65 and with prior peptic ulcer disease.

Management

The combination is not prescribed. If aspirin is required for cardioprotection (75–100 mg/day), replace ketorolac with paracetamol, metamizole, or a short opioid course. Ketorolac courses are limited to 5 days under all circumstances.

Mechanism

Aspirin irreversibly blocks platelet cyclooxygenase; apixaban directly inhibits factor Xa. Dual antithrombotic action roughly doubles major bleeding risk versus apixaban alone.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

Combine only for strict indications: after coronary stenting or in acute coronary syndrome. Limit aspirin to 75–100 mg/day, and dual therapy to 1–6 months. PPI cover with pantoprazole is mandatory.

Mechanism

Citalopram, like other selective serotonin reuptake inhibitors (SSRIs), blocks serotonin uptake into platelets, and platelets need serotonin to stop bleeding. Aspirin irreversibly blocks platelet cyclooxygenase and injures the stomach lining. Together they raise the risk of bleeding, above all from the upper gastrointestinal tract (aspirin and citalopram labels).

Symptoms

Gum bleeding, epistaxis, bruising without trauma. Severe cases: GI bleeding.

Management

Aspirin SmPCs, including those for 100 mg products, advise avoiding selective serotonin reuptake inhibitors (SSRIs) with aspirin whenever possible because of the bleeding risk, especially from the upper gastrointestinal tract (aspirin 100 mg SmPCs). If the combination is needed, use it with caution (aspirin and citalopram SmPCs) and explain the signs of bleeding to the patient in advance: black stools, vomiting blood, low blood pressure, cold sweat, abdominal pain, dizziness. If they appear, the patient stops treatment and sees a doctor at once (aspirin 100 mg SmPC). The US Food and Drug Administration (FDA) also asks prescribers to inform patients about the higher bleeding risk when citalopram is combined with aspirin and other antiplatelet drugs (citalopram FDA label).

Mechanism

Additive ulcerogenic effect. Dexamethasone suppresses GI mucosal repair; aspirin blocks protective prostaglandins.

Symptoms

Epigastric pain, nausea, heartburn. With prolonged therapy: peptic ulcer and GI bleeding risk (black stools, vomiting blood or coffee-ground material). Older patients and prior peptic ulcer disease: higher risk.

Management

Aspirin SmPCs, including those for 100 mg tablets, advise against combining aspirin with systemic glucocorticoids because together they raise the risk of ulcers and gastrointestinal bleeding (aspirin 100 mg and 500 mg SmPCs). The exception is hydrocortisone used as replacement therapy in Addison's disease. If the combination cannot be avoided, use it with caution: tell the patient in advance about the signs of bleeding (black stools, vomiting blood, marked weakness, low blood pressure, cold sweat, abdominal pain, dizziness) and that if they appear, aspirin is stopped and they must see a doctor at once (aspirin SmPCs). In patients with peptic ulcer disease, give an anti-ulcer drug together with dexamethasone (dexamethasone SmPC). Corticosteroids can increase salicylate clearance, and in hypoprothrombinaemia the patient is monitored for aspirin toxicity on this combination (US dexamethasone label).

Mechanism

Diclofenac competitively inhibits platelet cyclooxygenase-1 and blocks aspirin's access for COX-1 acetylation. Co-administration loses aspirin's cardioprotective effect. Additive ulcerogenic effect of two NSAIDs.

Symptoms

Black or tarry stools (melena), vomiting blood or coffee-ground material, epigastric pain. Risk multiplies in older patients and with prior peptic ulcer disease.

Management

If the patient takes aspirin for cardioprotection, give aspirin 30 minutes before or 8 hours after diclofenac. Alternative analgesic without this issue: paracetamol or a selective COX-2 inhibitor (celecoxib).

Mechanism

Like other NSAIDs, aspirin reduces renal excretion of digoxin, so digoxin blood levels rise, sometimes to toxic values (aspirin 100 mg and 500 mg SmPCs). The US digoxin label (FDA) links this to the fall in glomerular filtration and tubular secretion caused by NSAIDs. Salicylates can also strengthen the effect of digoxin through potassium and magnesium loss, because a heart short of these ions is more sensitive to digoxin (Spanish digoxin SmPC).

Symptoms

Signs of digoxin overdose: nausea, vomiting, loss of appetite, fatigue, visual changes with yellow-green colour vision, and rhythm and conduction disorders, from slow pulse and heart block to ventricular arrhythmias. The risk is higher in older patients, with low body weight, reduced kidney function, or low potassium or magnesium.

Management

Aspirin SmPCs, including those for 100 mg products, do not recommend combining aspirin with digoxin. If the combination cannot be avoided, measure digoxin blood levels when aspirin is started, when its dose changes and when it is stopped (aspirin 100 mg and 500 mg SmPCs). The US digoxin label (FDA) asks for closer monitoring of digoxin levels and signs of toxicity whenever an interacting drug is started, adjusted or stopped, and for individual digoxin dosing with drugs that impair kidney function. Check electrolytes and kidney function periodically, since low potassium and magnesium raise the risk of digoxin toxicity (US digoxin label).

Mechanism

Escitalopram (SSRI) depletes the platelet serotonin pool, impairing primary haemostasis. Aspirin irreversibly blocks platelet cyclooxygenase. Combined, GI bleeding risk roughly doubles.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black tarry stools, blood in urine. Severe cases include gastrointestinal or intracranial haemorrhage.

Management

The combination is acceptable at low aspirin doses (75–100 mg as cardioprotection). Mandatory PPI cover with pantoprazole. Alternative antidepressants with minimal platelet effect: mirtazapine or agomelatine.

Mechanism

Fluoxetine, like other SSRIs, blocks serotonin uptake into platelets, and platelets need serotonin to stop bleeding. Aspirin irreversibly blocks platelet cyclooxygenase and injures the stomach lining. Together they raise the risk of bleeding, above all from the upper gastrointestinal tract (aspirin 100 mg and fluoxetine labels).

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black stools, blood in urine. Severe cases include gastrointestinal or intracranial haemorrhage.

Management

Aspirin SmPCs, including those for 100 mg products, advise avoiding SSRIs with aspirin whenever possible because of bleeding risk, especially gastrointestinal (aspirin 100 mg and 500 mg SmPCs). If the combination is needed, use it with caution (fluoxetine SmPC) and explain the signs of bleeding to the patient in advance: black stools, vomiting blood, abdominal pain, weakness, dizziness, cold sweat. If they appear, the patient stops treatment and seeks medical care at once (aspirin 100 mg SmPC). The FDA also asks prescribers to warn patients about the higher bleeding risk when fluoxetine is combined with aspirin (US fluoxetine label).

Mechanism

Fluvoxamine, like other selective serotonin reuptake inhibitors (SSRIs), blocks serotonin uptake into platelets, and platelets need serotonin to stop bleeding. Aspirin irreversibly blocks platelet cyclooxygenase and injures the stomach lining. Together they raise the risk of bleeding, above all from the upper gastrointestinal tract (aspirin and fluvoxamine labels).

Symptoms

Gum bleeding, epistaxis, bruising without trauma. Severe cases: GI bleeding.

Management

Aspirin SmPCs, including those for 100 mg products, advise avoiding selective serotonin reuptake inhibitors (SSRIs) with aspirin whenever possible because of the bleeding risk, especially from the upper gastrointestinal tract (aspirin 100 mg SmPCs). If the combination is needed, use it with caution, particularly in older people (fluvoxamine SmPC), and explain the signs of bleeding to the patient in advance: black stools, vomiting blood, low blood pressure, cold sweat, abdominal pain, dizziness. If they appear, the patient stops treatment and sees a doctor at once (aspirin 100 mg SmPC). The US Food and Drug Administration (FDA) also requires prescribers to warn patients about the higher bleeding risk when fluvoxamine is combined with aspirin (fluvoxamine FDA label).

Mechanism

Ibuprofen reversibly binds platelet COX-1 and blocks aspirin's access to its irreversible acetylation site. Aspirin's antiplatelet effect is lost – cardiovascular event risk.

Symptoms

No symptoms – risk is loss of cardioprotection.

Management

If ibuprofen needed – take 8 hours BEFORE or 30 minutes AFTER aspirin. Alternative in cardiovascular risk – paracetamol.

Mechanism

Meloxicam and aspirin are both NSAIDs. Together they damage the stomach and gut lining more, and the risk of ulcers and bleeding rises through a synergistic effect (meloxicam and aspirin 100 mg SmPCs). In a clinical study cited in the US meloxicam label (FDA), an NSAID plus aspirin caused significantly more gastrointestinal adverse reactions than the NSAID alone. Aspirin also inhibits platelet aggregation for several days after a dose (aspirin 100 mg SmPC).

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools. Severe cases: GI bleeding.

Management

The meloxicam SmPC does not recommend combining it with aspirin at 500 mg or more per dose or 3 g or more a day, and the aspirin 100 mg SmPC advises avoiding NSAIDs with aspirin whenever possible (meloxicam and aspirin 100 mg SmPCs). The FDA does not generally recommend meloxicam with either low-dose or analgesic-dose aspirin because of bleeding risk, and notes that meloxicam is not a substitute for low-dose aspirin for cardiovascular protection (US meloxicam label). If meloxicam is still needed with low-dose aspirin, consider gastroprotection with misoprostol or a proton pump inhibitor (meloxicam SmPC). Warn the patient in advance about signs of bleeding: black stools, vomiting blood, abdominal pain, weakness, dizziness, cold sweat. If they appear, the patient stops the medicines and seeks medical care at once (aspirin 100 mg SmPC).

Mechanism

Aspirin suppresses tubular secretion of methotrexate and displaces it from albumin binding. Methotrexate plasma levels rise – particularly dangerous at oncologic doses.

Symptoms

Mouth ulcers (mucositis), nausea, diarrhoea, hair loss. Blood counts fall: leukocytes, platelets, erythrocytes. Severe cases include fatal pancytopenia, nephrotoxicity, and hepatotoxicity.

Management

Aspirin SmPCs, including those for 100 mg products, contraindicate aspirin during methotrexate treatment at 15 mg a week or more (aspirin 100 mg and 500 mg SmPCs). Below 15 mg a week the interaction still has to be taken into account, especially with impaired kidney function; if the combination is needed, monitor full blood count and kidney function, particularly in the first days (aspirin SmPCs). The methotrexate SmPC for rheumatological use allows NSAIDs and salicylates to continue with low-dose methotrexate only under strict medical supervision; with any kidney impairment, even mild, NSAIDs are not recommended, and while they are taken blood counts and kidney function are checked more often than the usual schedule (methotrexate 2.5 mg SmPC). With high oncological methotrexate doses, NSAIDs are not given before or together with methotrexate (methotrexate 100 mg/ml SmPC). If the combination cannot be avoided, the FDA advises close monitoring for methotrexate adverse reactions (US methotrexate label).

Mechanism

Glucocorticoids damage the gastric mucosa and suppress protective prostaglandin production. Aspirin compounds the risk of GI ulcer and bleeding.

Symptoms

Epigastric pain, nausea, heartburn. With prolonged therapy: peptic ulcer and GI bleeding risk (black stools, vomiting blood). Older patients and prior peptic ulcer disease: higher risk.

Management

Aspirin SmPCs, including those for 100 mg tablets, advise against combining aspirin with systemic glucocorticoids because together they raise the risk of ulcers and gastrointestinal bleeding (aspirin 100 mg and 500 mg SmPCs). If the combination cannot be avoided, use it with caution: tell the patient in advance about the signs of bleeding (black stools, vomiting blood, marked weakness, low blood pressure, cold sweat, abdominal pain, dizziness) and that if they appear, aspirin is stopped and they must see a doctor at once (aspirin SmPCs). The methylprednisolone SmPC also asks for patient monitoring: methylprednisolone can speed up salicylate elimination and weaken its effect (methylprednisolone SmPC). In patients on long-term high-dose aspirin, salicylate levels can rise to toxic values when methylprednisolone is withdrawn (US methylprednisolone label).

Mechanism

Aspirin and naproxen are both NSAIDs: together they damage the stomach lining more and cause ulcers and bleeding more often (aspirin 100 mg and naproxen SmPCs). Naproxen taken for more than one day in a row also blunts the antiplatelet effect of low-dose aspirin, and this can last several days after naproxen is stopped; the Spanish SmPC calls its clinical relevance unknown (naproxen SmPC). In a study cited in the US naproxen label (FDA), the interaction was stronger when naproxen was taken 30 minutes before aspirin and most marked in the first days after naproxen was stopped.

Symptoms

Black tarry stools, vomiting blood, abdominal pain, weakness, dizziness and cold sweat are signs of gastrointestinal bleeding. Bruising, bleeding gums and nosebleeds are less common. The weaker antiplatelet effect of aspirin causes no symptoms by itself, but in patients with high cardiovascular risk it can reduce the cardiovascular protection aspirin gives.

Management

The naproxen SmPC contraindicates naproxen with other NSAIDs and asks for special caution with low-dose aspirin (naproxen SmPC). Avoid NSAIDs with aspirin whenever possible (aspirin 100 mg SmPC). The FDA does not generally recommend naproxen with analgesic doses of aspirin because of bleeding risk. For patients on low-dose aspirin for cardioprotection who need occasional pain relief, the FDA advises an NSAID that does not interfere with aspirin or a non-NSAID analgesic; naproxen is not a substitute for low-dose aspirin (US naproxen label). If naproxen is still needed with low-dose aspirin, consider gastroprotection with misoprostol or a proton pump inhibitor (naproxen SmPC) and watch for signs of bleeding (US naproxen label).

Mechanism

Similar to ASA + methylprednisolone. Prednisolone + antiplatelet – additive risk of GI ulcer and bleeding.

Symptoms

Epigastric pain, nausea, heartburn. With prolonged therapy: peptic ulcer and GI bleeding risk (black stools, vomiting blood). Older patients and prior peptic ulcer disease: higher risk.

Management

Aspirin SmPCs, including those for 100 mg tablets, advise against combining aspirin with systemic glucocorticoids because together they raise the risk of ulcers and gastrointestinal bleeding (aspirin 100 mg and 500 mg SmPCs). If the combination cannot be avoided, use it with caution: tell the patient in advance about the signs of bleeding (black stools, vomiting blood, marked weakness, low blood pressure, cold sweat, abdominal pain, dizziness) and that if they appear, aspirin is stopped and they must see a doctor at once (aspirin SmPCs). The prednisolone SmPC also asks for patient monitoring: prednisolone can speed up salicylate elimination and weaken its effect (prednisolone SmPC). In hypoprothrombinaemia, aspirin is used cautiously with corticosteroids (US prednisolone label).

Mechanism

Aspirin irreversibly blocks platelet cyclooxygenase; rivaroxaban directly inhibits factor Xa. No clinically significant pharmacokinetic or pharmacodynamic interaction was found with acetylsalicylic acid 500 mg. But the EMA SmPC lists acetylsalicylic acid among drugs that typically increase bleeding risk, and the effects on haemostasis add up.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

The combination itself is an approved use of rivaroxaban. Rivaroxaban 2.5 mg twice daily with acetylsalicylic acid 75–100 mg daily is given after acute coronary syndrome (EMA SmPC). The same regimen is used in coronary artery disease or peripheral artery disease at high risk of ischaemic events (EMA SmPC and FDA label). The EMA SmPC contraindicates the combination in two groups: acute coronary syndrome in patients with prior stroke or transient ischaemic attack, and coronary or peripheral artery disease in patients with prior haemorrhagic or lacunar stroke or any stroke within the past month. On full-dose rivaroxaban (atrial fibrillation, deep vein thrombosis), add aspirin only for a separate indication and with caution. Patients at risk of peptic ulcer may receive gastric prophylaxis (EMA SmPC). Add NSAIDs to this pair only if the benefit outweighs the bleeding risk.

Mechanism

Sertraline (SSRI) depletes the platelet serotonin pool, weakening platelet aggregation. Aspirin irreversibly blocks platelet cyclooxygenase. Combined, GI bleeding risk roughly doubles.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black stools, blood in urine. Severe cases include gastrointestinal or intracranial haemorrhage.

Management

The combination is acceptable at low aspirin doses (75–100 mg as cardioprotection). PPI cover with pantoprazole is mandatory. Alternative antidepressants with minimal platelet effect: mirtazapine or agomelatine.

Mechanism

Aspirin suppresses renal prostaglandin synthesis that maintains glomerular perfusion. Diuretic and natriuretic effects of spironolactone diminish and potassium accumulates.

Symptoms

Oedema, weight gain, rising blood pressure. Weakness, paraesthesia, and arrhythmias from hyperkalaemia. Reduced diuretic effect emerges within 1–2 weeks of starting aspirin.

Management

At low aspirin doses (75–100 mg for cardioprotection), the clinical effect is minimal; co-prescription is acceptable with potassium and creatinine monitoring. At full anti-inflammatory doses, the diuretic response drops markedly – titrate spironolactone clinically.

Mechanism

Aspirin irreversibly blocks platelet cyclooxygenase and reduces aggregation. Warfarin blocks vitamin K-dependent clotting factor synthesis. Two different antithrombotic mechanisms add up. Aspirin also injures the gastric mucosa, raising bleeding risk independently of coagulation parameters.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, blood in urine or stool, menorrhagia. Severe cases include gastrointestinal or intracranial haemorrhage. Risk rises in patients over 65 and with prior peptic ulcer disease.

Management

High doses of aspirin and other salicylates are contraindicated with warfarin (warfarin SmPC). Analgesic doses of aspirin are not recommended with warfarin and are used only when there is no alternative (aspirin 500 mg SmPC). Aspirin is added to warfarin deliberately, for specific indications: the US warfarin label (FDA) allows it with prosthetic heart valves depending on valve type and position, and for high-risk patients after myocardial infarction lists warfarin plus aspirin up to 100 mg a day. With this combination, monitor the INR carefully (aspirin 100 mg SmPC) and watch for signs of bleeding (US warfarin label). Tell the patient not to start or stop aspirin or other salicylates, including over-the-counter products, without the doctor's advice (US warfarin label).

Mechanism

At high aspirin doses (above 1 g/day), vasodilator prostaglandins are suppressed, weakening amlodipine's antihypertensive effect. At cardioprotective doses (75–100 mg/day), the effect is minimal.

Symptoms

Gradual blood pressure rise 1–2 weeks after starting the NSAID. In chronic kidney disease: risk of fluid retention and oedema.

Management

Cardioprotective aspirin doses (75–100 mg) are acceptable without adjustment. At anti-inflammatory aspirin doses, monitor blood pressure and increase amlodipine if needed.

Mechanism

Additive ulcerogenic effect with oral budesonide (used in inflammatory bowel disease). Inhaled forms have minimal systemic effect.

Symptoms

Epigastric pain, nausea, heartburn. With prolonged therapy: peptic ulcer and GI bleeding risk (black stools, vomiting blood or coffee-ground material). Older patients and prior peptic ulcer disease: higher risk.

Management

Inhaled budesonide for asthma or COPD requires no special measures. For oral therapy (Crohn's disease, ulcerative colitis): PPI cover with pantoprazole, cardioprotective aspirin no more than 100 mg/day.

Mechanism

At analgesic doses (above 1 g/day), aspirin suppresses vasodilator prostaglandins and weakens the ACE-I's hypotensive effect. At cardioprotective doses (75–100 mg), the effect is minimal.

Symptoms

Gradual blood pressure rise at high aspirin doses. At cardioprotective doses, no significant changes.

Management

Cardioprotective aspirin doses (75–100 mg) are acceptable without adjustment. At high doses, monitor blood pressure and increase captopril if needed. Alternative analgesic: paracetamol.

Mechanism

Celecoxib is a selective COX-2 inhibitor and does not displace aspirin from COX-1 (unlike ibuprofen/naproxen). Aspirin's antiplatelet effect is preserved. Additive GI bleeding risk persists.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools. Severe cases: GI bleeding.

Management

The combination is acceptable. Aspirin's cardioprotective effect is preserved. PPI cover with pantoprazole is mandatory in chronic celecoxib therapy. Check blood pressure and creatinine every 3 months.

Mechanism

Old experimental data suggested NSAIDs combined with fluoroquinolones increase CNS excitability and seizure risk (via GABAergic suppression). Clinical data are very limited.

Symptoms

Mostly asymptomatic. In patients with prior epilepsy or head injury: rare seizure cases.

Management

The combination is acceptable in patients without prior epilepsy. In epilepsy or eating disorders: alternative antibiotics (a cephalosporin, nitrofurantoin) and paracetamol for analgesia.

Mechanism

Additive antiplatelet effect via different targets: aspirin irreversibly blocks platelet cyclooxygenase; clopidogrel inhibits the P2Y12 receptor. The combination causes more bleeding than aspirin alone: in the CURE trial, major bleeding occurred in 3.7% of patients on clopidogrel plus aspirin and in 2.7% on placebo plus aspirin (FDA Plavix label, Table 1).

Symptoms

Gum bleeding, epistaxis, bruising without trauma. Severe cases: GI bleeding.

Management

Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is given after an acute coronary syndrome (ACS) and after coronary stenting. After ACS the default duration is 12 months unless bleeding risk is high. If the patient has been event-free for 3–6 months and is not at high ischaemic risk, switching to a single antiplatelet agent should be considered; at high bleeding risk this may be considered after 1 month (ESC 2023). After elective stenting for chronic coronary syndrome the default is up to 6 months, or 1–3 months at high bleeding risk (ESC 2024). Aspirin 75–100 mg/day; the clopidogrel label advises against aspirin doses above 100 mg. A proton pump inhibitor (PPI) is recommended when the risk of gastrointestinal bleeding is increased. With clopidogrel, use pantoprazole: the label advises against omeprazole and esomeprazole because they reduce formation of clopidogrel's active metabolite.

Mechanism

Diltiazem impairs platelet function via calcium channel blockade; aspirin is an antiplatelet. Mild additive bleeding risk, rarely clinically significant.

Symptoms

Usually asymptomatic. In patients with bleeding risk factors (peptic ulcer, older age): rare gum bleeding and epistaxis.

Management

Standard combination in ischaemic heart disease. Cardioprotective aspirin doses (75–100 mg) are acceptable without special measures. In patients with bleeding risk factors: PPI cover with pantoprazole.

Mechanism

Duloxetine inhibits the reuptake of serotonin and noradrenaline. Platelets release serotonin when they stop bleeding, so such antidepressants raise the risk of bleeding, including from the upper gastrointestinal tract. Aspirin irreversibly blocks platelet cyclooxygenase and injures the stomach lining. According to the US Food and Drug Administration (FDA) duloxetine label, aspirin may add to the bleeding risk during duloxetine treatment.

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools. Severe cases: GI bleeding.

Management

The combination can be used with caution: the Spanish and EU duloxetine SmPCs ask for caution in patients taking drugs that affect platelet function and name aspirin. The US Food and Drug Administration (FDA) requires prescribers to warn patients about the higher bleeding risk when duloxetine is combined with aspirin (duloxetine FDA label). Explain the signs of bleeding to the patient in advance: bruising without injury, nosebleeds, black stools, vomiting blood. With black stools, vomiting blood or any other sign of gastric bleeding, the patient stops aspirin and sees a doctor at once (aspirin 100 mg SmPC).

Mechanism

High aspirin doses (above 1 g/day) weaken the hypotensive and cardioprotective effects of the ACE-I via vasodilator prostaglandin suppression. At cardioprotective doses (75–100 mg/day), the clinical effect is minimal.

Symptoms

Gradual blood pressure rise at high aspirin doses. At cardioprotective doses, no significant changes.

Management

Cardioprotective aspirin doses (75–100 mg) are acceptable without adjustment. At high aspirin doses, monitor blood pressure and increase enalapril if needed. Alternative analgesic: paracetamol.

Mechanism

Dual mechanism: aspirin competes with furosemide for organic anion tubular secretion in the renal tubules (so furosemide does not reach its target in the loop of Henle lumen), and concurrently suppresses renal prostaglandin synthesis supporting glomerular perfusion.

Symptoms

Reduced urine output, worsening oedema, weight gain. In heart failure: dyspnoea, orthopnoea. Blood pressure and creatinine may rise.

Management

Per the acetylsalicylic acid SmPC, when aspirin and a diuretic are given together, ensure adequate hydration and check renal function (creatinine) at the start of treatment. The risk of acute kidney injury is higher with dehydration or hypovolaemia. The same SmPC links the fall in glomerular filtration to high aspirin doses. At anti-inflammatory doses furosemide diuresis may drop: adjust the furosemide dose by weight, oedema and urine output, or withhold aspirin during decompensation. Furosemide competes with salicylates for renal excretion, so with high-dose aspirin salicylate toxicity can occur at lower doses (FDA Lasix label).

Mechanism

Additive nephrotoxicity. Aspirin suppresses prostaglandin-dependent renal blood flow (at high doses); gentamicin causes direct tubulotoxicity.

Symptoms

Reduced urine output, rising creatinine. Symptoms appear earlier in older patients and chronic kidney disease.

Management

Cardioprotective aspirin doses (75–100 mg) do not require withdrawal. At high doses, check creatinine before and 3–5 days into gentamicin therapy. Ensure adequate hydration; consider switching to a less nephrotoxic antibiotic (a cephalosporin, carbapenem).

Mechanism

The European monograph lists antiplatelet drugs alongside anticoagulants among treatments that raise bleeding risk with ginkgo. Aspirin blocks platelet cyclooxygenase irreversibly and ginkgo inhibits platelet-activating factor: two brakes on the same function at different points.

Symptoms

Easy bruising, prolonged bleeding from small wounds, nosebleeds. With antiplatelet-dose aspirin the gastrointestinal risk adds on, which ginkgo neither changes nor offsets.

Management

Declare ginkgo to whoever prescribes the aspirin. The monograph asks for consultation before use in patients on antiplatelets and for stopping it two weeks before surgery. If ginkgo is being taken for memory, weigh the fact that benefit in that indication is not established.

Mechanism

High aspirin doses displace glibenclamide from albumin binding and suppress hepatic gluconeogenesis. Hypoglycaemia risk at aspirin doses above 3 g/day.

Symptoms

Sweating, tremor, hunger, tachycardia, confusion. Severe cases: seizures and coma. Symptoms appear 1–2 days after starting high aspirin doses.

Management

Cardioprotective aspirin doses (75–100 mg) are acceptable without adjustment. At high doses, monitor glucose 4 times daily in the first week; reduce glibenclamide if needed.

Mechanism

At high, anti-inflammatory doses aspirin suppresses renal prostaglandin synthesis. Together with losartan this lowers glomerular filtration, which in older or dehydrated patients can lead to acute kidney failure, and it can raise blood potassium (aspirin 100 mg and losartan SmPCs). Loss of vasodilating prostaglandins also weakens the blood-pressure-lowering effect of losartan. The US label for low-dose aspirin (FDA) describes the same kidney and blood pressure risks.

Symptoms

Blood pressure creeps up. If kidney function worsens, urine output falls, oedema appears, and creatinine and potassium rise on blood tests. The risk is higher in older patients, with dehydration, on diuretics, or with already reduced kidney function.

Management

The Spanish SmPCs describe the interaction mainly for high, anti-inflammatory aspirin doses (losartan and aspirin 100 mg SmPCs). With such doses, keep the patient well hydrated and check kidney function after starting the combination and periodically afterwards, with particular care in older patients (losartan SmPC). The FDA asks for periodic kidney checks even with low-dose aspirin when the patient is elderly, volume-depleted, on diuretics or has reduced kidney function (US aspirin label). Blood pressure is kept under close medical supervision (aspirin 100 mg SmPC), since losartan may work less well (losartan labels).

Mechanism

The metamizole label states it literally: it can reduce the antiplatelet effect of acetylsalicylic acid when given concomitantly, so caution is needed in patients on low-dose aspirin for cardioprotection. The mechanism mirrors the one described for ibuprofen, competition for access to platelet cyclooxygenase, and it hits the very indication that tolerates no loss of efficacy.

Symptoms

Loss of antiplatelet effect gives no warning symptom. What shows up is the event the aspirin was meant to prevent, and only in patients with coronary disease or previous stroke. Metamizole keeps its own haematological warning signs.

Management

For a patient on 100 mg aspirin for cardioprotection, paracetamol is the analgesic of choice, as it does not compete for platelet cyclooxygenase. If metamizole is necessary, use short courses and avoid giving it right before the aspirin dose.

Mechanism

High aspirin doses (above 1 g/day) may reduce the ARB's antihypertensive effect via vasodilator prostaglandin suppression. Cardioprotective doses (75–100 mg) are clinically minor.

Symptoms

Gradual blood pressure rise at high aspirin doses. At cardioprotective doses, no significant changes.

Management

Cardioprotective aspirin doses (75–100 mg) are acceptable without adjustment. At high doses, monitor blood pressure and increase telmisartan if needed. Alternative analgesic: paracetamol.

Mechanism

Aspirin irreversibly blocks platelet cyclooxygenase and ticagrelor reversibly blocks the P2Y12 receptor, so their antiplatelet effects add up. This is standard dual antiplatelet therapy after an acute coronary syndrome, and the ticagrelor label pairs it with a low daily dose of aspirin. The risk depends on the aspirin dose. In an exploratory analysis of the PLATO trial, ticagrelor's advantage over clopidogrel shrank as the aspirin dose rose. The Spanish label (AEMPS) therefore does not recommend maintenance aspirin doses above 300 mg, and the US label (FDA) advises keeping daily aspirin at 100 mg or less.

Symptoms

Bleeding risk adds up: bruising, gum bleeding, nosebleeds, black stools, blood in urine. Ticagrelor dyspnoea appears in the first weeks and does not by itself require stopping. High aspirin doses also add gastric discomfort.

Management

Aspirin stays at a low dose, usually 75–100 mg daily (FDA label, ESC guidelines), and is not raised to analgesic regimens while ticagrelor lasts. For pain or fever use paracetamol rather than raising the aspirin dose or adding another NSAID. Dual antiplatelet therapy is not interrupted on personal initiative.

Mechanism

Aspirin displaces valproate from albumin binding and suppresses its metabolism. The free valproate fraction rises, raising neurotoxicity risk (tremor, sedation, hyperammonaemia).

Symptoms

Tremor, drowsiness, nausea, confusion. Severe cases: hyperammonaemic encephalopathy. Symptoms appear within 1–2 weeks at high aspirin doses.

Management

Cardioprotective aspirin doses (75–100 mg) are usually acceptable. At high doses, check valproate level at 1 week. For chronic analgesia on valproate: paracetamol.

Mechanism

Analgesic aspirin doses weaken the ARB's antihypertensive effect via vasodilator prostaglandin suppression. Cardioprotective doses are clinically minor.

Symptoms

Gradual blood pressure rise at high aspirin doses. At cardioprotective doses, no significant changes.

Management

Cardioprotective aspirin doses (75–100 mg) are acceptable without adjustment. At high doses, monitor blood pressure and increase valsartan if needed. Alternative analgesic: paracetamol.

Mechanism

Venlafaxine inhibits the reuptake of serotonin and noradrenaline. Platelets low in serotonin are worse at stopping bleeding, and the venlafaxine label describes bleeding from bruising and nosebleeds to life-threatening gastrointestinal haemorrhage. Aspirin irreversibly blocks platelet cyclooxygenase and injures the stomach lining, so together the drugs raise the risk of bleeding (Spanish and US venlafaxine labels).

Symptoms

Gum bleeding, epistaxis, bruising without trauma, black or tarry stools. Severe cases: GI bleeding.

Management

The combination can be used with caution: the venlafaxine SmPC asks for caution in patients taking platelet inhibitors, and aspirin is one of them. The US Food and Drug Administration (FDA) requires prescribers to warn patients about the higher bleeding risk when venlafaxine is combined with aspirin (venlafaxine FDA label). Explain the signs of bleeding to the patient in advance: bruising without injury, nosebleeds, black stools, vomiting blood. With black stools, vomiting blood or any other sign of gastric bleeding, the patient stops aspirin and sees a doctor at once (aspirin 100 mg SmPC).

Mechanism

At high doses, aspirin weakens verapamil's antihypertensive effect via vasodilator prostaglandin suppression. At cardioprotective doses, there is no clinically significant effect.

Symptoms

Gradual blood pressure rise at high aspirin doses. At cardioprotective doses, no significant changes.

Management

Cardioprotective aspirin doses (75–100 mg) are acceptable without adjustment. At high doses, monitor blood pressure and increase verapamil if needed. Alternative analgesic: paracetamol.

Mechanism

Antacids accelerate renal aspirin elimination via urinary alkalinisation. At cardioprotective doses (75–100 mg/day), the effect is clinically minimal.

Symptoms

The combination usually causes no specific symptoms. Each drug's individual side effects remain.

Management

At cardioprotective aspirin doses, no adjustment needed. At high anti-inflammatory doses (over 3 g/day) with simultaneous antacid for several days, efficacy may slightly drop — separate dosing by 2 hours.

Mechanism

Paracetamol does not inhibit platelet cyclooxygenase, so it neither competes with acetylsalicylic acid for the binding site nor interferes with cardioprotection, unlike ibuprofen. The paracetamol label proposes it as the alternative to salicylates in anticoagulated patients, with one condition: chronic use above 2 g a day can potentiate acenocoumarol and warfarin.

Symptoms

No symptoms attributable to the pair. With analgesic doses of aspirin the gastrointestinal risk, gum bleeding and bruising remain; at 100 mg the profile is the usual cardioprotective one. If an oral anticoagulant is also on board with chronic paracetamol, INR may rise.

Management

Paracetamol is the analgesic of choice for patients on 100 mg aspirin for cardioprotection: no dose spacing is needed. On oral anticoagulants keep sustained use below 2 g a day, or check INR if more is required.