Aspirin clinical relevance

Acetylsalicylic acid irreversibly inhibits both COX-1 and COX-2 by acetylating the enzymes. Since mature platelets lack a nucleus, they are unable to synthesise new enzyme. The anti-platelet effects of acetylsalicylic acid persist therefore throughout the lifetime of the platelet and the half-life of this effect is thus being much longer than the elimination half-life of acetylsalicylic acid (15 min). Since new platelets are continuously launched into the circulation, the clinically relevant anti-platelet effect of aspirin lasts for up to five days. This is the reason why low doses of acetylsalicylic acid (ca. 100 mg per day) are sufficient in the prophylaxis of heart attacks. 

I Campbell CL, Steinhubl SR. Variability in response to aspirin do we understand the clinical relevance J Thromb Haemost 2005 3 665-669. 

The clinical relevance of studies in the Folts-model has been questioned because the model is very sensitive to antithrombotic compounds. However, the lack of a reversal of the effect by epinephrine or increase in degree of stenosis differentiates any new drug from aspirin. Electrical coronary thrombosis is less sensitive e.g. aspirin has no effect and with some drugs higher dose levels are required but in principle, most drug mechanisms act in both models if at all. 

Aspirin and methotrexate compete for renal tubular secretion, and aspirin alters the systemic and renal clearances of intravenous methotrexate (131). However, the clinical relevance of this interaction is not clear. In one study, aspirin (mean dose 4.5 g) in 12 patients did not cause more toxicity than other NSAIDs taken by 22 other patients (132). 

Would clopidogrel in addition to aspirin (intervention) prevent death or coronary events (clinically relevant outcome) in this patient with unstable angina (patient with a problem) who is currently on aspirin alone (comparison intervention) ... 

Indometacin may attenuate the antihypertensive effect of losar-tan, valsartan, or other angiotensin II receptor antagonists. However, low-dose aspirin does not appear to alter the antihypertensive effect of losartan. No clinically relevant pharmacokinetic interactions occur between telmisartan and ibuprofen or paracetamol (acetaminophen), or between valsartan and indometacin. The combination of an NSAID and angiotensin II receptor antagonist can increase the risk of renal impairment and hyperkalaemia. 

Kaolin-pectin causes a small reduction in the absorption of aspirin, which is not clinically relevant. 

Early studies evaluating non-aspirin NSAIDs in rheumatoid arthritis commonly permitted the concurrent use of aspirin, which was then in wide use for this condition. The unexpected finding that indometacin was no more effective than placebo in patients taking aspirin in one study led to a number of pharmacokinetic studies with this combination (see Indometacin, below), and subsequently other NSAID/aspirin combinations. These studies generally have little clinical relevance to current clinical practice where anti-inflammatory doses of aspirin should not be used in combination with NSAIDs because of the increased risk of gastrointestinal bleeding (see above) and lack of proven additional benefit. However, the pharmacokinetic studies are briefly summarised below. 

Oral contraceptives increase diflunisal clearance in women, but only to the level normally seen in men. One study showed modestly reduced levels of ibuprofen with oral contraceptives, but another study did not. Oral contraceptives reduced the levels of aspirin, but not phenylbutazone. There are no clinically relevant changes in the pharmacokinetics of oxaprozin with conjugated oestrogens. 

Paracetamol levels are increased by diflunisal. Aspirin, diclofenac, nabumetone and sulindac pharmacokinetics do not appear to be affected by paracetamol. There is no pharmacokinetic interaction between ibuprofen and paracetamol. Propacetamol, and possibly paracetamol, increase the antiplatelet effects of diclofenac, although the evidence is limited and the clinical relevance of this is uncertain. 

The antiplatelet activity and the pharmacokinetics of aspirin do not appear to be affected by omeprazole. There was no clinically relevant pharmacokinetic interaction between omeprazole and diclofenac, enteric-coated ketoprofen, naproxen or piroxicam, or between pantoprazole and diclofenac or naproxen, or between esomeprazole and naproxen or rofecoxib. 

Any effects in the study with aspirin where not considered to be clinically relevant. The manufacturer notes that danaparoid may be used with drugs that interfere with platelet function, such as aspirin and NSAIDs, but considers that caution remains necessary This is considered particularly important in patients undergoing peridural or spinal anaesthesia or spinal puncture, in whom the use of NSAIDs, and probably also danaparoid, are risk factors for epidural or spinal haematoma resulting in prolonged or permanent paralysis. 

Sixteen healthy subjects took a single 5-mg dose of glibenclamide both before and on the fourth day of taking aspirin 975 mg four times daily for 4 days. It was found that the aspirin reduced the AUC0.4 of the glibenclamide by 68% and reduced its mean peak serum levels by 35%. The effects of this on glucose tolerance tests and insulin responses were difficult to interpret, but there was no clear evidence that any clinically relevant changes occurred. ... 

Direct information seems to be limited to the studies cited. Clinically relevant interactions appear rare, probably because in most cases the effects of aspirin on free valproate levels cancel each other out. The combination need not necessarily be avoided, but it would seem prudent to be aware of this interaction if valproate and high-dose aspirin are used. 

Anagrelide should not be used with other phosphodiesterase III inhibitors (e.g. milrinone) because of the potential for increased inotropic effects. Inhibitors of CYP1A2 (e.g. fluvoxamine) are predicted to increase anagrelide levels. Some caution might be required with concurrent aspirin and other platelet inhibitors. Whether anagrelide inhibits theophylline metabolism to a clinically relevant extent is not known. No pharmacokinetic interaction occurs with digoxin or warfarin. 

There is an increased risk of bleeding if clopidogrel is given with aspirin, but the use of low-dose aspirin and clopidogrel can be beneficial. Ticlopidine increases the antia r ant effects of aspirin and there is an increased risk of bleeding on concurrent use. Cilostazol appears not to interact to a clinically relevant extent with low-dose aspirin, and the addition of dipyridamole to aspirin does not appear to increase the incidence of bleeding. 

Both aspirin and paracetamol slight reduce the levels of rimantadine, but this is unlikely to be clinically relevant... 

In a study in healthy subjects, rimantadine 100 mg twice daily was given for 13 days. On day 11, aspirin 650 mg four times daily was started and continued for 8 days. The peak plasma levels and AUC of rimantadine were reduced by about 10% in the presence of aspirin. This reduction is unlikely to be clinically relevant. 

There is evidence that most NSAIDs can increase blood pressure in patients treated with antihypertensives, although some studies have not found the increase to be clinically relevant. In various small studies, indometacin appeared not to reduce the hypotensive effects of amlodipine, felodipine, nicardipine, nimodipine or verapamil, but it did in one of two studies with nifedipine, and one study with nitrendipine. Similarly, ibuprofen caused a small reduction in the antihypertensive effects of amlodipine. Diclofenac and sulindac appear not to interact with nifedipine, nor ibuprofen, naproxen, piroxicam or sulindac with verapamil, nor naproxen with nicardipine. Low-dose aspirin did not alter the antihypertensive effect of felodipine or nifedipine in one study, and long-term aspirin did not alter the cardiovascular benefits of nitrendipine in another. Diclofenac reduces verapamil serum levels and raises those of isradipine, but these changes are probably unimportant. 

Aspirin may cause a moderate rise in serum digoxin levels, but no interaction of clinical relevance seems to occur. 

The manufacturer notes that in phase IH osteoporosis studies of risedronate, no clinically relevant interaetions were noted, even though aspirin and NSAIDs being used by 33% and 45% of patients, respectively. Similarly, in a retrospective analysis of a 2-year placebo-controlled study, in those using regular NSAIDs (about two-thirds of patients) there was no difference in incidence of upper gastrointestinal adverse events between those given risedronate and those given placebo. ... 

The absorption of raloxifene is reduced by colestyramine, and their concurrent use is not recommended. No clinically relevant changes in raloxifene pharmacokinetics occur with alumini-um/magnesium hydroxide, amoxicillin, ampicillin or calcium carbonate. Raloxifene does not alter digoxin or methylprednisolone levels. Oral antibacterials, antihistamines, aspirin, benzodiazepines, H2-receptor antagonists, ibuprofen or paracetamol (acetaminophen) were used in clinical studies without any obvious effect on raloxifene levels. Smoking does not appear to alter the efficacy of raloxifene. 

Studies of the pathophysiology of acute renal failure has classically considered both tubular and vascular mechanisms [227,228]. In vitro techniques isolating either the vascular or tubular components have been developed. For example, the use of isolated proximal tubules in suspension or in culture allows the study of tubular mechanisms of injury in the absence of vascular factors [229] [230]. There are both in vitro and in vivo models to study vascular injury in the kidney. In vitro models include the study of vascular smooth muscle cells or endothelial cells in culture. In this section, the in vivo methods to evaluate the renal micro-circulation will be discussed. This is of relevance as many nephrotoxins exert their deleterious effects through pharmacologic actions on the resistance vasculature with parenchymal injury occurring as a consequence of ischemia. In clinical practice nephrotoxins may cause prerenal azotemia as a result of increased renal vascular resistance. Nephrotoxins that cause acute renal failure on a vascular basis include prostaglandin inhibitors e.g. aspirin, non-steroidal anti-... 

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