Identifying Determinants to Tailor Aspirin Therapy
Identifying Determinants to Tailor Aspirin Therapy
There are some areas of therapeutic uncertainty regarding the net benefit or the pharmacology of low-dose aspirin, namely, Type 2 diabetes mellitus (T2DM), obesity, myeloproliferative disorders and aging. These conditions are likely associated with a higher variability in aspirin response due to PK and/or PD changes. Other sources of inter- or intra-individual variability in aspirin effect might derive from poor adherence, drug formulations, interactions, pharmacogenomics of specific platelet proteins. Some mechanisms of variability might be temporary, such as poor adherence or drug interactions and can be identified and corrected without changing aspirin regimen. Other causes may be long lasting, have more complex mechanisms or might require exploring new aspirin strategies.
Lack of compliance is a main concern for chronic (possibly lifelong) treatments, independent of a specific drug. In the case of aspirin, it has been shown that poor compliance might explain up to 50% of the so-called aspirin resistance or failure.
Early studies in the 1980s, described a potential PD competition between aspirin and some NSAIDs such as ibuprofen, diflunisal, sulphinpyrazone, indomethacin or high concentrations of salicylate in humans and animals. Those observations reported that if aspirin is administered a few hours after an NSAIDs, its effect on platelets is transient rather than irreversible, mirroring the reversible effect of the NSAID alone. Some years later, Catella-Lawson et al. further characterized this PD interaction, demonstrating that NSAID–aspirin competition occurs on a common Arg docking site within the COX-1 catalytic channel; it is observed for ibuprofen, but not for diclofenac, acetaminophen or for selective COX-2 inhibitors (coxibs) and is blunted by administering aspirin first. Some meta-analyses indicated that this PD interaction might lower the clinical efficacy of aspirin. Based on this evidence, regulatory agencies and major cardiological societies recommend using some NSAIDs after low-dose aspirin intake. Due to the worldwide over-the-counter access of NSAIDs, it is hard to estimate the real impact of this phenomenon on the efficacy and safety of aspirin's cardiovascular prevention.
Recently, a large retrospective nationwide study showed that proton-pump inhibitors (PPIs) are associated with an increased risk in cardiovascular events in aspirin-treated patients. It is unknown whether this effect is due to a drug interaction, where PPIs reduce aspirin's bioavailability by increasing stomach pH, or whether there is an increased risk of cardiovascular events specifically associated with PPIs, independently of aspirin.
Obesity, diabetes, aging, conditions associated with high platelet regenerations, some genotypes, or some EC formulations are settings where a persistent and different sensitivity to aspirin can be hypothesized or has been documented, based on changes of the PK or PD.
Pharmacogenetic studies of aspirin focused mainly on the COX-1 and/or COX-2 genes. Associations between single nucleotide polymorphisms (SNPs) of the COX-1 gene (including promoter and noncoding regions) and platelet responses to aspirin or cardiovascular complications have been inconsistent so far. Conflicting results have been reported on some SNPs of the P2Y1 purinergic receptor gene, but the pathogenetic link of SNPs in genes that are not the aspirin molecular targets (e.g., COX-1 and/or COX-2) and poor aspirin response remain to be further explored.
Ethnic variations can influence cardiovascular disease risk factors and disease profile. Ethnicity might also affect the pharmacological response to antiplatelet drugs such as clopidogrel: Asians have a higher prevalence of poor-metabolizers of CYP2C19 substrates. Beyond ethnic-based differences in underlying cardiovascular disease profiles, it is unknown whether aspirin PK or PD might be affected by geographic variations.
EC formulations are largely used in chronic cardiovascular prevention, based on the hypothesis that gastroprotection would prevent the disintegration of the pill in the acid environment of the stomach, avoiding local gastric damage by acetylsalicylic acid, instead releasing the drug into the upper small intestine. However, the superior gastrointestinal safety of EC versus plain aspirin remains unproven. Moreover, in the upper small intestine, a higher pH may facilitate hydrolysis and human carboxylesterase of the intestinal mucosa may reduce bioavailability of EC formulations. It has been reported that subjects fully responsive to plain aspirin show an incomplete suppression of serum TXB2 when exposed to some EC formulations, thus hypothesizing differences in the bioavailability of EC as compared with plain formulations. However, it should be considered that EC formulations contain 75 to 160 mg of aspirin, largely exceeding the dose shown to maintain full platelet TXA2 inhibition upon repeated administration (i.e., 20–40 mg of plain aspirin). Moreover, even if the plasma peak of acetylsalicylic acid concentration might be lower, in some EC formulations, free drug is detectable for up to 12 h, while plain aspirin quickly disappears from the systemic blood. The clinical consequences of these biochemical observations, if any, remain unknown.
Obesity is a worldwide epidemic associated with an excess of cardiovascular deaths. Obesity generates several pathophysiological changes in body composition, regional hepatic blood flow, plasma proteins and/or tissue components, distribution volume, kidney and hepatic clearance, which might affect different PK processes as compared with lean subjects. The activity of some CYP450s, Phase II conjugation enzymes and intestinal HCE1 are also increased in obese subjects, thus lipophilic drugs, which usually undergo Phase I and II biotransformation, might be particularly affected. It has been shown that obesity modifies the PK of some chemotherapics, psychotropics, anesthetics, opioids, β-blockers and warfarin. There is a raising need to tailor antithrombotic therapy specifically in obesity due to its high cardiovascular risk. The metabolic changes in obesity might affect the presystemic and hepatic bioinactivation of aspirin: being highly lipophilic, degraded by esterases, biotransformed by Phase II conjugation enzymes and excreted by the kidney. In preliminary studies on a limited number of cases, an increase in body weight or BMI appears associated with a lower responsiveness to aspirin, as assessed by high residual serum TXB2, platelet function or urinary TXA2 metabolites. Consistent with data suggesting that obesity might reduce aspirin bioavailability, small proof-of-concept studies show that by increasing the aspirin daily dose, obese subjects become fully responsive, as indicated by a nearly-complete inhibition of serum TXB2. However, another recent study, which measured urinary metabolites of TXA2 as an index of aspirin response, showed that doubling the aspirin dose did not further inhibit platelet functional response to AA or urinary TX metabolite excretion. Some preliminary observations suggest a lower cardiovascular protection of low-dose aspirin in the obese compared with lean subjects in different settings, including primary prevention, stable patients, percutaneous coronary intervention procedures, diabetic or high cardiovascular risk settings. However, obese subjects are usually under-represented or excluded in cardiovascular clinical trials, especially in the initial, placebo-controlled trials with aspirin, performed more than 20 years ago when obesity was not the medical burden it is today. Thus, additional proof-of-concept as well as large studies are needed to explore the PK of aspirin and cardiovascular protection in obese patients compared with lean ones, considering that obesity will be an even bigger health concern in the near future.
Age-related physiological changes may affect the PK and/or PD of a variety of medications. A decrease in the excretory capacity of the kidney and in hepatic blood flow, hepatocyte mass and consequent reduced hepatic function, changes in body composition (decreased total body water) may all affect drug bioavailability and biotransformation. In addition, comorbidities and drug interactions due to concomitant medicines, which are rather common in the elderly, can interfere with drug PK or PD, thus increasing an age-related variability of drug response. Moreover, aging is a known cardiovascular risk factor. It is associated with several changes in hemostasis, but also with a higher bleeding tendency both under anticoagulants and aspirin. Aspirin esterase and cholinesterase activities appear reduced in frail elderly people, thus a modified PK (bioinactivation) of aspirin might contribute to a more effective aspirin inhibition. Moreover, a different PD is also plausible, considering that aging is associated with a significant trend toward a reduction in platelet count, suggesting a slower megakaryopoiesis rate, which might favor full aspirin response. Patients aged ≥65 years appear more protected by aspirin in primary prevention studies but are also at higher risk of gastrointestinal bleeding complications. Several studies report age as an independent predictor of the degree of TXB2 inhibition by aspirin in different clinical settings. Altogether, these data may suggest a higher sensitivity to aspirin in elderly subjects. However, they have generally been under-represented or excluded from large clinical trials. Thus, ongoing trials are addressing the risk–benefit profile of aspirin in aged subjects. The JPPP trial has enrolled 14,460 patients aged between 60 and 85 years with at least one risk factor (diabetes, hypertension or hyperlipemia) randomized to placebo or 100 mg/day EC aspirin. The primary end point of JPPP is a composite cardiovascular events. The ASPREE trial is also a primary prevention, placebo-controlled study in subjects aged ≥70 years, with or without risk factors, assessing the efficacy of daily 100 mg EC aspirin in reducing death from any cause, incident dementia or persistent physical disability.
Platelet turnover was initially hypothesized to influence aspirin response and the percentage of circulating young reticulated platelets associated with high-residual, uninhibited TXA2 from platelets in healthy subjects. Thus, a variable platelet turnover might generate a PD-based variability in aspirin response. Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by enhanced primary platelet generation and high cardiovascular risk requiring antiplatelet prophylaxis or treatment. A large fraction of aspirin-treated (100 mg, once daily) ET patients show high levels of residual, uninhibited serum TXB2, which can be further suppressed by adding more aspirin to blood samples in vitro, thus ruling out molecular changes in the drug target and indicating the presence of unacetylated platelet COX enzymes in peripheral ET platelets. Due to the accelerated platelet turnover, it is conceivable that more unacetylated COX-1 and/or COX-2 is generated during the 24-h aspirin dosing interval, accounting for a partial recovery of TX-dependent platelet function. Consistently with this hypothesis, the absolute number or percentage of immature platelets independently predicted poor platelet response in once-daily aspirin-treated (75 or 100 mg) healthy subjects in different clinical settings, such as ET, stent thrombosis and renal transplant recipients. This hypothesis may also explain the lack of lag interval and the early, linear recovery of serum TXB2 after aspirin withdrawal in ET patients (Figure 6A). Due to an accelerated turnover of COX-1 and -2 in ET platelets, proplatelets and megakaryocytes, it can be hypothesized that more frequent low-dose aspirin, rather than higher dose, could restrain variability and correct the abnormal response. In a proof-of-concept study from our group, a small number of ET patients (n = 21) were given aspirin 100 mg once daily (standard of care), 100 mg twice daily (every 12 h) or 200 mg once daily (dose control). As shown in Figure 6B, only 100 mg every 12 h was almost completely able to block the residual platelet TXA2 generation in these patients, while doubling the once-daily dose was less effective than a twice-daily regimen. Similar findings were recently reported by Dillinger et al. showing that 100 mg twice-daily was inhibiting platelet aggregation induced by AA more profoundly than 250 or 100 mg once-daily. ET can be considered as an extreme condition of enhanced platelet turnover, modulating aspirin responsiveness. Thus, providing that low-dose aspirin PK is preserved and that the drug target molecule has not changed (e.g., oxidatively damaged or structurally modified), in conditions of accelerated megakaryopoiesis a more frequent, rather than a higher doses, may improve response lowering variability.
T2DM has been repeatedly associated with a lower clinical or laboratory-defined response to antiplatelet agents in primary or secondary prevention. In T2DM, platelets display several acquired abnormalities, including increased mean platelet volume, mass and turnover and megakaryopoiesis displays atypical features, both in human and animal models. PD- or PK-related mechanisms might contribute to a reduced aspirin response in T2DM. The PD of aspirin might be affected by a different platelet turnover or dysmegakaryopoiesis in T2DM. Aspirin PK in T2DM may be affected by obesity, often associated with T2DM. Finally, enhanced formation of lipid hydroperoxides may limit COX-isozyme acetylation by aspirin in both megakaryocytes and circulating platelets, and this mechanism might be facilitated by the high oxidative status described in T2DM. However, studies investigating indexes of lipid peroxidation and aspirin response have been negative in different clinical settings.
(Enlarge Image)
Figure 6.
Effect of different aspirin regimens on serum TXB2 in patients with essential thrombocythemia. (A) Absolute values of serum TXB2 in two essential thrombocythemia patients at baseline, on different aspirin regimens and after aspirin withdrawal. Patient 1 (open circles) was treated with 50 mg aspirin once-daily for 7 days, followed by 100 mg once daily for 7 more days. Patient 2 (closed circles) was treated as patient 1 with 1 more week on 150 mg aspirin once daily. In both patients, no lag in serum TXB2 recovery was observed in the first 36 h after aspirin withdrawal and by day 3 after aspirin suspension the serum TXB2 had almost completely recovered (>70%). (B) Box-whisker plots of serum TXB2 levels measured at baseline, after 200 mg aspirin once daily or 100 mg twice daily in 22 essential thrombocythemia patients. Each box-whisker plot represents the median, interquartile range, minimum and maximum values and outlying values.
*p < 0.05 versus baseline.
**p < 0.001 versus baseline and enteric-coated 100 mg twice daily.asa: Apirin.
Data not shown from [140,145].
Once-daily administration of low-dose aspirin (75–100 mg) has been associated with incomplete inhibition of platelet activity in T2DM, especially when response was measured by the end of the daily dosing interval – that is, 24 h after aspirin intake. At least in a fraction of aspirin-treated T2DM patients, accelerating kinetics in the recovery of serum TXB2 has been observed between 12 and 24 h after 100 mg EC aspirin intake. The full suppression of TXB2 12 h after aspirin intake would rule out PK modifications, and thus PD-related mechanisms, such as an increased platelet turnover or intraplatelet neosynthesis of COX-1 and/or -2 in the last hours of the dosing interval might possibly explain these observations. Two studies measured reticulated platelets and/or mean platelet volumes as peripheral indexes of increased platelet turnover and those parameters were positively correlated with a poor aspirin response measured as higher residual platelet function or TXA2 biosynthesis in aspirin-treated patients. To improve responsiveness to aspirin and reduce variability in T2DM, small randomized studies have recently compared different strategies: increasing the once-daily aspirin dose versus a more frequent administration (twice daily) of the standard low-doses aspirin. In spite of differences in study design and methodology, a more frequent administration of low-dose aspirin (75 or 100 mg, twice daily) was consistently the best strategy to reach an almost-complete and steady platelet inhibition compared with increasing the once-daily dose (320 or 200 mg once daily) or to standard daily low-dose aspirin. Consistently with the kinetics of recovery of TXB2 generation over 24 h, the superior effectiveness of a twice-daily dosing rather than a single higher dose is consistent with a mechanism associated with a higher platelet turnover and aspirin PD, rather than with a PK modification (absorbance, bioavailability and distribution). However, large, randomized studies are needed to validate this strategy in primary or secondary prevention of T2DM in terms of clinical efficacy and safety.
Tailoring Aspirin Therapy: Identifying & Restraining Sources of Variability
There are some areas of therapeutic uncertainty regarding the net benefit or the pharmacology of low-dose aspirin, namely, Type 2 diabetes mellitus (T2DM), obesity, myeloproliferative disorders and aging. These conditions are likely associated with a higher variability in aspirin response due to PK and/or PD changes. Other sources of inter- or intra-individual variability in aspirin effect might derive from poor adherence, drug formulations, interactions, pharmacogenomics of specific platelet proteins. Some mechanisms of variability might be temporary, such as poor adherence or drug interactions and can be identified and corrected without changing aspirin regimen. Other causes may be long lasting, have more complex mechanisms or might require exploring new aspirin strategies.
Transient Sources of Poor Responsiveness to Low-dose Aspirin
Lack of compliance is a main concern for chronic (possibly lifelong) treatments, independent of a specific drug. In the case of aspirin, it has been shown that poor compliance might explain up to 50% of the so-called aspirin resistance or failure.
Early studies in the 1980s, described a potential PD competition between aspirin and some NSAIDs such as ibuprofen, diflunisal, sulphinpyrazone, indomethacin or high concentrations of salicylate in humans and animals. Those observations reported that if aspirin is administered a few hours after an NSAIDs, its effect on platelets is transient rather than irreversible, mirroring the reversible effect of the NSAID alone. Some years later, Catella-Lawson et al. further characterized this PD interaction, demonstrating that NSAID–aspirin competition occurs on a common Arg docking site within the COX-1 catalytic channel; it is observed for ibuprofen, but not for diclofenac, acetaminophen or for selective COX-2 inhibitors (coxibs) and is blunted by administering aspirin first. Some meta-analyses indicated that this PD interaction might lower the clinical efficacy of aspirin. Based on this evidence, regulatory agencies and major cardiological societies recommend using some NSAIDs after low-dose aspirin intake. Due to the worldwide over-the-counter access of NSAIDs, it is hard to estimate the real impact of this phenomenon on the efficacy and safety of aspirin's cardiovascular prevention.
Recently, a large retrospective nationwide study showed that proton-pump inhibitors (PPIs) are associated with an increased risk in cardiovascular events in aspirin-treated patients. It is unknown whether this effect is due to a drug interaction, where PPIs reduce aspirin's bioavailability by increasing stomach pH, or whether there is an increased risk of cardiovascular events specifically associated with PPIs, independently of aspirin.
Long-lasting Possible Sources of Variable Aspirin Response
Obesity, diabetes, aging, conditions associated with high platelet regenerations, some genotypes, or some EC formulations are settings where a persistent and different sensitivity to aspirin can be hypothesized or has been documented, based on changes of the PK or PD.
Pharmacogenetic studies of aspirin focused mainly on the COX-1 and/or COX-2 genes. Associations between single nucleotide polymorphisms (SNPs) of the COX-1 gene (including promoter and noncoding regions) and platelet responses to aspirin or cardiovascular complications have been inconsistent so far. Conflicting results have been reported on some SNPs of the P2Y1 purinergic receptor gene, but the pathogenetic link of SNPs in genes that are not the aspirin molecular targets (e.g., COX-1 and/or COX-2) and poor aspirin response remain to be further explored.
Ethnic variations can influence cardiovascular disease risk factors and disease profile. Ethnicity might also affect the pharmacological response to antiplatelet drugs such as clopidogrel: Asians have a higher prevalence of poor-metabolizers of CYP2C19 substrates. Beyond ethnic-based differences in underlying cardiovascular disease profiles, it is unknown whether aspirin PK or PD might be affected by geographic variations.
EC formulations are largely used in chronic cardiovascular prevention, based on the hypothesis that gastroprotection would prevent the disintegration of the pill in the acid environment of the stomach, avoiding local gastric damage by acetylsalicylic acid, instead releasing the drug into the upper small intestine. However, the superior gastrointestinal safety of EC versus plain aspirin remains unproven. Moreover, in the upper small intestine, a higher pH may facilitate hydrolysis and human carboxylesterase of the intestinal mucosa may reduce bioavailability of EC formulations. It has been reported that subjects fully responsive to plain aspirin show an incomplete suppression of serum TXB2 when exposed to some EC formulations, thus hypothesizing differences in the bioavailability of EC as compared with plain formulations. However, it should be considered that EC formulations contain 75 to 160 mg of aspirin, largely exceeding the dose shown to maintain full platelet TXA2 inhibition upon repeated administration (i.e., 20–40 mg of plain aspirin). Moreover, even if the plasma peak of acetylsalicylic acid concentration might be lower, in some EC formulations, free drug is detectable for up to 12 h, while plain aspirin quickly disappears from the systemic blood. The clinical consequences of these biochemical observations, if any, remain unknown.
Obesity is a worldwide epidemic associated with an excess of cardiovascular deaths. Obesity generates several pathophysiological changes in body composition, regional hepatic blood flow, plasma proteins and/or tissue components, distribution volume, kidney and hepatic clearance, which might affect different PK processes as compared with lean subjects. The activity of some CYP450s, Phase II conjugation enzymes and intestinal HCE1 are also increased in obese subjects, thus lipophilic drugs, which usually undergo Phase I and II biotransformation, might be particularly affected. It has been shown that obesity modifies the PK of some chemotherapics, psychotropics, anesthetics, opioids, β-blockers and warfarin. There is a raising need to tailor antithrombotic therapy specifically in obesity due to its high cardiovascular risk. The metabolic changes in obesity might affect the presystemic and hepatic bioinactivation of aspirin: being highly lipophilic, degraded by esterases, biotransformed by Phase II conjugation enzymes and excreted by the kidney. In preliminary studies on a limited number of cases, an increase in body weight or BMI appears associated with a lower responsiveness to aspirin, as assessed by high residual serum TXB2, platelet function or urinary TXA2 metabolites. Consistent with data suggesting that obesity might reduce aspirin bioavailability, small proof-of-concept studies show that by increasing the aspirin daily dose, obese subjects become fully responsive, as indicated by a nearly-complete inhibition of serum TXB2. However, another recent study, which measured urinary metabolites of TXA2 as an index of aspirin response, showed that doubling the aspirin dose did not further inhibit platelet functional response to AA or urinary TX metabolite excretion. Some preliminary observations suggest a lower cardiovascular protection of low-dose aspirin in the obese compared with lean subjects in different settings, including primary prevention, stable patients, percutaneous coronary intervention procedures, diabetic or high cardiovascular risk settings. However, obese subjects are usually under-represented or excluded in cardiovascular clinical trials, especially in the initial, placebo-controlled trials with aspirin, performed more than 20 years ago when obesity was not the medical burden it is today. Thus, additional proof-of-concept as well as large studies are needed to explore the PK of aspirin and cardiovascular protection in obese patients compared with lean ones, considering that obesity will be an even bigger health concern in the near future.
Age-related physiological changes may affect the PK and/or PD of a variety of medications. A decrease in the excretory capacity of the kidney and in hepatic blood flow, hepatocyte mass and consequent reduced hepatic function, changes in body composition (decreased total body water) may all affect drug bioavailability and biotransformation. In addition, comorbidities and drug interactions due to concomitant medicines, which are rather common in the elderly, can interfere with drug PK or PD, thus increasing an age-related variability of drug response. Moreover, aging is a known cardiovascular risk factor. It is associated with several changes in hemostasis, but also with a higher bleeding tendency both under anticoagulants and aspirin. Aspirin esterase and cholinesterase activities appear reduced in frail elderly people, thus a modified PK (bioinactivation) of aspirin might contribute to a more effective aspirin inhibition. Moreover, a different PD is also plausible, considering that aging is associated with a significant trend toward a reduction in platelet count, suggesting a slower megakaryopoiesis rate, which might favor full aspirin response. Patients aged ≥65 years appear more protected by aspirin in primary prevention studies but are also at higher risk of gastrointestinal bleeding complications. Several studies report age as an independent predictor of the degree of TXB2 inhibition by aspirin in different clinical settings. Altogether, these data may suggest a higher sensitivity to aspirin in elderly subjects. However, they have generally been under-represented or excluded from large clinical trials. Thus, ongoing trials are addressing the risk–benefit profile of aspirin in aged subjects. The JPPP trial has enrolled 14,460 patients aged between 60 and 85 years with at least one risk factor (diabetes, hypertension or hyperlipemia) randomized to placebo or 100 mg/day EC aspirin. The primary end point of JPPP is a composite cardiovascular events. The ASPREE trial is also a primary prevention, placebo-controlled study in subjects aged ≥70 years, with or without risk factors, assessing the efficacy of daily 100 mg EC aspirin in reducing death from any cause, incident dementia or persistent physical disability.
Platelet turnover was initially hypothesized to influence aspirin response and the percentage of circulating young reticulated platelets associated with high-residual, uninhibited TXA2 from platelets in healthy subjects. Thus, a variable platelet turnover might generate a PD-based variability in aspirin response. Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by enhanced primary platelet generation and high cardiovascular risk requiring antiplatelet prophylaxis or treatment. A large fraction of aspirin-treated (100 mg, once daily) ET patients show high levels of residual, uninhibited serum TXB2, which can be further suppressed by adding more aspirin to blood samples in vitro, thus ruling out molecular changes in the drug target and indicating the presence of unacetylated platelet COX enzymes in peripheral ET platelets. Due to the accelerated platelet turnover, it is conceivable that more unacetylated COX-1 and/or COX-2 is generated during the 24-h aspirin dosing interval, accounting for a partial recovery of TX-dependent platelet function. Consistently with this hypothesis, the absolute number or percentage of immature platelets independently predicted poor platelet response in once-daily aspirin-treated (75 or 100 mg) healthy subjects in different clinical settings, such as ET, stent thrombosis and renal transplant recipients. This hypothesis may also explain the lack of lag interval and the early, linear recovery of serum TXB2 after aspirin withdrawal in ET patients (Figure 6A). Due to an accelerated turnover of COX-1 and -2 in ET platelets, proplatelets and megakaryocytes, it can be hypothesized that more frequent low-dose aspirin, rather than higher dose, could restrain variability and correct the abnormal response. In a proof-of-concept study from our group, a small number of ET patients (n = 21) were given aspirin 100 mg once daily (standard of care), 100 mg twice daily (every 12 h) or 200 mg once daily (dose control). As shown in Figure 6B, only 100 mg every 12 h was almost completely able to block the residual platelet TXA2 generation in these patients, while doubling the once-daily dose was less effective than a twice-daily regimen. Similar findings were recently reported by Dillinger et al. showing that 100 mg twice-daily was inhibiting platelet aggregation induced by AA more profoundly than 250 or 100 mg once-daily. ET can be considered as an extreme condition of enhanced platelet turnover, modulating aspirin responsiveness. Thus, providing that low-dose aspirin PK is preserved and that the drug target molecule has not changed (e.g., oxidatively damaged or structurally modified), in conditions of accelerated megakaryopoiesis a more frequent, rather than a higher doses, may improve response lowering variability.
T2DM has been repeatedly associated with a lower clinical or laboratory-defined response to antiplatelet agents in primary or secondary prevention. In T2DM, platelets display several acquired abnormalities, including increased mean platelet volume, mass and turnover and megakaryopoiesis displays atypical features, both in human and animal models. PD- or PK-related mechanisms might contribute to a reduced aspirin response in T2DM. The PD of aspirin might be affected by a different platelet turnover or dysmegakaryopoiesis in T2DM. Aspirin PK in T2DM may be affected by obesity, often associated with T2DM. Finally, enhanced formation of lipid hydroperoxides may limit COX-isozyme acetylation by aspirin in both megakaryocytes and circulating platelets, and this mechanism might be facilitated by the high oxidative status described in T2DM. However, studies investigating indexes of lipid peroxidation and aspirin response have been negative in different clinical settings.
(Enlarge Image)
Figure 6.
Effect of different aspirin regimens on serum TXB2 in patients with essential thrombocythemia. (A) Absolute values of serum TXB2 in two essential thrombocythemia patients at baseline, on different aspirin regimens and after aspirin withdrawal. Patient 1 (open circles) was treated with 50 mg aspirin once-daily for 7 days, followed by 100 mg once daily for 7 more days. Patient 2 (closed circles) was treated as patient 1 with 1 more week on 150 mg aspirin once daily. In both patients, no lag in serum TXB2 recovery was observed in the first 36 h after aspirin withdrawal and by day 3 after aspirin suspension the serum TXB2 had almost completely recovered (>70%). (B) Box-whisker plots of serum TXB2 levels measured at baseline, after 200 mg aspirin once daily or 100 mg twice daily in 22 essential thrombocythemia patients. Each box-whisker plot represents the median, interquartile range, minimum and maximum values and outlying values.
*p < 0.05 versus baseline.
**p < 0.001 versus baseline and enteric-coated 100 mg twice daily.asa: Apirin.
Data not shown from [140,145].
Once-daily administration of low-dose aspirin (75–100 mg) has been associated with incomplete inhibition of platelet activity in T2DM, especially when response was measured by the end of the daily dosing interval – that is, 24 h after aspirin intake. At least in a fraction of aspirin-treated T2DM patients, accelerating kinetics in the recovery of serum TXB2 has been observed between 12 and 24 h after 100 mg EC aspirin intake. The full suppression of TXB2 12 h after aspirin intake would rule out PK modifications, and thus PD-related mechanisms, such as an increased platelet turnover or intraplatelet neosynthesis of COX-1 and/or -2 in the last hours of the dosing interval might possibly explain these observations. Two studies measured reticulated platelets and/or mean platelet volumes as peripheral indexes of increased platelet turnover and those parameters were positively correlated with a poor aspirin response measured as higher residual platelet function or TXA2 biosynthesis in aspirin-treated patients. To improve responsiveness to aspirin and reduce variability in T2DM, small randomized studies have recently compared different strategies: increasing the once-daily aspirin dose versus a more frequent administration (twice daily) of the standard low-doses aspirin. In spite of differences in study design and methodology, a more frequent administration of low-dose aspirin (75 or 100 mg, twice daily) was consistently the best strategy to reach an almost-complete and steady platelet inhibition compared with increasing the once-daily dose (320 or 200 mg once daily) or to standard daily low-dose aspirin. Consistently with the kinetics of recovery of TXB2 generation over 24 h, the superior effectiveness of a twice-daily dosing rather than a single higher dose is consistent with a mechanism associated with a higher platelet turnover and aspirin PD, rather than with a PK modification (absorbance, bioavailability and distribution). However, large, randomized studies are needed to validate this strategy in primary or secondary prevention of T2DM in terms of clinical efficacy and safety.
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