Identifying Determinants to Tailor Aspirin Therapy
Identifying Determinants to Tailor Aspirin Therapy
Individual drug response is a multifactorial, highly variable trait, being the final phenotypic result of different components: pharmacokinetics (PK), which includes compliance, absorption, bioavailability, distribution, biotransformation; pharmacodynamics (PD) comprising the status of drug target, resistance, tolerance; environment, for example interaction with xenobiotics (drugs, hormones and habits), which may impact on PK and/or PD; and physiological and pathological conditions such as aging, kidney or liver function, underlying disease and genetic background. The interindividual variability in the response to any drug can be defined as "an effect of varying intensity occurring in different individuals at a specified dose of a drug", or as "a requirement of a range of concentrations (doses) in order to produce an effect of specified intensity in all of the patients".
Drug response can be measured with different methods spanning from direct measurements of drug plasma concentrations, to indirect biochemical or functional assays, such as blood cholesterol for statins, blood pressure for antihypertensive drugs, prothrombin time expressed as international normalized ratio for warfarin. Ideally, drug response should be measured with a 'drug-tailored' assay, tightly reflecting its mechanism of action (PD), drug concentration, associated with the clinical outcome, with a small assay-related coefficient of variation. These features allow identifying true, drug-related variability in response rather than the variation of the laboratory test itself, which is unrelated to drug's PD.
Pharmacological drug resistance is only one possible cause of variability in drug response. It is a well characterized phenomenon for antibiotics, antiblastics and warfarin. It usually affects drug PD, by directly or indirectly modifying the drug–target interaction. It is triggered by the drug itself, is a stable phenotype during treatment and requires drug interruption and a change of molecule. The main features of pharmacological variability versus resistance are depicted in Table 1. Therefore, based on antibiotics or chemotherapics, one would expect that true aspirin resistance is aspirin-induced, based on a time-dependent change in the interaction between aspirin and its target (platelet COX-1 and/or -2), measurable by a standardized assay mirroring PD, reverted by drug suspension and successfully treated with a different antiplatelet agent. None of these features have ever been reported in the case of aspirin.
Aspirin resistance had diverse and inconsistent definitions: clinically as treatment failure, functionally as a lower-than-expected platelet response using different assays of platelet function, or by using a mechanism-based, biochemical criterion, as reduced inhibition of thromboxane (TX) generation, both in vivo as urinary metabolites, or ex vivo, as assessed by the maximal capacity of platelets to synthesize TXA2 (Figure 1). Aspirin response across different studies has been measured with different, nonstandardized assays, having low coefficient of agreement and with a poor reproducibility even in the absence of aspirin. As a consequence, it is not surprising that the incidence of aspirin resistance is highly variable (from 0 to 65%), assay-dependent, and inconsistent over repeated measurements. The International Society of Thrombosis and Haemostasis has defined this phenomenon as 'variability in laboratory test response', rather than 'resistance' to aspirin, which rather should be assay-independent. On the top of these methodological biases, the majority of papers dealing with aspirin resistance are retrospective, descriptive, on relatively small populations, significantly heterogeneous (different aspirin doses, cutoffs, populations and end points), relying on a single measurement over time, without an objective assessment of compliance or formal exclusion of NSAIDs intake. As a consequence, the clinical correlate of such a blurred laboratory definition of aspirin resistance is highly uncertain, with odds ratios (OR) for any cardiovascular outcome ranging from a substantial benefit (OR: 0.2; 95% CI: 0.0–4.5) to a clear-cut harm (OR: 14.5; 95% CI: 5.2–40.9), with a large uncertainty surrounding estimates (wide CI) associated with a thrombosis incidence paradoxically higher than any placebo arm of early aspirin trials on high-risk patients. Moreover, a review concluded that increasing the aspirin dose is beneficial, which substantially disagreed with results from large, randomized, prospective trials showing that higher doses do not add any further cardiovascular protection while increasing the bleeding risk. Thus, aspirin resistance still remains without consensus on definition, standardized reference assay, pathogenetic mechanism(s), clinical impact or evidence-based efficacy of alternative antiplatelet therapy. Prospective trials are needed to investigate the relevance of nonstandardized assays as biomarkers predicting cardiovascular outcomes and guiding changes of antiplatelet therapy. The GRAVITAS randomized trial, which tested the hypothesis of modifying clopidogrel therapy based on platelet reactivity testing in acute coronary syndrome, gave negative results.
(Enlarge Image)
Figure 1.
Methods used to assess aspirin 'resistance' between 2000 and 2011. The plot depicts the distribution of the methods used in 153 original articles between the year 2000 and 2011 to assess aspirin 'resistance'. Reviews or editorials were excluded from the analysis. Several papers used more than one method to assess aspirin response. AA: Arachidonic acid; LTA: Light transmittance aggregometry; PFA: Platelet function analyzer; TX: Thromboxane.
Recently the existence of aspirin resistance has been questioned and slowly replaced by a different pharmacological category, such as the individual variability in aspirin responsiveness in selected conditions based on drug's PK or PD (Figure 2).
(Enlarge Image)
Figure 2.
Aspirin 'resistance' versus variability in the literature. The plot depicts the number of papers published until 2011 dealing with aspirin 'resistance' (black columns) or variability in drug response (grey columns). Data were obtained from PubMed searches using 'aspirin and resistance' or 'aspirin and variability' as keywords. The content of each paper was checked to evaluate the appropriateness of content.
Before analyzing determinants of variability in aspirin response, the authors will briefly resume the early description of aspirin pharmacology, its methodology and main findings, which remain the basis for understanding determinants of variability and designing future, patient-tailored aspirin regimens.
Interindividual Response Variability, Laboratory Variability or Aspirin 'Resistance'?
Individual drug response is a multifactorial, highly variable trait, being the final phenotypic result of different components: pharmacokinetics (PK), which includes compliance, absorption, bioavailability, distribution, biotransformation; pharmacodynamics (PD) comprising the status of drug target, resistance, tolerance; environment, for example interaction with xenobiotics (drugs, hormones and habits), which may impact on PK and/or PD; and physiological and pathological conditions such as aging, kidney or liver function, underlying disease and genetic background. The interindividual variability in the response to any drug can be defined as "an effect of varying intensity occurring in different individuals at a specified dose of a drug", or as "a requirement of a range of concentrations (doses) in order to produce an effect of specified intensity in all of the patients".
Drug response can be measured with different methods spanning from direct measurements of drug plasma concentrations, to indirect biochemical or functional assays, such as blood cholesterol for statins, blood pressure for antihypertensive drugs, prothrombin time expressed as international normalized ratio for warfarin. Ideally, drug response should be measured with a 'drug-tailored' assay, tightly reflecting its mechanism of action (PD), drug concentration, associated with the clinical outcome, with a small assay-related coefficient of variation. These features allow identifying true, drug-related variability in response rather than the variation of the laboratory test itself, which is unrelated to drug's PD.
Pharmacological drug resistance is only one possible cause of variability in drug response. It is a well characterized phenomenon for antibiotics, antiblastics and warfarin. It usually affects drug PD, by directly or indirectly modifying the drug–target interaction. It is triggered by the drug itself, is a stable phenotype during treatment and requires drug interruption and a change of molecule. The main features of pharmacological variability versus resistance are depicted in Table 1. Therefore, based on antibiotics or chemotherapics, one would expect that true aspirin resistance is aspirin-induced, based on a time-dependent change in the interaction between aspirin and its target (platelet COX-1 and/or -2), measurable by a standardized assay mirroring PD, reverted by drug suspension and successfully treated with a different antiplatelet agent. None of these features have ever been reported in the case of aspirin.
Aspirin resistance had diverse and inconsistent definitions: clinically as treatment failure, functionally as a lower-than-expected platelet response using different assays of platelet function, or by using a mechanism-based, biochemical criterion, as reduced inhibition of thromboxane (TX) generation, both in vivo as urinary metabolites, or ex vivo, as assessed by the maximal capacity of platelets to synthesize TXA2 (Figure 1). Aspirin response across different studies has been measured with different, nonstandardized assays, having low coefficient of agreement and with a poor reproducibility even in the absence of aspirin. As a consequence, it is not surprising that the incidence of aspirin resistance is highly variable (from 0 to 65%), assay-dependent, and inconsistent over repeated measurements. The International Society of Thrombosis and Haemostasis has defined this phenomenon as 'variability in laboratory test response', rather than 'resistance' to aspirin, which rather should be assay-independent. On the top of these methodological biases, the majority of papers dealing with aspirin resistance are retrospective, descriptive, on relatively small populations, significantly heterogeneous (different aspirin doses, cutoffs, populations and end points), relying on a single measurement over time, without an objective assessment of compliance or formal exclusion of NSAIDs intake. As a consequence, the clinical correlate of such a blurred laboratory definition of aspirin resistance is highly uncertain, with odds ratios (OR) for any cardiovascular outcome ranging from a substantial benefit (OR: 0.2; 95% CI: 0.0–4.5) to a clear-cut harm (OR: 14.5; 95% CI: 5.2–40.9), with a large uncertainty surrounding estimates (wide CI) associated with a thrombosis incidence paradoxically higher than any placebo arm of early aspirin trials on high-risk patients. Moreover, a review concluded that increasing the aspirin dose is beneficial, which substantially disagreed with results from large, randomized, prospective trials showing that higher doses do not add any further cardiovascular protection while increasing the bleeding risk. Thus, aspirin resistance still remains without consensus on definition, standardized reference assay, pathogenetic mechanism(s), clinical impact or evidence-based efficacy of alternative antiplatelet therapy. Prospective trials are needed to investigate the relevance of nonstandardized assays as biomarkers predicting cardiovascular outcomes and guiding changes of antiplatelet therapy. The GRAVITAS randomized trial, which tested the hypothesis of modifying clopidogrel therapy based on platelet reactivity testing in acute coronary syndrome, gave negative results.
(Enlarge Image)
Figure 1.
Methods used to assess aspirin 'resistance' between 2000 and 2011. The plot depicts the distribution of the methods used in 153 original articles between the year 2000 and 2011 to assess aspirin 'resistance'. Reviews or editorials were excluded from the analysis. Several papers used more than one method to assess aspirin response. AA: Arachidonic acid; LTA: Light transmittance aggregometry; PFA: Platelet function analyzer; TX: Thromboxane.
Recently the existence of aspirin resistance has been questioned and slowly replaced by a different pharmacological category, such as the individual variability in aspirin responsiveness in selected conditions based on drug's PK or PD (Figure 2).
(Enlarge Image)
Figure 2.
Aspirin 'resistance' versus variability in the literature. The plot depicts the number of papers published until 2011 dealing with aspirin 'resistance' (black columns) or variability in drug response (grey columns). Data were obtained from PubMed searches using 'aspirin and resistance' or 'aspirin and variability' as keywords. The content of each paper was checked to evaluate the appropriateness of content.
Before analyzing determinants of variability in aspirin response, the authors will briefly resume the early description of aspirin pharmacology, its methodology and main findings, which remain the basis for understanding determinants of variability and designing future, patient-tailored aspirin regimens.
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