PRACTICE
Inhibition of Antiplatelet Effects of Aspirin by Nonopioid Analgesics T Hohlfeld1 and K Schr€ or1 In patients undergoing coronary bypass grafting, we noticed that low-dose aspirin failed to inhibit platelet aggregation, potentially elevating the risk of thrombotic bypass occlusion. This “high on-treatment platelet reactivity” was reproducible in vitro and could be transferred with patient plasma or urine to aspirin-sensitive donor platelets, suggesting a drug/drug interaction. Loss of aspirin efficacy was associated with analgesia by dipyrone (metamizol) and initiated further study of the interaction between aspirin and other nonopioid analgesics.
INTRODUCTION
Aspirin has proven beneficial in the prevention of atherothrombotic cardiovascular events. However, accumulating evidence suggests that platelet reactivity on aspirin may be higher than expected despite proven adherence to the medication. Potential mechanisms for “high on aspirin platelet reactivity” include variable absorption or increased degradation, increased platelet turnover, platelet activation by aspirin-insensitive pathways, and genetic polymorphisms of platelet cyclooxygenase (COX)-1, which renders this enzyme less sensitive to inactivation by aspirin. Moreover, it has emerged that high on aspirin platelet reactivity may also be caused by drug interactions, especially by inhibitors of the COX enzyme (i.e., nonsteroidal anti-inflammatory drugs [NSAIDs] and other nonopioid analgesic drugs).1 Remarkably, aspirin failed to block aggregation and thromboxane synthesis in platelets from patients undergoing coronary artery bypass graft even at very high concentrations – up to 100 lM in vitro, which exceeds 20-fold the maximum plasma concentration (cmax) reached after a 100 mg oral dose.2 Therefore, we decided to examine the underlying pharmacological mechanisms in greater detail. Having excluded many other causes of high on aspirin platelet reactivity, a key experiment yielded a clue as to how the nonresponsiveness might be explained. When platelet-poor plasma prepared from aspirin nonresponders after coronary surgery was added to normal aspirin-naive platelets from healthy donors,
these platelets underwent an immediate switch from a healthy to an aspirin nonresponsive “phenotype.” Urine from aspirin nonresponders elicited a similar effect, even at 20-fold dilution. This suggested the involvement of a transferable chemical factor interfering with the mechanism of action of aspirin. Screening of fractionated patient plasma for interfering compounds indicated that high on aspirin platelet reactivity could be associated with metabolites of the pyrazolinone compound dipyrone (metamizol), a common analgesic in surgical anesthesia. Although dipyrone is not approved in some countries due to its risk of agranulocytosis, it is widely used elsewhere, including in Germany, because of its potent analgesic effect and an assumed better gastrointestinal tolerability compared with traditional NSAIDs. Dipyrone’s analgesic action is based, at least partly, on nonselective inhibition of the COX isoforms COX-1 and possibly COX-2. The observed dipyrone/aspirin interaction is reminiscent of earlier reports by us and others that NSAIDs, such as ibuprofen, may prevent the antiplatelet action of aspirin (Figure 1). Further in vitro studies of the suspected aspirin/dipyrone interaction confirmed that dipyrone interferes with aspirininduced platelet inhibition.3 Indeed, dipyrone (in the form of its active metabolite 4-methylaminoantipyrine) prevented aspirininduced inhibition of platelet thromboxane synthesis at low micromolar concentrations, which are well within the therapeutic range. Inhibition of both platelet aggregation and P-selectin expression by aspirin were also largely blunted by dipyrone. We could confirm the aspirin/dipyrone interaction in patients with coronary artery disease in a recent observational study.4 Studies in other patient cohorts, such as cerebrovascular disease, are currently underway. How can the interaction of nonopioid analgesics with aspirin be explained?
The consensus mechanism of aspirin’s antiplatelet activity is the irreversible acetylation of platelet COX-1, which prevents formation of prostaglandin H2 and thromboxane A2. This offsets one of the initial self-amplification mechanisms of platelet activation,
1
€ t Du €r Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universita €sseldorf, Du €sseldorf, Germany. Correspondence: T Hohlfeld (hohlfeld@ Institut fu uni-duesseldorf.de) Received 19 August 2014; accepted 30 September 2014; advance online publication 00 Month 2014. doi:10.1002/cpt.21
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2014
1
PRACTICE
Figure 1 Interaction of oral ibuprofen with aspirin in a healthy subject demonstrated by light transmission aggregometry. Normal aggregation at time zero (black trace). Low-dose aspirin for four days completely inhibits aggregation (dark blue trace). Co-treatment with ibuprofen at medium analgesic doses (400 mg t.i.d.) abolishes the inhibition by aspirin despite continued aspirin treatment (red trace). Four days after ibuprofen has been discontinued, platelet inhibition by aspirin has restored (light blue trace). Black dots represent addition of 1 mM arachidonic acid for platelet activation ex vivo. Actual €r, In: Waksman et al. (ed.). Antiplatelet therapy in cardiovascular disibuprofen plasma concentrations are also indicated. (Modified after Hohlfeld & Schro ease, Wiley, Chichester, 2014, p. 8–13.)
namely feedback stimulation via platelet thromboxane receptors. Other pathways of platelet activation are not affected by aspirin. It is established that nonopioid analgesics, including dipyrone, are inhibitors of platelet COX-1, thromboxane synthesis, and platelet aggregation. This may contribute to bleeding complications of this class of drugs.
Nevertheless, nonopioid analgesics, such as dipyrone and others, differ from aspirin in that their antiplatelet action is transient and relatively weak. The reason is that nonopioid analgesics other than aspirin act in a reversible manner, allowing platelet COX-1 to recover when plasma concentrations have fallen during the dosing intervals. In addition, high local arachidonic
Figure 2 Substrate channel of cyclooxygenase (COX)-1 located in the inner of the enzyme below the heme group (red). Figure derived from crystal structure analysis. Selected amino acid side chains are shown, which are essential for substrate binding and catalytic function. (a) Empty channel with Ser 530 acetylated by aspirin (yellow). (b) Putative position of several nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) within the substrate channel of COX-1. NSAIDs are located next to Ser 530 with their carboxyl function directed toward Arg 120. These NSAIDs likely consume the space required for initial binding of aspirin, which is essential for enzyme acetylation by aspirin. See text for further details. (Figure kindly provided by P. Loll, Philadelphia.) 2
VOLUME 00 NUMBER 00 | MONTH 2014 | www.wileyonlinelibrary/cpt
PRACTICE acid concentrations, released by platelet phospholipases during platelet activation, may displace nonopioids from the COX-1 enzyme, because the KM of human COX-1 for arachidonic acid is similar to the Ki of reversible nonopioid analgesics (both in the low micromolar range). In contrast, the binding of aspirin to platelet COX-1 occurs with relatively low affinity (Ki18 mM). Aspirin binds in an initial step to the COX enzyme reversibly and then relocates within the hydrophobic substrate channel to another position from where its acetyl moiety is transferred to serine 530. COX-1 acetylation at this position prevents arachidonic acid from associating with the enzyme in a correct (“productive”) steric position within the substrate channel, which irreversibly shuts off COX-1 activity. Because low-dose aspirin (100 mg daily) achieves plasma concentrations in the low lmolar range, which is far below Ki, the initial binding of aspirin is weak. Furthermore, the pharmacokinetic characteristics of aspirin (slow absorption, partial presystemic deacetylation) may sometimes limit its pharmacological activity. Reversible COX inhibitors (nonopioid analgesics) bind to the COX-1 enzyme at a similar position and possibly compete with aspirin. The binding sites of aspirin and many other nonopioid analgesics sterically overlap with the binding position and acetylation site of aspirin (Figure 2). In the case of coadministration of aspirin and a nonopioid analgesic, platelet inhibition through irreversible COX-1 acetylation will not occur. As mentioned, nonopioid analgesics are transient platelet inhibitors, allowing COX-1 activity to recover if plasma concentrations have fallen. At the same time, aspirin is rapidly deacetylated to salicylate by plasmatic and red cell esterases (t1/220 min). Because salicylate has no antiplatelet activity (being unable to acetylate COX-1), function and capacity of platelets to form thromboxane are preserved. In other words, platelet inhibition by aspirin may fail in the presence of nonopioid analgesics. Experimental and clinical evidence
The described interaction has been demonstrated experimentally with a number of further nonopioid analgesics.5 Even low concentrations showing little COX-1 inhibition by themselves were sufficient to attenuate or abolish the antiplatelet action of aspirin. Highly selective COX-2 inhibitors lacking affinity to COX-1, such as rofecoxib and etoricoxib, do not to interfere with this aspirin action, whereas celecoxib does, because it binds not only to COX-2 but also, although less potently, to COX-1. Most evidence has been gathered on ibuprofen as an NSAID that interferes with low-dose aspirin. Catella-Lawson and coworkers demonstrated this in a prospective clinical study that appeared in the New England Journal of Medicine in 2001.6 They administered ibuprofen (400 mg o.d.) to healthy subjects two hours before aspirin (81 mg/day) for six days, which blunted platelet inhibition by aspirin. Administration of both agents in reverse order did not influence the effect of aspirin, which is not surprising because the 400 mg dose of ibuprofen (t1/2 5 2–4 hours) was near-completely eliminated within 24 hours, when the next aspirin dose was given. This study also reported that neither acetaminophen nor diclofenac interacted with aspirin, suggesting differences between the nonopioids. We have examined this with a large numCLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2014
ber of NSAIDs using platelets from healthy donors and also observed remarkable differences among individual compounds.5 Acetaminophen and diclofenac, as well as ketorolac did not interfere with aspirin at all. Accompanying molecular docking studies suggested that the number and location of hydrogen bonds formed between these inhibitors and specific amino acid residues in the COX-1 substrate channel may determine the potential of nonopioid COX inhibitors to interfere with aspirin. Studies of differing design and sample size have examined whether nonopioid analgesics interfere with low-dose aspirin in the clinical setting. Most were based on laboratory assays of platelet function. Co-medication with ibuprofen, naproxen, and some other NSAIDs was indeed found to attenuate or even eliminate the antiplatelet action of aspirin. There is still uncertainty regarding the clinical relevance, because assays of platelet function do not accurately predict the risk of atherothrombosis, even in patients with coronary artery disease. On the other hand, it is established that short-term interruption of treatment with lowdose aspirin can be deleterious. Thus, it may be assumed that blunting the pharmacological effect of aspirin by drug interactions may be similarly detrimental. Unfortunately, very few studies have addressed this (for review, see ref. 1). It is important to mention that there are other reasons why NSAID analgesics may impair cardiovascular prognosis. This class of drugs inhibits prostaglandin synthesis in the vasculature. Particularly the inhibition of endothelial COX-2 may have unfavorable consequences, such as increase in blood pressure, renal dysfunction, and disturbed endothelial control of thrombogenesis. This aspect must not be confounded with the pharmacodynamic interaction of nonopioid analgesics with aspirin, which is discussed here. What is the message for the clinician?
Unexpected unfavorable interactions obviously do not only occur with complex innovative drugs, but also with the traditional ones, such as aspirin and nonopioid analgesics. Although it seems counterintuitive that reversible COX inhibitors may abolish the effect of aspirin, which is another COX inhibitor, this interaction may be explained by a rational pharmacodynamic mechanism. The importance of this drug interaction for cardiovascular outcome cannot be definitively answered at this time, but leading health agencies (such as the European Medicines Agency and the Food and Drug Administration) have released warning letters. There are simple implications for therapeutic practice. It may be worthwhile to apply the daily dose of low-dose aspirin at a time when the plasma levels of nonopioid analgesics are low, as described above for ibuprofen. This may be easier with immediate release formulations, because actual concentrations in blood are less predictable with the slow release formulations. Whether such drug interactions may be avoided by an increased dose of aspirin (how much?) or more than once daily dosing (how often?) is presently not clear. The available nonopioid analgesics differ with respect to their drug-interaction potential with aspirin. If analgesic potency allows, patients on low-dose aspirin should prefer acetaminophen to ibuprofen, dipyrone, or other interfering analgesics. Whether 3
PRACTICE diclofenac can be recommended as well is difficult to answer. Although it seems not to interfere with the antiplatelet effect of aspirin, it has recently been recognized to bear an additional cardiovascular risk, possibly in relation to its COX-2 inhibitory potential that does not modify platelet function.
2.
3.
CONFLICT OF INTEREST The authors declared no conflict of interest.
4.
C 2014 American Society for Clinical Pharmacology and Therapeutics V
5.
€r, K. High on treatment platelet 1. Hohlfeld, T., Saxena, A. & Schro reactivity against aspirin by non-steroidal anti-inflammatory
6.
4
drugs – pharmacological mechanisms and clinical relevance. Thromb. Haemost. 109, 825–833 (2013). Zimmermann, N. et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 108, 542–547 (2003). Hohlfeld, T. et al. Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis. J. Thromb. Haemost. 6, 166–173 (2008). €r, K., Kelm, M. & Hohlfeld, T. Dipyrone (metaPolzin, A., Zeus, T., Schro mizole) can nullify the antiplatelet effect of aspirin in patients with coronary artery disease. J. Am. Coll. Cardiol. 62, 1725–1726 (2013). Saxena, A., Balaramnavar, V.M., Hohlfeld, T. & Saxena, A.K. Drug/drug interaction of common NSAIDs with antiplatelet effect of aspirin in human platelets. Eur. J. Pharmacol. 721, 215–224 (2013). Catella-Lawson, F. et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin N. Engl. J. Med. 345, 1809–1817 (2001).
VOLUME 00 NUMBER 00 | MONTH 2014 | www.wileyonlinelibrary/cpt
Inhibition of Antiplatelet Effects of Aspirin by Nonopioid Analgesics T Hohlfeld1 and K Schr€ or1 In patients undergoing coronary bypass grafting, we noticed that low-dose aspirin failed to inhibit platelet aggregation, potentially elevating the risk of thrombotic bypass occlusion. This “high on-treatment platelet reactivity” was reproducible in vitro and could be transferred with patient plasma or urine to aspirin-sensitive donor platelets, suggesting a drug/drug interaction. Loss of aspirin efficacy was associated with analgesia by dipyrone (metamizol) and initiated further study of the interaction between aspirin and other nonopioid analgesics.
INTRODUCTION
Aspirin has proven beneficial in the prevention of atherothrombotic cardiovascular events. However, accumulating evidence suggests that platelet reactivity on aspirin may be higher than expected despite proven adherence to the medication. Potential mechanisms for “high on aspirin platelet reactivity” include variable absorption or increased degradation, increased platelet turnover, platelet activation by aspirin-insensitive pathways, and genetic polymorphisms of platelet cyclooxygenase (COX)-1, which renders this enzyme less sensitive to inactivation by aspirin. Moreover, it has emerged that high on aspirin platelet reactivity may also be caused by drug interactions, especially by inhibitors of the COX enzyme (i.e., nonsteroidal anti-inflammatory drugs [NSAIDs] and other nonopioid analgesic drugs).1 Remarkably, aspirin failed to block aggregation and thromboxane synthesis in platelets from patients undergoing coronary artery bypass graft even at very high concentrations – up to 100 lM in vitro, which exceeds 20-fold the maximum plasma concentration (cmax) reached after a 100 mg oral dose.2 Therefore, we decided to examine the underlying pharmacological mechanisms in greater detail. Having excluded many other causes of high on aspirin platelet reactivity, a key experiment yielded a clue as to how the nonresponsiveness might be explained. When platelet-poor plasma prepared from aspirin nonresponders after coronary surgery was added to normal aspirin-naive platelets from healthy donors,
these platelets underwent an immediate switch from a healthy to an aspirin nonresponsive “phenotype.” Urine from aspirin nonresponders elicited a similar effect, even at 20-fold dilution. This suggested the involvement of a transferable chemical factor interfering with the mechanism of action of aspirin. Screening of fractionated patient plasma for interfering compounds indicated that high on aspirin platelet reactivity could be associated with metabolites of the pyrazolinone compound dipyrone (metamizol), a common analgesic in surgical anesthesia. Although dipyrone is not approved in some countries due to its risk of agranulocytosis, it is widely used elsewhere, including in Germany, because of its potent analgesic effect and an assumed better gastrointestinal tolerability compared with traditional NSAIDs. Dipyrone’s analgesic action is based, at least partly, on nonselective inhibition of the COX isoforms COX-1 and possibly COX-2. The observed dipyrone/aspirin interaction is reminiscent of earlier reports by us and others that NSAIDs, such as ibuprofen, may prevent the antiplatelet action of aspirin (Figure 1). Further in vitro studies of the suspected aspirin/dipyrone interaction confirmed that dipyrone interferes with aspirininduced platelet inhibition.3 Indeed, dipyrone (in the form of its active metabolite 4-methylaminoantipyrine) prevented aspirininduced inhibition of platelet thromboxane synthesis at low micromolar concentrations, which are well within the therapeutic range. Inhibition of both platelet aggregation and P-selectin expression by aspirin were also largely blunted by dipyrone. We could confirm the aspirin/dipyrone interaction in patients with coronary artery disease in a recent observational study.4 Studies in other patient cohorts, such as cerebrovascular disease, are currently underway. How can the interaction of nonopioid analgesics with aspirin be explained?
The consensus mechanism of aspirin’s antiplatelet activity is the irreversible acetylation of platelet COX-1, which prevents formation of prostaglandin H2 and thromboxane A2. This offsets one of the initial self-amplification mechanisms of platelet activation,
1
€ t Du €r Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universita €sseldorf, Du €sseldorf, Germany. Correspondence: T Hohlfeld (hohlfeld@ Institut fu uni-duesseldorf.de) Received 19 August 2014; accepted 30 September 2014; advance online publication 00 Month 2014. doi:10.1002/cpt.21
CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2014
1
PRACTICE
Figure 1 Interaction of oral ibuprofen with aspirin in a healthy subject demonstrated by light transmission aggregometry. Normal aggregation at time zero (black trace). Low-dose aspirin for four days completely inhibits aggregation (dark blue trace). Co-treatment with ibuprofen at medium analgesic doses (400 mg t.i.d.) abolishes the inhibition by aspirin despite continued aspirin treatment (red trace). Four days after ibuprofen has been discontinued, platelet inhibition by aspirin has restored (light blue trace). Black dots represent addition of 1 mM arachidonic acid for platelet activation ex vivo. Actual €r, In: Waksman et al. (ed.). Antiplatelet therapy in cardiovascular disibuprofen plasma concentrations are also indicated. (Modified after Hohlfeld & Schro ease, Wiley, Chichester, 2014, p. 8–13.)
namely feedback stimulation via platelet thromboxane receptors. Other pathways of platelet activation are not affected by aspirin. It is established that nonopioid analgesics, including dipyrone, are inhibitors of platelet COX-1, thromboxane synthesis, and platelet aggregation. This may contribute to bleeding complications of this class of drugs.
Nevertheless, nonopioid analgesics, such as dipyrone and others, differ from aspirin in that their antiplatelet action is transient and relatively weak. The reason is that nonopioid analgesics other than aspirin act in a reversible manner, allowing platelet COX-1 to recover when plasma concentrations have fallen during the dosing intervals. In addition, high local arachidonic
Figure 2 Substrate channel of cyclooxygenase (COX)-1 located in the inner of the enzyme below the heme group (red). Figure derived from crystal structure analysis. Selected amino acid side chains are shown, which are essential for substrate binding and catalytic function. (a) Empty channel with Ser 530 acetylated by aspirin (yellow). (b) Putative position of several nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) within the substrate channel of COX-1. NSAIDs are located next to Ser 530 with their carboxyl function directed toward Arg 120. These NSAIDs likely consume the space required for initial binding of aspirin, which is essential for enzyme acetylation by aspirin. See text for further details. (Figure kindly provided by P. Loll, Philadelphia.) 2
VOLUME 00 NUMBER 00 | MONTH 2014 | www.wileyonlinelibrary/cpt
PRACTICE acid concentrations, released by platelet phospholipases during platelet activation, may displace nonopioids from the COX-1 enzyme, because the KM of human COX-1 for arachidonic acid is similar to the Ki of reversible nonopioid analgesics (both in the low micromolar range). In contrast, the binding of aspirin to platelet COX-1 occurs with relatively low affinity (Ki18 mM). Aspirin binds in an initial step to the COX enzyme reversibly and then relocates within the hydrophobic substrate channel to another position from where its acetyl moiety is transferred to serine 530. COX-1 acetylation at this position prevents arachidonic acid from associating with the enzyme in a correct (“productive”) steric position within the substrate channel, which irreversibly shuts off COX-1 activity. Because low-dose aspirin (100 mg daily) achieves plasma concentrations in the low lmolar range, which is far below Ki, the initial binding of aspirin is weak. Furthermore, the pharmacokinetic characteristics of aspirin (slow absorption, partial presystemic deacetylation) may sometimes limit its pharmacological activity. Reversible COX inhibitors (nonopioid analgesics) bind to the COX-1 enzyme at a similar position and possibly compete with aspirin. The binding sites of aspirin and many other nonopioid analgesics sterically overlap with the binding position and acetylation site of aspirin (Figure 2). In the case of coadministration of aspirin and a nonopioid analgesic, platelet inhibition through irreversible COX-1 acetylation will not occur. As mentioned, nonopioid analgesics are transient platelet inhibitors, allowing COX-1 activity to recover if plasma concentrations have fallen. At the same time, aspirin is rapidly deacetylated to salicylate by plasmatic and red cell esterases (t1/220 min). Because salicylate has no antiplatelet activity (being unable to acetylate COX-1), function and capacity of platelets to form thromboxane are preserved. In other words, platelet inhibition by aspirin may fail in the presence of nonopioid analgesics. Experimental and clinical evidence
The described interaction has been demonstrated experimentally with a number of further nonopioid analgesics.5 Even low concentrations showing little COX-1 inhibition by themselves were sufficient to attenuate or abolish the antiplatelet action of aspirin. Highly selective COX-2 inhibitors lacking affinity to COX-1, such as rofecoxib and etoricoxib, do not to interfere with this aspirin action, whereas celecoxib does, because it binds not only to COX-2 but also, although less potently, to COX-1. Most evidence has been gathered on ibuprofen as an NSAID that interferes with low-dose aspirin. Catella-Lawson and coworkers demonstrated this in a prospective clinical study that appeared in the New England Journal of Medicine in 2001.6 They administered ibuprofen (400 mg o.d.) to healthy subjects two hours before aspirin (81 mg/day) for six days, which blunted platelet inhibition by aspirin. Administration of both agents in reverse order did not influence the effect of aspirin, which is not surprising because the 400 mg dose of ibuprofen (t1/2 5 2–4 hours) was near-completely eliminated within 24 hours, when the next aspirin dose was given. This study also reported that neither acetaminophen nor diclofenac interacted with aspirin, suggesting differences between the nonopioids. We have examined this with a large numCLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2014
ber of NSAIDs using platelets from healthy donors and also observed remarkable differences among individual compounds.5 Acetaminophen and diclofenac, as well as ketorolac did not interfere with aspirin at all. Accompanying molecular docking studies suggested that the number and location of hydrogen bonds formed between these inhibitors and specific amino acid residues in the COX-1 substrate channel may determine the potential of nonopioid COX inhibitors to interfere with aspirin. Studies of differing design and sample size have examined whether nonopioid analgesics interfere with low-dose aspirin in the clinical setting. Most were based on laboratory assays of platelet function. Co-medication with ibuprofen, naproxen, and some other NSAIDs was indeed found to attenuate or even eliminate the antiplatelet action of aspirin. There is still uncertainty regarding the clinical relevance, because assays of platelet function do not accurately predict the risk of atherothrombosis, even in patients with coronary artery disease. On the other hand, it is established that short-term interruption of treatment with lowdose aspirin can be deleterious. Thus, it may be assumed that blunting the pharmacological effect of aspirin by drug interactions may be similarly detrimental. Unfortunately, very few studies have addressed this (for review, see ref. 1). It is important to mention that there are other reasons why NSAID analgesics may impair cardiovascular prognosis. This class of drugs inhibits prostaglandin synthesis in the vasculature. Particularly the inhibition of endothelial COX-2 may have unfavorable consequences, such as increase in blood pressure, renal dysfunction, and disturbed endothelial control of thrombogenesis. This aspect must not be confounded with the pharmacodynamic interaction of nonopioid analgesics with aspirin, which is discussed here. What is the message for the clinician?
Unexpected unfavorable interactions obviously do not only occur with complex innovative drugs, but also with the traditional ones, such as aspirin and nonopioid analgesics. Although it seems counterintuitive that reversible COX inhibitors may abolish the effect of aspirin, which is another COX inhibitor, this interaction may be explained by a rational pharmacodynamic mechanism. The importance of this drug interaction for cardiovascular outcome cannot be definitively answered at this time, but leading health agencies (such as the European Medicines Agency and the Food and Drug Administration) have released warning letters. There are simple implications for therapeutic practice. It may be worthwhile to apply the daily dose of low-dose aspirin at a time when the plasma levels of nonopioid analgesics are low, as described above for ibuprofen. This may be easier with immediate release formulations, because actual concentrations in blood are less predictable with the slow release formulations. Whether such drug interactions may be avoided by an increased dose of aspirin (how much?) or more than once daily dosing (how often?) is presently not clear. The available nonopioid analgesics differ with respect to their drug-interaction potential with aspirin. If analgesic potency allows, patients on low-dose aspirin should prefer acetaminophen to ibuprofen, dipyrone, or other interfering analgesics. Whether 3
PRACTICE diclofenac can be recommended as well is difficult to answer. Although it seems not to interfere with the antiplatelet effect of aspirin, it has recently been recognized to bear an additional cardiovascular risk, possibly in relation to its COX-2 inhibitory potential that does not modify platelet function.
2.
3.
CONFLICT OF INTEREST The authors declared no conflict of interest.
4.
C 2014 American Society for Clinical Pharmacology and Therapeutics V
5.
€r, K. High on treatment platelet 1. Hohlfeld, T., Saxena, A. & Schro reactivity against aspirin by non-steroidal anti-inflammatory
6.
4
drugs – pharmacological mechanisms and clinical relevance. Thromb. Haemost. 109, 825–833 (2013). Zimmermann, N. et al. Functional and biochemical evaluation of platelet aspirin resistance after coronary artery bypass surgery. Circulation 108, 542–547 (2003). Hohlfeld, T. et al. Pyrazolinone analgesics prevent the antiplatelet effect of aspirin and preserve human platelet thromboxane synthesis. J. Thromb. Haemost. 6, 166–173 (2008). €r, K., Kelm, M. & Hohlfeld, T. Dipyrone (metaPolzin, A., Zeus, T., Schro mizole) can nullify the antiplatelet effect of aspirin in patients with coronary artery disease. J. Am. Coll. Cardiol. 62, 1725–1726 (2013). Saxena, A., Balaramnavar, V.M., Hohlfeld, T. & Saxena, A.K. Drug/drug interaction of common NSAIDs with antiplatelet effect of aspirin in human platelets. Eur. J. Pharmacol. 721, 215–224 (2013). Catella-Lawson, F. et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin N. Engl. J. Med. 345, 1809–1817 (2001).
VOLUME 00 NUMBER 00 | MONTH 2014 | www.wileyonlinelibrary/cpt
