Drug interactions in the setting of acute coronary syndromes and dual anti-platelet therapy
Department of Cardiology, University Hospital Jean Minjoz, Boulevard Fleming, 25000 Besançon, France
Corresponding author. Tel: +33 381 668 539; fax: +33 381 668 582. E-mail address: jean-pierre.bassand{at}ufc-chu.univ-fcomte.fr
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Abstract |
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 Top Abstract IntroductionInteractions between drugs...Potential interaction between...References |
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Modern treatment of acute coronary syndromes (ACS) with or without ST-segment elevation involves the use of at least five pharmacological groups during the acute phase, namely anti-platelet agents (including aspirin and clopidogrel), anti-thrombotic agents (unfractionated heparin, enoxaparin or fondaparinux), beta-blockers and/or calcium channel blockers, ACE inhibitors, and statins. Long term treatment also involves the same combination of drugs, except anti-thrombins. Few interactions have been described between these drugs. In particular, interactions between clopidogrel and statins described in vitro have never been shown to have any clinical implications. In fact, the two drugs have been shown clinically to have an additional effect. Non-steroidal anti-inflammatory drugs should, however, be used with caution, due to possible interactions with aspirin.
Key Words: Clopidogrel • Drug interactions • Pharmacokinetics
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Introduction |
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Initial and long-term treatment of patients suffering from acute coronary syndromes (ACS), including non-ST- segment elevation ACS, involves multidrug therapy, including anticoagulants, antiplatelet agents, aspirin in combination with clopidogrel, beta-blockers, nitrates, and angiotensin converting enzyme (ACE)-inhibitors. In many instances, other treatments should also be prescribed because of co-morbidities such as hypertension or diabetes. Most of these drugs have to be prescribed for the long term, so attention must be paid to possible interactions that can limit the efficacy of certain drugs and compromise both outcome and the therapeutic benefit.
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Interactions between drugs recommended in the pharmacological treatment of ACS and dual antiplatelet therapy |
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No known interactions have been identified for ACE-inhibitors, angiotensin receptor antagonists, unfractionated heparin (UFH), low molecular weight heparins (LMWH), or fondaparinux. Similarly, there is no known interaction with beta-blockers in dual antiplatelet therapy.
In fact, potential interactions that could limit the efficacy of antiplatelet agents are known for aspirin and clopidogrel only. Concomitant administration of aspirin and non-steroidal anti-inflammatory drugs such as ibuprofen may interfere with the inhibition of COX 1 owing to a competitive action on the docking site of aspirin in the COX channel.1 This possible interaction is not observed with COX 2 inhibitors, such as coxibs and other anti-inflammatory drugs like diclofenac. On a clinical basis, it has never been confirmed that this possible interaction has a meaningful clinical effect. However, in some reports, it has been shown that more events occur in patients treated with this association.2–4
The situation for clopidogrel is more complex. The association of clopidogrel with vitamin K antagonists is not recommended, not because of any interaction between the two drugs, but rather because of the potential difficulty of controlling bleeding occurring in patients receiving these two drugs simultaneously. This association can be necessary in some cases, especially in patients with ACS submitted to stent implantation in the context of mechanical heart valve or high risk of thrombo-embolic events due to atrial fibrillation, for example. In these cases, no strict recommendation exists, except to control very tightly the efficacy of the vitamin K antagonists by controlling international normalized ratio (INR) frequently. The association of aspirin plus vitamin K antagonists was shown to be associated with a two-fold increase in the risk of bleeding, from 0.7% with aspirin alone to 1.4% with warfarin plus aspirin, in patients with a history of myocardial infarction.5 In a more recent report, only a modest increase in bleeding risk was observed with a combination of aspirin, thienopyridine derivatives, and warfarin in elderly patients following acute myocardial infarction.6 This report showed that in patients receiving a triple combination with aspirin, thienopyridine derivatives, and warfarin, the excess of bleeding was quite limited, provided strict control of INR could be obtained.
No interaction has been shown between clopidogrel and unfractionated heparin or LMWH or fondaparinux. There are no known interactions with ACE-inhibitors, angiotensin receptor antagonists, or IIb/IIIa inhibitors. It has been reported that clopidogrel metabolites can inhibit the enzyme activity of cytochrome P450 2C9 and lead to an increase in plasma level of non-steroidal anti-inflammatory drugs, which are metabolized by this cytochrome, and to an increased risk of gastro-intestinal bleeding. In healthy volunteers receiving naproxen 250 mg bid, concomitant administration of clopidogrel was associated with increased occult gastro-intestinal blood loss. However, owing to the lack of interaction studies with other NSAIDs, it is presently unclear whether there is any increased risk of gastro-intestinal bleeding with all NSAIDs.7
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Potential interaction between clopidogrel and lipid-lowering agents |
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Interaction studies with clopidogrel and some drugs commonly administered in patients with atherothrombotic disease have not been performed. However, patients entered into clinical trials with clopidogrel received a variety of concomitant medications including diuretics, beta-blockers, ACE-inhibitors, calcium antagonists, cholesterol-lowering agents (including statins), coronary vasodilators, antidiabetic agents (including insulin), antiepileptic agents, hormone replacement therapy, and GPIIb/IIIa inhibitors, without evidence of clinically significant adverse interactions.
Actually, the most controversial possible interaction is with lipid-lowering agents, particularly statins. It has been shown in vitro that the metabolism of clopidogrel could be inhibited at a level of up to 90% in the presence of atorvastatin.8 This interaction is thought to be linked to a common metabolic pathway in the liver through enzyme CYP3A4.9,10
However, although the metabolic pathways of both clopidogrel and atorvastatin are thought to be predominantly linked to CYP3A4, other metabolic pathways might exist. In addition, many other drugs are also metabolized by the same cytochrome, so on this basis, several other medications could have the potential to partly inhibit clopidogrel activity. This is in contrast with clinical observations. No study has ever shown to date that the association of lipophilic statins such as atorvastatin and simvastatin with clopidogrel results in an increased risk of thrombotic events.11–13 On the basis of extensive clinical data from CAPRIE, CURE, CLASSICS, and CREDO, as well as from the PRONTO and INTERACTION trials, there is currently no clinical evidence of an interaction between statins (particularly atorvastatin) and clopigodrel.14–19 The concomitant prescription of a statin and clopidogrel was not shown to negatively interact on clinical efficacy. A recent report from the GRACE registry showed that the association of clopidogrel and statins might have synergistic effects on the clinical outcomes of patients with non-ST-segment elevation ACS.20
All in all, few interactions have been described with drugs used in the setting of non-ST-segment elevation ACS. However, it is recommended not to associate non-steroidal anti-inflammatory drugs with either aspirin or clopidogrel. There is no clinical evidence that the association of clopidogrel and statins leads to partial or total inactivation of antiplatelet activity and clinical meaningful effect. Potential interactions are summarized in Table 1.
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Conflict of interest: J.-P. B. has received consulting fees from sanofi-aventis and given paid lectures on behalf of sanofi-aventis, Servier, Eli Lilly and GSK.
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References |
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