약물상호작용, Clopidogrel, PPI drug interaction, 플라빅스 & 넥시움 같이 먹으면 안 되나요?

😀 플라빅스 먹고 있는데 넥시움 먹어도되나요?

👩‍🔬약동학적으로 동시 복용하면 플라빅스 정(클로피도그렐)의 효과가 감소할 수 있지만 실제 임상적으로 중요한 차이를 보인다는 결과를 입증한 연구는 없습니다. 하지만 우선적으로 의사 선생님과 상담하여 PPI를 꼭 먹어야하는지, 만약 먹는다면 충분한 시간을 띄우고 복용하거나 약물 상호작용이 적다고 알려진 pantoprazole로 복용하는 등의 대처 방법을 세웁니다.

 

 

 

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1) Uptodate

 

Proton pump inhibitors – In most patients, we believe that PPIs and clopidogrel can be used together. We agree with the 2009 US Food and Drug Administration notice that suggests that patients who take clopidogrel should consult with their clinician if they are taking a PPI or considering PPI use [20,21]. Despite the known pharmacodynamic interaction between PPIs and clopidogrel, which decreases the antiplatelet effect of clopidogrel, the available evidence suggests that PPIs do not decrease the clinical efficacy of clopidogrel [22-26].

Examples of studies supporting this approach include the following:

-In a systematic review of published data, simultaneous use of a P2Y12 inhibitor and a PPI did not significantly increase the risk of major adverse cardiovascular events (4.5 versus 4.7 percent in the PPI group; relative risk [RR] 0.99, 95% CI 0.76-1.28) [26].

-In one of the largest trials in the meta-analysis, 3761 patients treated with clopidogrel were randomly assigned to either omeprazole or placebo [24]. There was no significant difference in cardiovascular events (4.9 versus 5.7 percent with placebo; hazard ratio [HR] 0.99, 95% CI 0.68-1.44) and a lower rate of gastrointestinal bleeding in patients assigned to omeprazole (1.1 versus 2.9 percent with placebo; HR 0.34, 95% CI 0.18-0.63).

 

 

 

2) 메타분석

PPIs Are Not Responsible for Elevating Cardiovascular Risk in Patients on Clopidogrel-A Systematic Review and Meta-Analysis.

 

Background: Clopidogrel and proton pump inhibitors (PPIs) are metabolized by cytochrome P450 enzymes. Contradictory results have been reported on possible complications of simultaneous PPI and clopidogrel use. Our aim was to investigate the clinical relevance of this debate with a systematic review and meta-analysis. Methods: The PubMed, Embase, and Cochrane Central Register of Controlled Trials electronic databases were searched for human studies [randomized controlled trials (RCTs) and observational studies] using the PICO format (P: patients on clopidogrel; I: patients treated with PPI; C: patients without PPI treatment; O: cardiovascular risk). We screened eligible studies from 2009 to 2016. After study exclusions, we extracted data from 27 articles for three outcomes: major adverse cardiac event (MACE), myocardial infarction (MI) and cardiovascular (CV) death. The meta-analysis was registered on PROSPERO (CRD42017054316). Results: Data were extracted on 156,823 patients from the 27 trials included (MACE: 23, CV death: 10, MI: 14). The risks of MACE (RR = 1.22, 95% CI = 1.06-1.396, p = 0.004) and MI (RR = 1.43, 95% CI = 1.24-1.66, p<0.001) were significantly higher in the PPI plus clopidogrel group. However, subgroup analysis demonstrated that this significance disappeared in RCTs (RR = 0.99, 95% CI = 0.76-1.28, p = 0.93) in the MACE outcome group. There was no effect of combined PPI and clopidogrel therapy on CV death outcome (RR = 1.21, 95% CI = 0.97-1.50, p = 0.09). Conclusion: Concomitant use of PPIs and clopidogrel has been proved not to be associated with elevated cardiovascular risks according to RCTs. Based on our results, no restrictions should be applied whenever PPIs and clopidogrel are administered simultaneously.

 

 

3) AHA

 

For clinicians uncertain how to address this drug interaction in practice, I propose 3 simple steps:

1. Evaluate the necessity of PPI therapy. Although PPIs are necessary for some patients, many others take the drugs for dubious indications. In these patients, treatment with a histamine H2 antagonist or antacid may suffice.
2. Consider using pantoprazole when a PPI is indicated. This suggestion stems from the observation that pantoprazole is less likely than omeprazole to inhibit CYP2C19,21 does not appear to attenuate the pharmacodynamic response to clopidogrel,10,13 and displayed no association with recurrent myocardial infarction in a large observational study of patients receiving clopidogrel.14 Other PPIs may also be relatively safe, but more data are needed. Lansoprazole is the most potent CYP2C19 inhibitor and is probably best avoided.21
3. Stagger the dosing of medications. This is perhaps the most important strategy and exploits the rapid metabolism of clopidogrel and the transient nature of PPI-mediated CYP2C19 inhibition. When dual therapy is necessary, taking a PPI at least 4 hours after clopidogrel should minimize the risk of interaction.

 

 

 

 

4) PPI별 CYP2C19 억제여부

Expert opinion on drug metabolism & toxicology &nbsp;14.4 (2018): 447-460.

 

 

Expert opinion on drug metabolism & toxicology &nbsp;10.2 (2014): 175-189.

 

 

성분명	상품명
Omeprazole
Esomeprazole
Pantoprazole
Lansoprazole
Rabeprazole

 

 

 

 

reference:

1) uptodate

2) Demcsak, Alexandra, et al. "PPIs are not responsible for elevating cardiovascular risk in patients on clopidogrel—a systematic review and meta-analysis." Frontiers in physiology 9 (2018): 417222.

3) https://doi.org/10.1161/CIRCULATIONAHA.109.907295Circulation. 2009;120:2310–2312

4) El Rouby, Nihal, John J. Lima, and Julie A. Johnson. "Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine." Expert opinion on drug metabolism & toxicology 14.4 (2018): 447-460.

5) Scott, Stuart A., Aniwaa Owusu Obeng, and Jean-Sébastien Hulot. "Antiplatelet drug interactions with proton pump inhibitors." Expert opinion on drug metabolism & toxicology 10.2 (2014): 175-189.