Guest Post: Identifying Interactions to Prevent Life-Threatening Complications
This guest post provided by pharmacists at St. Paul’s Hospital and Burnaby Hospital examines a fatal case whereby an overlooked drug interaction is believed to have contributed to a heart attack in a 65-year-old patient. It highlights the vital role pharmacists in community and hospital settings have in identifying interactions between antiretroviral and cardiac medications to prevent life-threatening complications. For support in managing drug interactions with antiretrovirals, pharmacists can call St. Paul’s Hospital Ambulatory Pharmacy at 1-888-511-6222 to consult with an HIV pharmacist.
A 65-year-old male with HIV, coronary artery disease, atrial fibrillation, hypertension, and dyslipidemia underwent an elective outpatient percutaneous coronary intervention (PCI) at a cardiac catheterization laboratory in the Lower Mainland. His HIV was well controlled on an antiretroviral regimen consisting of abacavir/lamivudine, atazanavir, and ritonavir. Following insertion of 3 drug-eluting stents, the patient was provided with prescriptions for clopidogrel 75mg daily for 1 year and dabigatran 110mg bid (dose decrease from 150mg bid) as standard care post-PCI for preventing stent thrombosis, which were filled by his community pharmacy.
Twenty-three days post-PCI, the patient was admitted after a fall. He reported adherence to his medications (including clopidogrel, dabigatran, and his antiretrovirals), which were continued in hospital. Three days into his admission, he experienced acute severe retrosternal discomfort. His troponin was over 22,000 ng/L (reference: <20 ng/L) and ECG showed evidence of an acute myocardial infarction (MI).
While pending repeat angiogram, a clinical pharmacist identified a drug-drug interaction (DDI) between clopidogrel and ritonavir, where ritonavir significantly reduces clopidogrel’s effect on inhibiting platelet aggregration. Given the concern of an acute MI and potential stent thrombosis, clopidogrel was switched to prasugrel and the infectious diseases service was consulted to reassess the antiretroviral regimen. The DDI was reported to the BC Centre for Excellence in HIV/AIDS and his antiretrovirals were changed to bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy). Unfortunately, the patient quickly deteriorated from post-MI complications and did not survive. Thrombosis of the recently inserted cardiac stents from suboptimal antiplatelet activity (due to the ritonavir—clopidogrel DDI) was suspected to have contributed to the MI.
Clopidogrel is a pro-drug that is bioactivated by a 2 step metabolic process involving CYP2C19, CYP3A4, and other cytochrome P450 enzymes.1-3 Inhibitors of these enzymes are expected to diminish concentrations of clopidogrel’s active metabolite, resulting in reduced antiplatelet activity1,4,5. Ritonavir, used for its potent CYP inhibition properties to boost serum antiretroviral concentrations,6 has been shown to significantly decrease concentrations of clopidogrel’s active metabolite and reduce platelet inhibition,7 leading to insufficient platelet inhibition in over 40% of patients.8
Though the reduced efficacy of clopidogrel may be acceptable in some cases, adequate antiplatelet therapy is critical in reducing the risk of stent thrombosis, the most serious complication following PCI. Stent thrombosis accounts for 20% of MIs that occur post-PCI and is associated with mortality rates of over 40%.9,10 Post-PCI, the risk of stent thrombosis is highest within the first month and declines thereafter;11 however, stent thrombosis can occur even after 1-year post-PCI.10
Cases of stent thrombosis have been reported to occur in patients receiving clopidogrel and ritonavir;12,13 DDI resources accordingly advise against the concomitant use of ritonavir and clopidogrel.14,15 The clopidogrel-ritonavir DDI can be resolved by switching the antiplatelet agent or the antiretroviral regimen. Ticagrelor is an antiplatelet agent metabolized by CYP3A4 and is contraindicated in the presence of strong CYP3A4 inhibitors such as ritonavir, due to the risk of increased drug levels and bleeding14,15. Prasugrel is an antiplatelet agent that is not expected to significantly interact with boosted antiretrovirals;8,14,15 it is also a regular benefit on the BC PharmaCare formulary. Due to an increased risk of bleeding, prasugrel is not recommended in people ≥75 years or <60kg and is contraindicated in patients with a history of transient ischemic attack (TIA) or stroke 16,17. For patients with atrial fibrillation requiring ongoing anticoagulation for stroke prevention who also require antiplatelet therapy post-PCI, guidelines recommend clopidogrel as the P2Y12 inhibitor of choice for double therapy11.
The optimal management of this DDI would have been the identification of the interaction following the initial PCI and notification of the prescriber of antiretrovirals, resulting in a prompt change to a regimen that does not contain ritonavir or cobicistat (an alternative pharmacokinetic booster). As of 2020, antiretrovirals dispensed to outpatients in BC appear on PharmaNet; pharmacists should carefully screen for DDIs in any patient receiving antiretrovirals, particularly when the regimen contains ritonavir or cobicistat. Whenever possible, HIV-specific resources, such as the Toronto HIV/HCV Drug Therapy Guide (https://hivclinic.ca/app/) or University of Liverpool (https://hiv-druginteractions.org/checker), should be used. For any outstanding concerns or questions, pharmacists can always call St. Paul’s Hospital Ambulatory Pharmacy at 1-888-511-6222 to consult with an HIV pharmacist.
The clopidogrel-ritonavir DDI in this case was identified as a contributor to the MI that led to this patient’s death. Pharmacists should be aware of the serious consequences of this interaction and always alert the prescriber(s) of this DDI, especially within the first 3-6 months post-PCI.
Erin Ready, BSc(Pharm), ACPR, MPH, AAHIVP
Clinical Pharmacy Specialist, HIV
St. Paul’s Hospital Ambulatory Pharmacy
Doson Chua, BSc(Pharm), PharmD, FCSHP, BCPS, BCCP
Interim Clinical Pharmacy Supervisor
Clinical Pharmacy Specialist, Cardiology
St. Paul’s Hospital
Osric Sin, BSc(Pharm), ACPR
St. Paul’s Hospital Ambulatory Pharmacy
Elaine Tung, BSc, BSc(Pharm), ACPR
Clinical Pharmacy Specialist
- Nhean S, Tseng A, Back D. The intersection of drug interactions and adverse reactions in contemporary antiretroviral therapy. Curr Opin HIV AIDS. 2021;16:292–302.
- Lee CH, Franchi F, Angiolillo DJ. Clopidogrel drug interactions: a review of the evidence and clinical implications. Expert Opin Drug Metab Toxicol. 2020;16(11):1079-1096.
- Sibbing D, Kastrati A. Risk of combining PPIs with thienopyridines: fact or fiction? Lancet. 2009;374:952-954.
- Bates ER, Lau WC, Angiolillo DJ. Clopidogrel-drug interactions. JACC. 2011; 57(11):1251-1263.
- Giguere P, Nhean S, Tseng A, et al. Getting to the heart of the matter: a review of drug interactions between HIV antiretrovirals and cardiology medications. Can J Cardiol. 2019;35(3): 326-340.
- Tseng A, Hughes CA, Wu J, et al. Cobicistat versus ritonavir: similar pharmacokinetic enhancers but some important differences. Ann Pharmacother. 2017; 51(11):1008-1022.
- Itkonen MK, Tornio A, Lapatto-Reiniluoto O, et al. Clopidogrel increases dasabuvir exposure with or without ritonavir, and ritonavir inhibits the bioactivation of clopidogrel. Clin Pharmacol Ther. 2019;105(1):219-228.
- Marsousi N, Daali Y, Fontana P, et al. Clin Pharmacokinet. Impact of boosted antiretroviral therapy on the pharmacokinetics and efficacy of clopidogrel and prasugrel active metabolites. 2018;57(10):1347-1354.
- Claessen BE, Henriques JPS, Jaffer FA, et al. Stent thrombosis: a clinical perspective. JACC Cardiovasc Interv. 2014;7(10):1081-1092.
- Gori T, Polimeni A, Indolfi C, et al. Predictors of stent thrombosis and their implications for clinical practice. Nat Rev Cardiol. 2019;16(4):243-256.
- Mehta SM, Bainey KR, Cantor WJ, et al. 2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Focused Update of the Guidelines for the Use of Antiplatelet Therapy. Can J Cardiol. 2018;34:214-233.
- Carvalho AS, Osório Valente, Almeida Morais L, et al. HIV and coronary disease - when secondary prevention is insufficient. Rev Port Cardiol. 2017;36(7-8):569.e1-569.e8.
- Bravo I, Álvarez H, Mariño A, et al. Recurrent coronary disease in HIV‐infected patients: role of drug–drug interactions. Br J Clin Pharmacol. 2018; 84(7):1617–1619.
- HIV/HCV Drug Therapy Guide. UHN- Toronto General Hospital, Immunodeficiency Clinic; 2022 [cited 2023 May 04]. Available from: https://app.hivclinic.ca/
- HIV Drug Interactions. University of Liverpool; 2023 [cited 2023 May 04]. Available from: https://www.hiv-druginteractions.org/
- Kamran H, Jneid H, Kayani WT, et al. Oral Antiplatelet Therapy After Acute Coronary Syndrome: A Review. JAMA. 2021;325(15):1545–1555.
- JAMP Prasugrel. Product Monograph; 2020. [cited 2023 May 04]. Available from: https://pdf.hres.ca/dpd_pm/00057073.PDF