PMID- 33234119 OWN - NLM STAT- MEDLINE DCOM- 20210211 LR - 20240330 IS - 1741-7015 (Electronic) IS - 1741-7015 (Linking) VI - 18 IP - 1 DP - 2020 Nov 25 TI - Multimorbidity, polypharmacy, and drug-drug-gene interactions following a non-ST elevation acute coronary syndrome: analysis of a multicentre observational study. PG - 367 LID - 10.1186/s12916-020-01827-z [doi] LID - 367 AB - BACKGROUND: The number of patients living with co-existing diseases is growing. This study aimed to assess the extent of multimorbidity, medication use, and drug- and gene-based interactions in patients following a non-ST elevation acute coronary syndrome (NSTE-ACS). METHODS: In 1456 patients discharged from hospital for a NSTE-ACS, comorbidities and multimorbidity (>/= 2 chronic conditions) were assessed. Of these, 698 had complete drug use recorded at discharge, and 652 (the 'interaction' cohort) had drug use and actionable genotypes available for CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, F5, SLCO1B1, TPMT, UGT1A1, and VKORC1. The following drug interactions were investigated: pharmacokinetic drug-drug (DDIs) involving CYPs (CYPs above, plus CYP1A2, CYP2C8, CYP3A4), SLCO1B1, and P-glycoprotein; drug-gene (DGIs); drug-drug-gene (DDGIs); and drug-gene-gene (DGGIs). Interactions predicted to be 'substantial' were defined as follows: DDIs due to strong inhibitors/inducers, DGIs due to variant homozygous/compound heterozygous genotypes, and DDGIs/DGGIs where the constituent DDI/DGI(s) both influenced the victim drug in the same direction. RESULTS: In the whole cohort, 727 (49.9%) patients had multimorbidity. Non-linear relationships between age and increasing comorbidities and decreasing coronary intervention were observed. There were 98.1% and 39.8% patients on >/= 5 and >/= 10 drugs, respectively (from n = 698); women received more non-cardiovascular drugs than men (median (IQR) 3 (1-5) vs 2 (1-4), p = 0.014). Overall, 98.7% patients had at least one actionable genotype. Within the interaction cohort, 882 interactions were identified in 503 patients (77.1%), of which 346 in 252 patients (38.7%) were substantial: 59.2%, 11.6%, 26.3%, and 2.9% substantial interactions were DDIs, DGIs, DDGIs, and DGGIs, respectively. CYP2C19 (49.5% of all interactions) and SLCO1B1 (18.4%) were involved in the largest number of interactions. Multimorbidity (p = 0.019) and number of drugs (p = 9.8 x 10(-10)) were both associated with patients having >/= 1 substantial interaction. Multimorbidity (HR 1.76, 95% CI 1.10-2.82, p = 0.019), number of drugs (HR 1.10, 95% CI 1.04-1.16, p = 1.2 x 10(-3)), and age (HR 1.05, 95% CI 1.03-1.07, p = 8.9 x 10(-7)), but not drug interactions, were associated with increased subsequent major adverse cardiovascular events. CONCLUSIONS: Multimorbidity, polypharmacy, and drug interactions are common after a NSTE-ACS. Replication of results is required; however, the high prevalence of DDGIs suggests integrating co-medications with genetic data will improve medicines optimisation. FAU - Turner, R M AU - Turner RM AD - Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, L69 3GL, UK. Richard.Turner@liverpool.ac.uk. FAU - de Koning, E M AU - de Koning EM AD - Franciscus Gasthuis & Vlietland, Rotterdam, the Netherlands. FAU - Fontana, V AU - Fontana V AD - Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, L69 3GL, UK. FAU - Thompson, A AU - Thompson A AD - Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, L69 3GL, UK. FAU - Pirmohamed, M AU - Pirmohamed M AD - Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, L69 3GL, UK. LA - eng GR - G1000417/MRC_/Medical Research Council/United Kingdom GR - MR/L006758/1/MRC_/Medical Research Council/United Kingdom GR - MR/S000933/1/MRC_/Medical Research Council/United Kingdom GR - Department of Health [UK]/International PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20201125 PL - England TA - BMC Med JT - BMC medicine JID - 101190723 SB - IM MH - Acute Coronary Syndrome/*diet therapy MH - Aged MH - Cohort Studies MH - Drug Interactions MH - Female MH - Humans MH - Male MH - Middle Aged MH - Multimorbidity/*trends MH - Non-ST Elevated Myocardial Infarction/*drug therapy MH - Pharmacogenetics/*methods MH - Polypharmacy MH - Prospective Studies PMC - PMC7687685 OTO - NOTNLM OT - Acute coronary syndrome OT - Interactions OT - Multimorbidity OT - Pharmacogenomics OT - Polypharmacy COIS- MP receives other research funding from various organisations including the EU Commission and NIHR. He has also received partnership funding for the following: MRC Clinical Pharmacology Training Scheme (co-funded by MRC and Roche, UCB, Eli Lilly and Novartis); a PhD studentship jointly funded by EPSRC and Astra Zeneca; and grant funding from Vistagen Therapeutics. He has also unrestricted educational grant support for the UKP harmacogenetics and Stratified Medicine Network from Bristol-Myers Squibb and UCB. He has developed an HLA genotyping panel with MC Diagnostics, but does not benefit financially from this. None of these of additional funding sources have been used for the current paper. The other authors declare that they have no competing interests. EDAT- 2020/11/26 06:00 MHDA- 2021/02/12 06:00 PMCR- 2020/11/25 CRDT- 2020/11/25 05:31 PHST- 2020/06/30 00:00 [received] PHST- 2020/10/27 00:00 [accepted] PHST- 2020/11/25 05:31 [entrez] PHST- 2020/11/26 06:00 [pubmed] PHST- 2021/02/12 06:00 [medline] PHST- 2020/11/25 00:00 [pmc-release] AID - 10.1186/s12916-020-01827-z [pii] AID - 1827 [pii] AID - 10.1186/s12916-020-01827-z [doi] PST - epublish SO - BMC Med. 2020 Nov 25;18(1):367. doi: 10.1186/s12916-020-01827-z.