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Multimorbidity, polypharmacy, and drug-drug-gene interactions following a non-ST elevation acute coronary syndrome: analysis of a multicentre observational study.

ABSTRACT: 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?×?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?×?10^-3), and age (HR 1.05, 95% CI 1.03-1.07, p?=?8.9?×?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.

SUBMITTER: Turner RM

PROVIDER: S-EPMC7687685 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Multimorbidity, polypharmacy, and drug-drug-gene interactions following a non-ST elevation acute coronary syndrome: analysis of a multicentre observational study.

Turner R M RM de Koning E M EM Fontana V V Thompson A A Pirmohamed M M

BMC medicine 20201125 1

<h4>Background</h4>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).<h4>Methods</h4>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 'intera ...[more]

PMID: 33234119

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Project description:Background Despite restoration of epicardial flow following primary percutaneous coronary intervention (PPCI), microvascular reperfusion as reflected by ST-elevation resolution (ST-ER) resolution remains variable and its pathophysiology remains unclear. Methods and Results Using principal component analyses, we explored associations between 91 serum biomarkers drawn before PPCI clustered into 14 pathobiologic processes (including NT-proBNP [N-terminal pro-B-type natriuretic peptide] as an independent cluster), and (1) ST-ER resolution ≥50% versus <50%; and (2) 90-day composite of death, shock, and heart failure. Network analyses were performed to understand interbiomarker relationships between the ST-ER groups. Among the 1160 patients studied, 861 (74%) had ST-ER ≥50% at a median 40 (interquartile range, 23-70) minutes following PPCI, yet both groups had comparable post-PPCI TIMI (Thrombolysis in Myocardial Infarction) grade 3 flow (86.6% versus 82.9%; P=0.25). ST-ER ≥50% was associated with significantly lower pre-PPCI concentrations of platelet activation cluster (particularly P-selectin, von Willebrand factor, and platelet-derived growth factor A) and NT-proBNP, including after risk adjustment. Across both ST-ER groups, strong interbiomarker relationships were noted between pathways indicative of myocardial stretch, platelet activation, and inflammation, whereas with ST-ER <50% correlations between iron homeostasis and inflammation were observed. Of all 14 biomarker clusters, only NT-proBNP was significantly associated with the 90-day clinical composite. Conclusions Suboptimal ST-ER is common despite achieving post-PPCI TIMI grade 3 flow. The cluster of platelet activation proteins and NT-proBNP were strongly correlated with suboptimal ST-ER and NT-proBNP was independently associated with 90-day outcomes. This analysis provides insights into the pathophysiology of microvascular reperfusion in ST-segment-elevation myocardial infarction and suggests novel pre-PPCI risk targets potentially amenable to enhancing tissue-level reperfusion following PPCI.

Project description:Background:High survival rates are commonly reported following primary percutaneous coronary intervention for ST-elevation myocardial infarction, with most contemporary studies reporting overall survival.Aims:The aim of this study was to describe survival following primary percutaneous coronary intervention for ST-elevation myocardial infarction corrected for non-cardiovascular deaths by reporting relative survival and investigate clinically significant factors associated with poor long-term outcomes.Methods and results:Using the prospective UK Percutaneous Coronary Intervention registry, primary percutaneous coronary intervention cases ( n=88,188; 2005-2013) were matched to mortality data for the UK populace. Crude five-year relative survival was 87.1% for the patients undergoing primary percutaneous coronary intervention and 94.7% for patients <55 years. Increasing age was associated with excess mortality up to four years following primary percutaneous coronary intervention (56-65 years: excess mortality rate ratio 1.61, 95% confidence interval 1.46-1.79; 66-75 years: 2.49, 2.26-2.75; >75 years: 4.69, 4.27-5.16). After four years, there was no excess mortality for ages 56-65 years (excess mortality rate ratio 1.27, 0.95-1.70), but persisting excess mortality for older groups (66-75 years: excess mortality rate ratio 1.72, 1.30-2.27; >75 years: 1.66, 1.15-2.41). Excess mortality was associated with cardiogenic shock (excess mortality rate ratio 6.10, 5.72-6.50), renal failure (2.52, 2.27-2.81), left main stem stenosis (1.67, 1.54-1.81), diabetes (1.58, 1.47-1.69), previous myocardial infarction (1.52, 1.40-1.65) and female sex (1.33, 1.26-1.41); whereas stent deployment (0.46, 0.42-0.50) especially drug eluting stents (0.27, 0.45-0.55), radial access (0.70, 0.63-0.71) and previous percutaneous coronary intervention (0.67, 0.60-0.75) were protective.Conclusions:Following primary percutaneous coronary intervention for ST-elevation myocardial infarction, long-term cardiovascular survival is excellent. Failure to account for non-cardiovascular death may result in an underestimation of the efficacy of primary percutaneous coronary intervention.

Dataset Information

Multimorbidity, polypharmacy, and drug-drug-gene interactions following a non-ST elevation acute coronary syndrome: analysis of a multicentre observational study.

Publications

Multimorbidity, polypharmacy, and drug-drug-gene interactions following a non-ST elevation acute coronary syndrome: analysis of a multicentre observational study.

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