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Cessation of dual antiplatelet therapy and cardiovascular events following acute coronary syndrome

Mazlan-Kepli W, Dawson J, Berry C, Walters M

Heart, 2019 01;105(1):67-74.
PMID: 30030335 DOI: 10.1136/heartjnl-2018-313148

OBJECTIVE: To assess whether cardiovascular events are increased after cessation of dual antiplatelet therapy (DAPT) following acute coronary syndrome (ACS) and to explore predictors for recurrent events after DAPT cessation during long-term follow-up.
METHODS: We did a retrospective observational cohort study. We included consecutive people with ACS who were discharged from Scottish hospitals between January 2008 and December 2013 and who received DAPT after discharge followed by antiplatelet monotherapy. The rates of cardiovascular events were assessed during each 90-day period of DAPT treatment and 90-day period after stopping DAPT. Cardiovascular events were defined as a composite of death, ACS, transient ischaemic attack or stroke. Cox regression was used to identify predictors of cardiovascular events following DAPT cessation.
RESULTS: 1340 patients were included (62% male, mean age 64.9 (13.0) years). Cardiovascular events occurred in 15.7% (n=211) during the DAPT period (mean DAPT duration 175.1 (155.3) days) and in 16.7% (n=188) following DAPT cessation (mean of 2.7 years follow-up). Independent predictors for a cardiovascular event following DAPT cessation were age (HR 1.07; 95% CI 1.05 to 1.08; p<0.001), DAPT duration (HR 0.997; 95% CI 0.995 to 0.998; p<0.001) and having revascularisation therapy during the index admission (HR 0.58; 95% CI 0.39 to 0.85; p=0.005).
CONCLUSIONS: The rate of cardiovascular events was not significantly increased in the early period post-DAPT cessation compared with later periods in this ACS population. Increasing age, DAPT duration and lack of revascularisation therapy were associated with increased risk of cardiovascular events during long-term follow-up after DAPT cessation.
Fulltext Interruption to antiplatelet therapy early after acute ischaemic stroke: a nested case-control study

Mazlan-Kepli W, Macisaac RL, Walters M, Bath PMW, Dawson J, VISTA Collaborators

Br J Clin Pharmacol, 2017 Sep;83(9):2045-2055.
PMID: 28299795 DOI: 10.1111/bcp.13290

AIMS: Antiplatelet drugs are often discontinued early after ischaemic stroke, either because of poor compliance, complications or withdrawal of care. It is unclear whether this places patients at increased risk of recurrence. We explored the association between cardiovascular event rate and persistence with prescribed antiplatelet drugs.
METHODS: We used a matched case-control design using the Virtual International Stroke Trials Archive (VISTA). Cases were patients who had an acute coronary syndrome, recurrent stroke or transient ischaemic attack within 90 days post-stroke and were matched for age ± 10 years and sex with up to four controls. Antiplatelet use was categorized as persistent (used for >3 days and continued up to day 90), early cessation (used antiplatelet <3 days) or stopped/interrupted users (used for >3 days but stopped prior to day 90). These categories were compared in cases and controls using a conditional logistic regression model that adjusted for potential confounders.
RESULTS: A total of 970 patients were included, of whom 194 were cases and 776 were matched controls. At 90 days, 10 cases (5.2%) and 58 controls (7.5%) stopped/interrupted their antiplatelet. The risk of cardiovascular event was not different in stopped/interrupted users (adjusted odds ratio 0.70, 95% confidence interval 0.33, 1.48; P = 0.352) and early cessations (adjusted odds ratio 1.04, 95% confidence interval 0.62, 1.74; P = 0.876) when compared to persistent users.
CONCLUSION: We found no increased risk in patients who stopped and interrupted antiplatelets early after stroke but the study was limited by a small sample size and further research is needed.
Multiple endocrine neoplasia type 1 (MEN1) in two Asian families

Teh BT, Hii SI, David R, Parameswaran V, Grimmond S, Walters MK, et al.

Hum Genet, 1994 Nov;94(5):468-72.
PMID: 7959678 DOI: 10.1007/bf00211009

Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disease characterized by neoplasia of the parathyroid glands, anterior pituitary and endocrine pancreas, is rarely reported in Asian populations. The MEN1 gene, mapped to chromosome 11q13 but yet to be cloned, has been found to be homogeneous in Caucasian populations through linkage analysis. Here, two previously unreported Asian kindreds with MEN1 are described; linkage analysis using microsatellite polymorphic markers in the MEN1 region was carried out. The first kindred, of Mongolian-Chinese origin, is a multigeneration family with over 150 living members, eight of whom are affected to date. The second kindred is of Chinese origin consisting of four affected members. Linkage to chromosome 11q13 was confirmed in both kindreds, supporting evidence for genetic homogeneity. A recombination in the larger kindred localizes the gene distal to marker D11S956, consistent with its placement from previous studies. We also show that it is feasible to use these markers for predictive testing, as four gene carriers were detected in 13 family members with unknown disease status in the first kindred.
Fulltext Behavioural effects of APH199, a selective dopamine D4 receptor agonist, in animal models

Chestnykh D, Graßl F, Pfeifer C, Dülk J, Ebner C, Walters M, et al.

Psychopharmacology (Berl), 2023 Apr;240(4):1011-1031.
PMID: 36854793 DOI: 10.1007/s00213-023-06347-1

RATIONALE: The dopamine D4 receptors (DRD4) play a key role in numerous brain functions and are involved in the pathogenesis of various psychiatric disorders. DRD4 ligands have been shown to moderate anxiety, reward and depression-like behaviours, and cognitive impairments. Despite a series of promising but ambiguous findings, the therapeutic advantages of DRD4 stimulation remain elusive.
OBJECTIVES: The investigation focused on the behavioural effects of the recently developed DRD4 agonist, APH199, to evaluate its impact on anxiety, anhedonia, behavioural despair, establishment and retrieval of alcohol reinforcement, and amphetamine (AMPH)-induced symptoms.
METHODS: Male C57BL/6 J mice and Sprague-Dawley rats were examined in five independent experiments. We assessed APH199 (0.1-5 mg/kg, i.p.) effects on a broad range of behavioural parameters in the open field (OF) test, conditioned place preference test (CPP), elevated plus maze (EPM), light-dark box (LDB), novelty suppressed feeding (NSF), forced swim test (FST), sucrose preference test (SPT), AMPH-induced hyperlocomotion test (AIH), and prepulse inhibition (PPI) of the acoustic startle response in AMPH-sensitized rats.
RESULTS: APH199 caused mild and sporadic anxiolytic and antidepressant effects in EPM and FST, but no remarkable impact on behaviour in other tests in mice. However, we found a significant increase in AMPH-induced hyperactivity, suggesting an exaggeration of the psychotic-like responses in the AMPH-sensitized rats.
CONCLUSIONS: Our data challenged the hypothesis of the therapeutic benefits of DRD4 agonists, pointing out a possible aggravation of psychosis. We suggest a need for further preclinical studies to ensure the safety of antipsychotics with DRD4 stimulating properties.