Satu J. Siiskonen

The effect of discontinuation of antihypertensives on the risk of acute myocardial infarction and stroke

ABSTRACT Objective: Adherence to antihypertensive drug treatment is suboptimal. The present study investigates the effect of early treatment discontinuation with antihypertensive drugs on the risk of acute myocardial infarction (AMI) or stroke in daily clinical practice. Methods: In the PHARMO Record Linkage System, which includes all records of drug dispensings and hospitalisations for ≥2 million subjects in the Netherlands, new users of antihypertensive (AHT) drugs ≥18 years of age were studied during the period 1 January 1993 – 1 October 2002 to determine the risk of AMI or stroke related to persistence with AHT. Patients were initially followed for 2 years to determine persistence with AHT, and then for a further 2 years or until the first hospital admission for AMI or stroke, death, or end of the study period. Patients using AHT for secondary prevention of cardiovascular disease were excluded from the study cohort. Results: The study cohort included 77 193 AHT users. The percentage of non-persistent patients was 55% at 2 years, with the lowest non-persistence rates for angiotensin-receptor blockers (ARBs) and ACE-inhibitors (40%) and the highest rates for β-blockers, calcium-channel blockers (CCBs) and diuretics (54–61%). Non-persistent AHT use was associated with a 15% increased risk of AMI (RR 1.15; 95% CI 1.00–1.33) and a 28% increased risk of stroke (RR 1.28; 95% CI 1.15–1.45). Conclusions: The results of this study show that in daily clinical practice early discontinuation of antihypertensive drug treatment in primary prevention increases the risk of subsequent AMI or stroke.

Effect of persistent use of antihypertensives on blood pressure goal attainment

ABSTRACT Objective: Discontinuation rates with antihypertensive drugs in real life are high. The present study investigates the relationship between persistence with antihypertensive drugs (AHT) and blood pressure (BP) goal attainment in daily clinical practice. Methods: In the PHARMO Record Linkage System, which includes drug dispensing and hospital records for > 2 million inhabitants in the Netherlands, new users of AHT ≥ 18 years were identified for the period 1999–2004. Patients with elevated blood pressure (systolic BP ≥140 and/or diastolic BP ≥ 90 mmHg) within 6 months prior to onset of AHT treatment and a BP measurement within 6–12 months of treatment onset were included in the study cohort. Persistent AHT use was determined by summing the number of days of continuous treatment (gap between dispensings < 30 days) from start of treatment onwards. Patients with a BP below 140/90 mmHg at the first BP measurement within 6–12 months of treatment onset were defined as having attained goal. Results: The study included 1271 patients with a mean systolic BP of 174 ± 22 mmHg and a mean diastolic BP of 100 ± 12 mmHg. Persistent AHT use was associated with a 40% increased chance of BP goal attainment (RRadj = 1.41; 95% CI: 1.08–1.85) after adjustment for gender, age, systolic blood pressure at start, and time to the BP measurement. Conclusion: Persistent use of AHT leads to increased blood pressure goal attainment in daily clinical practice.

A genome-wide association study of cutaneous squamous cell carcinoma among European descendants

Background: No GWAS on the risk of cutaneous squamous cell carcinoma (SCC) has been published. We conducted a multistage genome-wide association study (GWAS) to identify novel genetic loci for SCC. Methods: The study included 745 SCC cases and 12,805 controls of European descent in the discovery stage and 531 SCC cases and 551 controls of European ancestry in the replication stage. We selected 64 independent loci that showed the most significant associations with SCC in the discovery stage (linkage disequilibrium r2 < 0.4) for replication. Results: Rs8063761 in the DEF8 gene on chromosome 16 showed the strongest association with SCC (P = 1.7 × 10−9 in the combined set; P = 1.0 × 10−6 in the discovery set and P = 4.1 × 10−4 in the replication set). The variant allele of rs8063761 (T allele) was associated with a decreased expression of DEF8 (P = 1.2 × 10−6). Besides, we validated four other SNPs associated with SCC in the replication set, including rs9689649 in PARK2 gene (P = 2.7 × 10−6 in combined set; P = 3.2 × 10−5 in the discovery; and P = 0.02 in the replication), rs754626 in the SRC gene (P = 1.1 × 10−6 in combined set; P = 1.4 × 10−5 in the discovery and P = 0.02 in the replication), rs9643297 in ST3GAL1 gene (P = 8.2 × 10−6 in combined set; P = 3.3 × 10−5 in the discovery; and P = 0.04 in the replication), and rs17247181 in ERBB2IP gene (P = 4.2 × 10−6 in combined set; P = 3.1 × 10−5 in the discovery; and P = 0.048 in the replication). Conclusion: Several genetic variants were associated with risk of SCC in a multistage GWAS of subjects of European ancestry. Impact: Further studies are warranted to validate our finding and elucidate the genetic function of these variants. Cancer Epidemiol Biomarkers Prev; 25(4); 714–20. ©2016 AACR.

BclI glucocorticoid receptor polymorphism and smoking in the general population

We studied the hypothesis that the BclI polymorphism of the glucocorticoid receptor gene is associated with an increased probability of being a (heavy) smoker and a decreased ability to quit smoking. The study cohort consisted of all subjects in the Rotterdam Study, a Dutch population‐based cohort of people aged 55 years and older, for whom BclI genotyping and smoking status at baseline were available. In prospective analyses, the smoking status was reassessed during three additional examination rounds. Logistic regression analysis was used to study the association between BclI polymorphism and being a smoker or a heavy smoker at baseline. Furthermore, the relationship between BclI polymorphism and incident smoking cessation was tested with Cox proportional hazards analysis within those who smoked at baseline. In total, 6358 subjects were included in the study. The presence of a G‐allele was not associated with current smoking at baseline [odds ratio (OR) = 0.96, 95%confidence interval (CI): 0.85–1.09] or with the incidence of smoking cessation during follow‐up [hazard ratio (HR) = 0.98, 95%CI: 0.80–1.19]. Within current smokers, having a G‐allele was not significantly associated with the risk of being a heavy smoker when measured by pack‐years smoked (OR = 1.07, 95%CI: 0.85–1.35) or daily consumption of tobacco (OR = 1.10, 95%CI: 0.88–1.37). We were not able to replicate the earlier findings indicating that the proportion of current smokers is lower among carriers of the CC‐genotype of the BclI glucocorticoid receptor. Furthermore, the BclI glucocorticoid receptor polymorphism did not predict the incidence of smoking cessation in the general elderly population.

Alcohol Intake is Associated with Increased Risk of Squamous Cell Carcinoma of the Skin: Three US Prospective Cohort Studies.

ABSTRACT The association between alcohol intake and cutaneous squamous cell carcinoma (cSCC) is unclear. We studied the association between alcohol intake and incident invasive cSCC in three cohorts of women and men with repeated assessments of alcohol intake in the US. Information on alcohol intake was collected repeatedly during follow-up. Cumulative average of alcohol intakes was used. Multivariable Cox proportional hazards models with time-dependent exposure were used to estimate relative risks (RRs) and 95% confidence intervals, followed by a meta-analysis. During a follow-up of 4,234,416 person-years, 2,938 cSCC were identified. Alcohol intake was associated with an increased risk of cSCC with a dose-response relationship. Each additional drink (12.8 gram of alcohol) per day was associated with a 22% increased risk of cSCC (RR 1.22, 95% confidence interval: 1.13–1.31). White wine consumption of ≥5 times/wk was associated with an increased risk of cSCC (RR 1.31, 95% confidence interval: 1.09–1.59). We found no increased risk of cSCC with other alcoholic beverages. The population-attributable risk associated with alcohol intake of ≥20 grams/d was 3% of cSCCs. In conclusion, alcohol intake was associated with an elevated risk of cSCC. Among alcoholic beverages, white wine was associated with cSCC.

PCV5 NON-PERSISTENT USE OF ANTIHYPERTENSIVE DRUGS INCREASES RISK OF HOSPITALIZATIONS FOR STROKE BY NEARLY 20%

PCV5 NON-PERSISTENT USE OF ANTIHYPERTENSIVE DRUGS INCREASES RISK OF HOSPITALIZATIONS FOR STROKE BY NEARLY 20% Breekveldt-Postma NS, Siiskonen SJ, Penning-van Beest FJA, Erkens JA,Vincze G, Falvey H, Herings RMC PHARMO Institute, Utrecht,The Netherlands, Novartis Pharma AG, Basel, Switzerland OBJECTIVES: Low persistence with antihypertensive drug treatment (AHT) is expected to limit patient’s benefits in terms of a reduction of cardiovascular and cerebrovascular disease. This study investigated the relationship between persistence with antihypertensive drugs and the risk of stroke in clinical practice. METHODS: From the PHARMO Record Linkage System comprising, among others, linked drug-dispensing and hospital records of >2 million inhabitants in The Netherlands, new users of AHT were identified in the period 1993–2002. Persistence with AHT was determined by summing the number of days of continuous treatment (gaps between dispensings of <60 days). Patients were classified as persistent if they remained on AHT for at least two years. The outcome of interest was the first hospital admission for stroke occurring two or more years after initiation of AHT therapy. Patients were classified as high, intermediate or low cardiovascular risk based on other cardiovascular drug use and hospitalizations during the first two years of follow-up. RESULTS: The study included 98,485 patients of whom 16% were at high cardiovascular risk. About 50% (n = 48,548) of all patients were persistent with AHT for two years, and 2.1% (n = 2093) were hospitalized for stroke in the period of two or more years after initiation of AHT therapy. Multivariate analyses showed that non-persistent users of AHT had a 16%–19% increased risk for stroke compared to persistent users (Low/intermediate risk group RRadj = 1.19; 95% CI: 1.07–1.32; high risk group RRadj = 1.16; 95% CI: 0.97–1.39). CONCLUSION: In clinical practice antihypertensive drug treatment is used over too short a time interval to have maximum benefit from preventing stroke.