Fernie J. A. Penning-van Beest

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.

Three-year dispensing patterns with long-acting inhaled drugs in COPD: A database analysis

BACKGROUND Long-acting muscarinic antagonists (LAMA), long-acting β2-agonists (LABA) and fixed dose combinations (FDC) of inhaled corticosteroids (ICS) and LABA are used as inhaled maintenance therapies for COPD. OBJECTIVE To estimate persistence rates from dispensing patterns of long-acting inhaled drugs for COPD. METHODS From the PHARMO-database, COPD patients starting LAMA, LABA or LABA-ICS FDC between 2002 and 2006 were selected. Persistence with the initial as well as with any long-acting inhaled drug was determined, defined as time between start and stop of initial/any therapy, allowing ≤ 60-days gaps between refills. For patients who did not continue to receive dispensings of the initial therapy for at least one year, the first change in therapy was determined. RESULTS The study included 2201 LAMA, 1201 LABA and 4146 LABA-ICS FDC users. Persistence rates with initial therapy alone at 1, 2, and 3 years were 25%, 14%, 8% for LAMA, 21%, 10%, 6% for LABA and 27%, 14%, 8% for LABA-ICS FDC. Of patients who did not persist with LAMA alone for one year, 15% added and 13% switched therapy (both mostly LABA-ICS FDC). Of patients not persisting with LABA alone, 9% added therapy (mostly LAMA) and 31% switched therapy (mostly to LABA-ICS FDC). In patients not persisting with LABA-ICS FDC, add-on and switch occurred equally frequent (11%, mostly LAMA). Persistence rates with any long-acting drug at 1, 2 and 3 years were 36%, 23% and 17% respectively. CONCLUSION Persistence with the initial as well as with any long-acting inhaled drug in COPD is low, with a substantial proportion of patients changing therapy.

Quality of life in relation to constipation among opioid users.

Abstract Objective: Opioid users often experience constipation. In this study the impact of constipation on QoL was assessed in patients using opioids either for non-advanced illness or advanced illness. Methods: Patients using opioids, recruited via public pharmacies, were asked to complete questionnaires on opioid use, constipation and the EuroQol five-dimension questionnaire (EQ-5D). Patients with a severe non-curable disease and relatively short life-expectancy were classified as having an advanced illness; a disabling yet not directly life-threatening condition was defined as non-advanced illness. Constipation was assessed based on questions on opioid side-effects and laxative use. EQ-5D index scores were compared between patients with and without constipation using Wilcoxon two-samples test. Results: Questionnaires were returned by 588 patients with non-advanced illness, of whom 326 (55%) were classified as having constipation and by 113 patients with advanced illness, of whom 76 (67%) were classified as having constipation. The median EQ-5D index, a weighted health state index score with 1 = full health, was lower in patients with constipation than in patients without constipation (0.31 vs. 0.65, p< 0.01 for non-advanced illness and 0.41 vs. 0.61, p=0.12 for advanced illness). Conclusion: The results of this study suggest that, in patients using opioids either for non-advanced illness or advanced illness, constipation negatively influences QoL. By separately analysing patients with advanced illness and patients with non-advanced illness, possible selective non-response and confounding was accounted for, but not completely solved.

Determinants of non-compliance with bisphosphonates in women with postmenopausal osteoporosis

ABSTRACT Objective: To identify determinants of non-compliance with bisphosphonates in women with postmenopausal osteoporosis. By considering the year of the introduction of weekly bisphosphonates important additional information is obtained. Methods: New female users of daily or weekly alendronate or risedronate between 1999 and 2004, aged ≥ 45 years were identified from PHARMO RLS, including drug-dispensing and hospitalisation data of > 2 million residents of the Netherlands. One-year compliance with bisphosphonates was measured using the Medication Possession Ratio (MPR). To identify determinants of non-compliance, non-compliant women (MPR < 50%) were compared to compliant women (MPR ≥ 80%). The effect of patient age, prescriber, initial dosing regimen, gastrointestinal adverse events, co-medication and fractures on non-compliance was investigated. Results: The study cohort included 8822 new users of bisphosphonates, of whom 5079 (58%) were compliant and 2720 (31%) were non-compliant after 1 year. Only 1023 women (11%) had a MPR between ≥ 50% and < 80%. Daily dosing at start, increased number of co-medications and new use of intestinal agents in the year after starting bisphosphonates were independently associated with an increased odds of non-compliance. In contrast, higher age, first prescription from a specialist, osteoporosis related hospitalisation and use of NSAIDs in the year preceding bisphosphonate therapy decreased the odds of non-compliance. Conclusion: This study revealed several determinants of non-compliance with bisphosphonates, the best controllable being the type of initial bisphosphonate, with daily dosing leading to more non-compliance than weekly dosing. However, compliance for both regimens is suboptimal, pointing to an unmet medical need.

Effect of non-persistent use of oral glucose-lowering drugs on HbA1c goal attainment

ABSTRACT Objectives: The aim of this study was to quantify the effect of non-persistence with oral glucose-lowering drugs (OGLD) on HbA1c goal attainment (< 7%) in daily practice. Methods: From the PHARMO Record Linkage System comprising among others linked drug dispensing and clinical laboratory data from approximately 2.5 million individuals in the Netherlands, new users of OGLD in the period 1999–2004 were identified. Patients with a baseline HbA1c ≥ 7% and at least one HbA1c measurement in the period of 6–12 months after treatment onset were included in the study cohort. Persistence with OGLD in the first year of treatment was determined using the method of Catalan. In case the first treatment episode overlapped the first HbA1c measurement within 6–12 months after treatment onset, a patient was considered persistent at that measurement. Patients with a HbA1c < 7% were defined as having attained goal. Results: The study cohort included 2023 patients with a mean baseline HbA1c of 8.9 ± 1.8%. Three-quarters (1512 patients) were persistent with any OGLD at the first HbA1c measurement within 6–12 months after treatment onset; of these, 861 (57%) were at goal. Of the 511 non-persistent patients, 239 (47%) were at goal. Non-persistent patients were about 20% less likely to attain goal (RRadj 0.82; 95%CI 0.74–0.91), compared to persistent OGLD users. Conclusion: Non-persistent use of OGLD leads to a 20% decreased probability of HbA1c goal attainment in daily practice. This effect of non-persistence seems modest, but represents around 12 000 new and 10 000 prevalent OGLD users a year in the Netherlands in whom OGLD use could be better controlled.

PREVALENCE AND INCIDENCE OF ACUTE AND CHRONIC COMORBIDITY IN PATIENTS WITH SQUAMOUS CELL CARCINOMA OF THE HEAD AND NECK

Limited data exist on the burden of comorbidity among patients with squamous cell head and neck cancer (SCCHN) before and during cancer treatment.

Relationship between duration of compliant bisphosphonate use and the risk of osteoporotic fractures .

ABSTRACT Objectives: To investigate the relationship between duration of compliant bisphosphonate use and the risk of osteoporotic fractures. Methods: The PHARMO database was used to identify new female bisphosphonate users, aged ≥ 45 years or with diagnosed post-menopausal osteoporosis in the period of January 1996 – June 2004. Within this cohort a matched case–control study was performed. Cases were defined as patients who were hospitalized for an osteoporotic fracture and were matched to ten controls without a fracture by duration of follow-up. The duration of compliant bisphosphonate use (i.e., medication possession ratio ≥ 80%) preceding the outcome date was determined. Results: Of 14 760 new female bisphosphonate users, 387 fracture patients fulfilled the inclusion criteria. These cases were matched to 3950 controls. Increasing duration of compliant bisphosphonate use was associated with a decreased risk of fracture (trend p < 0.01). Adjusted for several cofactors, 1–2 years of compliant bisphosphonate use and 3–4 years of compliant bisphosphonate use decreased fracture risk by 12% and 46%, respectively, compared to < 1 year of compliant bisphosphonate use (OR 0.88; 95% CI 0.66–1.18 and OR 0.54; 95% CI 0.35–0.84, respectively). Unexpectedly, 5–6 years of compliant bisphosphonate use was no longer associated with a decreased risk of fractures compared to < 1 year of compliant bisphosphonate use (OR 1.12, 95% CI 0.66–1.88). Conclusions: These results show a direct link between duration of compliant bisphosphonate use and fracture risk, and confirm the importance of continuing the use of bisphosphonates to maintain optimal bone protection. However, this link is inconclusive for bisphosphonate use for more than 4 years.

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.

Overanticoagulation associated with combined use of antifungal agents and coumarin anticoagulants.

Several case reports have associated combined use of coumarins and antifungal agents with overanticoagulation. However, we are not aware of epidemiologic studies that quantify the risk of overanticoagulation caused by antifungal agents. We conducted a follow‐up study in a large population‐based cohort to investigate the antifungal agents that are associated with overanticoagulation during therapy with coumarins.

Quantity and quality of potential drug interactions with coumarin anticoagulants in the Netherlands

ObjectiveCoumarin anticoagulants are prone to potentially life-threatening drug-drug interactions due to a combination of unfavorable properties. However, real life data on the actual occurrence are scarce. The aim of this study was to quantify and qualify potential drug interactions with coumarin anticoagulants in daily practice.MethodsA cohort study including all users of phenprocoumon or acenocoumarol during the period 1991–2003 in the PHARMO Record Linkage System. All 24 individual drugs and 11 drug groups interacting with coumarins according to central database used in the Dutch pharmacies were considered.Main outcome measureFrequency and type of potential drug interactions during anticoagulant therapy with coumarins.Results48,627 out of 76,455 mainly acenocoumarol-users (64%) were dispensed at least one potentially interacting drug (PID) during anticoagulant therapy. About 35% of these cases were dispensed a (very) strongly interacting drug, whereas 3% were dispensed a contraindicated drug. Antibacterial drugs and NSAIDs (39% and 37% of all users, respectively) were the most frequently dispensed PIDs.ConclusionPotential drug interactions with coumarins frequently occur in daily practice, confronting two-thirds of patients with an increased risk of bleeding. To a large part, this is attributable to commonly prescribed medication like antibacterial drugs and NSAIDs. This situation substantiates the need for proper monitoring or new anticoagulants with less drug–drug interactions.