Pharmaco-epidemiology as a Tool in Pharmacovigilance: Studying cancer as adverse drug reaction

Pharmacovigilance is defined by the World Health Organization (WHO) as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other possible drug-related problem. There has been concern about the safety of medicines since the discovery of congenital abnormalities in babies delivered by women who had taken thalidomide during pregnancy in 1961. An adverse drug reaction is defined as a response to a medicinal product which is noxious and unintended and which occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the restoration or modification of physiological function. Two types of adverse drug reactions are distinguished: type A reactions which are predictable from the known pharmacology of the medical substance and which are dose-dependent, and type B reactions which are idiosyncratic and unpredictable. It is clear that this is a very crude distinction which is, however, useful from the point of view of discovering unknown adverse reactions as early as possible. During drug development, the efficacy and safety of the active substance is investigated in clinical trials in a relatively small selected homogenous patient population, during a limited period of time. As around 80% of the adverse drug reactions is estimated to be of type A, a large number of the potential adverse drug reactions is documented during the clinical phase. After regulatory review and approval, during which all available information is reviewed, the marketing phase starts. Through marketing, the product is available for the entire population which is obviously far more heterogeneous than the study population. In contrast to the limited timeframe available during the clinical drug development phase, the post-marketing phase continues until the drug is withdrawn from the market. As a consequence, previously unknown adverse drug reactions might come to light, especially those of type B. Therefore, the obligation for the marketing authorization holder, as well as for regulatory authorities, for the continuous evaluation of safety and efficacy during the post marketing phase of a drug, have been legally laid down

No association between blood-based markers of immune system and migraine status:a population-based cohort study

Background: Although some evidence implicates the immune system in migraine attacks, its role during attack-free periods remains largely unexplored. Therefore, we assessed the association between the immune system and migraine status. Methods: From the population-based Rotterdam Study, we included 6593 participants who underwent blood sampling and migraine assessments. In the blood samples, we measured white blood-cell-based immune markers. As a marker for the innate immune system, granulocyte and platelet counts were determined, whereas lymphocyte counts were used as a marker for the adaptive immune system. Migraine was assessed using a validated questionnaire based on ICHD-2 criteria. We investigated associations between blood-cell counts and migraine using logistic regression models adjusting for age, sex and other variables. Results: Mean age of participants was 65.6 ± 11.2 years and 56.7% were female. The lifetime prevalence of migraine was 15.1% (995/6593). We found no statistically significant associations between granulocyte (odds ratio [OR] per standard deviation increase 1.01 95% Confidence Interval [CI]: 0.93–1.09), platelet (OR 1.01 CI: 0.94–1.09) or lymphocyte counts (OR 1.01 CI: 0.93–1.08) and migraine status.Conclusions: Our results do not support an association between white blood-cell-based immunity markers and migraine status.</p

Under-representation of elderly in clinical trials: An analysis of the initial approval documents in the Food and Drug Administration database

Aims: To evaluate the availability of pharmacokinetic, safety and efficacy analyses specifically targeted at elderly, prior to the authorization of drugs. Methods: A cross‐sectional, structured review of publicly available initial approval documents of Food and Drug Administration‐approved drugs was performed. The 10 most frequently on‐label prescribed drug classes, drugs with known pharmacokinetic differences in the elderly or drugs that are relatively contraindicated in elderly (e.g. anticholinergics or benzodiazepines) were included in the analyses. Results: In total, 1129 unique active pharmaceutical ingredients were found eligible for the analyses, of

Reference values for white blood-cell-based inflammatory markers in the Rotterdam Study

Novel prognostic inflammatory markers of cancer survival and cardiovascular disease are; the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR) and the systemic immune-

Isotretinoin exposure during pregnancy: A population-based study in the Netherlands

Objective: To estimate isotretinoin exposure in Dutch pregnant women despite the implemented pregnancy prevention programme (PPP) and second, to analyse the occurrence of adverse fetal or neonatal outcomes in these isotretinoin exposed pregnancies.Design: Population-based study.Setting: The Netherlands.Participants: A cohort of 203 962

Pathology-confirmed versus non pathology-confirmed cancer diagnoses: incidence, participant characteristics, and survival

Cancer diagnoses which are not confirmed by pathology are often under-registered in cancer registries compared to pathology-confirmed diagnoses. It is unknown how many patients have a non pathology-confirmed cancer diagnosis, and whether their characteristics and survival differ from patients with a pathology-confirmed diagnosis. Participants from the prospective population-based Rotterdam Study were followed between 1989 and 2013 for the diagnosis of cancer. Cancer diagnoses were classified into pathology-confirmed versus non pathology-confirmed (i.e., based on imaging or tumour markers). We compared participant characteristics and the distribution of cancers at different sites. Furthermore, we investigated differences in overall survival using survival curves adjusted for age and sex. During a median (interquartile range) follow-up of 10.7 (6.3–15.9) years, 2698 out of 14,024 participants were diagnosed with cancer, of which 316 diagnoses (11.7%) were non pathology-confirmed. Participants with non pathology-confirmed diagnoses were older, more often women, and had a lower education. Most frequently non pathology-confirmed cancer sites included central nervous system (66.7%), hepato-pancreato-biliary (44.5%), and unknown primary origin (31.2%). Survival of participants with non pathology-confirmed diagnoses after 1 year was lower compared to survival of participants with pathology-confirmed diagnoses (32.6% vs. 63.4%; risk difference of 30.8% [95% CI 25.2%; 36.2%]). Pathological confirmation of cancer is related to participant characteristics and cancer site. Furthermore, participants with non pathology-confirmed diagnoses have worse survival than participants with pathology-confirmed diagnoses. Missing data on non pathology-confirmed diagnoses may result in underestimation of cancer incidence and in an overestimation of survival in cancer registries, and may introduce bias in aetiological research

Dietary mineral intake and lung cancer risk: the Rotterdam Study

Objective: Limited data are available on the role of mineral intake in the development of lung cancer (LC). We investigated whether dietary calcium, copper, iron, magnesium, selenium and zinc intake were associated with LC risk. Methods: We analyzed data from 5435 participants of the Rotterdam Study, a prospective population-based cohort study among subjects aged 55 years and older. At baseline (1990–1993), diet was measured by a validated food frequency questionnaire. LC events were diagnosed on the basis of pathology data and medical records. Hazard ratios (HRs) on LC for energy-adjusted mineral intake were calculated using Cox regression models while adjusting for potential confounders. Results: During a follow-up period of 22 years, we identified 211 incident cases of LC. A higher zinc intake was associated with 42 % reduction in risk of LC (top tertile vs. first tertile: HR 0.58, 95 % CI 0.35; 0.94, P-for trend = 0.039). Similarly, high intake of iron was associated with reduced risk of LC (top tertile vs. first tertile: HR 0.58, 95 % CI 0.37; 0.92, P-for trend = 0.02

The association of innate and adaptive immunity, subclinical atherosclerosis, and cardiovascular disease in the Rotterdam Study: A prospective cohort study

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is driven by multifaceted contributions of the immune system. However, the dysregulation of immune cells that leads to ASCVD is poorly understood. We determined the association of components of innate and adaptive immunity longitudinally with ASCVD, and assessed whether arterial calcifications play a role in this association. METHODS AND FINDINGS: Granulocyte (innate immunity) and lymphocyte (adaptive immunity) counts were determined 3 times (2002-2008, mean age 65.2 years; 2009-2013, mean age 69.0 years; and 2014-2015, mean age 78.5 years) in participants of the population-based Rotterdam Study without ASCVD at baseline. Participants were followed-up for ASCVD or death until 1 January 2015. A random sample of 2,366 underwent computed tomography at baseline to quantify arterial calcification volume in 4 vessel beds. We studied the association between immunity components with risk of ASCVD and assessed whether immunity components were related to arterial calcifications at baseline. Of 7,730 participants (59.4% women), 801 developed ASCVD during a median follow-up of 8.1 years. Having an increased granulocyte count increased ASCVD risk (adjusted hazard ratio for doubled granulocyte count [95% CI] = 1.78 [1.34-2.37], P < 0.001). Higher granulocyte counts were related to larger calcification volumes in all vessels, most prominently in the coronary arteries (mean difference in calcium volume [mm3] per SD increase in granulocyte count [95% CI] = 32.3 [9.9-54.7], P < 0.001). Respectively, the association between granulocyte count and incident coronary heart disease and stroke was partly mediated by coronary artery calcification (overall proportion mediated [95% CI] = 19.0% [-10% to 32.3%], P = 0.08) and intracranial artery calcification (14.9% [-10.9% to 19.1%], P = 0.05). A limitation of our study is that studying the etiology of ASCVD remains difficult within an epidemiological setting due to the limited availability of surrogates for innate and especially adaptive immunity. CONCLUSIONS: In this study, we found that an increased granulocyte count was associated with a higher risk of ASCVD in the general population. Moreover, higher levels of granulocytes were associated with larger volumes of arterial calcification. Arterial calcifications may explain a proportion of the link between granulocytes and ASCVD

The neutrophil-to-lymphocyte ratio is associated with mortality in the general population: The Rotterdam Study

Inflammation is a risk factor for morbidity and mortality in the elderly. The neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation that integrates the information of the leukocyte differentials into one variable. We aimed to assess whether the NLR is a risk indicator for overall and cause-specific mortality in the general population. We analyzed data (2002–2014) from the Rotterdam Study, a long-standing, population-based, prospective cohort study in a community-dwelling ageing population. The association between the NLR and time to all-cause mortality was assessed with Cox proportional hazard models. We additionally assessed cardiovascular, cancer and other mortality. The multivariable analyses were adjusted for age, gender, socio-economic status (SES), smoking status, body mass index, type 2 diabetes, and history of cancer and cardiovascular disease (CVD). Data of 8715 individuals were included. The mean age was 65.9 years (SD 10.5) and the majority were women (57.1%). The NLR was higher in men, higher age categories, smokers and among individuals with lower SES, prevalent diabetes, or a history of cancer or CVD. During the 11.7 years follow-up period, 1641 individual