Statin Intolerance and Risk of Coronary Heart Events and All-Cause Mortality Following Myocardial Infarction.

BACKGROUND: Many patients report adverse reactions to, and may not tolerate, statin therapy. These patients may be at increased risk for coronary heart disease (CHD) events and mortality. OBJECTIVES: This study evaluated the risk for recurrent myocardial infarction (MI), CHD events, and all-cause mortality in Medicare beneficiaries with statin intolerance and in those with high adherence to statin therapy. METHODS: We studied 105,329 Medicare beneficiaries who began a moderate- or high-intensity statin dosage after hospitalization for MI between 2007 and 2013. Statin intolerance was defined as down-titrating statins and initiating ezetimibe therapy, switching from statins to ezetimibe monotherapy, having International Classification of Diseases, 9th revision, diagnostic codes for rhabdomyolysis or an antihyperlipidemic adverse event, followed by statin down-titration or discontinuation, or switching between ≥3 types of statins within 1 year after initiation. High statin adherence over the year following hospital discharge was defined as proportion of days covered ≥80%. Recurrent MI, CHD events (recurrent MI or a coronary revascularization procedure), and mortality were identified from 1 year after hospital discharge through December 2014. RESULTS: Overall, 1,741 patients (1.65%) had statin intolerance, and 55,567 patients (52.8%) had high statin adherence. Over a median of 1.9 to 2.3 years of follow-up, there were 4,450 recurrent MIs, 6,250 CHD events, and 14,311 deaths. Compared to beneficiaries with high statin adherence, statin intolerance was associated with a 36% higher rate of recurrent MI (41.1 vs. 30.1 per 1,000 person-years, respectively), a 43% higher rate of CHD events (62.5 vs. 43.8 per 1,000 person-years, respectively), and a 15% lower rate of all-cause mortality (79.9 vs. 94.2 per 1,000 person-years, respectively). The multivariate-adjusted hazard ratios (HR) comparing beneficiaries with statin intolerance versus those with high statin adherence were 1.50 (95% confidence interval [CI]: 1.30 to 1.73) for recurrent MI, 1.51 (95% CI: 1.34 to 1.70) for CHD events, and 0.96 (95% CI: 0.87 to 1.06) for all-cause mortality. CONCLUSIONS: Statin intolerance was associated with an increased risk for recurrent MI and CHD events but not all-cause mortality.

Prevalence and characteristics of patients with low levels of low-density lipoprotein cholesterol in northern Denmark: a descriptive study.

BACKGROUND: With the emergence of new lipid-lowering therapies, more patients are expected to achieve substantial lowering of low-density lipoprotein cholesterol (LDL-C). However, there are limited data examining the clinical experience of patients with low (<1.3 mmol/L) or very low (<0.65 mmol/L) levels of LDL-C. To provide information on patients with low LDL-C, we identified and characterized persons with low LDL-C using data from Danish medical databases. METHODS: Using a population-based clinical laboratory database, we identified adults with at least one LDL-C measurement in northern Denmark between 1998 and 2011 (population approximately 1.5 million persons). Based on the lowest measurement during the study period, we divided patients into groups with low (<1.3 mmol/L), moderate (1.3-3.3 mmol/L), or high (>3.3 mmol/L) LDL-C. We described their demographic characteristics, entire comorbidity history, and 90-day prescription history prior to the lowest LDL-C value measured. Finally, we further restricted the analysis to individuals with very low LDL-C (<0.65 mmol/L). RESULTS: Among 765,503 persons with an LDL-C measurement, 23% had high LDL-C, 73% had moderate LDL-C, and 4.8% had low LDL-C. In the latter group, 9.6% (0.46% of total) had very low LDL-C. Compared with the moderate and high LDL-C categories, the low LDL-C group included more males and older persons with a higher prevalence of cardiovascular disease, diabetes, chronic pulmonary disease, ulcer disease, and obesity, as measured by hospital diagnoses or relevant prescription drugs for these diseases. Cancer and use of psychotropic drugs were also more prevalent. These patterns of distribution became even more pronounced when restricting to individuals with very low LDL-C. CONCLUSION: Using Danish medical databases, we identified a cohort of patients with low LDL-C and found that cohort members differed from patients with higher LDL-C levels. These differences may be explained by various factors, including prescribing patterns of lipid-lowering therapies.

Off-label topical calcineurin inhibitor use in children.

OBJECTIVE: To assess off-label use of the topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, in children during periods before and after regulatory action by the US Food and Drug Administration (FDA) in 2005. METHODS: We identified new pediatric (age <20 years) users of topical tacrolimus or pimecrolimus in US Medicaid from 2001 to 2009, and examined the annual rate of drug use (pre- and postregulatory action) by age. We assessed medical claims for diagnoses consistent with an indication for a TCI, and assessed prescriptions for evidence of first-line atopic dermatitis therapy use before TCI initiation. RESULTS: There were 57,664 eligible pediatric tacrolimus users and 425,242 eligible pediatric pimecrolimus users at baseline. The rate of TCI use decreased substantially after FDA regulatory action. The proportion of new users younger than 2 years of age significantly decreased for both tacrolimus (36.7% to 22.5%, P < .001) and pimecrolimus (47.0% to 33.7%, P < .001) after regulatory actions. Previous use of topical corticosteroids increased by ≈ 7% for both TCIs from the pre- to postregulatory period. However, after regulatory actions, there was only a small increase in the proportion of tacrolimus or pimecrolimus users with an atopic dermatitis or eczema diagnosis before drug initiation, and high strength use of tacrolimus was unchanged. CONCLUSIONS: The rate of TCI use in children younger than 2 years of age fell substantially after FDA regulatory action in 2005. Off-label use of TCI as first-line therapy changed little.

Non-steroidal anti-inflammatory drug use and the risk of Parkinson's disease.

BACKGROUND: Experimental evidence supports a preventative role for non-steroidal anti-inflammatory drugs (NSAIDs) in Parkinson's disease (PD). METHODS: We investigated associations between use of aspirin, nonaspirin NSAIDs, and acetaminophen and PD in a large population-based case-control study using Danish health and pharmacy registries. We identified 1,931 PD cases reported in hospital or outpatient clinic records who had received a primary diagnosis of PD between 2001 and 2006, and 9,651 age- and sex-matched controls from the Danish population register. Prescription medication use was documented in a pharmacy database covering all residents of Denmark since 1995. RESULTS: Adjusting for age, sex, use of cardiovascular disease drugs, diagnosis of chronic pulmonary obstructive disorder, and Charlson comorbidity scores, and excluding prescriptions filled within 5 years before diagnosis, we found no evidence for an association between PD and either aspirin use (OR = 0.97; 95% CI 0.82, 1.14) or nonaspirin NSAID use (OR = 0.97; 95% CI 0.86, 1.09), regardless of intensity of use; further, there was no association between use of ibuprofen or acetaminophen and PD. CONCLUSION: Our findings provide no evidence for a protective effect of nonaspirin and aspirin NSAID prescription drug use shortly before PD onset.

Characterization of acetaminophen overdose-related emergency department visits and hospitalizations in the United States.

PURPOSE: To estimate the number of acetaminophen overdose-related emergency department (ED) visits and hospitalizations in the United States, characterize these by intentionality, age, and gender, and compare the strengths and limitations of the utilized databases. METHODS: We used data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) and the National Electronic Injury Surveillance System (NEISS) to estimate the number of relevant ED visits in the United States between 2000 and 2007, and the National Hospital Discharge Survey (NHDS) to estimate the number of relevant hospitalizations in the United States between 1991 and 2006. National estimates and their standard errors were calculated using information provided in each database. We used the standard United States population in 2000 to calculate age-adjusted rates. RESULTS: We estimate an annual average of 44,348 (NHAMCS, 2000-2007) or 78,414 (NEISS, 2006-2007) acetaminophen overdose-related ED visits and 33,520 (NHDS, 2000-2006) hospitalizations. For 2000-2006 we calculated an age-adjusted rate of 13.9 acetaminophen overdose-related hospitalizations per 100,000 US population, with the highest rate (15.7) occurring from 2005 to 2006. Between 1991 and 2006, there was no decrease noted in hospitalizations for intentional or unintentional overdoses. The majority of overdoses reported in NEISS (69.8%) and NHDS (74.2%) were classified as intentional (suicides or suicidal gestures), whereas in NHAMCS, intentionality was evenly distributed. CONCLUSIONS: Our results suggest that acetaminophen overdose, both intentional and unintentional, remains a significant public health concern. With an understanding of their methodological characteristics and limitations, these national databases can be useful tools to characterize acetaminophen overdose-related ED visits and hospitalizations.

Statin use and Parkinson's disease in Denmark.

The objective of this study was to investigate whether statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor) use is associated with risk of Parkinson's disease (PD) in Denmark. We identified 1,931 patients with a first time diagnosis of PD reported in hospital or outpatient clinic records between 2001 and 2006. We density matched to these patients 9,651 population controls by birth year and sex relying on the Danish population register. For every participant, we identified pharmacy records of statin and anti-Parkinson drug prescriptions since 1995 and before index date from a prescription medication use database for all Danish residents. Whenever applicable, the index dates for cases and their corresponding controls were advanced to the date of first recorded prescription for anti-Parkinson drugs. In our primary analyses, we excluded all statin prescriptions 2-years before PD diagnosis. Employing logistic regression adjusting for age, sex, diagnosis of chronic obstructive pulmonary disease, and Charlson comorbidity, we observed none to slightly inverse associations between PD diagnosis and statin prescription drug use. Inverse associations with statin use were only observed for short-term (

α-Synuclein gene may interact with environmental factors in increasing risk of Parkinson's disease.

BACKGROUND: Although of great interest and suggested in prior reports, possible α-synuclein (SNCA) gene-environment interactions have not been well investigated in humans. METHODS: We used a population-based approach to examine whether the risk of Parkinson's disease (PD) depended on the combined presence of SNCA variations and two important environmental factors, pesticide exposures and smoking. RESULTS/CONCLUSIONS: Similar to recent meta- and pooled analyses, our data suggest a lower PD risk in subjects who were either homozygous or heterozygous for the SNCA REP1 259 genotype, and a higher risk in subjects who were either homozygous or heterozygous for the REP1 263 genotype, especially among subjects with an age of onset ≤68 years. More importantly, while analyses of interactions were limited by small cell sizes, risk due to SNCA variations seemed to vary with pesticide exposure and smoking, especially in younger onset cases, suggesting an age-of-onset effect.

Paraoxonase 1, agricultural organophosphate exposure, and Parkinson disease.

BACKGROUND: Human, animal and cell models support a role for pesticides in the etiology of Parkinson disease. Susceptibility to pesticides may be modified by genetic variants of xenobiotic enzymes, such as paraoxonase, that play a role in metabolizing some organophosphates. METHODS: We examined associations between Parkinson disease and the organophosphates diazinon, chlorpyrifos, and parathion, and the influence of a functional polymorphism at position 55 in the coding region of the PON1 gene (PON1-55). From 1 January 2001 through 1 January 2008, we recruited 351 incident cases and 363 controls from 3 rural California counties in a population-based case-control study. Participants provided a DNA sample, and residential exposure to organophosphates was determined from pesticide usage reports and a geographic information system (GIS) approach. We assessed the main effects of both genes and pesticides in unconditional logistic regression analyses, and evaluated the effect of carrying a PON1-55 MM variant on estimates of effects for diazinon, chlorpyrifos, and parathion exposures. RESULTS: Carriers of the variant MM PON1-55 genotype exposed to organophosphates exhibited a greater than 2-fold increase in Parkinson disease risk compared with persons who had the wildtype or heterozygous genotype and no exposure (for diazinon, odds ratio = 2.2 [95% confidence interval = 1.1-4.5]; for chlorpyrifos, 2.6 [1.3-5.4]). The effect estimate for chlorpyrifos, was more pronounced in younger-onset cases and controls (

Dopamine transporter genetic variants and pesticides in Parkinson's disease.

BACKGROUND: Research suggests that independent and joint effects of genetic variability in the dopamine transporter (DAT) locus and pesticides may influence Parkinson's disease (PD) risk. METHODS: In 324 incident PD patients and 334 population controls from our rural California case-control study, we genotyped rs2652510, rs2550956 (for the DAT 5' clades), and the 3' variable number of tandem repeats (VNTR). Using geographic information system methods, we determined residential exposure to agricultural maneb and paraquat applications. We also collected occupational pesticide use data. Employing logistic regression, we calculated odds ratios (ORs) for clade diplotypes, VNTR genotype, and number of susceptibility (A clade and 9-repeat) alleles and assessed susceptibility allele-pesticide interactions. RESULTS: PD risk was increased separately in DAT A clade diplotype carriers [AA vs. BB: OR = 1.66; 95% confidence interval (CI), 1.08-2.57] and 3' VNTR 9/9 carriers (9/9 vs. 10/10: OR = 1.8; 95% CI, 0.96-3.57), and our data suggest a gene dosing effect. Importantly, high exposure to paraquat and maneb in carriers of one susceptibility allele increased PD risk 3-fold (OR = 2.99; 95% CI, 0.88-10.2), and in carriers of two or more alleles more than 4-fold (OR = 4.53; 95% CI, 1.70-12.1). We obtained similar results for occupational pesticide measures. DISCUSSION: Using two independent pesticide measures, we a) replicated previously reported gene-environment interactions between DAT genetic variants and occupational pesticide exposure in men and b) overcame previous limitations of nonspecific pesticide measures and potential recall bias by employing state records and computer models to estimate residential pesticide exposure. CONCLUSION: Our results suggest that DAT genetic variability and pesticide exposure interact to increase PD risk.

Well-water consumption and Parkinson's disease in rural California.

INTRODUCTION: Investigators have hypothesized that consuming pesticide-contaminated well water plays a role in Parkinson's disease (PD), and several previous epidemiologic studies support this hypothesis. OBJECTIVES: We investigated whether consuming water from private wells located in areas with documented historical pesticide use was associated with an increased risk of PD. METHODS: We employed a geographic information system (GIS)-based model to estimate potential well-water contamination from agricultural pesticides among 368 cases and 341 population controls enrolled in the Parkinson's Environment and Genes Study (PEG). We separately examined 6 pesticides (diazinon, chlorpyrifos, propargite, paraquat, dimethoate, and methomyl) from among 26 chemicals selected for their potential to pollute groundwater or for their interest in PD, and because at least 10% of our population was exposed to them. RESULTS: Cases were more likely to have consumed private well water and to have consumed it on average 4.3 years longer than controls (p = 0.02). High levels of possible well-water contamination with methomyl [odds ratio (OR) = 1.67; 95% confidence interval (CI), 1.00-2.78]), chlorpyrifos (OR = 1.87; 95% CI, 1.05-3.31), and propargite (OR = 1.92; 95% CI, 1.15-3.20) resulted in approximately 70-90% increases in relative risk of PD. Adjusting for ambient pesticide exposures only slightly attenuated these increases. Exposure to a higher number of water-soluble pesticides and organophosphate pesticides also increased the relative risk of PD. CONCLUSION: Our study, the first to use agricultural pesticide application records, adds evidence that consuming well water presumably contaminated with pesticides may play a role in the etiology of PD.