Amphetamines, atomoxetine and the risk of serious cardiovascular events in adults.

MAIN OBJECTIVE: To compare the incidence rates of serious cardiovascular events in adult initiators of amphetamines or atomoxetine to rates in non-users. METHODS: This was a retrospective cohort study of new amphetamines (n=38,586) or atomoxetine (n=20,995) users. Each medication user was matched to up to four non-users on age, gender, data source, and state (n=238,183). The following events were primary outcomes of interest 1) sudden death or ventricular arrhythmia, 2) stroke, 3) myocardial infarction, 4) a composite endpoint of stroke or myocardial infarction. Cox proportional hazard regression was used to calculate propensity-adjusted hazard ratios for amphetamines versus matched non-users and atomoxetine versus matched non-users, with intracluster dependence within matched sets accounted for using a robust sandwich estimator. RESULTS: The propensity-score adjusted hazard ratio for amphetamines use versus non-use was 1.18 (95% CI: 0.55-2.54) for sudden death/ventricular arrhythmia, 0.80 (95% CI: 0.44-1.47) for stroke, 0.75 (95% CI: 0.42-1.35) for myocardial infarction, and 0.78 (95% CI: 0.51-1.19) for stroke/myocardial infarction. The propensity-score adjusted hazard ratio for atomoxetine use versus non-use was 0.41 (95% CI: 0.10-1.75) for sudden death/ventricular arrhythmia, 1.30 (95% CI: 0.52-3.29) for stroke, 0.56 (95% CI: 0.16-2.00) for myocardial infarction, and 0.92 (95% CI: 0.44-1.92) for stroke/myocardial infarction. CONCLUSIONS: Initiation of amphetamines or atomoxetine was not associated with an elevated risk of serious cardiovascular events. However, some of the confidence intervals do not exclude modest elevated risks, e.g. for sudden death/ventricular arrhythmia.

Methylphenidate and risk of serious cardiovascular events in adults.

OBJECTIVE: The authors sought to determine whether use of methylphenidate in adults is associated with elevated rates of serious cardiovascular events compared with rates in nonusers. METHOD: This was a cohort study of new users of methylphenidate based on administrative data from a five-state Medicaid database and a 14-state commercial insurance database. All new methylphenidate users with at least 180 days of prior enrollment were identified. Users were matched on data source, state, sex, and age to as many as four comparison subjects who did not use methylphenidate, amphetamines, or atomoxetine. A total of 43,999 new methylphenidate users were identified and matched to 175,955 nonusers. Events of primary interest were 1) sudden death or ventricular arrhythmia, 2) stroke, 3) myocardial infarction, and 4) a composite endpoint of stroke or myocardial infarction. RESULTS: The age-standardized incidence rate per 1,000 person-years of sudden death or ventricular arrhythmia was 2.17 (95% CI=1.63-2.83) in methylphenidate users and 0.98 (95% CI=0.89-1.08) in nonusers, for an adjusted hazard ratio of 1.84 (95% CI=1.33-2.55). Dosage was inversely associated with risk. Adjusted hazard ratios for stroke, myocardial infarction, and the composite endpoint of stroke or myocardial infarction did not differ statistically from 1. CONCLUSIONS: Although initiation of methylphenidate was associated with a 1.8-fold increase in risk of sudden death or ventricular arrhythmia, the lack of a dose-response relationship suggests that this association may not be a causal one.

Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study.

BACKGROUND: Bleeding is the most common and worrisome adverse effect of warfarin therapy. One of the factors that might increase bleeding risk is initiation of interacting drugs that potentiate warfarin. We sought to evaluate whether initiation of an antidepressant increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. METHODOLOGY/PRINCIPAL FINDINGS: Medicaid claims data (1999-2005) were used to perform an observational case-control study nested within person-time exposed to warfarin in those ≥18 years. In total, 430,455 warfarin users contributed 407,370 person-years of warfarin use. The incidence rate of hospitalization for GI bleeding among warfarin users was 4.48 per 100 person-years (95% CI, 4.42-4.55). Each gastrointestinal bleeding cases was matched to 50 controls based on index date and state. Warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of citalopram (OR = 1.73 [95% CI, 1.25-2.38]), fluoxetine (OR = 1.63 [95% CI, 1.11-2.38]), paroxetine (OR = 1.64 [95% CI, 1.27-2.12]), amitriptyline (OR = 1.47 [95% CI, 1.02-2.11]). Also mirtazapine, which is not believed to interact with warfarin, increased the risk of GI bleeding (OR = 1.75 [95% CI, 1.30-2.35]). CONCLUSIONS/SIGNIFICANCE: Warfarin users who initiated citalopram, fluoxetine, paroxetine, amitriptyline, or mirtazapine had an increased risk of hospitalization for gastrointestinal bleeding. However, the elevated risk with mirtazapine suggests that a drug-drug interaction may not have been responsible for all of the observed increased risk.

The effect of selective serotonin re-uptake inhibitors on the risk of myocardial infarction in a cohort of patients with depression.

AIM: To evaluate whether selective serotonin re-uptake inhibitor (SSRI) exposure influences the risk of myocardial infarction (MI) in patients with depression. METHODS: This study included 693 patients with MI (cases) and 2772 controls. Conditional logistic regression was used to calculate the odds ratio (OR). RESULTS: SSRI exposure may be associated with a reduced MI risk (OR = 0.77, 95% CI 0.57, 1.03). However, reduced risk was only observed with longer term use (OR = 0.73, 95% CI 0.53, 1.00) and not with shorter term use (OR = 1.15, 95% CI: 0.65, 2.05). CONCLUSIONS: Only longer term use of SSRIs was associated with reduced MI risk, suggesting that other mechanisms, besides an acute anti-platelet effect, may reduce MI risk.

Exposure to CYP3A4-inducing and CYP3A4-non-inducing antiepileptic agents and the risk of fractures.

PURPOSE: To evaluate whether exposure to Cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)-inducing antiepileptics increases fracture risk compared to CYP3A4-non-inducing antiepileptics. METHODS: We performed a retrospective cohort study of initiators of antiepileptic agents using a UK medical record database (The Health Improvement Network) from 1995 to 2007. We considered an antiepileptic user an initiator if he or she had not received a prescription for an antiepileptic agent within the first year after entry in the database. Proportional hazards regression was used to calculate hazard ratios for fracture during long-term (≥ 6 months) exposure to CYP3A4 inducing versus CYP3A4 non-inducing antiepileptics. RESULTS: We identified 4077 initiators of CYP3A4-inducing antiepileptics and 6433 initiators of CYP3A4-non-inducing antiepileptics with at least 6 months of antiepileptic exposure. During 6006 person-years exposed to CYP3A4-inducing antiepileptics, 118 fractures were identified for an incidence rate of 1.96 (95% confidence interval (CI): 1.63-2.35) fractures per 100 person-years. During 7184 person-years exposed to CYP3A4-non-inducing antiepileptics, 127 fractures were identified, for an incidence rate of 1.77 (95% CI: 1.47-2.10) fractures per 100 person-years. The adjusted hazard ratio for CYP3A4-inducing antiepileptic versus CYP3A4-non-inducing antiepileptic was 1.21 (95% CI: 0.93-1.56). No duration-response relationship was evident. CONCLUSIONS: Our results do not support the hypothesis that CYP3A4 induction by antiepileptic agents increases the fracture risk. Further research will be needed to evaluate whether mechanisms other than CYP3A4 induction might explain some of the elevated risk of fractures associated with long-term use of antiepileptic agents.

Cardiovascular events and death in children exposed and unexposed to ADHD agents.

OBJECTIVE: The objective of this study was to compare the rate of severe cardiovascular events and death in children who use attention-deficit/hyperactivity disorder (ADHD) medications versus nonusers. PATIENTS AND METHODS: We performed a large cohort study using data from 2 administrative databases. All children aged 3 to 17 years with a prescription for an amphetamine, atomoxetine, or methylphenidate were included and matched with up to 4 nonusers on the basis of data source, gender, state, and age. Cardiovascular events were validated using medical records. Proportional hazards regression was used to calculated hazard ratios. RESULTS: We identified 241 417 incident users (primary cohort). No statistically significant difference between incident users and nonusers was observed in the rate of validated sudden death or ventricular arrhythmia (hazard ratio: 1.60 [95% confidence interval (CI): 0.19-13.60]) or all-cause death (hazard ratio: 0.76 [95% CI: 0.52-1.12]). None of the strokes identified during exposed time to ADHD medications were validated. No myocardial infarctions were identified in ADHD medication users. No statistically significant difference between prevalent users and nonusers (secondary cohort) was observed (hazard ratios for validated sudden death or ventricular arrhythmia: 1.43 [95% CI: 0.31-6.61]; stroke: 0.89 [95% CI: 0.11-7.11]; stroke/myocardial infarction: 0.72 [95% CI: 0.09-5.57]; and all-cause death: 0.77 [95% CI: 0.56-1.07). CONCLUSIONS: The rate of cardiovascular events in exposed children was very low and in general no higher than that in unexposed control subjects. Because of the low number of events, we have limited ability to rule out relative increases in rate.

New genetic variant that might improve warfarin dose prediction in African Americans.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Variants in the CYP2C9 (i.e. *2 and *3) and VKORC1 (i.e. 1173C/T or -1639G/A) genes have been shown to influence warfarin dose requirements. However, these factors seem to explain less of the dose variability in African Americans who have a lower prevalence of the CYP2C9*2 and *3 and VKORC1 1173T alleles. WHAT THIS STUDY ADDS: In African Americans, the VKORC1 rs17886199 variant was statistically significantly associated with log-transformed warfarin maintenance dose, independent of the influence of VKORC1 1173C>T and CYP2C9*2 and *3. However, replication of our finding is needed to confirm the association of rs1786199 SNP in African Americans, since Limdi et al.[3] did not examine the effect of this SNP because the prevalence of the rs1786199 A-allele was too low. AIMS: To raise hypotheses with regards to whether genetic variants in the VKORC1, CYP2C9, EPHX1, GGCX and ALB genes might influence warfarin dose in African Americans and Caucasians, independent of the effects of the VKORC1 1173C>T and CYP2C9*2 and *3 variants. METHODS: From a prospective cohort study, we obtained additional DNA on 36 Caucasian and 22 African American warfarin users who reached maintenance dose and genotyped them for tagSNPs (r2<0.8) in VKORC1, EPHX1, GGCX and ALB genes, and one exonic CYP2C9 SNP. Linear regression models were fitted to estimate the relationship (P value) between log-transformed maintenance dose and each SNP and the amount of the warfarin dose variability accounted for by each SNP (partial R2). RESULTS: In African Americans, the VKORC1 rs17886199 A-allele was associated with a lower dose (GG=46.3 mg and GA=25.6 mg; P=0.002), independent of the VKORC1 1173C>T and CYP2C9*2 and *3 variants. Even after applying Bonferroni correction, the P value would still be considered statistically significant. The VKORC1 rs17886199 variant was not found in Caucasians. In Caucasians, the EPHX1 rs1051741 T-allele was associated with a lower dose (CC=41.3 mg and CT=30.0 mg; P=0.04). The latter was no longer statistically significant after applying Bonferroni correction. CONCLUSIONS: Our pilot study suggests that the VKORC1 rs17886199 variant could influence warfarin maintenance dose among African Americans, even after accounting for the influence of the VKORC1 1173C>T variant. Future studies with a larger sample size will be needed to confirm our findings.

Cardiovascular safety of ADHD medications: rationale for and design of an investigator-initiated observational study.

PURPOSE: To describe the design and rationale of an investigator-initiated observational study to examine the cardiovascular safety of the following commonly-used medications to treat attention deficit hyperactivity disorder (ADHD): amphetamines, methylphenidate, and atomoxetine. METHODS: We are conducting an observational cohort study using data from five large Medicaid programs and the HealthCore Integrated Research Database (HIRD(SM)), which is derived from administrative data from commercial health plans. Our primary outcomes of interest are (1) sudden death/ventricular arrhythmia, (2) stroke, (3) myocardial infarction, and (4) stroke or myocardial infarction as a composite outcome. These claims diagnoses have been previously validated in adults, and the positive predictive value in children will be examined as part of this study. Secondary outcomes are (1) all-cause death, (2) non-suicide death, and (3) non-accident death. All design decisions have been made to minimize bias toward the null. Based on our pilot data, we expect to have at least 90% power to detect a minimum detectable hazard ratio (HR) of 3.0 in children and adolescents who initiate an ADHD medication for each outcome of interest (except for MI, for which the expected minimum detectable HR is 7.9). The expected minimum detectable HR is 1.7 for each outcome for adult incident ADHD medication users. RESULTS: Forthcoming. CONCLUSIONS: Potential limitations to this study include a low expected event rate in children and adolescents, potentially incomplete ascertainment of outcomes, and potential confounding by unmeasured variables. Nevertheless, this study will provide important information about the cardiovascular safety of ADHD medications.

Fibrate/Statin initiation in warfarin users and gastrointestinal bleeding risk.

PURPOSE: To evaluate whether initiation of a fibrate or statin increases the risk of hospitalization for gastrointestinal bleeding in warfarin users. METHODS: We used Medicaid claims data (1999-2003) to perform an observational case-control study nested within person-time exposed to warfarin in those > or =18 years (n=353,489). Gastrointestinal bleeding cases were matched to 50 controls based on index date and state. RESULTS: Chronic warfarin users had an increased odds ratio of gastrointestinal bleeding upon initiation of gemfibrozil (1.88; 95% confidence interval [CI], 1.00-3.54] for the first prescription; 1.75; 95% CI, 0.77-3.95 for the second prescription); simvastatin (1.46; 95% CI, 1.03-2.07 for the first prescription; 1.60; 95% CI, 1.07-2.39 for the second prescription); or atorvastatin (1.39; 95% CI, 1.07-1.81 for the first prescription; 1.05; 95% CI, 0.73-1.52 for the second prescription). In contrast, no increased risk was found with pravastatin initiation (0.75; 95% CI, 0.39-1.46 for the first prescription; 0.90; 95% CI, 0.43-1.91 for the second prescription). CONCLUSIONS: Initiation of a fibrate or statin that inhibits CYP3A4 enzymes, including atorvastatin, was associated with an increased risk of hospitalization for gastrointestinal bleeding. Initiation of pravastatin, which is mainly excreted unchanged, was not associated with an increased risk.

Ethnic differences in warfarin maintenance dose requirement and its relationship with genetics.

Warfarin is a highly efficacious drug, but management of warfarin is difficult, in part because of the large interindividual maintenance dose differences. Warfarin dose requirements differ by race and it has been suggested that some of these differences are owing to genetic diversity. For example, persons of African descent have lower allele frequencies of the CYP2C9*2 and *3 and VKORC1 1173T allele, which have been associated with lower warfarin dose requirements in Caucasians. Since there is currently debate whether genetic information should be used in clinical practice to determine the starting dose for a warfarin initiator, it is of great importance to determine whether everyone will benefit from this knowledge.

Clinical and genetic risk factors of self-reported penicillin allergy.

BACKGROUND: Patients with self-reported penicillin allergy are frequently denied beta-lactam antibiotics. OBJECTIVE: To identify and correlate clinical and genetic risk factors of self-reported penicillin allergy. METHODS: We conducted a case-control study of adults recruited from allergists' offices. Cases had a history of urticaria, angioedema, wheeze, hypotension, vomiting, or anaphylaxis after a dose of penicillin. DNA from buccal swabs was genotyped for variants associated with candidate genes linked to immediate hypersensitivity (IL4, IL4R, and IL10) and penicillin metabolism (LACTB). Logistic regression was used to calculate the association between penicillin allergy and clinical and genetic factors. RESULTS: Seventeen allergists identified 76 adults. Complete data were available for 23 cases and 39 controls. Penicillin allergy was associated with a history of penicillin allergy in first-degree relatives (P = .002), a history of other adverse drug reactions (P = .008), and atopy (P = .039). However, in the multivariable analysis, only family history of penicillin allergy remained significant. IL4 single nucleotide polymorphisms (SNPs) rs11740584 (P = .012), rs10062446 (P = .021), and rs2070874 (P = .035) were associated and LACTB SNP rs2729835 (P = .058) was marginally associated with penicillin allergy. Adding rs11740584 or rs10062446 individually improved the clinical multivariable model (R(2) increased from 0.23 to 0.33). Haplotype analysis did not provide additional information to the SNP analysis. CONCLUSION: Self-reported penicillin allergy may be influenced by clinical and genetic factors such as IL4.

Angiotensinogen M235T polymorphism and the risk of myocardial infarction and stroke among hypertensive patients on ACE-inhibitors or beta-blockers.

Angiotensinogen is an essential component of the renin-angiotensin system. ACE-inhibitors and beta-blockers both have a direct influence on this system. To investigate whether the association between use of ACE-inhibitors or beta-blockers and the risk of myocardial infarction (MI) or stroke is modified by the T-allele of the angiotensinogen M235T polymorphism. In this study, 4097 subjects with hypertension , aged 55 years and older, were included from the Rotterdam Study, a population-based prospective cohort study in The Netherlands, from July 1, 1991 onwards. Follow-up ended at the diagnosis date of MI, stroke, death, or the end of the study period (January 1, 2002). The drug-gene interaction on the risk of MI or stroke was determined with a Cox proportional hazard model with adjustments for each drug class as time-dependent covariates. The risk of MI was increased in current use of ACE-inhibitors with the MT or TT genotype compared to ACE-inhibitors with the MM genotype (Synergy Index (SI): 4.00; 95% CI: 1.32-12.11). A significant drug-gene interaction was not found on the risk of stroke (SI: 1.83; 95% CI: 0.95-3.54) in ACE-inhibitor users or between current use of beta-blockers and the AGT M235T polymorphism on the risk of MI or stroke. ACE-inhibitor users with at least one copy of the 235T-allele of the AGT gene might have an increased risk of MI and stroke.

The influence of the alpha-adducin G460W polymorphism and angiotensinogen M235T polymorphism on antihypertensive medication and blood pressure.

Despite the availability of a variety of effective antihypertensive drugs, inadequate control of blood pressure is common in hypertensive patients. The aim of this study was investigate whether the alpha-adducin G460W polymorphism or angiotensinogen M235T polymorphism has an effect on the mean difference in blood pressure in subjects using antihypertensive drugs. Data from the Rotterdam Study, a population-based prospective cohort study in the Netherlands, was used. This study started in 1990 and included 7983 subjects of 55 years and older. Data from three examination rounds were used. Subjects were included when their blood pressure was elevated at 1 or more examinations and/or a diuretic, beta-blocker, calcium antagonist, or ACE inhibitor was used. A marginal generalized linear model was used to assess the drug-gene interaction. In total, 3025 hypertensives were included. No drug-gene interaction on blood pressure levels was found. The mean difference in systolic blood pressure (SBP) between subjects with the W-allele and GG genotype of the alpha-adducin gene was for diuretic users 1.25 mmHg (95% CI:-2.86 to 5.35), for beta-blockers 0.02 mmHg (95% CI:-3.39 to 3.42), for calcium antagonists -0.70 mmHg (95% CI:-5.61 to 4.21), and for ACE inhibitors -3.50 mmHg (95% CI:-9.02 to 2.02). The mean difference in SBP between subjects with the TT and MM genotype was for diuretic users -2.33 mmHg (95% CI:-8.32 to 3.66), for beta-blocker -0.06 mmHg (95% CI:-4.91 to 4.79), for calcium antagonist 0.59 mmHg (95% CI:-5.95 to 7.13), and for ACE inhibitor -2.33 mmHg (95% CI:-9.66 to 5.01). The G460W polymorphism and the M235T polymorphism did not modify the difference in blood pressure levels among subjects who used diuretics, beta-blockers, calcium antagonists, or ACE inhibitors.

Drug-gene interaction between the insertion/deletion polymorphism of the angiotensin-converting enzyme gene and antihypertensive therapy.

BACKGROUND: Despite the availability of a variety of effective drugs, inadequate control of blood pressure is common. There are some indications that the angiotensin-converting enzyme (ACE) gene modifies the response to antihypertensive drugs, but the results have been inconclusive. OBJECTIVE: To investigate whether the insertion/deletion polymorphism of the ACE gene modifies blood pressure differences among subjects using diuretics, beta-blockers, calcium-channel antagonists, or ACE inhibitors. METHODS: Data were used from the Rotterdam Study, a population-based, prospective, cohort study in the Netherlands, which started in 1990 and included 7983 subjects aged 55 years or older. Data from 3 subsequent cross-sectional investigations were used, as well. Subjects were included if they had high blood pressure during one or more examinations and/or used monotherapy with a diuretic, beta-blocker, calcium-channel antagonist, or ACE inhibitor. A marginal, generalized, linear model was used to assess the association between the mean difference in systolic/diastolic blood pressure and antihypertensive classes stratified by the 3 genotypes. RESULTS: In total, 3025 hypertensive individuals were included, and 6500 measurements of blood pressure were taken. The percentages of DD, ID, and II genotypes were 28.3%, 51.4%, and 20.3%, respectively. The mean differences in systolic blood pressure between the II and DD genotypes were 0.23 mm Hg (95% CI -5.48 to 5.94) for diuretics, -2.41 mm Hg (95% CI -6.72 to 1.90) for beta-blockers, 2.12 mm Hg (95% CI -4.64 to 8.89) for calcium-channel antagonists, and -2.01 mm Hg (95% CI -9.82 to 5.79) for ACE inhibitors. CONCLUSIONS: The adjusted mean difference in diastolic and systolic blood pressure among diuretic, beta-blocker, calcium-channel antagonist, or ACE inhibitor users was not modified by the ACE insertion/deletion polymorphism.

DAT1, DRD4, and DRD5 polymorphisms are not associated with ADHD in Dutch families.

Recent meta-analyses have indicated that the dopamine transporter gene (DAT1) and the dopamine receptor genes D4 (DRD4) and D5 (DRD5) are associated with attention-deficit hyperactivity disorder (ADHD), although single studies frequently failed to show significant association. In a family-based sample of 236 Dutch children with ADHD, we have investigated the previously described variable number of tandem repeat (VNTR) polymorphisms and two additional microsatellites at the DAT1 and DRD4 loci. DRD5 was investigated using the microsatellite that was previously found to be associated. Transmission disequilibrium tests (TDTs) did not show preferential transmission of alleles or two-marker haplotypes to affected offspring. These data suggest that DAT1, DRD4, and DRD5 do not contribute substantially to ADHD in the Dutch population.

Drug-gene interactions between genetic polymorphisms and antihypertensive therapy.

Genetic factors may influence the response to antihypertensive medication. A number of studies have investigated genetic polymorphisms as determinants of cardiovascular response to antihypertensive drug therapy. In most candidate gene studies, no such drug-gene interactions were found. However, there is observational evidence that hypertensive patients with the 460 W allele of the alpha-adducin gene have a lower risk of myocardial infarction and stroke when treated with diuretics compared with other antihypertensive therapies. With regard to blood pressure response, interactions were found between genetic polymorphisms for endothelial nitric oxide synthase and diuretics, the alpha-adducin gene and diuretics, the alpha-subunit of G protein and beta-adrenoceptor antagonists, and the ACE gene and angiotensin II type 1 (AT(1)) receptor antagonists. Other studies found an interaction between ACE inhibitors and the ACE insertion/deletion (I/D) polymorphism, which resulted in differences in AT(1) receptor mRNA expression, left ventricular hypertrophy and arterial stiffness between different genetic variants. Also, drug-gene interactions between calcium channel antagonists and ACE I/D polymorphism regarding arterial stiffness have been reported. Unfortunately, the quality of these studies is quite variable. Given the methodological problems, the results from the candidate gene studies are still inconclusive and further research is necessary.