Adjustment For Medication Use Research Articles

C-Reactive Protein and Risk of Incident Heart Failure in Patients With Cardiovascular Disease

BackgroundPatients with established cardiovascular disease (CVD) are at high risk of incident heart failure (HF), which may in part reflect the impact of systemic inflammation. ObjectivesThe goal of this study was to determine the association between C-reactive protein (CRP) and incident HF in patients with established CVD. MethodsPatients from the prospective UCC-SMART (Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease) cohort with established CVD, but without prevalent HF were included (n = 8,089). Incident HF was defined as a first hospitalization for HF. The association between baseline CRP and incident HF was assessed using Cox proportional hazards models adjusted for established risk factors (ie, age, sex, myocardial infarction, smoking, diabetes mellitus, body mass index, blood pressure, cholesterol, and kidney function). ResultsDuring a median follow-up of 9.7 years (IQR 5.4-14.1 years), 810 incident HF cases were observed (incidence rate 1.01/100 person-years). Higher CRP was independently associated with an increased risk of incident HF: HR per 1 mg/L: 1.10 (95% CI: 1.07-1.13), and for last vs first CRP quartile: 2.22 (95% CI: 1.76-2.79). The association was significant for both HF with reduced (HR: 1.09; 95% CI: 1.04-1.14) and preserved ejection fraction (HR: 1.12; 95% CI: 1.07-1.18) (P for difference = 0.137). Additional adjustment for medication use and interim myocardial infarction did not attenuate the association, and the association remained consistent beyond 15 years after the CRP measurement. ConclusionsIn patients with established CVD, CRP is an independent risk marker of incident HF. These data support ongoing trial efforts to assess whether anti-inflammatory agents can reduce the burden of HF.

Association of Mental Disorders and Related Medication Use With Risk for Major Osteoporotic Fractures

ImportanceOsteoporotic fractures are a leading cause of disability, costs, and mortality. FRAX is a tool used to assess fracture risk in the general population. Mental disorders and medications to treat them have been reported to adversely affect bone health, but, to date, they have not been systematically studied in relation to osteoporotic fractures.ObjectiveTo examine the association of mental disorders and psychotropic medication use with osteoporotic fracture risk in routine clinical practice.Design, Setting, and ParticipantsIn this population-based cohort study, bone mineral density and risk factors were used to calculate FRAX scores using data from the Manitoba Bone Density Program database of all women and men 40 years of age or older in Manitoba, Canada, referred for a baseline dual-energy x-ray absorptiometry scan from January 1, 1996, to March 28, 2013. Population-based health services data were used to identify primary mental disorders during the 3 prior years, psychotropic medication use during the prior year, and incident fractures. Cox proportional hazards regression models estimated the risk for incident fractures based on mental disorders and use of psychotropic medications. Data analysis was conducted from November 25, 2013, to October 15, 2016. Main Outcomes and MeasuresIncident nontraumatic major osteoporotic fractures (MOFs) and hip fractures.ResultsOf the 68 730 individuals (62 275 women and 6455 men; mean age, 64.2 [11.2] years) in the study, during 485 322 person-years (median, 6.7 years) of observation, 5750 (8.4%) sustained an incident MOF, 1579 (2.3%) sustained an incident hip fracture, and 8998 (13.1%) died. In analyses adjusted for FRAX score, depression was associated with MOF (adjusted hazard ratio [aHR], 1.39; 95% CI, 1.27-1.51; P < .05) and hip fracture (aHR, 1.43; 95% CI, 1.22-1.69; P < .05) before adjustment for medication use, but these associations were not significant after adjustment for medication use. In contrast, the use of selective serotonin reuptake inhibitors (aHR for MOF, 1.43; 95% CI, 1.27-1.60; P < .05; aHR for hip fracture, 1.48; 95% CI, 1.18-1.85; P < .05), antipsychotics (aHR for MOF, 1.43; 95% CI, 1.15-1.77; P < .05; aHR for hip fracture, 2.14; 95% CI, 1.52-3.02; P < .05), and benzodiazepines (aHR for MOF, 1.15; 95% CI, 1.04-1.26; P < .05; aHR for hip fracture, 1.24; 95% CI, 1.05-1.47; P < .05) were each independently associated with significantly increased risk for both MOF and hip fracture. FRAX significantly underestimated the 10-year risk of MOF by 29% and of hip fracture by 51% for those with depression. It also underestimated the 10-year risk of MOF by 36% for use of selective serotonin reuptake inhibitors, by 63% for use of mood stabilizers, by 60% for use of antipsychotics, and by 13% for use of benzodiazepines. FRAX underestimated the 10-year risk of hip fracture by 57% for use of selective serotonin reuptake inhibitors, by 98% for use of mood stabilizers, by 171% for use of antipsychotics, and by 31% for use of benzodiazepines. FRAX correctly estimated fracture risk in people without mental disorders and those not taking psychotropic medications.Conclusions and RelevanceMental disorders and medication use were associated with an increased risk for fracture, but in simultaneous analyses, only medication use was independently associated with fracture. Depression and psychotropic medication use are potential risk indicators that are independent of FRAX estimates.

Abstract WP198: Sex Differences in Outcomes After Stroke in Patients With Diabetes in Ontario, Canada

Background: Diabetes is a cardiovascular disease risk factor that exerts a higher risk for coronary heart disease and stroke among females compared to males. Outcomes after first stroke in those with diabetes are not well characterized, especially by sex and age, and studies have been limited by short follow-up and biased samples. We sought to calculate the sex- and age-specific risk of cardiovascular outcomes after ischemic stroke among those with diabetes using a study with full population coverage. Methods: Using population-based demographic and administrative health care databases in Ontario, Canada, we selected all patients with diabetes hospitalized with first ischemic stroke between 4/1/2002 and 3/31/2012. Participants were followed for death, stroke, and myocardial infarction (MI). Kaplan-Meier survival analysis and Fine-Gray competing risk models were used to estimate hazards and adjusted hazards of outcomes by sex and age strata. Models were adjusted for demographics and vascular risk factors. Sensitivity analysis including adjustment for medication use was performed in those aged &gt;=65 years. Results: There were 25495 ischemic stroke patients with diabetes. The incidence of death was higher in women than in men (14.08 per 100 person-years [95% CI 13.73-14.44] vs. 11.89 [11.60-12.19]), but was lower after adjustment for age and other risk factors (adjusted hazard ratio [HR] 0.95 [0.92-0.99]). The incidence of recurrent stroke was similar in women and men, but men were more likely to be readmitted for MI (1.99 per 100 person-years [1.89-2.10] vs 1.58 [1.49-1.68] among females). In multivariable models, females had a lower risk of readmission for any event (HR 0.96 [95% CI 0.93-0.99]). Conclusions: In this retrospective study with full population coverage among diabetics with index stroke in Ontario, there was a higher unadjusted rate of death among females compared to males, and higher unadjusted incidence of MI among males. In adjusted models, females had a lower risk of death compared to males, although the increased risk of MI among males persisted. These findings confirm and quantify sex differences in outcomes after stroke in patients with diabetes.

Stroke recurrence among South Asians with diabetes in Ontario, Canada.

Background South Asians have more vascular risk factors, earlier cardiovascular disease onset, and higher stroke mortality than non-South Asians. However, ethnic differences in long-term outcomes post-stroke in diabetics are unclear. Aims We compared cardiovascular outcome risk after first ischemic stroke between South Asian and non-South Asian diabetics. Methods Using population-based health care databases in Ontario, Canada, we selected all patients with diabetes hospitalized with first ischemic stroke between 1 April 2002 and 31 March 2012, and assigned South Asian versus non-South Asian ethnicity using a validated surname algorithm. Kaplan-Meier survival analysis estimated survival functions, and competing risk models estimated hazards of death, stroke, and myocardial infarction. The primary predictor was ethnicity, and models were adjusted for demographics and vascular risk factors. Sensitivity analysis including adjustment for medication use was performed in those aged ≥65 years. Results There were 25,495 diabetics with first ischemic stroke; 840 were South Asian. South Asians were younger, more often male, had lower income, and had shorter Ontario residency compared to non-South Asians. South Asians had higher incidence and cumulative risk of recurrent stroke. In fully adjusted competing risk models, recurrent stroke rate was increased among South Asians compared to non-South Asians (HR 1.17 [95% CI 1.00-1.38]) in the whole cohort and in those aged ≥65 years, both with adjustment for medication use (HR 1.23 [1.01-1.50]) and without (1.27 [1.04-1.54]). Conclusions In this large population-based study, South Asian diabetic stroke patients had higher recurrent stroke rates compared to non-South Asians, despite a younger age profile. Further research is needed to reduce stroke burden in South Asians.

Abstract TP176: Stroke Recurrence Among South Asians With diabetes in Ontario, Canada

Introduction: South Asians have earlier cardiovascular disease onset and higher stroke mortality than non-South Asians, but disparities in long-term outcomes after stroke in patients with diabetes are not well described. We compared risk of cardiovascular outcomes after first ischemic stroke between South Asian and non-South Asian patients with diabetes. Hypothesis: We hypothesized that South Asian stroke patients with diabetes were younger and had higher stroke recurrence, even accounting for competing risk of death. Methods: Using population-based health care databases in Ontario, Canada, we selected all patients with diabetes hospitalized with first ischemic stroke between April 1, 2002 and March 31, 2012, and assigned South Asian vs. non-South Asian ethnicity using a validated surname algorithm. Kaplan-Meier survival analysis and competing risk models estimated risk of death, stroke, and myocardial infarction. The primary predictor was ethnicity; models were adjusted for demographics and vascular risk factors. Sensitivity analysis including adjustment for medication use was performed in those aged &gt;=65 years. Results: There were 25495 diabetics with first ischemic stroke; 840 were South Asian and were younger, more often male, had lower income, and had shorter Ontario residency compared to non-South Asians. South Asians had higher incidence and cumulative risk of recurrent stroke (Figure). In adjusted competing risk models, recurrent stroke risk was increased among South Asians compared to non-South Asians (HR 1.17 [95% CI 1.00-1.38]) in the whole cohort and in those aged &gt;=65 years, both with adjustment for medication use (HR 1.23 [1.01-1.50]) and without (1.27 [1.04-1.54]). Conclusions: In this large population-based study, South Asian stroke patients with diabetes had higher recurrent stroke risk compared to non-South Asians, despite younger age. Further research and targeted interventions are needed to reduce stroke burden in South Asians.

Imputing Observed Blood Pressure for Antihypertensive Treatment: Impact on Population and Genetic Analyses

Elevated blood pressure (BP), a heritable risk factor for many age-related disorders, is commonly investigated in population and genetic studies, but antihypertensive use can confound study results. Routine methods to adjust for antihypertensives may not sufficiently account for newer treatment protocols (i.e., combination or multiple drug therapy) found in contemporary cohorts. We refined an existing method to impute unmedicated BP in individuals on antihypertensives by incorporating new treatment trends. We assessed BP and antihypertensive use in male twins (n = 1,237) from the Vietnam Era Twin Study of Aging: 36% reported antihypertensive use; 52% of those treated were on multiple drugs. Estimated heritability was 0.43 (95% confidence interval (CI) = 0.20-0.50) and 0.44 (95% CI = 0.22-0.61) for measured systolic BP (SBP) and diastolic BP (DBP), respectively. We imputed BP for antihypertensives by 3 approaches: (i) addition of a fixed value of 10/5mm Hg to measured SBP/DBP; (ii) incremented addition of mm Hg to BP based on number of medications; and (iii) a refined approach adding mm Hg based on antihypertensive drug class and ethnicity. The imputations did not significantly affect estimated heritability of BP. However, use of our most refined imputation method and other methods resulted in significantly increased phenotypic correlations between BP and body mass index, a trait known to be correlated with BP. This study highlights the potential usefulness of applying a representative adjustment for medication use, such as by considering drug class, ethnicity, and the combination of drugs when assessing the relationship between BP and risk factors.

Lifestyle Factors, Medication Use and Risk for Ischaemic Heart Disease Hospitalisation: A Longitudinal Population-Based Study

BackgroundLifestyle factors have been implicated in ischaemic heart disease (IHD) development however a limited number of longitudinal studies report results stratified by cardio-protective medication use.PurposeThis study investigated the influence of self-reported lifestyle factors on hospitalisation for IHD, stratified by blood pressure and/or lipid-lowering therapy.MethodsA population-based cohort of 14,890 participants aged 45+ years and IHD-free was identified from the Western Australian Health and wellbeing Surveillance System (2004 to 2010 inclusive), and linked with hospital administrative data. Adjusted hazard ratios for future IHD-hospitalisation were estimated using Cox regression.ResultsCurrent smokers remained at higher risk for IHD-hospitalisation (adjusted HR=1.57; 95% CI: 1.22-2.03) after adjustment for medication use, as did those considered overweight (BMI=25-29 kg/m2; adjusted HR=1.28; 95% CI: 1.04-1.57) or obese (BMI of ≥30kg/m2; adjusted HR=1.31; 95% CI: 1.03-1.66). Weekly leisure-time physical activity (LTPA) of 150 minutes or more and daily intake of 3 or more fruit/vegetable servings reduced risk by 21% (95% CI: 0.64-0.97) and 26% (95% CI: 0.58-0.96) respectively. Benefits of LTPA appeared greatest in those on blood pressure lowering medication (adjusted HR=0.50; 95% CI: 0.31-0.82 [for LTPA<150 mins], adjusted HR=0.64; 95% CI: 0.42-0.96 [for LTPA>=150 mins]). IHD risk in smokers was most pronounced in those taking neither medication (adjusted HR=2.00; 95% CI: 1.41-2.83).ConclusionThis study confirms the contribution of previously reported lifestyle factors towards IHD hospitalisation, even after adjustment for antihypertensive and lipid-lowering medication use. Medication stratified results suggest that IHD risks related to LTPA and smoking may differ according to medication use.

Changes in novel biomarkers of disease activity in juvenile and adult dermatomyositis are sensitive biomarkers of disease course

Muscle enzyme levels are insensitive markers of disease activity in juvenile and adult dermatomyositis (DM), especially during the active treatment phase. To improve our ability to monitor DM disease activity longitudinally, especially in the presence of immunomodulating agents, we prospectively evaluated whether interferon (IFN)-dependent peripheral blood gene and chemokine signatures could serve as sensitive and responsive biomarkers for change in disease activity in adult and juvenile DM. Peripheral blood and clinical data were collected from 51 patients with juvenile or adult DM prospectively over 2 study visits. We performed disease activity measurements and calculated whole-blood type I IFN gene and chemokine scores. We also measured serum levels of other proinflammatory cytokines, including interleukin-6 (IL-6). Changes in juvenile and adult DM global disease activity correlated positively and significantly with changes in the type I IFN gene score before adjustment for medication use (r = 0.33, P = 0.023) and with changes in the IFN chemokine score before and after adjustment for medication use (r = 0.53, P < 0.001 and r = 0.50, P < 0.001, respectively). Changes in muscle and extramuscular visual analog scale (VAS) scores correlated positively with changes in IFN gene and chemokine scores (P = 0.002, P < 0.001, P = 0.095, P < 0.001). Serum levels of IL-6, IL-8, and tumor necrosis factor α (TNFα) correlated positively with changes in global, muscle, and extramuscular VAS scores (P < 0.05). Our findings suggest that changes in type I IFN gene and chemokine scores as well as in levels of IL-6, IL-8, and TNFα may serve as sensitive and responsive longitudinal biomarkers of change in disease activity in juvenile and adult DM, even in the presence of immunomodulating agents.

Fatigue, Inflammation, and ω-3 and ω-6 Fatty Acid Intake Among Breast Cancer Survivors

Evidence suggests that inflammation may drive fatigue in cancer survivors. Research in healthy populations has shown reduced inflammation with higher dietary intake of ω-3 polyunsaturated fatty acids (PUFAs), which could potentially reduce fatigue. This study investigated fatigue, inflammation, and intake of ω-3 and ω-6 PUFAs among breast cancer survivors. Six hundred thirty-three survivors (mean age, 56 years; stage I to IIIA) participating in the Health, Eating, Activity, and Lifestyle Study completed a food frequency/dietary supplement questionnaire and provided a blood sample assayed for C-reactive protein (CRP) and serum amyloid A (30 months after diagnosis) and completed the Piper Fatigue Scale and Short Form-36 (SF-36) vitality scale (39 months after diagnosis). Analysis of covariance and logistic regression models tested relationships between inflammation and fatigue, inflammation and ω-3 and ω-6 PUFA intake, and PUFA intake and fatigue, controlling for three incremental levels of confounders. Fatigue was analyzed continuously (Piper scales) and dichotomously (SF-36 vitality ≤ 50). Behavioral (P = .003) and sensory (P = .001) fatigue scale scores were higher by increasing CRP tertile; relationships were attenuated after adjustment for medication use and comorbidity. Survivors with high CRP had 1.8 times greater odds of fatigue after full adjustment (P < .05). Higher intake of ω-6 relative to ω-3 PUFAs was associated with greater CRP (P = .01 after full adjustment) and greater odds of fatigue (odds ratio, 2.6 for the highest v lowest intake; P < .05). Results link higher intake of ω-3 PUFAs, decreased inflammation, and decreased physical aspects of fatigue. Future studies should test whether ω-3 supplementation may reduce fatigue among significantly fatigued breast cancer survivors.

Associations between immunologic, inflammatory, and oxidative stress markers with severity of depressive symptoms: An analysis of the 2005–2006 National Health and Nutrition Examination Survey

Previous studies have demonstrated increased levels of serum markers of systemic inflammation and immune system function among individuals with depressive symptoms. Despite these observations, the biological mechanisms behind this association remain elusive. The objective of the present analysis was to examine the individual and joint associations of white blood cell counts, platelet counts, and C-reactive protein with depression severity and to determine whether oxidative stress might mediate these associations. We conducted an analysis of 3867 subjects from the 2005–2006 National Health and Nutritional Examination Survey. Ordinal logistic regression was used to assess associations between three levels of depression symptom severity (as measured by the nine-item Patient Health Questionnaire) and serum C-reactive protein, white blood cell counts, platelet counts, and four surrogate markers of oxidative stress. Covariates included sex, age, smoking status, physical activity, education, poverty to income ratio, as well as medication use and medical conditions influencing inflammation levels. In separate models, the risk of moderate to severe depression was significantly greater in the highest quartiles of CRP (OR = 1.84. 95 percent confidence interval (CI) = 1.35–2.52), WBC (OR = 1.70, CI = 1.31–2.19), and platelet counts (OR = 1.41, CI = 1.13–1.76) after adjusting for basic sociodemographic and behavioral factors. After additional adjustment for medication use and oxidative stress surrogate measures, the highest quartile of WBC counts remained associated with depression (OR = 1.60, CI = 1.23–2.09). Adjustment for oxidative stress measures did not substantially affect estimated associations of inflammation/immunologic markers. In summary, we observed significantly elevated white blood cell counts among subjects with moderate and severe depression, and oxidative stress and a medical history of inflammatory diseases do not appear to mediate this association. Although limited through its use of cross-sectional data, this is the first analysis to simultaneously consider immunologic and oxidative stress markers. Further research is needed to identify the biological basis for this persistent association.

Outcome following acute myocardial infarction: are differences among physician specialties the result of quality of care or case mix?

Studies to determine whether care by cardiologists improves the survival of patients with acute myocardial infarction (MI) have produced conflicting results, and it is not known what accounts for differences in patient outcome by physician specialty. To evaluate whether cardiologists provide more recommended therapies to elderly patients with acute MI and, if so, to determine whether variations in processes of care account for differences in patient outcome. Retrospective cohort study using medical chart data and administrative data files. All nonfederal acute care hospitals in California. A cohort of 7663 Medicare beneficiaries 65 years and older directly admitted to the hospital with a confirmed acute MI from April 1994 to July 1995 with complete data regarding potential contraindications to recommended therapies. Percentage of "good" and "ideal" candidates for a given acute MI therapy who actually received that therapy, percentage who received exercise stress testing or coronary angiography, percentage who underwent revascularization, and 1-year mortality, stratified by specialty of the attending physician. During hospitalization, good candidates for aspirin were more likely to receive aspirin if they were treated by cardiologists (87%) than by medical subspecialists (73%; P<.001), general internists (84%; P = .003), or family practitioners (81%; P<.001). Cardiologists were also more likely to treat good candidates with thrombolytic therapy (51%) than were medical subspecialists (29%; P<.001), general internists (40%; P<.001), or family practitioners (27%; P<.001). Patients of cardiologists were 2- to 4-fold more likely to undergo a revascularization procedure. Despite these differences in utilization, we found similar 30-day mortality rates across physician specialties. However, 1-year mortality rates were greater for patients treated by medical subspecialists (odds ratio [OR], 1.9; 95% confidence interval [CI], 1.6-2.3), general internists (OR, 1.4; 95% CI, 1.3-1.6), and family practitioners (OR, 1.7; 95% CI, 1.4-1.9) than for those treated by cardiologists. Adjusting for differences in patient and hospital characteristics markedly reduced the ORs for those treated by medical subspecialists (OR, 1.2; 95% CI, 0.9-1.4), general internists (OR, 1.1; 95% CI, 1.0-1.3), and family practitioners (OR, 1.3; 95% CI, 1.1-1.6), whereas further adjustment for medication use and revascularization procedures had little effect. Differences in the use of recommended therapies by physician specialty are generally small and do not explain differences in patient outcome. In comparison, differences among patients treated by physicians of various specialties (case mix) have a large impact on patient outcome and may account for the residual survival advantage of patients treated by cardiologists. With the exception of the in-hospital use of aspirin, recommended MI therapies are markedly underused, regardless of the specialty of the physician.

Mental distress and risk of hip fracture. Do broken hearts lead to broken bones?

OBJECTIVE: Mental distress may entail increased risk of hip fracture, but it is uncertain whether the effect consists solely of an indirect effect through use of medication, or whether it...