The modifying effect of the serum-to-dialysate potassium gradient on the cardiovascular safety of SSRIs in the hemodialysis population: a pharmacoepidemiologic study.

BACKGROUND: Hypokalemia is a risk factor for drug-induced QT prolongation. Larger serum-to-dialysate potassium gradients during hemodialysis (HD) may augment the proarrhythmic risks of selective serotonin reuptake inhibitors (SSRIs). METHODS: We conducted a cohort study using 2007-2017 data from the United States Renal Data System and a large dialysis provider to examine if the serum-to-dialysate potassium gradient modifies SSRI cardiac safety. Using a new-user design, we compared 1-year sudden cardiac death (SCD) risk among HD patients newly treated with higher (citalopram, escitalopram) versus lower (fluoxetine, fluvoxamine, paroxetine, sertraline) QT-prolonging potential SSRIs, overall and stratified by baseline potassium gradient (≥4 versus <4 mEq/l). We used inverse probability of treatment-weighted survival models to estimate weighted hazard ratios (HRs) and 95% confidence intervals (CIs) and conducted a confirmatory nested case-control study. RESULTS: The study included 25 099 patients: 11 107 (44.3%) higher QT-prolonging potential SSRI new users and 13 992 (55.7%) lower QT-prolonging potential SSRI new users. Overall, higher versus lower QT-prolonging potential SSRI use was not associated with SCD [weighted HR 1.03 (95% CI 0.86-1.24)]. However, a greater risk of SCD was associated with higher versus lower QT-prolonging potential SSRI use among patients with baseline potassium gradients ≥4 mEq/l but not among those with gradients <4 mEq/l [weighted HR 2.17 (95% CI 1.16-4.03) versus 0.95 (0.78-1.16)]. Nested case-control analyses yielded analogous results. CONCLUSIONS: The serum-to-dialysate potassium gradient may modify the association between higher versus lower QT-prolonging SSRI use and SCD among people receiving HD. Minimizing the potassium gradient in the setting of QT-prolonging medication use may be warranted.

Statin initiation and acute kidney injury following elective cardiovascular surgery: a population cohort study in Denmark†.

OBJECTIVES: Acute kidney injury (AKI) is a serious complication of cardiac surgery. Statins may prevent post-surgical AKI, yet methodological concerns about existing studies raise questions about the magnitude of a protective effect. We sought to determine the effect of initiating a statin prior to elective cardiac surgery on post-surgical AKI in a regional Danish surgical cohort. METHODS: We identified adults who underwent cardiac surgery during 2006-11 using the Western Denmark Heart Registry. Presurgical medication use, pre- and post-surgical serum creatinine (sCr) measures, and other patient characteristics were obtained from Danish population-based registries. Post-surgical AKI was assessed using sCr measures within 5 days of surgery. The adjusted risk ratio (RR) of AKI and 95% confidence interval (CI) were estimated for patients who initiated a statin within 100 days prior to surgery compared with patients without prior statin use; long-term statin users were excluded to reduce healthy-user bias. Subanalyses were stratified by surgery type: coronary artery bypass grafting (CABG) and non-CABG surgeries. RESULTS: We identified 1929 CABG and 1775 non-CABG patients. AKI occurred in 25% of CABG and 28% of non-CABG surgeries, and in 29% of the non-users and 21% of the statin initiators. Half of CABG patients and 9% of non-CABG patients initiated a statin prior to surgery. The adjusted RRs for the effect of statin initiation on AKI were as follows: all surgeries combined, RR = 0.86 (95% CI: 0.74, 0.98); CABG, RR = 0.88 (0.74, 1.05); non-CABG RR = 0.87 (0.68, 1.11). CONCLUSIONS: Presurgical statin initiation is associated with a reduction in AKI risk after cardiac surgery.

Trends and Determinants of Oral Anti-Diabetic Initiation in Youth with Suspected Type 2 Diabetes.

OBJECTIVE: To evaluate trends and identify predictors of treatment initiation of oral anti-diabetic drugs (OAD) in youth. PATIENTS AND METHODS: We identified a select population of children, ages 8-18 years, with at least 13 months of continuous health plan coverage within the years 2001-2012 in a large US commercial insurance claims database. New use of an OAD was defined as the first claim for an outpatient dispensing following a 12-month wash out period. Treatment incidence was estimated monthly over the study period, and stratified by age, gender, geographic region, and provider specialty. RESULTS: The median size of the source population during the study period was 2.2 million children. A total of 13,824 initiators (mean monthly incidence of 4.6 (95% CI = 3.6, 5.5) per 100,000 youths) were identified. Initiators were more likely to be females, age 15-18, from the southern region, and have visited a family practitioner (versus a general pediatrician) prior to initiation. Time trends demonstrate a 43% increase in initiation from 2002-2012, with a gradual decrease starting from early 2008. CONCLUSION: Incidence of filled OAD medications in youth increased over time, especially for patients treated by family practitioners. Additional research is needed into factors influencing prescribing by family practitioners and pediatricians.

Enrollment factors and bias of disease prevalence estimates in administrative claims data.

PURPOSE: Considerations for using administrative claims data in research have not been well-described. To increase awareness of how enrollment factors and insurance benefit use may contribute to prevalence estimates, we evaluated how differences in operational definitions of the cohort impact observed estimates. METHODS: We conducted a cross-sectional study estimating the prevalence of five gastrointestinal conditions using MarketScan claims data for 73.1 million enrollees. We extracted data obtained from 2009 to 2012 to identify cohorts meeting various enrollment, prescription drug benefit, or health care utilization characteristics. Next, we identified patients meeting the case definition for each of the diseases of interest. We compared the estimates obtained to evaluate the influence of enrollment period, drug benefit, and insurance usage. RESULTS: As the criteria for inclusion in the cohort became increasingly restrictive the estimated prevalence increased, as much as 45% to 77% depending on the disease condition and the definition for inclusion. Requiring use of the insurance benefit and a longer period of enrollment had the greatest influence on the estimates observed. CONCLUSIONS: Individuals meeting case definition were more likely to meet the more stringent definition for inclusion in the study cohort. This may be considered a form of selection bias, where overly restrictive inclusion criteria definitions may result in selection of a source population that may no longer represent the population from which cases arose.

Estimation of biomarker distributions using laboratory data collected during routine delivery of medical care.

PURPOSE: To examine the extent to which commonly ordered laboratory values obtained from large health care databases are representative of the distribution of laboratory values from the general population as reflected in the National Health and Nutrition Examination Survey. METHODS: Means of test values from commercial insurance laboratory data and National Health and Nutrition Examination Survey data were compared. Inverse probability of selection weighting was used to account for possible selection bias and to create comparability between the two data sources. RESULTS: The average values of most of the laboratory results from routine care were very close to their population means as estimated from NHANES. Tests that were more selectively ordered tended to differ. The inverse probability of selection weighting approach generally had a small effect on the estimated means but did improve estimation of some of the more selected tests. CONCLUSIONS: Commonly ordered laboratory tests appear to be representative of values from the underlying population. This suggests that trends and other patterns in biomarker levels in the population may be reasonably studied using data collected during the routine delivery of medical care.

Prevalent but moderate variation across small geographic regions in patient nonadherence to evidence-based preventive therapies in older adults after acute myocardial infarction.

BACKGROUND: Patient long-term adherence to ß-blockers, HMG-CoA reductase inhibitors (statins), and angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) after acute myocardial infarction (AMI) is alarmingly low. It is unclear how prevalent patient adherence may be across small geographic areas and whether this geographic prevalence may vary. METHODS: This is a retrospective cohort study using Medicare service claims files from 2007 to 2009 with Medicare beneficiaries 65 years and above who were alive 30 days after the index AMI hospitalization between January 1, 2008 and December 31, 2008 (N=85,017). The adjusted proportions of patients adherent to ß-blockers, statins, and ACEIs/ARBs, respectively, in the 12 months after discharge across the 306 Hospital Referral Regions (HRRs) were measured and compared by control chart. The intracluster correlation coefficient (ICC) and the additional prediction power from this small-area variation on individual patient adherence were assessed. RESULTS: The adjusted proportion of patients adherent across HRRs ranged from 58% to 74% (median, 66%) for ß-blockers, from 57% to 67% (median, 63%) for ACEIs/ARBs, and from 58% to 73% (median, 66%) for statins. The ICC was 0.053 (95% CI, 0.043-0.064) for ß-blockers, 0.050 (95% CI, 0.039-0.061) for ACEIs/ARBs, and 0.041 (95% CI, 0.031-0.052) for statins. The adjusted proportion of patients adherent across HRRs increased the c-statistic by 0.01-0.02 (P < 0.0001). CONCLUSIONS: Nonadherence to evidence-based preventive therapies post-AMI among older adults was prevalent across small geographic regions. Moderate small-area variation in patient adherence exists.

Identifying specific chemotherapeutic agents in Medicare data: a validation study.

BACKGROUND: Large health care databases are increasingly used to examine the dissemination and benefits and harms of chemotherapy treatment in routine practice, particularly among patients excluded from trials (eg, the elderly). Misclassification of chemotherapy could bias estimates of frequency and association, warranting an updated assessment. METHODS: We evaluated the validity of Medicare claims to identify receipt of chemotherapy and specific agents delivered to elderly stage II/III colorectal (CRC), in situ/early-stage breast, non-small-cell lung, and ovarian cancer patients using the National Cancer Institute's Patterns of Care studies (POC) as the gold standard. The POC collected data on chemotherapy treatment by reabstracting hospital records, contacting physicians, and reviewing medical records. Patients' POC data were linked and compared with their Medicare claims for 2 to 12 months postdiagnosis. κ, sensitivity, specificity, positive and negative predictive values and 95% confidence intervals were calculated for the receipt of any chemotherapy and specific agents. RESULTS: Sensitivity and specificity of Medicare claims to identify any chemotherapy were high across all cancer sites. We found substantial variation in validity across agents, by site and administration modality. Capecitabine, an oral CRC treatment, was identified in claims with high specificity (98%) but low sensitivity (47%), whereas oxaliplatin, an intravenously administered CRC agent had higher sensitivity (75%) and similar specificity (97%). CONCLUSIONS: Receipt of chemotherapy and specific intravenous agents can be identified using Medicare claims, showing improvement from prior reports; yet, variation exists. Future studies should assess newly approved agents and the impact of coverage decisions for these agents under the Medicare Part D program.

Placebo adherence, clinical outcomes, and mortality in the women's health initiative randomized hormone therapy trials.

BACKGROUND: Medication adherence may be a proxy for healthy behaviors and other factors that affect outcomes. Prior studies of the association between placebo adherence and health outcomes have been limited primarily to men enrolled in clinical trials and cardiovascular disease outcomes. We examined associations between adherence to placebo and the risk of fracture, coronary heart disease, cancer, and all-cause mortality in the 2 Women's Health Initiative hormone therapy randomized trials. METHODS: Postmenopausal women randomized to placebo with adherence measured at least once were eligible for analysis. Time-varying adherence was assessed by dispensing history and pill counts. Outcome adjudication was based on physician review of medical records. Cox proportional hazards models evaluated the relation between high adherence (≥80%) to placebo and various outcomes, referent to low adherence (<80%). RESULTS: A total of 13,444 postmenopausal women were under observation for 106,066 person-years. High placebo adherence was inversely associated with most outcomes including hip fracture [hazard ratio (HR), 0.50; 95% confidence interval (CI), 0.33-0.78], myocardial infarction (HR, 0.69; 95% CI, 0.50-0.95), cancer death (HR, 0.60; 95% CI, 0.43-0.82), and all-cause mortality (HR, 0.64; 95% CI, 0.51-0.80) after adjustment for potential confounders. Women with low adherence to placebo were 20% more likely to have low adherence to statins and osteoporosis medications. CONCLUSIONS: In the Women's Health Initiative clinical trials, high adherence to placebo was associated with favorable clinical outcomes and mortality. Until the healthy behaviors and/or other factors for which high adherence is a proxy can be better elucidated, caution is warranted when interpreting the magnitude of benefit of medication adherence.

Rationale and design of the Study Assessing the Effect of Cardiovascular Medications Provided as Low-cost, Evidence-based Generic Samples (SAMPLES) trial.

BACKGROUND: Highly effective generic cardiovascular medications are frequently underused, leading to greater overall drug costs and cost-related nonadherence. OBJECTIVE: We sought to assess an intervention to stimulate appropriate generic cardiovascular drug use without creating administrative or financial barriers that may impede essential medication use. TRIAL DESIGN: The SAMPLES (Study Assessing the Effect of Cardiovascular Medications Provided as Low-cost, Evidence-based Generic Samples) trial is a clustered, randomized controlled trial of the effect of providing physicians with free generic samples of hydrochlorothiazide for hypertensive patients and simvastatin for patients with hyperlipidemia. We will randomize 660 primary care physicians in Pennsylvania, clustered by physician practice, to receive free samples for both conditions or to receive no samples. We will use data on filled prescriptions obtained from a state-sponsored prescription drug assistance program to perform an intention-to-treat evaluation of the impact of the intervention on physician prescribing behavior (proportion of prescriptions that are generic) and patient adherence. Secondary outcomes will include physician adherence to established guidelines and overall prescription drug costs. CONCLUSION: This trial will define the potential role of an innovative approach to stimulate clinically appropriate cost-effective prescribing. We will determine whether free generic samples can reduce overall drug costs as well as out-of-pocket costs to the patient without sacrificing efficacy and whether this approach results in improved adherence to essential cardiovascular medications. This intervention may also improve adherence to practice guidelines and improve the quality of care received. If effective, this strategy could be used broadly by private insurers or government payers aiming to stimulate more cost-effective and higher-quality care.