Urate-lowering therapy in patients with hyperuricemia and heart failure: A retrospective cohort study using the UK Clinical Practice Research Datalink.

BACKGROUND: Elevated serum uric acid (sUA) is associated with heart failure (HF). HYPOTHESIS: Urate-lowering therapy (ULT) in HF is associated with lower risk of HF hospitalization (hHF) and mortality. METHODS: Data on patients with HF and gout or hyperuricemia in the Clinical Practice Research Datalink database linked to the Hospital Episode Statistics and the Office for National Statistics in the United Kingdom were analyzed. Risks of hHF and all-cause mortality or cardiovascular-related mortality by ULT exposure (ULT initiated within ≤6 months of gout or hyperuricemia diagnosis) were analyzed in a propensity score-matched cohort using adjusted Cox proportional hazards regression models. RESULTS: Of 2174 propensity score-matched pairs, patients were predominantly male, aged >70 years, with mean ± standard deviation sUA 9.3 ± 1.8 (ULT-exposed) and 9.4 ± 1.9 mg/dL (ULT-unexposed). At 5 years, ULT-exposed patients had a 43% lower risk of hHF or all-cause mortality (adjusted hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.51-0.65) and a 19% lower risk of hHF or cardiovascular-related mortality (adjusted HR: 0.81; 95% CI: 0.71-0.92) versus no ULT exposure. CONCLUSION: ULT was associated with reduced risk of adverse clinical outcomes in patients with HF and gout or hyperuricemia over 5 years.

Multimorbidity, functional impairment, and mortality in older patients stable after prior acute myocardial infarction: Insights from the TIGRIS registry.

BACKGROUND: Data on the association of multimorbidity and functional impairment with cardiovascular (CV) and non-CV outcomes among older myocardial infarction (MI) patients are limited. HYPOTHESIS: Multimorbidity and functional impairment among older MI patients are associated with CV and non-CV mortality. METHODS: Patients aged ≥65 years, 1-3 years post-MI, and enrolled between June 2013 and Novemeber 2014 from 349 sites in 25 countries in the global TIGRIS registry were categorized by age, number of comorbidities, and presence and degree of functional impairment. Functional impairment was calculated using five-dimension EuroQol based on three domains-mobility, self-care, and usual activities. The association between age, number of comorbid conditions, and degree of functional impairment with 2-year incidence of CV and non-CV death was evaluated using Poisson regression analysis. RESULTS: Older age was associated with higher number of comorbidities and functional impairment; after adjustment, increasing age was significantly associated with non-CV mortality (p = .03) but not CV mortality (p = .38). Greater functional impairment was associated with a higher rate and relatively equal magnitude risk of CV (rate ratios [RR] 1.52, 95% confidence intervals [CI]: 1.29-1.79, per one-step increase) and non-CV mortality (RR 1.42, 95% CI: 1.17-1.73). Multimorbidity was more strongly associated with CV mortality (RR 1.52, 95% CI: 1.38-1.67, per additional comorbidity) versus non-CV mortality (RR 1.29, 95% CI: 1.14-1.47, per additional comorbidity). CONCLUSIONS: Multimorbidity and functional impairment are prevalent among older post-MI patients and are associated with increased CV and non-CV mortality. These findings highlight the importance of considering comorbid conditions and functional impairment as predictors of risk for adverse outcomes and aspects of medical decision making. Clinical Trial Registration: NCT01866904.

Determinants of long-term dual antiplatelet therapy use in post myocardial infarction patients: Insights from the TIGRIS registry.

BACKGROUND: Patterns of dual antiplatelet therapy (DAPT) use beyond 1 year post-myocardial infarction (MI) have not been well studied. METHODS: TIGRIS (NCT01866904) was a prospective, multi-center (369 centers in 24 countries), observational study of patients 1 to 3 years post-MI. We sought to identify the prevalence and determinants of DAPT use ≥1 year post-MI in patients enrolled in TIGRIS. We used multivariable logistic regression to identify determinants of DAPT use at 396 days post-MI (365 days plus a 31day overrun period to account for intended DAPT discontinuation at 1 year). Patients treated with an oral anticoagulant were excluded. RESULTS: Of 7708 patients (median age 67 years, women 25%, ST-elevation MI 50%), 39% and 16% were on DAPT at 396 days and 5 years post-MI, respectively. DAPT use at 396 days post-MI was more prevalent in patients <65 years of age, treated with percutaneous coronary intervention (versus coronary artery bypass grafting or medical therapy), and with multivessel disease or a history of angina. Additional clinical determinants of ischemic and/or bleeding events following MI (diabetes, second prior MI, hypertension, peripheral artery disease, heart failure, smoking, and renal insufficiency) were not independently associated with DAPT use at 396 days. There were geographic variations in the use of DAPT at 396 days (p<0.001), with the lowest use in Europe and the highest in Asia and Australia. CONCLUSION: In a contemporary patient cohort, DAPT use beyond 1 year post MI was prevalent and associated with patient and index event characteristics. There were marked geographical variations in DAPT use beyond 1 year post MI.

Assessment of The High risk and unmEt Need in patients with CAD and type 2 diabetes (ATHENA): US healthcare resource use, cost, and burden of illness in a commercially insured population.

AIMS: THEMIS (NCT01991795) demonstrated cardioprotective benefits of ticagrelor plus acetylsalicylic acid (ASA) compared with placebo plus ASA in patients with type 2 diabetes (T2D), stable coronary artery disease (CAD) and no history of myocardial infarction (MI) or stroke. To complement these findings, we assessed clinical outcomes and healthcare costs in commercially insured US patients similar to those in THEMIS. METHODS: This retrospective, observational study used data from Optum. The T2D-CAD cohort (n = 154,369) included patients (≥50 years old) either with high cardiovascular risk or taking a P2Y12 inhibitor. The THEMIS-like cohort (n = 126,938) comprised patients (≥50 years old) at high cardiovascular risk; the THEMIS-PCI-like cohort comprised a subset of these patients with prior percutaneous coronary intervention (PCI) (n = 18,394). RESULTS: Mean follow-up was 2.4-2.5 years. Incidence rates of the composite outcome (death, MI, and stroke) were 6.56 (95% CI 6.50-6.63), 6.21 (6.14-6.28), and 5.57 (5.39-5.74) per 100 person-years, and annualized healthcare costs per patient were US$15,848, US$16,044, and US$20,934 for the T2D-CAD, THEMIS-like, and THEMIS-PCI-like cohorts, respectively. CONCLUSIONS: Commercially insured patients similar to those in THEMIS had high cardiovascular event rates and healthcare costs, highlighting a need for improved preventive strategies.

Demonstrating that Real World Evidence Is Fit-For-Purpose to Support Labeling: Parallels to Patient Reported Outcomes in the Pursuit of Labeling Claims.

INTRODUCTION: In December 2021, U.S. Food & Drug Administration (FDA) will issue guidance on the use of real-world evidence (RWE) to support new indications or expanded product labeling. While difficult to foresee what FDA will require, learnings can be gleaned from previous paradigm shifts at FDA, such as for patient reported outcomes (PROs) in 2006-2009. METHODS: We contrast published requirements for justifying PROs as fit-for-purpose for a specific labeling claim with a potential approach to justify RWE as fit-for-purpose to support expanded labeling or a new indication. RESULTS: PRO labeling claims require a PRO Evidence Dossier that includes: specific wording of claim, clinical trial hypothesis structure and endpoint model, and justification that the PRO is relevant and meaningful to patients in the target population (content validity) with adequate psychometric properties. FDA's 2018 RWE Framework outlined critical considerations for using RWE to support regulatory decisions, including data quality, relevancy, provenance, and transparency. Strong parallels exist between the evidence required to justify that PROs are fit-for-purpose to support specific labeling claims and evidence to justify RWE as fit-for-purpose for specific research questions and labeling. Early discussion with FDA is encouraged. CONCLUSION: Drawing on parallels with use of PROs in labeling, RWE for regulatory purposes should be evaluated within the context of specific labeling or indication, specific study design and analysis plans, and the data attributes of data source. Sponsors seeking a new indication or labeling expansion based on RWE should justify that a specific data source and specific study design are fit-for-purpose.

Two-year outcomes among stable high-risk patients following acute MI. Insights from a global registry in 25 countries.

BACKGROUND: Evidence is lacking on long-term outcomes in unselected patients surviving the first year following myocardial infarction (MI). METHODS AND RESULTS: The TIGRIS (long-Term rIsk, clinical manaGement and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients) prospective registry enrolled 9176 eligible patients aged ≥50 years, 1-3 years post-MI, from 25 countries. All had ≥1 risk factor: age ≥ 65 years, diabetes mellitus, second prior MI, multivessel coronary artery disease, chronic kidney disease (CKD). Primary outcome was a composite of MI, unstable angina with urgent revascularization, stroke, or all-cause death at 2-year follow-up. Bleeding requiring hospitalization was also recorded. 9027 patients (98.4%) provided follow-up data: the primary outcome occurred in 621 (7.0%), all-cause mortality in 295 (3.3%), and bleeding in 109 (1.2%) patients. Events accrued linearly over time. In multivariable analyses, qualifying risk factors were associated with increased risk of primary outcome (incidence rate ratio [RR] per 100 patient-years [95% confidence interval]): CKD 2.06 (1.66, 2.55), second prior MI 1.71 (1.38, 2.10), diabetes mellitus 1.63 (1.39, 1.92), age ≥ 65 years 1.53 (1.28, 1.83), and multivessel disease 1.24 (1.05, 1.48). Risk of bleeding events was greater in older patients (vs <65 years) 65-74 years 2.68 (1.53, 4.70), ≥75 years 4.62 (2.57, 8.28), and those with CKD 1.99 (1.18, 3.35). CONCLUSION: In stable patients recruited 1-3 years post-MI, recurrent cardiovascular and bleeding events accrued linearly over 2 years. Factors independently predictive of ischemic and bleeding events were identified, providing a context for deciding on treatment options.

Predicting risk of cardiovascular events 1 to 3 years post-myocardial infarction using a global registry.

BACKGROUND: Risk prediction tools are lacking for patients with stable disease some years after myocardial infarction (MI). HYPOTHESIS: A practical long-term cardiovascular risk index can be developed. METHODS: The long-Term rIsk, Clinical manaGement and healthcare Resource utilization of stable coronary artery dISease in post-myocardial infarction patients prospective global registry enrolled patients 1 to 3 years post-MI (369 centers; 25 countries), all with ≥1 risk factor (age ≥65 years, diabetes mellitus requiring medication, second prior MI, multivessel coronary artery disease, or chronic non-end-stage kidney disease [CKD]). Self-reported health was assessed with EuroQoL-5 dimensions. Multivariable Poisson regression models were used to determine key predictors of the primary composite outcome (MI, unstable angina with urgent revascularization [UA], stroke, or all-cause death) over 2 years. RESULTS: The primary outcome occurred in 621 (6.9%) of 9027 eligible patients: death 295 (3.3%), MI 195 (2.2%), UA 103 (1.1%), and stroke 58 (0.6%). All events accrued linearly. In a multivariable model, 11 significant predictors of primary outcome (age ≥65 years, diabetes, second prior MI, CKD, history of major bleed, peripheral arterial disease, heart failure, cardiovascular hospitalization (prior 6 months), medical management (index MI), on diuretic, and poor self-reported health) were identified and combined into a user-friendly risk index. Compared with lowest-risk patients, those in the top 16% had a rate ratio of 6.9 for the primary composite, and 18.7 for all-cause death (overall c-statistic; 0.686, and 0.768, respectively). External validation was performed using the Australian Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events registry (c-statistic; 0.748, and 0.849, respectively). CONCLUSIONS: In patients >1-year post-MI, recurrent cardiovascular events and deaths accrue linearly. A simple risk index can stratify patients, potentially helping to guide management.

Adherence to antidepressants among women and men described with trajectory models: a Swedish longitudinal study.

PURPOSE: The purpose of this study are to analyse adherence to antidepressant treatment over 2 years in Sweden among women and men who initiated treatment with citalopram and to identify groups at risk of non-adherence using trajectory models. METHODS: The study population, including individuals 18-85 years who initiated citalopram use between 1 July 2006 and 30 June 2007, was identified in the Swedish Prescribed Drug Register and followed for 2 years. Adherence was estimated with continuous measure of medication acquisition (CMA) and group-based trajectory modelling, a method which describes adherence patterns over time by estimating trajectories of adherence and the individual's probability of belonging to a specific trajectory. RESULTS: The study population included 54,248 individuals, 64 % women. Mean CMA was 52 % among women and 50 % among men (p < 0.001). Five different adherence patterns (Trajectories) were identified. Similar proportion of women and men belonged to each Trajectory. Around 29 % of the women and 27 % of the men belonged to the Trajectory which showed full adherence throughout the 2-year study period. The other four Trajectories showed adherence that declined to different degrees and at different stages in time. Having low socioeconomic status was more common among individuals in Trajectories showing declining adherence than in the adherent Trajectory. CONCLUSIONS: Using trajectory modelling, five Trajectories describing different patterns of adherence to citalopram treatment over time were identified. A large proportion discontinued treatment early and having low socioeconomic status increased the risk of being non-adherent.

Refill Adherence in Relation to Substitution and the Use of Multiple Medications: A Nationwide Population Based Study on New ACE-Inhibitor Users.

OBJECTIVE: Generic substitution has contributed to economic savings but switching products may affect patient adherence, particularly among those using multiple medications. The aim was to analyse if use of multiple medications influenced the association between switching products and refill adherence to angiotensin-converting-enzyme (ACE) inhibitors in Sweden. STUDY DESIGN AND SETTING: New users of ACE-inhibitors, starting between 1 July 2006 and 30 June 2007, were identified in the Swedish Prescribed Drug Register. Refill adherence was assessed using the continuous measure of medication acquisition (CMA) and analysed with linear regression and analysis of covariance. RESULTS: The study population included 42735 individuals whereof 51.2% were exposed to switching ACE-inhibitor and 39.6% used multiple medications. Refill adherence was higher among those exposed to switching products than those not, but did not vary depending on the use of multiple medications or among those not. Refill adherence varied with age, educational level, household income, country of birth, previous hospitalisation and previous cardiovascular diagnosis. CONCLUSION: The results indicate a positive association between refill adherence and switching products, mainly due to generic substitution, among new users of ACE-inhibitors in Sweden. This association was independent of use of multiple medications.

Consumer preferences for over-the-counter drug retailers in the reregulated Swedish pharmacy market.

Following a large regulatory reform in 2009, which ended the state's pharmacy monopoly, non-pharmacy retailers in Sweden today sell certain over-the-counter (OTC) drugs. The aim of this study was to investigate consumer preferences regarding OTC drug retailers and the reasons for choosing a pharmacy versus non-pharmacy retailer. We conducted a web survey aimed at Swedish adults. Out of a stratified sample of 4058 persons, 2594 agreed to take part (48% women; mean age: 50.3 years). Questions related to OTC drug use, retailer choice and factors affecting the participants' preferences for OTC drug retailers. Logistic regression was conducted to analyse OTC drug use and reasons for retailer choice in relation to sex, age and education. Nine in ten participants reported OTC drug use in the 6 months prior to the study. For their last OTC purchase, 76% had gone to a pharmacy, 20% to a grocery shop and 4% to a convenience store, gas station or online. Geographic proximity, opening hours and product range were reported as the most important factors in retailer choice. Counselling by trained staff was important to 57% of participants. The end of the state's pharmacy monopoly and the increase in number of pharmacies seem to have impacted more on Swedish consumers' purchase behaviours compared with the deregulation of OTC drug sales.

Effects of generic substitution on refill adherence to statin therapy: a nationwide population-based study.

BACKGROUND: Several countries have introduced generic substitution, but few studies have assessed its effect on refill adherence. This study aimed to analyse whether generic substitution influences refill adherence to statin treatment. METHODS: Between 1 July 2006 and 30 June 2007, new users of simvastatin (n = 108,806) and atorvastatin (n = 7,464) were identified in the Swedish Prescribed Drug Register . The present study included atorvastatin users as an unexposed control group because atorvastatin was patent-protected and thus not substitutable. We assessed refill adherence using continuous measure of medication acquisition (CMA). To control for potential confounders, we used analysis of covariance (ANCOVA). Differences in CMA associated with generic substitution and generic substitution at first-time statin purchase were analysed. RESULTS: Nine of ten simvastatin users were exposed to generic substitution during the study period, and their adherence rate was higher than that of patients without substitution [84.6% (95% CI 83.5-85.6) versus 59.9% (95% CI 58.4-61.4), p < 0.001]. CMA was higher with increasing age (60-69 years 16.7%, p < 0.0001 and 70-79 years 17.8%, p < 0.0001, compared to 18-39 years) and secondary prevention (12.8%, p < 0.0001). CMA was lower among patients who were exposed to generic substitution upon initial purchase, compared to those who were exposed to a generic substitution subsequently [80.4% (95% CI 79.4-90.9) versus 89.8% (88.7-90.9), p < 0.001]. This difference decreased when those with only one statin purchase were excluded. CONCLUSIONS: Statin refill adherence was higher among patients who exposed to generic substitution compared to those who were not. Increasing age and previous cardiovascular disease affected refill adherence.

Socio-economic determinants of early discontinuation of anti-depressant treatment in young adults.

BACKGROUND: Early discontinuation of anti-depressant treatment is common. This study analysed whether socio-economic factors influence early discontinuation among new anti-depressant users aged 20-34 years. METHODS: Our study population included all Swedes aged 20-34 years who purchased anti-depressants in 2006 and had not purchased such drugs in the preceding 6 months (n = 25,003). We obtained prescription data from the Swedish Prescribed Drug Register. Information about demographic and socio-economic factors (country of birth, marital status, household size, education level, occupation, income and social assistance) was collected from Statistics Sweden by record linkage. We defined early discontinuation as filling only one anti-depressant prescription within a 6-month period. We used multiple logistic regression analysis to analyse the socio-economic factors associated with early discontinuation. RESULTS: We identified 6536 individuals (26.1%) as early discontinuers. Early discontinuation was less common among women [odds ratio (OR) = 0.82; 95% confidence intervals (CI) 0.75-0.87] and in those with at least two years of higher education (OR = 0.71; 95% CI 0.61-0.83), whereas it was more common among those born outside Sweden (OR = 1.76; 95% CI 1.48-2.10) and those who received social assistance (OR = 1.26; 95% CI 1.11-1.44). Compared with selective serotonin re-uptake inhibitors, SSRI, early discontinuation was more common among individuals who started treatment with a tri-cyclic anti-depressant, TCA, (OR = 2.58; 95% CI 2.24-2.98) or an anti-depressant other than SSRIs, TCAs or selective serotonin-norepinephrine re-uptake inhibitors/norepinephrine (noradrenaline) re-uptake inhibitors (OR = 2.90; 95% CI 2.05-4.10). CONCLUSION: Early discontinuation occurred more commonly among social assistance recipients and those with immigrant background, suggesting that those groups might require greater support when initiating anti-depressant therapy.

A comparison of two methods for estimating refill adherence to statins in Sweden: the RARE project.

PURPOSE: To analyse and compare refill adherence to statins estimated with two different methods with a focus on sensitivity to definitions. METHODS: Individuals aged 18-85 years who filled a statin prescription for the first time in 1.5 years during 1 January-30 June 2007 were followed until emigration or death or until 2 years after their first statin purchase. The data were collected via linkage between the Swedish Prescribed Drug Register, the National Patient Register and the Total Population Register. Days' supply was estimated based on amount dispensed and prescribed dosage. Refill adherence was estimated with the continuous measure of medication acquisition (CMA) and the maximum gap method (cut-off 45 days). The impact of altering definitions, for example, regarding hospitalisations, length of observation period and management of overlapping supply, was analysed. RESULTS: The study included 36, 661 individuals (mean age 64 years, 47% women). The median proportion of days with statins was 95%, and 76% were classified as adherent with a cut-off at ≥ 80% with CMA. With the maximum gap method, 65% were adherent. Disregarding hospitalisations did not alter the results. Emigration or death at least one year after statin initiation was associated with a lower adherence with both methods, and a shorter observation period and adding overlapping supply to the subsequent prescription increased the adherence estimates. CONCLUSIONS: The choice of method and definitions, particularly regarding the management of overlapping supplies and the length of observation period, has a substantial impact on estimates of refill adherence to statins.

Clinical use and effectiveness of lipid lowering therapies in diabetes mellitus--an observational study from the Swedish National Diabetes Register.

OBJECTIVES: To describe the use and evaluate the effectiveness of different lipid lowering therapies in unselected patients with type 1 and type 2 diabetes in clinical practice. DESIGN: Observational population-based study using the personal identification number to link information from the National Diabetes Register, the Prescribed Drug Register and the Patient register in Sweden. All patients in the NDR aged 18-75 years with diabetes more than one year were eligible, but only patients starting any lipid lowering treatment with at least three prescriptions 1 July 2006-30 June 2007 were included (n = 37,182). The mean blood lipid levels in 2008 and reductions in LDL cholesterol were examined. RESULTS: Blood lipid levels were similar in patients treated with simvastatin, atorvastatin and rosuvastatin, showing similar lipid lowering effect as currently used. Users of pravastatin, fluvastatin, ezetimib and fibrate more seldom reach treatment goals. Moderate daily doses of the statins were used, with 76% of simvastatin users taking 20 mg or less, 48% of atorvastatin users taking 10 mg, 55% of pravastatin users taking 20 mg, and 76% of rosuvastatin users taking 5 or 10 mg. CONCLUSIONS: This observational study shows that the LDL-C levels in patients taking simvastatin, atorvastatin or rosuvastatin are very similar as currently used, as well as their LDL-C lowering abilities. There is potential to intensify lipid lowering treatment to reduce the remaining high residual risk and achieve better fulfilment of treatment goals, since the commonly used doses are only low to moderate.

Antidepressant utilization patterns and mortality in Swedish men and women aged 20-34 years.

PURPOSE: To compare antidepressant utilization patterns and mortality in relation to antidepressant use in men and women aged 20-34 years. METHODS: We used data from the Swedish Prescribed Drug Register to identify adults aged 20-34 years who purchased at least one antidepressant in 2006. Information on death and migration was obtained from the Total Population Register by record linkage. One-year prevalence and proportion of new users, amount of purchased antidepressants, concurrent use of other antidepressants, mood stabilizers and antipsychotics and mortality were assessed. RESULTS: The one-year prevalence of antidepressant use was 5.6% among all Swedes aged 20-34 years (n = 94,239) and was higher among women than men (7.2 vs. 4.0%, p < 0.001). Selective serotonin reuptake inhibitors were the most dominant class of antidepressants at baseline and were more common among women than men (78.7 vs. 71.7%, p < 0.001). Of the new users, 22.3% filled only one prescription during the study period, men more often than women (24.1 vs. 21.4%, p < 0.001). The mortality rate was higher in men than in women (24 vs. 14 per 10,000, p = 0.009). Concurrent use of mood stabilizers (48 vs. 16 per 10,000, p < 0.001) and antipsychotics (50 vs. 14 per 10,000, p < 0.001) was associated with increased mortality in men and women. CONCLUSIONS: Almost twice as many Swedish women than men aged 20-34 years purchased antidepressants in 2006. Differences in utilization patterns between sexes were rather small. Discontinuation rates were high, indicating that health care providers need to acquire an increased awareness on attitudes to treatment. In both sexes, mortality rates were elevated among those concurrently using mood stabilizers and antipsychotics, which needs further investigation.