Healthy Adherer Bias Research Articles

Initiator Types and the Causal Question of the Prevalent New-User Design: A Simulation Study.

New-user designs restricting to treatment initiators have become the preferred design for studying drug comparative safety and effectiveness using nonexperimental data. This design reduces confounding by indication and healthy-adherer bias at the cost of smaller study sizes and reduced external validity, particularly when assessing a newly approved treatment compared with standard treatment. The prevalent new-user design includes adopters of a new treatment who switched from or previously used standard treatment (i.e., the comparator), expanding study sample size and potentially broadening the study population for inference. Previous work has suggested the use of time-conditional propensity-score matching to mitigate prevalent user bias. In this study, we describe 3 "types" of initiators of a treatment: new users, direct switchers, and delayed switchers. Using these initiator types, we articulate the causal questions answered by the prevalent new-user design and compare them with those answered by the new-user design. We then show, using simulation, how conditioning on time since initiating the comparator (rather than full treatment history) can still result in a biased estimate of the treatment effect. When implemented properly, the prevalent new-user design estimates new and important causal effects distinct from the new-user design.

Are patients more adherent to newer drugs?

The annual preventable cost from non-adherence in the US health care system amounts to $100 billion. While the relationship between adherence and the health system, the condition, patient characteristics and socioeconomic factors are established, the role of the heterogeneous productivity of drug treatment remains ambiguous. In this study, we perform cross-sectional retrospective analyses to study whether patients who use newer drugs are more adherent to pharmacotherapy than patients using older drugs within the same therapeutic class, accounting for unobserved heterogeneity at the individual level (e.g. healthy adherer bias). We use US Marketscan commercial claims and encounters data for 2008–2013 on patients initiating therapy for five chronic conditions. Productivity is captured by a drug’s earliest Food and Drug Administration (FDA) approval year (“drug vintage”) and by FDA” therapeutic potential” designation. We control for situational factors as promotional activity, copayments and distribution channel. A 10-year increase in mean drug vintage is associated with a 2.5 percentage-point increase in adherence. FDA priority status, promotional activity and the share of mail-order prescription fills positively influenced adherence, while co-payments had a negative effect. Newer drugs not only may be more effective in terms of clinical benefits, on average. They provide means to ease drug therapy to increase adherence levels as one component of drug quality, a notion physicians and pharmacy benefit managers should be aware of.

The healthy user and healthy adherer bias: a nested case-control study among statin users in the Rotterdam Study

Objective Failure to correct for lifestyle in routinely collected data may lead to the healthy user or healthy adherer bias, because patients who initiate or adhere to preventive therapy (e.g. statins) may have a healthier lifestyle than patients who do not use or adhere to statins, respectively. We aimed to assess if there is a difference in lifestyle between statin users and non-users and between adherent and nonadherent statin users.

Does Good Medication Adherence Really Save Payers Money?

Despite a growing consensus that better adherence with evidence-based medications can save payers money, assertions of cost offsets may be incomplete if they fail to consider additional drug costs and/or are biased by healthy adherer behaviors unobserved in typical medical claims-based analyses. The objective of this study was to determine whether controlling for healthy adherer bias (HAB) materially affected estimated medical cost offsets and additional drug spending associated with higher adherence. A total of 1273 Medicare beneficiaries with diabetes enrolled in Part D plans between 2006 and 2009. Using survey and claims data from the Medicare Current Beneficiary Survey, we measured medical and drug costs associated with good and poor adherence (proportion of days covered ≥ 80% and <80%, respectively) to oral antidiabetic drugs, ACE inhibitors/ARBs, and statins over 2 years. To test for HAB, we estimated pairs of regression models, one set containing variables typically controlled for in conventional claims analysis and a second set with survey-based variables selected to capture HAB effects. We found consistent evidence that controlling for HAB reduces estimated savings in medical costs from better adherence, and likewise, reduces estimates of additional adherence-related drug spending. For ACE inhibitors/ARBs we estimate that controlling for HAB reduced adherence-related medical cost offsets from $6389 to $4920 per person (P<0.05). Estimates of additional adherence-related drug costs were 26% and 14% lower in HAB-controlled models (P < 0.05). These results buttress the economic case for action by health care payers to improve medication adherence among insured persons with chronic disease. However, given the limitations of our research design, further research on larger samples with other disease states is clearly warranted.

Statin use and breast cancer survival: a nationwide cohort study from Finland.

Recent studies have suggested that statins, an established drug group in the prevention of cardiovascular mortality, could delay or prevent breast cancer recurrence but the effect on disease-specific mortality remains unclear. We evaluated risk of breast cancer death among statin users in a population-based cohort of breast cancer patients. The study cohort included all newly diagnosed breast cancer patients in Finland during 1995–2003 (31,236 cases), identified from the Finnish Cancer Registry. Information on statin use before and after the diagnosis was obtained from a national prescription database. We used the Cox proportional hazards regression method to estimate mortality among statin users with statin use as time-dependent variable. A total of 4,151 participants had used statins. During the median follow-up of 3.25 years after the diagnosis (range 0.08–9.0 years) 6,011 participants died, of which 3,619 (60.2%) was due to breast cancer. After adjustment for age, tumor characteristics, and treatment selection, both post-diagnostic and pre-diagnostic statin use were associated with lowered risk of breast cancer death (HR 0.46, 95% CI 0.38–0.55 and HR 0.54, 95% CI 0.44–0.67, respectively). The risk decrease by post-diagnostic statin use was likely affected by healthy adherer bias; that is, the greater likelihood of dying cancer patients to discontinue statin use as the association was not clearly dose-dependent and observed already at low-dose/short-term use. The dose- and time-dependence of the survival benefit among pre-diagnostic statin users suggests a possible causal effect that should be evaluated further in a clinical trial testing statins’ effect on survival in breast cancer patients.

Healthy users, healthy adherers, and healthy behaviors?

In this issue of JBMR, Curtis colleagues (1) use data from the placebo group of a randomized, controlled osteoporosis trial to argue for a possible healthy adherer effect. Our understanding of this effect began when some randomized, controlled clinical trials in cardiovascular disease had cardiovascular outcomes that contradicted findings in prior observational studies. These findings highlighted the fact that several sources of bias can occur in observational studies. These biases can be related to patient behaviors, including both healthy user and healthy adherer effects. The best known examples of these biases have appeared in studies of cardiovascular disease. For example, a large observational study, the Nurses’ Health Study, showed decreased coronary heart disease in women taking hormonereplacement therapy (HRT) in 1985, a finding that was confirmed by other observational studies. However, more than 10 years later, two randomized, controlled clinical trials contradicted the observational findings: The Heart and Estrogen/ Progestin Replacement Study (HERS) showed no cardiovascular benefit from estrogen supplementation, and the Women’s Health Initiative showed increased incidence of cardiovascular events in women taking estrogen. How can we explain this divergence of results? First, we must identify and understand this divergence by understanding sources of bias. The first potential bias, the healthy user effect, occurs when patients who choose to receive one preventive service such as estrogen or a lipid-lowering agent also choose to receive other preventive services such as immunizations and screening tests. For example, patients who adhere to statins more frequently receive vaccinations and screening services. These same patients also may have less comorbidity and better functional status, increasing the likelihood of other healthy behaviors These patients also may be involved in fewer accidents, suggesting possible risk aversion. A second potential bias—the healthy adherer bias—was first demonstrated in 1980 when decreased mortality and fewer cardiovascular events were found in good adherers of placebo in a

Adherence to osteoporosis drugs and fracture prevention: no evidence of healthy adherer bias in a frail cohort of seniors

Adherence to osteoporosis drugs and fracture prevention: no evidence of healthy adherer bias in a frail cohort of seniors

Methods to examine the impact of compliance to osteoporosis pharmacotherapy on fracture risk: systematic review and recommendations

The objective of this study was to review the methods of prior studies that estimate the association between compliance to osteoporosis pharmacotherapy on fracture risk, and make recommendations to guide future research. We completed a systematic search of MEDLINE to identify all English language nonexperimental studies that examined the impact of adherence to osteoporosis pharmacotherapy on fracture risk. Studies that measured compliance were eligible and those that only examined persistence were excluded. We summarized the methodology of each study and make recommendations for future research. We identified 14 eligible articles: nine cohort and five nested case-control. Length of baseline (lookback) periods ranged between 3 months and 2 years, with nearly all studies (86%) restricting inclusion to treatment-naïve users. A threshold of 80% was most commonly used to define compliance (n = 10), with few studies providing a more thorough analysis through categorical (n = 3) or continuous (n = 1) measures. All nine cohort studies adjusted for age, sex, prior fracture, and at least one other comorbidity or drug; two cohort studies adjusted for a comorbidity score. Two of the five case-control studies clearly controlled for age, sex, drug exposure, event date and length of follow up. One study considered a theoretical sensitivity analysis to account for potential healthy adherer bias, yet all mentioned limitations related to possible residual confounding. We identify great variability in methods of prior studies that evaluate the impact of compliance to osteoporosis pharmacotherapy on fracture risk, and make recommendations to guide future research.

Adherence to osteoporosis drugs and fracture prevention: no evidence of healthy adherer bias in a frail cohort of seniors

We examined new users of osteoporosis drugs among seniors in Pennsylvania and found no evidence of healthy adherer bias on observed associations between adherence to treatment and non-vertebral fracture risk; we document fracture reduction with better adherence to bisphosphonates, yet no fracture reduction with better adherence to calcitonin or raloxifene. We examined the potential for "healthy adherer bias" when studying the effects of adherence to osteoporosis pharmacotherapy on fracture risk. Based on clinical trial evidence, bisphosphonates, calcitonin, and raloxifene reduce vertebral fracture risk; yet only bisphosphonates are documented to reduce non-vertebral fracture risk. This is a cohort study of older women in Pennsylvania who initiated osteoporosis drugs between 1995 and 2005. We included new users of bisphosphonates, calcitonin, and raloxifene. Adherence was categorized based on a measure of compliance as high [proportion of days covered (PDC) ≥ 80%], intermediate (50% < PDC < 80%), or low (PDC ≤ 50%) according to a 180-day ascertainment period. Non-vertebral fracture rates within 365 days after the ascertainment period were compared between adherence categories (reference = low) using Cox proportional hazard models and adjusting for fracture risk factors. Primary and secondary prevention cohorts were examined separately. Adherence to calcitonin and raloxifene were control analyses. We found little difference in fracture rates between levels of adherence to calcitonin, bisphosphonates for primary prevention, or raloxifene for secondary prevention. We document lower fracture rates among high versus low adherent bisphosphonate users for secondary prevention (HR = 0.53, 95%CI = 0.38-0.74) and higher fracture rates among high versus low adherent raloxifene users for primary prevention (HR = 2.01, 95%CI = 1.04-3.87). We document little evidence of healthy adherer bias when studying the association between better adherence to osteoporosis drugs and fracture risk reduction, with only better adherence to bisphosphonates reducing fracture risk. The higher fracture risk among highly adherent raloxifene users for primary prevention is likely due to residual confounding.