Patterns of Lipid Lowering Therapy, Adherence and Up-titration in Older Adults

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2019-08

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  1. Background and rationale: Cardiovascular (CV) diseases are one of the leading causes of death in adults in the United States and are associated with a significant economic burden costing $200 billion each year which includes the cost of lost productivity. Additionally the US population is aging and increasing age is a risk factor for CV events. In 2014, 14.5% of the US population was aged 65 or older. Much of the chronic disease burden results from known risk factors which need to be effectively addressed to improve health outcomes. High levels of low-density lipoprotein cholesterol (LDL-C) has been associated with the development of CV diseases. Several classes of lipid lowering therapies (LLT) are available for reduction of LDL-C levels. Of the available LLT, statins have been the main stay of therapy for several decades and have been recommended in the clinical practice guidelines as the primary pharmacologic agents for LDL-C lowering. In recent years, new classes of drugs have become available in addition to existing agents now available as generic drugs, allowing more options for patient treatment. Results from recent clinical trials have also demonstrated that lower LDL-C values reduce the risk of CV events, with unprecedented mean values of 30 mg/dl achieved in these trials.

1.1. Current guidelines for LDL-C management: The 2018 American College of Cardiology and American Heart Association (ACC/AHA) guidelines identified patient groups that benefit from statin treatment; 1) secondary atherosclerotic cardiovascular disease (ASCVD) prevention 2) primary severe hypercholesterolemia i.e. LDL-C ≥190 mg/dl; 3) diabetes and age 40-75 years or 4) primary prevention of ASCVD. There is scarcity of evidence regarding the benefits of LLT in patients aged 75 years and above. For these patients, the ACC/AHA 2018 guidelines suggest continuing a statin if the patient is already tolerating a statin, initiation of a moderate intensity statin for secondary prevention and not starting a statin for primary prevention based on patient risk, frailty and preferences. The publication of new trial results, the availability of new therapy and the increasing prevalence of older adults using LLT coupled with less evidence regarding benefit in patients >75 make it pertinent to understand the current patterns of use of LLT in older adults.

1.2. Lipid lowering therapy management: Patients on LLT may have treatment modifications due to reasons ranging from adverse events to goal achievement or even formulary changes. If a patient does not achieve goal LDL-C reduction, a physician may up-titrate i.e., increase the potency of the LLT with an intention to lower LDL-C incrementally. On the other hand, LLT may be down-titrated or switched due to various reasons including but not limited to poor tolerability, attainment of lipid goals, or introduction of a new therapy into the regimen. Failure to intensify LLT in patients who have not achieved the goal LDL-C reduction could result in suboptimal LDL-C lowering in patients. Often times, the term clinical inertia has been used to characterize the failure of providers to modify therapy based on guidelines when the patients have suboptimal responses from existing medications. Even though clinical inertia appears to be physician behavior, it may actually result from various physician, patient or system related factors. As the evidence generated since the publication of recent trials emphasizes up-titration of LLT to achieve lower LDL-C, an understanding of the factors that predict treatment up-titration in older adults is important. The focus again is older adults as they are more prone to adverse events from statins but are also at a higher risk of CV events.

1.3. The role of adherence in management of therapy: Medication adherence is an important factor which affects achievement of the maximal therapeutic effect from the LLT. Management of therapy via switching, medication up-titration or down titration may include a window of repeated exposure to the healthcare system. This could include lipid testing, physician and pharmacy visits allowing opportunities for patient education and clarification which in turn may positively impact a patient’s adherence. Studies evaluating the relationship between medication adherence and treatment up-titration for chronic conditions have inconsistent results.

Although there is some evidence that treatment modification can potentially affect adherence, there were no studies specifically assessing the association of LLT up-titration with change in medication adherence. Both up-titration and medication adherence however, affect the cumulative exposure of the patient to the drug which affects disease control and management. It is therefore important to determine what effect treatment up-titration has on adherence and whether it could compromise or enhance the ability to attain treatment goals.

  1. Objectives: Aim 1: To describe the real-world treatment patterns and characteristics of patients on lipid lowering therapy in a Medicare Advantage Plan. This was a descriptive aim to understand the current patterns of LLT in clinical settings. Aim 2: To identify the sociodemographic and clinical predictors of treatment up-titration in older adults on lipid lowering therapy with a subgroup analysis in patients with uncontrolled LDL-C values at baseline (LDL-C > 70 mg/dl in patients with ASCVD). Hypothesis: There is variation in the up-titration of LLT across patient sociodemographic and clinical factors. Aim 3: Measure changes in adherence to lipid lowering therapy over time after treatment up-titration. Hypothesis: Up-titration of lipid lowering therapy affects subsequent LLT adherence.

  2. Main findings: The study aims 1 and 2 had 14,360 patients using LLT. Most of them (99%) were on monotherapy and using statins (99%). Non-statin use was 2.1% either as monotherapy or as a combination. A majority of the LLT users were prevalent users (92.6%), i.e. they had some LLT use in the 1-year pre-index period. Prevalent users had fewer changes, interruptions and discontinuations as compared to new users. In a subgroup analysis of patients ≥ 75 years of age as compared to patients 65-74, it was observed that older patients were more likely to be on stable therapy, i.e. have fewer changes, up- and down titrations. Switching, interruption and discontinuation of therapy was not significantly different between patients aged 65 - 74 and patients ≥ 75 years. Predictors of treatment up-titration included younger age groups, having low income subsidization for pharmacy, hypertension and pre-index down titrations. Patients with higher CMS risk score, ASCVD, prevalent users and patients with pre-index up-titration were less likely to receive treatment up-titration in the follow-up period. In the subgroup of patients with ASCVD and with LDL-C values ≥ 70 mg/dl, increasing LDL-C value was associated with increased likelihood of up-titration. Differences in the subgroup from the overall cohort included increased likelihood to up-titrate among patients with diabetes and among patients who were adherent (proportion of days covered for LLT ≥ 0.8) at baseline. In the evaluation of the relationship between treatment up-titration and adherence, it was found that patients with no changes in the pre-index period had overall higher mean (SE) adherence measured as proportion of days covered (PDC) of 0.88 (0.12) but it decreased to 0.86 (0.16) in the follow-up period. Patients with an up-titration had a pre-PDC of 0.72 (0.26) and patients with other changes such as down-titration and switching had a pre-index mean PDC of 0.62 (0.27). In the model which evaluated the change in PDC over time, there was a decrease in monthly PDC for all the three study groups (no change, up-titration, and other changes) pre-index but all the groups had a significant increase in the PDC each month after the index date. The PDC for the no change group changed from a mean decrease by 1.4% each month to an increase by 0.3% each month after the index date. Similarly the PDC change was 1.1% decrease pre-index which changed to an increase of 1% each month for the group which had an up-titration at the index date. Lastly for the group which had other changes on or prior to the index date, the change in PDC each month pre-index was a 0.9% decrease and it shifted to a mean increase of 1.9% each month post index date.

  3. Summary: Older adults on lipid lowering therapy were more likely to be stable users with fewer treatment changes, but new users had greater interruptions and discontinuations requiring more care for these high risk patients. Older patients, prevalent users, and patients with a higher risk score (indicating sicker patients) were less likely to receive treatment up-titration. High risk conditions for CV events like diabetes and hypertension were associated with an increased likelihood of up-titration. This cohort of patients was being prescribed LLT in accordance with recommendations from the guidelines. Both up-titration as well as other treatment changes were associated with an improvement in adherence to LLT indicating that regular monitoring of patients by providers may act as an effective intervention to counter the decline in adherence seen with chronic medications over time.

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Keywords

LDL-C lowering, Retrospective cohort study, Older adults, Cardiovascular diseases

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