In clinical settings, poor compliance is a major obstacle in achieving the full benefits of statin therapy. We examined switching, discontinuation, and reinitiation of statins among older adults.
Pharmaceutical Benefits Scheme (PBS) data for a 10% random sample of the Australian population were analyzed (1). Adults ≥65 years of age newly dispensed (without dispensation in the previous 12 months) atorvastatin, simvastatin, rosuvastatin, pravastatin, or fluvastatin between January 1, 2007 and December 31, 2015 were followed until death or December 31, 2016, whichever occurred first. Statins were stratified into low, moderate, or high intensity according to their low-density lipoprotein cholesterol–lowering capacity. Analysis was restricted to individuals for whom complete dispensing records were available (1).
Switching was defined as the first change in statin or intensity. For each person, we calculated the number of days on statin assuming a dosage of 1 tablet daily. Discontinuation was defined as the first ≥90 days without statin coverage and reinitiation as statin dispensation between discontinuation and end of follow-up.
We characterized users who switched, discontinued, or restarted statins by demographics, prescriber-type, statin type and intensity, comorbidities, other cardiovascular medication use, lifestyle factors, and polypharmacy. Comorbidities were identified using medication records for the 12 months preceding statin initiation via the validated Rx-Risk-V tool (2). The association between covariates and switching, discontinuation, and reinitiation of statins were examined using competing-risk (of death) proportional regression models. Analyses were performed using STATA version 14.0/IC (StataCorp, College Station, Texas). The Monash University Human Research Ethics Committee approved the study.
A total of 49,380 statin initiators (mean age 73.4 ± 6.9 years) were followed over a mean duration of 5.2 ± 2.7 years, and 7,998 deaths occurred. Of the cohort, 19.9% (9,820 of 49,380) switched statin and 20.7% (10,226 of 49,380) switched intensity. Overall, 63.6% (31,407 of 49,380) discontinued, of whom 60.4% (18,977 of 31,407) restarted. The median number of days to first discontinuation was 246 (interquartile range [IQR]: 120 to 653). Among the reinitiators, the median number of days from discontinuation to restarting was 102 (IQR: 34 to 335). The unadjusted rates of switching, discontinuation, and reinitiation per 100 person-years are presented in Table 1.
TABLE 1.
Statin Switching, Discontinuation, and Reinitiation Rates (Per 100 Person-Years)
| Number Initiated | Switching | Discontinuation | Reinitiation | ||
|---|---|---|---|---|---|
| Statin | Intensity | ||||
| All | 49,380 | 3.7 | 3.9 | 24.4 | 33.1 |
| Female | 26,795 | 3.8 | 3.7 | 25.1 | 30.2 |
| Age, yrs | |||||
| 65–74 | 31,105 | 4.2 | 4.3 | 23.2 | 37.6 |
| 75–84 | 14,179 | 3.2 | 3.4 | 24.8 | 28.9 |
| ≥85 | 4,096 | 1.6 | 2.1 | 36.0 | 16.9 |
| Statin | |||||
| Simvastatin | 5,470 | 4.8 | 4.0 | 29.0 | 28.9 |
| Atorvastatin | 24,223 | 4.1 | 4.0 | 23.9 | 32.1 |
| Rosuvastatin | 18,529 | 2.8 | 3.6 | 23.5 | 37.2 |
| Other statin type | 1,158 | 5.5 | 5.8 | 29.2 | 23.5 |
| GP prescriber | 21,597 | 3.6 | 3.8 | 28.9 | 31.3 |
| Diabetes | 6,351 | 3.9 | 4.1 | 26.6 | 45.6 |
| Dementia | 299 | 0.4 | 0.8 | 32.9 | 9.3 |
| Malignancy | 602 | 2.9 | 3.5 | 24.0 | 30.8 |
| Psychotic illness | 898 | 2.3 | 2.9 | 27.7 | 26.5 |
| Platelet inhibitor use | 12,639 | 3.6 | 4.1 | 21.3 | 33.2 |
| Use of ACE inhibitor/ARB | 27,139 | 3.7 | 3.9 | 22.4 | 33.5 |
| β-blocker use | 11,177 | 3.6 | 4.1 | 20.9 | 32.9 |
| Nicotine dependence | 694 | 4.5 | 5.5 | 26.6 | 52.3 |
| Polypharmacy (≥5 meds) | 23,659 | 3.6 | 3.9 | 23.9 | 31.1 |
ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; GP = general practitioner.
Results of the multivariable regression analyses indicated that compared with simvastatin, atorvastatin (hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.73 to 0.87) and rosuvastatin (HR: 0.40; 95% CI: 0.36 to 0.44) were associated with less statin switching and discontinuation (HR: 0.83; 95% CI: 0.80 to 0.87 and HR: 0.79; 95% CI: 0.76 to 0.82, respectively). People 75 to 84 years of age and ≥85 years of age were more likely to discontinue (HR: 1.06; 95% CI: 1.03 to 1.09 and HR: 1.14; 95% CI: 1.09 to 1.19, respectively) and less likely to reinitiate statins (HR: 0.78; 95% CI: 0.76 to 0.81 and HR: 0.44; 95% CI: 0.41 to 0.47, respectively) compared with 65- to 74-year-olds. Females and those initiated by GPs had higher likelihoods of discontinuation (HR: 1.05; 95% CI: 1.03 to 1.08 and HR: 1.10; 95% CI: 1.07 to 1.13, respectively) and lower likelihoods of reinitiation (HR: 0.93; 95% CI: 0.91 to 0.96 and HR: 0.96; 95% CI: 0.92 to 0.98, respectively). Diabetes was associated with both higher likelihood of discontinuation (HR: 1.07; 95% CI: 1.04 to 1.11) and reinitiation (HR: 1.28; 95% CI: 1.21 to 1.32). The likelihoods of reinitiating statin were lower among people with dementia (HR: 0.31; 95% CI: 0.23 to 0.44), malignancies (HR: 0.80; 95% CI: 0.68 to 0.94), psychotic illness (HR: 0.83; 95% CI: 0.73 to 0.95), and those experiencing polypharmacy (HR: 0.90; 95% CI: 0.87 to 0.93). The use of cardiovascular pharmacotherapies including antiplatelet (HR: 0.84; 95% CI: 0.82 to 0.87), β-blockers (HR: 0.88; 95% CI: 0.86 to 0.91), and ACE inhibitors or ARBs (HR: 0.87; 95% CI: 0.85 to 0.89) was associated with lower likelihood of statin discontinuation.
Among people who reinitiated statins, 73.5% (13,947 of 18,977) maintained same statin and intensity, 5.5% (1,040 of 18,977) changed statin and down-titrated intensity, 4.1% (773 of 18,977) changed statin and up-titrated intensity, 10.4% (1,980 of 18,977) changed statin and maintained intensity, 3.1% (579 of 18,977) maintained statin and down-titrated intensity, and 3.4% (658 of 18,977) maintained statin and up-titrated intensity. Overall, 67.6% (12,830 of 18,977) of reinitiators discontinued again. Compared with restarting on the same statin and intensity, switching statin plus down-titrating intensity (HR: 0.90; 95% CI: 0.83 to 0.98), switching statin plus up-titrating intensity (HR: 0.87; 95% CI: 0.80 to 0.96), and switching statin plus maintaining same intensity (HR: 0.89; 95% CI: 0.84 to 0.95) were associated with less likelihood of discontinuation. Conversely, restarting the same statin plus down-titrating intensity (HR: 0.89; 95% CI: 0.81 to 1.01) and restarting the same statin plus up-titrating intensity (HR: 0.92; 95% CI: 0.81 to 1.02) did not decrease the risk of discontinuation.
Our analysis suggests that ~1 in 5 older adults changed the statin or intensity they started with. Around 64% discontinued, although most (>60%) restarted. Statin switching, discontinuation, and reinitiation varied according to individual-level, prescriber, and therapy-related factors.
There is a compelling need to address the issue of statin discontinuation, incorporating a mix of patient-tailored strategies (3). The very old, females, and patients with comorbidities such as diabetes may require additional attention to improve statin compliance. Our finding that higher persistence is associated with atorvastatin and rosuvastatin, as well as with restarting on a different statin may assist clinicians with therapy selection.
Our study was limited by the inability to stratify results by primary and secondary prevention, for which statin-taking behaviors may differ. Furthermore, although taking statins every other day is uncommon, by assuming 1 tablet daily, such individuals would be classified as noncompliant. Last, the use of medication data to identify comorbidities precludes identification of comorbidities managed via non-pharmacological approaches.
In conclusion, despite high statin discontinuation among older adults, a significant proportion restart. Reinitiation with a different statin is associated with better persistence. Innovative strategies are required to improve statin compliance.
Acknowledgments
Please note: Mr. Ofori-Asenso is supported by a Monash Graduate Scholarship and Monash International Postgraduate Research Scholarship for his doctoral studies. Dr. Ilomaki is funded by a National Health and Medical Research Council Early Career Fellowship. Dr. Zullo is funded by an Agency for Healthcare Research and Quality award (5K12HS022998) and a U.S. Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship in Health Services Research and Development. Dr. Zoungas is funded by a National Health and Medical Research Council Senior Research Fellowship. Dr. Zoungas has participated in advisory boards/educational meetings/research on behalf of Monash University with AstraZeneca Pty. Ltd., Eli Lilly Australia Pty. Ltd., Merck Sharp & Dohme (Australia) Pty. Ltd., and Novo Nordisk Pty. Ltd. Dr. Liew has received honoraria or study grants from Abbvie, Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Pfizer, Sanofi, and Shire. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors thank the Australian Government Department of Health and Human Services for the provision of the data, and Ms. Samanta Lalic for providing the codes for the updated Rx-Risk-V tool.
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