Introduction
In this issue of the journal Cicero et al.Citation1 describe several options to lower plasma low density lipoprotein cholesterol (LDL-C) levels in patients who were intolerant to statins due to myalgia but were taking ezetimibe. Indeed we need several options to try to resolve this key issue. In this editorial we will briefly consider four issues related to adherence to statin treatment. (1) Extent of the problem. (2) Does discontinuation matter? (3) Why do patients discontinue statins? (4) How to address discontinuation.
Extent of the problem
Establishing exact figures for statin adherence is difficult because of differences in study design. For example, was adherence assessed as pill counts, proportion of days covered (PDC), medication possession ratio (MPR: percentage of days when medication was available) or gap between filled prescriptions? Were more advanced measures used (electronic tablet or container)? What was the duration of monitoring adherence? Patient characteristics may also matter. Furthermore, run-in phases in trials may have excluded those intolerant to statins and intensive follow-up during a study may favourably affect adherence. Older studies may also have different motivational factors (positive or negative) for prescribers and patients. This may include information from guidelines and adverse publicity about side effectsCitation2. Even the definition of statin intolerance is not uniformCitation3!
Despite the limitations mentioned above, some studies have attempted to assess adherence to statin therapy. It is beyond the remit of this editorial to consider all these studies. We briefly consider the most recent one we identified. In a Finnish registers studyCitation4 (97,575 new statin users; age 45–75 years in 2001 to 2004 with no cardiovascular [CV] diseases at baseline), 53% displayed good (PDC ≥80%), 26% intermediate (PDC 40–79%) and 21% poor (PDC <40%) adherence during the first year of follow up. Therefore, only about 50% of the patients had good adherence at 1 year; a further deterioration with time may be expected. Statin adherence has also been considered elsewhereCitation3.
Does discontinuation matter?
In the Finnish registers described aboveCitation4, there was a 25% relative risk reduction (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.71–0.79) in the rate of any CV event or death among good vs. poor adherers after adjustments. There is even evidence of a dose–response relationship between adherence level and the risk of ischemic stroke (relative risk [RR] 0.63, 95% CI 0.53–0.75) for PDC ≥80% vs. PDC <20%, p for trend <0.0001)Citation5. In a national cohort study (423,786 individuals; Korean National Health Insurance Claims Database)Citation6 non-adherence to statins was associated with an increased risk of CV hospitalization (HR 2.18, 95% CI: 2.02–2.35) and all-cause mortality (HR 1.75, 95% CI: 1.66–1.84). In a Kaiser Permanente Georgia members studyCitation7 including patients (n = 1066) with a history of coronary heart disease or risk equivalent(s), after multivariable adjustment, and compared with those with high adherence, the risk ratios for not achieving a ≥30% LDL-C reduction were 1.31 (95% CI 1.13–1.52) and 1.88 (95% CI 1.67–2.11) for participants with intermediate and low adherence, respectively (p < 0.01). It follows that non-adherence not only increases the risk of CV events but also decreases the probability of achieving LDL-C targets.
Why do patients discontinue statins?
Many factors have been shown to influence statin discontinuation. Among these are real or perceived adverse effects or lack of efficacy, patient preference (rather than provider preference) and motivation, cost, polypharmacy or complex drug regimes, drug interactions, age, ethnicity, type of exercise and its intensity, gender, presence of kidney or liver disease, adverse publicity in the media and even use of generic tabletsCitation2,Citation3,Citation8–11. The key issue is for prescribers to identify any factors affecting adherence and then address them. Statin intolerance has some scientific basis because links with genetic patterns have been reportedCitation12. Also, elevated creatine kinase (CK) activity has been associated with statin-related myositisCitation3.
How to address discontinuation
The points raised above, the Cicero et al.Citation1 study and expert statementsCitation3,Citation13 provide suggestions regarding dealing with statin discontinuation. In this “battle for adherence”, pharmacists, nurses and the “poly pill” (or drug combination tablets; e.g. statin + ezetimibe) may prove usefulCitation14,Citation15. Regular follow-up visits, auto-reminders and refill reminders may also help. Excluding hypothyroidism and drug interactions is relevantCitation3. Whether correcting vitamin D deficiencyCitation16 or administering coenzyme Q10 supplementsCitation17 is helpful remains to be established. However, it is of interest that statin administration is associated with a fall in circulating coenzyme Q10 levelsCitation18. For patients unable to tolerate any statin, ezetimibe, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor or a combination of both would be alternative options. Cost may limit this option to high risk patients. A more extensive review of this topic has been recently publishedCitation19.
Conclusions
Ensuring good adherence to statins is currently a major clinical problem with consequences in terms of vascular events. Several factors contribute to this situation and they need to be identified and then addressed.
Transparency
Declaration of funding
This editorial was not funded. It was written independently; no company or institution supported the authors financially or by providing a professional writer.
Declaration of financial/other relationships
V.G.A. has disclosed that he has given talks, attended conferences and participated in trials sponsored by MSD, Sanofi, and Amgen. D.P.M. has disclosed that he has given talks and attended conferences sponsored by MSD, AstraZeneca and Libytec. N.K. has disclosed that she has given talks, attended conferences and participated in trials sponsored by for MSD, Novartis, Amgen, Sanofi, Novo Nordisk and Libytec.
The CMRO peer reviewer on this manuscript has no relevant financial or other relationships to disclose.
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