Practice Update: Endocrinology | Volume 1. Number 2. 2016

METABOLIC & ENDOCRINE DISORDERS

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EXPERT OPINION My approach to the patient with memory loss who needs a statin By Dr Karol Watson and Dr Tamer Sallam Statins are among the most powerful cholesterol-lowering medications, and they are also associated with the greatest cardiovascular risk reduction. For these reasons, the 2013 American College of Cardiology–American Heart Association (ACC–AHA) cholesterol guidelines recommend statin therapy for patients at elevated cardiovascular risk. When we encounter such a patient, our approach is to prescribe moderate- or high-intensity statin therapy by the guidelines. But what if the patient has memory loss? I f a patient’s major threat to life

memory problems? There is a well- known “detection bias,” whereby people are more likely to recognise health problems when they start a newmedication. Also, memory prob- lems are common. We often forget where we put our keys or forget an acquaintance’s name; however, pa- tients may be more likely to blame memory problems on a new drug. Also, when patients are prescribed a new medication, they are likely to see a clinician more often, which can also add to detection bias. So, our approach to the patient with memory problems who need a statin is this: before prescribing a statin, and as part of comprehensive lifestyle assessment, we take a brief history of muscular symptoms and memory symptoms. Common ques- tions we ask are: Do you exercise regularly? Do you have muscle or joint pain? How often do you take any pain relievers for this pain? In regard to cognition, we ask about common memory complaints such as minor forgetfulness or word-finding difficulties. We may ask: Do you ever have minor absent-mindedness such as forgetting where you put your keys

they said, were nonspecific and de- scribed as unfocused thinking. The US FDA concluded that these “... symptoms were not serious and were reversible within a few weeks after the patient stopped using the statin.” But do statins really cause memory impairment? Mild memory loss is commonly seen in clinical practice. Most cases are due to normal ag- ing, but progressive and significant memory loss may signal a more seri- ous condition such as dementia. The statin clinical trials have been incon- sistent about cognition. Statins have been associated with better cognition in observational trials, but the only randomised controlled trial of statin therapy performed exclusively in old- er individuals, the PROSPER trial, conducted neurocognitive testing and found no differences between groups (neither harm nor benefit). More intriguingly, results of a recent analysis of 482,543 statin users and 26,484 users of other lipid-lowering agents, showed the same percentage in each group reporting short-term memory loss after beginning therapy. So why might patients who are newly prescribed statin therapy report more

is an atherosclerotic cardiovas- cular disease (ASCVD), a statin is still indicated. It may, in fact, protect the patient from further cognitive decline due to the vas- cular protective benefits. Also, it may protect the patient from stroke and vascular dementia, the second most common cause of dementia. In addition, ASCVD risk reduction benefits may be seen within the first 2 years of beginning statin therapy. Therefore, if the patient has a rea- sonable quality of life and at least a 2-year life expectancy, statin therapy is appropriate. But what if a patient develops memory problems while on statin therapy? Muscular symptoms are well-known statin side effects, but recently memory problems have been attributed to some to statins (whether correctly or incorrectly). In 2012, after receiving reports that some statin users experienced short-term memory lapses, the US Dood and Drug Administration (FDA) released an advisory saying that it had investigated “... reports of cognitive impairment from statin use for several years....” The symptoms,

or why you went into a certain room? Do you ever find a certain word “on the tip of your tongue” but are unable to find the word? Do you ever forget the name of an acquaintance? The purpose of such questions is to cre- ate a baseline for comparison should future symptoms arise. If the patient does complain of symptoms that he/ she is certain are attributable to the statin, we hold the statin to see if there is clear symptom resolution. If there is, we usually rechallenge the patient with a different statin, a dif- ferent dose of the same statin, or a different dosing schedule. We often go to the lowest dose of our statin of choice and give alternate-day dosing. This is a strategy that has been tested for statin-intolerant patients using atorvastatin and rosuvastatin. Once we find a dose/dosing schedule that the patient can tolerate, we reinforce

adherence. Formal cognitive testing is not usually necessary. Ultimately, whether the patient has cognitive impairment or not, before initiating statin therapy we recommend a cli- nician-patient discussion as outlined in the 2013 ACC–AHA cholesterol guidelines to discuss the potential for ASCVD risk reduction, possible adverse effects, potential drug–drug interactions and patient preferences. Dr Karol Watson is Professor of Medicine/Cardiology and a board- certified, full-time cardiologist at the Geffen School of Medicine at the University of California, and Dr Tamer Sallam is Assistant Professor of Medicine at the David Geffen School of Medicine at UCLA and a clinical cardiologist at Ronald Reagan UCLA Medical Center. adherent (proportion of days cov- ered ≥80%) to statin therapy during the previous adherence assessment year was 0.78 (95% CI 0.65–0.94) when compared with everybody remaining non-adherent (proportion of days covered <80%). The result was robust against alternative model specifications. Statin adherers had a potentially reduced risk of experienc- ing low-energy fractures compared with non-adherers (HR 0.90, 95% CI 0.76–1.07). CONCLUSIONS Our study, which took into account the time dependence of adherence and confounders, as well as temporal order between these factors, is support for the concept that adherence to statins in women in primary prevention decreases the risk of acute cardiovascular events by about one-fifth in comparison to non-adherence. However, part of the observed effect of statin adherence on acute cardiovascular events may be due to the healthy-adherer effect. Statin adherence and risk of acute cardiovascular events among women: A cohort study accounting for time-dependent confounding affected by previous adherence . BMJ Open 2016;6(6)e011306, Lavikainen P, Helin-Salmivaara A, Eerola M, et al.

EXPERT COMMENTARY Penalty of nonadherence to statin therapy by women By Dr Peter Lin W e have always known that many patients are nonad- herent to therapy. We have

Statin adherence reduces the risk of acute cardiovascular events among women BMJ Open Take-home message

• In this retrospective analysis, the authors evaluated the effect of statins used for primary prevention in 42,807 women aged 45 to 64 years over a 3-year follow-up period while taking account of time dependence of adherence and confounders. The hazard ratio for acute cardiovascular events was 0.78 for women who remained adherent to statin therapy compared with those who were non-adherent. The women who were adherent to treatment had a lower risk of low-energy fractures compared with those not adhering to therapy, suggesting a possible healthy- adherer effect. • Adherence to statins for primary prevention in women reduces the risk of a subsequent cardiovascular event by one-fifth, but this may be due in part to the healthy-adherer effect. Abstract

acute cardiovascular events. This 12% reduction is a significant amount and the only thing that the patients had to do was to take their pill every day. Perhaps instead of saying that the adherent patients had a benefit, maybe we should start saying that the nonadherent patients will have to pay a penalty by having an acute event. That concept of penalty might wake us all up and force all of us to pay more attention to this issue of adherence.

also known that nonadherence leads to increased risks for our patients. Yet when we see that patients have not renewed their medications, we do not hit the panic button. In a sense, we do not see nonadherence as an immedi- ate concern. This study looked at over 42,000 women taking statin therapy. The researchers divided them into two groups based on their adherence rates. Good adherence was defined as tak- ing prescribed medications more than 80% of the time; poor adherence was defined as less than 80%. The adherent patients had a hazard ratio of 0.78 (95% CI, 0.65–0.94) for

years initiating statin use for primary prevention of cardiovascular disease in 2001–2004 (n = 42807). OUTCOMES Acute cardiovascular event defined as a composite of acute coro- nary syndrome and acute ischaemic stroke was our primary outcome. Low-energy fractures were used as a negative control outcome to evaluate the healthy-adherer effect. RESULTS During the 3-year follow-up, 474 women experienced the primary outcome event and 557 suffered a low-energy fracture. The causal HR estimated with marginal structural model for acute cardiovascular events for all the women who remained

OBJECTIVES Previous studies on the effect of statin adherence on cardio- vascular events in the primary preven- tion of cardiovascular disease have adjusted for time-dependent con- founding, but potentially introduced bias into their estimates as adherence and confounders were measured si- multaneously. We aimed to evaluate the effect when accounting for time- dependent confounding affected by previous adherence as well as time sequence between factors. DESIGN Retrospective cohort study. SETTING Finnish healthcare registers. PARTICIPANTS Women aged 45–64

Dr Peter Lin is Director of Primary Care Initiatives at the Canadian Heart Research Centre, Canada.

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