Statins are one of the most heavily prescribed medications. The 2018 ACC/AHA guidelines support statin therapy for most older adults, but recommendations are less clear for those over 75. The literature was systematically reviewed for evidence of the efficacy of statin treatment in different patient populations. Significant evidence was found supporting a decreasing association between low-density lipoprotein cholesterol (LDL-C) and mortality as well as decreasing statin efficacy with increasing age. The consequences of unnecessary statin therapy can be severe for older adults. Improved methods for evaluating atherosclerotic cardiovascular disease (ASCVD) risk, such as using negative markers to help identify those who may not benefit from statin therapy, should be more widely employed.https://dune.une.edu/pharm_studpost/1001/thumbnail.jp

Hills, Ronald D., Jr

Mishcon, Hillary R.

Redwanski, John

White, Alyssa M. B.

English

University of New England

University of New England DUNE: DigitalUNE Pharmacy Student Posters Pharmacy Student Works 2019 Efficacy Of Statin Therapy In The Elderly Alyssa M. B. White Hillary R. Mishcon John Redwanski Ronald D. Hills Jr Follow this and additional works at: https://dune.une.edu/pharm_studpost  Part of the Pharmacy and Pharmaceutical Sciences Commons ABSTRACTStatins are one of the most heavily prescribed medications. The 2018 ACC/AHA guidelines supportstatin therapy for most older adults, but recommendations are less clear for those over 75. Theliterature was systematically reviewed for evidence of the efficacy of statin treatment in differentpatient populations. Significant evidence was found supporting a decreasing association betweenlow-density lipoprotein cholesterol (LDL-C) and mortality as well as decreasing statin efficacy withincreasing age. The consequences of unnecessary statin therapy can be severe for older adults.Improved methods for evaluating atherosclerotic cardiovascular disease (ASCVD) risk, such as usingnegative markers to help identify those who may not benefit from statin therapy, should be morewidely employed.THERAPEUTIC OUTCOMESCONCLUSIONSStatins are often prescribed using a treat-all approach to prevent ASCVD. Despite such widespread use, availableevidence does not support the use of statins for primary prevention in very old adults without diabetes. The risk ofadverse events is amplified in the elderly population. Healthcare providers could do better to balance the benefits andharms of statin therapy, and treatment recommendations should be individualized for this population. For predictingASCVD risk, metrics such as CAC are superior to plasma LDL-C and the Framingham risk calculator, which is heavilyweighted for age. Future steps in our analysis will involve assessing evidence for the U.S. Preventive Services Task Forcerecommendation to raise the 10-year risk threshold for treatment from 7.5% to 10% for adults 40–75 with no history ofASCVD.Plasma LDL-C has been the principal target of cholesterol-lowering therapy for the past threedecades, and statins are effective in lowering LDL-C. Data on the relationship between LDL-C andmortality, however, reveal a paradoxical relationship between LDL-C and ASCVD. In 2016, Ravnskovet al. conducted a review of 19 clinical studies involving 68,094 patients 60 years or older. In 16different cohorts accounting for 92% of participants, an inverse association was found betweenLDL-C and all-cause mortality. A population study of 269,391 Korean adults over 40 revealed thatchanges in total cholesterol within a two-year period increased the risk of subsequent all-causemortality relative to those who maintained levels in the second tertile.3Among the elderly, frailty and poor health status likely contribute to increased risk of death inthose with low cholesterol. Low cholesterol can also be a marker of severe diseases such as cancer.In the general population, LDL is not the best ASCVD predictor. LDL-C was dropped from the 2008Framingham calculator for 10-year ASCVD risk because it did not improve the model fit. LDL-C is aconfounded variable, consisting of several subclasses of particles of different sizes and densities.Small-dense LDL and covalently modified lipoprotein(a) are considerably more atherogenic thanlarger LDL particles. Other blood lipids such as triglycerides, apolipoprotein B, HDL, and remnantcholesterol are now emerging as more useful ASCVD predictors.ACKNOWLEDGMENTSThe authors are grateful to Sydney Springer of Mid Coast-Parkview Health in Brunswick, Maine for synergisticcollaboration and valuable discussion.For more information, see our publication, “Statin treatment in specific patient groups: Role for improved cardiovascularrisk markers,” Journal of Clinical Medicine 9:3748. DOI: 10.3390/jcm9113748SPECIAL  CONSIDERATIONSAdverse Musculoskeletal EffectsMuscle weakness can be serious adverse effects in the elderly, potentially leading to life-threatening falls orsevere injury.4 For muscle pain, estimates of the 5-year number needed to harm (NNH) vary from 19 to 47.Statins deplete endogenous levels of coenzyme Q. Ubiquinol supplemention may provide protective benefits.CognitionDespite the Food and Drug Administration’s 2012 warning about memory loss in statins, meta-analysis of 25RCTs indicated that statins are not associated with cognitive impairment.6New-Onset DiabetesStatins can increase blood glucose and long-term statin use increases the risk of developing diabetes relative tonon-users (RR: 1.44, 95% CI: 1.31–1.58).5 High potency statins had the highest risk (rosuvastatin, RR: = 1.61, 95%CI: 1.30−1.98). 1-year NNH: atorvastatin=172, rosuvastatin=210, simvastatin=363 (Carter 2013).Drug InteractionsOver 36% of older adults take ≥5 prescription medications. Atorvastatin and simvastatin are metabolized byCYP3A4, which metabolizes half of all drugs on the market. St. John’s Wort induces CYP3A4, while grapefruit isan inhibitor. Myopathy risk may be increased by drug interactions from polypharmacy as well as comorbidities.INTRODUCTIONCardiovascular disease, a leading cause of morbidity, accounts for 1 in 3 deaths in U.S. adults. Statindrugs have become a mainstay in the primary prevention and treatment of ASCVD. From 2002 to2013, statin use among US adults 40 years and older increased by 80%, from 18% of the generalpopulation to 28% (39 million individuals). The Medical Expenditure Panel Survey found that statinuse for primary prevention in adults 80 years and older increased 4-fold, from 9% in 1999 to 34% in2012. Recent meta- and post-hoc analyses have attempted to address whether available clinicalevidence supports such widespread statin use.Early statin trials excluded elderly patients, and less evidence exists for the efficacy of statins in thisheterogenous clinical group.1 Statins are associated with adverse musculoskeletal event: myopathy,muscle weakness and pain, arthropathies, and rhabdomyolysis. This is problematic for the elderly,in whom statins can contribute to deconditioning and frailty. The current literature reflects acomplex relationship between statin efficacy and patient age. While no randomized control trials(RCTs) have been conducted of patients older than 80 years at baseline, the independent STAREEtrial (NCT02099123) is currently assessing high intensity statin therapy in adults 70 and older.2RELATION BETWEEN CHOLESTEROL AND CLINICAL OUTCOMESSECONDARY PREVENTION IN THE ELDERLYELDERLY PATIENTS WITH DIABETESCORONARY ARTERY CALCIFICATIONDiabetes No Diabetes75−84 yrN=6,641≥ 85 yrN=1,23975−84 yrN=31,916≥ 85 yrN=7,068ASCVD(95% Confidence Interval)0.76(0.65 - 0.89)0.82(0.53 - 1.26)0.94(0.86 - 1.04)1.00(0.80 - 1.24)All-Cause Mortality(95% Confidence Interval)0.84(0.75 - 0.94)1.05(0.86 - 1.28)0.98(0.91 - 1.05)1.00 (0.90 - 1.11)* Primary prevention, i.e., no history of ASCVD. According to the 2013 ACC/AHA cholesterol guidelines, most of the population was eligible for statin treatment [10% ASCVD risk at 10 years (Ramos 2018)].Ramos et al. conducted a retrospective cohortstudy of 46,864 participants 75 years and olderwith no history of ASCVD. To prevent survivorbias, new statin users were selected rather thanall statin users. A Cox proportional regressionmodel was used to calculate the hazard ratios ofstatin use for outcome events. Statins wereeffective in reducing all-cause mortality [1-yearnumber needed to treat (NNT): 306] and theincidence of ASCVD (NNT: 164) in diabeticpatients aged 75−84 (Table 1). The reduction inASCVD began to lose statistical significance atage 85 and disappeared completely at age 92.The protective effect of statins against all-causemortality in began to lose significance at age 82in diabetes patients and disappeared definitivelyat age 88. Remarkably, statins did not reduceASCVD or all-cause mortality in patients ≥75without diabetes.The meta-analysis by Ponce et al. also assessed the effect of statins in the treatment of patients diagnosed with clinically significantASCVD. In contrast to primary prevention, high-certainty evidence was obtained for the use of statins in adults 65 and over forsecondary prevention of ASCVD. Compared to placebo, statins significantly decreased the risk of all-cause mortality (RR: 0.80, 95% CI:0.73–0.89), cardiovascular mortality (RR: 0.68, 95% CI: 0.58–0.79), CAD (RR: 0.68, 95% CI: 0.61–0.77), and myocardial infarction (RR:0.68, 95% CI: 0.59–0.79). No separate data on subgroups, such as those specifically over 75 years of age or patients with type 2diabetes, was available from the eight trials reviewed.The severity of CAD and plaque formation can be assessed based on the level of coronaryartery calcification (CAC) in a computed tomography scan. The CAC score is a robustindependent risk factor for ASCVD and all-cause mortality. A meta-analysis was conducted of49 studies involving 85,000 patients (Sarwar 2009). During a mean follow-up period of 50months, 0.47% of patients with no CAC suffered a cardiovascular event, compared to 4.1% ofpatients with CAC, highlighting the metric’s negative predictive power.A retrospective cohort study of 13,644 participants assessed the impact of statins on ASCVDoutcomes stratified by baseline CAC score (Mitchell 2018). The median follow-up period was9.4 years. Compared to those with no CAC, individuals with CAC who took a statin within 5years of CAC testing had a lower risk of a first major adverse cardiovascular event (MACE). TheNNT depended on CAC severity (Table 2). To put this into context, a small longitudinal study ofmiddle-aged adults found that 22% of statin-naïve patients with CAC = 0 were eligible forstatins based on the 2013 ACC/AHA guidelines (Pursnani 2015).CAC ScoreHR (95% CI) NNT *0 1.00  (0.79-1.27) ->0 0.76  (0.60-0.95) -1−100 0.83  (0.60-1.16) 100101−400 0.32  (0.21-0.48) 12STATINS IN PRIMARY PREVENTIONEVIDENCE-BASED FINDINGS FOR CLINICAL PRACTICETABLE 1.  Hazard ratios (HR) in new statin users vs. non-statin users.*TABLE 2.  HRs for first MACE in statin-users vs. non-statin users.2013 guidelines cite a 28% reduction in RR per mmol LDL-C reduction (39 mg/dL). Meta-analysisof intensive statin therapy found a modest RR of 14% in adults with LDL > 100 (Navarese 2018).In patients with diabetes, statins are protective for primary prevention of ASCVD up to age 85.CAC < 10 is a strong negative risk marker that can be used to rule out statin treatment in low-risk individuals.In adults over 75 with no history of ASCVD or diabetes, statins have not been shown to reduceASCVD, stroke, or cardiovascular/all-cause mortality.A 2019 meta-analysis by Ponce et al. included 23 RCTs comprising 60,194 patients 65 and over. Forprimary prevention in those with no history of ASCVD, statins reduced the risk of coronary arterydisease [CAD; relative risk (RR): 0.79, 95% CI: 0.68–0.91] and myocardial infarction (MI; RR: 0.45,95% CI: 0.31–0.66) but not all-cause or cardiovascular mortality (Figure 1).Statins have not been shown to reduce mortality in adults over 65 with no history of ASCVD. Lackof benefit in heart failure may be due to decreased coenzyme Q levels (Alehagen 2015).Citation Study Type N Age Notable OutcomesSTATIN USERS vs. CONTROLSHan 2017.JAMA Intern. Med. 177:955.ALLHAT-LLT: open-label RCT; North America 2,867 ≥ 65Increased all-cause mortality [HR = 1.34 (95% CI: 0.98-1.84; P = .07)] for patients ≥75 with moderate hyperlipidemia/hypertension taking a moderate intensity statin vs. usual care (primary prevention).Ponce 2019.J. Clin. Endocrinol. Metab. 104:1585.Meta-analysis, 23 trials 60,194 ≥ 65 Statins reduced the risk of all-cause and cardiovascular mortality in secondary but not primary prevention.Ramos 2018.BMJ 362:k3359.Retrospective cohort, new user design; Spain 46,864 ≥ 75Statins reduced ASCVD and mortality in diabetic patients younger than 82 years. No benefit was observed in non-diabetic patients.Mitchell 2018.J. Am. Coll. Cardiol. 72:3233.Retrospective cohort 13,644 > 18 Adults who took a statin had a reduced risk of first MACE according to their baseline CAC score. Those with no CAC had no benefit.IRRESPECTIVE OF STATIN USERavnskov 2016.BMJ Open 6:010401.Meta-analysis, 30 cohorts 68,094 ≥ 60 Inverse association between LDL-C and all-cause mortality for 92% of participants.Miedema 2019.JAMA Network Open2:e197440.Multicenter retrospective cohort 22,346 30-49Patients with CAC > 100 had 10-fold higher CHD mortality (coronary heart disease) than those with CAC = 0.TABLE 3. MAJOR STUDIES AND PRINCIPAL FINDINGS1. Leya M, Stone NJ. Statin prescribing in the elderly: Special considerations. Curr. Atheroscler. Rep. 2017; 19:47.2. Strandberg TE. Role of statin therapy in primary prevention of cardiovascular disease in elderly patients. Curr. Atheroscler. Rep. 2019; 21:28.3. Jeong S-M et al. Association of change in total cholesterol level with mortality: A population-based study. PLOS ONE 2018; 13: e019603.4. Singh S, et al. Statins for primary prevention in older adults—moving towards evidence-based decision-making. J. Am. Geriatr. Soc. 2018; 66:2188.5. Casula M, et al. Statin use and risk of new-onset diabetes: A meta-analysis of observational studies. Nutr. Metab. Cardiovasc. Dis. 2017; 27:396.6. Ott BR, et al. Do statins impair cognition? A systematic review and meta-analysis of randomized controlled trials. J. Gen. Intern. Med. 2015; 30:348.Efficacy of Statin Therapy in the ElderlyAlyssa M. B. White,1 Hillary R. Mishcon,1 John L. Redwanski,2 and Ronald D. Hills Jr.1Department of Pharmaceutical Sciences and Administration,1 Department of Pharmacy Practice,2 UNE School of Pharmacy, Portland, MaineFIGURE 1. Forest plot comparing statin use relative to placebo for primary prevention of ASCVD (RRR:ratio of RRs). *Diabetic patients were 65-75 years. Image reproduced from J. Clin. Endocrinol. Metab. 2019; 104:1585.0.25          0.50          1.00          2.00          4.00*NNT for preventing MACE through 10 years (Mitchell 2018).34%Seniors over 80 taking a statin for primary prevention

Efficacy Of Statin Therapy In The Elderly

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Efficacy Of Statin Therapy In The Elderly

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