Curr Atheroscler Rep (2017) 19:47 DOI 10.1007/s11883-017-0683-9
STATIN DRUGS (B. WIGGINS, SECTION EDITOR)
Statin Prescribing in the Elderly: Special Considerations M. Leya 1 & N. J. Stone 2
# Springer Science+Business Media, LLC 2017
Abstract Purpose of Review Our aim was to examine the current evidence behind prescribing statins to individuals over 65 years of age with emphasis on those older than 75. Individuals over 75 years of age may often have multiple comorbidities and take many medications. Additionally, they are often underrepresented in randomized controlled trials (RCTs) of statins in older populations. While results of RCTs demonstrate the benefit of statin therapy in both primary and secondary prevention patients, clinicians must more carefully consider adverse effects and drug–drug interactions before prescribing statin therapy as well as determining the intensity in older individuals. Recent Findings Four primary prevention trials support statins for primary prevention following a clinician–patient risk discussion. Of these, JUPITER and HOPE-3 studied participants 70 years of age and over who derived benefit. However, in those over 85 years, available information is inadequate to guide decisions regarding statin therapy. Documented statin adverse effects include new onset diabetes, myopathy, and medication interactions. Although cognitive decline has been reported anecdotally, its incidence was comparable to placebo in two RCTs with validated cognitive evaluations. Concerns about significant liver and kidney injury with statins were not corroborated in RCTs. For most patients,
the potential for reducing ASCVD risk outweighs possible adverse effects; however, in the elderly, the impact of drug treatment on cognition, musculoskeletal ability, and independence must be heavily weighed. Summary Given the limited high quality evidence for primary prevention in individuals over 75 years of age, neither the ACC–AHA nor USPSTF cholesterol guidelines recommend statin therapy for primary prevention in this patient population. If prescribed, physician judgment and shared decision-making are crucial. To aid clinicians, imaging studies of subclinical atherosclerosis may improve specificity of statin therapy to prevent ASCVD in the elderly in primary prevention. Keywords Statin . Elderly . Treatment risk paradox . Primary prevention . Secondary prevention . Adverse effects
“The contemporary statin treatment-risk paradox is striking; despite the high attributable risk of hypercholesterolemia at elderly age, and the statin-associated reduction in all-cause mortality in this population, statin use declines sharply at elderly age.” – Nanette Wenger, M.D. [1]
This article is part of the Topical Collection on Statin Drugs * M. Leya [email protected]
1
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
2
Division of Cardiology; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Introduction Dr. Wenger summarized the statin treatment risk paradox in older individuals well. The elderly carry a disproportionate burden of cardiovascular disease, with octogenarians in particular accounting for only 5% of the population but representing 20% of hospitalizations for myocardial infarction
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(MI) and 30% of all MI-related hospital deaths [2]. Despite their increased risk of events, the elderly are less likely to receive therapy directed at reducing atherosclerotic cardiovascular disease (ASCVD) events [3, 4]. Of note, observational data from the Global Registry of Acute Coronary Events (GRACE) indicates that fewer than 40% of patients older than 75 are prescribed statins at discharge [4, 5].
explain this association well. Those with chronic illnesses such as end-stage renal disease, liver disease, and malignancies (and often poor nutritional status) have lower cholesterol profiles. After adjusting for nutritional status via albumin, ferritin, and other surrogates, total cholesterol and LDL-C demonstrated a similar correlation to cardiovascular risk as in young patients [13].
Definitions
Demographic Differences in Prevention of Myocardial Infarction and Stroke
The literature often defines elderly as individuals 65 years and over. However, recent guidelines, including those from the American College of Cardiology–American Heart Association (ACC–AHA) and U.S Preventive Services Task Force (USPSTF), consider those over 75 as a group that merits special consideration for risk attenuation in primary prevention and risk reduction for secondary prevention [6••, 7••]. Thus, those over 75 will serve as the focus for this review.
Should Cholesterol Risk Be Treated in the Elderly? Pitfalls in Decision-Making Cholesterol and LDL-C Are Poor Markers of Risk in the Elderly Assessing ASCVD risk in the elderly is complicated compared to risk assessment in younger individuals. Cholesterol and LDL-C are less reliable markers in older populations. ASCVD events may occur in elderly without the traditional risk factor profile [8]. Therefore, HDL-C is often the best lipid risk predictor in these individuals [9]. Older patients have a high burden of risk factors for ASCVD. Multiple medications prescribed for hypertension, diabetes, and cholesterol alter the prevalence and presentation of textbook cardiovascular disease and are only a part of the total pill burden of older individuals. Depression can further reduce medication adherence and correlates with increased vascular morbidity [10]. LDL-C levels in the elderly do not correlate as well with ASCVD risk compared to younger cohorts for multiple reasons. For example, those with elevated LDL-C may have died, leaving behind an elderly population with lower average LDL-C, but still at increased risk owing to their advanced age and comorbidities. They are on a higher LDL-C risk curve [11]. This is a way of visualizing how an increasing burden of risk factors and/or clinical atherosclerosis places an individual at enhanced risk of an ASCVD event at the same level of LDL-C. Also, observational studies have reported an association of lower cholesterol concentrations with higher rates of all-cause mortality in older patients [12]. The Honolulu Heart Study suggested that pre-existing diseases
Subclinical vascular disease, as manifested by abnormal echocardiograms, ankle–brachial indices, and increased carotid intima-media thickness, increases with age. The Cardiovascular Health Study demonstrated that for patients aged 65 to 70 years old, subclinical disease was present in 22% of women and 33% of men and in patients over 85 years old increased to 43% in women and 45% in men [13]. Strokes are the leading precipitants of disability in older American women and in African Americans often presenting with cerebrovascular events before MIs. Based on 2015 statistics from the AHA, among those 65 to 84 years of age, 53% of stroke patients were women, which increased to 66% for patients older than 85 [14]. African American patients have higher stroke risk and stroke mortality and tend to present at younger ages compared to their counterparts [15]. Advocating for appropriate therapy for patients requires understanding different patterns of presentation of cardiovascular disease and aggressively managing those at higher risk of events. Trial Data Needs to Be Appropriately Applied to Elderly Subgroups One should exercise caution in interpreting early statin trial data for elderly patients. Many studies excluded the very elderly. Also, results of meta-analyses are weighted by studies with the most participants. If the largest study has important limitations, then the conclusion of the meta-analysis may be misleading. Consider a recent post hoc secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Trial (ALLHAT– LLT) by Han et al. [16] Their analysis examined the primary outcome of all-cause mortality and secondary outcomes of cause-specific mortality and nonfatal MI. They reported no significant differences in all-cause mortality or cardiovascular outcomes for older adults receiving pravastatin versus usual care [16]. An important observation that did not receive emphasis was the 29% crossover rate in the placebo group to statins. This “drop-in” statin effect in the placebo group along with the effects of decreased adherence with time resulted in a smaller difference in LDL-C between the intervention and comparator groups. A 15% difference in LDL-C
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between those assigned pravastatin versus those receiving usual care may not be large enough to show a difference, even if a difference exists. This points out the need for an adequately powered RCT where at least a 30% lowering of LDL-C is seen before one can conclude that a moderate intensity statin is not beneficial in this group. On the other hand, a joint analysis of two large RCTs (Heart Outcomes Prevention Evaluation-3 (HOPE-3) and Justification for the Use of Statins in Primary Prevention (JUPITER)) showed that the pooled estimate of benefit of those older than 70 years of age were at higher risk yet still derived significant benefit from statins [17]. Whether these data can be generalized to a larger population, however, requires further evaluation.
subgroups were often not adequately powered to draw statistically significant conclusions [20–22]. Both the 2013 ACC–AHA ASCVD guidelines and current USPSTF recommendations acknowledge the limited evidence for statin use in primary prevention for patients older than 75 years of age [6••, 7••]. For patients 65 to 75 years old, there is a recommendation for statin therapy if ASCVD risk is ≥ 7.5% for ACC–AHA guidelines and a risk of > 10% with one or more ASCVD risk factors in the USPSTF guidelines (Table 1). Before treatment, however, both recommend patientcentered risk discussions. The clinician–patient risk discussion makes the actual threshold less important as statins are not automatically prescribed with either guideline.
Quality over Quantity of Life: The Need to Address the 3 Ds
Elderly Patients Are Different
When considering whether prescribing a statin is appropriate in the elderly, one must weigh the benefit to the quality of life over the number of life years gained as a result of treatment. The critical quality of life considerations in elderly patients can be summarized as “The 3 Ds”: dementia (cognitive decline), disability, and dependence [18]. Decisions to prescribe therapy in older patients should consider the risk and benefit of a new medication and whether it would prevent or slow the progression of these conditions. Investigators in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial assessed the effect of pravastatin to track fluid abilities in cognition such as memory, general speed, and attention. They found no significant difference with pravastatin therapy.
Should Elderly Patients Receive a Statin? The decision to prescribe statins to the elderly starts with consideration of the individual’s age, atherosclerosis status, and risk factor burden. The first large-scale RCT of secondary prevention, the Simvastatin Scandinavian Survival Study (4S) showed convincingly with Kaplan–Meier curves for all-cause mortality that the beneficial effects of simvastatin 40 mg/day on mortality occurred sooner in those 65 years of age and older as compared to those under 65 years of age [19]. In this landmark RCT, the absolute risk reduction for all-cause and coronary heart disease mortality was more than twice that seen in the under 65 year age group. Since the relative risk reduction with statin therapy was the same, this reduction was due to the rates for these two outcomes being more than twice as high in the older placebo group than the younger one. Other statin trials and registries, including the Cholesterol and Recurrent Events (CARE) trial, Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study, and Heart Protection Study (HPS), excluded those over 85 years and meta-analyses with subgroup analyses of these trials’ older
A hierarchical Bayesian analysis reviewed evidence that statins reduce all-cause mortality in secondary prevention in older patients [23]. The 2013 ACC–AHA guidelines strike a more cautionary note in those with clinical ASCVD over 75 than they do for those 75 years and under [6••]. In the latter group, a high intensity statin is recommended if there are no contraindications. In the older group, the ACC–AHA guidelines specifically state: “In individuals with clinical ASCVD >75 years of age, it is reasonable to evaluate the potential for ASCVD risk-reduction benefits and for adverse effects and drug–drug interactions and to consider patient preferences when initiating a moderate- or high-intensity statin. It is reasonable to continue statin therapy in those who are tolerating it.” In the text, the authors noted that the “limited amount of information available did not clearly support the initiation of high-intensity statin therapy for secondary prevention in individuals >75 years.” Guideline authors were concerned that those who participated in RCTs who were over 75 years of age did not necessarily represent many in this group who have more co-morbidities and polypharmacy with an increased risk for drug–drug interactions than those enrolled in the RCTs. Nonetheless, the actual recommendation allowed individual clinician judgment to prescribe a high intensity statin if deemed most likely to provide greater net benefit. Importantly, since the evidence behind prescribing statins for primary prevention in those over 75 is limited, and more so for those over 85, deciding to prescribe a statin in these primary prevention groups must reflect a risk discussion [6••]. This is especially important in those over 75 with good functional status who prioritize independence and quality of life. As noted above, they are concerned with treatments affecting cognitive decline, disability, or dependence. For example, more than 10 years ago, an elderly man with orthopedic issues was asked to start a statin due an LDL-C of 145 mg/dl. Our second opinion included a discussion of the potential of statins to cause
47 Table 1
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Page 4 of 7 The evidence behind statins in the elderly
Age groups (years)
Evidence for net benefit by RCT*/meta-analysis**
2013 ACC/AHA guidelines
USPSTF recommendations
65–75
Primary prevention: yes AFCAPS/TexCAPS*, CARDS Trial*, PROSPER*, ASCOT-LLA*, HOPE-3*, JUPITER*, Savarese et al.**, Cochrane** Secondary prevention: yes MRC/BHF HPS*, CARE Trial*, LIPID Study*, CTTC** Primary prevention: no Secondary prevention: yes CTTC** Primary prevention: no Secondary prevention: no
Primary prevention with risk discussion: yes
Primary prevention with risk discussion: yes
Secondary prevention: yes
Secondary prevention: no
Primary prevention: no Secondary prevention: yes Primary prevention: no Secondary prevention: no
Primary prevention: no Secondary prevention: no Primary prevention: no Secondary prevention: no
76–85 > 86
AFCAPS/TexCAPS Air Force/Texas Coronary Atherosclerosis Prevention Study, CARDS Collaborative Atorvastatin Diabetes Study Trial, PROSPER Pravastatin in Elderly Individuals at Risk of Vascular Disease Trial, ASCOT–LLA Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm, HOPE-3 Heart Outcomes Prevention Evaluation Trial, JUPITER Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin, MRC/BHF HPS Heart Protection Study, CARE Cholesterol and Recurrent Events Trial, LIPID The Long-Term Intervention with Pravastatin in Ischemic Disease Study Group, CTTC Cholesterol Treatment Trialists’ Collaboration *
indicates RCT; ** indicates meta-analysis
muscular weakness. Although infrequent, this consideration caused him to forgo statin therapy as any musculoskeletal weakness would clearly affect his independence. Katz et al. suggested that discussing the “5 Ms” could be useful for organizing the risk discussions regarding statin safety [24]. The 5 Ms are metabolic, musculoskeletal, memory/dementia, medication side effects, and major organ dysfunction (liver, kidney) (see Table 2). Metabolic changes with statins include new onset of diabetes (NODM). An increased incidence was seen in the JUPITER trial and subsequently in many of the other statin RCTs [24]. In both JUPITER, a large-scale primary prevention RCT, and Treating to New Targets (TNT) trial, a large-scale secondary prevention RCT, the likelihood of progression to NODM with a statin was dependent on whether diabetes risk factors were present [25, 26]. Indeed, absence of a body mass index (BMI) Table 2
≥ 30, fasting blood sugar (FBS) ≥ 100, A1c ≥ 6.0%, or the metabolic syndrome made the progression to NODM unlikely. In those with such diabetes risk factors who progressed to NODM, this occurred approximately 5.4 weeks earlier in JUPITER. Most importantly, in JUPITER participants with and without risk factors for NODM, the absolute benefit of statin therapy in preventing ASCVD events was greater than the risk of developing NODM. As seen in the placebo group of the 4S RCT, the absolute risk of ASCVD events is so much greater in those over 65; the potential for benefit would seem to outweigh the potential for NODM in older patients [19]. Since metabolic factors such as BMI, hyperglycemia, and other metabolic syndrome risk factors relate to NODM, elderly who are considered for statins should also work on a heart-healthy lifestyle designed to lower such risk factors.
Statin side effect considerations in older individuals Evidence of RCT*/meta-analysis**
Comments
Metabolic: new onset of DM/weight gain
JUPITER, TNT
Musculoskeletal
SEARCH, STOMP
Memory (cognitive decline, dementia)
PROSPER, HPS, HOPE-3
Medication (drug-drug interactions) especially CYP 450 Major organ dysfunction
RCTs avoided use of medications that would elevate statin concentrations PROSPER, SAGE, TNT
Both primary and secondary prevention trials show that new onset DM unlikely if no DM risk factors. Weight gain important to avoid if on a statin. Overall benefit outweighs risks in those who progress to NODM. Avoid simvastatin 80 mg/day; atorvastatin 80 mg/day elevates CK significantly, but no objective decrease in strength. Rhabdomyolysis is very rare. None of these trials showed significant increase in cognitive decline with statins. Pharmacists should be consulted for those on multiple drug regimens. Especially important in elderly on multiple drugs. FDA found no reason to monitor liver tests routinely.
TNT Treating to New Targets, SEARCH Study of the Effectiveness of the Additional Reductions in Cholesterol and Homocysteine Collaborative Group, STOMP The Effect of Statin Medications on Muscle Performance, SAGE The Study Assessing Goals in the Elderly *
indicates RCT; ** indicates meta-analysis
Curr Atheroscler Rep (2017) 19:47
Musculoskeletal symptoms are common in older individuals. This makes it especially difficult to know if a musculoskeletal ache, pain, muscle tenderness, or cramp is due to the statin or a different etiology. Indeed, meta-analyses of RCTs have shown only small differences between those assigned to statins versus placebo [27]. Illustrative of the difficulty in deciding if statins are causative in muscle aches are three trials worth considering. The first was a RCT that failed to show that CoQ10 therapy reduced muscle pain in those with statin myalgia. Despite the fact that all individuals had statin myalgia, investigators noted hat only 36% of such individuals developed myalgia symptoms during the RCT [28]. The second was the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3 (GAUSS-3) RCT that used a similar design of rechallenging those with statin intolerance with either statin or placebo [29]. They noted that 26.5% of patients reported similar symptoms with placebo but not atorvastatin, demonstrating the lack of specificity of a history of statin intolerance based on myalgia. Finally, although small, the insights gained from the N-of-1 trial reported by Joy TR et al. are worth noting [30]. This study looked at eight patients with a mean age of 66, 88% women with high 10-year Framingham Risk Scores. After three double-blind crossover comparisons separated by 3-week washout periods, seven of the eight patients did not show statistically significant greater myalgia symptom scores employing visual analogue scales during statin treatment versus placebo. These three studies do not refute the relationship between muscle symptoms and statins but make it clear that the symptom of statin-associated myalgia lacks specificity. Since the absolute potential for benefit is greater in the older secondary prevention patient, it may be that N-of-1 trials could especially benefit those over 65 if they could determine that up to Fig. 1 The importance of the clinician-patient risk discussion
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one third of patients complaining of statin associated myalgias do not need to discontinue statin therapy for this reason. Medication or drug–drug interactions are especially important in older patients. In those on multiple medications, the aid of a pharmacist to see if drug–drug interactions exist is important both at the time of the prescription and especially when a new drug is added. Patients need to be warned about over-the-counter remedies such as St. John’s wort, as well as other over-the-counter anti-depression remedies that can cause multiple drug–drug interactions [31]. Careful review of the patient’s medication lists including vitamins and supplements should be conducted at regular intervals. Major organ effects include those of statins on liver or kidney function. Although major organ dysfunction was historically of concern, more contemporary monitoring and studies indicate that the rate of organ damage, particularly liver damage, is comparable to rates with placebo [32]. Several studies, including subgroup analysis of the TNT trial and the Study Assessing Goals in the Elderly (SAGE) trial, demonstrated elevated liver function tests with higher intensity statins that were rarely clinically significant [12, 32]. As of 2012, the FDA no longer recommends periodic monitoring of liver function tests for patients on statins. When adverse effects do occur, they are generally reversible with discontinuing a statin or switching to a statin that is metabolized differently [12].
Conclusion A growing body of evidence supports statin prescribing for both primary and secondary prevention in patients up to 75 years of age. As reflected in RCTs and meta-analyses, older
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patients have greater absolute reductions in risk with statin therapy compared to their younger counterparts because of their higher burden of cardiovascular risk factors and disease. In the very elderly, high quality data is limited and clinicians must use clinical judgment. The decision to initiate a statin should only occur after a careful discussion of the potential for benefit versus the potential for adverse effects from additional medication that could impair quality of life (Fig. 1). Recent data from the BioImage Study suggests that the specificity of statin prescribing in older individuals can be greatly improved with either a coronary artery calcium score and/or a carotid plaque imaging score [33]. This offers the promise of focusing therapy on those most likely to benefit. Compliance with Ethical Standards Conflict of Interest Marysa V. Leya and Neil J. Stone declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
Wenger NK. Alice in lipidland. J Am Coll Cardiol. 2014;64(21): 2193–5. 2. William MA, Fleg JL, Ades PA, et al. Secondary prevention of coronary heart disease in the elderly (with emphasis on patients > or =75 years of age): an American Heart Association scientific statement from The Council on Clinical Cardiology Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention. Circulation. 2002;105(14):1735–43. 3. Ko DT, Mamdani M, Alter DA. Lipid-lowering therapy with statins in high-risk elderly patients: the treatment-risk paradox. JAMA. 2004;291(15):1864–70. 4. Gransbo K, Melander O, Wallentin L. Cardiovascular and cancer mortality in very elderly post-myocardial infarction patients receiving statin treatment. JACC. 2010;55(13):1363–9. 5. Gaye B, Canonico M, Perier M, Samieri C, Berr C, Dartigues J, et al. Ideal cardiovascular health, mortality, and vascular events in elderly subjects. JACC. 2007;69(25):3015–26. 6.•• Stone NJ, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. JACC. 2014;63(25 Pt B):2889–934. The latest guidelines from the ACC/AHA on statin prescribing, with special consideration of evidence-based practices doe prescribing in individuals over 65 years. Statins for secondary prevention are recommended for patients up to 85 years old, and for primary prevention with a risk discussion for patients 65 to 75 years old
Curr Atheroscler Rep (2017) 19:47 7.•• US Preventive Services Task Force. Statin use for the primary prevention of cardiovascular disease in adults. US Preventive Services Task Force recommendation statement. JAMA. 2016;316(19): 1997–2007. The current recommendations from the USPSTF for prescribing statins in those 40 to 75 years of age based on their degree of cardiovascular risk recognizes the current limited evidence for prescribing statins for primary prevention in those older than 75 years of age 8. Ali R, Alexander KP. Statins for the primary prevention of cardiovascular events in older adults: a review of the evidence. Am J Geri Pharmacotherapy. 2007;5(1):52–63. 9. Corti MC, Guralnik JM, Salive ME, Harris T, Field TS, Wallace RB, et al. HDL cholesterol predicts coronary heart disease mortality in older persons. JAMA. 1995;274(7):539–44. 10. Savarese G, Gotta AM, Paolillo S, et al. Benefits of statins in elderly subjects without established cardiovascular disease: a meta-analysis. JACC. 2013;62(22):2090–9. 11. Robinson JG, Stone NJ. Identifying patients for aggressive cholesterol lowering: the risk curve concept. Am J Cardiol. 2006;98(10): 1405–8. 12. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388: 2532–61. 13. Kuller L, Borhani N, Furberg C, Gardin J, Manolio T, O’Leary D, et al. Prevalence of subclinical atherosclerosis and cardiovascular disease and association with risk factors in the Cardiovascular Health Study. Am J Epidemiol. 1994;139(12):1164–79. 14. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics-2015 update: a report from the American Heart Association. Circulation. 2015;131:e29–e322. 15. Flack JM, Ferdinand KC, Nasser SA. Epidemiology of hypertension and cardiovascular disease in African Americans. J Clin Hyperten. 2003;5(1):5–11. 16. Han BH, Sutin D, Williamston JD, et al. Effect of statin treatment vs usual care in primary cardiovascular prevention among older adults: the ALLHAT-LLT randomized clinical trial. JAMA. 2017;177(7): 955–65. 17. Ridker PM, Lonn E, Paynter NP, Glynn R, Yusuf S. Primary prevention with statin therapy in the elderly: new meta-analyses from the contemporary JUPITER and HOPE-3 randomized trials. Circulation. 2017;135(20):1979–81. 18. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–30. 19. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383–9. 20. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events trial investigators. NEJM. 1996;335:1001–9. 21. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study group. N Engl J Med. 1998;339:1349–57. 22. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20, 536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7–22. 23. Afilalo J, Duque G, Steele R, et al. Statins for secondary prevention in elderly patients: a hierarchical Bayesian meta-analysis. JACC. 2008;51(1):37–45.
Curr Atheroscler Rep (2017) 19:47 24.• Katz DH, Intwala SS, Stone NJ. Addressing statin adverse effects in the clinic. J Cardiovasc Pharmacol Ther. 2014;19(6):533–42. Provides a framework for addressing the most relevant adverse effects of statins in the clinic setting 25. Ridker PM, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–207. 26. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart J, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. New Engl J Med. 2005;352:1425–35. 27. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a metaanalysis of data from 170000 participants in 26 randomized trials. Lancet. 2010;376:1670–81. 28. Taylor BA, Lorson L, White CM, Thompson PD. A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy. Atherosclerosis. 2015;238(2):329–35.
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Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 Randomized Clinical Trial. JAMA 2016;315(15):1580–1590. Joy TR, Monjed A, Zou GY, Hegele RA, McDonald CG, Mahon JL. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;160(5):301–10. Davis SA, Feldman SR, Taylor SL. Use of St. John’s Wort in potentially dangerous combinations. J Altern Complement Med. 2014;20(7):578–9. Russo MW, Hoofnagle JH, Gu J, Fontana RJ, Barnhart H, Kleiner DE, et al. Spectrum of statin hepatotoxicity: experience of the druginduced liver injury network. Hepatology. 2014;60:679–86. Fuster V, Muntendam P, Mehran R, Baber U, Sartori S, Falk E. A simple disease-guided approach to personalize ACC/AHArecommended statin allocation in elderly people: the BioImage Study. J Am Coll Cardiol. 2016;68(9):881–91.
STATIN DRUGS (B. WIGGINS, SECTION EDITOR)
Statin Prescribing in the Elderly: Special Considerations M. Leya 1 & N. J. Stone 2
# Springer Science+Business Media, LLC 2017
Abstract Purpose of Review Our aim was to examine the current evidence behind prescribing statins to individuals over 65 years of age with emphasis on those older than 75. Individuals over 75 years of age may often have multiple comorbidities and take many medications. Additionally, they are often underrepresented in randomized controlled trials (RCTs) of statins in older populations. While results of RCTs demonstrate the benefit of statin therapy in both primary and secondary prevention patients, clinicians must more carefully consider adverse effects and drug–drug interactions before prescribing statin therapy as well as determining the intensity in older individuals. Recent Findings Four primary prevention trials support statins for primary prevention following a clinician–patient risk discussion. Of these, JUPITER and HOPE-3 studied participants 70 years of age and over who derived benefit. However, in those over 85 years, available information is inadequate to guide decisions regarding statin therapy. Documented statin adverse effects include new onset diabetes, myopathy, and medication interactions. Although cognitive decline has been reported anecdotally, its incidence was comparable to placebo in two RCTs with validated cognitive evaluations. Concerns about significant liver and kidney injury with statins were not corroborated in RCTs. For most patients,
the potential for reducing ASCVD risk outweighs possible adverse effects; however, in the elderly, the impact of drug treatment on cognition, musculoskeletal ability, and independence must be heavily weighed. Summary Given the limited high quality evidence for primary prevention in individuals over 75 years of age, neither the ACC–AHA nor USPSTF cholesterol guidelines recommend statin therapy for primary prevention in this patient population. If prescribed, physician judgment and shared decision-making are crucial. To aid clinicians, imaging studies of subclinical atherosclerosis may improve specificity of statin therapy to prevent ASCVD in the elderly in primary prevention. Keywords Statin . Elderly . Treatment risk paradox . Primary prevention . Secondary prevention . Adverse effects
“The contemporary statin treatment-risk paradox is striking; despite the high attributable risk of hypercholesterolemia at elderly age, and the statin-associated reduction in all-cause mortality in this population, statin use declines sharply at elderly age.” – Nanette Wenger, M.D. [1]
This article is part of the Topical Collection on Statin Drugs * M. Leya [email protected]
1
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
2
Division of Cardiology; Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Introduction Dr. Wenger summarized the statin treatment risk paradox in older individuals well. The elderly carry a disproportionate burden of cardiovascular disease, with octogenarians in particular accounting for only 5% of the population but representing 20% of hospitalizations for myocardial infarction
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(MI) and 30% of all MI-related hospital deaths [2]. Despite their increased risk of events, the elderly are less likely to receive therapy directed at reducing atherosclerotic cardiovascular disease (ASCVD) events [3, 4]. Of note, observational data from the Global Registry of Acute Coronary Events (GRACE) indicates that fewer than 40% of patients older than 75 are prescribed statins at discharge [4, 5].
explain this association well. Those with chronic illnesses such as end-stage renal disease, liver disease, and malignancies (and often poor nutritional status) have lower cholesterol profiles. After adjusting for nutritional status via albumin, ferritin, and other surrogates, total cholesterol and LDL-C demonstrated a similar correlation to cardiovascular risk as in young patients [13].
Definitions
Demographic Differences in Prevention of Myocardial Infarction and Stroke
The literature often defines elderly as individuals 65 years and over. However, recent guidelines, including those from the American College of Cardiology–American Heart Association (ACC–AHA) and U.S Preventive Services Task Force (USPSTF), consider those over 75 as a group that merits special consideration for risk attenuation in primary prevention and risk reduction for secondary prevention [6••, 7••]. Thus, those over 75 will serve as the focus for this review.
Should Cholesterol Risk Be Treated in the Elderly? Pitfalls in Decision-Making Cholesterol and LDL-C Are Poor Markers of Risk in the Elderly Assessing ASCVD risk in the elderly is complicated compared to risk assessment in younger individuals. Cholesterol and LDL-C are less reliable markers in older populations. ASCVD events may occur in elderly without the traditional risk factor profile [8]. Therefore, HDL-C is often the best lipid risk predictor in these individuals [9]. Older patients have a high burden of risk factors for ASCVD. Multiple medications prescribed for hypertension, diabetes, and cholesterol alter the prevalence and presentation of textbook cardiovascular disease and are only a part of the total pill burden of older individuals. Depression can further reduce medication adherence and correlates with increased vascular morbidity [10]. LDL-C levels in the elderly do not correlate as well with ASCVD risk compared to younger cohorts for multiple reasons. For example, those with elevated LDL-C may have died, leaving behind an elderly population with lower average LDL-C, but still at increased risk owing to their advanced age and comorbidities. They are on a higher LDL-C risk curve [11]. This is a way of visualizing how an increasing burden of risk factors and/or clinical atherosclerosis places an individual at enhanced risk of an ASCVD event at the same level of LDL-C. Also, observational studies have reported an association of lower cholesterol concentrations with higher rates of all-cause mortality in older patients [12]. The Honolulu Heart Study suggested that pre-existing diseases
Subclinical vascular disease, as manifested by abnormal echocardiograms, ankle–brachial indices, and increased carotid intima-media thickness, increases with age. The Cardiovascular Health Study demonstrated that for patients aged 65 to 70 years old, subclinical disease was present in 22% of women and 33% of men and in patients over 85 years old increased to 43% in women and 45% in men [13]. Strokes are the leading precipitants of disability in older American women and in African Americans often presenting with cerebrovascular events before MIs. Based on 2015 statistics from the AHA, among those 65 to 84 years of age, 53% of stroke patients were women, which increased to 66% for patients older than 85 [14]. African American patients have higher stroke risk and stroke mortality and tend to present at younger ages compared to their counterparts [15]. Advocating for appropriate therapy for patients requires understanding different patterns of presentation of cardiovascular disease and aggressively managing those at higher risk of events. Trial Data Needs to Be Appropriately Applied to Elderly Subgroups One should exercise caution in interpreting early statin trial data for elderly patients. Many studies excluded the very elderly. Also, results of meta-analyses are weighted by studies with the most participants. If the largest study has important limitations, then the conclusion of the meta-analysis may be misleading. Consider a recent post hoc secondary analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid-Lowering Trial (ALLHAT– LLT) by Han et al. [16] Their analysis examined the primary outcome of all-cause mortality and secondary outcomes of cause-specific mortality and nonfatal MI. They reported no significant differences in all-cause mortality or cardiovascular outcomes for older adults receiving pravastatin versus usual care [16]. An important observation that did not receive emphasis was the 29% crossover rate in the placebo group to statins. This “drop-in” statin effect in the placebo group along with the effects of decreased adherence with time resulted in a smaller difference in LDL-C between the intervention and comparator groups. A 15% difference in LDL-C
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between those assigned pravastatin versus those receiving usual care may not be large enough to show a difference, even if a difference exists. This points out the need for an adequately powered RCT where at least a 30% lowering of LDL-C is seen before one can conclude that a moderate intensity statin is not beneficial in this group. On the other hand, a joint analysis of two large RCTs (Heart Outcomes Prevention Evaluation-3 (HOPE-3) and Justification for the Use of Statins in Primary Prevention (JUPITER)) showed that the pooled estimate of benefit of those older than 70 years of age were at higher risk yet still derived significant benefit from statins [17]. Whether these data can be generalized to a larger population, however, requires further evaluation.
subgroups were often not adequately powered to draw statistically significant conclusions [20–22]. Both the 2013 ACC–AHA ASCVD guidelines and current USPSTF recommendations acknowledge the limited evidence for statin use in primary prevention for patients older than 75 years of age [6••, 7••]. For patients 65 to 75 years old, there is a recommendation for statin therapy if ASCVD risk is ≥ 7.5% for ACC–AHA guidelines and a risk of > 10% with one or more ASCVD risk factors in the USPSTF guidelines (Table 1). Before treatment, however, both recommend patientcentered risk discussions. The clinician–patient risk discussion makes the actual threshold less important as statins are not automatically prescribed with either guideline.
Quality over Quantity of Life: The Need to Address the 3 Ds
Elderly Patients Are Different
When considering whether prescribing a statin is appropriate in the elderly, one must weigh the benefit to the quality of life over the number of life years gained as a result of treatment. The critical quality of life considerations in elderly patients can be summarized as “The 3 Ds”: dementia (cognitive decline), disability, and dependence [18]. Decisions to prescribe therapy in older patients should consider the risk and benefit of a new medication and whether it would prevent or slow the progression of these conditions. Investigators in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial assessed the effect of pravastatin to track fluid abilities in cognition such as memory, general speed, and attention. They found no significant difference with pravastatin therapy.
Should Elderly Patients Receive a Statin? The decision to prescribe statins to the elderly starts with consideration of the individual’s age, atherosclerosis status, and risk factor burden. The first large-scale RCT of secondary prevention, the Simvastatin Scandinavian Survival Study (4S) showed convincingly with Kaplan–Meier curves for all-cause mortality that the beneficial effects of simvastatin 40 mg/day on mortality occurred sooner in those 65 years of age and older as compared to those under 65 years of age [19]. In this landmark RCT, the absolute risk reduction for all-cause and coronary heart disease mortality was more than twice that seen in the under 65 year age group. Since the relative risk reduction with statin therapy was the same, this reduction was due to the rates for these two outcomes being more than twice as high in the older placebo group than the younger one. Other statin trials and registries, including the Cholesterol and Recurrent Events (CARE) trial, Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study, and Heart Protection Study (HPS), excluded those over 85 years and meta-analyses with subgroup analyses of these trials’ older
A hierarchical Bayesian analysis reviewed evidence that statins reduce all-cause mortality in secondary prevention in older patients [23]. The 2013 ACC–AHA guidelines strike a more cautionary note in those with clinical ASCVD over 75 than they do for those 75 years and under [6••]. In the latter group, a high intensity statin is recommended if there are no contraindications. In the older group, the ACC–AHA guidelines specifically state: “In individuals with clinical ASCVD >75 years of age, it is reasonable to evaluate the potential for ASCVD risk-reduction benefits and for adverse effects and drug–drug interactions and to consider patient preferences when initiating a moderate- or high-intensity statin. It is reasonable to continue statin therapy in those who are tolerating it.” In the text, the authors noted that the “limited amount of information available did not clearly support the initiation of high-intensity statin therapy for secondary prevention in individuals >75 years.” Guideline authors were concerned that those who participated in RCTs who were over 75 years of age did not necessarily represent many in this group who have more co-morbidities and polypharmacy with an increased risk for drug–drug interactions than those enrolled in the RCTs. Nonetheless, the actual recommendation allowed individual clinician judgment to prescribe a high intensity statin if deemed most likely to provide greater net benefit. Importantly, since the evidence behind prescribing statins for primary prevention in those over 75 is limited, and more so for those over 85, deciding to prescribe a statin in these primary prevention groups must reflect a risk discussion [6••]. This is especially important in those over 75 with good functional status who prioritize independence and quality of life. As noted above, they are concerned with treatments affecting cognitive decline, disability, or dependence. For example, more than 10 years ago, an elderly man with orthopedic issues was asked to start a statin due an LDL-C of 145 mg/dl. Our second opinion included a discussion of the potential of statins to cause
47 Table 1
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Page 4 of 7 The evidence behind statins in the elderly
Age groups (years)
Evidence for net benefit by RCT*/meta-analysis**
2013 ACC/AHA guidelines
USPSTF recommendations
65–75
Primary prevention: yes AFCAPS/TexCAPS*, CARDS Trial*, PROSPER*, ASCOT-LLA*, HOPE-3*, JUPITER*, Savarese et al.**, Cochrane** Secondary prevention: yes MRC/BHF HPS*, CARE Trial*, LIPID Study*, CTTC** Primary prevention: no Secondary prevention: yes CTTC** Primary prevention: no Secondary prevention: no
Primary prevention with risk discussion: yes
Primary prevention with risk discussion: yes
Secondary prevention: yes
Secondary prevention: no
Primary prevention: no Secondary prevention: yes Primary prevention: no Secondary prevention: no
Primary prevention: no Secondary prevention: no Primary prevention: no Secondary prevention: no
76–85 > 86
AFCAPS/TexCAPS Air Force/Texas Coronary Atherosclerosis Prevention Study, CARDS Collaborative Atorvastatin Diabetes Study Trial, PROSPER Pravastatin in Elderly Individuals at Risk of Vascular Disease Trial, ASCOT–LLA Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm, HOPE-3 Heart Outcomes Prevention Evaluation Trial, JUPITER Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin, MRC/BHF HPS Heart Protection Study, CARE Cholesterol and Recurrent Events Trial, LIPID The Long-Term Intervention with Pravastatin in Ischemic Disease Study Group, CTTC Cholesterol Treatment Trialists’ Collaboration *
indicates RCT; ** indicates meta-analysis
muscular weakness. Although infrequent, this consideration caused him to forgo statin therapy as any musculoskeletal weakness would clearly affect his independence. Katz et al. suggested that discussing the “5 Ms” could be useful for organizing the risk discussions regarding statin safety [24]. The 5 Ms are metabolic, musculoskeletal, memory/dementia, medication side effects, and major organ dysfunction (liver, kidney) (see Table 2). Metabolic changes with statins include new onset of diabetes (NODM). An increased incidence was seen in the JUPITER trial and subsequently in many of the other statin RCTs [24]. In both JUPITER, a large-scale primary prevention RCT, and Treating to New Targets (TNT) trial, a large-scale secondary prevention RCT, the likelihood of progression to NODM with a statin was dependent on whether diabetes risk factors were present [25, 26]. Indeed, absence of a body mass index (BMI) Table 2
≥ 30, fasting blood sugar (FBS) ≥ 100, A1c ≥ 6.0%, or the metabolic syndrome made the progression to NODM unlikely. In those with such diabetes risk factors who progressed to NODM, this occurred approximately 5.4 weeks earlier in JUPITER. Most importantly, in JUPITER participants with and without risk factors for NODM, the absolute benefit of statin therapy in preventing ASCVD events was greater than the risk of developing NODM. As seen in the placebo group of the 4S RCT, the absolute risk of ASCVD events is so much greater in those over 65; the potential for benefit would seem to outweigh the potential for NODM in older patients [19]. Since metabolic factors such as BMI, hyperglycemia, and other metabolic syndrome risk factors relate to NODM, elderly who are considered for statins should also work on a heart-healthy lifestyle designed to lower such risk factors.
Statin side effect considerations in older individuals Evidence of RCT*/meta-analysis**
Comments
Metabolic: new onset of DM/weight gain
JUPITER, TNT
Musculoskeletal
SEARCH, STOMP
Memory (cognitive decline, dementia)
PROSPER, HPS, HOPE-3
Medication (drug-drug interactions) especially CYP 450 Major organ dysfunction
RCTs avoided use of medications that would elevate statin concentrations PROSPER, SAGE, TNT
Both primary and secondary prevention trials show that new onset DM unlikely if no DM risk factors. Weight gain important to avoid if on a statin. Overall benefit outweighs risks in those who progress to NODM. Avoid simvastatin 80 mg/day; atorvastatin 80 mg/day elevates CK significantly, but no objective decrease in strength. Rhabdomyolysis is very rare. None of these trials showed significant increase in cognitive decline with statins. Pharmacists should be consulted for those on multiple drug regimens. Especially important in elderly on multiple drugs. FDA found no reason to monitor liver tests routinely.
TNT Treating to New Targets, SEARCH Study of the Effectiveness of the Additional Reductions in Cholesterol and Homocysteine Collaborative Group, STOMP The Effect of Statin Medications on Muscle Performance, SAGE The Study Assessing Goals in the Elderly *
indicates RCT; ** indicates meta-analysis
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Musculoskeletal symptoms are common in older individuals. This makes it especially difficult to know if a musculoskeletal ache, pain, muscle tenderness, or cramp is due to the statin or a different etiology. Indeed, meta-analyses of RCTs have shown only small differences between those assigned to statins versus placebo [27]. Illustrative of the difficulty in deciding if statins are causative in muscle aches are three trials worth considering. The first was a RCT that failed to show that CoQ10 therapy reduced muscle pain in those with statin myalgia. Despite the fact that all individuals had statin myalgia, investigators noted hat only 36% of such individuals developed myalgia symptoms during the RCT [28]. The second was the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects 3 (GAUSS-3) RCT that used a similar design of rechallenging those with statin intolerance with either statin or placebo [29]. They noted that 26.5% of patients reported similar symptoms with placebo but not atorvastatin, demonstrating the lack of specificity of a history of statin intolerance based on myalgia. Finally, although small, the insights gained from the N-of-1 trial reported by Joy TR et al. are worth noting [30]. This study looked at eight patients with a mean age of 66, 88% women with high 10-year Framingham Risk Scores. After three double-blind crossover comparisons separated by 3-week washout periods, seven of the eight patients did not show statistically significant greater myalgia symptom scores employing visual analogue scales during statin treatment versus placebo. These three studies do not refute the relationship between muscle symptoms and statins but make it clear that the symptom of statin-associated myalgia lacks specificity. Since the absolute potential for benefit is greater in the older secondary prevention patient, it may be that N-of-1 trials could especially benefit those over 65 if they could determine that up to Fig. 1 The importance of the clinician-patient risk discussion
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one third of patients complaining of statin associated myalgias do not need to discontinue statin therapy for this reason. Medication or drug–drug interactions are especially important in older patients. In those on multiple medications, the aid of a pharmacist to see if drug–drug interactions exist is important both at the time of the prescription and especially when a new drug is added. Patients need to be warned about over-the-counter remedies such as St. John’s wort, as well as other over-the-counter anti-depression remedies that can cause multiple drug–drug interactions [31]. Careful review of the patient’s medication lists including vitamins and supplements should be conducted at regular intervals. Major organ effects include those of statins on liver or kidney function. Although major organ dysfunction was historically of concern, more contemporary monitoring and studies indicate that the rate of organ damage, particularly liver damage, is comparable to rates with placebo [32]. Several studies, including subgroup analysis of the TNT trial and the Study Assessing Goals in the Elderly (SAGE) trial, demonstrated elevated liver function tests with higher intensity statins that were rarely clinically significant [12, 32]. As of 2012, the FDA no longer recommends periodic monitoring of liver function tests for patients on statins. When adverse effects do occur, they are generally reversible with discontinuing a statin or switching to a statin that is metabolized differently [12].
Conclusion A growing body of evidence supports statin prescribing for both primary and secondary prevention in patients up to 75 years of age. As reflected in RCTs and meta-analyses, older
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patients have greater absolute reductions in risk with statin therapy compared to their younger counterparts because of their higher burden of cardiovascular risk factors and disease. In the very elderly, high quality data is limited and clinicians must use clinical judgment. The decision to initiate a statin should only occur after a careful discussion of the potential for benefit versus the potential for adverse effects from additional medication that could impair quality of life (Fig. 1). Recent data from the BioImage Study suggests that the specificity of statin prescribing in older individuals can be greatly improved with either a coronary artery calcium score and/or a carotid plaque imaging score [33]. This offers the promise of focusing therapy on those most likely to benefit. Compliance with Ethical Standards Conflict of Interest Marysa V. Leya and Neil J. Stone declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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