Use of Statins in the Nursing Home Population. Objectives

Transcription

1 Use of Statins in the Nursing Home Population Cari Levy, MD, PhD University of Colorado Health Sciences Center and the Rocky Mountain Regional Medical Center Objectives Discuss the evidence base for use of statins across various populations of older adults: Primary prevention Statin use in nursing homes Deprescribing 1

2 The Art and Adventure of Geriatrics Why does this matter? 25-30% >75yrs in US take statins 17-39% in nursing homes take statins Our examination of studies requires a microscope Thompson W et al. Drugs Aging 2018 Guidelinegate Assess 10-year risk of MI and CVA Only up to age 79 2

3 Four Major Statin Benefit Groups 1) Clinical ASCVD 2) LDL >190 3) DM yo with LDL and without clinical ASCVD 4) Without clinical ASCVD or DM ages years with LDL and estimated 10-year ASCVD risk >7.5-10% 3

4 Statin Potency High Lowers LDL >50% Atorvastatin 40-80mg Moderate Lowers LDL by 30-50% Atorvastatin 10-20mg Low Lowers LDL by < 30% Rosuvastatin 20-40mg Rosuvastatin 5-10mg Statin of choice in Elderly Simvastatin 20-40mg Simvastatin 10mg Pravastatin 40-80mg Pravastatin 10-20mg Lovastatin 40mg Lovastatin 20mg Fluvastatin 40mg bid (or CL 80 mg) Fluvastatin 20mg The Drama Guidelinegate Doubles the number of patients eligible for statin treatment Harvard investigators applied calculator to 3 large databases and found overestimation of risk 40-50% of those with a calculated risk >7.5% threshold by the calculator do not actually have that risk 4

5 National Lipid Association Guidelines Stratifies by risk calculator, includes coronary calcium score Returns to LDL goals <100 mg/dl primary prevention <70 mg/dl secondary prevention Apolipoprotein B goals <90mg/dL primary prevention <80mg/dL secondary prevention Meet Harry 5

6 Case Presentation #1 Harry is a 79yo male with lipids from a health fair No PMH Active - goes to the health club 5 days per week to run (yes, run!) 30 minutes on treadmill Chol Ttl 221mg/dL, LDL-C 140, HDL-C 45 SBP 148/84mmHg, Non-smoker Should we do anything about his lipids? 6

7 Life Expectancy Based on Age Age Male Female

8 What is Harry s 10-year Risk? 10-year ASCVD event risk 23% What if Ttl 130, HDL 100 and SBP 115mmHg? 9% Is his cardiac age lower than expected given activity? 8

9 >85 years consider atorvastatin 20 mg as statins may be of benefit in reducing the risk of non-fatal myocardial infarction Where do we start with Harry? Primary prevention 9

10 Major Clinical Trials in Elderly 1 prevention AFCAPS/TexCAPS JUPITER MEGA ALLHAT 2 prevention CARE 4S LIPID 1 and 2 prevention HPS PROSPER Pre-existing coronary, cerebral, or peripheral Fibrates, ezetimibe improve lipids for those unresponsive of intolerant of statins but outcome data for elderly scarce. From: Effect of Statin Treatment vs Usual Care on Primary Cardiovascular Prevention Among Older AdultsThe ALLHAT-LLT Randomized Clinical Trial JAMA Intern Med. 2017;177(7): doi: /jamainternmed Figure Legend: Copyright 2017 American Medical Association. All Rights Reserved. 10

11 From: Effect of Statin Treatment vs Usual Care on Primary Cardiovascular Prevention Among Older Adults The ALLHAT-LLT Randomized Clinical Trial JAMA Intern Med. 2017;177(7): doi: /jamainternmed Higher all cause mortality trend with Pravastatin Figure Legend: Age >75yrs Copyright 2017 American Medical Association. All Rights Reserved. How about Harry? At age 79yrs life expectancy 8yrs 23% chance of event in 10 years Already exercising Fitzgerald JD. J Am Heart Assn

12 What about the calculator? Prediction is not a perfect science Let patients know their risk and decide what makes sense for them The calculator is a step forward with inclusion of CVA risk and more accurate predictions for African Americans Meet Bob (Harry s brother) 12

13 Case Presentation #2 Bob is an 82yo male with lipids from a hospitalization CAD s/p multiple CABGs and stents Not Active watches news programs all day at his nursing home where was admitted after a recent fall for rehab Chol Ttl 210mg/dL, LDL-C 143, HDL-C 40 SBP 135mmHg, Occasional pipe smoker Should we do anything about his lipids? Do we have data for patients like Bob? Major Clinical Trial Results (%RRR) JUPITER CARE 4S LIPID AGE All-cause mortality 34 * 21^ CHD death 39 ^ 45^ 43^ 24^ Major CHD events 32 * 34^ Nonfatal MI 30 33^ CHD death/nonfatal MI 39^ 22 * Stroke 40^ 12 Revascularization 32^ 41^ * Primary endpoint for subgroup analysis; p<0.05 ^Statistically significant reduction 13

14 Statin Trials Focused on Elderly HPS PROSPER N 20, Age (28% age 70-80) (100%) LDL Drug Simvastatin 40mg Pravastatin 40mg Length 5.5 yrs 3.2 yrs Tx LDL PROSPER: Primary Endpoint Proportion with event (%) P= Follow-up (years) Placebo Pravastatin Lancet 2002;360:

15 Meta-analyses in Older Adults (RRR%) Study Design Prevention Type N Age Range All Cause Mortality CVA 9 RCTs Secondary 19, % 28% 18 RCTs Primary Secondary 51,351 15% 24% 8 RCTs Primary 24, yrs 6% NS 24% Benefit occurs regardless of absolute LDL value. Nursing Home Cohorts with CAD Study Design N % Relative Risk Reduction Matched Cohort All Cause Mortality 2, % % >85 28% Stroke Coronary Events Heart Failure Observational 1,410 60% 50% 48% Observational % Observational % 37% 15

16 Observational Data in Elderly Jerusalem Longitudinal Study Birth cohort Studied at age 70, 78 and 85 High total cholesterol was not associated with an increase in mortality ages however All cause mortality lower among those >85 taking statins independent of cholesterol levels Jacobs JM et. al. JAMDA 14 (2013) Retrospective Missouri Study Age >80yrs (mean 85.2yrs ), 56% female hospitalization for CAD/MI N=913 Statin N=349 No Statin Outcome: All-cause mortality over 3 yrs Propensity-matched subjects HR = 0.88 (95% CI ) Statins had no effect on all cause mortality Other outcomes? Rothschild et al. JAGS

17 Retrospective MDS Study 11,192 NH residents >65yrs hospitalization for MI 41% 1 med, 22% 2 meds for secondary prevention (statin, ASA, beta-blocker) Fewer Rx s if older, women, DNR, functional dependence, cognitive impairment Zullo et al. JAGS 2017 Is this the art and adventure of geriatrics at work? 17

18 Should we treat Bob? AHA Algorithm not applicable Data from PROSPER yes? (primary care) Observational data mixed, mortality as an outcome? Life expectancy, risk, side effects Meet Ruth and Jim (Harry and Bob s sister) 18

19 Case Presentation #3 Ruth is an 89yo female with lipids from a hospitalization for a new CVA transferred for hospice in your facility Her husband is reluctantly admitting her to hospice for metastatic breast cancer diagnosis He is frustrated with the health system and accuses you of trying to save a buck and risking another CVA when you ask about her statin Chol Ttl 220mg/dL, LDL-C 150, HDL-C 30 SBP 163/90mmHg Do we have data for patients like Ruth? From: Safety and Benefit of Discontinuing Statin Therapy in the Setting of Advanced, Life-Limiting IllnessA Randomized Clinical Trial JAMA Intern Med. 2015;175(5): doi: /jamainternmed Figure Legend: CONSORT Flow DiagramA total of 189 patients were randomized to discontinue statin therapy and 192 were randomized to continue therapy. a Contraindications to continuing or discontinuing statin therapy. b Distribution of withdrawals between study arms; P =.85. c Copyright 2015 American Medical Date Distribution of download: of outcomes 8/16/2018 between study arms; P =.58. Association. All rights reserved. 19

20 Deprescribing Statins in Hospice Kutner et al. JAMA Int Med 2015 From: Safety and Benefit of Discontinuing Statin Therapy in the Setting of Advanced, Life-Limiting Illness Randomized Clinical Trial JAMA Intern Med. 2015;175(5): doi: /jamainternmed Figure Legend: Date of download: 8/16/2018 Copyright 2015 American Medical Association. All rights reserved. 20

21 Dyslipidemia Summary Most data up to age % RRR for CAD events/death over years Who will benefit most? 2 prevention Considerations Polypharmacy, myalgias, patient preference Cognition, diabetes, cancer? No Medication is without RISK Muscle-related symptoms Elevated hepato-cellular enzymes New diabetes Hemorrhagic stroke Fatigue Neuro-psychiatric effects and insomnia Cancer? Carter A et al.. BMJ 2013 PMID Dormuth et al. BMJ 2013; Available at: Padala JAGS

22 No Medication is without RISK Higher potency statins vs. lower potency statins Higher risk of diabetes Exertional fatigue Carter A et al.. BMJ 2013 PMID Dormuth et al. BMJ 2013; Available at: Padala JAGS 2010 Statins and Cognitive Impairment FDA review of case reports, observational data and randomized clinical trials FDA concluded: Some individuals over 50 years old suffer notable, but ill-defined memory loss / impairment Reversible on discontinuation of statin Variable time of onset (1 day to years) No fixed or progressive dementia Not related to specific statin FDA Safety Communication 22

23 Muscle Adverse Effects of Statin Major symptom limiting the use of statins Clinical features include Muscle aches, myalgia, weakness Stiffness, and cramps CK not increased in most patients Compromises quality of life Reduces medication adherence Mancini GB et al. CJC 2011; 27: Statins and Fatigue Randomized subset of a controlled trial 397 of 1016 subjects Equal randomization to simvastatin 20mg, pravastatin, or placebo 6 month follow-up Conclusions: Statins may worsen energy and or exertional fatigue Women appear more affected than men Golomb BA et al. Arch Intern Med. 2012; 172(15): doi: /archinternmed

24 Statin Intolerance Impact of Adverse Effects on Adherence Survey of 10,138 current or former statin users Muscle related side effects reported in 60% former users 25% current users Primary reason for discontinuation was side effects (62%) Cohen JD et al. J Clin Lipid 2012; 6 (3): Clinical Trials and Muscle-Related Adverse Effects Why the low incidence in clinical trials? Patients highly selected Often have pre-randomisation run-in Motivated trial patients may minimize symptoms Muscle aches are common in placebo group Mancini GB et al. CJC 2011; 27:

25 Mechanisms of Statin Myopathy Impaired calcium handling in muscle Statin induced myocellular dysfunction Immune mediated inflammatory myopathy Mancini GB et al. CJC 2011; 27: Prevention of Statin Intolerance Pre-treatment assessment Assess risk (e.g. elderly, prior muscle pains, renal disease, DM, hypothyroidism) Consider exogenous factors (e.g. statin dose, alcohol use, drug-drug interactions, excessive grapefruit juice use) Measure baseline CK, ALT, TSH, creatinine Counseling Inform that statins are very well tolerated in most people Inform about muscular symptoms and when to discontinue Monitoring Check CK / ALT when monitoring lipid lowering efficacy At 6-8 weeks after starting or with dose increase and then every 6-12 m Avoid severe exercise for several days prior to testing 25

26 Statin based Options for LDL-Cholesterol Lowering in Statin Intolerant Patient Lower statin dose Switch to alternative statin Altered dosing regimens Rosuvastatin mg 3 x weekly or alternate days Rosuvastatin 5-20 mg once weekly Low dose / alternative statin /alternating day rosuvastatin + Summary: Adverse Effects of Statins More common than clinical trials suggest Probably more frequent at higher doses Causes poor adherence to treatment Manage adverse events Use alternative statin Reduce frequency of statin Use non-statin agents as monotherapy or together with reduced dose or frequency statin 26

27 Summary of Objectives Discuss the evidence base for: Primary prevention in elderly Statin use in nursing homes Deprescribing 27

28 Supplemental Material Drugs don t work in people who don t take them. C. Everett Koop Adherence With Statin Therapy in Elderly Patients Jackevicius, Mamdani and Tu, University of Toronto Increasing the effectiveness of adherence interventions may have a far greater impact on the health of the population than any improvement in specific medical treatments. Haynes et al., World Health Organization,

29 Adherence to Lipid Lowering Therapy and Outcomes Adherence rates at 1 year 26-85% Muscle related symptoms more frequent in non-adherent patients Patient perception of short-term disadvantages outweighs any long-term benefits Outcomes worse in non-adherent patients RRR for CV event according to adherence RRR % Fully adherent 39.3% 50% adherent 26.1% 25% adherent 10.9% Lipid Research Clinic. Miller NH Am J Med 1997; 102 Suppl 1:43-49 Lack of Risk of Cancer with Statins Meta-analysis of 175,000 subjects in 27 trials Incidence of or mortality from cancer not related to Age Sex Anatomical site of cancer Type statin 5 years of statin therapy had no effect on the incidence of, or mortality from cancer CTT Lancet DOI: /S (12)

30 Effect of Lipid Lowering Cognition/Function - HOPE HOPE-3 Trial N=12,705 Candesartan/HCTZ vs. placebo Rosuvastatin vs. placebo Outcomes No relative reduction in cognition or functional status Statins and Neuropsychiatric Effects Dementia Systematic review showed no increased risk of cognitive decline Law et al. Am J Cardiol 2006; 97:52C Suicide / violent death Conflicting evidence on relationship between statin use mood states: depression, anxiety, fatigue, confusion and vigour While et al. Eur J Cardiovasc Nurs 2010 Insomnia Initial studies suggested insomnia with lovastatin compared with pravastatin Black et al. JAMA 1990; 264:1105 Study with objective measures of sleep showed no effect Ehrenberg et al. Sleep 1999; 22:117 30

31 Liver Injury Associated with Statins Type of liver injury Frequency Comment Asymptomatic elevations in aminotransferases Clinically significant acute liver injury Fulminant hepatic failure Autoimmune hepatitis 0.1%-3.0% Very rare Extremely rare (isolated case reports) Case reports Dose-dependent; class effect; clinically not significant May be seen in combination with other medications It was estimated that risk of fulminant liver failure is 2 per million Statins may induce AIH in genetically susceptible individuals Bhardwaj SS et al. Clin Liver Dis 2007; 11: Statins and New-Onset Diabetes Study WOSCOPS (N=5974) HPS (N=14,543) ASCOT (N=7773) LIPID (N=7937) CORONA (N=3534) JUPITER (N=17,802) Combined all above (N=57,593) Proportion of patients with new-onset diabetes (%) Statins 1.9% 4.6% 3.9% 4.3% 5.6% 3.0% 3.8% 4.0% Placebo 2.8% 4.0% 3.5% 4.6% 5.0% 2.4% 3.5% 3.5% RR, statin vs placebo % CI (P=0.38) (P=0.008) Absolute risk of developing DM % Note Patient reported diabetes No formal testing for diabetes Risk factors for Statin associated DM Obesity IFG Elevated TG / HDL Sattar N et al. Lancet 2010; 375:

32 Statins and New-Onset Diabetes Treatment of 255 patients with statins results in 1 additional case of diabetes over 4 years Statin treatment prevented of 5.4 vascular events in these 255 patients Benefit of statin treatment exceeds risk Fluvastatin, Ezetimibe or Both in the Management of Statin Intolerance 199 patients with statin Intolerance Received either Fluvastatin XL 80mg or Ezetimibe 10mg or Fluvastatin + Ezetimibe 97% tolerated treatment 17% develop tolerable muscle symptoms LDL-C (mg/dl) 160 Ezetimibe -15.6% Fluvastatin XL -32.8% % 80 Fluvastatin/Ezetimibe Time (weeks) Stein EA et al. Am J Cardiol 2008; 101:

33 Statin Intolerance Treatment with Low Dose Statins Degreef et al. Eur J Int Med 2010; 21:293 Simvastatin 10-80mg 57% able to tolerate, 30% recurrent muscle pains LDL-C 26% 20% able to tolerate statin achieved Glueck et al. Clin Ther 2006; 6: patients years 50 with myalgia Moderate risk Rx rosuvastatin 5 mg High risk Rx 10mg LDL-C reduction 5 mg % 10mg % Only 1 /61 unable to tolerate statin Statin Intolerance Strategies Alternate day Retrospective analysis 51 patients (76% myalgia) Alternate day rosuvastatin (mean dose 5.6mg) 72.5% able to tolerate LDL-C reduced 34.5% P<0.001 in patients tolerating statin Two patients intolerant of Backes atorvastatin JM et al. Ann Phamacotherapy 2008; 42: Changed to rosuvastatin 2.5-5mg 3x / week Well tolerated LDL-C reduced 20-38% Once weekly Mackie BD et al. Am J Cardiol 2007; 99: patients (7 myalgias; 3 GI complaint on prior statin) Weekly rosuvastatin 5-20 mg LDL-C reduced 29% (range 6-62%) 2 patients discontinued because of similar symptoms Backes JM et al. Am J Cardiol 2007; 100:

34 NCEP Diet Lowers LDL-C Only when Combined with Exercise Change (%) Control group Exercise group Diet group Diet-plus-exercise group NCEP Step 2 Diet Cholesterol < 200mg/d <30% calories from fat <7% saturated fat Women Men Women Men HDL Cholesterol LDL Cholesterol Stefanick ML et al. N Engl J Med 1998; 339: