The Clinical Debates Speakers: Round 2: Statins for Primary Prevention of Cardiovascular Disease Matthew Cantrell, PharmD, BCPS, is a 2000 graduate of Mt. Mercy College and 2005 graduate from the University of Iowa College of Pharmacy. He has completed a residency in primary care at the VA Medical Center in Iowa City. He currently works as a clinical pharmacy specialist at the VA Medical Center in Iowa City and is Assistant Professor at the University of Iowa. Clinical areas include primary care, lipid, and anticoagulation. Douglas Geraets, PharmD, obtained his BSc degree in Pharmacy from South Dakota State University and his post-bs Doctor of Pharmacy degree from the University of Tennessee. Following this he completed a oneyear post-pharmd clinical residency in Adult Internal Medicine at the City of Memphis Hospital. In addition, he completed a Research Fellowship in cardiology at the Ohio State University. He has held faculty positions at the Ohio State University, the University of Missouri at Kansas City, and the University of Iowa. Currently he is Clinical Pharmacy Specialist in Ambulatory Care at the VA Medical Center in Iowa City and Adjunct Professor at the University of Iowa College of Pharmacy. He co-manages the VA s ~1200 patient anticoagulation clinic, is a provider in the ICVA s pharmacist-managed lipid clinic, and provides pharmaceutical care to a variety of other general medicine patients. He has published numerous research and clinical papers, is active in several pharmacy organizations (IPA, ACCP, and ASHP) and is a Fellow of the American College of Clinical Pharmacy. His main pharmacotherapeutic interests include cardiovascular disease, anticoagulation, and dyslipidemia. Dr. Geraets research interests include issues of anticoagulation therapy particularly warfarin effectiveness and safety and clinical management of dyslipidemia. Speaker Disclosures: Matt Cantrell and Doug Geraets report they have no actual or potential conflicts of interest in relation to this program. The speakers have indicated that off-label use of medications will be discussed during this presentation.
Statins for Primary Prevention of CVD Faculty Disclosure Dr. Cantrell & Geraets have no actual or potential conflicts of interest associated with this presentation. Dr. Cantrell & Geraets have indicated that no off-label use of medication will be discussed during this presentation. Douglas R. Geraets, Pharm.D., FCCP Clinical Pharmacy Specialist AmCare VA Medical Center Iowa City, IA & Matthew Cantrell, Pharm.D., BCPS Clinical Pharmacy Specialist AmCare VAMC Iowa City, IA Clinical Assistant Professor UI College of Pharmacy Learning Objectives Upon completion of this program pharmacists (or pharmacy technicians) will be able to: Discuss the incidence and general trends for CVD and CVD risk factors in the U.S. population. Describe results from primary prevention studies including Jupiter and how this information applies to primary prevention with statins. Select statements that describe pros & cons of statin use in primary prevention. Patient Case 48 year old male Past Medical History: GERD Osteoarthritis Impaired fasting glucose Gout Social History: ½ pack per day smoker 4-6 beers per week Family History: Non-contributory Medications: Lansoprazole 30 mg daily APAP 500 mg two tabs twice daily Febuxostat (Uloric ) 40 mg daily Laboratory Results: Total Chol. 200 mg/dl LDL 128 mg/dl HDL 45 mg/dl Triglycerides 135 mg/dl ALT 28 IU/L AST 32 IU/L Scr 1.3 mg/dl Fast. glucose 112 mg/dl hs-crp 2.3 mg/l Vital signs: BP 128/75 mm Hg, HR 72, Resp. 20, Temp. 36.8 C Body Mass Index: 26 10 year CHD risk Framingham=11% Reynolds=5% Pre-Assessment Questions Q. Would you recommend this patient take a statin for primary prevention of CVD? Magnitude of the Problem: Atherosclerotic CVD Leading cause of death for both men and women in the U.S. Mortality decline in last several decades; slowing of decline in 90 s-00 s If all major CVD eliminated, life expectancy 7 years Long asymptomatic latent period
Risks for CVD Annual Number (in Thousands) of New Cases of Diagnosed Diabetes Among Adults Aged 18 79 Years, United States, 1980 2008 Increasing Prevalence (%) of Metabolic Syndrome Among U.S. Adults NHANES III ( 88-94) NHANES ( 99-00) Unadjusted 23.1 26.7 Age-Adjusted 24.1 27.0 Ford ES, et al. Diabetes Care October 2004;27(10):2444-9. Centers for Disease Control and Prevention (CDC), National Center for Health Statistics, Division of Health Interview Statistics, data from the National Health Interview Survey. Treatment vs. Prevention Current algorithms for preventing CVD events/death: statins for patients with established CVD, DM, overt hyperlipidemia ½ of MI/CVA occur among apparently healthy men/women with LDL-C below treatment thresholds Atherosclerosis starts early progresses continually throughout life If individual has an event then we do something about it! Patients want prevention of first event Prevention of CVD Nine modifiable risk factors account for ~90% of initial MI risk 1. Elevated cholesterol 2. Smoking 3. Psychosocial events 4. Hypertension 5. Abdominal obesity 6. DM 7. Unhealthy diet 8. Excessive alcohol 9. Lack of exercise Attributes of Ideal Agent for Primary Prevention CVD Easy to take Affordable Highly effective (surrogate vs. hard endpoints) Well-tolerated No or limited drug-drug, drug-disease, drug-diet interactions Statins in CVD Prevention In recent years large clinical trials of statins in relatively low-risk groups Without CVD With CVD risk factors Low levels LDL-C WOSCOPS, AFCAPS/TexCAPS, PROSPER, ALLHAT-LLT, ASCOT-LLA, HPS, CARDS, ASPEN, MEGA, and JUPITER
Estimated 5-YR NNT for Primary Prevention of CVD Trial Population Endpt 5-YR NNT WOSCOPS (lovastatin) AFCAPS (pravastatin) JUPITER (rosuvastatin) Hypercholesterolemia Average cholesterol Low LDL, hscrp MI, stroke, any death 86 MI & cardiac death 44 MI, stroke, death 29 Ridker PM, et al. Circ Cardiovasc Qual 2009; 2:616-23. Estimated 5-YR NNT for Primary Prevention of CVD Among Middle-Aged Populations Intervention Population Endpt 5-YR NNT Rosuvastatin Low LDL, hscrp MI, stroke, death 29 Diuretics Hypertension MI, stroke, any 86 death -blockers Hypertension Fatal/nonfatal CHD 140 and stroke Aspirin Men; Women MI, stroke, CV death 346; 426 Ridker PM, et al. Circ Cardiovasc Qual 2009; 2:616-23. Summary of Statin Tolerance in Recent Primary Prevention Studies (versus placebo) Parameter WOSCOP (Pravastatin) AFCAPS/ TexCAPS (Lovastatin) ASCOT-LLA (Atorvastatin) JUPITER (Rosuvastatin) Withdrawals N/R No Difference N/R No Difference Myopathic Event No Difference No Difference N/R No Difference CK 10X ULN No Difference No Difference No Difference No Difference AST/ALT 10X ULN No Difference No Difference No Difference No Difference SAE N/R No Difference No Difference No Difference N/R = Not Reported; SAE = Serious Adverse Events Summary Progressing from secondary prevention to primary prevention CVD Statins with many attributes of ideal primary preventive agent Rosuvastatin in primary prevention (CVD) with better NNT values than other CVD preventive therapy Three-quarters of the patients taking statins are taking them for primary prevention. (Arch Int Med 2010; 170(12): 1007-8.)?
Reasons to consider judicious use of statins for primary prevention 1. Limited benefits in all-cause mortality 2. JUPITER trial & limitations 3. Adverse effects of statin therapy 4. Pharmacoeconomics Established indications for statins In patients with & without established CHD, statins: Reduce risk of MI, stroke, revasc. procedures, & angina In patients with type 2 DM & other CV risk factors Reduce the risk of MI and stroke Slow progression of atherosclerosis High risk patients receive the most benefits Primary prevention vs. secondary prevention Absolute risk reduction vs. relative risk reduction Statin therapy & all cause mortality Relationship between age and all cause mortality rates in primary prevention statin trials 11 randomized clinical trials 65,229 patients without CHD Statin (32,623) Placebo (N=32,606) Risk Ratio 95% CI All cause death 1,346 (4.1%) 1,447 (4.4%) 0.91 (0.83-1.01) Participant age at baseline accounted for an estimated 66% of the variation in mortality rates The clinical utility of statins to reduce non-fatal MI and stroke is not in question Ray et al. Arch Int Med. 2010;170(12):1024-31 Ray et al. Arch Int Med. 2010;170(12):1024-31 Effect of statins on all-cause mortality in primary prevention randomized controlled trials JUPITER Subjects w/o CV disease with baseline LDL <130 mg/dl & CRP >2.0 mg/l Rosuvastatin (Crestor ) 20 mg vs. placebo Primary endpoint Composite nonfatal MI & stroke, hospit. for unstable angina, arterial revasc., CV death Ray et al. Arch Int Med. 2010;170(12):1024-31 44% relative risk reduction in primary endpoint 142 vs. 251 events (p<0.00001) Ridker et al. NEJM 2008;359(21):2195-2207.
JUPITER Absolute risk reduction 0.59 events/100 person years NNT=95 for 2 years Adverse effects: myopathy CK elevation >10,000 U/L RHABDO Frequency 1/10,000 Limitations 1.Excluded those with poor compliance 2.Not so low risk? 3.Generalizability? 4.Role of CRP as biomarker? 5.Potential biases >1,000 U/L Normal or increased None MYOPATHY MYALGIA 1/1,000 5-10% Cases / 100,000 person years Adverse effects: dose related transaminase elevations with statin therapy 250 200 150 100 50 0 Overall risk is approximately 1.3% 10 mg 80 mg Atorvastatin dose Potential adverse effects: Diabetes? 13 randomized trials of 91,140 participants Statin use resulted in 9% increased risk of diabetes (OR = 1.09, 95% CI = 1.02-1.17) Number needed to harm (NNH) was 255 Statin therapy for 4 years to produce 1 additional case of diabetes Cases of diabetes in JUPITER 270 (3.0%) vs. 216 (2.4%) (P = 0.01) Sattar et al. Lancet 2010;375(9716):735-742 Pharmacoeconomics 80% of middle-aged & elderly would meet criteria for statin therapy Rosuvastatin 20 mg $1,200 annually NNT to prevent 1 primary endpoint 95 for 2 years x $1,200 =$228,000 Costs associated with screening those not eligible Patient Case 48 year old male Past Medical History: GERD Osteoarthritis Impaired fasting glucose Gout Social History: ½ pack per day smoker 4-6 beers per week Laboratory Results: Total Chol. 200 mg/dl LDL 128 mg/dl HDL 45 mg/dl Triglycerides 135 mg/dl ALT 28 IU/L AST 32 IU/L Scr 1.3 mg/dl Fast. glucose 112 mg/dl hs-crp 2.3 mg/l Where are health care dollars best spent? Treating a low risk, asymptomatic population? Targeting high risk secondary prevention patients where gains are statistically & clinically significant Family History: Non-contributory Medications: Lansoprazole 30 mg daily APAP 500 mg two tabs twice daily Febuxostat (Uloric ) 40 mg daily Vital signs: BP 128/75 mm Hg, HR 72, Resp. 20, Temp. 36.8 C Body Mass Index: 26 10 year CHD risk Framingham=11% Reynolds=5%
Would you recommend this patient take a statin for primary prevention? 1. Yes 2. No 50% 50% 1 2
Baseline LDL and follow up in primary prevention trials comparing statin therapy to placebo Trial; Intervention (follow up) N; (age) Baseline & Follow up LDL (mg/dl) Event rate per 1000 Person years Comment ASCOT LLA (2003) atorvastatin 10 mg (3.3 yrs) 131 8,715; (63) T: 90 P: 126 T: 10.9 P: 12.4 36% in non fatal MI & CV death; 27% in strokes; All cause mortality non significantly reduced 13% WOSCOPS (1995) pravastatin 40 mg (4.9 yrs) 192 5,981; (55) T: 142 P: 192 T: 6.4 P:8.2 22% reduction in total mortality (not significant (P=0.051); 5.5% vs. 7.9% event rate (p<0.001) ALLHAT (2002) pravastatin 40 mg (4.8 yrs) 148 8,880; (66) T: 105 P: 129 T: 24.3 P: 24.3 No difference in total mortality or CHD event rate AFCAPS /TexCAPS (1998) lovastatin 20 40 mg (5.2 yrs) 6,605; (58) 150 T: 114 P: 156 T: 4.6 P: 4.4 37% in CV events (fatal and nonfatal MI, unstable angina, or sudden cardiac death; No difference in total mortality HYRIM (2005) fluvastatin 40 mg (4.0 yrs) 150 568; (57) T: 117 P: 136 T: 3.5 P: 4.4 CARDS (2004) atorvastatin 10 mg (4.0 yrs) 2,838; (62) 117 T: 81 P: 120 T: 10.7 P: 14.5 100% of subjects had Type 2 DM 37% reduction in primary endpoint JUPITER (2008) rosuvastatin 20 mg (2.2 yrs) 17,802 (66) 108 T: 54 P: 108 T: 12.5 P: 10.0 44% relative risk reduction in primar endpoint MEGA (2006) pravastatin 10 20 mg (4.6 yrs) 7,832 (58) 156 T: 128 P: 151 T: 2.4 P: 3.6 100% Japanese population; Event Rate 3.3 vs. 5.5% (p=0.01) Adapted with permission from: Ray et al. Arch Intern Med. 2010;170(12):1024-1031.
PREVEND IT (2004) pravastatin 40 mg (3.8 yrs) 864; (51) 154 T: 120 P: 158 T: 7.7 P: 7.2 ASPEN (2006) atoravastatin 10 mg (4.3 yrs) 1,905; (61) 114 T: 79 P: 114 T: 10.8 P: 10.2 100% of subjects had Type 2 DM PROSPER (2002) pravastatin 40 mg (3.2 yrs) 3,239 (75) 146 T: 96 P: 143 Cumulative 65,229 138 (62) T: 94 P: 134 T=subjects randomized to treatment with statin, T: 27.2 P: 26.0 T: 10.7 P: 11.4 P=subjects randomized to treatment with placebo Relationship between baseline age of participants and all cause mortality rates in primary prevention trials Adapted with permission from: Ray et al. Arch Intern Med. 2010;170(12):1024-1031.
Effect of statin therapy on all cause mortality in primary prevention trials Adapted with permission from: Ray et al. Arch Intern Med. 2010;170(12):1024-1031.