Slide 1. Slide 2. Slide 3 STATINS & THE PLACEBO EFFECT K.C. KALTENBORN, M.D OBJECTIVES STATINS & THE PLACEBO EFFECT

Transcription

1 Slide 1 STATINS & THE PLACEBO EFFECT K.C. KALTENBORN, M.D Slide 2 OBJECTIVES Examine Data that half of statin discontinuation is not due to a drug effect. Other Explanations for discontinuation Implications of statin discontinuation Goals Understand possible approaches to restarting statin therapy Develop awareness of the nocebo effect in medical practice Slide 3 STATINS & THE PLACEBO EFFECT Statins are considered some of the safest drugs a success story in modern medicine and the most effective way to present cardiovascular disease. Professor B. Nordestgaard, Chief Copenhagen University Statins are one of the most well proven treatments doctors can use for any disease. Dr. T. Chic, University Sheffield

2 Slide 4 STATINS IN PRIMARY PREVENTION Lifestyle Interventions MRFIT no effect on cardiac, mortality outcomes Non-Statin Therapy Michael Pignone, MD, MPH, member of the US Preventative Services Task Force, current author of UpToDate Lipids, Primary Prevention, In patients who do not tolerate statins, no lipid-lowering therapy should be administered...non-statin trials found a disturbing increase in non-cardiovascular mortality. Statin Studies 20-40% reduction in all causes of mortality, cardiovascular endpoints (WOSCOPS, AFCAPS, ASCOT, Jupiter, etc.) Slide 5 WHO TO TREAT Calculate CV Risk Assume 20-30% reduction in that risk with statin therapy Discuss if absolute risk reduction is worth the cost burden and risk of therapy Example 45-year-old female: TC 240 HDL 40 : 1% risk decreases to.7% 60-year-old male: TC 240 HDL 40 : 12% risk decreases to 8% Slide 6 DOSE OF STATIN Moderate doses (used in trials showing 20-30% benefit) 40mg Lovastatin (Mevacor), Pravastatin (Provachol), Simvastatin (Zocor), Fluvastatin (Lescol) 20mg Atorvastatin (Lipitor) 5-10mg Rosuvastatin (Crestor)

3 Slide 7 STATINS SIDE EFFECTS In randomized trials only slight increase compared to placebo. Diabetes: 1/500 risk, dose dependent Idiosyncratic: Hepatic, renal, CNS, cancer, cataracts (pregnancy/breastfeeding: X) Muscle symptoms 5-20% main reason for discontinuation by 5-10% of users. Slide 8 STATIN MUSCLE PARADOX Large difference in muscle side effect rate between original prospective studies and clinical observation. Meta-analysis of 42 randomized trials no excess muscle risk. Not duration related (75% of intolerance develops in first three months) Confounder were intolerant patients eliminated in the run-in phase before start of randomized studies? Nocebo Effect? Slide 9 CAN STATIN INTOLERANT PATIENTS TAKE STATINS? Stein, et al AmJ.Cardiol patients (CPK < 3x nl) 17% recurred on Fluvastatin XL (LDL 33%) 24% recurred on Ezetimibe (Zetia) (LDL 16%) 14% recurred on combination of both (LDL 48%)

4 Slide 10 CAN STATIN INTOLERANT PATIENTS TAKE STATINS? Gauss-3 Randomized Clinical Trial JAMA April 3, 2016, Steve Nissen, et al Objective: Select patients with statin muscle intolerance confirmed by rechallenge and examine effect of Ezetimibe (Zetia) or Evolocumab (anti-pcsk9 antibody) 491 patients, 35% with CAD Mean age 61, half women Mean LDL 212 Slide 11 GAUSS-3 (PHASE A) 18% intolerant of 2 statins 82% intolerant of 3 statins 84% myalgia, 16% myositis (3 patients had rhabdo) 4 Week Washout 10 weeks of Atorvastatin (20mg) followed by 10 weeks of placebo OR 10 weeks of placebo followed by 10 weeks of Atorvastatin Slide 12 GAUSS-3 (PHASE B) CAN ATORVASTATIN INTOLERANT PATIENTS TOLERATE EZITIMIBE OR EVOLOCUMAB 26 weeks after study started Atorvastatin intolerant patietns (n = 218) randomized to: Evolocumab sq and oral placebo OR Placebo sq and oral Ezitimibe

5 Slide 13 GAUSS-3 PHASE A RESULTS Symptoms with Atorvastatin, not placebo 42.6% Symptoms with Placebo, not Atorvastatin 26.5% Symptoms with both 9.8% No symptoms either 17.3% 10 fold increase in CPK 3.9% Slide 14 GAUSS-3 PHASE B RESULTS Muscle Symptoms LDL Drop Ezetimibe 28.8% (stopped in 5 patients) -17% (-31mg/dl) Evolocumab 20.7% (stopped in 1 patient) - 54% (-107 mg/d) Slide 15 HOW CAN 50% OF MULTIPLE STATIN INTOLERANT PATIENTS MISIDENTIFY THE STATIN PHASE WHEN RE-CHALLENGED FOR 10 WKS? Why do 30% of patients have symptoms from a drug that is not absorbed and cannot reach muscle tissue (Ezitimibe)?

6 Slide 16 PLACEBO (LATIN FOR I SHALL PLEASE ) A pharmacologically inert substance (e.g. starch tablet) producing effects similar to an active substance (such as an antibiotic) Nocebo Adverse effects during placebo administration Slide 17 PLACEBOS IN MODERN ERA (1955, HK BEECHER) 35% of 1,082 patients in 15 clinical trials relieved by placebo alone Follow-up studies placebos effective in 50% of patients with pain, depression, GI complaints, as effective as SSRI in certain groups of depressed patients. Slide 18 COMPONENTS OF THE PLACEBO EFFECT Spontaneous improvement (time alone) Fluctuating symptoms Answers of politeness ( I see you are less depressed. ) Conditioned (Pavlovian) responses (placebo analgesic IV therapy peaks at 1 hour) Stress reduction due to touch, caring, safe environment, patientpractitioner relationship

7 Slide 19 INTERPRETING PLACEBO INTERVENTION Surgeon Bruce Moseley: 8/10 knee surgeries had incision only, 2/10 had internal corrections 10/10 patients had relief at 6 months Seattle cardiologist, Leonard Cobb (circa 1970) fake ligation of internal mammory artery (90% response) Not a placebo effect, but spontaneous improvement. Slide 20 REGRESSION TO THE MEAN If a variable is extreme in its first measurement, it will tend to be closer to average on its second measurement. To address this issue a third group may need to be included (no treatment added to placebo and active arms) e.g. depressed patients put on a waiting list in a placebo controlled SSRI study Slide 21 CAM Aromatherapy, chelation therapy, homeopathy, candling, iridology, trepanation, reflexology, energy healing. Means to enlist placebo, conditioned, psychological responses?

8 Slide 22 NEWS STORIES & STATIN PERSISTENCE S Nielsen, European Heart J (2016) N = 6,780, 83 Year ,900 Statin Users Risk of discontinuation in first 6 months association with 1,931 news stories Key Findings: Increased risk of discontinuation per negative news story 4% increased risk per year of discontinuation during 15 years of study Slide 23 SUMMARY (S Nielsen) % Using Statin <1% 11% News Stories 30/year 400/year % Early discontinuation 6% 18% Stories: 110 negative, 1090 neutral, 731 positive Slide 24 IMPLICATIONS 29% of all MI and 1% of CVASC Death associated with early discontinuation Discontinued vs continued use 26% risk of MI 18% risk CVASC Death (S Nielsen)

9 Slide 25 MANAGEMENT OF DISCONTINUATION N of 1 Trial: Joy, Ann, IMed cycles of placebo vs statin Average of pain scores on/off statin 5/8 patients able to resume therapy Slide 26 MANAGEMENT OF DISCONTINUATION Not Helpful: CoQ10 Routine CPK Measurement Lipophilic vs hydrophilic Red yeast (lowers LDL, but lack of outcome studies, concerns re purity) Slide 27 OTHER MEDICATIONS: IMPLICATIONS OF NOCEBO EFFECT Bisphosphonates and GI, dental, joint symptoms Proton pump inhibitor and cognitive impairment Childhood vaccinations Anti-hypertensives and fatigue, ED Gluten Sensitivity AI and musculoskeletal symptoms Use of thyroxine instead of Armour Thyroid

10 Slide 28 MANAGEMENT OF DISCONTINUATION Helpful Change to Pravastatin (Pravachol) Fluvastatin (Lescol) Assess drug interactions Alternate day therapy Lower dose in Chinese ethnicity Slide 29 ROSUVASTATIN (CRESTOR) ONCE WEEKLY Tolerated by 74% 10mg/week (or 5mg twice/week) 23% reduction in LDL Outcomes not measured Ruisinger AmJCardiol, 2009 Slide 30 OBJECTIVES Examine Data that half of statin discontinuation is not due to a drug effect. Other Explanations for discontinuation Implications of statin discontinuation Goals Understand possible approaches to restarting statin therapy Develop awareness of the nocebo effect in medical practice

11 Slide 31 STATINS & THE PLACEBO EFFECT