Disclosure. A New Partnership. Objectives 03/27/2014. What is the main way you have obtained information about the 2013 ACC/AHA Cholesterol Guideline?

Transcription

1 Disclosure Lindsey Clark, PharmD, BCPS Cardiology-Medicine Pharmacy Specialist University of Cincinnati Medical Center April 10, 2014 I, Lindsey Clark, do not have a financial interest or affiliation with one or more organization that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. What is the main way you have obtained information about the 2013 Cholesterol Guideline? A. Reading the full report B. Skimming the report C. Attending a continuing education session D. Through the news media E. Summaries on professional websites or journal articles F. Other The most surprising aspect of the 2013 cholesterol guidelines for me: A. The 10-year atherosclerotic cardiovascular disease risk () calculator B. The transition away from treat-to-target C. The recommendations for primary and/or secondary prevention D. The recommendations for monitoring requirements for drug therapy E. thing, I predicted all of the recommendations through my previous knowledge of the evidence F. I haven t read the guidelines yet, so I m not sure what changed Objectives Discuss major changes and controversies with the new hyperlipidemia guidelines Identify four major statin benefit groups Make recommendations for monitoring and optimizing therapy for hyperlipidemia 2002: National Cholesterol Education Program by Adult Treatment Panel (ATP) III A New Partnership We cannot be a strong nation unless we are a healthy nation. And so we must recruit knowledge and science in the service of national strength. F.D. Roosevelt 2011: Institute of Medicine issues report on systematic reviews and trustworthy clinical guidelines October 8, 2013: announce partnership with for development of five clinical practice guidelines Apply treatment recommendations to patient care 2008: convened ATP IV to perform systematic evidence reviews and develop critical questions = National Heart, Lung, and Blood Institute ACC = American College of Cardiology AHA = American Heart Association June 19, 2013: announces they will refocus efforts vember 12, 2013: Practice Guidelines Released Obesity Lifestyle Interventions CV Risk Assessment Cholesterol Guidelines 1

2 Independent Contractors Task Force Adult Treatment Panel IV The Expert Panel Formal Peer Review Endorsed by: American Society for Preventive Cardiology American Pharmacists Association American Association of Cardiovascular and Pulmonary Rehabilitation Association of Black Cardiologists Preventive Cardiovascular Nurses Association WomenHeart: The National Coalition for Women with Heart Disease Who: Scope of the Guideline Blood cholesterol treatment of adults ( 21 years of age) For those most likely to benefit What: Strong evidence-based foundation for the treatment of cholesterol for primary and secondary prevention of atherosclerotic cardiovascular disease () When: Released in vember 2013 Literature covered through 2011, unless otherwise noted in methodology Will begin continual review and update in 2014 How: Intended for primary care providers and specialists concerned with prevention Designed to be easy to use in the clinical setting to facilitate the implementation of a strategy of risk assessment and treatment Limitations Recognized by the Expert Panel Significant departure from current strategies Overwhelming body of evidence came from statin randomized controlled trials (RCTs) Recommendations focused on groups that are well represented in RCTs or validated meta-analyses (MAs) Guidelines do not answer questions regarding complex lipid disorders Refer to clinicians with lipid expertise for management Recommendations designed to inform clinical judgment, not replace it Transitioning from s and Quality of Evidence to Class and Level of Evidence s and Quality of Evidence: Strength of Recommendations A Strong recommendation B Moderate recommendation C Weak recommendation D Recommendation against E Expert opinion N recommendation for or against Quality of Evidence Type of Evidence Available High (H) Well-designed, well-executed RCTs that adequately represent populations to which the results are applied and directly assess effects on health outcomes. MAs of such studies. Moderate (M) RCTs with minor limitations affecting confidence in, or applicability of, the results. Well-designed, well-executed nonrandomized controlled studies and well-designed, wellexecuted observational studies. MAs of such studies. Low (L) RCTs with major limitations. nrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results. Uncontrolled clinical observations without an appropriate comparison group (e.g., case series, case reports). Physiological studies in humans. MAs of such studies. Insufficient (I) Insufficient evidence Class and Level of Evidence: Definitions Atherosclerotic Cardiovascular Disease () Acute coronary syndromes or a history of myocardial infarction (MI) Stable or unstable angina Coronary or other arterial revascularization Stroke or Transient Ischemic Attack (TIA) Peripheral arterial disease All presumed to be of atherosclerotic origin 10-Year Risk In ages predicts 10 year risk of: nfatal MI Coronary heart disease death nfatal and fatal stroke 2

3 Age (Years) Reassess every 4-6 years Reassess every 4-6 years Reassess every 4-6 years Major Benefit Groups Benefit Groups 190 ( if not Estimated 10-y risk 7.5% Estimate 10-y Risk Prevention Benefit of Therapy Less Clear in Benefit Groups 190 Why treat a patient with a normal LDL? Estimate 10-y Risk Prevention Benefit of Therapy Less Clear in ( if not Estimated 10-y risk 7.5% Why treat a patient with a normal LDL? CTT 2010: s for Patients with rmal LDL Meta-analysis of 26 RCTs (170,000 participants) 21 trials statin vs. control 5 trials more vs. less statin Results: Further reductions in LDL cholesterol safely produce definite further reductions in the incidence of heart attack, of revascularisation, and of ischaemic stroke With each 1.0 mmol/l reduction reducing the annual rate of these major vascular events by just over a fifth. There was no evidence of any threshold within the cholesterol range studied, suggesting that reduction of LDL cholesterol by 2 3 mmol/l would reduce risk by about 40 50%. Cholesterol Treatment Trialists (CTT) Collaboration. Lancet 2010; 376: LDL 1 mmol/l = 39 LDL 1.8 mmol/l = 70 Why treat a patient with a normal LDL? Benefit Groups LDL C eligibility criteria versus age eligibility criteria in placebo groups for primary-prevention RCTs. > < 40 JUPITER CARDS AFCAPS MEGA 190 Estimate 10-y Risk Why was 10 year risk lowered from 10% to 7.5%? What is the 10 year risk? ( if not Estimated 10-y risk 7.5% LDL-C () Prevention Benefit of Therapy Less Clear in 3

4 What is the 10 year risk? 10 Year Risk Calculator New Pooled Cohort Equations Goal: Accurately identify higher risk individuals with hope to focus on those most likely to benefit Estimates 10-year risk in both white and black men and women, years of age, who do not have clinical Age is heavily weighted Person aged 70 years (risk 7.5%) without other risk factors will receive statin treatment on the basis of age alone Risk assessment tools or novel risk markers examined or recommended have not been formally evaluated Why was risk lowered to 7.5%? Why was risk lowered to 7.5%? HIGH INTENSITY STATIN TREATMENT Assumes a 45% relative risk reduction in from high intensity statin treatment NNT to prevent 1 event varies by baseline estimated 10-year risk NNH based on 3 excess cases of incident diabetes* per 100 individuals treated with statins for 10 years. CTT 2012: s in Low Risk Patients Major Vascular Events: Major coronary events (non-fatal MI or coronary death) Strokes Coronary revascularizations Results: For risk 10%, each 1 mmol/l (1 mmol/l = 39 ) reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years Meta-analysis of 27 RCTs 22 trials statin vs. control 5 trials more vs. less statin Five categories of baseline 5-year major vascular event risk on control therapy What if 10 year risk is < 7.5%? If a risk-based treatment decision is uncertain, consider assessing one or more of the following to inform treatment decision making: 5 to <7.5% 10-year risk Primary 160 or other evidence of genetic hyperlipidemias Family history of premature High sensitivity C-reactive protein 2 mg/l Coronary artery calcium score 300 Agatston units or 75th percentile for age, sex, and ethnicity Ankle-brachial index <0.9 Lifetime risk of Cholesterol Treatment Trialists (CTT) Collaborators. Lancet 2012; 380:

5 Reassess every 4-6 years Benefit Groups Medication Strategies to Reduce 190 Where are goal lipid levels? ( if not Treat-to-cholesterol target Lower cholesterol is better Risk-based treatment approaches Treat level of risk Lifetime Risk Estimate 10-y Risk Estimated 10-y risk 7.5% Fixed Doses of Cholesterol Lowering Drugs to Reduce Risk of Prevention Benefit of Therapy Less Clear in Definitions of Therapy High-Intensity Therapy Daily dose lowers LDL C by approximately 50% Atorvastatin mg Rosuvastatin 20 (40) mg Moderate-Intensity Therapy Low-Intensity Therapy Daily dose lowers LDL C by Daily dose lowers LDL C approximately 30% to <50% by <30% Atorvastatin 10 (20) mg Simvastatin 10 mg Rosuvastatin (5) 10 mg Pravastatin mg Simvastatin mg Lovastatin 20 mg Pravastatin 40 (80) mg Fluvastatin mg Lovastatin 40 mg Pitavastatin 1 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2 4 mg Bold = evaluated in RCTs and demonstrated reduction in major adverse cardiovascular events Italics = not tested in RCTs reviewed Percent reduction in LDL C can be used as an indication of response and adherence to therapy, but is not in itself a treatment goal Problems with Treat to Target Secondary prevention If patient achieves an LDL C of 78 on a dose of 80 mg of atorvastatin, he/she is receiving evidence-based therapy. Family History with LDL C >190 This patient may only achieve an LDL C of 120 despite use of 3 cholesterol-lowering drugs. Although this patient may have fallen short of the 100 goal, if starting from an untreated LDL-C level of ~ they have decreased their LDL C by >50%. Type 2 diabetes Those with diabetes often have lower LDL-C levels than those without diabetes, "goal" directed therapy often encourages use of a lower statin dose than is supported by RCTs, and nonstatin drugs may be added to address low HDL C or high triglycerides, for which RCT evidence of an event reduction is lacking. Critical Question 1 Reviewed 19 RCTs Supported conceptually by an extrapolation of observational studies and observational data from RCTs data were identified regarding treatment or titration to a specific LDL-C goal in adults with clinical Majority of studies used a single fixeddose to lower LDL-C levels 4S trial: 37% had the dose of simvastatin raised from 20 mg to 40 mg per day to achieve a total cholesterol level <200 mg/day Unable to find any RCTs that: Evaluated titration of all individuals in a treatment group to specific LDL-C targets Compared two LDL-C treatment targets Reported on-treatment non-hdl-c levels Trials reviewed for CQ1 4D A Z ACCORD ALLIANCE ASPEN AURORA CARE CORONA GREACE HATS HPS IDEAL LIPID LIPS MIRACL MUSHASHI- AMI PROVE-IT SPARCL TNT 5

6 Reassess every 4-6 years CQ1: Excerpt from Full Panel Report Critical Question 2 Reviewed 6 RCTs Four studies used fixed-dose statin therapy AFCAPS/TexCAPS trial 50% of participants lovastatin dose was raised from 20 mg to 40 mg/day to achieve an LDL-C <110 MEGA trial the dose of pravastatin could be uptitrated from 10 mg to 20 mg to achieve a total cholesterol <220 RCTs found: Evaluated titration of all individuals in a treatment group to specific LDL-C targets Compared 2 LDL-C treatment targets Reported on-treatment non-hdl-c levels Trials reviewed for CQ2 AFCAPS/ TexCAPS ASPEN Comments Age Moderate Intensity Age yrs with LDL-C <140 mg/dl if prior MI Or < 160 if not AURORA Aged Included primary and secondary prevention patients CARDS JUPITER Diabetics only Age Moderate Intensity Individuals with LDL- C <130 mg/dl MEGA Age CQ2: Excerpt from Full Panel Report What happened to goal lipid levels? The panel makes no recommendations for or against specific LDL-C or non-hdl-c targets for the primary or secondary prevention of. COR = Class of Recommendation LOE = Level of Evidence COR LOE N N/A N/A EVIDENCE STATEMENTS Data are not available regarding treatment or titration to a specific LDL-C goal in adults with CHD/CVD. The panel found insufficient evidence to support setting LDL-C goals in CHD/CVD patients. We did not identify any trials in adults with CHD/CVD reporting mean or median ontreatment non-hdl-c levels in adults with CHD/CVD. LDL-C goals <130 or <100 in patients without CHD/CVD. Randomized trial data are not available regarding dose titration to achieve a specific LDL-C goal. There was insufficient evidence in women without CHD/CVD to evaluate the reduction in CVD risk with achieved LDL-C levels <130 or <100. Can we give up Treat-to-Target? Benefit Groups Deliberated extensively over a 3-year period Many clinicians use targets RCT evidence shows events are reduced by using the maximum tolerated statin intensity Compared fixed doses of statins with placebo or untreated controls Compared fixed doses of higher-intensity statins with moderate-intensity statins AIM-HIGH: Niacin therapy added to vs. Alone Additional niacin therapy DID NOT further reduce risk in individuals treated to LDL C levels of Implications of treating to an LDL-C goal may mean: Suboptimal dose of statin is used because the goal has been achieved Adding a non- to achieve a specific target Addition of non- that has not been shown to reduce Prevention Benefit of Therapy Less Clear in 190 Estimate 10-y Risk If we don t treat to target is any monitoring required? ( if not Estimated 10-y risk 7.5% 6

7 Reassess every 4-6 years Efficacy Monitoring of s targets? Safety? Adherence to medication and lifestyle, therapeutic response to statin therapy, and safety should be regularly assessed. Fasting lipid panel performed within 4 to 12 weeks after initiation or dose adjustment, and every 3 to 12 months thereafter. The maximum tolerated intensity of statin should be used in individuals for whom a high- or moderate-intensity statin is recommended, but not tolerated. In individuals who have a less-than-anticipated therapeutic response or are intolerant of the recommended intensity of, the following should be performed: Reinforce medication adherence. Reinforce adherence to intensive lifestyle changes. Exclude secondary causes of hyperlipidemia. It is reasonable to use the following as indicators of anticipated therapeutic response to the recommended intensity of. Focus is on the intensity of the. As an aid to monitoring: High-intensity : LDL C reduction of 50% from the untreated baseline Moderate-intensity : average LDL C reduction of 30 to <50% from the untreated baseline LDL C levels and percent reduction are to be used only to assess response to therapy and adherence. They are not to be used as performance standards. Decreasing the statin dose may be considered when 2 consecutive values of LDL C levels are <40. COR LOE A I A B I B A I A E IIa B C IIb C Safety Monitoring of s To maximize the safety of statins, selection of the appropriate statin and dose in men and non-pregnant/non-nursing women should be based on patient characteristics, level of risk, and potential for adverse effects. Moderate-intensity should be used in individuals in whom high-intensity would otherwise be recommended when characteristics predisposing them to statinassociated adverse effects are present. CK should not be routinely measured in individuals receiving. Baseline measurement of CK is reasonable for individuals believed to be at increased risk for adverse muscle events based on a personal or family history of statin intolerance or muscle disease, clinical presentation, or concomitant drug therapy that might increase the risk for myopathy. Baseline measurement of hepatic transaminase levels (ALT) should be performed before initiating. During, it is reasonable to measure hepatic function if symptoms suggesting hepatotoxicity arise (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine or yellowing of the skin or sclera). COR LOE A I B A III: Benefit A E IIa C B I B E IIa C Safety Monitoring of s Individuals receiving should be evaluated for newonset diabetes mellitus according to the current diabetes screening guidelines. Those who develop diabetes mellitus during should be encouraged to adhere to a heart healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue to reduce their risk of events. For individuals taking any dose of statins, it is reasonable to use caution in individuals : >75 years of age Taking concomitant medications that alter drug metabolism Taking multiple drugs Taking drugs for conditions that require complex medication regimens For individuals presenting with a confusional state or memory impairment while on, it may be reasonable to evaluate the patient for nonstatin causes, such as exposure to other drugs, as well as for systemic and neuropsychiatric causes, in addition to the possibility of adverse effects associated with statin drug therapy. COR LOE B I B E IIa C E IIb C intensity Moderateintensity statin vs. placebo/control High-intensity vs. moderateintensity statin High-intensity (rosuvastatin) vs. placebo Risk with s Fewer major CVD events/1,000 individuals treated for 1 year vs. placebo Excess cases of incident diabetes per 1,000 individuals treated for 1 year vs. placebo NNT per year NNH per year , Lipid Panel LFTs CK Myopathy Symptoms Blood glucose Cognitive Function Overview of Monitoring Requirements Baseline Every 1 3 months after initiation/dose change or Every 3 12 months As ly Indicated Benefit Groups 190 Estimate 10-y Risk Where is non-statin therapy? ( if not Estimated 10-y risk 7.5% Prevention Benefit of Therapy Less Clear in 7

8 Critical Question 3 Interventions evaluated included pharmacotherapy with single-drug therapies or combination-drug therapies with any drug therapy used for treating blood cholesterol s Fibrates (fenofibrate, gemfibrozil) Nicotinic acid (niacin in immediate-, slow-, or extended-release form) Bile acid sequestrants Ezetimibe Omega-3 fatty acids (also called marine fatty acids, including eicosapentaenoic acid alone, docosahexanoic acid alone, eicosapentaenoic acid plus docosahexanoic acid, and alpha-linolenic acid). There were no outcomes identified for plant sterols, sterol esters, stanols, or stanol esters Xuezhikang Extract from red yeast Chinese rice One RCT from China was not available in the United States during the timeframe for evidence review, so no recommendations were made regarding its use n- RCTs Evaluated nstatin drug Niacin Cholestyramine Ezetimibe Gemfibrozil Fenofibrate EPA EPA = eicosapentaenoic acid nstatin vs. placebo CDP (men with HLD and CHD) LRC (primary prevention in men with HLD) HHS (in men with HLD) VA-HIT (men with hx of CHD) FIELD (with diabetes) - Primary Preventinon; Secondary Prevention Coadministered and nonstatin vs. placebo HATS (with simvastatin in pts with CHD) SEAS (with simvastatin in pts with aortic stenosis) SHARP (with Simvastatin in pts with CKD) Coadministered statin and nonstatin vs. statin AIM-HIGH (vs. Simvastatin in pts with CHD) ACCORD (vs. simvastatin in pts with DM) JELIS (vs. pravastatin in Japanese adults with HLD) Where is non-? For individuals 21 years of age with an untreated primary LDL C 190, after the maximum intensity of statin therapy has been achieved, addition of a non-statin drug may be considered to further lower LDL C. Evaluate the potential for risk reduction benefits, adverse effects, drug-drug interactions, and consider patient preferences. In individuals at higher risk receiving the maximum tolerated intensity of who continue to have a less-than-anticipated therapeutic response, addition of a nonstatin cholesterol-lowering drug(s) may be considered if the risk-reduction benefits outweigh the potential for adverse effects. Preference should be given to nonstatin cholesterol-lowering drugs shown to reduce events in RCTs. In individuals who are candidates for statin treatment but are completely statin intolerant, it is reasonable to use nonstatin cholesterol-lowering drugs that have been shown to reduce events in RCTs if the risk-reduction benefits outweigh the potential for adverse effects. COR LOE E IIb C IIb IIa C B Questions for Future Guidelines Treatment of hypertriglyceridemia Use of non-hdl-c in treatment decision-making Whether on-treatment markers such as Apo B, Lp(a), or LDL particles are useful for guiding treatment decisions Best approaches to using noninvasive imaging for refining risk estimates to guide treatment decisions How lifetime risk should be used to inform treatment decisions and the optimal age for initiating to reduce lifetime risk of ; Subgroups of individuals with heart failure or undergoing hemodialysis that might benefit from Long-term effects of statin-associated new onset diabetes and management Efficacy and safety of statins in patient groups excluded from RCTs to date (e.g., HIV positive or solid organ transplant) Role of pharmacogenetic testing Patient Case #1 63 M s/p STEMI 2 weeks ago PMH: HTN, HLD SH: Smoker Medications: Atorvastatin 80 mg QHS Aspirin 81 mg daily Clopidogrel 75 mg daily Lisinopril 5 mg daily Metoprolol 25 mg PO BID Patient was previously on simvastatin 80 mg QHS, but discontinued 2 weeks after starting due to leg cramps. Prior to that he had tolerated simvastatin 40 mg QHS He is concerned about his previous reaction and would like to decrease the atorvastatin to 20 mg QHS. How do you respond to his concern? A. RCTs of high intensity vs. moderate intensity have not shown significant difference in outcomes., we can decrease to atorvastatin 20 mg QHS. B. Meta-analyses of RCTs support the use of high intensity statin over moderate intensity. The best choice is to stay on atorvastatin 80 mg. C. Due to previous reaction he should be followed with creatine kinase values when his lipids are checked at each visit for the first year. D. Although his liver panel was normal in the hospital, he should have an ALT done at each subsequent visit. E. Check his LDL-C to determine if a dose reduction is appropriate. Adapted from Prevention Guidelines Vignettes: Vignettes.pdf 8

9 Patient Case #2 Patient Case #3 44 F with 10-year history of type 2 diabetes PMH: HTN, microalbuminuria SH: non-smoker FH: diabetes BP 134/78 BMI 36 LDL-C 95 Triglycerides 350, HDL-C 38 HgbA1c 7.5% Medications: Dietary management Metformin 1000 mg BID Omega-3 fatty acid capsule with 840 mg of EPA and DHA. Lisinopril/HCTZ What is the next step for management? A. LDL < 100 so she is at goal. B. She should start simvastatin 20 mg and fenofibrate 160 mg daily. C. To reduce her risk of an event, increase omega-3 to 4 capsules daily. D. If she does not want to start a statin, a bile acid sequestrant is the next best choice for her. E. Her 10-year risk should be calculated to determine if high- or moderate-intensity statin should be initiated. 60 AAF asking whether she should take a statin to reduce risk of stroke, but worried about statin causing diabetes. FH: mother diabetes & stroke at 62 SH: nonsmoker BP 142/88 on 2 medications HDL 55 ; TG 100 ; LDL 125 Blood glucose 109 mm/dl; HgbA1c 5.9% According to pooled cohort equation for African American women her estimated 10 year risk is 8.7% Which statement is true? A. She should focus on lifestyle change to improve her risk factors because lifestyle has been shown to reduce events more than statin therapy. B. Risk of progression to diabetes with a statin outweighs any risk reduction benefits from. She should defer a statin at this time. C. She should start a moderate or high intensity statin. D. A high sensitivity C-reactive protein> 2 would be needed before making a recommendation. Adapted from Prevention Guidelines Vignettes: Vignettes.pdf Adapted from Prevention Guidelines Vignettes: Vignettes.pdf Top 10 Key Points to Remember 10. A new Expert Panel 9. Lifestyle modification remains a critical component to therapy 8. Pooled cohort equations for 10 year risk 7. Greater emphasis on RCTs and meta-analysis 6. Four major statin benefit groups - excluding heart failure and dialysis - LDL Diabetics age years with - n-diabetics, age 40-75, and 10 Year Risk 7.5% 5. recommendations for people not in the four major benefit groups 4. Monitoring requirements 3. Less emphasis on non-statin therapies 2. Say Goodbye to Treat to Target & Lower is Better 1. New Goal: Treat to Level of risk with Appropriate Intensity of Therapy Lindsey Clark, PharmD, BCPS Cardiology-Medicine Pharmacy Specialist University of Cincinnati Medical Center April 10,