S.H.R Ghafelehbashi M.D Shahid Beheshti medical unioersity 30 october 2017

2. S.H.R Ghafelehbashi M.D Shahid Beheshti medical unioersity 30 october 2017

3. Expert consensus documents are intended to provide guidance for clinicians in areas where evidence may be limited are new and evolving or lack sufficient data ACC Presidential Task Force 2014 Expert Consensus Decision Pathways ECDP Expert consensus documents ( traditional longer documents ) concise decision pathways and/or key points of care ECDPs are designed to complement the guidelinesand bridge the gaps in clinical guidance that remain.

4. 2013 : ACC/AHA published the new Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults “net ASCVD risk-reduction benefit” Likelihood of preventing a major ASCVD event or death > Likelihood of a serious adverse event with a given drug therapy? the vast majority of evidence indicating efficacy and safety of LDL-C lowering for risk reduction came from trials of Statindrugs 4 major statin benefit groups were identified for whom the atherosclerotic cardiovascular disease (ASCVD) risk reduction clearly outweighs the risk of adverse events

7. Thiazide, Beta blocker, Oral estrogens, Anti psychotics, Anti HIV,…

8. Since the publication of the 2013 ACC/AHA cholesterol guidelines, RCTs evaluating the safety and efficacy of non-statin therapies (including large trials of ezetimibe; extended-release niacin with laropiprant; and the PCSK9 inhibitors, evolocumab,alirocumab, bococizumab) added to statins in higher-risk patients have provided important information regarding the potential benefits and harms of these agents in ASCVD risk reduction when used in combination with evidence-based statin therapy. 2015Think Tank meeting : the need for expert consensus guidance regarding the incorporation of non-statin therapies into treatment strategies for higher risk patients as a critical gap in clinical care.

9. 2016 ACC published the firstexpert consensus decision pathway (ECDP) Role of non-statin therapies for LDL–cholesterol lowering in the risk management of atherosclerotic cardiovascular disease(ASCVD). Evidence from RCTs FOURIER, SPIRE-1 and -2 , … A focused update regarding the use of ezetimibe and PCSK9 inhibitors in patients with clinical ASCVD with or without comorbidities 2017 Focused Update of the2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk

10. The committee endorses use of the Friedewald equation in most cases, given that the majority of RCTs used this method, that it is the most widely available means in clinical practice, and that it tends to cost less. Nonetheless, the committee acknowledges that there can be significant discrepancies in levels of directly measured versus calculated LDL-C within the same sample, especially at lower LDL-C levels. Friedewald Equation LDL = Total cholesterol - ( HDL + TG / 5)

11. Recommendation for monitoring of response to LDL-C lowering therapies Use of an initial fasting lipid panel (TC, triglycerides, HDL-C, and LDL-C) followed by a second lipid panel 4 to 12 weeks after initiation of treatment Thereafter, assessments should be performed every 3 to 12 months as clinically indicated. When anymodification is made to LDL-C lowering therapy, including intensification of lifestyle intervention, increase in statin intensity, or the addition of non-statin therapies, the writing committee recommends the use of a fasting lipid panel 4 to 12 weeks after treatment modification to determine a patient’s adherence and response to therapy. Thereafter, assessments should be performed every 3 to 12 months as clinically indicated. It is critical that the clinician assess and reinforce adherence to intensive lifestyle changes (i.e., adherence to a heart-healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight) before and in concert with the use of these additional agents.

12. The clinician-patient discussion should address: 1 )The potential for additional ASCVD risk reduction that could be expected from the addition of a non-statin therapy 2 ) The potential for adverse events or drug–drug interactions from addition of non-statin therapy (Table 4) 3 ) patient preferences : patient’s perception of net benefit Convenience Burden of additional therapy Cost Quality of life Potential to jeopardize adherence to other evidence-based therapies. Statin adherence : assessing the number of missed statin doses per month and evaluating any barriers to adherence

13. † Use the Pooled Cohort Equations to estimate 10-year ASCVD risk. High-risk markers include 10-year ASCVD risk $20%, primary LDL-C $160 mg/dL at baseline; poorly controlled other major ASCVD risk factor(s); family history of premature ASCVD with or without elevated Lp(a); evidence of accelerated subclinical atherosclerosis (e.g., coronary artery calcification); elevated hs-CRP; and other risk-modifying conditions, such as CKD, HIV, and chronic inflammatory disorders.

14. ‡Such evidence exists for ezetimibe from the IMPROVE-IT study, with a 6%relative/2% absolute risk reduction in a composite ASCVD endpoint over 7 years when added to a moderate intensity statin. Short-term data (<18 months) from PCSK9 inhibitors alirocumab and evolocumab suggest more substantial ASCVD risk reduction. Data are lacking for addition of BAS to statins. Niacin preparations have been associated with no benefit and potential for significant harms when added to statin therapy. For example, when added to statins, ezetimibe may lower LDL-C an additional 20-25% on average; PCSK9 inhibitors may lower LDL-C an additional 60% on average. For each 40 mg/dL reduction in LDL-C using safe and evidence-based therapies, there appears to be an approximate 20% relative risk reduction in ASCVD. This number, combined with the baseline absolute risk, may inform the number-needed-to-treat.

15. Approaches to statin intolerance: The most commonly reported being muscle-related symptomsbut True statin intolerance is uncommon Work up A careful history (myalgia or weakness in large proximal muscle groups) Other causes of muscle symptoms must be ruled out (e.g., hypothyroidism, vitamin D deficiency, recent exercise) Drug– drug interactions that can increase systemic statin exposure must be considered. High risk patients ( women, individuals of Asian descent, and the elderly ) Treatment Discontinuation of statin therapy until resolution of symptoms and subsequent rechallengeto verify recurrence of muscle-related symptom (at least 2 to 3 statins preferably ones that use different metabolic pathways and have different lipophilicity, and 1 of which is prescribed at the lowest approved dose) if the lowest dose of multiple statins cannot be tolerated on a daily basis, consideration should be given to alternative dosing strategies such as the use of long half-life statins (atorvastatin, pitavastatin, rosuvastatin) administered 3 times per week or once per week. Patients who are unable to tolerate even a moderate intensity statin should be evaluated for statin intolerance and considered for referral to a lipid specialist. RosensonRS, Baker SK, Jacobson TA, et al. An assessment by the Statin Muscle Safety Task Force: 2014 update. J ClinLipidol. 2014;8:S58–71. Guyton JR, Bays HE, Grundy SM, et al. An assessment by the Statin Intolerance Panel: 2014 update. J ClinLipidol. 2014;8:S72–81.

17. >> Non-statin therapies are not considered to be an alternative to evidence based statin therapy unless statin intolerance has been systematically and rigorously evaluated and documented. >> On the basis of currently available evidence of non-efficacy and potential harms, the committee judged that there are no clear indicationsfor the routine use of niacin preparations as additional non-statin therapies, and niacin is not recommended for use in any of the clinical situations. >> A bile acid sequestrant (BAS) may be considered as an optional alternative agent for those with ezetimibe intoleranceand with triglycerides <300 mg/dL or due to patient preference, but there is no evidence for net cardiovascular risk reduction benefit of BAS + statins . The BAS are, therefore, noted only as an option in the footnotes of the following algorithms. Mora S, Rifai N, Buring JE, et al. Comparison of LDL cholesterol concentrations by Friedewald calculation and direct measurement in relation to cardiovascular events in 27,331 women. Clin Chem. 2009;55:888–94. Schandelmaier S, Briel M, Saccilotto R, et al. Niacin for primary and secondary prevention of cardiovascular events. Cochrane Database Syst Rev. 2017;6:CD009744.

19. IMPROVE-IT Improved Reduction of Outcomes: Vytorin Efficacy International Trial

20. IMPROVE-IT Patients: age ≥50 years, ACS (Recent 10 days), LDL-C between 50mg/dL and 100 - 125 mg/dL 18,144 9,067 9,077 Simvastatin40 mg + Placebo Simvastatin40 mg + Ezetimibe 10 mg CV mortality Major CV event (death from CAD, MI, stroke or revascularization more than 30 days after randomization) Nonfatal stroke

21. IMPROVE-IT Clinical Question Among individuals with ACS, does ezetimibe+simvastatin reduce CV mortality, major CV event, or nonfatal stroke when compared to simvastatin alone? Design • Multicenter, double-blind, randomized controlled trial • N=18,144 patients Simvastatin (n=9,077) , Simvastatin+ezetimibe (n=9,067) • Setting: 1,147 sites in 39 countries • Enrollment: 2005-2010, Median follow-up: 6 years • Primary outcome: CV mortality, major CV event, or nonfatal stroke • major CV event : composite of death from coronary heart disease, myocardial infarction, stroke, or revascularization more than 30 days after randomization Inclusion Criteria >> Either sex, age ≥50 years >> Hospitalized in prior 10 days for ACS (acute MI with or without ST-segment elevation) or high-risk unstable angina >> LDL-C ≥50mg/dL >> Maximum LDL-C: Patients who were not receiving long-term lipid-lowering therapy, the maximum LDL-C for enrollment was 125 mg/dL and Patients on chronic lipid-lowering therapy, the maximum LDL-C was 100 mg/dL >> Fasting TG ≤350 mg/dL

22. IMPROVE-IT Exclusion Criteria • Clinically-unstable (eg, cardiogenic shock) • Recurrent ischemia symptoms • Stroke or TIA • Arrhythmia (eg, VF, SVT >30 sec, high-grade second-degree heart block) • Planned CABG for ACS event • CrCl <30 mL/min • Active liver disease • Use of statin therapy that had LDL-C lowering potency greater than 40mg of simvastatin (including any simvastatin+ezetimibe combinations) • Need to continue medications with CYP3A4 activity • Alcohol or drug abuse • Lactating women or women of childbearing potential without effective contraception • Investigator discretion • Investigational drug in prior 30 days or prior enrollment in the study Interventions • Randomization to simvastatin 40mg daily + placebo or simvastatin 40mg daily + ezetimibe 10mg daily • For patients with LDL-C >79 mg/dL on two consecutive measurements, the simvastatin dose was increased to 80mg daily (This was subsequently modified to reflect FDA recommendations against use of simvastatin 80 mg) • Both groups received standard medical and interventional treatment for ACS

23. IMPROVE-IT

24. IMPROVE-IT

25. IMPROVE-IT

26. IMPROVE-IT Result Primary Outcome CV mortality, major CV event, or nonfatal stroke 34.7% vs. 32.7% (HR 0.94; 95% CI 0.89-0.99; P=0.016; NNT 50) Secondary Outcomes All-cause mortality, major CV event , or nonfatal stroke 40.3% vs. 38.7% (HR 0.95; 95% CI 0.90-1.00; P=0.03) CV mortality, nonfatal MI, urgent coronary revascularization ≥30 days 18.9% vs. 17.5% (HR 0.91; 95% CI 0.85-0.98; P=0.02) CV mortality, nonfatal MI, unstable angina hospitalization, any revascularization ≥30 days, nonfatal stroke 36.2% vs. 34.5% (HR 0.95; 95% CI 0.90-1.00; P=0.04)

27. IMPROVE-IT Result Tertiary Outcomes Mortality type All-cause: 15.3% vs. 15.4% (HR 0.99; 95% CI 0.91-1.07; P=0.78) CV: 6.8% vs. 6.9% (HR 1.00; 95% CI 0.89-1.13; P=1.00) CHD: 5.8% vs. 5.7% (HR 0.96; 95% CI 0.84-1.09; P=0.50) MI 14.8% vs. 13.1% (HR 0.87; 95% CI 0.80-0.95; P=0.002) Non-fatal: 14.4% vs. 12.8% (HR 0.87; 95% CI 0.80-0.95; P=0.002) Fatal: 0.7% vs. 0.5% (HR 0.84; 95% CI 0.55-1.27; P=0.41) Stroke 4.8% vs. 4.2% (HR 0.86; 95% CI 0.73-1.00; P=0.05) Ischemic: 4.1% vs. 3.4% (HR 0.79; 95% CI 0.67-0.94; P=0.008) Hemorrhagic: 0.6% vs. 0.8% (HR 1.38; 95% CI 0.93-2.04; P=0.11) LDL at 1 year Both groups had baseline LDL of 94 mg/dL 69.9 vs. 53.2 mg/dL (P<0.001) Mortality from CV causes, MI, or stroke 22.2% vs. 20.4% (HR 0.90; 95% CI 0.84-0.96; P=0.003)

28. IMPROVE-IT

29. IMPROVE-IT

30. IMPROVE-IT Kaplan–Meier Curves for the Primary Efficacy End Point. Shown are the cumulative event rates for the primary composite end point of death from cardiovascular disease, a major coronary event (nonfatal myocardial infarction, documented unstable angina requiring hospital admission,or coronary revascularization occurring at least 30 days after randomization), or nonfatal stroke in the intention-to-treat population during the overall study period (i.e., beginning from the time of randomization to the day of the first occurrence of a primary end-point event, the day of the last office or phone visit, or the day of death during follow-up). The inset shows the same data on an enlarged y axis.

31. IMPROVE-IT • Major vascular events : composite of • death from • Coronary heart disease • Myocardial infarction • Stroke • Revascularization more than 30 days after randomization a : GruppoItaliano per lo Studio dellaSopravvivenzanell’InfartoMiocardico (GISSI Prevenzione) b: Antihypertensive &Lipid-Lowering Treatment to Prevent Heart Attack Trial–Lipid Lowering Trial (ALLHAT-LLT) c: Assessment of Lescol in Renal Transplantation (ALERT) d: Lescol Intervention Prevention Study (LIPS) e: Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) f: Cholesterol and Recurrent Events (CARE) g: Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) h: Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) i: Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA) j: West of Scotland Coronary Prevention Study (WOSCOPS) k: Post–Coronary Artery Bypass Graft (Post CABG) l: Collaborative Atorvastatin Diabetes Study (CARDS) m: Heart Protection Study (HPS) n: Scandinavian Simvastatin Survival Study (4S) Vertical bars indicate 1 SE. The size of the box is proportional to the number of end points in the study.

32. IMPROVE-IT Result Adverse Events There was no difference in the pre specified safety endpoint between the groups liver and gallbladder abnormalities Rhabdomyolysis Myopathy Cancer Cancer mortality. Discontinuation of study medication because of an adverse event 10.1% vs. 10.6%

33. IMPROVE-IT

34. IMPROVE-IT Limitations • 42% of the patients discontinued the study medication for any reason prematurely, with an equal proportion in both groups • Overall treatment effect on the composite primary end point was modest considering the large sample size and relatively long follow-up period (NNT of 50 with ARR of 2%) • As the trial was designed prior to contemporary guidelines, these patients were treated with a moderate-intensity statin rather than with a standard-of-care high-intensity statin

35. IMPROVE-IT Conclusion MPROVE-IT is the first trial to show that adding a non-statin lipid-modifying agent in concert with a statin improves CV outcomes in addition to enhancing lipid lowering effects. The event reduction was consistent with the predicted effects seen with statins, even in the range of low LDL cholesterol levels in this trial, and no offsetting adverse events or toxic effects were observed.

36. IMPROVE-IT 2017 by the American College of Cardiology Foundation

37. IMPROVE-IT

38. OSLER Open-Label Study of Long-Term Evaluation against LDL Cholesterol

39. OSLER Clinical Question Is evolocumab safe and effective to decrease LDL and cardiovascular events in patients who were enrolled in phase 2 and phase 3 trials ? Design Multicenter, open-label, parallel-group, randomized, controlled trial N=4,465 Evolocumab + standard (n=2,976) Standard (n=1,489) Median follow-up: 11.1 months Primary outcome: adverse events OSLER-1 : for patients completing phase 2 trials OSLER-2 : for patients completing phase 3 trials

40. OSLER Inclusion Criteria • Completed parent study • No adverse event leading to discontinuation of study drug • No unstable medical condition • Not expected to need unblinded lipid measurements or adjustment of background lipid- regulating therapy during the first 12 weeks of participation Interventions • Evolocumab 420 mg subcutaneously once monthly (OSLER-1) • Evolocumab 420 mg subcutaneously once monthly OR 140 mg every 2 weeks based on patient preference (OSLER-2) • All patients received standard-of-care background therapy based on local guidelines for treatment of LDL cholesterol

41. OSLER Primary Outcome • Adverse events • Serious adverse events • Adverse events leading to drug discontinuation • Abnormalities in CK levels and LFTs • Development of binding and neutralizing antibodies against evolocumab Secondary Outcome • Percent change in LDL level Exploratory Outcome • Cardiovascular events (MI, UA requiring hospitalization, revascularization, stroke, TIA, heart failure requiring hospitalization)

42. OSLER

43. OSLER

44. OSLER

45. OSLER

46. OSLER Result Neurocognitiveadverse events were reported more frequently in the evolocumab group. However, neurocognitive events were also non-statistically increased in the evolocumab group. Of note, the incidence of neurocognitive adverse events did not appear to be related to the LDL cholesterol level during Treatment.

47. OSLER

48. OSLER Result New evolocumab-binding antibodies were detected in 9 patients (0.3%) in the evolocumab group and in 4 patients (0.3%) in the standard-therapy group, and binding-antibody titers were transient in patients who had repeat testing. No neutralizing antibodies against evolocumab were detected.

49. OSLER

50. OSLER Result -60.9% Secondary Outcome