DISCLOSURES OBJECTIVES CARDIOLOGY GUIDELINE UPDATES: HEART FAILURE, CARDIAC ARREST & HYPERLIPIDEMIA

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1 CARDIOLOGY GUIDELINE UPDATES: HEART FAILURE, CARDIAC ARREST & HYPERLIPIDEMIA Michael Gillette, Pharm.D., BCPS-AQ Cardiology, AACC Clinical Pharmacy Specialist, Cardiology Michael DeBakey VA Medical Center April 28, DISCLOSURES FINANCIAL DISCLOSURE: There are no financial or other relationships to disclose related to this presentation. UNLABELED/UNAPPROVED USES DISCLOSURE: The unlabeled/unapproved use of medications will not be discussed. The views expressed in this presentation reflect those of the author, and not necessarily those of the Department of Veterans Affairs. 2 OBJECTIVES Discuss the most recent updates to the guidelines for the management of cardiac arrest and heart failure Briefly review the 2013 ACC/AHA guidelines for hyperlipidemia Introduce the most recent guidelines for the role of nonstatin therapies in the management of hyperlipidemia Highlight a recent landmark trial that may impact the treatment and management of hyperlipidemia Be able to apply the guideline updates to patient care 3 1

2 Classes of recommendations and level of evidence used in ACCF/AHA clinical practice guidelines. Raymond J. Gibbons et al. Circulation. 2003; 107: Copyright American Heart Association, Inc. All rights reserved. READY? 6 2

3 2015 AHA GUIDELINE UPDATES FOR CARDIOPULMONARY RESUSCITATION AHA KEY NON-DRUG UPDATES 2010 Guideline Recommendation 2015 Guideline Update Although conflicting evidence exists, expert consensus recommended systematic identification of patients at risk of cardiac arrest, an organized response to such patients, and an evaluation of of outcomes to foster continuous quality improvement. For adult patients, rapid response team (RRT) or medical emergency team (MET) systems can be effective in reducing the incidence of cardiac arrest, particularly in the general care wards (Class IIa, LOE C-LD) It is reasonable for lay rescuers and HCPs to perform chest compressions (CCs) at a rate of at least 100/min. In adult victims of cardiac arrest, it is reasonable for rescuers to perform chest compressions at a rate of /min. (Class IIa, LOE-C-LD) The adult sternum should be depressed at least 2 inches (5 cm). rescuers should perform CCs to a depth of at least 2 inches (5 cm) for an avg. adult, while avoiding excessive CC depths (greater than 2.4 inches [6 cm]). (Class I, LOE C-LD) Kleinman ME, Brennan EE, Goldberger ZD, et al. Circulation 2015; 132:s414-s

4 2015 NEW DRUG" GUIDELINES For patients with known or suspected opioid addiction who are unresponsive with no normal breathing but a pulse, it is reasonable for appropriately trained lay rescuers and BLS providers, in addition to providing standard BLS care, to administer intramuscular (IM) or intranasal (IN) naloxone (Class IIa, LOE-C-LD) There is inadequate evidence to support the routine use of lidocaine after cardiac arrest. However, the initiation or continuation of lidocaine may be considered immediately after ROSC from SCA due to VF/pVT. (Class IIb, LOE C-LD) There is inadequate evidence to support the routine use of a β-blocker after SCA. However, the initiation or continuation of an oral or IV β- blocker may be considered early after hospitalization from cardiac arrest due to VF/pVT. (Class IIb, LOE C-LD). For patients with OHCA, use of steroids during CPR is of uncertain benefit (Class IIb, LOE C-LD) Link MS, Berkow LC, Kudenchuk PJ, et al. Circulation. 2015; 132:s444-s DRUG GUIDELINE UPDATES Standard-dose epinephrine (1 mg every 3 to 5 minutes) may be reasonable for patients in cardiac arrest. (Class IIb, LOE B-R) Vasopressin offers no advantage as a substitute for epinephrine in cardiac arrest (Class IIb, LOE B-R) It may be reasonable to administer epinephrine as soon as feasible after the onset of cardiac arrest due to an initial non-shockable rhythm. (Class IIb, LOE C-LD) The routine use of magnesium for VF/pVT is NOT recommended in adult patients Class III, LOE B-R). Amiodarone may be considered for VT/pVT that is unresponsive to CPR, defibrillation, and a vasopressor therapy (Class IIb, LOE B-R). Link MS, Berkow LC, Kudenchuk PJ, et al. Circulation. 2015; 132:s444-s FOCUSED UPDATE ON NEW PHARMACOLOGICAL THERAPY FOR HEART FAILURE 12 4

5 13 RECOMMENDATIONS FOR RENIN-ANGIOTENSIN SYSTEM (RAS) INHIBITION WITH ACE-I or ARB or ARNI COR LOE Recommendations I ACE: A ARB: A ARNI: B-R The clinical strategy of inhibition of the RAS with ACE-Is OR ARBs OR ARNI in conjunction with beta-blockers, and aldosterone antagonists in selected patients is recommended for patients with chronic HFrEF to reduce morbidity and mortality. I I I ACE: A ARB: A ARNI: B-R The use of ACE-Is is beneficial for patients with prior or current symptoms of chronic HFrEF to reduce morbidity and mortality The use of ARBs to reduce morbidity and mortality is recommended in patients with prior or current symptoms of chronic HFrEF who are intolerant to ACE-Is because of cough or angioedema. In patients with chronic symptoms HFrEF NYHA Class II or III who tolerate an ACE-inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality. Key: Angiotensin Converting Enzyme Inhibitor (ACE-I); Angiotensin Receptor Blocker (ARB); Angiotensin-Receptor-Neprilysin Inhibitor (ARNI); Heart Failure with reduced Ejection Fraction (HFrEF); New York Heart Association (NYHA) Yancy CW, Jessup M, Bozkurt B, et al. Circulation. 2016; 134(13);e RECOMMENDATIONS FOR ARNI (cont.) COR LOE Recommendations III: Harm B-R ARNI should not be administered concomitantly with ACE-Is or within 36 hours of the last dose of an ACE-I. III: Harm C-EO ARNI should not be administered to patients with a history of angioedema. Key: Angiotensin Converting Enzyme Inhibitor (ACE-I); Angiotensin Receptor Blocker (ARB); Angiotensin-Receptor-Neprilysin Inhibitor (ARNI) Yancy CW, Jessup M, Bozkurt B, et al. Circulation. 2016; 134(13);e

6 RECOMMENDATIONS FOR IVABRADINE (CORLANOR ) COR LOE Recommendations IIa B-R Ivabradine can be beneficial to reduce HF hospitalizations for patients with symptomatic (NYHA Class II-III) stable chronic HFrEF (LVEF 35%) who are receiving GDEM, including a beta-blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest. Key: Heart Failure with reduced Ejection Fraction (HFrEF); New York Heart Association (NYHA); Left Ventricular Ejection Fraction (LVEF); Guideline directed evidence and management (GDEM); beats per minute (bpm) Yancy CW, Jessup M, Bozkurt B, et al. Circulation. 2016; 134(13);e ACC EXPERT CONSENSUS ON THE ROLE OF NON-STATIN THERAPY FOR HYPERLIPIDEMIA

7 2013 ACC/AHA GUIDELINE REVIEW Used an evidence review based largely on RCT data. Central approach: To identify populations for whom benefit > risk for a given drug therapy. Clear net benefit with statin treatment for the 4 statin benefit groups. The amount of ASCVD risk reduction observed with statins was directly related to the amount of % LDL-C reduction from baseline. RCT data suggested: 50% LDL-C reduction with high-intensity statins; 30% to <50% reduction with moderate intensity statins No specific LDL-C targets to guide therapy; however majority of patients on high intensity statins had LDL-C level <100 mg/dl Consensus statement suggested these could be used as an indicator for adequate response and adherence to therapy. Stone NJ, Robinson JG, Lichtenstein AH, et al. J Am Coll Cardiol. 2014; 63: STATIN BENEFIT GROUPS Secondary Prevention Clinical ASCVD* Primary Prevention Adults with LDL 190 mg/dl Primary Prevention Diabetics, Age years & LDL mg/dl Primary Prevention Estimated 10- year ASCVD risk 7.5%, years old who have LDL *Atherosclerotic cardiovascular disease Requires risk discussion between clinician and patient before statin initiation Statin therapy may be considered if risk decision is uncertain after use of ASCVD risk calculator Stone NJ, Robinson JG, Lichtenstein AH, et al. J Am Coll Cardiol. 2014; 63: STATIN INTENSITY *Atherosclerotic cardiovascular disease Requires risk discussion between clinician and patient before statin initiation Statin therapy may be considered if risk decision is uncertain after use of ASCVD risk calculator *Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. There might be a biologic basis for a less-than-average response. Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Pedersen et al). Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is not recommended by the FDA due to the increased risk of myopathy, including rhabdomyolysis. 21 Stone NJ, Robinson JG, Lichtenstein AH, et al. J Am Coll Cardiol. 2014; 63:

8 USE OF NON-STATIN DRUGS IN 2013 ACC/AHA GUIDELINES At the time of the 2013 ACC/AHA Guideline publication: No data supporting the routine use of FDA-approved non-statin drugs combined with statin therapy for LDL-C reduction with the goal of further reducing ASCVD events. There were no published RCTs that assessed outcomes in statin-intolerant patients. (HPS2-THRIVE, IMPROVE-IT, PCSK9 inhibitor trials were ongoing) Therefore, the panel recommended: clinicians treating high-risk patients who have a less than-anticipated response to statins, who are unable to tolerate a less-than-recommended intensity of a statin, or who are completely statin intolerant, may consider the addition of a non-statin cholesterol lowering therapy. Stone NJ, Robinson JG, Lichtenstein AH, et al. J Am Coll Cardiol. 2014; 63: THE EXPERT CONSENSUS UPDATES Incorporate newer clinical trial data on niacin, ezetimibe, and the recently approved PCSK9 inhibitors to evidence base established by 2013 guideline. Provide practical guide for use of non-statin drugs for risk reduction in situations not covered by the 2013 ACC/AHA guideline. The process did not involve formal systematic reviews/evidence grading consensus statement. 23 COMPLETED TRIALS HPS2-THRIVE (NEJM 2014): in patients with clinical ASCVD: no benefit and significant harms from a long-acting niacin/laropiprant preparation in addition to simvastatin compared with simvastatin alone. IMPROVE-IT (NEJM 2015): in patients with recent ACS, addition of ezetimibe to simvastatin compared with statin monotherapy led to further reductions in LDL-C and statistically significant but clinically modest reduction in MACE over 7 years of follow up. FOURIER (NEJM 2017): in patients with established atherosclerotic cardiovascular disease, the addition of evolocumab on top of guideline directed statin therapy compared with statin monotherapy led to further reductions in LDL-C and statistically significant reductions in MACE over a period of 2.2 years. 24 8

9 KEY QUESTIONS ADDRESSED BY COMMITTEE 1) In what patient populations should non-statin therapies be considered? 2) In what situations should non-statin therapies be considered (i.e. when is the amount of LDL lowering less than anticipated, less than desired, or inadequate, and which treatment options should be considered in patients who are truly statin intolerant)? 3) If non-statin therapies are added, which agent or therapies should be considered and in what order? 25 APPROACHES TO STATIN INTOLERANCE Healthy lifestyle modification remains key to all patient groups (i.e., adhering to a heart healthy diet, regular exercise habits, avoidance of tobacco products, and maintenance of a healthy weight). Non-statin therapies are not considered to be an alternative evidence-based statin therapy. Statin intolerance should be systematically and rigorously evaluated and documented (i.e. obtain careful history; rule out other potential causes such as hypothyroidism, vitamin D deficiency, exercise; re-trial to verify recurrence of symptoms, etc). If unable to tolerate a statin then trial of lower doses/alternative statins and/or modified dosing intervals (i.e. every other day). 26 FACTORS TO CONSIDER WHEN USING NON-STATIN THERAPIES Pill Burden Available scientific evidence & clinical trials Adherence & lifestyle Preference in specific populations (i.e. pregnancy, elderly) Patient Preferences Efficacy & cost Drug-Drug interactions Safety & tolerability 27 9

10 I) In what patient populations should non-statin therapies be considered? QUESTIONS 1 AND 2 Numerous Algorithms Developed II) In what situations should non-statin therapies be considered? Adults 21 years old with clinical ASCVD, on Statin for Secondary Prevention Stable Clinical ASCVD without Comorbidities, on Statin for Secondary Prevention Clinical ASCVD with Comorbidities, on Statin for Secondary Prevention Clinical ASCVD and Baseline LDL 190 not due to Secondary Causes, on Statin for Secondary Prevention Adults 21 years old with LDL-C 190 not due to Secondary Causes, on Statin for Primary Prevention LDL-C 190 with Clinical ASCVD LDL-C 190 with or without Concomitant ASCVD Risk Factors Others (i.e. LDL-C 190 & Pregnancy; Familial Hyperlipidemia in Children/Adolescents, etc.) 28 QUESTION 3 3) If non-statin therapies are added, which agent or therapies should be considered and in what order? 29 NON-STATIN INTERVENTIONS **Referral to lipid specialist and dietitian Ezetimibe (Zetia ) PCSK9 Inhibitors (i.e. Alirocumab, Evolocumab) Phytosterols Soluble/Viscous Fiber Bile Acid Sequestrants (Colesevelam, Colestipol, etc) Mipomersen Lomitapide LDL apheresis 30 10

11 FDA APPROVED PCSK9 INHIBITORS Alirocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial (HeFH) or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. Evolocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous (HeFH) or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. Evolocumab is indicated as an adjunct to diet and other LDL-lowering therapies (e.g., statins, ezetimibe, LDL apheresis) for the treatment of patients with homozygous (HoFH) who require additional lowering of LDL-C. 31 LDL CLEARANCE ON HEPATIC SURFACE Plasma LDL Increased LDL-R surface concentration LDL LDL-R Clathrin vesicle Vesicle Lysosome LDL-R recycling Apo-B Hepatocyte Clathrin-coated vesicle Lysosomal degradation 1. Brown MS, et al. Proc Natl Acad Sci USA. 1979;76: Steinberg D, et al. Proc Natl Acad Sci USA. 2009;106: Brown MS, et al. Science. 1986;232: PCSK9 MECHANISM OF ACTION PCSK9 secretion LDL Decreased surface LDL-R PCSK9 Clathrin vesicle Lysosome Lysosomal degradation LDL-R/PCSK9 routed to lysosome Endosome 1. Horton JD, et al. J Lipid Res. 2009;50:S172-S Qian YW, et al. J Lipid Res. 2007;48: Zhang DW, et al. J Biol Chem. 2007; 282:

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14 40 41 STABLE ASCVD ON STATIN (NO COMORBIDITIES) 42 14

15 CLINICAL ASCVD (LDL 190) ON STATIN 43 SUMMARY OF GUIDELINE UPDATES Ezetimibe is the first non-statin medication that should be considered in most patient scenarios, given its safety and tolerability, as well as demonstrated, though modest, efficacy when added to moderate-dose statin in one trial of patients with acute coronary syndrome. Bile acid sequestrants (BAS) may be considered as second-line therapy for patients in whom ezetimibe is not tolerated, but they should be avoided in patients with triglycerides >300 mg/dl. Alirocumab and Evolocumab : higher-risk patients with clinical ASCVD or familial hypercholesterolemia. Given the lack of long-term safety and efficacy data on these agents, they are not recommended for use in primary prevention patients in the absence of familial hypercholesterolemia. Don t recommend use of niacin given side effects/poor tolerability and data suggesting harm. For patients with HoFH or severe HeFH, referral to a lipid specialist is strongly recommended. Non-statin options include ezetimibe, BAS, PCSK-9 inhibitors with consideration for use of lomitapide, mipomerson, and LDL apheresis as necessary. 44 QUESTION 1 PT is a 59 year old man with a history of IV drug abuse who was found unconscious in the park. There was a bottle of oxycodone pills found immediately next to him. He is discovered to have a pulse but is not visibly breathing. BLS is instituted immediately until EMS arrives on the scene. Which of the following medications is included in the CPR guidelines as a reversal agent in those with known or suspected opioid overdose? A) Lidocaine B) Amiodarone C) Epinephrine D) Naloxone For patients with known or suspected opioid addiction who are unresponsive with no normal breathing but a pulse, it is reasonable for appropriately trained lay rescuers and BLS providers, in addition to providing standard BLS care, to administer intramuscular (IM) or intranasal (IN) naloxone (Class IIa, LOE-C-LD) 45 15

16 QUESTION 2 RS is a 67 year old man with a history of CAD s/p 4V CABG as well as NYHA Class III HFrEF (EF 25-30%) who presents to your clinic. His electrolytes and renal function are within normal limits. He is currently on lisinopril 40mg by mouth daily but is being switched by his cardiologist to Sacubitril/Valsartan. If he takes his lisinopril every morning. When should he take his first dose of Sacubitril/Valsartan? A) He may begin tonight after stopping Lisinopril B) He may begin tomorrow AM after stopping Lisinopril C) He should take it immediately and overlap with 1 dose of Lisinopril D) He should wait until at least tomorrow night after stopping Lisinopril COR LOE Recommendations III: Harm B-R ARNI should not be administered concomitantly with ACE-Is or within 36 hours of the last dose of an ACE-I. 46 QUESTION 3 Which of the following is a potential barrier to use of PCSK9 inhibitors? A) Must be injected everyday B) Lack of clinical outcomes C) Provides modest LDL lowering D) Potential to form drug neutralizing antibodies 47 ACKNOWLEDGEMENTS Salim Virani, M.D., Ph.D. Vijay Nambi, M.D., Ph.D. American College of Cardiology American Heart Association 48 16

17 QUESTIONS? 49 17