Disclosures. Objectives 9/14/2017. I have nothing to disclose. Update in Cardiovascular Pharmacotherapy

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1 Update in Cardiovascular Pharmacotherapy Dave L. Dixon, PharmD, BCACP, CDE, CLS, FCCP, FNLA, FACC Vice Chair for Clinical Services and Associate Professor Department of Pharmacotherapy & Outcomes Science Office: (804) Disclosures I have nothing to disclose. Objectives Discuss the role of PCSK9 inhibitors in the prevention of cardiovascular events. Summarize key updates in the management of hypertension and chronic heart failure. Evaluate the role of newer anti hyperglycemic therapies in the management of cardiovascular disease in patients with diabetes. 1

2 Based on data only from RCTs and meta analyses Shifted to a risk based approach and use of select statin intensities to achieve a desired % reduction in LDL C Recommended a new ASCVD risk estimator in place of Framingham Made no recommendation for or against LDL C or non HDL C goals Continued to recommend routine lipid profile monitoring Non statins de emphasized, mostly due to the lack of clinical data supporting their use in combination with statin therapy Lloyd Jones DM, et al. J Am Coll Cardiol 2017; DOI: /j.jacc Lloyd Jones DM, et al. J Am Coll Cardiol 2017; DOI: /j.jacc

3 Summary of Non Statin Recommendations Clinical ASCVD ( ) comorbidities Clinical ASCVD (+) comorbidities and/or baseline LDL C > 190 Baseline LDL C > 190 without ASCVD Diabetes b ( ) comorbidities LDL C <70 Non HDL C <100 LDL C <70 Non HDL C <100 LDL C <100 Non HDL C <130 LDL C <100 Non HDL C <130 1 st line: Ezetimibe a 2 nd line: PCSK9 inhibitor 1 st line: Ezetimibe a OR PCSK9 inhibitor 1 st line: Ezetimibe a a Bile acid sequestrants may be use in place of ezetimibe if TG <300 b Role of PCSK9 inhibitors have not been evaluated for primary prevention use in the diabetes population Lloyd Jones DM, et al. J Am Coll Cardiol 2017; DOI: /j.jacc Comorbidities Defined Recent (< 3 months) ASCVD event while taking a statin Poorly controlled major ASCVD risk factors Elevated Lp(a) Chronic kidney disease Symptomatic heart failure Maintenance hemodialysis Diabetes Age >65 years Current daily cigarette smoking Symptomatic PAD with prior history of MI or stroke HDL C <40 (men) or <50 (women) hs CRP > 2mg/L Metabolic syndrome Lloyd Jones DM, et al. J Am Coll Cardiol 2017; DOI: /j.jacc IMPROVE IT Trial Ezetimibe/Simvastatin vs. Placebo/Simvastatin 18,144 patients stabilized <10 days post ACS Mean age at baseline was 64 years Baseline LDL C at time of ACS event was 95 mg/dl Primary composite endpoint: CV death, MI, hospital admission for UA, revascularization, or stroke. Group Ezetimibe/Simva Placebo/Simva Achieved LDL C 53.2 mg/dl 69.9 mg/dl Cannon CP, et al. N Engl J Med 2015;372:

4 IMPROVE IT: Individual CV Endpoints and CVD/MI/Stroke *7 year event rates (%) Risk ratio & 95% CI EZ/Simva* Simva* HR p value All cause death Cardiovascular disease Coronary heart disease Myocardial Infarction Stroke Ischemic Stroke Revascularization Unstable angina CVD/MI/Stroke EZ/Simva better Simva better Cannon CP, et al. N Engl J Med 2015;372: IMPROVE IT: Key Subgroup and Safety Findings Patients >75 years of age (n=2798) experienced a 8.9% lower event rate in the EZ/Simva group compared to placebo/simva group (p=0.005) Patients with diabetes experienced a 5.5% lower event rate in the EZ/simva group compared to placebo/simva group (p=0.023) No significant difference in cancer or muscle or gallbladder related adverse events Cannon CP, et al. N Engl J Med 2015;372: Progression of PCSK9 from discovery to clinical use 2013 Phase 3 data published 2017 FOURIER? 2003 PCSK9 discovery 2006 Human target validation 2015 FDA approval for alirocumab & evolocumab 4

5 Model of PCSK9 LDL R Activity Endosome Endosome Lysosomes LDL receptor LDL PCSK9 mab Trial Design 27,564 high risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) Screening, Lipid Stabilization, and Placebo Run in High or moderate intensity statin therapy (± ezetimibe) LDL C 70 mg/dl or non HDL C 100 mg/dl Evolocumab SC 140 mg Q2W or 420 mg QM RANDOMIZED DOUBLE BLIND Placebo SC Q2W or QM Follow-up Q 12 weeks Sabatine MS et al. Am Heart J 2016;173: Baseline Characteristics Characteristic Value Age, years, mean (SD) 63 (9) Male sex (%) 75 Type of CVD (%) Myocardial infarction 81 Stroke (non hemorrhagic) 19 Symptomatic PAD 13 Cardiovascular risk factor (%) Hypertension 80 Diabetes mellitus 37 Current cigarette use 28 Characteristic Value Statin use (%)* High intensity 69 Moderate intensity 30 Ezetimibe use (%) 5 Median lipid measures (IQR) mg/dl LDL C 92 (80 109) Total cholesterol 168 ( ) HDL C 44 (37 53) Triglycerides 133 ( ) Pooled data; no differences between treatment arms Sabatine MS, et al. N Engl J Med. 2017;376:

6 Sabatine MS, et al. N Engl J Med. 2017;376: Sabatine MS, et al. N Engl J Med. 2017;376: Types of CV Outcomes Endpoint Evolocumab (N=13,784) Placebo (N=13,780) 3 yr Kaplan Meier rate HR (95% CI) CV death, MI, or stroke ( ) Cardiovascular death ( ) Death due to acute MI ( ) Death due to stroke ( ) Other CV death ( ) MI ( ) Stroke ( ) Sabatine MS, et al. N Engl J Med. 2017;376:

7 Documentation tips to improve PCSK9 inhibitor access Indication and documentation of medical conditions Statin use history Failure to achieve LDL C goal despite maximally tolerated statin therapy Use of adjunctive lipid lowering therapies A recent lipid panel (<30 days old) MB is a 54 yo AAF with a PMH of 3 vessel CABG (2011) and HeFH presents for f/u. Two months prior, she was started on on rosuvastatin 10 mg/d, for which she is tolerating but she remains concerned about SE. Previously, she has not tolerated atorvastatin or pravastatin, and has failed cholestyramine, niacin, and ezetimibe in the past (poor efficacy). Mother age 54 (CHD), sister age 44 (stroke), and another sister had a CABG at age 40 Baseline Rosuvastatin 10mg Rosuvastatin + Evolocumab TC 547 mg/dl 277 mg/dl 117 mg/dl LDL C 448 mg/dl 201 mg/dl 61 mg/dl Omega 3 Fatty Acids: Ongoing Trials REDUCE IT (N=8,000) STRENGTH (N=13,000) Patients Mixed dyslipidemia on statin therapy ASCVD Risk High (CHD or DM + additional risk factors) TG Level 200 to <500 mg/dl 180 to <500 mg/dl Intervention icosapent ethyl omega 3 carboxylic acids Primary Endpoint Major adverse cardiovascular outcomes (MACE) Timeline Vascepa = icosapent ethyl Epanova = omega 3 carboxylic acids accessed 7/5/16. accessed 7/5/16. 7

8 2017 Focused Update of the 2013 Guideline for the Management of Heart Failure 1) Recommendation: In patients at increased risk of developing HF (Stage A), the optimal BP in those with HTN should be <130/80 mmhg (Class I) 2) Recommendation: In patients with HF (regardless of EF) and hypertension, guideline directed medical therapy should be titrated to achieve a SBP <130 mmhg (Class I) J Am Coll Cardiol [published online ahead of print]. Doi: /j.jacc SPRINT: SBP <120 vs. <140 mmhg Outcome SBP <120 # pts (%) SBP <140 # pts (%) Hazard Ratio P Value Primary 243 (5.2%) 319 (6.8%) 0.75 < Secondary MI ACS Stroke Heart failure CVD death Any death 97 (2.1) 40 (0.9) 62 (1.3) 62 (1.3) 37 (0.8) 155 (3.3) 116 (2.5) 40 (0.9) 70 (1.5) 100 (2.1) 65 (1.4) 210 (4.5) Ref: N Engl J Med. 2015;373: ACS=acute coronary syndrome; NNT=number needed to treat NNT N Engl J Med. 2015;373: SPRINT: Important caveats Excluded patients with diabetes Used a very specific method for measuring BP Stopped early, which may have led to overestimation of effect Patients >75 yo derived more benefit than those <75 yo Low use of ASA and statins More adverse events in the intensive treatment group Hypotension, syncope, electrolyte abnormality, acute kidney injury, orthostasis Overall number needed to harm = 45 N Engl J Med. 2015;373:

9 Medical Therapy for Stage C HFrEF: Magnitude of Benefit Demonstrated in RCTs GDMT RR Reduction in Mortality (%) NNT for Mortality Reduction RR Reduction in Hospitalizations (%) Diuretics??? ACE I or ARB ARNI Beta blocker Aldosterone antagonist Hydralazine/nitrate Ivabradine 26 GDMT=guideline directed medical therapy; RR=relative risk; NNT=number needed to treat; ARNI=angiotensin receptor neprilysin inhibitor Natriuretic Peptide System Renin Angiotensin Aldosterone System pro BNP NT pro BNP BNP Neprilysin Sacubitril LCZ696 Angiotensinogen Angiotensin I Inactive fragments Valsartan Angiotensin II Angiotensin I Receptor Renin Angiotensin System Inhibition With Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blocker or ARNI: Recommendations Recommendations for Renin-Angiotensin System Inhibition With ACE Inhibitor or ARB or ARNI COR LOE Recommendations Comment/Rationale I I ACE-I: A ARB: A ARNI: B-R ARNI: B-R The clinical strategy of inhibition of the reninangiotensin system with ACE inhibitors (Level of Evidence: A) ( ), OR ARBs (Level of Evidence: A) ( ), OR ARNI (Level of Evidence: B-R) (138) in conjunction with evidencebased beta blockers (9, 139, 140), and aldosterone antagonists in selected patients (141, 142), is recommended for patients with chronic HFrEF to reduce morbidity and mortality. In patients with chronic symptomatic 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 (138). NEW: New clinical trial data prompted clarification and important updates. NEW: New clinical trial data necessitated this recommendation. J Am Coll Cardiol [published online ahead of print]. Doi: /j.jacc

10 Step 1 Assess volume Initiate GDMT Step 2 Consider the following scenarios Step 3 Implement indicated GDMT Step 4 Reassess symptoms HFrEF NYHA FC I IV Stage C ACEI or ARB AND beta blocker Diuretics PRN NYHA Class II IV CrCl >30 and K <5 NYHA Class II III Adequate BP, tolerating ACEI or ARB NYHA Class III IV In African Americans NYHA Class II III, NSR, HR >70, on max tolerated beta blocker Aldosterone antagonist D/C ACEI or ARB Initiate ARNI ISDN/hydralazine Ivabradine Stage D/Refractory: Palliative care Transplant LVAD Clinical trials J Am Coll Cardiol Doi: /j.jacc Cardiovascular safety of anti hyperglycemic therapies: How did we get here? 2007 Meta analysis published in NEJM showed rosiglitazone was associated with a 43% increased risk of MI FDA published guidance for industry requiring them to conduct studies to assess cardiovascular safety of novel therapies. FDA placed restrictions on rosiglitazone prescribing RECORD trial showed no increase in risk of MI 2013 FDA lifted restrictions on rosiglitazone prescribing WARNINGS SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term, prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes, 19 supp. 2: , 1970). UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2-1/2 times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in overall mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of AMARYL (glimepiride tablets) and of alternative modes of therapy. Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure. 10

11 Cardiovascular outcome trials (CVOT) Anti hyperglycemic therapies Schernthaner G et al. Therapeutics and Clinical Risk Management 2017: Cardiovascular Safety of Anti hyperglycemic Therapies BENEFIT NEUTRAL POSSIBLE HARM Canagliflozin (CANVAS) Lixisenatide 14% reduction in CV death, nonfatal MI/stroke (ELIXA) 33% reduction in HF related hospitalizations Empagliflozin (EMPA REG OUTCOME) Reduced CV and all cause mortality Reduced nonfatal MI/stroke 35% reduction in HF related hospitalizations Liraglutide (LEADER) Reduced CV mortality, nonfatal MI/stroke No effect on HF hospitalizations Pioglitazone (IRIS) Reduced nonfatal and fatal stroke and MI Reduced ACS in insulin resistant patients w/o diabetes Sitagliptin (TECOS) Saxagliptin (SAVOR TIMI) 27% increased risk of HF hospitalization (NNH = 143) Alogliptin (EXAMINE) 19% increased risk of HF hospitalization (NNH=166) Diabetes Care 2017;40(Suppl. 1):S64 S74 11

12 SGLT2 Inhibitor Mechanism of Action 125 SGLT2 Inhibitors Lower Renal Threshold for Glucose Excretion Urinary Glucose Excretion, g/d T2DM + SGLT2i Healthy 180 mg/dl SGLT2 Inhibition T2DM 240 mg/dl Plasma Glucose, mg/dl Endocr Pract. 2008;14: J ClinEndocrinol. 2010;95:34 42 Warning/Precaution Empagliflozin Canagliflozin Dapagliflozin Hypotension Ketoacidosis AKI and renal impairment Urosepsis/pyelonephritis Hypoglycemia a Genital mycotic infections IncreasedLDL C (3 8%) Bone fractures b Amputations c Bladder cancer d a May consider reducing dose of insulin or insulin secretagogue b Mostly fractures of the upper extremities due to low trauma c Black box warning mostly toe/mid-foot; absolute risk is small d Avoid in patients with active, or a history of, bladder cancer Invokana (canagliflozin). Package Insert. Jardiance (empagliflozin). Package Insert. Farxiga (dapagliflozin). Package Insert. 12

13 SGLT2 Inhibitors and Patient Selection Strongly consider Use with caution AVOID Type 2 DM + CVD and/or HF Hypertensive Overweight/ obese Poorly controlled HbA1c (> 9%) Type 1 diabetes History of mycotic infections Active mycotic infection Patients on diuretics Severe renal impairment Mild-moderate renal impairment (egfr <30, on dialysis) (egfr 30-60)* Severe hepatic Normal or low blood pressure impairment (not studied) Patients at high risk of falls Patients at high risk of fractures Patients at high risk for lower limb amputations (CANA only) *CANA and EMPA=do not initiate if egfr <45; DAPA=do not initiate if egfr <60 SGLT2 Inhibitor Use in Patients with HF Cherney DZ et at. Circulation 2016;134: Effects of GLP 1 Receptor Agonists 13

14 GLP1 Agonists and Patient Selection Strongly consider Use with caution AVOID Type 2 DM + CVD and/or HF Requiring mealtime coverage At high risk of hypoglycemia Overweight/obese In combination with Type 1 diabetes sulfonylureas History of pancreatitis In combination with insulin History of medullary Mild-moderate hepatic thyroid carcinoma impairment Severe hepatic Patient concerns over using impairment an injectable agent Take Home Points 1. Consider ezetimibe and PCSK9 inhibitors in high risk patients not meeting treatment goals (on maximally tolerated statin) to further reduce risk for cardiovascular events. 2. Consider sacubitril/valsartan in patients on stable doses of ACE I or ARB to further reduce mortality and risk of HF related hospitalizations. 3. Consider empagliflozin and liraglutide in patients with diabetes and cardiovascular disease (especially heart failure) to reduce mortality and risk of HF related hospitalizations. 14

15 New hypertension guidelines expected Fall 2017 New cholesterol guidelines expected in