Cardiology Updates 2020

Getting to the Heart of It: Cardiology Updates 2020

PATRICK MCCABE, PHARMD, MBA, BCACP ALEX DELUCENAY, PHARMD, BCACP Objectives

▪ Discuss clinical trial outcomes for angiotensin receptor antagonist/neprilysin inhibitor (ARNI) and sodium-glucose co-transporter 2 (SGLT2) inhibitors in heart failure and high-risk cardiac patients. ▪ Effectively utilize ARNI and SGLT2 inhibitors in various case scenarios based on patient specific characteristics. ▪ Explain the role of three pathophysiological pathways in pulmonary arterial hypertension (PAH) and the respective medications which target these pathways. ▪ Develop an effective pharmacotherapy plan for a patient with PAH based on patient specific characteristics. ▪ Discuss clinical trial data that influenced development of the newest hypertension and hyperlipidemia guidelines. ▪ Identify new and emerging therapies in the treatment of hyperlipidemia. Disclosure of Relevant Financial Relationships

▪ Neither speaker has any relevant financial conflicts of interest to disclose

▪ This activity was prepared by the speaker as a subject matter expert. Any opinions expressed are the speaker's own and do not necessarily reflect the views of PSSNY, its employees, staff, officers, Board of Directors or Affiliates Pre-Test Question 1

A 66 YOF with a PMH of HFrEF, HTN, MI (2013), osteoarthritis, and GERD presents for MTM. Meds are:

▪ Lisinopril 20 mg PO daily

▪ Amlodipine 10 mg PO daily

▪ Metoprolol succinate 50 mg PO daily

▪ Atorvastatin 80 mg PO daily

▪ Acetaminophen 500 mg PO Q6-8 hours PRN pain

▪ Famotidine 20 mg PO daily PRN heart burn

BMP is all within normal limits

What changes to her medication regimen would you recommend?

a) Switch from metoprolol succinate to carvedilol 12.5 mg PO BID

b) Switch from lisinopril 20 mg PO daily to sacubitril/valsartan 49/51 mg PO BID

c) Switch from amlodipine 10 mg PO daily to diltiazem ER 120 mg PO daily

d) Increase metoprolol succinate to 100 mg PO daily Pre-Test Question 2

▪ Which medication below is FDA-approved to reduce risk of cardiovascular death and heart failure hospitalization in patients with heart failure with reduced ejection fraction with or without diabetes? a) Liraglutide b) Dapagliflozin c) Canagliflozin d) Empagliflozin e) Ertugliflozin Pre-Test Question 3

▪ A male patient comes into your pharmacy to pick up a new prescription for sildenafil written by his PCP. You review his other medications for drug interactions and find no clinically relevant problems. However, when you review the list with him at counseling, he tells you "I also have a few medications I get through the mail from a specialty pharmacy for high blood pressure in my lungs, but I can never pronounce their names..." ▪ Which of the following PAH medications would have a dangerous drug interaction with his new prescription? a) Riociguat b) Macitentan c) Selexipag d) Treprostinil Pre-Test Question 4

A 63 YOF is checking her BP at your store machine and asks you what her goal BP is. You see her medication list for:

▪ Lisinopril 20 mg PO daily

▪ Amlodipine 5 mg PO daily

▪ Atorvastatin 40 mg PO daily

▪ Aspirin 81 mg PO daily

▪ Clopidogrel 75 mg PO daily

You know your patient well, and know that two years ago she underwent PCI and had a stent inserted. She has been stable since. What BP goal do you tell your patient?

a) 120/80

b) 130/80

c) 140/90

d) 150/90 Pre-Test Question 5

Select all that apply. Which of the following classes of medications have evidence for decreasing mortality? a) Statins (HMG-CoA-reductase inhibitors) b) Fibrates c) Fish Oil d) CETP-2 inhibitors (ezetimibe) e) PCSK-9 inhibitors Heart Failure Updates

SACUBITRIL-VALSARTAN COVID: STAY ON YOUR HF MEDS!

This Photo by Unknown Author is licensed under CC BY-SA https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19 Case

▪ A 55 YOM has PMH significant for HFrEF (EF 35%) for 2 years, Stage C/III who is having shortness of breath with ordinary activities that you notice as he walks up to your pharmacy counter. Using the local RHIO you notice his BMP is within normal limits (including potassium and serum creatinine), and you perform a MTM encounter to improve his morbidity and mortality with HF. ▪ Meds: ▪ Lisinopril 20 mg PO daily ▪ Metoprolol succinate 50 mg PO daily ▪ Aspirin 81 mg PO daily ▪ Rosuvastatin 20 mg PO daily The Not-So-New Kid on the Block…Sacubatril- Valsartan (Entresto®) The Not-So-New Kid on the Block…Sacubitril-Valsartan (Entresto®) – 2017 ACC/AHA Guidelines

Circulation. 2013; 128:e240-e327 The Not-So-New Kid on the Block…Sacubitril-Valsartan (Entresto®) – Brief Review of Current Data

▪ PARADIGM ▪ Enalapril vs LCZ696 (Sacubitril/valsartan)

McMurray JJV, et al. N Engl J Med 2014;371:993-1004. The Not-So-New Kid on the Block…Sacubitril-Valsartan (Entresto®) – Brief Review of Newer Data PROVE-HF Trial

▪ Pat – I can’t find the results of this trial. Do you have it easily? Improvement in NT Pro-BNP

Januzzi JL, et.al. JAMA. 2019;322(11):1085-1095. Improvement in Ejection Fraction

Januzzi JL, et.al. JAMA. 2019;322(11):1085-1095. Case Follow Up

▪ What would you do? ▪ Zoom Polling Question

a) Add Sacubitril/Valsartan 24/26 mg PO daily b) Add spironolactone 25 mg PO daily c) Increase metoprolol succinate to 100 mg PO daily d) Change metoprolol succinate to carvedilol 25 mg PO BID Heart Failure Updates

SGLT2 INHIBITORS Case:

▪ A 50 yoF with history of T2DM, HFrEF, HTN. ▪ Her BP in the pharmacy today is 110/70 mmHg; last A1c was 9.0%; BMI is 33 kg/m2 ▪ She is not experiencing any symptoms of shortness of breath, edema, or fatigue at rest or with activity ▪ Medications: ▪ Atorvastatin 40mg daily ▪ Aspirin 81mg ▪ Carvedilol 25mg twice daily ▪ Entresto 49/51mg twice daily ▪ Furosemide 20mg daily ▪ Metformin 500mg twice daily ▪ Spironolactone 25mg daily The Newer-Kids-On-The-Block: SGLT-2 Inhibitors SGLT2 Inhibitors in DM

▪ A1c lowering: ~0.5 - 1%

▪ Glucose excretion = Weight loss! ▪ ~300-400 Calories/day

▪ Adverse effects ▪ Volume depletion, urinary tract infection, mycotic infections ▪ Fractures, electrolyte disturbances

▪ Warnings/Rare but serious ADRs ▪ "Euglycemic" Ketoacidosis ▪ Fournier's Gangrene? ▪ Amputation? SGLT2 Inhibitors: Beyond Diabetes

Empagliflozin Canagliflozin Dapagliflozin (Jardiance) (Invokana) (Farxiga) Trial EMPA-REG CANVAS DECLARE-TIMI

MACE Composite 14% 14% 7% (NS) % in Endpoint Non-inferior; but did Relative not meet superiority Risk criteria Reduction CV Death 38% 13% (NS) No difference (RRR)

HF Hospitalization 35% 33% 27% Reduction HF Hospitalization or 34% 22% 17% CV death MACE Indication Yes Yes No

Zinman B, et.al. N Engl J Med 2015;373:2117-28. Neal B, et.al. N Engl J Med 2017;377:644-57. Wiviott SD, et.al. N Engl J Med 2019;380:347-57. A Class Effect? The Case of Ertugliflozin

▪ Latest to market Me Too?

▪ Significantly less expensive

▪ VERTIS-CV ▪ Ertugliflozin (Steglatro) Cardiovascular Outcomes trial ▪ Non-inferior, but not superior to placebo ▪ HF hospitalization reduction (not a primary endpoint)

▪ Awaiting full published trial results (June?)

Clinical Endocrinology News. 2020. Lexi-Drugs. In Lexicomp Online [Internet]. Proposed Mechanism for CV risk reduction Side Note: GLP1s

Liraglutide Semaglutide (Ozempic, Dulaglutide Exenatide (Victoza) Rybelsus) (Trulicity) (Byetta, Bydureon)

% in Trial LEADER SUSTAIN PIONEER REWIND EXCSEL Relative Risk MACE Composite 13% 26% ** 21% (NS) 12% 9% Reduction Endpoint Non-inferior (RRR) CV Death 22% No difference 51%* 9% (NS) 12% (NS)

HF Hospitalization 13% (NS) 11% increase 14% (NS) 7% (NS) 6% (NS) Reduction (NS)

Marso SP, et.al. N Engl J Med Marso SP, et.al. N Engl J Med Husain M, et.al. N Engl J Med Gerstein HC, et.al. Lancet Holman RR, et.al. N Engl J Med 2016;375:311-22. 2016;375:1834-44. 2019;381:841-51. 2019; 394: 121–30 2017;377:1228-39. SGLT-2s: Diving Deeper Into Heart Failure DAPA-HF DAPA-HF Study Design

▪ Double-blinded, placebo-controlled, Phase 3 randomized control trial

▪ Primary Outcome: composite of worsening heart failure or death from cardiovascular causes. ▪ Defined as: unplanned hospitalization or an urgent visit for IV therapy

▪ Secondary Outcomes: ▪ Composite of hospitalization for HF or CV death. ▪ Improvement in quality of life questionnaire ▪ Worsening renal function

McMurray JJV, et.al. N Engl J Med 2019; 381:1995-2008 DAPA-HF Inclusion Criteria

Inclusion Exclusion ▪ >18 y.o. ▪ Recent treatment with or intolerant to SGLT2 Patients with or without ▪ EF <40% Type 2 Diabetes▪ Type 1 diabetes ▪ Symptomatic hypotension or SBP ▪ NYHA Class II-IV <95mmHg ▪ GFR <30ml/min/1.73m2 ▪ BNP & Pro-BNP cutoffs

McMurray JJV, et.al. N Engl J Med 2019; 381:1995-2008 Results

Dapagliflozin Group (%) Placebo Group (%) HR (95% CI) N=2373 N=2371 P value

Primary Composite 16.3 21.2 0.74 (0.64-0.85) Outcome <0.001 Death From 9.6 11.5 0.82 (0.69-0.98) Cardiovascular Causes Heart Failure 9.7 13.4 0.70 (0.59-0.83) Hospitalizations

McMurray JJV, et.al. N Engl J Med 2019; 381:1995-2008 Results (con't)

McMurray JJV, et.al. N Engl J Med 2019; 381:1995-2008 Outcomes: Diabetes Status

Petrie MC, et.al. JAMA. 2020;323(14):1353-1368. Adverse Events

Dapagliflozin Placebo Group (%) Group (%) P value N=2373 N=2371

Volume depletion 7.5 6.8 0.4

Renal AE 6.5 7.2 0.36 Fracture 2.1 2.1 1.0

Amputation 0.5 0.5 1.0 Severe Hypoglycemia 0.2 0.2 N/A

Ketoacidosis 0.1 0 N/A

Petrie MC, et.al. JAMA. 2020;323(14):1353-1368. McMurray JJV, et.al. N Engl J Med 2019; 381:1995-2008 Dapagliflozin: New Indication

▪ On May 5th 2020, FDA approved dapagliflozin: ▪ To reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure with reduced ejection fraction (NYHA class II-IV)

▪ Labeled contraindications also updated: ▪ Severe renal impairment (eGFR less than 30mL/min/1.73 m2) in patient who are being treated for glycemic control without established cardiovascular disease or cardiovascular risk factors

FARXIGA (Dapagliflozin) [package insert]. Dapagliflozin and Renal Function

Of note: DAPA-CKD trial recently ended early due to benefit in reducing adverse renal outcomes

FARXIGA (Dapagliflozin) [package insert]. A Class Effect in HF?

▪ Empagliflozin: ▪ EMPERIAL-Reduced & -Preserved ▪ With and without diabetes

▪ Study Outcomes ▪ Primary Outcome: Change in exercise capacity as measured by 6MWD ▪ Secondary Outcomes: Patient Subjective Quality of Life Questionnaires

▪ Results: ▪ No significant differences (results not published yet)

CardiologyToday. 2019. More to Come...

Trial Drug Population Diabetes an Expected Results Inclusion Criteria?

PRESERVED-HF Dapagliflozin HFpEF No 2/2021

DAPA-CKD Dapagliflozin CKD No Soon!

EMPEROR-Reduced Empagliflozin HFrEF No 7/2020

EMPEROR- Empagliflozin HFpEF No 11/2020 Preserved

ClinicalTrials.gov In other HF news...

▪ Pipeline Drugs ▪ VICTORIA-HF

▪ GALACTIC-HF

Teerlink JR, et.al. JACC Heart Fail. 2020 Apr;8(4):329-340. Armstrong PW, et.al. N Engl J Med 2020;382:1883-93. Case Follow-Up: Zoom Polling Question

▪ Which of the following changes would you recommend to optimize this patient's regimen? (Select al that apply) a) Increase sacubitril/valsartan to 97/103mg twice daily b) Start dapagliflozin 10mg daily c) Start liraglutide 0.6mg daily for 1 week, then increase to 1.2mg daily d) Increase metformin to 1000mg twice daily e) Stop furosemide 20mg daily Pulmonary Hypertension Case:

▪ A patient with a history of heart failure with preserved ejection fraction undergoes routine ECHO in the setting of ongoing dyspnea on exertion. Her ECHO reveals EF 60% with moderate pulmonary hypertension. She then undergoes right heart catheterization for diagnosis and categorization of pulmonary hypertension. ▪ Her initial readings are: ▪ MPAP = 29 mmHg ▪ PAWP = 21 mmHg. ▪ PVR = 1.9 Wood units. ▪ She is given a dose of furosemide 80mg IV and after 30 minutes her readings are: ▪ mPAP = 21mmHg ▪ PAWP = 14 mmHg ▪ PVR = 1.9 Wood units What is Pulmonary Hypertension?

▪ High pressure in the lungs ▪ Mean Pulmonary Artery Pressure (mPAP) ≥ 25 mmHg

▪ Pulmonary Artery Wedge Pressure (PAWP) ≤ 15 mmHg ▪ Associated with volume status

▪ Pulmonary Vascular Resistance >3 Wood units

▪ Measured by Right Heart Catheterization Pictures, Please! Symptoms

• Shortness of breath ▪ Fatigue ▪ Lightheadedness ▪ Dry coughing ▪ Swollen ankles or legs ▪ Chest pain ▪ Rapid weight gain ▪ Abdominal bloating So, Is It "PH" or "PAH"?

"PAH"

"PH" Treatment... In General...

Group Description

1 Pulmonary Arterial Hypertension Disease-Specific PAH Medications

2 PH owing to left heart disease Treat Underlying Cause

3 PH owing to lung diseases or hypoxia Treat Underlying Cause

4 Chronic Thromboembolic Pulmonary Hypertension One PAH Medication Currently Indicated 5 PH with unclear multifactorial mechanisms Treat Underlying Cause 3 "Paths" to PH Pathways as Drug Targets Drug Key Points

PDE-5 inhibitors sGC stimulator Endothelin Receptor Prostacyclin Analogs (oral) Antagonist Dosing Sildenafil: 20mg Riociguat: 0.5mg to Ambrisentan: 5 to 10mg Treprostinil: 0.125mg up three times daily 2.5mg three times daily daily to 5mg two to three times daily Tadalafil: 40mg Only medication Bosentan: 62.5 to- daily indicated for Group 4 PH 125mg twice daily Selexipag: 200mcg twice daily up to 1600mg twice Macitentan: 10mg daily daily

Adverse Headache, Headache, Fluid retention/edema, Flushing, Headache Effects flushing, visual dyspepsia/GERD, anemia, flushing; Diarrhea, N/V, Jaw pain, disturbances, hypotension/ dizziness, Hepatotoxicity, Pregana myalgias, hypotension priapism, nausea, N/V, edema, ncy Category X hypotension Preganancy Category X Lexi-Drugs. In Lexicomp Online [Internet]. Treatment Key Points

Klinger JR, et.al. CHEST 2019; 155(3):565-586 What do I need to know?

▪ Only Group 1 pulmonary hypertension is treatment with disease specific therapy

▪ Most are specialty, narrow distribution network meds

▪ ERAs and riociguat have REMS programs due to teratogenic effects

▪ Generic PDE-5s play a role here

▪ Medications are not curative; alleviate symptoms and slow progession

▪ Drug interactions ▪ Many CYP interactions: 3A4, 2C8, 1A1-smoking (riociguat) Case Recap:

▪ She is given a dose of furosemide 80mg IV and after 30 minutes her new values are: ▪ mPAP = 21mmHg ▪ PAWP = 14 mmHg ▪ PVR = 1.9 Wood units ▪ Which of the following disease state specific medication regimens is appropriate for her? a) Tadalafil 40mg daily b) Macitentan 10mg daily c) Tadalafil 40mg + Macitentan 10mg daily d) Treprostinil 10 ng/kg/min IV e) None of the above Updates in Hypertension & Hyperlipidemia Case

▪ A 44 YOM with a history of HTN, dyslipidemia, and MI is having trouble getting his blood pressure goal of 130/80. His BMP is notable for a potassium of 4.9 and a SCr of 1.1 (CrCl 98mL/min). What recommendations do you have?

Meds:

• Hydrochlorothiazide 25 mg PO daily

• Amlodipine 5 mg PO daily

• Metoprolol succinate 25 mg PO daily

• Atorvastatin 40 mg PO daily

• Aspirin 81 mg PO daily

a) Increase hydrochlorothiazide to 50 mg PO daily

b) Change hydrochlorothiazide to chlorthalidone 25 mg PO daily.

c) Change metoprolol to carvedilol 12.5 mg PO BID

d) Add spironolactone 12.5 mg PO daily Case (Part 2)

▪ You see from the RHIO that his lipid panel is: ▪ LDL 155 ▪ HDL 33 ▪ Trig 177

What do you recommend for changes to his medication therapy?

a) Increase atorvastatin to 80 mg PO daily b) Change atorvastatin to rosuvastatin 40 mg PO daily c) Add ezetimibe 10 mg PO daily d) Add insurance-covered PCSK-9 inhibitor therapy The Systolic Blood Pressure Intervention Trial (SPRINT)

Thanks to Kassandra Hizny, PharmD for Wright JT, et al. N Engl J Med. 2015;373(22):2103-16. allowing usage of charts for this trial! The Systolic Blood Pressure Intervention Trial (SPRINT)

▪ Multicenter, randomized, clinical controlled, open label trial with 9361 patients ▪ Intensive: SBP<120 ▪ Standard: SBP <140 ▪ Primary Outcome: Composite of first occurrence of MI, ACS, stroke, HF, CV death ▪ Secondary Outcomes: Individual components of the primary, death form any cause ▪ Prespecified Outcomes of CKD progression or albumineuria Wright JT, et al. N Engl J Med. 2015;373(22):2103-16. The Systolic Blood Pressure Intervention Trial (SPRINT)

INCLUSION EXCLUSION ▪ ≥50 years old ▪ Diabetes, history of stroke ▪ Not on indicated agent ▪ SBP >130-180 mmHg ▪ Known secondary cause of HTN ▪ CVD event within 3 months ▪ Increased cardiovascular risk ▪ Assisted living patients ▪ ESRD, proteinuria, eGFR <20 ▪ Symptomatic HF within 6 months or EF <35%

Wright JT, et al. N Engl J Med. 2015;373(22):2103-16. The Systolic Blood Pressure Intervention Trial (SPRINT)

▪ Baseline characteristics very similar

▪ ~30% of patients in each arm were 75 YO and older ▪ Important when we look at older patient outcomes

▪ 57.7% Caucasian in both arms ▪ ~30% African American ▪ ~10% Hispanic

Wright JT, et al. N Engl J Med. 2015;373(22):2103-16. The Systolic Blood Pressure Intervention Trial (SPRINT)

▪ Medications to be used: ▪ Thiazides first line, then ACE/ARBs, CCBs, beta-blockers with cardiac disease ▪ Note well – chlorthalidone was encouraged ▪ How does this differ from other trials?

▪ Monitoring ▪ Patients seen monthly X 3 months, then every 3 months ▪ Adjusted intensive group monthly ▪ Adjusted standard group to maintain SBP of 135-139

Wright JT, et al. N Engl J Med. 2015;373(22):2103-16. The Systolic Blood Pressure Intervention Trial (SPRINT)

Intensive Treatment Standard Treatment HR (95% CI) Group (%) Group (%) P value N=4678 N=4683 Primary Composite 5.2 6.8 0.75(0.64-0.89) Outcome <0.001 Death From 0.8 1.4 0.57(0.38-0.85) Cardiovascular Causes 0.005 Death From Any Cause 3.3 4.5 0.73(0.60-0.90) 0.003 Heart Failure 1.3 2.1 0.62(0.45-0.84) 0.002

Primary Outcome or 7.1 9.0 0.78(0.67-0.90) Death <0.001

Wright JT, et al. N Engl J Med. 2015;373(22):2103-16. The Systolic Blood Pressure Intervention Trial (SPRINT)

NNT Primary 63 Avg. Meds Avg. BP Composite used (mmHg) Outcome Intensive Death From 2.8 121.5 167 Group Cardiovascular Causes Death From Any 83 Cause Standard 1.8 134.6 Group Heart Failure 125

Primary Outcome 53 or Death The Systolic Blood Pressure Intervention Trial (SPRINT)

Intensive Treatment Standard Treatment HR (95% CI) Group (%) Group (%) P value

≥30% Reduction in 127 (3.8) 37 (1.1) 3.49 (2.44-5.10) eGFR to <60 in <0.001 Patients w/o CKD at Baseline NNH: 37 The ACCORD trial showed no difference though…

▪ Keep in mind that the ACCORD trial was in patients who have diabetes. ▪ ACCORD n = 4733 ▪ SPRINT n = 9361 The ACCORD trial showed no difference though…

J Am Heart Assoc. 2017;6:e007509 Cholesterol Guidelines

2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease Cholesterol Guidelines

J Am Coll Cardiol. 2019 Jun, 73 (24) e28 5-e350. IMPROVE-IT

https://www.nejm.org/d o/10.1056/NEJMdo005 025/full/ PCSK9s: Fourier Trial

Patients already on high- intensity statin

Placebo Evolucumab

2.2 years

N Engl J Med. 2017;376(18):1713‐1722 PCSK9s: Fourier Trial Primary Efficacy Endpoint: Composite of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization

NNT: 74 over 2 years PCSK9s: Fourier Trial Interesting to note…

N Engl J Med. 2017;376(18):1713‐1722 PCSK9s: Odyssey Trial

Patients already on high- intensity statin

Placebo Alirocumab

2.8 years

J Am Coll Cardiol. 2019;73(4):387‐396. PCSK9s: Odyssey Trial

J Am Coll Cardiol. 2019;73(4):387‐396. Vascepa New Indication: REDUCE-IT

▪ Inclusion criteria: ▪ Age >45 years with established CV disease or age >50 years with diabetes and ≥1 additional risk factor

▪ Fasting TG level from 150-499 mg/dl

▪ Low-density lipoprotein (LDL) cholesterol level from 41 and 100 mg/dl

▪ Stable dose of statin for ≥4 weeks Vascepa New Indication: REDUCE-IT Primary Endpoint: composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina

N Engl J Med. 2019;380(1):11‐22. Vascepa New Indication: REDUCE-IT

N Engl J Med. 2019;380(1):11‐22. A "CLEAR" Choice?: Bempedoic Acid

▪ Studied in the "CLEAR" series of trials

CLEAR-Wisdom

Goldberg AC, et.al. JAMA. 2019;322(18):1780-1788. Bempedoic Acid: Caveats

▪ No cardiovascular outcomes; LDL lowering data only

▪ CLEAR OUTCOMES in progress Goldberg AC, et.al. JAMA. 2019;322(18):1780-1788. Case: Zoom Polling Question

Meds:

• Hydrochlorothiazide 25 mg PO daily

• Amlodipine 5 mg PO daily

• Metoprolol succinate 25 mg PO daily

• Atorvastatin 40 mg PO daily

• Aspirin 81 mg PO daily

a) Increase hydrochlorothiazide to 50 mg PO daily

b) Change hydrochlorothiazide to chlorthalidone 25 mg PO daily.

c) Change metoprolol to carvedilol 12.5 mg PO BID

d) Add spironolactone 12.5 mg PO daily Case (Part 2): Zoom Polling Question

▪ You see from the RHIO that his lipid panel is: ▪ LDL 155 ▪ HDL 33 ▪ Trig 177

What do you recommend for changes to his medication therapy?

a) Increase atorvastatin to 80 mg PO daily b) Change atorvastatin to rosuvastatin 40 mg PO daily c) Add ezetimibe 10 mg PO daily d) Add insurance-covered PCSK-9 inhibitor therapy Miscellaneous Updates Brilinta New Indication: THEMIS Primary Endpoint: composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke

Dose: 60mg twice daily added to 81mg aspirin

NNT: 125 at 36 month Steg PG, et.al. N Engl J Med 2019;381:1309-20. Brilinta New Indication: THEMIS

NNH: 83 patient to cause 1 major bleeding event

Steg PG, et.al. N Engl J Med 2019;381:1309-20. Aspirin for Primary Prevention

▪ ASPREE ▪ ARRIVE ▪ Aspirin 100 mg PO daily vs placebo ▪ Aspirin 100 mg PO daily vs placebo ▪ >=70 years old ▪ Men ≥55 with two to four risk factors ▪ African Americans or US Hispanics >= and women ≥60 years of age with 65 years of age three or more risk factors (an ▪ No reduction in CV events estimated 10-year CV risk of about 10% to 20% per the 2013 ACC/AHA ▪ Increased risk of major bleeding (8.6 pooled cohort equations calculator) vs 6.2 events per 1,000 person-years, p<0.001) ▪ NO DIABETES! ▪ Doubled GI bleeding ▪ No benefit in CV events

Clinical Resource, Aspirin for CV Primary Prevention and More. Pharmacist’s Letter/Prescriber’s Letter. November 2018. Aspirin for Primary Prevention

▪ ASCEND ▪ Aspirin 100 mg PO daily vs placebo ▪ WITH DIABETES ▪ Benefit for prevention of serious vascular event (8.5% vs 9.6%, rate ratio 0.88, 95% CI 0.79 to 0.97, p= 0.01, NNT = 91 over 7.4 years to prevent one event). ▪ This benefit was largely offset by bleeding events (NNH = 112 over 7.4 years to cause one major bleeding event).

Clinical Resource, Aspirin for CV Primary Prevention and More. Pharmacist’s Letter/Prescriber’s Letter. November 2018. References

1. FARXIGA (Dapagliflozin) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020.

2. McMurray JJV, Packer M, Desai AS, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.

3. Solomon SD, McMurray JJV, Anand IS, et.al. Angiotensin–Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med 2019; 381:1609-1620

4. Huang C, Dhurva SS, Coppi AC, et al. Systolic Blood Pressure Response in SPRINT (Systolic Blood Pressure Intervention Trial) and ACCORD (Action to Control Cardiovascular Risk in Diabetes): A Possible Explanation for Discordant Trial Results. J Am Heart Assn 2017; 6:e007509

5. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2017;Nov 13.

6. Yancy CW, Jessup M, Biykem B, et al. 2013 ACCF/AHA Guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013; 128:e240-e327

7. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140(11):e596‐e646.

8. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372; 25: 2387-2397

9. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019;380(1):11‐22.

10. Clinical Resource, Aspirin for CV Primary Prevention and More. Pharmacist’s Letter/Prescriber’s Letter. November 2018. References (con't)

11. Steg PG, Bhatt DL, Simon T, et.al. Ticagrelor in Patients with Stable Coronary Disease and Diabetes. N Engl J Med 2019;381:1309-20.

12. Goldberg AC, Leiter LA, Stroes ESG, et.al. Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial. JAMA. 2019;322(18):1780-1788.

13. Zinman B, Wanner C, Lachin JM, et.al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015;373:2117- 28.

14. Neal B, Perkovic V, Mahaffey KW, et.al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 2017;377:644-57.

15. Wiviott SD, Raz I, Bonaca MP, et.al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019;380:347-57.

16. Januzzi JL, Prescott MF, Butler J, et.al. Association of Change in N-Terminal Pro–B-Type Natriuretic Peptide Following Initiation of Sacubitril- Valsartan Treatment With Cardiac Structure and Function in Patients With Heart Failure With Reduced Ejection Fraction. JAMA. 2019;322(11):1085- 1095.

17. Armstrong PW, Pieske K, Anstrom KJ, et.al. Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 2020;382:1883- 93.

18. Teerlink JR, Diaz R, Felker GM, et.al. Omecamtiv Mecarbil in Chronic Heart Failure With Reduced Ejection Fraction: Rationale and Design of GALACTIC-HF. JACC Heart Fail. 2020 Apr;8(4):329-340.

19. Marso SP, Daniels GH, Brown-Frandsen K, et.al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2016;375:311-22.

20. Marso SP, Bain SC, Consoli A, et.al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375:1834- 44. References (con't)

21. Husain M, Birkenfeld AL, Donsmark M, et.al. Oral Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2019;381:841-51.

22. Gerstein HC, Colhoun HM, Dagenais GR, et.al.Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 2019; 394: 121–30

23. Holman RR, Bethel MA, Mentz RJ, et.al. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.N Engl J Med 2017;377:1228-39.

24. McMurray JJV, Solomon SD, Inzucchi SE, et.al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 2019; 381:1995-2008

25. Petrie MC, Verma S, Docherty KF, et.al. Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes. JAMA. 2020;323(14):1353-1368.

26. Lexi-Drugs. [cited 2020 June 11 ] In Lexicomp Online [Internet]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.

27. "SGLT2 inhibitor ertugliflozin shows no CV death or renal benefit". Clinical Endocrinology News. 2020. Available at: https://www.medscape.com/viewarticle/929647

28. "EMPERIAL top-line results: Empagliflozin for HFpEF, HFrEF fails to improve exercise ability". CardiologyToday. 2019. Available at: https://www.boehringer-ingelheim.com/press-release/emperial-heart- failure-toplineresults

29. Klinger JR, Elliot G, Levine DJ, et.al, Therapy for Pulmonary Arterial Hypertension in Adults: Update of the CHEST Guideline and Expert Panel Report. CHEST 2019; 155(3):565-586

30. Huang C, Dhurva SS, Coppi AC, et al. Systolic Blood Pressure Response in SPRINT (Systolic Blood Pressure Intervention Trial) and ACCORD (Action to Control Cardiovascular Risk in Diabetes): A Possible Explanation for Discordant Trial Results. J Am Heart Assn 2017; 6:e007509

31. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713‐1722.

32. Szarek M, White HD, Schwartz GG, et al. Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events: The ODYSSEY OUTCOMES Trial. J Am Coll Cardiol. 2019;73(4):387‐396. Post-Test Question 1

A 66 YOF with a PMH of HFrEF, HTN, MI (2013), osteoarthritis, and GERD presents for MTM. Meds are:

▪ Lisinopril 20 mg PO daily

▪ Amlodipine 10 mg PO daily

▪ Metoprolol succinate 50 mg PO daily

▪ Atorvastatin 80 mg PO daily

▪ Acetaminophen 500 mg PO Q6-8 hours PRN pain

▪ Famotidine 20 mg PO daily PRN heart burn

BMP is all within normal limits

What changes to her medication regimen would you recommend?

a) Switch from metoprolol succinate to carvedilol 12.5 mg PO BID

b) Switch from lisionpril 20 mg PO daily to sacubatril/valsartan 49/51 mg PO BID

c) Switch from amlodipine 10 mg PO daily to diltiazem ER 120 mg PO daily

d) Increase metoprolol succinate to 100 mg PO dailly Post-Test Question 2

A 63 YOF is checking her BP at your store machine and asks you what her goal BP is. You see her medication list for:

▪ Lisinopril 20 mg PO daily

▪ Amlodipine 5 mg PO daily

▪ Atorvastatin 40 mg PO daily

▪ Aspirin 81 mg PO daily

▪ Clopidogrel 75 mg PO daily

You know your patient well, and know that two years ago she underwent PCI and had a stent inserted. She has been stable since. What BP goal do you tell your patient?

a) 120/80

b) 130/80

c) 140/90

d) 150/90 Post-Test Question 5

Select all that apply. Which of the following classes of medicaitons have evidence for decreasing mortality? a) Statins (HMG-CoA-reductase inhibitors) b) Fibrates c) Fish Oil d) CETP-2 inhibitors (ezetibimide) e) PCSK-9 inhibitors