Updates in Cardiology: An Interactive Approach

Antoine T. Jenkins, Pharm.D., BCPSClinical Associate Professor

Chicago State University---College of PharmacyInternal Medicine Clinical Pharmacist

Ingalls Memorial Hospital

Disclosure and Conflict of Interest

I, Antoine T. Jenkins, declares no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria.

Presentation Objectives

At the conclusion of this program, attendees will be able to:

1) Compare and contrast former vs. current practice recommendations involving the management of hypertension, dyslipidemia, chronic heart failure, and atherosclerotic disease.

2) Discuss recent clinical trials related to the above stated disease states.

3) Discuss novel medications (if available) involving the management of the above stated disease states.

4) Evaluate the applicability of updated recommendations/new drugs in the day-to-day management of the above stated disease states

Hypertension Updates

List of Abbreviations

• Medical Organization Listing– JNC= Joint National Committee

– ISHIB= International Society of Hypertension in Blacks

– ACC/AHA= American College of Cardiology/American Heart Association

– ASH/ISH= American Society of Hypertension/International Society of Hypertension

– ESH/ESC= European Society Hypertension/European Society of Cardiology

– CHEP= Canadian Hypertension Education Program

Pre-Test Question #1

Which landmark trial demonstrated reductions in CV events and all-cause mortality with intensive blood pressure control (compared to conservative blood pressure control) in a population of patients aged ≥ 50 years with at least one CV risk factor or renal disease?

A) SPIRIT trial

B) HYVET study

C) ACCORD—BP trial

D) HOPE-3 study

Meet Mr. Hye BP

A 70-year-old black male presents to

clinic for a blood pressure recheck.

During his annual physical

exam 3 months ago, his blood

pressure (BP) was elevated 155/90 mm

Hg. PMH remarkable for gout,

glaucoma, and GERD. He has been

attempting to lower the sodium in

his diet and to increase exercise.

Today, his blood pressure is 154/86

mmHg, similar upon repeat, and his

heart rate is 75 bpm. Electrolytes

and renal function are WNL. FLP

shows TC 160 mg/dL , LDL 80 mg/dL,

TG 150 mg/dL, HDL 45 mg/dL.

Which BP goal would be the most suitable for Mr. Hye BP?

A) < 150/90 mm Hg

B) < 135/85 mm Hg

C) <140/90 mm Hg

D) SBP < 120 mm Hg

Hypertension…Quick Facts

• Well known risk factor for the development of CV disease and stroke.

• In 2000, an estimated that > 970 million individuals globally have hypertension (HTN).

• The prevalence of HTN increases with age, with 64.9% among those aged 60 and over.

• Multiple stakeholders have voiced commentary regarding suitable BP goals.

Lancet. 2005;365:217–223.http://www.cdc.gov/nchs/datadatabriefs/db200.htm. Accessed Jun 14, 2016.

Comparison of BP Goals Across Guidelines

Guideline Comparison of Blood Pressure Goals (BP in mmHg)

Organization Uncomplicated HTN Older Adults

2003 JNC 7 <140/90 No recommendation

2010 ISHIB <135/85 or <130/80 No recommendation

2011 ACC/AHA Expert Consensus

<140/90 (ages 55-79) SBP 140-145 if tolerable ages ≥ 80 yrs. SBP ≥ 150 acceptable for some.

2013 ASH/ISH <140/90 <150/90 ages ≥ 80 yrs

2014 JNC 8 <140/90 <150/90 ages ≥ 60 yrs

2013 ESH/ESC <140/90 <150/90 ages ≥ 80 yrs

2013 CHEP

Hypertension 2003;42:1206-52.Hypertension. 2010;56:780-800.Circulation. 2011;123:2434-2506J Clin Hypertens 2014;16:14-26.

JAMA 2014;311:507-20.J Hypertens 2013;31:1281-357.Can J Cardiol 2013;29:528-42.

Hypertension Updates—Recent Clinical Data

SPRINT (Systolic Blood Pressure Intervention Trial)

9361 individuals ≥ 50 yrs with at least one CV risk factor (excluding diabetes) or renal disease

4678 patientsIntensive BP goal

(SBP < 120 mmHg)

4673 patientsStandard BP goal

(SBP < 140 mmHg)

Primary Endpoints: Myocardial infarction (MI), acute coronary syndrome (not resulting in MI), stroke, heart

failure, mortality from cardiovascular causes

N Engl J Med 2015;373;2103-16.

Hypertension Updates—SPRINT

SPRINT ResultsEndpoints Intensive Treatment Standard Treatment Hazard Ratio (95% CI)

[p-value]

Primary Outcome 5.2% 6.8% 0.75 (0.64–0.89)[p<0.001]

Heart Failure 1.3% 2.1% 0.62 (0.45–0.84) [p=0.002]

Mortality from CV causes

0.8% 1.4% 0.57 (0.38–0.85) [p=0.005]

Mortality from all causes

3.3% 4.5% 0.73 (0.60–0.90) [p=0.003]

N Engl J Med 2015;373;2103-16.

Hypertension Updates—SPRINT

SPRINT Results (Safety)Adverse Effects Intensive Treatment Standard Treatment p-value

Hypotension 2.4% 1.4% 0.001

Electrolyteabnormalities

3.1% 2.3% 0.02

Acute renal failure 4.1% 2.5% <0.001

Fall risk 2.2% 2.3% 0.71

N Engl J Med 2015;373;2103-16.

Hypertension Updates—ACCORD-BP vs SPRINT

Comparison of ACCORD-BP and SPRINT Studies

Characteristic ACCORD-BP(n=4733)

SPRINT(n=9361)

Patients All with DM either with CV disease or had at least 2 risk factors for CV disease.(mean BP: 139/76 mmHg)

SBP ≥ 130 mmHg plus one CV risk factor or renal disease (no DM). (mean BP: 139/78 mmHg)

PrimaryEndpoints

Composite of nonfatal stroke,MI, death from CV causes

MI, ACS (not resulting in MI), stroke, HF, mortality from CV causes

Mean BP afterfirst year

Intensive group: 119/64 mmHgStandard group: 134/71 mmHg

Intensive group: 121/68 mmHgStandard group: 136/76 mmHg

Results No difference in annual rate between groups: 1.87% vs. 2.09%. (HR 0.88; 0.73-1.06; p = 0.20).

Significantly lower annual rate noted in intensive group vs. standard 1.65% vs. 2.19%; HR 0.75; CI, 0.64–0.89; p<0.001).

N Engl J Med 2010;362:1575-85.N Engl J Med 2015;373;2103-16.

BP=Blood Pressure DM=Diabetes mellitusCV=Cardiovascular HF= Heart Failure MI=Myocardial InfarctionACS=Acute Coronary Syndrome

Hypertension Updates—ACCORD-BP vs. SPRINT

• ACCORD-BP vs. SPRINT– Other Similarities

• ACCORD– Significant improvement noted in some of the individual

components

» All strokes: 0.32% vs 0.53% (HR 0.59; 0.39–0.89; p=0.01)

– Other Differences• SPRINT

– Greater statistical power

– Greater number of endpoints within the primary outcome that were more receptive to BP reduction

N Engl J Med 2010;362:1575-85.N Engl J Med 2015;373;2103-16.

Hypertension Updates: Applying Literature to Real World Practice

Factors in Determining Blood Pressure Goals for Daily Practice

Aggressive Goals(<135/85 mmHg, <130/80

mmHg, or SBP <120 mmHg)

Standard Goal(<140/90 mmHg)

Conservative Goals(SBP 140-145 mmHg,<150/90 mmHg, or SBP ≥ 150 mmHg)

*Younger Patients (age <65 years old)

*Minimal comorbidities

*African-American patients

*Presence of renal disease with proteinuria or CVD

* Older patients (age ≥ 65 yrs old) who demonstrates tolerability

*Most healthy patients

*Diabetics

*Older individuals (age ≥ 65 years old)

*Multiple comorbidities (frailty, orthostasis)

*Limited life expectancy

*High sensitivity to adverse effects from antihypertensive agents

*Any individual who demonstrates intolerability to intensive treatment

Back to Mr. Hye BP…

Which BP goal would be the most suitable for Mr. Hye BP?

A) < 150/90 mm Hg

B) < 135/85 mm Hg

C) <140/90 mm Hg

D) SBP < 120 mm Hg

Individualize approach to BP management:

**Thoroughly evaluate yourpatient

**Shared decision making

**May go from a conservative to an aggressive BP goal ifsafe

**BP goals may change over time

Post-Test Question #1

Which landmark trial demonstrated reductions in CV events and all-cause mortality with intensive blood pressure control (compared to conservative blood pressure control) in a population of patients aged ≥ 50 years with at least one CV risk factor or renal disease?

A) SPIRIT trial

B) HYVET study

C) ACCORD—BP trial

D) HOPE-3

Dyslipidemia Updates

List of Abbreviations

• Medical Organization List– ACC/AHA= American College of Cardiology/American

Heart Association

– IAS= International Atherosclerosis Society

– NLA= National Lipid Association

– AACE= American Association of Clinical Endocrinologists

– KDIGO= Kidney Disease Improving Global Outcomes

– VA/DoD= Veteran Affairs/Department of Defense

– ADA= American Diabetes Association

Pre-Test Question #2

Which patient would be the best candidate for evolocumab?

A) 55 year-old female with stage 3 chronic kidney disease, premature family history of MI, and current smoker, LDL 125 mg/ dL, receiving atorvastatin 80mg daily.

B) 24-year-old woman with polycystic ovarian syndrome with an LDL 195 mg/dL. She doesn’t wish to take a statin because she heard on the news that they can cause diabetes.

C) 64-year-old male with DM and h/o NSTEMI 2 years ago, LDL 140 mg/dL, receiving high-intensity statin therapy plus ezetimibe. He is compliant with all of his medications

D) 45-year-old male with homozygous familial hypercholesterolemia, LDL 350 mg/dL, receiving a low dose statin and cholestyramine.

Meet Mrs. LD Long…

RW is a 55-year-old white female who presents to the emergency room with chest pain indicative of angina. PMH: HTN. Home meds include lisinopril 10mg daily. FLP reveals TC 275 mg/dL, HDL 31 mg/dL, LDL 126 mg/dL, and TG 590 mg/dL. Her BP is 166/90 mm Hg. Based on EKG findings, RW is given a diagnosis of NSTEMI. Catheterization shows 80% occlusion in the proximal left anterior descending artery.

Which option would be the best for managing her dyslipidemia?A) Add niacin since it has

positively affects all components of the lipid profile

B) Add atorvastatin 80 mg daily

C) Add simvastatin 40mg plus ezetimibe

D) Add alirocumab 75 mg SubQ q 2 wks

Dyslipidemia: Quick Facts

• Well known risk factor for the development of CV disease and stroke.

• Per 2013 blood cholesterol management guidelines, 1 in every 3 Americans would be deemed eligible for statin therapy.

• Multiple stakeholders have voiced commentary regarding suitable BP goals.

Lancet. 2013;382:1762–65.

Dyslipidemia Updates: Comparison of Treatment Goals

Guideline Comparison of Lipid Goals (lipid components in mg/dL)

Lipid Management Organizations Other Organizations

2013 ACC/AHA Abolished LDL and non-HDLnumeric treatment goals

2012 AACE

LDL < 100 for—high risk. LDL < 70 very high risk. Non-HDL goal 30 higher than LDL.

2013 IAS Defines optimal levels: LDL < 100 and non-HDL < 130 (LDL < 70 and non-HDL < 100 for secondary prevention)

2013 KDIGO

Abolished LDL and non-HDLnumeric treatment goals

2014 NLA--Part I

2015 NLA--Part II

LDL goal < 100—high risk. LDL goal < 70—very high risk. Non-HDL goal 30 mg/dL higher than LDL.

2015 VA/DoD

2016 ADA

2016 ACC ExpertConsensusDocument

LDL reduction “thresholds” for statin compliant patients.(Endorses 2013 ACC/AHA)

Circulation. 2014;129[suppl 2]:S1-S45.http://www.athero.org. Accessed Oct 19, 2013.J Clin Lipidol 2014 (8), 473-88. J Am Coll Cardiol 2016, doi: 10.1016/j.jacc.2016.03.519

Endocr Pract 2012;18(1),1-78.http://www.kidney-international.org. Accessed Dec 13, 2013.Ann Intern Med. 2015;163:291-297.Diabetes Care 2016;39(Suppl. 1):S1–S112.

Dyslipidemia Updates: The Role of Non-Statins

2013 ACC/AHA

• Recommends against the use on non-statins due to no demonstrable net benefit

2014/

2015

NLA

• Advocates for the potential utility of non-statins if required to achieve LDL goals

• States that non-statin agents should be added in a particular order.

2016

ACC

• Advocates for intensifying statins and lifestyle modifications first

• States that non-statin agents should be added in a particular order.

Circulation. 2014;129[suppl 2]:S1-S45.J Clin Lipidol 2014 (8), 473-88.J Am Coll Cardiol 2016, doi: 10.1016/j.jacc.2016.03.519.

Dyslipidemia Updates: The Role of Non-Statins

Proposed Order of Adding Non-Statins for Appropriate Patients

NLA

1) Ezetimibe2) Colesevelam3) Extended-

release niacin

ACC

1) Ezetimibe. May use a BAS (if ezetimibe intolerant and TG<300mg/dL

2) PCSK9-inhibitors (for select patients only)

3) Niacin not recommended

BAS= Bile acid sequestrantPCSK9= Proprotein Convertase Subtilisin-Kexin Type 9

J Clin Lipidol 2014 (8), 473-88.J Am Coll Cardiol 2016, doi: 10.1016/j.jacc.2016.03.519.

PCSK-9 Inhibition: Novel Method of LDL Lowering

• Proprotein convertases– Family of serine

proteinases (PC1/3, PC2, furin, PC4, PC5/6, PACE4, PC7, SKI-1/S1P).

– Typically synthesized as zymogens and become active once inside a cell.

– Some are ubiquitous, while others are localized to specific locations.

• Proprotein Convertase Subtilisin-Kexin Type 9(PCSK9)– Liver, intestine, kidney,

and CNS

– Regulates plasma LDL levels through increased degradation of LDL receptor proteins

N Engl J Med 2011;365:2507-18.

PCSK-9 Inhibition: Novel Method of LDL Lowering

http://caltagmedsystems.blogspot.com/2014/09/pcsk9-target-for-next-blockbuster-drug_44.html. Accessed Jun 20, 2016.

PCSK-9 Inhibition: Novel Method of LDL Lowering

Currently Available PCSK-9 Inhibitors

Alirocumab (Praluent™) Evolocumab (Repatha™)

FDA approvedindications

Both agents: Adjunct to diet and maximally tolerated statin for the treatment of heterozygous familial hypercholesterolemia or clinical ASCVD for patients who require additional LDL lowering.Evolocumab: Above indications plus homozygous familial hypercholesterolemia (HoHC), along with statins, ezetimibe, etc.

Dose 75 mg SubQ q 2 weeks; may increase to 150 mg SubQ q 2 weeks if an adequate response is not achieved within 4-8 weeks.

140 mg SubQ q 2 weeks or 420 mg SubQ q month.

HoHC: 420 mg SubQ q month.

Storage Do not keep at room temp for >24 hrs Can store at room temp if used within 30 days

Administration Allow to warm to room temp for 30 mins. Then, inject into thigh (stretch), abdomen, or upper arm (pinch). Rotate sites.

Cost $14,600/year (alirocumab), $14,000/year (evolocumab)

ASCVD=Atherosclerotic cardiovascular disease

http://www.medscape.com/viewarticle/850715. Accessed Jun 21, 2016.http://pi.amgen.com/united_states/repatha/repatha_pi_hcp_english.pdf. Accessed Jun 21, 2016.http://products.sanofi.us/praluent/praluent.pdf. Accessed Jun 21, 2016.

PCSK-9 Inhibition: Novel Method of LDL Lowering

Example Trials Involving PCSK-9 Inhibitors

Study Description

DESCARTES(n=901)

Patients: Individuals received either (a) diet alone, (b) atorvastatin 10 mg daily, or (c) atorvastatin 80 mg daily with or w/o ezetimibe.Treatment groups: Evolocumab 420 mg per month or placeboResults: Evolocumab demonstrated statistically significant decreases in LDL vs placebo in all groups, with an overall reduction of 57% from baseline in the entire cohort, which persisted even in the presence of high-intensity statin therapy.

OSLER(n=4465)

Patients: Individuals recruited from prior evolocumab studies. All received standard dyslipidemia therapies.Treatment groups: Evolocumab 420 mg per month or 140 mg q 2 weeks plus standard therapy or standard therapy plus placebo.Results: Evolocumab decreased LDL by 61% in the overall population and statistically significantly reduced the incidence of CV events at 1 year by 53% vs standard therapy alone.

ODYSEEY-LONGTERM(n=2341)

Patients: Individuals considered high risk for CV events who already receiving max tolerated statin.Treatment groups: Alirocumab 150 mg q 2 weeks plus statin or statin plus placebo.Results: Alirocumab group experienced a statistically significant 62% LDL decrease vs. placebo; post hoc analysis noted a statistically significant lower rate of major adverse CV events with alirocumab

N Engl J Med 2014;370:1809-19. N Engl J Med 2015;372:1500-9. N Engl J Med 2015;372:1489-99.

Dyslipidemia Updates: Candidates for PCSK9 Inhibitors

ACC Recommendations(Considered 2nd line with

continued statin use)

NLA Recommendations (Continued statin ±

ezetimibe

Stable ASCVD with or without comorbidities*

Baseline LDL ≥ 190

Stable ASCVD with baseline

LDL ≥ 190

ASCVD with LDL-C ≥100 (non-HDL ≥130)

HeFH w/o ASCVD with LDL (non-HDL ≥160 )

High risk patients deemed statin

intolerant (replaces statin)

Recurrent ASCVD with LDL-C ≥70 (non-HDL ≥100)

J Clin Lipidol 2014 (8), 473-88.J Am Coll Cardiol 2016, doi: 10.1016/j.jacc.2016.03.519.

ASCVD=Atherosclerotic cardiovascular diseaseHeFH=Heterozygous familial hypercholesterolemia

*Includes DM, recent ASCVD event (< 3 months), LDL ≥ 190 with noidentifiable secondary cause, ASCVD event while already on statin, poorly controlled ASCVD major risk factors, elevated Lp (a), or CKD

Dyslipidemia Updates: The Rise, Fall, and Partial “Re-Rise” of

Ezetimibe 2002

Ezetimibe introduced to market

2006ENHANCE Study

2008SEAS Study

2015—IMPROVE-IT Study results

Dyslipidemia: Recent Trial Updates

IMPROVE-IT(Ezetimibe Added to Statin Therapy After Acute Coronary Syndrome)

18,444 patients admitted with ACS ≤ 10 days, LDL 50-125mg/dL, plus one high risk feature present

(Mean age 64 yrs, 30% had DM, mean LDL 95)

9077 patients simvastatin 40 mg

group

9067 patients simvastatin 40

mg/ezetimbe 10 mg group

Primary Outcome: CV death, MI, hospitalization for UA, coronary revascularization, or stroke

N Engl J Med 2015;372:2387-97.

Dyslipidemia Updates: IMPROVE-IT

NNT=50(RR=34.7%; 2742 events)

(RR=32.7%;2572 events)

N Engl J Med 2015;372:2387-97.

Dyslipidemia Updates: IMPROVE-IT

Assessment of Individual Endpoints

Clinical Endpoint Simva Group Combo Group p-values

MI 14.8% 13.1% 0.002

CV death, nonfatal MI, nonfatal stroke

22.2% 20.4% 0.003

Ischemic stroke 4.8% 4.2% 0.052

All cause death 15.3% 15.4% 0.782

Death from CVD 6.9% 6.8% 0.997

Unstable angina 2.1% 1.9% 0.618

N Engl J Med 2015;372:2387-97.

Dyslipidemia Updates: IMPROVE-IT

• New FDA indication for ezetimibe: Secondary prevention for reducing CV events in patients with CAD??

70% of the advisory panel voted NO

http://www.medscape.com/viewarticle/855958. Accessed Jun 24, 2016.

Back Mrs. LD Long…

Which option would be the best for managing her dyslipidemia?

A) Add niacin since it has positively affects all components of the lipid profile

B) Add atorvastatin 80 mg daily

C) Add simvastatin 40mg plus ezetimibe

D) Add alirocumab 75 mg SubQ q 2 wks

When managing patients with dyslipidemia/ASCVD:** Statins remain the agent of choice.

** LDL goal vs no goals??

**Majority combination therapy studies have no demonstrated improved clinical outcomes.

** PCSK9 inhibitors may be useful in some patients, but consider the cons of these agents

Post-Test Question #2

Which patient would be the best candidate for evolocumab?

A) 55 year-old female with stage 3 chronic kidney disease, premature family history of MI, and current smoker, LDL 125 mg/ dL, receiving atorvastatin 80mg daily.

B) 24-year-old woman with polycystic ovarian syndrome with an LDL 195 mg/dL. She doesn’t wish to take a statin because she heard on the news that they can cause diabetes.

C) 64-year-old male with DM and h/o NSTEMI 2 years ago, LDL 140 mg/dL, receiving high-intensity statin therapy plus ezetimibe. He is compliant with all of his medications

D) 45-year-old male with homozygous familial hypercholesterolemia, LDL 350 mg/dL, receiving a low dose statin and cholestyramine.

Chronic Heart Failure Updates

Pre-Test Question #3

Ivabradine should routinely used instead of beta blockers in stable heart failure patients with reduced ejection fraction due to its ability to reduce hospitalization rates.

A) True

B) False

Class Recommendations

• Class I---Benefits >>> Risks

• Class IIA—Benefits >> Risks

• Class IIB---Benefits ≥ Risks

• Class III—Harm or No Benefit

Meet NE Heartbreak…

She is a 65 year old white female with chronic HF (LVEF 30%, NYHA class II) who presents for a routine clinic visit. She has no complaints today. Home meds: furosemide 40 mg BID, enalapril 10 mg BID, and bisoprolol 2.5 mg daily. PE/Vitals/Labs: (-) peripheral edema, BP 110/70 mmHg, HR 95 bpm, RR 14 bpm, K 4.5 mmol/L, BUN 28 mg/dL, and SCr 1.1 mg/dL.

How should her HF regimen be optimized? 1. Add spironolactone 2. Increase bisoprolol dose3. Add ivabradine 4. Change enalapril to

sacubitril/valsartan

Chronic Heart Failure: Quick Facts

• Estimated cost of treatment in Medicare patients is $31 billion with an expected increase to $53 billion by the year 2030.

• Patients often have a high medication burden; on average 6.8 Rx meds/day for HF alone.

• Clinical research for HFeREF>>> clinical research for HFpEF.

HRrEF=Heart failure with reduced ejection fractionHFpEF=Heart failure with preserved ejection fraction

Circ Heart Fail. 2013; 6:606-19.

Chronic Heart Failure: Current Treatment Standard for HFrEF Patients

HFrEF Stage C

NYHA Class I – IV

Treatment:

For NYHA class II-IV patients.

Provided estimated creatinine

>30 mL/min and K+ <5.0 mEq/dL

For persistently symptomatic

African Americans,

NYHA class III-IV

Class I, LOE A

ACEI or ARB AND

Beta Blocker

Class I, LOE C

Loop Diuretics

Class I, LOE A

Hydral-Nitrates

Class I, LOE A

Aldosterone

Antagonist

AddAdd Add

For all volume overload,

NYHA class II-IV patients

. Circulation 2013;128:e240-e327.

Angiotensin-Neprilysin Receptor Inhibition: Novel Approach to Heart Failure Management

J Am Coll Cardiol HF 2014;2:663–70.

Chronic Heart Failure Updates: Recent Trial Updates

PARADIGM-HF (Angiotensin–Neprilysin Inhibition vs. Enalapril in Heart Failure)

8,442 NYHA class II-IV HF patients with an EF ≤ 40%, either a BNP ≥ 150 pg/mL or prior HF hospitalization within past 12 months with BNP ≥ 100, stable ACEI/ARB

and beta blocker dose 4 weeks before enrollment(Mean age 64 yrs, 22% female, 71% of patients had NYHA II HF)

4187 patients Sacubitril/Valsartan (LCZ696)

200 mg BID

4212 PatientsEnalapril 10 mg BID

Primary endpointsComposite of death from CV

causes or HF hospital admission

.

Secondary endpointsChange in QOL scores from baseline to 8 mos

Time to reduction in renal function and new onset atrial fibrillation.

N Engl J Med 2014; 371:993-1004.

Chronic Heart Failure Updates: PARADIGM-HF

21.8%

26.5%

N Engl J Med 2014; 371:993-1004.

Chronic Heart Failure Updates: PARADIGM-HF

PARADIGM-HF Results (Safety)

Adverse Effect LCZ696 (n=4187) Enalapril (n=4212) p-value

Symptomatic hypotension

14% 9.2% <0.001

SCr ≥ 2.5 mg/dL 3.3% 4.5% 0.007

Serum Potassium > 6.0 mmol/mL

4.3% 5.6% 0.007

Cough 11.3% 14.3% <0.001

Angioedema requiring hospitalization

0.1% <0.1% 0.31

N Engl J Med 2014; 371:993-1004.

Chronic Heart Failure: Sacubitril/Valsartan Recommendations for Usage

2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure

Clinical Question Recommendation Class Rec.

Inclusion in core chronic HFrEF treatment regimen?

Inhibition of the RAAS with ACEI, ARB or ARNI in conjunction with evidence-based beta blockers and an aldosterone antagonist in select patients is recommended to reduce morbidity and mortality.

I

Should an ANRI replace ACEIs or ARBs?

Patients with chronic symptomatic HFrEF NYHA class II or III who can tolerate an ACEI or ARB, replacement with sacubitril/valsartan is recommended to further reduce morbidity and mortality

ANRIs plus ACEI or ARBs for even further benefit?

Sacubitril/valsartan should not be administered concomitantly with ACEI or within 36 hours of the last dose of an ACEI.

III

J Am Coll Cardiol 2016, doi: 10.1016/ j.jacc.2016.05.011.

RAAS=Renin Angiotensin Aldosterone SystemACEI= ACE inhibitorARB=Angiotensin Receptor Blocker

Chronic Heart Failure: Sacubitril/Valsartan

Sacubitril/Valsartan (Entresto™)

Indication Reduce the risk of CV death and HF hospitalization in patients with heart failure with reduced ejection fraction.

Administer in conjunction with other HF treatments, IN PLACE OF an ACE or ARB

Dose Starting dose 49/51 mg BID. Titrate after 7-14 days to target dose of 97/103 mg BID.

Dose adjustments:*Severe renal/moderate hepatic impairment: Starting dose 24/26 mg BID*Severe hepatic impairment: Not recommended*If on enalapril ≤ 10 mg/day, valsartan ≤ 160 mg/day, or equivalent ACEI/ARB or if ACEI/ARB naïve: Starting dose 24/26 mg BID

Contraindications Concomitant use of ACEI, history of angioedema with ACEI or ARB, concomitant use with aliskiren in diabetic patients.

D-D interactions Potassium-sparing diuretics, potassium supplements

Adverse Effects Cough, hypotension, angioedema

Cost $450.00/month

https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/entresto.pdf. Accessed Jun 25, 2016.

If Channel Inhibition: Novel Approach to Heart Failure Management

• Hyperpolarization-activated cyclic nucleotide-gated channel inhibition– Elevated heart rates in HF patients is associated with negative

outcomes

http://www.arthurkilmurray.com/2013/12/11/the-sinoatrial-node. Accessed Jun 27, 2016.Ann Pharmacother 2016;50:475-85.

Chronic Heart Failure Updates: SHIFT and BEAUTIFUL

• Patients with EF ≤ 35%, initial HR > 70 bpm, prior HF admission.; all received HF standard therapies.

• Ivabradine group had 2% reduction in all-cause readmissions (1,231 readmissions), compared to placebo (1,356 re-hospitalizations); p=0.003.

SHIFT (n=6,000)(Systolic heart failure treatment with

the If inhibitor ivabradine Trial)

• Stable CAD patients with EF ≤40%, initial HR ≥ 60 bpm, with a prior HF hospital admission; all received HF standard therapies.

• HR ↓ in the ivabradine group compared to placebo, there was no difference in the primary outcomes (composite of CV death, hospitalization for MI or HF).

• Patients with HR > 70 bpm demonstrated no difference in primary outcomes, but differences were detected in secondary endpoints (admission due to MI or revascularization).

BEAUTIFUL (n=10,917)(morBidity-mortality EvAlUaTion of the

If inhibitor ivabradine in patients with coronary disease and left-ventricULar dysfunction)

Lancet 2010; 376: 875–85.

Lancet 2008; 372: 807–16.

Chronic Heart Failure: IvabradineRecommendations for Usage

2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure

Clinical Question Recommendation Class Rec.

Current place in HFrEF treatment?

Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF ≤35%) who are receiving guideline directed medical therapy, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of ≥70 bpm at rest.

IIA

J Am Coll Cardiol 2016, doi: 10.1016/j.jacc.2016.05.011.

Chronic Heart Failure Updates: Ivabradine

Ivabradine (Corlanor®) Indication Reduce the risk of hospitalization of HF in patients with stable,

persistently symptomatic chronic disease.

Dose Staring Dose: 5 mg BIDDose Adjustments:HR > 60 bpm: ↑ to 7.5 mg BIDHR 50-60 bpm: Maintain doseHR < 50 bpm or s/sx bradycardia: ↓ to 2.5 mg BID

Contraindications Initial HR < 60 bpm prior to treatment, ADHF, BP < 90/50 mm Hg, patients who are dependent on a pacemaker (HR maintained exclusivelyby pacemaker), significant bradyarrhythmias, concomitant use of strong CPY 3A4 inhibitors, severe hepatic impairment

Disease State considerations

Atrial fibrillation, ventricular dyssynchrony, 1st or 2nd degree heart block

D-D Interactions Strong CPY 3A4 inhibitors---AVOID

Adverse Effects Atrial fibrillation, development of phosphenes

Cost $450.00/month

http://pi.amgen.com/united_states/corlanor/corlanor_pi_hcp.pdf. Accessed Jun 27, 2016. ADHF=Acute decompensated heart failure

Back to NE Heartbreak…

How should her HF regimen be optimized?

1. Add spironolactone

2. Increase bisoprolol dose

3. Add ivabradine

4. Change enalapril to sacubitril/valsartan

When managing patients with chronic HF:

** Always assess the low-hanging fruit first

**Mortality improving agents take precedence

**Place in therapy for:

--Sacubitril/valsartan?

--Ivabradine ?

Post-Test Question #3

Ivabradine should routinely used instead of beta blockers in stable heart failure patients with reduced ejection fraction due to its ability to reduce hospitalization rates.

A) True

B) False

Atherosclerotic Disease Updates

Pre-Test Question #4

Which statement is correct involving vorapaxar?

A) Can be used instead of aspirin and clopidogrel in patients with a history of CAD.

B) Can be used in conjunction with strong CPY 3A4 inhibitors.

C) Use is contraindicated in patients with a history of stroke due to increased bleeding risks.

D) Demonstrated a similar bleeding event rate compared to placebo

Mrs. LD Long Revisited…

55-year-old white female who presents to the emergency room with chest pain indicative of angina. PMH: HTN. Home meds include lisinopril 10mg daily. FLP reveals TC 275 mg/dL, HDL 31 mg/dL, LDL 126 mg/dL, and TG 590 mg/dL. Her BP is 166/100 mm Hg. She does not smoke. Based on EKG findings, RW is given a diagnosis of NSTEMI. Catheterization shows 80% occlusion in the proximal left anterior descending artery.

She had an everolimus stent deployed in the occluded artery. Which antiplatelet option would be most appropriate for her at this time?A) Aspirin 81 mg daily indefinitely plus clopidogrel 75 mg daily for 12 months.B) Aspirin 81 mg daily indefinitely plus clopidogrel 75 mg daily for 6 months.C) Aspirin 81 mg daily indefinitely vorapaxar 2.5 mg daily, plus clopidogrel 75 mg daily for 12 months.D) Vorapaxar 2.5 mg daily only

Atherosclerotic Disease: Quick Facts

• Myocardial infarction ranked amongst the top five most expensive hospital principal discharge diagnoses in 2011.

• Antithrombotic therapy is cornerstone in the management of coronary heart disease.

• Combination therapy with antiplatelet agents (and anticoagulants) can improve thrombotic risks, but increase bleeding risk.

US Agency for Healthcare Research and Quality; December 2013. HCUP Statistical Brief #168.

PAR-1 Blockade: Novel Method of Platelet Inhibition

• Protease Activated Receptor-1 Inhibitor

– Drug development targeting platelet inhibition continues to be on the forefront of research.

http://www.haematologica.org/content/94/5/700. Accessed Jun 28, 2016.

Atherosclerotic Disease Updates: Recent Trial Updates

TRA 2P- TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic

Ischemic Events—TIMI 50)26,449 patients with h/o MI, CVA, PAD

(Mean age 61 yrs, 98% taking ASA, 80% on clopidogrel, all had high risk features present )

Vorapaxar 2.5 mg daily Placebo

Primary Endpoint: Composite of CV death, CVA, and stroke, revascularization

Safety Endpoints: Bleeding

N Engl J Med 2012;366:1404-13.

All CVA patients removed

from studyat year 2

Atherosclerotic Disease Updates: TRA 2P-TIMI 50 Trial

TRA 2P-TIMI Trial Results

Efficacy Safety (Bleeding)

Vorapaxar(n=13,225)

Placebo(n=13,224)

HRp-value

Vorapaxar(n=13,225)

Placebo(n=13,224)

HRp-value

CV death, MI, or CVA

9.3% 10.5% 0.87 (0.80–0.94) p=<0.001

GUSTO moderate or severe

4.2% 2.5% 1.66 (1.43–1.93) p=<0.001

CV death, MI, or CVA, revasc.

11.2% 12.4% 0.88(0.82-0.95) p=0.001

TIMIclinically sig.

15.8% 11.1% 1.46(1.36–1.57) p=<0.001

CV death 2.7% 3.0% 0.89(0.76–1.04) p=0.15

Fatal 0.3% 0.2% 1.46 (0.82–2.58) p=0.19

All causedeath

5.0% 5.3% 0.95 (0.85–1.07) p=0.41

ICH 1.0% 0.5% 1.94 (1.39–2.70) p=<0.001

N Engl J Med 2012;366:1404-13. revasc.=ravascularizationsig.=significant

Atherosclerotic Disease Updates: Vorapaxar

Vorapaxar (Zontivity)Indication Reduces thrombotic CV events in patients with a h/o prior MI or

documented PAD.

Dose 2.08 mg daily to be given in combination with ASA ± clopidogrel

Contraindications History of stroke, TIA, or ICH; active bleeding

Disease State considerations

Severe hepatic impairment

D-D Interactions Avoid with strong CYP3A4 inhibitors/inducers

Cost $350.00/month

http://www.merck.com/product/usa/pi_circulars/z/zontivity/zontivity_pi.pdf. Accessed Jun 28, 2016.

Back to Mrs. LD Long…

She had an everolimus stent deployed in the occluded artery. Which antiplatelet option would be most appropriate for her at this time?

A) Aspirin 81 mg daily indefinitely plus clopidogrel 75 mg daily for 12 months.

B) Aspirin 81 mg daily indefinitely plus clopidogrel 75 mg daily for 6 months.

C) Aspirin 81 mg daily indefinitely vorapaxar 2.5 mg daily, plus clopidogrel 75 mg daily for 12 months.

D) Vorapaxar 2.5 mg daily only

When managing CAD patients:**Dual antiplatelet therapy (DAPT) has its benefits, but also carries its risk.

** New ACC/AHA recommendations available regarding duration of DAPT in CAD patients

**DAPT plus oral anticoagulant increases bleeding risk even further.

** Place in therapy for vorapaxar?

Post-Test Question #4

Which statement is correct involving vorapaxar?

A) Can be used instead of aspirin and clopidogrel in patients with a history of CAD.

B) Can be used in conjunction with strong CPY 3A4 inhibitors.

C) Use is contraindicated in patients with a history of stroke due to increased bleeding risks.

D) Demonstrated a similar bleeding event rate compared to placebo

Final Thoughts

• Hypertension– BP goals---Conflicting recommendations

• Dyslipidemia– Treat to LDL goal or not?– Role of the PCSK-9..are we ready?– Resurgence of non-statins

• Chronic Heart Failure– Should we ACE-it or not?– ifunny or not so ifunny?

• Atherosclerotic Disease – Vorapaxar…ready or not, is it coming?– DAPT…for how long?

Resources & References

• Lancet. 2005;365:217–223.• http://www.cdc.gov/nchs/datadatabriefs/db200.

htm. Accessed Jun 14, 2016.• Hypertension 2003;42:1206-52.• Hypertension. 2010;56:780-800.• Circulation. 2011;123:2434-2506• J Clin Hypertens 2014;16:14-26.• JAMA 2014;311:507-20.• J Hypertens 2013;31:1281-357.• Can J Cardiol 2013;29:528-42.

Resources & References

• N Engl J Med 2015;373;2103-16.

• N Engl J Med 2010;362:1575-85.

• Lancet. 2013;382:1762–65.

• Circulation. 2014;129[suppl 2]:S1-S45.

• http://www.athero.org. Accessed Oct 19, 2013.

• J Clin Lipidol 2014 (8), 473-88.

• J Am Coll Cardiol 2016, doi: 10.1016/j.jacc.2016.03.519

• Endocr Pract 2012;18(1),1-78.

• http://www.kidney-international.org. Accessed Dec 13, 2013.

Resources & References

• Ann Intern Med. 2015;163:291-7.• Diabetes Care 2016;39(Suppl. 1):S1–S112.• Circulation. 2014;129[suppl 2]:S1-S45.• J Clin Lipidol 2014 (8), 473-88.• J Clin Lipidol 2014 (8), 473-88.• N Engl J Med 2011;365:2507-18.• http://caltagmedsystems.blogspot.com/2014/09/pcsk9-target-for-

next-blockbuster-drug_44.html. Accessed Jun 20, 2016.• http://www.medscape.com/viewarticle/850715. Accessed Jun 21,

2016.• http://pi.amgen.com/united_states/repatha/repatha_pi_hcp_englis

h.pdf. Accessed Jun 21, 2016.• http://products.sanofi.us/praluent/praluent.pdf. Accessed Jun 21,

2016.

Resources & References

• N Engl J Med 2014;370:1809-19. • N Engl J Med 2015;372:1500-9. • N Engl J Med 2015;372:1489-99.• N Engl J Med 2015;372:2387-97.• http://www.medscape.com/viewarticle/85598Accessed Jun

24, 2016.• Circ Heart Fail. 2013; 6:606-19.• Circulation 2013;128:e240-e327.• J Am Coll Cardiol HF 2014;2:663–70.• N Engl J Med 2014; 371:993-1004.• J Am Coll Cardiol 2016, doi: 10.1016/ j.jacc.2016.05.011.

Resources & References

• https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/entresto.pdf. Accessed Jun 25, 2016.

• http://www.arthurkilmurray.com/2013/12/11/the-sinoatrial-node. Accessed Jun 27, 2016.

• Ann Pharmacother 2016;50:475-85.• Lancet 2010; 376: 875–85.• Lancet 2008; 372: 807–16.• http://pi.amgen.com/united_states/corlanor/corlanor_pi_hcp.pdf.

Accessed Jun 27, 2016.• US Agency for Healthcare Research and Quality; December 2013. HCUP

Statistical Brief #168.• http://www.haematologica.org/content/94/5/700. Accessed Jun 28, 2016.• N Engl J Med 2012;366:1404-13.• http://www.merck.com/product/usa/pi_circulars/z/zontivity/zontivity_pi.

pdf. Accessed Jun 28, 2016.

Speaker Contact Information

Antoine T. Jenkins, PharmD., BCPS

at-jenkins@csu.edu