Paxos Prescribing Pearls from your Friendly …...APA Practice Guidelines Avoid long‐acting...

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Prescribing Pearls from Your Friendly Neighborhood Pharmacists

Jaclyn A. Boyle, PharmD, MS, MBA, BCACP, BCPSChris Paxos, PharmD, BCPP, BCPS, BCGPMate M. Soric, PharmD, BCPS

Northeast Ohio Medical UniversityCollege of PharmacyRootstown, Ohio

OHIO ASSOCIATION OF ADVANCED PRACTICE NURSES

Disclosures

The speakers have no actual or potential conflicts of interest in relation to this presentation.

Session Objectives

1. Compare and contrast second generation antipsychotics with regard to indications, adverse effects, and dosage forms

2. Describe the existing evidence supporting the use of new and established pharmacologic options for heart failure with reduced ejection fraction

3. Describe the existing evidence supporting the use of pharmacologic options for atrial fibrillation

4. Describe the existing evidence supporting the use of pharmacologic options for secondary stroke prevention

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Session Overview

Antipsychotic pharmacotherapy

Heart failure pharmacotherapy

Atrial fibrillation pharmacotherapy

Secondary stroke prevention pharmacotherapy

AntipsychoticPharmacotherapy


Psychopharmacology TriviaWhen was the first antipsychotic FDA approved?

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Psychopharmacology TriviaAnswer: Chlorpromazine (Thorazine®) in 1954.

Evolution of Antipsychotics

First Generation Antipsychotics

Second Generation Antipsychotics

Clozapine

1950s

1958 – discovered 1989 – approved

1990s


First generation antipsychotics

Typical, conventional, traditional, classical antipsychotics

Decrease central dopamine neurotransmission via D2 receptor antagonism

Second‐line agents due to higher risk of EPS and tardive dyskinesia

Pharmacotherapy: A Pathophysiologic Approach, 2017.Stahl’s Essential Psychopharmacology, 2013.

FGAs

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Generic Brand

Chlorpromazine Thorazine®

Thioridazine Mellaril®

Loxapine Loxitane®

Perphenazine Trilafon®

Molindone Moban®

Trifluoperazine Stelazine®

Thiothixene Navane®

Fluphenazine Prolixin®

Haloperidol Haldol®

ChlorpromazineEquivalents

100

100

10

8‐10

10

5

4

2

2

Potency relates to D2 blockade

Low potency

Mid potency

High potency

Lexi‐Comp Online, 2018.Pharmacotherapy: A Pathophysiology Approach, 2017.


Primary Care Companion J Clin Psychiatry. 2003;5[suppl 3]:9‐13.

Substance‐Induced Psychosis

Cocaine Levodopa Phencyclidine Hallucinogens

Amphetamines Amantadine Ketamine Corticosteroids

MethylphenidateDopamine agonists

Memantine Cannabinoids

Kaplan & Sadock’s Synopsis of Psychiatry, 2015.

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Assessment Question #1Which of the following second generation antipsychotics does NOT havean FDA approved indication as an adjunct to antidepressant therapy forthe treatment of major depressive disorder?

A. Aripiprazole (Abilify®)

B. Brexpiprazole (Rexulti®)

C. Lurasidone (Latuda®)

D. Quetiapine (Seroquel XR®)


Generic Brand U.S. Approval

Clozapine Clozaril® 1989

Risperidone Risperdal® 1993

Olanzapine Zyprexa® 1996

Quetiapine Seroquel® 1997

Ziprasidone Geodon® 2001

Aripiprazole Abilify® 2002

Paliperidone Invega® 2006

Asenapine Saphris® 2009

Iloperidone Fanapt® 2009

Lurasidone Latuda® 2010

Brexpiprazole Rexulti® 2015

Cariprazine Vraylar® 2015Lexi‐Comp Online, 2018.


Second generation antipsychotics

Atypical, novel antipsychotics

Dopamine (D2) and serotonin (5HT2A) receptor antagonism

First‐line agents due to lower risk of EPS and tardive dyskinesia

Pharmacotherapy: A Pathophysiologic Approach, 2017.Stahl’s Essential Psychopharmacology, 2013.

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Clozapine

Risperidone

Olanzapine

Quetiapine

Ziprasidone

Aripiprazole

Paliperidone

Asenap

ine

Iloperidone

Lurasidone

Brexp

iprazole

Cariprazine

Schizophrenia

Bipolar disorder (mania)

Bipolar disorder (depression)

Schizoaffective disorder

Depression (adjunct)

Tourette’s disorder

Autism (irritability)

Reducing suicidal behavior

Lexi‐Comp Online, 2018.


Generic BrandMax Dosage(mg/day)



























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Assessment Question #1Which of the following second generation antipsychotics does NOT havean FDA approved indication as an adjunct to antidepressant therapy forthe treatment of major depressive disorder?

A. Aripiprazole (Abilify®)

B. Brexpiprazole (Rexulti®)

C. Lurasidone (Latuda®)

D. Quetiapine (Seroquel XR®)

Assessment Question #2Which of the following second generation antipsychotics must be takenwith food to enhance bioavailability?

A. Asenapine (Saphris®)

B. Olanzapine (Zyprexa®)

C. Risperidone (Risperdal®)

D. Ziprasidone (Geodon®)

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The BIG picture

As a medication class, SGAs share a number of adverse effects

But the risk of these adverse effects varies among individual agents

Cardiometabolic disturbances

Extrapyramidal symptoms

Hyper‐prolactinemia

QT interval prolongation

SedationOrthostatic hypotension

Anticholinergic activity

Decreased seizure threshold

Pharmacotherapy: A Pathophysiologic Approach, 2017.


Olanzapine (Zyprexa®)

Cardiometabolic disturbances

Sedation, constipation

Risperidone (Risperdal®)

EPS, hyperprolactinemia

Doses ≥ 6mg increase EPS risk

Quetiapine (Seroquel®)

Sedation, low EPS risk

Off‐label use; misuse risk

Ziprasidone (Geodon®)


Take with food (500 calories)

Asenapine (Saphris®)

Sublingual; < 2% if swallowed

Oral hypoesthesia, dysgeusia

Paliperidone (Invega®)

Risperidone active metabolite

Hyperprolactinemia

Lexi‐Comp Online, 2018.Pharmacotherapy: A Pathophysiologic Approach, 2017.


Aripiprazole (Abilify®)

Partial D2 receptor agonist

Activating; akathisia, insomnia

Brexpiprazole (Rexulti®)


Less activating, more weight gain

Cariprazine (Vraylar®)


High rates of EPS

Iloperidone (Fanapt®)


Dose titration lessens orthostasis

Lurasidone (Latuda®)

Pregnancy category B

Take with food (350 calories)

Clozapine (Clozaril®)

Most effective antipsychotic

Agranulocytosis risk

Lexi‐Comp Online, 2018.Pharmacotherapy: A Pathophysiologic Approach, 2017.

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Monitoring Parameters Monitoring Frequency

Cardiometabolicdisturbances

Weight/BMI Baseline; months 1, 2, 3; every 3 months

Waist circumference Baseline; then annually

Blood pressure Baseline; 3 months; then annually

Fasting plasma glucose Baseline; 3 months; then annually

Fasting plasma lipids Baseline; 3 months; then annually

Extrapyramidalsymptoms

Assess for presence of movement disorders

Dystonia, parkinsonism, and akathisia:Baseline; weekly during acute phase; each visit

Tardive dyskinesia:Baseline, every 6 months (FGAs); annually (SGAs)

QT prolongation ElectrocardiogramBaseline; then annuallyMore often in high risk patients

HyperprolactinemiaScreen for symptoms;if present, draw level

As clinically indicated

Pregnancy status Pregnancy test As clinically indicated

World J Biol Psychiatry. 2012;13(5):318‐78.American Psychiatric Association, 2004.

Assessment Question #2Which of the following second generation antipsychotics must be takenwith food to enhance bioavailability?

A. Asenapine (Saphris®)

B. Olanzapine (Zyprexa®)

C. Risperidone (Risperdal®)

D. Ziprasidone (Geodon®)

Patient Case Study #1Peter was diagnosed with schizophrenia two years ago. Adequate trialsof perphenazine, risperidone long‐acting injection, and quetiapine weretried with either limited success or intolerable adverse effects. Theprescriber determines Peter is treatment resistant, initiates clozapinetherapy, and sends an order to the lab for routine blood work. Howoften should Peter’s absolute neutrophil count (ANC) be monitored?

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Clozapine (Clozaril®)

Clozapine

Superior efficacy; reduces suicidal behavior; very low EPS risk

Cardiometabolic disturbances; seizure potential; anticholinergic; sialorrhea

Agranulocytosis (1%); not dose‐dependent; requires routine monitoring

REMS program established to ensure safe use; NO BLOOD, NO DRUG

ANC Value Situation Frequency

General populationANC ≥ 1500/L

BEN populationANC ≥ 1000/L

0 – 6 months Once per week

7 – 12 months Every 2 weeks

Over 1 year Every 4 weeks

Clin Schizophr Relat Psychoses. 2014;6(3):134‐44.Arch Gen Psychiatry. 2003;60(1):82‐91.

www.clozapinerems.com

Aripiprazole (Abilify MyCite®)

Aripiprazole

Each tablet contains a sensor activated by gastric fluid

Transmits data to patch worn on torso, then smartphone, online portal

Allows prescriber and up to four caregivers to receive electronic data

No data are available demonstrating that this improves adherence

If a dose is not detected, educate patient not to repeat the dose

Abilify MyCite [package insert]. November 2017.

Pimavanserin (Nuplazid®)

Pimavanserin

FDA approved in 2016 for Parkinson’s disease psychosis

Only antipsychotic available without dopamine receptor antagonism

Inverse agonist and antagonist at 5HT2A and 5HT2C receptors

Institute for Safe Medication Practices

Conducted analysis of 2,236 reported events through March 2017

Revealed 244 reports of death possibly linked to pimavanserin

FDA Adverse Event Reporting System

Publicly available dashboard of reported events; updated quarterly

Currently, over 800 reports of death possibly linked to pimavanserin

Nuplazid [package insert]. March 2018.FDA Adverse Event Reporting System, 2018.Institute for Safe Medication Practices, 2017.

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Long‐Acting Injections

Generic Name(Brand Name)

How to Initiate Strengths (mg) Interval Oral Overlap

Aripiprazole(Abilify Maintena®)

Same dose for all 300, 400 4 weeks 2 weeks

Aripiprazole(Aristada®)

Based on oral dose 441, 662, 882, 1064 4, 6, or 8 weeks 3 weeks

Aripiprazole(Aristada Initio®)

One time loading dose 675 One time dose 30mg tab x 1

Olanzapine(Zyprexa Relprevv®)

Based on oral dose 150, 300, 405 2 or 4 weeks None

Risperidone(Risperdal Consta®)

Dose titration 12.5, 25, 37.5, 50 2 weeks 3 weeks

Paliperidone(Invega Sustenna®)

Two loading doses 39, 78, 117, 156, 234 4 weeks None

Paliperidone(Invega Trinza®)

Based on monthly dose 273, 410, 546, 819 12 weeks None

Establish tolerability to oral formulation before use

Lexi‐Comp Online, 2018.CNS Drugs. 2013;27(8):637‐52.

Long‐Acting Injections

Olanzapine Pamoate

Post‐injection delirium/sedation syndrome (PDSS)

Results from inadvertent, rapid rise in plasma concentrations

Sedation (mild to coma) and/or delirium (anxiety, agitation, confusion)

Can occur after any injection; highest risk in first hour post‐injection

REMS program requirements

Patient, prescriber, pharmacy, and health facility enrollment

Facility must have access to emergency response services

Patient must be continuously monitored for 3 hours post‐injection

Patient must be accompanied by someone to their next destination

Zyprexa Relprevv [package insert]. January 2018.U.S. Food and Drug Administration, 2015.

VMAT2 Inhibitors

Valbenazine (Ingrezza®)

Tardive dyskinesia (TD)

Dosed 40‐80 mg per day

Suicidality and depression


Avoid with CYP inducers*

Deutetrabenazine (Austedo®)

TD and Huntington’s disease

Suicidality and depression

QT interval prolongation VMAT2: vesicular monoamine transporter 2

N Engl J Med. 2017;376(26):2503‐06.Ingrezza [package insert]. October 2017.Austedo [package insert]. August 2017.*Carbamazepine, rifampin, St. John’s wort.

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Patient Case Study #1Peter was diagnosed with schizophrenia two years ago. Adequate trialsof perphenazine, risperidone long‐acting injection, and quetiapine weretried with either limited success or intolerable adverse effects. Theprescriber determines Peter is treatment resistant, initiates clozapinetherapy, and sends an order to the lab for routine blood work.

Patient Case Study #2A patient with dementia has had a diagnosis of Alzheimer’s disease forthe past 4 years. The patient is currently experiencing notable apathy,sleep disturbances, and physical aggression in the form of striking out atstaff. Behavioral management strategies are implemented, and thetreatment team discusses possibly initiating low dose haloperidol. Whatdo recent practice guidelines recommend with regard to antipsychoticsfor the treatment of dementia‐related psychosis?

Dementia‐Related Psychosis

Black box warning – 2005 (SGAs), 2008 (FGAs)

Agitation and psychotic symptoms are common in dementia

No medications are FDA approved for dementia‐related psychosis

Benefits of antipsychotic medications are modest at best

All antipsychotics appear to be associated with increased mortality

www.fda.gov.BMJ. 2014;349:g6420.

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Antipsychotics and Dementia

BMJ. 2012;344:e977.

Huybrechts and colleagues

Nursing home population (N=75,445)

Patients (≥ 65) new to antipsychotics

Evaluated 180 day mortality

Reference medication = risperidone

Haloperidol had increased mortality risk

Quetiapine had decreased morality risk

No differences between other agents

Effects strongest shortly after initiation

Possibly higher risk with higher doses


Kales and colleagues

Outpatient VA population (N=33,604)

Outpatients (≥ 65) with dementia

Starting antipsychotic treatment

Evaluated 180 day mortality

Reference medication = risperidone

Haloperidol had highest mortality rate

Haloperidol risk highest in first 30 days

Crude 6‐month mortality rate = 20%

Quetiapine had lowest mortality rate

Am J Psychiatry. 2012;169(1):71‐79.


Maust and colleagues

VA patients (N=90,786) ≥ 65 with dementia diagnosis over 180 days

New prescription for antipsychotic, valproic acid, or antidepressant

Assessed NNH (number needing to receive treatment for 1 death to occur)

JAMA Psychiatry. 2015;72(5):438‐45.

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APA Practice Guidelines

Avoid long‐acting injectables unless indicated for co‐occurring psychiatric disorder

In the absence of delirium, haloperidol should not be used as a first‐line agent

When tapering, assess symptoms regularly and for at least 4 months afterwards

With adequate response, attempt to D/C within 4 months unless prior recurrence

If no significant response after 4 weeks of an adequate dose, taper and D/C

Initiate at a low dose and titrate to the minimum effective dose as tolerated

Am J Psychiatry. 2016;173(5):543‐46.

Patient Case Study #2A patient with dementia has had a diagnosis of Alzheimer’s disease forthe past 4 years. The patient is currently experiencing notable apathy,sleep disturbances, and physical aggression in the form of striking out atstaff. Behavioral management strategies are implemented, and thetreatment team discusses possibly initiating low dose haloperidol.

Antipsychotic Summary

All second generation antipsychotics antagonize D2 and 5HT2Areceptors in addition to several other receptor subtypes

Second generation antipsychotics vary with regard to adverse effect profiles, dosage form availability, and FDA approved indications

All antipsychotics increase the risk of mortality when used for dementia‐related psychosis

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Heart FailurePharmacotherapy


Background

5.1 million Americans have clinically manifest heart failure

Though survival has improved, 5‐year mortality rates remain as high as 50%

Causes more than 1 million hospitalizations annually

25% 30‐day readmission rate

Yancy CW, et al. Circulation 2013; 128: e240‐e327.

Causes of Heart Failure

HFrEFHFrEFHypertensionHypertension

Ischemic EventsIschemic Events

ValvulopathyValvulopathy

Atrial Fibrillation

Atrial Fibrillation

MedicationsMedications

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The Neurohormonal Model

Schrier RW, et al. N Engl J Med 1999; 341 (8): 577‐85.

The Neurohormonal Model

In the short term:

Water retention, vasoconstriction, increased contractility and increase heart rate

Increase cardiac output

In the long term:

These neurohormones lead to ventricular remodeling, further reductions in cardiac output and the downward spiral continues

The Vicious Cycle

Injury and RemodelingInjury and Remodeling

Decreased Cardiac OutputDecreased

Cardiac Output

RAAS and SNS Activation

RAAS and SNS Activation

Short Term ImprovementShort Term

Improvement

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Breaking the Cycle

Medications known to impact mortality in HFrEF

ACE Inhibitors

ARBs

Beta Blockers

Mineralocorticoid Receptor Antagonists

Hydralazine/Isosorbide Dinitrate

HFrEF therapy largely unchanged over last decade

Breaking the Cycle

Hydralazine/ Isosorbide

ACE Inhibitors/ARBs

Beta Blockers

Aldosterone Antagonists


Breaking the Cycle

Hydralazine/ Isosorbide


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The first pharmacological agents shown to improve mortality in HFrEF

Benefits in HFrEF extend beyond the blood pressure effects of the agents

Hypothesized to decrease oxidative stress brought on by compensation

Cole RT, et al. Circulation 2011;123:2414–22. Cohn JN, et al. N Engl J Med. 1986; 314(24):1547‐52.


Specific benefit in African Americans

Unknown benefit as add‐on in non‐African Americans

Used when ACE/ARB is contraindicated

Underutilized

Multiple doses per day

Side effects

Hypotension

Expensive combination product

Taylor AL, et al. N Engl J Med 2004;351:2049–57.

2013 Heart Failure Guidelines

Recommended as add‐on therapy to ACE or ARB and beta blocker in self‐described African Americans

Recommended as a replacement for ACE or ARB in patients that cannot tolerate them

Yancy CW, et al. JACC 2013; 62(16): e147‐e239.

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Breaking the Cycle

ACE Inhibitors/ARBs


ACE Inhibitors

Revolutionized the treatment of HFrEF

Beat the mortality benefit of hydralazine/isosorbide

Remain the cornerstone of treatment (until now?)

Inhibit RAAS activation with far‐reaching benefits

Reduced mortality (greater impact than hydralazine/isosorbide)

Reduced HF progression

Symptom improvement

Benefits seen in patients across HF etiologies and severities

Likely class‐wide effectsCohn JN, et al. N Engl J Med 1991;325:303–10.

Angiotensin Receptor Blockers

Theoretical benefit by avoiding ACE‐escape

Not shown superior to ACE inhibitors

Some conflicting data in studies

Candesartan and valsartan studied more extensively than other ARBs

Not to be used in combination with ACE inhibitors

Granger CB, et al. Lancet. 2003; 362: 772‐6.McMurray JJ, et al. Lancet. 2003; 362: 767‐71.

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Reserved for those that are ACE inhibitor intolerant

Avoid ACE plus ARB plus aldosterone antagonist


Breaking the Cycle

Beta Blockers


Beta Blockers

Initially thought to be contraindicated in HFrEF

Decrease contractility

Decrease cardiac output

Now recommended in all patients with stable HFrEFbecause of

Reduced mortality

Reduced hospitalizations

Questionable impact on symptoms

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Beta Blockers

Mechanisms of action

Preventing/reversing cardiac remodeling

Antiarrhythmic effects

Decreased ventricular wall stress

Decreased renin release

Careful initiation and titration to target doses

Willenheimer R, et al. Circulation 2005;112:2426–35.

Beta Blockers

Three agents with proven mortality benefits

Carvedilol

Metoprolol Succinate

Bisoprolol

Class effect?

Bucindolol

Dargie HJ, et al. Lancet. 1999; 353(9146): 9‐13.Hjalmarson A, et al. JAMA. 2000; 283: 1295‐302.Packer M, et al. N Engl J Med. 2001; 344: 1651‐8.

Eichhorn EJ, et al. N Engl J Med. 2001; 344(22): 1659‐67.


Recommend use of 1 of 3 proven beta blockers

Should be initiated shortly after ACE inhibitor


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Breaking the Cycle




ACE inhibitor/ARB use diminishes the impact of aldosterone, but not completely

Aldosterone antagonists thought of as diuretics, but these effects are of little importance in HFrEF

By blocking mineralocorticoid receptors, the effects of aldosterone are further reduced Increased sodium excretion

Decreased cardiac remodeling

Anti‐inflammatory effects?


Spironolactone

Studied in NYHA class III and IV patients

Improved mortality when added to baseline ACE inhibitor therapy (not much beta blocker use)

Ten‐fold increase in gynecomastia compared to placebo

Eplerenone

Studied in NYHA class II, III and IV patients

Improved mortality when added to appropriate therapies (ACEs and beta blockers)

No gynecomastiaPitt B, et al. N Engl J Med. 1999; 341(10): 709‐17.

Pitt B, et al. N Engl J Med. 2003; 348(14): 1309‐21.Zannad F, et al. N Engl J Med 2011;364:11–21.

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In the appropriate population, risk of adverse events is low (especially at the lower doses used in this condition)

Underutilization

Of eligible patients, only 1/3 receive aldosterone antagonists

Albert NM, et al. JAMA 2009;302:1658–65.


Recommended in NYHA Class II‐IV patients with LVEF≤35% (or a LVEF≤40% in post‐MI patients)

Should be used in appropriate patient populations

Renal function

Potassium levels


Other Therapies

Digoxin

First described as a treatment for dropsy (edema) in 1785

Lower target concentrations associated with better outcomes

No established mortality benefit

Most studies completed before widespread beta blocker use

Diuretics

Only required in patients with fluid overload for symptom control

No mortality benefit

Over diuresis may worsen cardiac output

Garg R, et al. N Engl J Med. 1997; 336(8): 525‐33.Faris R, et al. Cochrane Database Syst Rev. 2012;2:CD003838.

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Diuretics are recommended in patients with fluid retention to improve symptoms

Digoxin may reduce risk of hospitalization


The 2017 ACC/AHA/HFSA Focused Update of the

2013 ACCF/AHA Guideline for the Management of

Heart Failure


Neprilysin Inhibition

Heart Failure

RAAS SystemNatriuretic System

Sacubitril/ValsartanNeprilysin

•Vasoconstriction

•Fluid Retention

•Fibrosis

•Hypertrophy

•Vasodilation

•Natriuresis

•Diuresis

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Neprilysin Inhibition

Initial attempts at inhibiting neprilysin resulted in limited benefits in heart failure patients

When combined with ACE inhibition, a significant increase in cases and severity of angioedema occurred

The latest entry in the field is sacubitril/valsartan

Neprilysin inhibitor/ARB combination

Designed to have a lower risk of angioedema

Early evidence suggest a greater impact on surrogate markers than an ARB alone

VardenyO, et al. JACC: Heart Fail 2014; 2(6): 663‐70.

Sacubitril/Valsartan

Formulation

More bioavailable formulation of valsartan

26mg, 51mg and 103mg equivalent to 40mg, 80mg and 160mg, respectively

Dosing

ACE‐naïve patients or those on less than or equal to 10mg of enalapril/day: sacubitril/valsartan 24/26mg BID

Patients receiving greater than 10mg enalapril/day: sacubitril/valsartan 49/51mg BID

Dose doubled every 2‐4 weeks to target of sacubitril/valsartan 97/103mg BID

Allow 36 hour washout when switching from ACE

Entresto [package insert]

PARADIGM‐HF Trial

Prospective, randomized, active‐controlled multi‐center trial with a single blind run‐in phase

All patients participated in a 2 week enalapril run‐in followed by a 4‐6 week run‐in of SV to ensure tolerability

Sacubitril/valsartan 200mg BID or enalapril 10mg BID

All patients on stable doses ACE inhibitor or ARB for 4 weeks

Excluded patients with an eGFR<30mL/min

McMurray JJV, et al. N Engl J Med 2014;371:993‐1004.

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PARADIGM‐HF Trial

Primary Outcome

Composite of death from cardiovascular causes or a first hospitalization for heart failure

Secondary Outcomes

Time to death from any cause

Quality of life questionnaire

Time to first occurrence of a decline in renal function

Adverse events


PARADIGM‐HF Trial


PARADIGM‐HF Trial


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2017 Guideline Update

Recommend the use of ACE or ARB or ARNI in conjunction with beta blockers and aldosterone antagonists improve morbidity and mortality

In patients that tolerate the use of an ACE or ARB, replacement with an ARNI is recommended to further reduce morbidity and mortality

Combination of ACE and ARNI is not recommended or within 36 hours of a dose of an ACE

ARNI should not be used in patients with a history of angioedema

Yancy CW, et al. Circulation 2017;136(6):e137‐e161.

Ivabradine

Resting heart rate is an important surrogate marker for outcomes in HFrEF

Beta blockers already treatment of choice and lower heart rate

Many patients are unable to reach target doses or have elevated heart rate despite reaching target doses of beta blockers

Ivabradine

Mechanism: If channel blocker

The “funny” channel

Heart rate reducer

No impact on other channels in the heart or in vasculature

No impact on blood pressure

No impact on contractility

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Ivabradine

Indicated for patients with HR≥70 despite beta blockade

Dosing

Initial: 5mg BID

2.5mg BID in patients with conduction defects

Maximum dose: 7.5mg BID

Titration

If HR>60bpm: increase dose by 2.5mg BID

If HR 50‐60bpm: maintain dose

If HR<50bpm or patient develops symptoms of bradycardia: decrease dose by 2.5mg BID. If current dose is 2.5mg BID, discontinue therapy

Not studied in patients with CrCl<15mL/minCorlanor [Package Insert]

SHIFT Trial

Randomized, double blind, prospective, placebo controlled study

Ivabradine 5mg versus placebo

Titrated to 2.5mg or 7.5mg based on heart rate

All patients had resting heart rate >70bpm

Excluded patients with atrial fibrillation

Ivabradine increases the risk of atrial fibrillation

Swedberg K, et al. Lancet 2010;376:875‐85.

SHIFT Trial

Primary Outcome

Composite of cardiovascular death and hospital admission for heart failure

Secondary Outcomes

Assorted versions of the primary endpoint

Adverse events


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SHIFT Trial


SHIFT Trial



Ivabradine may be beneficial to reduce hospitalizations in symptomatic patients on maximally tolerated beta blocker with a HR ≥70bpm in sinus rhythm


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Cases

CG is a 68yowm with NYHA III HFrEF presenting for routine follow‐up. Reports no new symptoms and is adherent to his current regimen. PMH includes HFrEF, NSTEMI s/p stenting, GERD, HTN, and Hyperlipidemia

MedsFurosemide 20mg dailyPantoprazole 20mg dailyMetoprolol succ. 25mg dailyAtorvastatin 80mg dailyLisinopril 40mg daily Aspirin 81mg dialySpironolactone 25mg daily

Labs/TestsCrCl: 65mL/minBNP: 80K: 3.9LDL: 78BP: 135/85HR: 89Hgb: 14.5EF: 30%

Should any changes be made to his regimen?

Cases

WT is a 58yoaaf recently discharged from a local hospital with a new diagnosis of NYHA II HFrEF presenting to your MTM clinic. Her PCP would like you to optimize her HF

medications. She has no known allergies.

MedsBisoprolol 1.25mg dailyEplerenone 25mg dailyFurosemide 10mg daily PRN 2lb weight gain

Labs/TestsCrCl: 102mL/minBNP: 50K: 4.1BP: 110/70HR: 64EF: 25%


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Cases

HS is a 70yolm with stable NYHA class II HFrEF. He is in the process of switching PCPs and would like a review of his medications. He has NKDA and has excellent

insurance coverage. PMH includes anxiety, depression, HFrEF, Alzheimer’s dementia, Afib and HTN.

MedsBumetanide 1mg dailyCarvedilol 12.5mg BIDWarfarin 4mg dailyLorazepam 0.5mg TID prn anx(rarely uses)Escitalopram 5mg dailyRamipril 10mg dailyDonepezil 10mg daily

Labs/TestsCrCl: 48mL/minBNP: 95K: 3.6BP: 122/86HR: 68EF: 30%INR: 2.6


Bonus Updates


Heart Failure with Preserved Ejection Fraction

ARB use


Nitrates

Phosphodiesterase 5 Inhibitors

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Heart Failure Summary

Medications that improve mortality in HFrEF include beta blockers, ACE‐Is, ARBs, ARNIs, Aldosterone antagonists and Hydralazine/Isosorbide

Ivabradine may be considered to reduce hospitalizations in patients with a HR ≥ 70 despite maximal beta blockade

Sacubitril/valsartan is the first agent to show additional mortality benefit over ACE‐Is in over a decade, but monitor closely

Atrial FibrillationPharmacotherapy


Atrial Fibrillation TriviaWhich anticoagulant is associated with a rare disorder of cholesterol microembolization called “Purple Toe Syndrome”?

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Atrial Fibrillation TriviaAnswer: Warfarin

Background

Most common arrhythmia seen in practice

Atrial rate of 400‐600 bpm Ventricular rate of 120‐180 bpm

Patients may present with symptoms, but not always

Go AS, et al. Circulation 2013;127:e6‐e245.

Risk factors

Risk increases with age

Heart failure

Coronary artery disease

Hypertension

Surgical procedures

Wolff‐Parkinson‐White Syndrome

Fuster V, et al. J Am Coll Cardio 2006;48:e149‐e246.Miyasaka Y, et al. Circulation 2006;114: 119‐125.

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American Academy of Family Physicians – 2017

Rate control in preference to rhythm control for the majority of patients (strong recommendation, moderate quality of evidence)

Preferred: Non‐dihydropyridine CCBs or beta‐blockers

Lenient rate control (<110 bpm) vs strict rate control (<80 bpm) (weak recommendation, low‐quality evidence)

Clinicians discuss the risk of stroke [(CHADS2 or CHA2DS2‐VASc) –weak recommendation, low‐quality evidence)] and bleeding [(HAS‐BLED)] – weak recommendation, low‐quality evidence) with all patients considering anticoagulation

Frost JL, et al. American Academy of Physicians 2017:1‐19.

American Academy of Family Physicians – 2017, con’t.

Patients who have atrial fibrillation receive chronic anticoagulation unless they are at low risk of stroke (CHADS2 <2) or have specific contraindications (strong recommendation, high‐quality evidence)

Options include: warfarin, apixaban, dabigatran, edoxaban, rivaroxaban

Recommends against dual treatment with anticoagulant and antiplatelet therapy in most patients who have atrial fibrillation (strong recommendation, moderate‐quality evidence)

Frost JL, et al. American Academy of Physicians 2017:1‐19.

Comparing stroke risk calculators

Congestive heart failure

Hypertension

Age > 75

Diabetes

Stroke or TIA (2 points)

Congestive heart failure Hypertension Age > 75 Diabetes Stroke or TIA (2 points) Vascular disease (2

points) Age 65‐74 Sex Category (female)

CHADS2 CHA2DS2‐VASc

https://www.mdcalc.com/chads2‐score‐atrial‐fibrillation‐stroke‐riskhttps://www.mdcalc.com/cha2ds2‐vasc‐score‐atrial‐fibrillation‐stroke‐risk

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Interpreting the Score

Anticoagulant options:

Warfarin (INR 2‐3)

Dabigatran

Rivaroxaban

Apixaban

CHADS2 ≥ 2 = High Risk = anticoagulant Dabigatran > warfarin

If not a candidate for anticoagulation: clopidogrel + aspirin

1 = Intermediate Risk = anticoagulant Dabigatran > warfarin

If not a candidate for anticoagulation: clopidogrel + aspirin

0 = Low Risk = no antithrombotic or aspirin alone

You JJ, et al. Chest 2012;141:e531S‐e575S.

Bleeding risk

Hypertension

Abnormal renal/liver function (1 point each)

Stroke

Bleeding (prior) or predisposition to bleeding

Labile INR

Elderly (age > 65)

Drugs (aspirin, NSAIDS, or clopidogrel) or alcohol use ≥ 8 drinks/week

https://www.mdcalc.com/has‐bled‐score‐major‐bleeding‐risk

Treatment goals

Control ventricular rate

Prevent thromboembolic complications

Restore and maintain sinus rhythm

Pharmacotherapy: A Pathophysiology Approach, 2017.

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Treatment options: Rate vs. Rhythm

Ischemic events occur at similar rates with either strategy

Rhythm options

Antiarrhythmics Less favorable due to proarrhythmic nature, monitoring, and side effect profiles

Direct current cardioversionMust have anticoagulated state before cardioversion unless symptoms < 48 hours

Ablation if patient has failed ≥ 1 antiarrhythmic


Atrial Fibrillation TriviaWhat did Vincent Van Gogh chew on while he was painting?

Atrial Fibrillation TriviaAnswer: The Foxglove plant

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Treatment options: Rate

Rate options:

Non‐dihydropyridine Calcium Channel Blockers (CCBs)

Beta blockers

Digoxin

ICD placement


Non‐dihydropyridine CCBs

MOA: prevents calcium from entering the “slow channels” in smooth muscle and myocardium; slows heart rate

Verapamil 240 mg to 480 mg PO in divided doses

Extended release 180‐480 PO daily

Diltiazem 120‐360 mg PO daily

SE: bradycardia, HA, constipation (verapamil > diltiazem), edema, hypotension

Lexi‐Comp. 2018.

Beta‐blockers

MOA: inhibits β1 +/‐ β2 receptors, lowering heart rate and blood pressure

Loss of selectivity at higher doses

Pearls:

Patients will be fatigued/tired ~ 2 weeks post initiation/titration

Exercise intolerance

Geriatric patients taking beta blockers may present with depression

Lexi‐Comp. 2018

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Digoxin

MOA: direct suppression of AV node conduction, positive ionotrope

Dosing: 0.125 mg PO daily

SE: acute – GI, chronic – CNS

Monitoring: HR, digoxin level (0.8‐1.2 ng/mL)

Note: digoxin level should be drawn at least 6 hours post administration

Lexi‐Comp. 2018

Treatment options: Rhythm

Rhythm options:

Antiarrythmics

Ablation

Direct Current Cardioversion


Amiodarone

Most effective*

First line for patients with LVEF ≤ 40%

MOA: affects sodium, potassium, and calcium channels, beta blocking effects

Side effects: CNS, GI, thyroid monitoring required, pulmonary fibrosis, corneal deposits, QT prolongation


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Other Antiarrhythmics

Flecanide Proarrhythmic, GI upset, HF exacerbation, CNS issues, blurred vision

Propafenone GI issues, blurred vision, bradycardia, dizziness, HF exacerbation, QT

prolongation

Sotalol May worsen heart failure, hypotension, CNS issues, fatigue, QT

prolongation, caution in renal impairment (risk of bradycardia)

Dofetilide Headache, dizziness, QT prolongation, ventricular tachycardia

Dronedarone Bradycardia, new onset heart failure, Increases mortality for patients

with heart failure: Contraindicated with NYHA Class IV or Class II or III heart failure with recent hospitalization


Patient Case Question #1A. An 80 yo male with a history of HTN, DM, hyperlipidemia, gout, and

atrial fibrillation presents to your primary care clinic. He hasn’t been feeling himself lately. Vitals: BP 134/80, HR 120, O2 sat 98%, RR 16. His medication list is as follows:

Lisinopril 5 mg PO daily

Metformin 1000 mg PO BID

Glimepiride 4 mg PO daily

Atorvastatin 40 mg PO daily

Allopurinol 100 mg PO daily

Digoxin 0.125 mg PO daily

Aspirin 81 mg PO daily

What is this patient’s CHADS2 score?










What changes would you make to this patient’s medication list?

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Would you start amiodarone?

Anticoagulation options

For all patients with AF regardless of rhythm control Aspirin Vitamin K antagonists

Warfarin

Direct Oral Anticoagulants Direct Thrombin Inhibitor Dabigatran

Factor Xa inhibitors Rivaroxaban Apixaban Edoxaban


Vitamin K antagonist:Warfarin

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Vitamin K antagonist: Warfarin

risk of stroke and all‐cause mortality

MOA: inhibits synthesis of Vitamin K‐dependent clotting factors

Side effects: Common: bleeding/bruising***

Uncommon: purple toe syndrome, skin necrosis, acute renal failure

Contraindications: Pregnancy (unless mechanical heart valve)

Hemorrhagic tendencies/blood dyscrasias

Recent or planned surgery of CNS or eye(s) or traumatic surgery

Hypersensitivity to warfarin

Malignant hypertension

Target INR: 2‐3 for most patients 2.5‐3.5 mechanical valve

Lexi‐Comp. 2018

Important counseling points with warfarin

Consistency is key.

Seek care if you fall and hit your head, notice an unexplained bruise larger than the size of your palm, or a nosebleed that won’t stop. Small bruises are normal.

Avoid certain OTC pain medications.

Use a soft bristled toothbrush.

Use an electric razor.

Report any changes in your diet or medications.

Vitamin K antagonist: Warfarin

Benefits:

Objective marker of effectiveness (INR)

Very patient‐specific dosing adjustments

Inexpensive

Disadvantages:

Higher risk of bleeding

More monitoring/clinic visits required

Drug/disease/food interactions

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Direct Thrombin Inhibitor: Dabigatran

Direct Thrombin Inhibitor: dabigatran

risk of stroke and ICH; GI bleeding risk vs. warfarin (RE‐LY)

MOA: direct thrombin inhibitor (Factor II)

Dosing for non‐valvular atrial fibrillation: 150 mg PO BID CrCl 15‐30 mL/min: lower dose to 75 mg PO BID**

CrCl < 15 mL/min: contraindicated

Side effects: Common: bleeding/bruising, GI symptoms

Contraindications: Hypersensitivity to dabigatran

Mechanical prosthetic heart valve

Lexi‐Comp. 2018.Connolly SJ, et al. N Engl J Med 2009;361:1139‐1151.

Transitioning to and from dabigatran

To dabigatran: From enoxaparin or fondaparinux: start dabigatran within 2 hours of next scheduled dose of former agent

From heparin: start dabigatran when infusion is stopped From warfarin: start dabigatran when INR < 2

From dabigatran: To heparin, enoxaparin, fondaparinux, : start agent after the last dose of dabigatran at 12 hours (CrCl ≥ 30 mL/min) or 24 hours (CrCl < 30 mL/min)

To warfarin: based on CrCl; initiate warfarin 3 days before discontinuing dabigatran for CrCl > 50 mL/min, 2 days prior for CrCl 30‐50 mL/min, and 1 day prior for CrCl 15‐30 mL/min

Lexi‐Comp. 2018

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Factor Xa inhibitors: Apixaban, Edoxaban, Rivaroxaban

Factor Xa inhibitor: Apixaban

risk of stroke and bleeding risk vs. warfarin (ARISTOTLE)

MOA: Factor Xa inhibitor Dosing: 5 mg PO BID

If patient has 2 of the following, dose to 2.5 mg PO BID: SCr ≥ 1.5 mg/dL, Age ≥ 80, Weight ≤ 60 kg

Side effects: Common: bleeding/bruising

Contraindications: Hypersensitivity to apixaban Active bleeding

Lexi‐Comp. 2018.Granger CB, et al. N Eng J Med 2011;365;981‐992.

Transitioning to and from apixaban

To apixaban: From enoxaparin or fondaparinux: start apixaban at the time of the next scheduled dose of former agent

From heparin: start apixaban when infusion is stopped

From warfarin: start apixaban when INR < 2

From apixaban: To heparin, enoxaparin, fondaparinux or another DOAC: start agent at the time that the next apixaban dose was scheduled

To warfarin: 2 days at least of overlap (apixaban can increase INR)

Lexi‐Comp. 2018

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Factor Xa inhibitor: Edoxaban

Non‐inferior stroke reduction and bleeding risk vs. warfarin (ENGAGE‐AF)

MOA: Factor Xa inhibitor Dosing for nonvalvular atrial fibrillation: 60 mg PO daily

Side effects: Common: bleeding/bruising, abnormal LFTs

Contraindications: Hypersensitivity to edoxaban Active bleeding CrCl > 95 mL/min or <15 mL/min

Lexi‐Comp. 2018.Giugliano RP, et al. N Engl J Med 2013;369:2093‐2014.

Transitioning to and from edoxaban

To edoxaban: From enoxaparin or fondaparinux: start edoxaban at time of next scheduled dose of former agent

From heparin: start edoxaban when infusion is stopped

From warfarin: start edoxaban when INR < 2.5

From edoxaban: To parenteral anticoagulant or a different DOAC: start agent at the time that the next edoxaban dose was scheduled

To warfarin: reduce dose by 50% and initiate warfarin; continue edoxaban until INR ≥ 2

Lexi‐Comp. 2018

Factor Xa inhibitor: Rivaroxaban

Non‐inferior in stroke reduction and bleeding vs. warfarin (ROCKET‐AF)

MOA: Factor Xa inhibitor

Dosing: 20 mg PO daily with the evening meal

Side effects: Common: bleeding/bruising, increased LFTs

Contraindications: Hypersensitivity to rivaroxaban

Active bleeding

Lexi‐Comp. 2018.Patel MR, et al. N Engl J Med 2011:365:883‐891.

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Transitioning to and from rivaroxaban

To rivaroxaban: From enoxaparin or fondaparinux: start rivaroxaban within 2 hours of next scheduled dose of former agent

From argatroban, bivalrudin, heparin: start rivaroxabanwhen infusion is stopped

From warfarin: start rivaroxaban when INR < 3

From rivaroxaban: To heparin, enoxaparin, fondaparinux, or a different DOAC: start agent at the time that the next rivaroxaban dose was scheduled

To warfarin: 2 days at least (rivaroxaban can increase INR)

Lexi‐Comp. 2018

Special populations

CrCl < 15 mL/min: warfarin preferred

Reversal agents:

Warfarin: Vitamin K (phytandione)

Dabigatran: Praxbind

Xa inhibitors: Andexanet Alfa

Wann SL, et al. Circulation 2010;123:104‐123.

Atrial fibrillation summary

Rate control (<110 bpm) preferred over rhythm control

Antithrombotic therapy should be considered for every patient

Patient‐specific factors including lifestyle, diet, adherence, and affordability will guide selection of anticoagulant

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Secondary Stroke Prevention Pharmacotherapy


Stroke TriviaWhat percent of strokes are considered “preventable”?

Stroke TriviaAnswer: 80%

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Epidemiology

Leading cause of disability in the United States

4th leading cause of death in the U.S.

Annual cost ~ $69 billion

National Center for Health Statistics, 2010.Roger VL, et al. Circulation 2012;125:e2‐e220.

Types of Strokes

Ischemic – 87% Hemorrhagic – 13%

2‐6x increased mortality

Source: National Heart Lung and Blood Institute


Risk Factors

Non‐modifiable: age, male gender, low birth weight, African American, Asian‐Pacific Islander, Hispanic , family history of stroke/TIA

Modifiable Hypertension

Cigarette smoking

Diabetes

Hyperlipidemia

*Atrial fibrillation*

Sickle Cell disease

Postmenopausal hormone therapy

Oral contraceptive use

Diet

Obesity

Physical inactivity

Other cardiac conditions: (coronary heart disease, heart failure, peripheral artery disease, patent foramen ovale)

Goldstein et al. Stroke 2011;42:517‐584.

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Transient ischemic attack (TIA)

“Mini‐stroke”

Temporary interruption of bloodflow to the brain

!Risk of stroke within the first few days after TIA!


Secondary Prevention: Non‐Pharmacologic Interventions

Ischemic stroke

Carotid endarterectomy

Hemmorhagic stroke

Surgical intervention


The ABC’s of Secondary Prevention for Ischemic Stroke

Antiplatelet therapy

Blood pressure management

Cholesterol management

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For non‐cardioembolic stroke:

Aspirin 81 mg PO daily OR

Aspirin 25 mg/dipyridamole 200 mg PO BID found to be most effective (ESPS‐2, ESPRIT); 37% RRR

Adherence

Cost

Side effect profile: headache

Pharmacotherapy: A Pathophysiology Approach, 2017.Diener HC, et al. J Neurol Sci 1996;143:1‐13.

ESPRIT Study Group. Lancet 2006;367:1665‐73.

Antiplatelet therapy, con’t.

If aspirin allergy: clopidogrel 75 mg PO daily

CAPRIE demonstrated 8% RRR vs. aspirin 325 mg PO daily

PRoFESS: clopidogrel = aspirin/dypyridamole, clopidogrel better tolerated

If minor TIA/stroke: aspirin 81 mg PO daily and clopidogrel 75 mg PO daily x 21 days may be considered

Not recommended for maintenance therapy

Pharmacotherapy: A Pathophysiology Approach, 2017.CAPRIE Steering Committee. Lancet 1996;348:1329‐39.

Sacco RL, et al. N Engl J Med 2008;359:1238‐1251.

Antiplatelet therapy, con’t.

Cilostazol?

2 RCTs in Asian patients demonstrated improvement in recurrent hemorrhagic stroke RRR 26% vs aspirin

…but more side effects (headache and GI upset)

Kamal et al. Cochrane Database Syst Rev 2011;(1):CD008076.

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For cardioembolic stroke:

Weren’t you paying attention during the last hour???

Ex: Atrial fibrillation, valvular heart disease, other heart deformities that can increase stroke risk

Secondary prevention of cardioembolic stroke

Dabigatran 150 mg PO BID

OR oral anticoagulant

Furie et al. Stroke 2011;42(1):227‐226..Lansberg et al. Chest 2012;141:e601S‐e636S.

Blood pressure management

Blood pressure goals:

Goal: less than 140/90

Lacunar stroke: consider SBP < 130

Start with ACE inhibitor or ARB

Add thiazide** or calcium channel blocker

Combination of ACE‐inhibitor and thiazide recurrent stroke rates

Lisinopril/hydrochlorothiazide combination

PROGRESS trial demonstrated 43% RR with combination of perindopril and hydrochlorothiazide

Smith SC et al. Circulation 2011;124:2458‐2473.KernanWN, et al. Stroke 2014:45:2160‐2236.

PROGRESS Collaborative Group. Lancet 2001;358:1033‐41.

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Cholesterol management

For all patients post ischemic stroke, regardless of cholesterol levels

Generally, use high‐intensity statin to lower LDL by at least 50% (SPARCL)

Patients 75‐79: moderate‐ or high‐intensity statin

Patients 80 or older: moderate‐intensity statin

SPARCL Investigators. N Engl J Med 2006;355:549‐559.

Statin TriviaWhat statin is contained in red yeast rice?

Stroke TriviaAnswer: lovastatin

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‐ Dr. Mate Soric

“Some statin is better than no statin.”

Side effects?

• Lower the dose• Every other day dosing• Three times a week dosing• Weekly dosing

Statin Intensity

Statin Rosuvastatin Atorvastatin Simvastatin Lovastatin Pravastatin

Low‐Intensity(LDL ≤30%)

N/A N/A 10 mg 20 mg 20 mg

Moderate‐Intensity (LDL 30% to < 50%)

5 mg, 10 mg 10 mg, 20 mg 20 mg, 40 mg 40 mg 40 mg, 80 mg

High‐Intensity(LDL ≥50%)

20 mg, 40 mg 40 mg, 80 mg N/A N/A N/A

Special Notes Can take at any time of day

Can take at any time of day

Least interactions & side effects

REMEMBER RASL= 10:20:40:80

Adapted from American College of Clinical Pharmacy Ambulatory Care Preparatory Review Materials 2017.

Secondary stroke prevention summary

Remember the ABCs of secondary prevention


Blood pressure management with ACE‐I + hydrochlorothiazide

Cholesterol management via statin therapy

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Questions?


Prescribing Pearls from Your Friendly Neighborhood Pharmacists

Jaclyn A. Boyle, PharmD, MS, MBA, BCACP, BCPSChris Paxos, PharmD, BCPP, BCPS, BCGPMate M. Soric, PharmD, BCPS

Northeast Ohio Medical UniversityCollege of PharmacyRootstown, Ohio


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