paxos prescribing pearls from your friendly …...apa practice guidelines avoid long‐acting...
TRANSCRIPT
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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
OHIO ASSOCIATION OF ADVANCED PRACTICE NURSES
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
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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First Generation Antipsychotics
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.
First Generation Antipsychotics
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®)
Second Generation Antipsychotics
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
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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Second Generation Antipsychotics
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.
Second Generation Antipsychotics
Generic BrandMax Dosage(mg/day)
Clozapine Clozaril® 900
Risperidone Risperdal® 16
Olanzapine Zyprexa® 20
Quetiapine Seroquel® 800
Ziprasidone Geodon® 160
Aripiprazole Abilify® 30
Paliperidone Invega® 12
Asenapine Saphris® 20
Iloperidone Fanapt® 24
Lurasidone Latuda® 160
Brexpiprazole Rexulti® 4
Cariprazine Vraylar® 6Lexi‐Comp Online, 2018.
Second Generation Antipsychotics
Generic BrandMax Dosage(mg/day)
Clozapine Clozaril® 900
Risperidone Risperdal® 16
Olanzapine Zyprexa® 20
Quetiapine Seroquel® 800
Ziprasidone Geodon® 160
Aripiprazole Abilify® 30
Paliperidone Invega® 12
Asenapine Saphris® 20
Iloperidone Fanapt® 24
Lurasidone Latuda® 160
Brexpiprazole Rexulti® 4
Cariprazine Vraylar® 6Lexi‐Comp Online, 2018.
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Second Generation Antipsychotics
Generic BrandMax Dosage(mg/day)
Clozapine Clozaril® 900
Risperidone Risperdal® 16
Olanzapine Zyprexa® 20
Quetiapine Seroquel® 800
Ziprasidone Geodon® 160
Aripiprazole Abilify® 30
Paliperidone Invega® 12
Asenapine Saphris® 20
Iloperidone Fanapt® 24
Lurasidone Latuda® 160
Brexpiprazole Rexulti® 4
Cariprazine Vraylar® 6Lexi‐Comp Online, 2018.
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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Second Generation Antipsychotics
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.
Second Generation Antipsychotics
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®)
QT interval prolongation
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.
Second Generation Antipsychotics
Aripiprazole (Abilify®)
Partial D2 receptor agonist
Activating; akathisia, insomnia
Brexpiprazole (Rexulti®)
Partial D2 receptor agonist
Less activating, more weight gain
Cariprazine (Vraylar®)
Partial D2 receptor agonist
High rates of EPS
Iloperidone (Fanapt®)
QT interval prolongation
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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Second Generation Antipsychotics
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
QT interval prolongation
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
Antipsychotics and Dementia
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.
Antipsychotics and Dementia
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
OHIO ASSOCIATION OF ADVANCED PRACTICE NURSES
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
Schrier RW, et al. N Engl J Med 1999; 341 (8): 577‐85.
Breaking the Cycle
Hydralazine/ Isosorbide
Schrier RW, et al. N Engl J Med 1999; 341 (8): 577‐85.
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Hydralazine/Isosorbide Dinitrate
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.
Hydralazine/Isosorbide Dinitrate
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
Schrier RW, et al. N Engl J Med 1999; 341 (8): 577‐85.
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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2013 Heart Failure Guidelines
Reserved for those that are ACE inhibitor intolerant
Avoid ACE plus ARB plus aldosterone antagonist
Yancy CW, et al. JACC 2013; 62(16): e147‐e239.
Breaking the Cycle
Beta Blockers
Schrier RW, et al. N Engl J Med 1999; 341 (8): 577‐85.
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.
2013 Heart Failure Guidelines
Recommend use of 1 of 3 proven beta blockers
Should be initiated shortly after ACE inhibitor
Yancy CW, et al. JACC 2013; 62(16): e147‐e239.
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Breaking the Cycle
Aldosterone Antagonists
Schrier RW, et al. N Engl J Med 1999; 341 (8): 577‐85.
Aldosterone Antagonists
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?
Aldosterone Antagonists
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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Aldosterone Antagonists
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.
2013 Heart Failure Guidelines
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
Yancy CW, et al. JACC 2013; 62(16): e147‐e239.
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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2013 Heart Failure Guidelines
Diuretics are recommended in patients with fluid retention to improve symptoms
Digoxin may reduce risk of hospitalization
Yancy CW, et al. JACC 2013; 62(16): e147‐e239.
The 2017 ACC/AHA/HFSA Focused Update of the
2013 ACCF/AHA Guideline for the Management of
Heart Failure
OHIO ASSOCIATION OF ADVANCED PRACTICE NURSES
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
McMurray JJV, et al. N Engl J Med 2014;371:993‐1004.
PARADIGM‐HF Trial
McMurray JJV, et al. N Engl J Med 2014;371:993‐1004.
PARADIGM‐HF Trial
McMurray JJV, et al. N Engl J Med 2014;371:993‐1004.
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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
Swedberg K, et al. Lancet 2010;376:875‐85.
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SHIFT Trial
Swedberg K, et al. Lancet 2010;376:875‐85.
SHIFT Trial
Swedberg K, et al. Lancet 2010;376:875‐85.
2017 Guideline Update
Ivabradine may be beneficial to reduce hospitalizations in symptomatic patients on maximally tolerated beta blocker with a HR ≥70bpm in sinus rhythm
Yancy CW, et al. Circulation 2017;136(6):e137‐e161.
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2017 Guideline Update
Yancy CW, et al. Circulation 2017;136(6):e137‐e161.
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%
Should any changes be made to his regimen?
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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
Should any changes be made to his regimen?
Bonus Updates
OHIO ASSOCIATION OF ADVANCED PRACTICE NURSES
Heart Failure with Preserved Ejection Fraction
ARB use
Aldosterone Antagonists
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
OHIO ASSOCIATION OF ADVANCED PRACTICE NURSES
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
Pharmacotherapy: A Pathophysiology Approach, 2017.
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
Pharmacotherapy: A Pathophysiology Approach, 2017.
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
Pharmacotherapy: A Pathophysiology Approach, 2017.
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
Pharmacotherapy: A Pathophysiology Approach, 2017.
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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
Pharmacotherapy: A Pathophysiology Approach, 2017.
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?
Patient Case Question #2A. 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 changes would you make to this patient’s medication list?
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Patient Case Question #3A. 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
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
Pharmacotherapy: A Pathophysiology Approach, 2017.
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
OHIO ASSOCIATION OF ADVANCED PRACTICE NURSES
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
Pharmacotherapy: A Pathophysiology Approach, 2017.
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!
Pharmacotherapy: A Pathophysiology Approach, 2017.
Secondary Prevention: Non‐Pharmacologic Interventions
Ischemic stroke
Carotid endarterectomy
Hemmorhagic stroke
Surgical intervention
Pharmacotherapy: A Pathophysiology Approach, 2017.
The ABC’s of Secondary Prevention for Ischemic Stroke
Antiplatelet therapy
Blood pressure management
Cholesterol management
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Antiplatelet therapy
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
Antiplatelet therapy
Blood pressure management with ACE‐I + hydrochlorothiazide
Cholesterol management via statin therapy
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Questions?
OHIO ASSOCIATION OF ADVANCED PRACTICE NURSES
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