ranolazine for a-fib? it’s not a...

Ranolazine for A-Fib? It’s Not a Lie

Justina Lipscomb, Pharm.D. PGY-2 Internal Medicine Pharmacy Resident

South Texas Veterans Health Care System, San Antonio, TX The University of Texas at Austin College of Pharmacy

UT Health San Antonio February 23, 2018

Learning Objectives:

• Describe the mechanism behind atrial fibrillation and potential treatment options

• Analyze the research using ranolazine to treat patients with atrial fibrillation

• Determine which patients with atrial fibrillation would benefit most from use with ranolazine

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I. Atrial Fibrillation (AF)

a. Background1 i. A supraventricular tachyarrhythmia with uncoordinated atrial activation leading to

ineffective atrial contractions ii. Most common arrhythmia in clinical practice iii. Electrocardiogram (ECG) characteristics of AF include:

1. Irregularly irregular rhythm 2. No p-waves 3. Rate may be fast or slow

iv. Patients can present without or with symptoms, which include irregular heartbeat, heart palpitations (rapid, fluttering, or pounding), lightheadedness, extreme fatigue, shortness of breath and chest pain

b. Prevalence and epidemiology i. 33 million adults worldwide with AF1,2 ii. 2.7 million to 6 million American adults with AF1 iii. Prevalence increases with age1

1. 2% of people < 65 years old have AF 2. 9% of people ≥ 65 years old have AF

iv. Mortality and morbidity1, 3-7 1. Associated with many cardiac and non-cardiac comorbidities (Table 1) 2. Stroke

a. Most feared complication of AF b. Non-valvular AF increases the risk of stroke 5 times c. Stroke risk increases with age d. Found to be associated with greater severity, disability and mortality

than in patients without underlying AF 3. Risk of heart failure (HF) increases 3-fold 4. Risk of dementia increases 2-fold 5. Hospitalizations and economic consequences

a. 25% of people with AF are hospitalized annually b. Accounts for > 750,000 hospitalizations annually in America c. 2014 – Associated with > $26 billion in healthcare costs

6. Deaths associated with AF a. Stroke (7.0%) b. Progressive HF (15.1%) c. Sudden cardiac death (22.25%) d. Non-cardiovascular death (35.8%) e. Contributes to an estimated 100,000 deaths per year

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c. Classifications of AF 1,4

i. First diagnosed – irrespective of arrhythmia duration or severity ii. Paroxysmal – terminates spontaneously within 7 days of onset iii. Persistent – continuously sustained for more than 7 days iv. Longstanding persistent – continuously sustained for more than 12 months v. Permanent – decision to not restore and/or maintain normal sinus rhythm (NSR) vi. Non-valvular – absence of rheumatic mitral stenosis, mechanical or bioprosthetic heart

valve, or mitral valve repair d. Atrial fibrillation burden (AFB)1,8

i. AFB = [(total time in AF)/(total recorded time)] x 100% ii. Evidence for the use of AFB to determine therapeutic modifications is limited but it

remains the basis for some recommendations

II. Mechanisms of Atrial Arrhythmias

a. Normal cardiac action potentials9-11

Figure 1. Action potential for atrial and ventricular myocytes. Abbreviations: Ca2+, calcium ions; Cl-, chloride ions; ICa-L, L-type calcium channels; IK1, inward potassium rectifier channels; IKS, slow potassium “delayed rectifier” channels; IKR, rapid potassium “delayed rectifier” channels; INa, sodium channels; Ito1, transient outward potassium channels; K+, potassium ions.11

Table 1. Most common comorbid chronic conditions among Medicare beneficiaries with atrial fibrillation in 20105 Table 1a. Patients ≥ 65 years of age (%) Table 1b. Patients < 65 years of age

Hypertension 83.0 Hypertension 81.1

Ischemic heart disease 63.8 Ischemic heart disease 64.5

Hyperlipidemia 62.1 Hyperlipidemia 60.6

Heart failure 51.4 Heart failure 59.3

Anemia 42.3 Diabetes mellitus 53.1

Arthritis 39.8 Anemia 45.6

Diabetes mellitus 36.5 Chronic kidney disease 40.3

Chronic kidney disease 32.3 Arthritis 33.0

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b. Sodium currents11-13 i. Peak sodium currents

1. Responsible for the influx of sodium in phase 0 2. Opens transiently and are quickly inactivated

ii. Late sodium currents 1. Sodium channels that remain open for an abnormally long-time period 2. Responsible for the influx of sodium in phases 2 and 3 3. Occurs when failure of channel inactivation due to heart damage or genetic

mutations c. Atrial arrhythmias (Figure 2)1,11-12

i. Structural abnormalities (e.g., fibrosis, inflammation, dilation) 1. Most commonly occur in the setting of heart disease such as hypertension,

coronary artery disease and HF 2. Associated with greater amounts of enhanced late sodium currents

ii. Electrical abnormalities 1. Abnormal impulse formation

a. Abnormal automaticity b. Triggered activity (i.e., early and late after depolarizations)

2. Abnormal conduction

Figure 2. The arrhythmogenic effects of increased enhanced late sodium channels.12,14

Increased late sodium currents

Abnormal automaticity

Increases spontaneous diastolic depolarization

Triggered activity

Increases action potential duration

Initation of early after depolarization

Increases intracellular calcium

Initiation of delayed after depolarizations

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III. Current Standards of Care in Atrial Fibrillation

a. Basic approaches for AF management (Table 2) i. Rate control strategy: ventricular rate control plus prevention of cardioembolic stroke ii. Rhythm control strategy: conversion and maintenance of NSR + prevention of

cardioembolic stroke Table 2. Vaughn-Williams classification of antiarrhythmic drugs.1,15-17

Class Medications Ion Block Arrhythmia Indications

Effect on APD

Metabolism/ Clearance

PA Effect

Select Side Effects

Ia

Disopyramide

Medium Na+

↑K+

Atrial Ventricular

↑

H/R Low • ACh symptoms, HF, QT prolongation

Quinidine H High • GI upset, HF, thrombocytopenia, QT

prolongation

Procainamide H/R Moderate • SLE, HF, agranulocytosis, hypotension,

QT prolongation (IV formulation only)

Ib Lidocaine Rapid

Na+ Ventricular ↓

H Low

• Confusion, seizures, tremor

Mexiletine H • Confusion, blurred vision, tremor

Ic

Flecainide

Slow Na+ Atrial ↔

H/R High • Blurred vision, HF, tremors, ↑QRS

Propafenone H/R Moderate • Bronchospasm, taste disturbances, HF

• Also has beta-blocking properties, ↑QRS

II Beta-blockers SA/AV Atrial ↔ H N/A • Fatigue, sexual dysfunction,

bronchospasm, altered mood

III

Amiodarone ↑↑ K+ ↑ Na+ ↑Ca2+

Atrial Ventricular

↑↑ H Low

• Bradycardia, corneal microdeposits, neuritis, pulmonary fibrosis, ↑LFTs, hypothyroidism, hyperthyroidism, photosensitivity, blue-gray skin discoloration, hypotension and phlebitis with IV, QT prolongation without marked TDP

Dofetilide K+ Atrial ↑↑ H/R High • Headache, dizziness, QT prolongation

Ibutilide K+ Atrial ↑↑ H High • Headache, hypotension, QT

prolongation with TDP

Sotalol K+ Atrial Ventricular

↑↑ R High • GI upset, bradycardia, bronchospasm,

HF, QT prolongation

Dronedarone ↑↑ K+ ↑ Na+, ↑Ca2+

Atrial ↑ H/R Low • GI upset, HF

IV Verapamil Diltiazem

Ca2+ (SA/AV)

Atrial ↑

(SA/AV) H N/A

• Negative inotropic effects, vasodilation, edema, headaches and constipation (especially with verapamil)

Misc Digoxin AV Atrial ↑

(SA/AV) R N/A

• Heart block, bradycardia, GI upset, vision changes

Abbreviations: Ach, anticholinergic; APD, action potential duration; AV, atrioventricular node; Ca2+, calcium ions; GI, gastrointestinal; HF, heart failure; H, hepatic; K+, potassium ions; LFTs, liver function tests; N/A, not applicable; Na+, sodium ions; PA, proarrhythmic; R, renal; SA, sinoatrial node; SLE, systemic lupus erythematosus; SVT, supraventricular tachycardia; TDP, torsades de pointes. (↑↑ - Significant, ↑ - Mild, ↔ - neutral, ↓ - decreased)

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b. Cardioembolic prevention1 i. Decision for antithrombotic therapy is based on risk of thromboembolism and bleeding ii. Risk-stratification tools: CHADS2 and CHA2DS2-VASc (Appendix A) iii. Oral anticoagulants: warfarin, dabigatran, rivaroxaban, apixaban, edoxaban (Appendix B)

c. Rate control strategy1-4,18 i. Basis of treatment for all patients with permanent AF ii. Goal is to minimize symptoms and adverse cardiovascular outcomes iii. Rate controlling agents have no effect on the cardioversion of AF iv. Medication class: beta-blockers, non-dihydropyridine calcium channel blockers (diltiazem

and verapamil), digoxin d. Rhythm control strategy (Table 3 and Appendix C)1-4,12,19-21

i. Direct-current cardioversion 1. Success rate ranging between 75% and 93% 2. Requires general anesthesia or conscious sedation and a fasting period

ii. Pharmacological cardioversion with antiarrhythmic drugs (AAD) 1. Most effective within 7 days after the onset of an episode of AF 2. After 7 days, electrical cardioversion is favored 3. About a 50% success rate (varies with AAD) 4. Reasonable cardioversion options include: flecainide, propafenone, dofetilide,

amiodarone, ibutilide iii. Pharmacological agents for preventing AF and maintaining sinus rhythm

1. AF recurrence ranges from 71% to 84% at year 1 if not properly managed 2. Amiodarone has a recurrence rate < 20% by in the first year of use 3. Other AADs have a recurrence rate of 30% to 50% in the first year of use 4. AADs should not be used for treatment of AF when AF becomes permanent 5. Depending on underlying heart disease and comorbidities, the following AADs

are reasonable options for maintenance of NSR: flecainide, propafenone, dofetilide, amiodarone, dronedarone and sotalol (Table 3 and Figure 3)

e. Landmark trials i. 1991 Cardiac Arrhythmia Suppression Trial (CAST)22

1. Tested hypothesis that suppression of arrhythmias with class I AADs after myocardial infarction would reduce mortality

2. Class I agents led to more arrhythmia-related deaths than placebo ii. 2002 Atrial Fibrillation Follow-up Investigation of Rhythm Management Trial (AFFIRM)23

1. Looked at the effects of mortality when using a rate versus rhythm control strategy in patients with non-valvular AF

2. Demonstrated no survival benefit between the two strategies 3. Nonsignificant decrease in mortality was associated with the rate-control

strategy, particularly in those older than 65 and those without a history of HF iii. 2004 AFFIRM Substudy24

1. NSR is an important determinant of survival 2. An effective method for maintaining NSR with fewer adverse effects is beneficial

https://en.wikipedia.org/wiki/Myocardial_infarction

https://en.wikipedia.org/wiki/Mortality_rate

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Table 3. Antiarrhythmic drugs pros and cons.1, 14, 25-26

AAD Agent Pros Cons

Amiodarone

• Most effective AAD for maintenance of NSR

• Long T1/2 = 15-100 days (average 53 days)

• Oral amiodarone is associated with benefit of effective rate control

• Can be used in patients with HF

• Weakly effective for cardioversion

• Toxic side effect profile – should only be used after consideration of risks and when other agents have failed or are contraindicated

• Many drug interactions

• 80-95% efficacy at 1 year

Dofetilide

• Relatively safe non-cardiac risk profile

• Can be used in patients with HF

• High risk for torsades de pointes

• For initiation or dose-escalation of therapy, inpatient ECG monitoring is mandatory


Dronedarone

• Reasonable when extra-cardiac side effects of amiodarone should be avoided

• Avoid in patients with permanent AF

• Contraindication: Decompensated HF in the past 4 weeks or NYHA class IV symptoms, depressed left ventricular function, liver or lung toxicities related to amiodarone use

• Significantly less effective than amiodarone


Flecainide Propafenone

• Reasonable “pill-in-the-pocket” agents to terminate AF out of hospital

• Avoid in patients with structural heart disease

• Should be given with a beta-blocker or CCB

• Pro-arrhythmic

• Negative inotropic properties

• 50% efficacy at 1 year

Ibutilide

• Intravenous administration restores NSR in ~50% of patients within 30 minutes

• Mainly used for chemical cardioversion


• Inpatient ECG monitoring is mandatory

Sotalol

• Easily absorbed and has a high bioavailability

• Avoid in patients with CKD


• 50-60% efficacy at 1 year Abbreviations: AAD, antiarrhythmic drug; AF, atrial fibrillation; CCB, calcium channel blocker; CKD, chronic kidney disease; ECG, electrocardiogram; HF, heart failure; NSR, normal sinus rhythm; NYHA, New York Heart Association.

Figure 3. Algorithm for antiarrhythmic drug selection for maintenance of sinus rhythm in select disease states.1-4

•Flecainide, propafenone, sotalol, dronedarone, amiodarone, dofetilide

No (or minimal) heart disease

•Sotolal, dronedarone, amiodarone, dofetilide

Coronary Artery Disease

•Amiodarone, dofetilide

Heart Failure

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Table 4. Considerations for rate versus rhythm control.1, 26

Rate control Rhythm control

Age ≥ 65 years old Asymptomatic AF Sedentary lifestyle Late persistent AF

Permanent AF Substantial atrial remodeling

Irremediable underlying heart disease Hypertension

Failed antiarrhythmic drugs

Age < 65 years old Symptomatic AF Active lifestyle Paroxysmal AF

Early persistent AF Little or no atrial remodeling

No or minimal underlying heart disease Inadequate rate control

Abbreviation: AF, atrial fibrillation.

IV. Ranolazine27

a. Introduction i. Piperazine derivative FDA approved in 2006 for chronic stable angina ii. Brand name: Ranexa® iii. How supplied

1. US: 500 mg or 1000 mg tablets 2. Europe: 375 mg, 500 mg, or 750 mg tablets

b. Mechanism in chronic stable angina

Figure 4. Mechanism of ranolazine in chronic stable angina14, 27-28

c. Pharmacokinetic and pharmacodynamics of ranolazine i. Absorption

1. Tablet bioavailability: 55-76% 2. Rate and extent of absorption is unaffected by food

ii. Distribution 1. Time to peak: 2-6 hours 2. T ½: 7-9 hours

iii. Metabolism: Extensive hepatic [CYP3A4 (major), CYP2D6 (minor)], some intestinal iv. Excretion: Urine (75%), feces (25%)

d. Adverse effects i. Dizziness, headache, constipation, nausea, vomiting ii. Little to no effect on blood pressure and heart rate iii. Dose-related QT prolongation

e. Contraindicated in hepatic cirrhosis

Inhibits the late inward sodium channel in ischemic myocytes

Decreases both intracellular sodium

and calcium load

Reduced ventricular tension and myocardial

oxygen consumption

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f. Drug interactions i. Avoid concurrent use with strong CYP3A inhibitors (i.e., ketoconazole, clarithromycin) ii. Avoid concurrent use with CYP3A inducers (i.e., phenytoin, carbamazepine) iii. Do not exceed doses of more than 500 mg BID with moderate CYP3A inhibitors iv. P-glycoprotein substrate and inhibitor

1. Titrate to clinical response with P-glycoprotein inhibitors (i.e., cyclosporine) v. Monitoring: ECG, renal function, maintain potassium within normal limits

g. Other proposed indications studied10,18 i. AF (prevention and treatment) ii. Ventricular arrhythmias iii. Acute coronary syndromes iv. Heart failure v. Diabetes

V. Proposed Mechanism of Ranolazine in atrial fibrillation 6, 11-13,29

Figure 5. Ranolazine mechanism in atrial fibrillation.

Figure 6. The effect of ranolazine on atrial myocytes. Abbreviations: APD, action potential duration; DAD, delayed afterdepolarization; EAD, early after depolarization; ERP, effective refractory period; IKr, delayed rectifier potassium current; INaP, rapid inward potassium channels; INaL, “Late” sodium channels; INa(rapid), Peak sodium ion channels. 6,14

Inhibits rapid inward sodium channels

Supresses diastolic depolarization and increases post-repolarization

refractoriness

Inhibits late inward sodium channels

Suppresses early after depolarizations and delayed

after depolarizations

Inhibits delayed rectifer potassium currents

Increased action potential and effective refractory period

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Table 5. Main characteristics and outcomes of ranolazine in various studies for atrial fibrillation

Authors Study type

Clinical Setting Treatment Intervention

Study Population Endpoints Results

Koskinas, et al. 201430

SC-R Conversion of symptomatic AF to NSR following STEMI

AM IV alone (60 patients) AM IV + RZ 1500 mg (61 patients)

Conversion rate and time to conversion

Significantly higher conversion rate and shorter conversion times in the combo group

Simopoulos, et al. 201431

SC-R Conversion of post-CABG AF to NSR

AM IV alone (21 patients) AM IV + RZ 375 mg (20 patients)

Time to conversion

Significantly shorter conversion rate in combo group

Tagarakis, et al. 201332

SC-R Prevention of post-CABG AF

Usual care (34 patients) Usual care + RZ 375 mg (68 patients)

Post-CABG AF Significantly fewer occurrences with RZ

Miles et al. 201133

NR-RCS Prevention of post-CABG AF

AM (211 patients) RZ (182 patients)

Post-CABG AF, LOS, 30-day readmission and 30-day mortality

Significantly fewer occurrences with RZ, no difference in other outcomes

Murdock et al. 200934

PCS Safety and efficacy of RZ as a “pill in the pocket” treatment of new or paroxysmal AF

18 patients Conversion rate RZ resulted in a 72% conversion rate to NSR within 6 h of administration

Abbreviations: ACS, acute coronary syndrome; AF, atrial fibrillation; AM, amiodarone; CABG, coronary artery bypass grafting; CTS, cardiothoracic surgery; IV, intravenous; LOS, length of stay; NSR, normal sinus rhythm; NR-RCS, non-randomized retrospective cohort study; PCS, prospective cohort study; RZ, ranolazine; SC-R, single centered randomized trial.


CLINICAL QUESTION: IS RANOLAZINE A SAFE AND EFFECTIVE OPTION FOR MAINTENANCE OF NORMAL SINUS RHYTHM IN PATIENTS WITH OR AT HIGH-RISK FOR ATRIAL FIBRILLATION?

VI. Evidence Review

MERLIN-TIMI 36 Trial35, 36

Objective To assess the effect of RZ on cardiovascular death and recurrent ischemic events

Design Prospective, multicenter, randomized, double-blind, placebo-control trial

Patient Population

Inclusion Criteria Exclusion Criteria

• Adults ≥ 18 years old

• NSTE-ACS and ischemic symptoms at rest (Presenting within 48 hours)

• Moderate to high risk of death or recurrent ischemic event

o Elevated cardiac labs o ST depression o Diabetes Mellitus o High TIMI Risk Score (Appendix D)

• Pacemaker, significant left ventricular hypertrophy, left bundle branch block

• Pregnant or lactating women

• Strong CYP3A inhibitors

• Concurrent digoxin use

• Concurrent use of medications known to prolong the QT interval

• ESRD requiring hemodialysis

• Hepatic dysfunction

• Life expectancy < 12 months

Study Groups

Control Intervention

Placebo Loading Dose: RZ 200 mg IV over 1 hour

Maintenance: RZ 80mg/hour x 12-96 hours Then switched to 1000 mg PO BID

Methods • Patients wore a cECG Holter for the first 7 days after randomization

• Continued oral therapy outside hospital for a median duration of 12 months

Outcomes

Efficacy Exploratory

• Cardiovascular death, recurrent myocardial infarction or other ischemic event

• Incidence of NOAF

• AFB o < 0.01%: Clinically insignificant o 0.01 – 98%: Paroxysmal AF pattern o > 98%: Chronic AF pattern

Statistics

• Continuous data were compared with a t-test for normally distributed data and Wilcoxon rank-sum test for non-normally distributed data

• Dichotomous variables were compared using a x2 test

• Time to new onset of AF was analyzed based on a Cox proportional-hazards regression model, and hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated

Results

• 6560 patients were enrolled, 6351 (97%) had interpretable cECG recordings o 3162 patients in RZ group and 3189 patients in the placebo group

• Baseline characteristics o Median age (63 years), cardiovascular history and utilization of cardiac medications

during index hospitalization and at discharge were well balanced amongst groups o Significantly less women in RZ group versus placebo group (33.8 vs 36.3%, P = 0.03) o Index event – unstable angina (47%); NSTEMI (51%)

• Efficacy outcome o No effect on the rate of cardiovascular death, recurrent myocardial infarction or other

ischemic event individually or as a composite

• Exploratory outcomes o First 7 days

▪ Fewer NOAF occurrences (1.7 vs 2.4%, P = 0.08) ▪ Lower AFB overall (P < 0.01)


▪ Lower AFB in patients with paroxysmal AF pattern (4.4 vs 16.1%, P = 0.015) o 1-year follow-up

▪ Significantly less AF events reported from RZ group 2.9 vs 4.1%, P = 0.01)

• Safety Ranolazine Placebo

Dizziness 13% 7%

Nausea 9% 6%

Constipation 9% 3%

Syncope 3.3% 2.3%

o No evidence of increased pro-arrhythmic risk compared to placebo

Presenter’s Critique

Strengths Limitations

• Patients received standard medical therapy

• Used cECG monitoring during first 7 days

• Post-hoc analysis

• Used IV ranolazine

• Low overall AF event rates observed

• Observations cannot be generalized

Conclusions Treatment with RZ did not have any effect on the primary efficacy outcome of the trial, but exploratory outcomes resulted in a non-significantly lower incidence of new-onset AF and AFB (especially in those with paroxysmal AF patterns) when compared to placebo.

Abbreviations: AAD, antiarrhythmic drug; AF, atrial fibrillation; AFB, atrial fibrillation burden; BID, twice daily; cECG, continuous electrocardiogram; ESRD, end stage renal disease; IV, intravenous; NOAF, new onset atrial fibrillation; NSTE-ACS, non-ST-elevation acute coronary syndrome; NSTEMI, non-ST-elevation myocardial infarction; RZ ranolazine.

RAFFAELLO Trial37

Objective To assess the efficacy of RZ in maintaining NSR after successful electrical cardioversion

Design Sixteen-week, prospective, multicenter, randomized, double-blind, placebo-control trial

Patient Population

Inclusion Criteria Exclusion Criteria

• Adults ≥ 18 years old

• Persistent AF (7 days to 6 months)

• Suitable for direct electrical cardioversion

• First diagnosis of AF or paroxysmal AF

• AF duration > 6 months or permanent AF

• CHF – NYHA functional class III or IV

• Creatinine clearance < 30 mL/min

• Class I or III AADs in the previous 3 days

• Dronedarone in the previous 2 weeks

• Amiodarone in the previous 3 months

• Use of potent CYP3A4 inhibitors or inducers

• Long QT syndrome or QTc interval ≥ 500ms

Study Groups

Control Interventions

Placebo RZ 375 mg BID RZ 500 mg BID RZ 750 mg BID

Outcomes

Primary Secondary

• Time to first documented AF recurrence

• AF recurrence

• Time to first documented AF recurrence (excluding patients with recurrence in the first 48 hours)


Statistics

• A sample size of 60 patients per arm provided 85% estimated power to detect a 50% RZ arm vs placebo reduction in the AF recurrence using a 2-sided log-rank test at alpha = 0.05, assuming exponential time-to-event and time-to-dropout distributions, an 80% recurrence rate in the placebo group, and a dropout rate of 5.3% at 4 months

• Patients who died or discontinued treatment without experiencing a documented AF recurrence were censored at the time of last available ECG

• Hazard ratios for AF recurrence were calculated using the Cox proportional hazards model

• Proportions were compared with x2 tests

Results

• 310 patients were screened and underwent electrical cardioversion o 241 patients remained in NSR after 2 hours and were randomized o 238 patients analyzed (3 patients did not take any study medications) o 217 patients remained without AF recurrence within 48 hours

• Baseline characteristics

Placebo (n=55)

RZ 375 (n=65) RZ 500 (n=60) RZ 750 (n=58) P-value

Age (SD) 65.2 (9.5) 66.9 (11.8) 65.5 (8.5) 63.6 (11.3) 0.197

Men (%) 41 (74.5) 46 (70.7) 51 (85) 46 (79.3) 0.264

HTN (%) 40 (72.7) 47 (72.3) 41 (68.3) 37 (63.8) 0.589

CAD (%) 3 (5.5) 7 (10.8) 4 (6.7) 6 (10.3) 0.54

Diabetes (%) 5 (9.1) 10 (18.2) 5 (9.1) 6 (10.9) 0.816

Medications

Previous AAD 10 (18.2) 14 (21.5) 8 (13.3) 10 (17.2) 0.31

Beta-blockers 23 (41.8) 22 (33.8) 29 (48.3) 23 (39.7) 0.77

Digoxin 7 (12.7) 5 (7.7) 12 (20.0) 7 (12.1) 0.52

o Median time from AF diagnosis was 2.5 months

• Time to AF recurrence o RZ 500 vs placebo, HR = 0.65 (P = 0.116) o RZ 750 vs placebo, HR = 0.64 (P = 0.121)

• Time to AF recurrence (excluding patients with recurrence in the first 48 hours) o RZ 500 vs placebo, HR = 0.56 (P = 0.05) o RZ 750 vs placebo, HR = 0.66 (P = 0.180)

• AF recurrence o 116 patients (48.7%) had AF recurrence

Outcome Placebo (n=55) RZ 375 (n=65) RZ 500 (n=60) RZ 750 (n=58) P-Value

Recurrence (%) 56.4 56.9 41.7 39.7 0.054

o RZ 500 + RZ 750 vs placebo, RR = 0.74 (P = 0.053) o RZ 500 + RZ 750 vs RZ 375, RR = 0.73 (P = 0.035)

• Safety outcomes Placebo (n=55) RZ 375 (n=65) RZ 500 (n=60) RZ 750 (n=58)

Fatigue 9.1% 16.9% 16.7% 15.5%

Dizziness 12.7% 9.2% 3.3% 24.1%

o No significant difference seen in QTc interval or other arrhythmias amongst the groups

Presenter’s Critique


• Assessed different doses of RZ to determine efficacy

• RZ dose were not maximized

• Not generalizable

• Small sample size in each group

• Underpowered

Conclusions This study did not reach its primary endpoint of time to first AF recurrence with RZ but it does suggest a possible antiarrhythmic role with higher RZ doses.

Abbreviations: AAD, antiarrhythmic drug; AF, atrial fibrillation; BID, twice daily; CAD, coronary artery disease; CHF, chronic heart failure; ECG, electrocardiogram; HTN, hypertension; IQ, interquartile range; NYHA, New York Heart Association; QTc, corrected QT interval; RZ 375, ranolazine 375 mg; RZ 500, ranolazine 500 mg; RZ 750, ranolazine 750 mg; SD, standard deviation.


HARMONY Trial38

Objectives To evaluate the effect of RZ and dronedarone when given alone or in combination to patients with paroxysmal AF

Design Prospective, multinational, randomized, double-blind, placebo-control trial

Patient Population

Inclusion Exclusion

• Paroxysmal AF

• Dual-chamber programmable pacemakers implanted within 3 months before screening

• 4-week run-in period prior to randomization with a AFB ≥ 2 % and ≤ 70%

• Persistent/permanent AF

• CHF – NYHA functional class III or IV, recent acute decompensated HF or LVEF ≤ 40%

• Recent coronary surgery, unstable angina or myocardial infarction within 3 months

• Prior serious ventricular arrhythmias or a family/personal history of QT prolongation

• Cardioversion within 1 month of screening

• Concomitant digoxin, dabigatran or AAD use

• Prior use of RZ or dronedarone ≤ 2 months before screening

Study Groups

Control Interventions

Placebo

Dronedarone 225 mg BID Ranolazine 750 mg BID

Ranolazine 750 mg + Dronedarone 150 mg BID Ranolazine 750 mg + Dronedarone 225 mg BID

Methods Pacemaker interrogations were performed at weeks 4, 8, 12

Outcomes AFB over 12 treatment weeks

Statistics

• Baseline demographic characteristics, cardiovascular history, and medications were summarized by treatment regimen for all dosed patients (N=131)

• Efficacies of the 5 treatment regimens on AFB over the 12-week treatment period were compared by log-transforming baseline AFB and AFB over 12 weeks

• AFB was summarized for the full analysis set, defined as all dosed patients with at least 14 days of AFB data obtained for both the baseline period and the post-baseline period (N=120)

• The primary analysis of AFB over 12 weeks was restricted to patients with at least 10 weeks of post-baseline data (N=101)

Results

• 327 patients were screened

• 131 patients were dosed and randomized

• Baseline characteristics o Well balanced

Placebo (n=26)

D225 (n=26)

RZ750 (n=26)

RD150 (n=26)

RD225 (n=27)

Age (SD) 72 (8.4) 75 (7.8) 70 (10.8) 73 (9.4) 71 (7.1)

Men (%) 13 (50) 10 (39) 10 (39) 15 (58) 15 (56)

HTN (%) 20 (77) 22/25 (88) 24 (92) 22 (85) 22 (82)

HF (%) 7 (27) 3(11) 6 (23) 3 (11) 5 (18)

CAD (%) 8 (31) 10/25 (40) 7/25 (28) 9/24 (38) 8/26 (31)

Diabetes (%) 7 (27) 7 (27) 4 (15) 5 (19) 8 (30)

Medications

Previous AAD 11 (42) 16 (62) 12 (46) 5 (19) 13 (48)

Beta-blockers 21 (81) 19 (73) 19 (73) 18 (69) 21 (78)

CCB 4 (15) 6 (23) 9 (35) 10 (39) 8 (30)

• Baseline AFB o Mean AFB was 17.4% o Thirty-four percent had AFB ≥20% o Eleven percent had AFB ≥40% o Median duration of AF episodes recorded was 2.1 hours across all groups


• AFB after 12-week treatment period Placebo D225 RZ750 RD150 RD225

AFB - 5.9% + 3.5% - 23.0% - 45.5% - 59.1%

o RD225 group significantly reduced AFB vs placebo (59% vs 6%, P=0.008) ▪ More than 45% of group achieved AFB reduction of ≥ 70%

o Non-significant reduction of AFB with RD150 vs placebo (45% vs 6%, P=0.072) ▪ More than 27% of group achieved AFB reduction of ≥ 70%

o No significant reduction of AFB occurred with either drug alone versus placebo

• Safety outcomes: AF recurrence, dizziness, dyspnea, constipation, increased INR, and nausea Placebo D225 RZ750 RD150 RD225

AEs 58% 69% 65% 62% 74%

AEs leading to D/C 12% 15% 19% 19% 19%

Conclusions This study demonstrated that in patients with paroxysmal atrial fibrillation who have an implantable pacemaker, RD225 combination may decrease AFB and be a safe/tolerable option in this population.

Presenter Critique


• Continuous AF monitoring using an implanted pacemaker

• Reduced dose of dronedarone used in combination with RZ

• Limited generalizability

• Full-strength RZ or dronedarone not used

• Inconsistencies in manuscript results

• Author conflict of interest

Abbreviations: AAD, antiarrhythmic drug; AE, adverse effects; AF, atrial fibrillation; AFB, atrial fibrillation burden; AV, atrioventricular; BID, twice daily; CAD, coronary artery disease; CHF, chronic heart failure; D225, dronedarone 225 mg; D/C, discontinuation; HF, heart failure; HTN, hypertension; INR, international normalized ratio; NYHA, New York Heart Association; RD150, ranolazine 750 mg plus dronedarone 150 mg; RD225, ranolazine 750 mg plus dronedarone 225 mg; RZ ranolazine; RZ750, ranolazine 750 mg.


VII. Summary of trials a. MERLIN-TIMI 36

i. Patients with non-ST-elevation acute coronary syndrome ii. Trend towards less AF occurrences within first 7 days iii. Less AFB overall (especially in patients with paroxysmal AF) within first 7 days iv. Less clinical AF events reported over 1-year follow-up

b. RAFFAELLO i. Patient with persistent AF (7 days to 6 months) ii. Trend towards prolonged time to AF recurrence with higher RZ doses iii. Trend towards less AF recurrence with higher RZ doses

c. HARMONY i. Patients with paroxysmal AF patterns ii. Reduction in AFB with RZ 750 mg + dronedarone 225 mg combo iii. Trend towards reduction in AFB with RZ 750 mg + dronedarone 150 mg combo

VIII. Summary and conclusion

a. Overall i. The ability to maintain NSR in patients with AF remains a clinical challenge ii. Currently available AADs are limited due to a lack of efficacy, safety profile or disease

state interactions iii. RZ has a unique inhibitory effect on the late inward sodium channels in cardiac myocytes

and has a potential antiarrhythmic role in the prevention of AF and maintenance of NSR b. Clinical recommendations

i. Avoid use as a monotherapy due to lack of evidence ii. Potential place in therapy

1. Adjunctive treatment in patients with refractory paroxysmal AF who have failed the currently available options

2. Stable ischemic heart disease c. Future directions

i. Adjunctive treatment to other AADs in a more generalized patient population ii. Higher doses of ranolazine (i.e. 1000 mg BID) versus placebo for maintenance of NSR iii. Long-term efficacy and safety studies for AF


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APPENDICES Appendix A. CHADS2 and CHA2DS2-VASc Risk Stratification Schemes1

Definition and Scores for CHADS2 and CHA2DS2-VASc Stroke Risk Stratification with the CHADS2 and CHA2DS2-VASc scores

Score Adjusted stroke rate

(%per y)

CHADS2 acronym CHADS2 acronym

Congestive Heart Failure 1 0 1.9%

Hypertension 1 1 2.8%

Age ≥ 75 years old 1 2 4.0%

Diabetes 1 3 5.9%

Stroke/TIA/Thromboembolism 2 4 8.5%

Maximum Score 6 5 12.5%

CHA2DS2-VASc acronym 6 18.2%

Congestive Heart Failure 1 CHA2DS2-VASc acronym

Hypertension 1 0 0%

Age ≥ 75 years old 2 1 1.3%

Diabetes 1 2 2.2%

Stroke/TIA/Thromboembolism 2 3 3.2%

Vascular disease (prior MI, PAD, or aortic plaque) 1 4 4.0%

Age 65–74 years old 1 5 6.7%

Sex category (i.e., female sex) 1 6 9.8%

Maximum Score 9 7 9.6%

Abbreviations: TIA, transient ischemic attack; MI, myocardial infarction; PAD, peripheral artery disease.

8 6.7%

9 15.20%

Appendix B: Direct Oral Anticoagulants1

DOAC Dosing Special Considerations

dabigatran (Pradaxa®)

• 150 mg BID

• Renal dosing – CrCl 15-30: 75mg PO BID

• Drug Interactions: o Avoid use with dronedarone or ketoconazole (oral) & CrCl 30-50 o Avoid use with P-gp inducers o Avoid use with any P-glycoprotein inhibitor & CrCl <30 o Reduced efficacy with drugs that increase pH level

• Major Side Effects: dyspepsia, GI problems (>20%), bleeding

• Must be kept in original container and discarded 4 months after opening

• Antidote idarucizumab (Praxbind®)

apixaban (Eliquis®)

• 5 mg BID

• If patient has any 2 of the following, age ≥ 80, weight ≤ 60 kg, SCr ≥ 1.5 mg/dL: 2.5mg BID

• Drug Interactions: o Reduce dose to 2.5 mg BID with strong CYP3A4 and P-gp inhibitors o Avoid use with strong CYP3A4 and P-gp inducers

• Can be crushed and mixed with apple juice/sauce

rivaroxaban (Xarelto®)

• 20mg QDay

• Renal dosing – CrCl 15-50: 15mg PO QDay

• Give with evening meal

• Drug Interactions: Avoid use with combined P-gp and strong CYP3A4 inducers and inhibitors

• Can be crushed and mixed with apple juice/sauce

edoxaban (Savaysa®)

• CrCl 51-95: 60mg QDay

• CrCl 15-50: 30mg PO QDay

• Do not use in patients with CrCl > 95 ml/min

• Boxed Warning: Reduced efficacy in patients with CrCl > 95 mL/min

• Drug Interactions: Avoid use with P-gp inducers


Appendix C. Characteristics of Antiarrhythmic Drugs Used for Rhythm Control of AF and Ranolazine36

Drug Route Half-Life Dose Pricing per dosage form

Amiodarone PO/IV ~50 days Oral: Load 10 g over 7-10 days followed by 200 mg daily IV: 150 mg bolus, then 1 mg/min infusion for 6 hours followed by 0.5 mg/min thereafter

$3.33

Dofetilide PO 6-10 hours CrCl > 60 mL/min: 500 mcg every 12 hours CrCl 40-60 mL/min: 250 mcg every 12 hours CrCl 20-39 mL/min: 125 mcg every 12 hours

$8.55

Dronedarone PO 13-19 hours

400 mg every 12 hours $12.61

Flecainide PO 7-23 hours 50-200 mg every 12 hours $2.00

Ibutilide IV 6 hours 1 mg infusion over 10 minutes; may repeat once if needed 10 minutes after initial infusion ends

N/A

Propafenone PO 9 hours Immediate release: 150-300 mg every 8 hours Extended release: 225-425 mg every 12 hours

$1.63 - $11.09

Ranolazine PO 7 hours 500-1000 mg every 12 hours $11.72

Sotalol PO 8 hours 80-160 mg every 12 hours $2.56 - $5.55

Appendix D: TIMI Risk Score Calculator40

TIMI Risk Score for UA/NSTEMI (1 point for each variable)

• Age ≥ 65

• Patient experiences chest pain despite ASA use in past 7 days

• ≥ 2 angina episodes in prior 24hrs

• ST segment deviations on ECG

• Elevated serum cardiac biomarkers

• Prior history of CAD (coronary stenosis ≥ 50%)

• ≥ 3 risk factors for CAD, such as:

• HTN

• Current cigarette smoker

• Low HDL cholesterol (< 40 mg/dL)

• Diabetes mellitus

• Family history of premature CAD (Male first-degree relative or father younger than 55; Female first-degree relative or mother younger than 65)

Low risk (score 0-2)

Medium risk (score 3-4)

High risk (score 5-7)

TIMI Risk Score All-cause mortality

0-1

2

3

4

5

6-7

4.7%

8.3%

13.2%

19.9%

26.2%

40.9%

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