Pam Lyons PharmD Candidate 2014 Pharmacotherapy Scholars Program University of Pittsburgh School of Pharmacy Ventricular Tachycardia and the Role of Ranolazine

Objectives 2 Be able to explain the mechanism of action of ranolazine Describe the role of ranolazine in ventricular tachycardia and ischemic heart disease Understand the difference between premature ventricular beats and ventricular tachycardia List the types of ventricular tachycardia

DN – Presentation 7/31/13 3 CC: “I don’t feel well” HPI: 61 yo male presented to ER with palpitations and lightheadedness that had been occurring for ~1 week, mild cough Feels similar to how he usually feels when in VT. No orthopnea, CP, LE edema, fever, chills, n/v/d Claims compliance with all medications

Saw his cardiologist the morning of 7/31/13 who recommended an ablation 150 episodes of VT since 5/2013 –10 episodes in the 24 hrs before appointment –ICD had not fired In ER: Several runs of non-sustained VT –ICD did not fire DN - Earlier that Morning… 4

DN -PMH 5 Mixed ischemic and non-ischemic cardiomyopathy EF: 25-30% (5/2013) Inferior wall hypokinesis Ventricular Tachycardia s/p radiofrequency ablation x2 (12/12, 2/13) DVT CKD COPD OSA

DN - Social History 6 Former smoker (-) EtOH, illicit drugs NKDA

7 Ranolazine 1000 mg BID Cavedilol 50 mg BID Furosemide 40 mg BID Simvastatin 20 mg daily Valsartan 80 mg daily Warfarin 4 mg q MWFSat Sildenafil 20 mg TID Albuterol 90 mcg/inhalation – 1 puff q 4 hr PRN Duoneb (albuterol-ipitropium) 3mg/0.5 mg – QID PRN Advair 500/50mcg – 1 puff BID Trazodone – 50 mg HS PRN Spirololactone 25 mg – ½ tab BID Senna – 2 tabs HS Pantoprazone 40 mg daily Mulitvitamin daily Potassium Chloride ER 20 mEq daily DN - Home Medications

8 Vitals: BP: /54-81 Pulse: bpm RR: SaO2: 95-99% Temp: 37.2 Ht: 74 in Wt: 101 kg, BMI: 28.6 Exam: No JVD Warm and dry Diminished breath sounds

Metabolic Panel: –Na 137, K 4.0, Cl 102, CO2 28, BUN 34, Cr 2.8, Gluc 137 CBC: –WBC 4.8, Hgb 15.4, Hct 47.1, Plts 234 Troponins (-) EKG: –Atrial paced rhythm with prolonged PR interval and PVCs –T wave inversions –Same as previous EKGs CXR: –Clear lungs with mild vascular congestion DN - Labs 9

DN - Initial treatment IV metoprolol 5 mg IV lidocaine 150 mg followed by drip at 2 mg/min IV magnesium sulfate 2 g Transferred to CCU

VT: likely secondary to previous infarct seen on stress test in 4/12 –Continue lidocaine drip at 2 mg/min Check level in the morning –Ranolazine 1000 mg PO BID –Consider another ablation HF: –Continue valsartan, lasix, carvedilol, simvastatin, sildenafil COPD –Give O2 as needed –Continue home medications DN – Day 1 Plan (7/31/13)

DVT –Warfarin –Check INR tomorrow morning CKD –Currently at baseline PPX –On warfarin for DVT prophylaxis CCU– Day 1 Plan (7/31/13) 12

13 Pt reports no palpitations since transfer New epigastric pain and R sided CP –Non-radiating –Bloated feeling Lidocaine level: 3.8 ug/ml –Goal: 1-5 ug/ml INR: 2.1 –Holding warfarin b/c of possible ablation Carvedilol decreased to 25 mg BID from 50 mg BID CCU - Day 2 (8/1/13)

CCU - Day 3 (8/2/13) Pt had HA overnight –Decrease lidocaine drip to 1 mg/min –Level: 4.1 ug/ml BP: / –Increase carvedilol from 25mg BID  37.5 mg BID –Increase valsartan from 40 mg BID  80 mg BID Plan for ablation next week –Holding Coumadin INR 2.2 –Start heparin drip

Stable  just waiting for ablation –No more VT –BP: /42-75, Pulse: Lidocaine changed to PO mexilitine 150 mg q8hr Transferred to Pavillion CCU - Day 4 (8/3/13)

Heart failure improving –Euvolemic, NYHA II Holding Lasix Development of AKI on CKD –Scr 3.0 –Possibly due to increase in valsartan – hold it –250 NS bolus Pavillion - Day 5 (8/4/13) 16

7/318/18/28/38/4 Na Scr BUN Mg Pavillion – Day 5 Lab Trends 17

VT –>90 short runs –Continue ranolazine –D/c mexilitine after tonight Heart Failure Stable –Euvolemic +695 ml from yesterday Holding lasix AKI on CKD –Not improving from yesterday –Scr 3.3 – up from 3.0 –UA normal –Hold valsartan until Scr improves DVT –Holding warfarin – ablation planned for 8/7 –INR – 1.3 Pavillion - Day 6 (8/5/13) 18

VT worsening –Frequent episodes of longer duration –Continue mexiletine today, then hold for ablation –Transferred to CCU –Restart lidocaine 100 mg IV once Then drip 2 mg/min –Awaiting ablation tomorrow –Sympotmatic AKI improving –Scr down to 2.7 Hemodynamically stable All other lab WNL Pavillion - Day 7 (8/6/13) 19

Ablation –Found scar on the LV – possible cause for VT –Multiple ablations to the mid  apex of the inferoseptal wall Back in the CCU: –DN complains of substernal CP Non-radiating, non-pleuritic, not reproducible –No further palpitations –2 episodes of Altered Mental Status – resolved spontaneously –Starting to get frustrated Vitals: –BP: /83-102, pulse Scr improving – 2.4 CCU – Day 8 (8/7/13) – Ablation Day 20

Stable overnight –Had some low BP: /40-50 Decrease Coreg from 37.5 BID to 25 BID VT –Pain from ablation improving –No further runs of VT Lidocaine drip d/ced Continue mexiletine and ranolazine HF –Restart valsartan 40 mg BID –Restart lasix 40 mg BID –Start spironolactone 12.5 mg daily –Continue sildenafil 20 mg TID CCU – Day 9 (8/8/13) 21

DVT –D/c warfarin completely CKD –AKI improving –Scr = 2.2 At baseline –Monitor Scr closely CCU – Day 9 (8/8/13) 22

Stable – only 1 run of VT overnight New toe pain –Suspected gout –Avoiding colchicine b/c of CKD –Start prednisone 30 mg Transferred to 4D CCU - Day 10 (8/9/13) 23

Ventricular Tachycardia 24 Goldberger: Clinical Electrocardiography, 8th ed.

What is it? –Premature = before the beat –Appear as a wide QRS wave T wave and QRS waves point in opposite directions Prevalence –Extremely common at all ages –Healthy and sick people Etiology –Ventricular pacemakers take over Caffeine, stress, cocaine, stimulants, digoxin, electrolyte imbalances –In heart disease Ischemia, fibrosis, scarring, from previous MI Premature Ventricular Beats 25 Goldberger: Clinical Electrocardiography, 8th ed.

Symptoms –Usually none –Severe palpitations Treatment –None –Possibly Beta blockers for symtomatic PVB Frequent VPB requires further workup Premature Ventricular Beats 26 Goldberger: Clinical Electrocardiography, 8th ed.

Three or more PVB in a row = Ventricular Tachycardia –Rate >100 BPM Causes –Reentrant –Focal Length of Arrhythmia –Sustained >30 seconds or requiring defibrillation –Non-sustained <30 sec Appearance on EKG –Monomorphic –Polymorphic Ventricular Tachycardia 27 Goldberger: Clinical Electrocardiography, 8th ed. Krannert Institute for Cardiology.. Cardiol Clin :459–479

Type of polymorphic VT Causes –QT prolongation Congenital Acquired –Class Ia AAD, sotalol, dofetilide, phenothiazines, TCAs, erythromycin, etc –Electrolyte imbalances: hypomagnesemia, hypokalemia –Severe bradyarrhythmias Torsades de Pointes 28 Goldberger: Clinical Electrocardiography, 8th ed.

Drug of Choice: –Amiodarone: 150 mg over 10 minutes  1mg/min drip x 6hrs  0.5mg/min drip Second line: –Lidocaine: 1.5 mg/kg repeated q 3-5 minutes Maintenance dose: 1-4 mg/min Third line: –Procainamide 30 mg/min Maintenance dose: 1-4 mg/min Polymorphic VT –Magnesium Sulfate 1-2 g IV over 10 minutes ACLS Guidelines for the treatment of VT 29 Goldman L et al. Goldman’s Cecil Maedicine Mizzi A et al. Anesthesiol Clin. 2011;29(3):

Ranolazine: Place in Treatment 30

Indication: –Chronic Stable Angina Ranolazine 31

Ranolazine Mechanism 32 Ranolazine Ranolazine package insert Bunch, JT. PACE. 2011;34: Scirica BM et al. Circulation. 2007;116:

33

Role of Ranolazine in Ventricular Tachycardia 34

Ranolazine for Ventricular Tachycardia 35 MERLIN-TIMI 36 Trial 6560 Patients with NSTEMI IV Ranolazine then Oral Ranolazine Placebo Primary Outcome: Effect of ranolazine on the compostie of CV death and ischemia Scirica BM et al. Circulation. 2007;116:

6351 patients with valid EKGs –Mean age: 63 years –Females: % –HTN: % –Smoker: % –Prior heart failure: % –Prior ventricular arrhythmia: % –Prior MI: 34% Median duration of EKG = 6.8 days MERLIN –TIMI 36 Patients 36 Scirica BM et al. Circulation. 2007;116:

Effects of Ranolazine on Heart Rhythm 37 Scirica BM et al. Circulation. 2007;116:

Patients: –12 patients with VT refractory to other treatments All on a Class III anti-arrhythmic and with an ICD –Frequent shocks 6 patients had failed a previous Class III 2 patients on IV anti-arrhythmic 6 on either lidocaine or mexilitine 5 with previous ablations 2 being referred for ablation –10 had ischemic heart disease –Average EF: 34% +/ Effect of Ranolazine in Refractory Patients: Case Series 38 Bunch TJ et al. PACE. 2011;34:

Effect of Ranolazine in Refractory Patients: Case Series patients with refractory VT Ranolazine 1000mg BID for 6 months Reduction in VT in 11 of 12 patients

Negatives: –QRS increased non-significantly –No benefit to 2 patients Arrhythmogenic right ventricular cardiomyopathy/dysplasia nonischemic cardiomyopathy –GI side effects limited use in 2 patients –4 hospitalizations –May lower blood glucose and A1c Effect of Ranolazine in Refractory Patients: Case Series 40

41 Questions?