1. Cheryl A. Abbas, PharmD Clinical Pharmacist Advanced Heart Failure and Heart Transplant Thomas Jefferson University Hospital

2. Review the physiological effects of a continuous-flow left-ventricular assist device (CF-LVAD) Understand the role of pharmacotherapy in the management of CF-LVADs Evaluate clinical symptoms and device findings in the diagnosis of CF-LVAD complications Describe the pharmacotherapy of device-related complications

3. Progression of heart failure leads to refractory treatments ~250,000 of 7 million patients will develop advanced disease Inotropic support survival rate of 10-30% at 1 year Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Fifth annual report: 7,000 patients in the United States Increase in implanting centers from ~109 to ~147 in January 2011 to 2012 Chetan PB. J Heart Lung Transplant 2014;33:667-674.

4. Implanted pump delivering blood from left ventricle to ascending aorta Flow rate up to 10 liters per minute Mean pressure of 100 mm HG Continuous flow vs. pulsatile devices Greater durability Reduced size and weight Silent operation Improved quality of life

5. BTT = Bridge to Transplant DT = Destination Therapy Slaughter, MS. J Heart Lung Transplant 2010;29:S1-S39.

6. Patient assessment: Appropriateness based on degree of illness Heart Failure Survival Score; Seattle Heart Failure Score Ability to undergo operative procedure Adequate family/caregiver support for long-term success Slaughter, MS. J Heart Lung Transplant 2010;29:S1-S39.

7. Rotary blood pump Percutaneous driveline to external controller External batteries or power-based unit Estimated lifespan of pump: 5-10 years

8. Slaughter, MS. N Engl J Med 2009;361:2241-51.

9. Speed: Fixed in range of 8,000 – 12,000 RPMs Power: Direct measure of voltage to motor (4-7 watts) Flow: Estimated speed x power (3-7 liters/minute) Afterload sensitive - affected by hypertension ↑AO → ↓ Flow ↓AO → ↑ Flow Pulsatility Index (PI): Flow pulse through pump (4-8) Native LV contractility and volume status Thoratec Press Kit: HMII Pivitol Trial Fact Sheet.

11. Hemodynamic effect of CF-LVAD: Increase in diastolic pressure and flow Reduced pulse pressure Difficult to palpate pulse Mean arterial blood pressure (MAP) measured by doppler Goal MAP: 70-80 mmHG Amount of cardiac output by CF-LVAD affected by afterload Maintaining goal = optimized cardiac output Reduces stroke due to hypertension

12. Vasoactive agents ACEi/ARB, β-blockade, hydralazine, nitrates Hypertension: assess BP and volume status CF-LVAD parameters Decrease in pump flow and power Increase in PI Management: Decrease afterload with medications Consider diuretics for volume overload Hypotension: symptoms, BP monitoring CF-LVAD parameters Increase in pump flow and power Decrease in PI Management: Adjust vasoactive agents Intravascular fluid volume management Slaughter, MS. J Heart Lung Transplant 2010;29:S1-S39.

13. Required to avoid thrombotic complications Early BTT HeartMate II trials included aggressive anticoagulation (AC) Target INR range 2.5 to 3.5 Incidence of thrombosis < bleeding  resulted in reduced AC therapy ISHLT MCS Guidelines Anticoagulation: Warfarin with target INR based upon manufacturer HeartMate II: 2.0 to 3.0 Antiplatelet: Aspirin 81-325 mg daily in addition to warfarin Additional agents may be added Feldman, D. J Heart Lung Transplant 2013;32:157-187.

14. Boyle, et al evaluated long term AC therapy in 331 HeartMate II outpatients Risk of thrombosis increased with INR < 1.5 Risk of hemorrhagic events present at all INR ranges; increased with INRs > 2.5 Slaughter, MS. J Heart Lung Transplant 2010;29:S1-S39.

15. Increased platelet activation from sheer stress Agents: Aspirin 81-325 mg daily Clopidogrel 7g mg daily Dipyridamole 75 mg tid Pentoxifylline 400 mg tid Lack of data: Ticagrelor and Prasugrel Hypo- or non-responsiveness is commonly seen Doubling of dose

16. RW is a 63 y/o M PMH DM, HL, dilated NICM s/p LVAD placement (HMII) in 2014. He presents to clinic, where the LVAD coordinator obtains a doppler BP of 130 mmHG. When interrogating the device, what LVAD parameters may be found? A. Decreased PI B. Increased power C. Decreased flow D. None of the above

18. Development of clot within the flow path or any/all components Leads to pump failure Uncommon complication ADVANCE trial 6.4% risk HMII up to 6.25% risk Pump-related risk factors: Inflow cannula malposition Outflow graft kink/compression Low flows from low speeds or right-sided dysfunction Goldstein DJ, et al. J Heart Lung Transplant 2013; 32:667–670. http://ejcts.oxfordjournals.org/content/39/3/414/F1.expansion.

19. Patient-related risk factors: Atrial fibrillation Pre-existent LV thrombus Prosthetic mechanical valve Sepsis Sub-therapeutic INR Inadequate anti-platelet therapy Pro-coagulant states Hemolysis is a result of shear stress!

20. Routine diagnosis of hemolysis Plasma Free Hemoglobin (pfHb) > 40 mg/dL Lactate Dehydrogenase (LDH) > 3x ULN Haptoglobin < 10 mg/dL Dark red (tea-colored) urine Power elevations (>10 watts) Imaging Chest x-ray and CT: malposition Echocardiogram: suboptimal LV unloading Right-heart catheterization: elevated pressures Goldstein DJ, et al. J Heart Lung Transplant 2013; 32:667–670.

21. Surgical: VAD exchange Significant morbidity Pharmacology GPIIbIIIa inhibitors Thrombolytics Intraventricular vs peripheral administration Modify antithrombotic therapy Increase aspirin dose (81 to 325 mg daily) Increase goal INR Add antiplatelet agent (clopidogrel, dipyridamole)

22. Goldstein DJ, et al. J Heart Lung Transplant 2013; 32:667–670.

23. Retrospective review; single center, Jan 2006-Nov 2012 Evidence of hemolysis + high clinical suspicion of VAD thrombosis, n=33 (of 217, 15.2%) Mortality: 15/33, 45.5% Treatment: (7 deaths) – Eptifibatide, n=9 – tPA, n=5 – Both, n=10 No treatment, n=9 (5 pump exchanges, 4 deaths) High mortality rate with and without pharmacologic treatment Lenneman AJ, et al. J Heart Lunt Translant 2013; 32:S186-187.

24. CW is a 56 y/o F w/ICM s/p LVAD (HMII) who presented to the hospital from LVAD clinic with an increase in LDH to 764 (baseline 295) and persistent elevations in power >10 watts PMH: CAD, sCHF with BiV ICD, COPD, DM CW was started on IV heparin upon admission, and resumed her outpatient warfarin (goal INR 2-2.5) and aspirin 325mg qday

25. Which of the following agents could be added to her anticoagulation regimen? A. Cilostazol 100mg po bid B. Clopidogrel 75mg po qday C. Dipyridamole 75mg po tid D. B or C E. None of the above

27. Most common adverse event after HMII Incidence: 17-31% Frequent and prolonged hospitalizations Gastrointestinal angiodysplasia (GIAD) Most common cause of GIB: 15-31% of total Arteriovenous malformations (AVMs) Gastric antral vascular ectasia (GAVE) Retrospective, single-center review of 172 patients 19% (32/172) rate of GIB AVMs: 31% (10/32) Bunte MC, et al. J Am Coll Cardiol 2013;62:2188-96. Draper K, et al. J Heart Lung Transplant 2015;34(1):132-4.

28. Narrow pulse pressure: ↓ intraluminal pressure Vascular dilatation  angiodysplasia, AVMs Hypoperfusion  intestinal mucosa ischemia Over-expression of angiogenic growth factors Acquired Von Willebrand Disease Increased shear stress, turbulence, and high velocities Von Willebrand factor cleavage  increased bleeding and decreased platelet-mediated hemostasis

29. Decrease in hemoglobin (Hgb) Obtain coagulation panel (PT/PTT/INR) Symptoms: symptomatic anemia Fatigue, dizziness, dyspnea on exertion Melena Hypotension (decreased MAP) Adjust vasoactive medications Decrease in PI Consider volume expansion

30. Blood transfusions to target Hgb Problematic for patients listed for transplant Addition of proton pump inhibitor Prophylaxis vs. treatment Colonoscopy +/- endoscopy: suspected bleeding sites Endoscopic ablation of AVMs Mechanical clipping Cauterization Argon plasma coagulation (APC) Surgical resection Ray R, et al. ASAIO Journal 2014;60:482-483.

31. Cessation of anticoagulation Hold warfarin in setting of clinically significant bleed Assess need for IV heparin when INR < goal Reduction of anticoagulation Decrease goal INR Modify or discontinue antiplatelet therapy Reduction of CF-LVAD speed Increase pulse pressure  reduce shear stress

32. Anticoagulation protocols Reductions in response to bleeding Octreotide Difficult to tolerate: mode of delivery (injection) Adverse effects: nausea and bradycardia Thalidomide: potent anti-angiogenic compount Inhibition of vascular endothelial growth factor (VEGF) Recurrent GIAD-related bleeding Associated thrombosis REMS program Lenalidomide: synthetic analog of thalidomide Less non-hematologic adverse effects Draper K, et al. J Heart Lung Transplant 2015;34(1):132-4.

33. Additional studies needed: Blood product use Platelet aggregometry Thromboelastography Use is currently insufficient to make recommendations Perioperative bleeding risk stratification Individualized bleeding score Could offer tailored post-operative AC to limit bleeding

35. JH is a 67 y/o M w/ICM s/p DT LVAD (HMII) implant in May 2015, p/w 2 episodes of melena overnight, dizziness, and fatigue. MAP on admission is 55 mmHG. LVAD interrogation shows multiple PI events (decreased). Labs on admission: Hgb 7.5 mg/dL (baseline 10.0 mg/dL) INR 3.3 (goal INR 2-2.5) Current medications: Amiodarone 200 mg po qday, aspirin 325 mg po qday, carvedilol 12.5 mg po bid, furosemide 20 mg po qday, pantoprazole 40 mg po qday, potassium chloride 20 mEq po qday, warfarin 5 mg po qday

36. JH was transfused 2 units of PRBC and Gastroenterology was consulted with plan for colonoscopy for ? lower GIB. In addition to holding warfarin, what other medication adjustments would you make at this time? A. Discontinue furosemide 20 mg po qday B. Discontinue carvedilol 25 mg po bid C. Lower aspirin to 81 mg po qday D. All of the above

38. CF-LVADs decreased rate of infection by 50% Goldstein, et al. INTERMACS registry: 2008-2013 implants; n = 9,372 2 nd most common cause of death post 6-month survival Most common: Sepsis = 23% Pneumonia = 20% Percutaneous site/driveline infection (PSI) = 19% Causative organisms Staphylococcus species Pseudomonas species Prominent w/longer VAD support Difficult to eradicate Goldstein DJ, et al. J Heart Lung Transplant 2012;31(11):1151-7.

39. Association with cerebrovascular events (CVEs) Persistence of bacteremia > 72 hours Persistent Pseudomonas aeruginosa blood stream infections  7-fold increase in CVEs Mycotic aneurysms Potential mechanisms of CVEs: Platelet activation Alterations in endothelial function Systemic inflammation Bacterial seeding of cerebral vasculature Aggarwal A, et al. ASAIO J 2012;94(5):1381-6.

40. Disruption or trauma to the barrier between skin and driveline Formation of biofilm Increase difficulty to eradicate bacteria Staphylococcus and Pseudomonas Peri-operatively and post-operatively Average time to occurrence of PSI = ~6 months PSI locations May remain superficial Spread along driveline path, into pocket or pump Deepen within abdominal wall to form abscess Trachtenberg B, et al. MDCVJ 2015;11(1):28-32.

41. CVC: central venous catheter BSI: blood stream infection SSI: surgical site infection Trachtenberg B, et al. MDCVJ 2015;11(1):28-32.

42. Immobilization of percutaneous lead at exit site Prevents disruption of subcutaneous tissue growth Methods: minimize trauma and tension Anchoring devices Stabilization belts Exercise sterile vs. clean technique for exit site care Patient education Report increased drainage or erythema immediately Gentle and non-traumatic exit site cleaning

43. REMATCH study (HeartMate XVE): Vancomycin 15 mg/kg IV 1 hour pre-op then q12h Levofloxacin 500 mg IV 1 hour pre-op then q24h Rifampin 600 mg po 1 hour pre-op then q24h Fluconazole 200 mg IV 2 hours pre-op then q24h Most centers omit rifampin, use β-lactams, or tailor to institutional antibiogram Continue for 48-hours HeartWare recommendations: Cover S. aureus, S. epidermidis, and Enterococcus according to institutional antibiogram Richenbacher WE, et al. Ann Thorac Surg 2003;75:S86-92.

44. Prompt culture of drainage 3 sets of blood cultures Imaging Chest radiography Echocardiogram: pacemakers or defibrillator leads Presence of valvular endocarditis or device infections Ultrasound or CT: Diagnose collections of fluid around driveline, pump, or pump pocket Guide aspiration or debridement Feldman D, et al. J Heart Lung Transplant 2013;32(2):157-87.

46. Hospitalization criteria: Signs of systemic infection = fever or leukocytosis Mild infection: Increase frequency of dressing changes Review dressing change protocols for compliance Moderate infection: Tailor antibiotic therapy Local debridement Weekly clinic visits Severe infection: purulent drainage and subcutaneous induration Target antimicrobial therapy with ID consult Imaging tests Surgical interventions: debridement or retunneling of driveline Trachtenberg B, et al. MDCVJ 2015;11(1):28-32.

47. Additional tools Wound vacuum-assisted closure therapy Antimicrobial beads Chronic suppressive oral antibiotics For recurrent VAD-specific or VAD-related infections 1/3 of patients have recurrence despite antibiotics Device exchange (severe cases) Expediting heart transplant listing Studies show no increase in mortality post-transplant

49. Newer devices  improvements in survival Every VAD patient is different! Importance of understanding VAD-specific parameters Balancing act between VAD thrombus and GIB Preventative measures of infection Need more data Publish your experience!!!