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Cheryl A. Abbas, PharmD
Clinical Pharmacist
Advanced Heart Failure and Heart Transplant
Thomas Jefferson University Hospital
Complications of Continuous-Flow Left
Ventricular Assist Devices
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
Objectives
Progression of heart failure leads to refractory treatments~250,000 of 7 million patients will develop advanced
diseaseInotropic 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
Role of Mechanical Circulatory Support
Chetan PB. J Heart Lung Transplant 2014;33:667-674.
Implanted pump delivering blood from left ventricle to ascending aortaFlow rate up to 10 liters per minuteMean pressure of 100 mm HG
Continuous flow vs. pulsatile devicesGreater durability Reduced size and weightSilent operationImproved quality of life
Left Ventricular Assist Devices (LVADs)
Continuous-flow Devices
BTT = Bridge to TransplantDT = Destination Therapy
Slaughter, MS. J Heart Lung Transplant 2010;29:S1-S39.
Patient assessment:Appropriateness based on degree of illness
Heart Failure Survival Score; Seattle Heart Failure ScoreAbility to undergo operative procedureAdequate family/caregiver support for long-term
success
LVAD Candidacy
Slaughter, MS. J Heart Lung Transplant 2010;29:S1-S39.
HeartMate II (HMII)
Rotary blood pump
Percutaneous driveline to external controller
External batteries or power-based unit
Estimated lifespan of pump: 5-10 years
CF-LVAD Physiology
Slaughter, MS. N Engl J Med 2009;361:2241-51.
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
CF-LVAD Parameters
Thoratec Press Kit: HMII Pivitol Trial Fact Sheet.
Pharmacotherapy in CF-LVAD
Blood Pressure MonitoringHemodynamic effect of CF-LVAD: Increase in
diastolic pressure and flowReduced pulse pressure
Difficult to palpate pulseMean arterial blood pressure (MAP) measured by
doppler
Goal MAP: 70-80 mmHGAmount of cardiac output by CF-LVAD affected
by afterloadMaintaining goal = optimized cardiac output
Reduces stroke due to hypertension
Blood Pressure ManagementVasoactive agents
ACEi/ARB, β-blockade, hydralazine, nitrates
Hypertension: assess BP and volume status CF-LVAD parameters
Decrease in pump flow and powerIncrease in PI
Management: Decrease afterload with medicationsConsider diuretics for volume overload
Hypotension: symptoms, BP monitoring CF-LVAD parameters
Increase in pump flow and powerDecrease in PI
Management: Adjust vasoactive agentsIntravascular fluid volume management
Slaughter, MS. J Heart Lung Transplant 2010;29:S1-S39.
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 GuidelinesAnticoagulation: Warfarin with target INR based upon
manufacturerHeartMate II: 2.0 to 3.0
Antiplatelet: Aspirin 81-325 mg daily in addition to warfarinAdditional agents may be added
Anticoagulation
Feldman, D. J Heart Lung Transplant 2013;32:157-187.
Boyle, et al evaluated long term AC therapy in 331 HeartMate II outpatientsRisk of thrombosis increased with INR < 1.5
Risk of hemorrhagic events present at all INR ranges; increased with INRs > 2.5
Anticoagulation
Slaughter, MS. J Heart Lung Transplant 2010;29:S1-S39.
Increased platelet activation from sheer stress
Agents:Aspirin 81-325 mg dailyClopidogrel 7g mg dailyDipyridamole 75 mg tidPentoxifylline 400 mg tid
Lack of data: Ticagrelor and Prasugrel
Hypo- or non-responsiveness is commonly seenDoubling of dose
Antiplatelet Agents
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 PIB. Increased powerC. Decreased flowD. None of the above
Patient Case
CF-LVAD Thrombosis
Development of clot within the flow path or any/all componentsLeads to pump failure
Uncommon complicationADVANCE trial 6.4% riskHMII up to 6.25% risk
Pump-related risk factors:Inflow cannula malpositionOutflow graft kink/compressionLow flows from low speeds or right-sided
dysfunction
Pump Thrombosis
Goldstein DJ, et al. J Heart Lung Transplant 2013; 32:667–670. http://ejcts.oxfordjournals.org/content/39/3/414/F1.expansion.
Patient-related risk factors:Atrial fibrillationPre-existent LV thrombusProsthetic mechanical valveSepsisSub-therapeutic INRInadequate anti-platelet therapyPro-coagulant states
Hemolysis is a result of shear stress!
Pump Thrombosis
Routine diagnosis of hemolysisPlasma Free Hemoglobin (pfHb) > 40 mg/dLLactate Dehydrogenase (LDH) > 3x ULNHaptoglobin < 10 mg/dLDark red (tea-colored) urine
Power elevations (>10 watts)
ImagingChest x-ray and CT: malpositionEchocardiogram: suboptimal LV unloadingRight-heart catheterization: elevated pressures
Diagnosis of Pump Thrombosis
Goldstein DJ, et al. J Heart Lung Transplant 2013; 32:667–670.
Surgical: VAD exchangeSignificant morbidity
PharmacologyGPIIbIIIa inhibitorsThrombolytics
Intraventricular vs peripheral administration
Modify antithrombotic therapyIncrease aspirin dose (81 to 325 mg daily)Increase goal INRAdd antiplatelet agent (clopidogrel, dipyridamole)
Treatment Options
Management of Pump Thrombosis
Goldstein DJ, et al. J Heart Lung Transplant 2013; 32:667–670.
• 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
Management of Pump Thrombosis
Lenneman AJ, et al. J Heart Lunt Translant 2013; 32:S186-187.
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
Patient Case
Which of the following agents could be added to her anticoagulation regimen?
A. Cilostazol 100mg po bidB. Clopidogrel 75mg po qday C. Dipyridamole 75mg po tidD. B or CE. None of the above
Patient Case Continued
Gastrointestinal Bleeding (GIB)
Most common adverse event after HMII Incidence: 17-31%Frequent and prolonged hospitalizations
Gastrointestinal angiodysplasia (GIAD)Most common cause of GIB: 15-31% of totalArteriovenous malformations (AVMs)Gastric antral vascular ectasia (GAVE)
Retrospective, single-center review of 172 patients19% (32/172) rate of GIB
AVMs: 31% (10/32)
Etiology
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.
Narrow pulse pressure: ↓ intraluminal pressureVascular dilatation angiodysplasia, AVMsHypoperfusion intestinal mucosa ischemia
Over-expression of angiogenic growth factors
Acquired Von Willebrand DiseaseIncreased shear stress, turbulence, and high
velocitiesVon Willebrand factor cleavage increased
bleeding and decreased platelet-mediated hemostasis
Pathogenesis
GIB: Patient Presentation
Decrease in hemoglobin (Hgb)Obtain coagulation panel (PT/PTT/INR)
Symptoms: symptomatic anemiaFatigue, dizziness, dyspnea on exertionMelena
Hypotension (decreased MAP)Adjust vasoactive medicationsDecrease in PI
Consider volume expansion
Treatment OptionsBlood 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 clippingCauterizationArgon plasma coagulation (APC)
Surgical resection
Ray R, et al. ASAIO Journal 2014;60:482-483.
Modification of Current Therapy
Cessation of anticoagulationHold warfarin in setting of clinically significant
bleedAssess need for IV heparin when INR < goal
Reduction of anticoagulationDecrease goal INRModify or discontinue antiplatelet therapy
Reduction of CF-LVAD speedIncrease pulse pressure reduce shear stress
Additional TherapiesAnticoagulation 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.
Preventative Strategies?
Additional studies needed:Blood product usePlatelet aggregometryThromboelastography
Use is currently insufficient to make recommendations
Perioperative bleeding risk stratification
Individualized bleeding scoreCould offer tailored post-operative AC to limit
bleeding
Balancing Act: GIB vs. Thrombus
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
Patient Case
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 qdayB. Discontinue carvedilol 25 mg po bidC. Lower aspirin to 81 mg po qdayD. All of the above
Patient Case Continued
CF-LVAD Infection
EpidemiologyCF-LVADs decreased rate of infection by 50%
Goldstein, et al. INTERMACS registry: 2008-2013 implants; n = 9,372 2nd 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 supportDifficult to eradicate
Goldstein DJ, et al. J Heart Lung Transplant 2012;31(11):1151-7.
Complications of InfectionAssociation with cerebrovascular events
(CVEs)Persistence of bacteremia > 72 hours
Persistent Pseudomonas aeruginosa blood stream infections 7-fold increase in CVEsMycotic aneurysms
Potential mechanisms of CVEs:Platelet activationAlterations in endothelial functionSystemic inflammationBacterial seeding of cerebral vasculature
Aggarwal A, et al. ASAIO J 2012;94(5):1381-6.
PathophysiologyDisruption 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.
Classification of Infection
CVC: central venous catheter
BSI: blood stream infection
SSI: surgical site infection
Trachtenberg B, et al. MDCVJ 2015;11(1):28-32.
PreventionImmobilization of percutaneous lead at exit
sitePrevents disruption of subcutaneous tissue
growthMethods: minimize trauma and tension
Anchoring devicesStabilization belts
Exercise sterile vs. clean technique for exit site care
Patient educationReport increased drainage or erythema
immediatelyGentle and non-traumatic exit site cleaning
Prevention: Perioperative Antibiotics
REMATCH study (HeartMate XVE):Vancomycin 15 mg/kg IV 1 hour pre-op then q12h Levofloxacin 500 mg IV 1 hour pre-op then q24hRifampin 600 mg po 1 hour pre-op then q24hFluconazole 200 mg IV 2 hours pre-op then q24h
Most centers omit rifampin, use β-lactams, or tailor to institutional antibiogramContinue 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.
DiagnosisPrompt culture of drainage
3 sets of blood cultures
ImagingChest radiographyEchocardiogram: pacemakers or defibrillator
leadsPresence of valvular endocarditis or device
infectionsUltrasound or CT:
Diagnose collections of fluid around driveline, pump, or pump pocket
Guide aspiration or debridementFeldman D, et al. J Heart Lung Transplant 2013;32(2):157-87.
Diagnosis
Treatment Options 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.
Treatment OptionsAdditional 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
Conclusion
Overview: CF-LVAD Complications
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 dataPublish your experience!!!
QUESTIONS??