iology 30 (2014) 1662e1667

Canadian Journal of Card

Clinical Research

Multicentre Canadian Experience With the HeartWareVentricular Assist Device: Concerns About Adverse

Neurological OutcomesJamil Bashir, MD,a Jean-Francois Legare, MD,b Darren H. Freed, MD, PhD,c

Anson Cheung, MD,a Vivek Rao, MD,d and Mustafa Toma, MDe

aUniversity of British Columbia, Division of Cardiovascular Surgery, Vancouver, British Columbia, CanadabDalhousie University, Division of Cardiovascular Surgery, Halifax, Nova Scotia, Canada

cUniversity of Manitoba, Section of Cardiac Surgery, Department of Surgery, Winnipeg, Manitoba, CanadadUniversity of Toronto, Division of Cardiac Surgery, Toronto, Ontario, Canada

eUniversity of British Columbia, Division of Cardiology, Vancouver, British Columbia, Canada

ABSTRACTBackground: The HeartWare left ventricular assist device (HVAD;HeartWare Inc, Framingham, MA) was first implanted in Canada in2010. We performed a multicentre analysis of the real world outcomesassociated with its use.Methods: Between May 2010 and January 2013, 4 Canadian centresinserted a total of 72 HVADs in 71 patients. Data were collected pro-spectively and analyzed retrospectively for the 1-year estimate of theprincipal outcome of transplant, explant for recovery, or death in pa-tients who had a bridge to transplantation indication. Adverse eventrates were estimated as events per patient-year (PPY).Results: In the 67 patients who received the HVAD with the indicationof bridge to transplant, 26 (38.8%) received a successful transplant, 2(3%) received an explant for recovery, and 10 (14.9%) patients diedduring support. Median follow-up time with the HVAD was 6.9 months(range, 2 days to 30.4 months). Despite having 74% of the patients

Received for publication June 4, 2014. Accepted July 27, 2014.

Corresponding author: Dr Jamil Bashir, St Paul’s Hospital, Suite 459,1081 Burrard St, Vancouver, British Columbia 6Z 1Y6, Canada. Tel.: þ1-604-806-9668; fax: þ1-604-806-9917.

E-mail: jmlbashir@gmail.comSee page 1666 for disclosure information.

http://dx.doi.org/10.1016/j.cjca.2014.07.7460828-282X/� 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. A

R�ESUM�EIntroduction : Le dispositif d’assistance ventriculaire gauche Heart-Ware (HVAD; HeartWare Inc., Framingham, MA) a �et�e implant�e pour lapremière fois au Canada en 2010. Nous avons r�ealis�e une analysemulticentrique des r�esultats en temps r�eel associ�es à son utilisation.M�ethodes : Entre mai 2010 et janvier 2013, 4 centres canadiens ontimplant�e un total de 72 HVAD chez 71 patients. Les donn�ees ont �et�erecueillies prospectivement et analys�ees r�etrospectivement quant àl’estimation à 1 an des principaux r�esultats de transplantation, d’ex-plantation à la suite d’une r�ecup�eration ou de d�ecès des patients chezqui il s’agissait d’un « pont vers la transplantation ». Les tauxd’�ev�enements ind�esirables ont �et�e �evalu�es comme des �ev�enementspar patient-ann�ee (PPA).R�esultats : Chez les 67 patients qui avaient reçu le HVAD comme« pont vers la transplantation », 26 (38,8 %) ont b�en�efici�e d’unetransplantation r�eussie, 2 (3 %) ont eu une explantation à la suite

Continuous flow left ventricular assist devices (LVADs) havelargely replaced older generation devices and outcomes havesteadily improved in the bridge to transplantation (BTT) anddestination therapy (DT) populations.1-4 The HeartWareLVAD (HVAD; HeartWare, Framingham, MA) is a next-generation centrifugal and continuous flow pump designedfor intrapericardial implantation. This pump was the subjectof investigation in the ADVANCE trial, which was a non-inferiority trial comparing the HVAD with the Heartmate II

(Thoratec, Pleasanton, CA) in a group of patients who werecontemporaneously implanted and registered in from theInteragency Registry for Mechanically Assisted CirculatorySupport (INTERMACS) registry.

The HVAD was developed with potential advantages overprevious devices. Its smaller size might improve the ease ofimplantation by reducing tissue dissection and the smallerdiameter of the outflow graft might facilitate aortic anasto-mosis. It has a single moving impeller that is suspended bypassive magnets and a hydrodynamic thrust-bearing system toreduce the risk of mechanical failure and wear.5 Despite morethan 3500 devices implanted worldwide, however, an un-derstanding of the performance of the device in a real-worldsetting is still lacking.

In Canada, the HVAD has only been used with theindication of BTT or bridge to candidacy until 2012 when the

ll rights reserved.

with Interagency Registry for Mechanically Assisted Circulatory Sup-port (INTERMACS) scores of level 1 and 2 at the time of implantation,the rate estimate for survival at 1 year was 86.3% (95% confidenceinterval, 76.7-93.3). With 48.2 total patient years of support, the ratesof ischemic and hemorrhagic strokes were 0.21 and 0.19 events PPY,respectively. Women made up 40% of the cohort and an adverseneurologic event occurred with an event rate of 0.38 PPY in women.Conclusions: The HVAD adequately supports acutely ill heart failurepatients until the time of transplant or recovery. A high incidence ofadverse neurologic outcomes might be related to the large percentageof female patients, the high INTERMACS levels, or unknown factors;further surveillance is required.

d’une r�ecup�eration et 10 (14,9 %) patients sont morts durant le sou-tien. Le temps de suivi m�edian des patients portant un HVAD �etait de6,9 mois (�etendue, 2 jours à 30,4 mois). En d�epit des 74 % de patientsayant des scores de stades 1 et 2 selon l’INTERMACS (InteragencyRegistry for Mechanically Assisted Circulatory Support) au moment del’implantation, l’estimation du taux de survie après 1 an �etait de 86,3%(intervalle de confiance à 95 %, 76,7-93,3). Pour un nombre total depatient-ann�ees de 48,2 avec soutien, les taux d’accident vasculairec�er�ebral isch�emique et h�emorragique ont respectivement �et�e de 0,21et 0,19 �ev�enement PPA. Les femmes constituaient 40 % de la cohorteet l’�ev�enement neurologique ind�esirable apparaissait selon un tauxd’�ev�enement de 0,38 PPA chez les femmes.Conclusions : Le HVAD offrait un soutien ad�equat aux patients souf-frant d’une insuffisance cardiaque en phase aiguë jusqu’au momentde la transplantation ou de la r�ecup�eration. Une incidence �elev�eed’issues neurologiques ind�esirables serait li�ee au pourcentage �elev�ede patientes, aux stades �elev�es selon l’INTERMACS ou à des facteursinconnus. D’autres populations devraient être soumises à unesurveillance.

Bashir et al. 1663Canadian HVAD Experience

devices were also approved for use with the indication of DTin Ontario. All patients who received the device had advancedheart failure during maximal medical therapy and werethought to be unable to survive without LVAD support. Allcentres implanting the HVAD were established LVAD centresthat had previously implanted the Heartmate II (Thoratec)device. Because of the early and widespread adoption of thisnew technology, we engaged in a study of the HVADsimplanted in Canada. The Canadian experience and outcomesof patients receiving the HVAD is relevant and uniquecompared with previous reports because of the publicly fun-ded health care system, variability in funding for ventricularassist devices (VADs) across provinces, lower proportion ofpatients who received an implant for DT, and tendency toreserve mechanical circulatory support (MCS) for the sickestpatients (ie, INTERMACS 1/2). To our knowledge, thisrepresents the largest multicentre examination of the perfor-mance of these pumps outside of a clinical trial setting.6

MethodsAll patients who had an HVAD implanted in 4 Canadian

centres (Vancouver, Toronto, Halifax, and Winnipeg) fromMay 13, 2010 until January 30, 2013 were included in thestudy. An additional 30 days was allowed for initial post-operative events and therefore data collection was complete asof February 28, 2013. Most Canadian centres did not use theHVAD device exclusively and continued to use the HeartmateII (Thoratec) device. Device selection was left to the discretionof the implanting surgeon. Data from Canadian centres thatimplanted the HVAD were collected locally and then centrallyanalyzed. Although the data were prospectively collected ineach centre, it was analyzed retrospectively.

The primary outcome was the proportion of patients who,at 12 months, survived to transplantation, had explantation oftheir pump for recovery, or who had ongoing mechanicalsupport to February 28, 2013. This analysis was done on theBTT population only. The preoperative acuity of the patientswas determined according to their INTERMACS score. Sec-ondary outcomes included frequency of adverse events in the

form of neurologic complications (ischemic stroke, hemor-rhagic stroke, and other), bleeding (gastrointestinal or other),and right ventricular failure. The secondary outcomes werecalculated on the entire cohort of patients receiving the pumpincluding the DT patients. An ischemic stroke was defined asa new neurologic deficit that was accompanied by a newcorresponding defect on computed tomography (CT) scan ofthe brain. A hemorrhagic stroke was defined as a newneurologic deficit or symptoms with corresponding CT of thebrain showing new intracranial bleeding. Gastrointestinalbleeding was defined as that requiring transfusion or change inthe anticoagulation protocol. Right ventricular failure wasdefined as failure that required right VAD or inotropes for> 5 days after the initial implant.

All centres followed the prescribed anticoagulation proto-col of acetylsalicylic acid with warfarin and transesophagealecho use was routine in every case to rule out ventricularthrombus and other pathology. International normalized ratio(INR) management was performed by community physiciansin conjunction with the implanting institution. Institutionalpreference for the target range of INR varied from 1.5-2.5 insome to 2.5-3.5 in other centres. Furthermore, intravenousunfractionated heparin or low molecular-weight heparin wereused in selected patients who remained nontherapeutic for anextended period of time (typically 4-7 days) unless contra-indicated because of recent active bleeding. Doppler-measuredblood pressure targets were consistent among institutions andfollowed guideline pressures of 70-80 mm Hg for the non-pulsatile patient.7

It is routine practice to clearly determine the patients’neurological status before implantation of the pump. Thistypically involves a CT examination of the head and/or aclinical evaluation by a neurologist. Informed consent wasreceived from each patient.

Statistical analysis

Baseline patient characteristics are presented as percentagesfor discrete variables and medians with 25th and 75th per-centiles for continuous variables. For the primary outcome of

Table 1. Baseline characteristics of the study population (n ¼ 71)

Characteristic Value

Median age (Q1, Q3), years 53 (47, 62)Male sex, n (%) 43 (60)Heart failure aetiology, n (%)

Dilated CMO 31 (44)Ischemic CMO 25 (35)Other 15 (21)

INTERMACS level, n (%)1 22 (31)2 28 (39)3 14 (20)4 7 (10)

Median LVEF (Q1, Q3) 19% (13, 21)ECMO, n (%) 12 (17)Destination therapy, n (%) 4 (6)

CMO, cardiomyopathy; ECMO, extra-corporeal membrane oxygenation;INTERMACS, Interagency Registry for Mechanically Assisted CirculatorySupport; LVEF, left ventricular ejection fraction; Q, quartile.

Figure 1. Competing risks analysis. Survival of patients accountingfor transplants and recovery is shown in red. Rate of ongoing supportis shown in orange. Cumulative incidence of death, transplant, andexplant are shown in black, green, and grey, respectively.

1664 Canadian Journal of CardiologyVolume 30 2014

transplantation, explant, or death, a competing risk analysiswas used to estimates rates and to plot the cumulative inci-dence curves of each event for patients waiting for trans-plantation.8 All 71 patients were included in the secondaryoutcomes analysis to characterize adverse events during use ofthe HVAD pump. Adverse events are presented as frequenciesand events per patient-year (event PPY).

Table 2. Rates of adverse events in counts and events PPY

Adverse Event Patients With Event Event Rate PPY

Pump thrombosis 3 0.06Ischemic stroke 10 0.21Hemorrhagic stroke 9 0.19Other neurologic 5 0.11RV failure 18 0.37GI bleeding 7 0.15RVAD 1 0.02

Median time with HVAD support 6.9 months; total support 48.2 patient-years.

GI, gastrointestinal; HVAD, HeartWare left ventricular assist device(HeartWare Inc, Framingham, MA); PPY, per patient-year; RV, right ven-tricular; RVAD, right ventricular assist device.

ResultsA total of 72 HVAD devices were implanted in 71 patients

in the 4 Canadian study centres. Four of the patients receivedthe device for DT indication and 67 patients received it for aBTT indication.

Baseline characteristics of the entire cohort are presented inTable 1. Female patients made up 40% of the study popu-lation and the median age was 53 years. The median ejectionfraction before implant was 19%. The aetiology of heartfailure was dilated cardiomyopathy in 44% (31 of 71),ischemic cardiomyopathy in 35% (25 of 71), and a mixture ofother causes in the remaining. A large proportion (70%) ofthe patients in the total cohort were INTERMACS level 1 and2 before implant and no patient had an INTERMACS level> 4. Extra-corporeal membrane oxygenation (ECMO) wasused before HVAD implantation in 12 of the 71 (16.9%)patients.

In the 67 patients examined using the competing risksanalysis for primary outcome, the rate estimate for survival at30 days was 91.0% (95% confidence interval, 82.7-96.4) andat 1 year was 86.3% (95% confidence interval, 76.7-93.3)(Fig. 1). Throughout the follow-up period, heart trans-plantation occurred in 26 of the 67 patients (38.8%) and 2patients (3%) had their devices explanted because ofmyocardial recovery. Support was ongoing at last follow-upfor 29 (43.3%) patients and 10 (14.9%) patients died dur-ing the follow-up period. Of the 10 patients who died, 4 diedfrom new intracranial bleeding (2 within the first 30 days and2 after 30 days), 4 died of ischemic stroke (2 perioperativestrokes and 2 after 30 days), and 2 died of multisystem organfailure. One of the patients who died from intracranialbleeding had 2 open heart surgeries in the 10 daysbefore implant and might have had heparin-induced

thrombocytopenia. One additional patient died from multi-ple small embolic strokes that started 3 weeks after implantand a final patient died from a global ischemic neurologicinsult after an arrest that occurred during a tracheostomy.

In the 71 patients analyzed for secondary outcomes in theform of adverse events, the median number of months withLVAD support was 6.9 with a range of 2 days to 30.4 months.The total number of patient-years with LVAD support was48.2 years. Two patients experienced a pump thrombosisalthough only 1 pump required exchange because the otherpatient received a transplant within 48 hours of presentation.The median time to extubation was 2 days (interquartile range[IQR], 1-5) and the median length of stay in the intensivecare unit was 9 days (IQR, 6-19). The median hospital lengthof stay was 28 days (IQR, 20-46).

The frequencies of serious adverse events are described inTable 2. Ischemic stroke occurred in 10 of the 71 patients(14.1%) and hemorrhagic stroke occurred in 9 of the 71patients (12.7%). One patient had an ischemic stroke and ahemorrhagic stroke that were 1 month apart. The event PPYrates for ischemic stroke and hemorrhagic stroke were 0.21and 0.19, respectively. Other neurologic events (includingperipheral neuropathy and transient ischemic attack) occurred

Table 3. Rates of adverse neurologic events in counts and events PPY stratified according to timing of event (0-30 days and > 30 days)

Adverse Neurologic EventPatients With Event

at 0-30 DaysPatients With Event

at > 30 DaysEvent Rate PPYat 0-30 Days

Event Rate PPYat > 30 Days

Ischemic stroke 4 6 0.80 0.14Hemorrhagic stroke 2 7 0.40 0.16

PPY, per patient year.

Bashir et al. 1665Canadian HVAD Experience

in 5 patients (7.0%) for an event PPY of 0.11. Gastrointes-tinal bleeding occurred in 7 patients (9.9%) for an event PPYof 0.15. Right ventricular failure was the most commonadverse event, affecting 18 patients (25.4%) for an event PPYof 0.37, although only 1 patient received a right VAD.

Neurologic events were noted to occur at a higher rate inwomen compared with men. Ischemic stroke and intracra-nial bleeding occurred in 7 of 43 men (16.3%) (0.24 eventsPPY) and 11 of 28 women (39.3%) (0.38 events PPY).Most patients who died (8 of 10) had had an associatedneurologic event in the form of either an ischemic stroke,intracranial bleeding, or both. Six of the neurologic eventsoccurred early after implant (< 30 days) and 13 of themwere late (� 30 days). Four of the 6 (67%) early neurologicevents were fatal whereas only 3 of the 13 (23%) laterevents were fatal (P ¼ 0.03). Timing of the neurologicevents with event rates are presented in Table 3. Of the 12patients who had been supported with ECMO beforeHVAD implant, 3 had fatal neurologic events in the first 3weeks of LVAD support.

DiscussionIn this multicentre experience with the HVAD, the 1-year

survival was 86.3%, despite a significant proportion of pa-tients (74%) having early or true cardiogenic shock(INTERMACS 1 and 2) at the time of implantation. Un-fortunately, however, the neurological event rate was surpris-ingly high and women fared worse outcomes when comparedwith men.

The 1-year survival rate in our cohort (86%) is similar tothe 86% survival at 360 days in the ADVANCE trialcohort.3 Transplantation occurred in 38.8% of our popula-tion and a significant number remained on support at 1 year,with the longest duration of support being 30 months.Postoperative outcomes were in keeping with how ill thepatients were at the time of device implantation. The mediantime to extubation was 2 days but the median length of stayin the intensive care unit was 9 days. The median length ofstay in-hospital was longer (28 days) than that in theADVANCE trial (20 days).

The HVAD was approved for use by the United StatesFood and Drug Administration in November 2012 princi-pally on the basis of the ADVANCE trial results. This wasnot a randomized trial but compared outcomes to theINTERMACS registry of continuous-flow LVAD devices.3

The survival outcomes in this trial were excellent, with86% of patients alive at 1 year and there were relatively fewadverse events. However, the acuity of patients in the trialwas also lower than our patient population because most(70%) patients were INTERMACS level 3. Strueber et al.examined 50 HVAD recipients from 5 international centres

and showed a 1-year survival of 84% with most of the pa-tients being INTERMACS level 3 at the time of implanta-tion.9 A recently published single-centre experience with 50patients showed a 1-year survival of 78% with few adverseevents.6

Because of the paucity of real-world experience with theHVAD, we conducted a study using prospectively collecteddata from 4 centres that had implanted the device in Canada.Patients who had the device implanted in Canada frequentlypresented with acute decompensation and most patientsreceive the device with the indication of BTT or bridge tocandidacy while being acutely ill. Because 74% of the BTTpatients in this study were INTERMACS 1 and 2, wedescribe a cohort that is more acutely ill than the patientsenrolled in the described clinical trials or smaller multicentrestudies.

As the use of the device was adopted by acute heart failureunits across the country, a natural predilection developed forimplanting this device in women because of its smaller size.Therefore, 40% of patients who received the LVAD in ourstudy were female. This is the largest proportion of womenfound in any LVAD series to our knowledge.1-3,6,8-10 Thishighlights the truly real-world nature of our experience withthe device.

An unexpectedly large number of patients suffered from anadverse neurologic event. The rates of hemorrhagic andischemic stroke (0.19 and 0.21 events PPY, respectively) aresignificantly greater in our cohort of patients than otherstudies in this area including trials of the Heartmate II(Thoratec) in DT.3,8,10,11 These neurologic events were sig-nificant because 7 of the 10 patients in our cohort who diedhad suffered a stroke or intracranial bleeding or both. Four ofthese fatal events were perioperative (within first 30 days),however, and might have been related to a diverse set of risksincluding those incurred at the time of pump implant. Inparticular, these risks included a high rate of ECMO usebefore implant because this is undoubtedly associated with anincreased incidence of early stroke.12 Also, a number of thepatients with early events were extremely ill and hadnumerous surgeries, a profound inflammatory response, andhypotension.

An additional 2 nonfatal neurologic events occurred withinthe first 30 days of implant. Excluding the events thatoccurred in the first 30 days, the rate of neurologic eventsremained high with a particularly high rate of hemorrhagicstroke after 30 days (0.16 events PPY). Furthermore, 7 of the9 hemorrhagic events occurred in women and many of theseevents occurred well after the acute phase of illness was overand the patients were ostensibly recovered. The occurrence oflate events and especially hemorrhagic stroke in women washighly consistent across institutions. This consistency withinmulticentre data argues against the issue being due to chance

1666 Canadian Journal of CardiologyVolume 30 2014

or small patient numbers and requires investigation andevaluation.

A neurologic event occurred in 39.3% of women in thisstudy. Increased rates of adverse events in the female VADpopulation have recently been described in 2 large series.Investigators from Baylor found over double the rate ofhemorrhagic stroke in women with the Heartmate II (Thor-atec) device in the BTT population (0.10 vs 0.04 eventsPPY).13 Also, an examination of outcome differences in theINTERMACS registry found female sex to be associated withan increased hazard of a first neurological event with a hazardratio of 1.44.14 The cause of a greater incidence of hemor-rhagic stroke in the female VAD population is unknown.Large epidemiologic studies in North America of patientswithout VADs do not seem to show an increased risk of stroke(ischemic or hemorrhagic) in women.15 Although an argu-ment can be made that the high event rates in our series are atleast partially because of the preponderance of women, theseevent rates are still significantly greater than the 0.10 totalevent PPY rate described for women with the Heartmate II(Thoratec) device and might be because of additional factors.

Hypertension and anticoagulation are closely associatedwith an increased risk of hemorrhagic stroke in the generalpopulation,15,16 and undoubtedly contribute to the risk ofintracranial bleeding in the LVAD population. A mean arterialpressure target of 80 mm Hg might be higher than necessaryand differential targets might be beneficial for men andwomen. Also, all manufacturers of continuous-flow LVADscurrently recommend a management strategy that includesanticoagulation. Although target INRs from the institutions inour study varied from 1.5-2.5 to 2.5-3.5, we were unable tofind an association between the institutional target INR andrisk of bleeding because the event rates were quite similaracross institutions. The most appropriate strategy for anti-coagulation with the HVAD is unknown although some in-stitutions have begun to target the lower range.

The nonpulsatile nature of continuous-flow VADs hasbeen anecdotally linked to bleeding from acquired von Wil-lebrand disease (VWD).17 Although the potential combina-tion of a high nonpulsatile mean arterial pressure and anincreased INR likely contribute significantly to the risk ofhemorrhagic stroke in the female LVAD population, this ef-fect might be exacerbated by other factors such as the rheologyof different pump designs or the effect of rheology on thecreation of acquired VWD. It is possible that the HVADpump design potentiates acquired VWD or has other rheo-logical effects.

Thromboembolic events were also significant in this studyand a smooth inflow cannula has been associated with embolicphenomenon in previous-generation VADs.17 The manufac-turer of the HVAD switched from a nonsintered (smooth) tosintered inflow cannula in March of 2011 and the first ofthese pumps were implanted in Canada in late 2012. Norelationship was found between the neurologic events and thetype of inflow cannula in our study.

Although our observational data show a significant patternof increased neurologic events in the acutely ill and particu-larly female HVAD patient, the cause of this is unknown.These results will need to be verified in larger studies. Thepatients in our series were gravely ill and this undoubtedlycontributed to adverse outcomes in the perioperative period.

It is uncertain, however, whether the acuity of presentationhad an effect on late adverse neurologic outcomes. Finally, it isunknown whether factors uniquely related to the HVADpump itself have contributed to the incidence of adverseneurologic events. Careful and frequent titration of meanarterial pressure and INR are, regardless, essential in theLVAD population.

Limitations

Although the data were analyzed retrospectively, they werecollected prospectively, which should reduce recall bias. Thedifference in neurological events between men and women arehypothesis-generating only because this outcome was notprespecified a priori.

The relationship between anticoagulation regimens and theincidence of adverse neurologic outcomes is not clear becauseindividual INR values closely preceding an adverse event werenot uniformly available. Also, the relationship between adverseoutcomes and the medical management of these patients,particularly blood pressure management, is not well under-stood because of the lack of accurate recording of meanarterial pressure before an event, especially in the out-patientsetting.

Conclusions

The HVAD continues to show the ability to support pa-tients in the BTT population with a high success rate. Highrates of adverse neurologic events need to be further investi-gated and might be related to the greater proportion ofwomen in our cohort, the high INTERMACS score at thetime of implantation, or other factors including pump design.

DisclosuresA. Cheung: consultant and speakers bureau for HeartWare

Inc; V. Rao, consultant for HeartWare Inc; the remainingauthors have no conflicts of interest to disclose.

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