Temporal Differences in Outcomes During Long-Term Mechanical Circulatory Support

Accepted Manuscript Title: Temporal Differences in Outcomes during Long-Term Mechanical Circulatory Support Author: Simon Maltais, Lucman A. Anwer, Nicholas A. Haglund, Jennifer Cowger, Palak Shah, Keith D. Aaronson, Francis D. Pagani, Shannon M. Dunlay, Ramesh Singh, Christopher T. Salerno, John M. Stulak PII: DOI: Reference:

S1071-9164(17)30622-X http://dx.doi.org/doi: 10.1016/j.cardfail.2017.07.403 YJCAF 4015

To appear in:

Journal of Cardiac Failure

Received date: Revised date: Accepted date:

11-1-2017 30-6-2017 25-7-2017

Please cite this article as: Simon Maltais, Lucman A. Anwer, Nicholas A. Haglund, Jennifer Cowger, Palak Shah, Keith D. Aaronson, Francis D. Pagani, Shannon M. Dunlay, Ramesh Singh, Christopher T. Salerno, John M. Stulak, Temporal Differences in Outcomes during Long-Term Mechanical Circulatory Support, Journal of Cardiac Failure (2017), http://dx.doi.org/doi: 10.1016/j.cardfail.2017.07.403. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Title: Temporal Differences in Outcomes during Long-Term Mechanical Circulatory Support Short Title: Mechanical Circulatory Support; Temporal Outcomes

Authors: Simon Maltais, MD, PhD1, Lucman A. Anwer, MD1, Nicholas A. Haglund, MD2, Jennifer Cowger, MS, MD3, Palak Shah, MD4, Keith D. Aaronson, MD, MS5, Francis D. Pagani, MD, PhD5, Shannon M. Dunlay, MD, MS1, Ramesh Singh, MD4, Christopher T. Salerno, MD3, John M. Stulak, MD1 1

Mayo Clinic College of Medicine, Rochester, MN, United States

2

Vanderbilt Heart and Vascular Center, Nashville, TN, United States

3

St. Vincent’s Hospital, Indianapolis, IN, United States

4

Inova Fairfax Hospital, Falls Church, VA, United States

5

University of Michigan Health System, Ann Arbor, MI, United States

Corresponding Author: Dr. Simon Maltais, MD, PhD Department of Cardiovascular Surgery Mayo Clinic, 200 First St SW, Rochester, MN, 55905 Email: [email protected] Telephone: 507-255-7067

Word Count: 2869 excluding tables, figures and references.

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Highlights: 

Placement indications for continuous-flow left ventricular assist devices have changed.



Three distinct time periods corresponding to landmark changes in practice can be identified.



Despite differences, survival is comparable between time periods.



Most recent period is at an increased risk of gastrointestinal bleeding and pump thrombus.



Temporal observations should help develop targeted guidelines to improve outcomes.

Abstract: (Word Count = 200 words) Background: Device indications have changed for placement of continuous-flow left ventricular assist devices (CF-LVADs). We performed a multicenter analysis evaluating temporal variations in outcomes after CF-LVAD implantation.

Methods & Results: We retrospectively defined three time intervals to reflect changes in CF-LVAD technology (Period 1: 2004 to 2009; Period 2: 2010 to 2012; and Period 3: 2012 to 2014). A total of 1,064 patients (HeartMate II (HMII)=835, HeartWare (HVAD)=229) underwent CF-LVAD implantation between May 2004 and October 2014. Device utilization was different between periods; Period 1: HMII=134(100%), Period 2: HMII=480(88%) vs. HW=63(12%), and Period 3: HMII=221(57%) vs HW=166(43%), p<0.001. Despite few baseline group differences, adjusted survival was comparable between time periods (p=0.96). Adjusted multivariable analysis revealed age (per 10

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years increase) and INTERMACS category (1 vs. all others) as the only independent predictors of mortality, p0.001 and p=0.008, respectively. Furthermore, it also showed the later periods to be at an increased risk of adverse events: 1) pump thrombus (period 2 and 3), and 2) gastrointestinal bleeding (period 3).

Conclusion: Despite significant differences in device types, indications, and patient characteristics, post-implant survival is comparable across time intervals. Most recent cohort seems to be at an increased risk of gastrointestinal bleeding and pump thrombus. Key Words: Ventricular Assist Devices, Continuous-flow, Outcomes, Temporal Analysis

Abbreviations: LVAD: Left Ventricular Assist Device CF-LVAD: Continuous-flow LVAD MCS: Mechanical Circulatory Support BTT: Bridge To Transplant DT: Destination Therapy HMII: HeartMate II HVAD: HeartWare Ventricular Assist System INTERMACS: Interagency Registry for Mechanically Assisted Circulatory Support AE: Adverse Event GIB: Gastrointestinal bleeding

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Background: Left ventricular assist devices (LVADs) have become the standard of care for patients with advanced heart failure refractory to medical management. (1) Recent trends in mechanical circulatory support (MCS) utilization continue to support an increasing use of this technology; both to bridge patients to transplantation (BTT), and as a final destination therapy (DT). (2, 3) Continued improvements in LVAD technology, increased survival rates, and reduction of adverse events, have created a paradigm shift in the management approach to these challenging patients. (4) Indications and strategies for preoperative patient optimization have evolved and lead to better overall outcomes. (5) Current FDA-Approved Continuous-flow LVADs (CF-LVADs) include the HeartMate II (HMII: Thoratec Corp., Pleasanton, CA) and the HeartWare Ventricular Assist System (HVAD, HeartWare Inc., Framingham, MA). The HVAD was recently approved as a BTT therapy in 2012 (6), and has since challenged the pump options for bridged patients. (7) While results of the HeartWare DT Trial (ENDURANCE I, ClinicalTrials.gov: NCT01166347) have been made public (International Society of Heart and Lung Transplant 2015, Nice, France), the HMII remains since January 2010 the only approved device for DT indication. (8) As our field has witnessed a constant growth in therapy over the last few years, our comprehension of the impact and consequences of introducing new technology continues to expand. Significant changes in clinical practice guidelines and recommendations for pump management may also have created a profile change, and a different spectrum of adverse events. (9, 10) Despite a large amount of existing data from landmark multicenter trials and INTERMACS registry for patients implanted with the

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two currently available therapies, very few reports exists analyzing large “real-world” multicenter research efforts. Understanding the variability of outcomes overtime is critical to improving our knowledge of the therapy. Hence, in this large collaborative study, we sought to stratify outcomes in different landmark eras to address and understand changes in device indications and clinical practices. With a main objective to evaluate outcomes from different time intervals, and to compare them to recently proposed “all comer” study designs (HeartMate III, ClinicalTrials.gov: NCT02224755), this report was prepared as an analysis evaluating outcomes in patients qualifying for overall LVAD therapy (irrespective of BTT or DT indications).

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Materials and Methods: Study Population The data collection process and analysis were performed following informed patient consent, and were approved by the Institutional Review Board at each center comprising the Mechanical Circulatory Support Research Network (University of Michigan, Mayo Clinic College of Medicine, Vanderbilt Heart and Vascular Institute, St-Vincent’s Hospital, and Inova Fairfax Hospital). Between May 2004 and August 2014, 1,064 patients underwent primary continuous-flow LVAD implantation at our centers. We identified 3 distinct critical periods that correspond to approval of currently available technology and landmark changes in our practice: Period 1: Pre-HMII DT approval (2004 to 2009); Period 2: Pre-HVAD BTT approval (2010 to 2012); Period 3: Post HVAD BTT approval (2012-2014). Demographic and other patient-related data were obtained from medical records and our prospectively collected clinical databases. Follow-up information was obtained from subsequent clinical visits and written correspondences from local physicians. The registry is regularly reviewed and audited by investigators for accuracy. Patients with biventricular long-term device implantation and congenital pathologies were excluded from the analysis.

Definitions The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Executive Committee publishes Adverse Event (AE) Definitions, which were utilized by all centers participating in our network to ensure standardization in reporting. Adverse

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events were prospectively collected and are in accordance with the 2013 published guidelines. Time to first AE was utilized to report univariate outcomes.

Statistical Analysis All statistical analysis was done using the SPSS 10.0 program (SPSS Inc.; Chicago, III). Data is expressed as number and percentage for discrete data, mean ± standard error of the mean for normally distributed data, and median with range for non-normally distributed data. Data between time intervals was compared using the χ2 test for categorical variables and the Wilcoxon rank sum test for continuous variables, respectively. A backward stepwise Cox regression analysis was used to identify those predefined perioperative variables that independently affected outcomes. Wilcoxon ranksum test was used to compare follow-up between periods. Survival between landmark periods (1, 2, and 3) was compared using a log-rank test and these periods were included in the multiple Cox-proportional hazards multivariable model for both mortality and any AE. Subsequently, each specific type of AE was also independently analyzed using the multiple Cox-proportional hazards multivariable model. Variables deemed significant in the univariate analysis were utilized during stepwise selection to create the final multivariable model. Kaplan-Meier survival was used to estimate time-related outcomes and produce plots, which were subsequently compared by the log-rank test. Statistical significance was considered at p < 0.05. Early operative mortality was defined as death occurring within 30 days of operation or at any time during the index hospitalization.

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Results: Patient Characteristics A total of 1,064 patients were included in the final analysis. Of these, 78% (835/1064) received a HMII, while 22% (229/1064) patients had a HVAD. 80% (850/1064) of the patients were males, and median age at the time of LVAD implantation was 59 years (range, 20-79 years). Preoperative and intraoperative clinical characteristics of the overall cohort and those stratified by periods are presented in Table 1. We observed significant differences between the different study periods. As expected, HVAD utilization increased overtime and was more frequent in the later periods, period 2 = 22% and period 3 = 43%, p<0.001. Period 1 exclusively used the HMII device. Cardiopulmonary bypass time was significantly longer in period 1 (p<0.001), and a significantly greater number of patients underwent a redo sternotomy in this period as well (p=0.006). Intra-aortic balloon pump utilization was significantly greater in period 2 (p<0.001), while preoperative atrial fibrillation was significantly more prevalent in period 3 (p=0.03). All remaining clinical characteristics were comparable between cohorts.

Survival and Clinical Outcomes Non-adjusted clinical outcomes are presented in Table 2. Importantly, median time of follow-up was significantly higher in Period 2 (p0.001). The cumulative incidence of driveline infections was significantly higher in Period 1 (p0.001), while Period 2 revealed a significantly higher incidence of pump thrombosis and hemolysis (p = 0.002). Total AE rate (p=0.13) and rates of other evaluated outcomes including gastrointestinal

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bleeding (GIB, p=0.61) and neurologic events (p=0.42) were comparable between periods. With limitations related to follow-up time, mortality was significantly higher in period 1 compared to later periods (p0.001). Survival analyses of all clinical outcomes assessed are presented in Figures 1-5. We observed no survival differences between the three time periods (p=0.955, Figure 1). Estimated freedom from any adverse event was significantly lower in period 3 compared to all other intervals (p=0.002, Figure 2). When evaluated individually, estimated freedom from neurological events was significantly lower in period 3 (p=0.02, Figure 3), and patients in this period were at a significantly increased estimated risk of GIB as well (p=0.006, Figure 4). Estimated freedom from pump thrombus-hemolysis was significantly lower in the second period (p=0.019, Figure 5), while the risk of confirmed driveline infection was consistent throughout the study periods (p=0.444, data not shown).

Multivariable Analysis Multivariable analyses were performed to evaluate the association of predetermined variables with mortality and AEs. Age (per 10 years increase) and INTERMACS category (1 vs. ≥ 4) were the only independent predictors of mortality in this study (p0.001 and p=0.008, respectively). Different time periods were not significant predictors of mortality. However, we did observe a significant association between study periods and adverse events; period 3 (latest interval) and ischemic etiology were independent predictors of AEs (p=0.002, and p0.001, respectively) . Detailed multivariable analyses data is presented in table 3.

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When evaluated separately, we observed interesting differences in factors associated with AEs. HVAD and ischemic etiology were both associated with an increased risk of neurological complications, HR=1.66 (1.11, 2.48) and 1.54 (1.06, 2.22), p=0.01 and 0.02, respectively. Younger age at the time of implantation and ischemic etiology predicted the risk of future driveline infections, HR=0.71 (0.6, 0.84) and 1.77 (1.1, 2.84), p0.001 and 0.02, respectively. Period 2 and 3 were associated with an increased risk of pump thrombus, HR=2.45 (1.17, 5.14) and 2.67 (1.19, 6.03), p=0.04. Period 3 was also associated with an increased risk of GIB, HR=2.99 (1.55, 5.76), p0.001. Additionally, increasing age and ischemic etiology were also associated with an increased risk of GIB, HR=1.6 (1.36, 1.87) and 1.42 (1.02, 1.97), p0.001 and 0.04 respectively.

Discussion: Rationale of the study Our manuscript evaluates outcomes post continuous-flow LVAD implantation in a large voluntary research network. We sought to describe clinical differences in outcomes according to landmark predetermined periods corresponding to major changes within our field.

Main findings of the study In this study, we demonstrate several variabilities between the different time periods. Redo-sternotomy was greater in period 1 (p=0.006), while the preoperative use of intraaortic balloon pumps (IABP) was higher in Period 2 (p0.001). Period 3 had a shorter

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observed cardiopulmonary bypass time (p0.001), and a greater proportion of HVAD utilization (p0.001). Despite these important time-related differences, survival remained comparable between periods (p=0.955). Interestingly, freedom from any adverse event was lower for the later period (period 3, p=0.002), and this was mostly driven by an increased incidence of GIB (p=0.006) and neurological events (p=0.02). Similarly, pump thrombus and hemolysis rates were high in period 2 (p=0.019). Multivariable analysis confirmed that the later two periods were associated with an increased risk of pump thrombus and period 3 was at an increased risk of GIB as well. Also, HVAD utilization was independently associated with an increased risk of neurological events (HR= 1.66 1.11-2.48, p=0.01). Our survival results between periods are encouraging and confirm numerous contemporary reports. (1, 11) Improvements in preoperative assessment and optimization, coupled with improvements in technology, have allowed survival outcomes to be maintained, despite significant changes in patient profiles. (12) Regardless of known differences between patient characteristics and outcomes, our study looks at the overall picture; without a distinction between BTT or DT therapy. (11) We identified significant differences between intervals (characterized mostly by DT or BTT technology approval), yet, we observed comparable survival outcomes when adjusted for preoperative differences. As ongoing trials are designed without indication designation (HeartMate III, ClinicalTrials.gov: NCT02224755), our community may expect changes from the 2013 policy in National Coverage Determination by the Centers for Medicare and Medicaid Services. This study reaffirms that our efforts in improving technology and patient management have led to sustained survival on support devices overtime. (13, 14)

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Implications for Adverse Events The current generation of CF-LVAD have superior durability and adverse event profiles compared to pulsatile devices. (7, 8) Limited organ availability, coupled with improvements in outcomes overtime have led to increased time on support devices. (11) With the incremental utilization of HVADs over the last few years, our understanding of fundamental clinical management differences between axial and centrifugal pumps continues to evolve. (15) Centrifugal pumps like the HVAD have a more direct current-to-flow relationship and hence, harbor an increased sensitivity to preload and afterload. (16) This higher afterload sensitivity creates the need for better systemic vascular resistance control to guarantee sustained output, maintain effective left ventricular unloading, and reduce potential adverse events. (17) As our utilization of the HVAD technology continues to increase (greatest proportion of HVAD in period 3), so does our appreciation of the importance of more rigorous blood pressure control for this device compared to its earlier counterpart. (18) Studies have shown fewer neurological events with HVADs in programs with more aggressive (mean arterial pressure 80 mmHg) antihypertensive protocols. (18) While the utilization of HVAD was associated with an increased risk of neurological events in our study (HR= 1.66, p=0.01), we anticipate that recognition of design differences and appropriate changes in clinical management (ENDURANCE II Trial, ClinicalTrials.gov: NCT01966458), will eventually lead to better AE profiles. Understanding AE profiles overtime is critical to assess changes in clinical practice. We observed that the later periods (2 and 3) were associated with increased risk

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of pump thrombus and period 3 was associated with an increased risk of GIB as well. These findings are consistent with recently published reports. (10, 19, 20) Among other causes, temporal changes proposing reduced anticoagulation for HMII patients, including the safe non-use of perioperative intravenous heparin, may explain some of the differential results observed in this study. (9, 21) Increased rate of observed pump thrombosis, coupled with a growing proportion of older patients implanted as DT (11), may explain the increase in GIB in the latest period. Nevertheless, bleeding and clotting continue to be frequent complications after CF-LVAD placement and are likely multifactorial in nature. (22) Trials like the ‘PREVENtion of HeartMate II® Pump Thrombosis Through Clinical Management (PREVENT)’ Study (ClinicalTrials.gov: NCT02158403) will hopefully help define best practices and reduce adverse events overtime. Mechanical Circulatory Support in the Elderly Advanced age prevailed as a consistently associated variable with AEs, across the different time periods. Older age, and its associated risk of GIB, is well documented in previous studies on CF-LVADs. (22) With the combination of a growing elderly population, increased burden of ischemic heart disease, and refinement of medical therapy, the prevalence of end-stage heart failure and device utilization in elderly patients is expected to continually rise. (23) Hence, a better comprehension of population profiles overtime may help with the development of alternate clinical practice guidelines targeted to minimize AEs in this subgroup of patients.

Limitations:

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This study has limitations inherent in its study design and retrospective nature. The study includes data from 5 different institutions, therefore, limitations exist in data extraction from registries; in terms of missing data fields and potential discrepancies in data entry. Furthermore, differences in clinical practice can occur between institutions, and these can affect overall outcomes. Nevertheless, the “institution factor” was weighted in the multivariable model and was not significant for all analyses performed. Lastly, the studied predetermined intervals were established arbitrarily, based on landmark device indication approvals.

Conclusions: Significant differences in device utilization and patient characteristics exist between landmark intervals studied. Despite these critical differences, post-LVAD implantation survival is comparable across periods. Most recent cohort seems to be at an increased risk of gastrointestinal bleeding and pump thrombus. These findings may reflect an evolution of our clinical guidelines overtime, or the generalized approval of the technology introducing greater practice variability. As our understanding of new technologies and differences between them continues to evolve, a better comprehension of adverse event profiles is necessary for the development of targeted best practice recommendations.

Acknowledgements and Disclosures: The authors would like to acknowledge that this is a collaborative effort of all institutions of the Mechanical Circulatory Support Research Network, which includes: University of Michigan Health System, Ann Arbor, Michigan; Mayo Clinic College of Medicine,

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Rochester, Minnesota; Vanderbilt Heart and Vascular Institute, Nashville, Tennessee; Inova Fairfax Hospital, Falls Church, Virginia, and St. Vincent Hospital, Indianapolis, Indiana. We would also like to acknowledge Dr. Frank E. Harrell, Jr., PhD, for his assistance with the statistical analyses and preparation of the manuscript. We have no specific funding sources or relevant disclosures to report in regards to this manuscript. In terms of general financial relationships to disclose, Doctors Pagani, Aaronson, Cowger and Maltais receive research funding from HeartWare, Inc., American Heart Association, and NHLBI. Dr. Dunlay further receives funding from PatientCentered Outcomes Research Institute (PCORI). We would also like to mention that the results of this manuscript have been presented at the 35th Annual International Society of Heart and Lung Transplantation in Nice, France. References: 1. Kirklin JK, Naftel DC, Pagani FD, et al.: Sixth INTERMACS annual report: a 10,000patient database. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2014;33:555-64. doi: 10.1016/j.healun.2014.04.010. 2. Toeg HD, Al-Atassi T, Garcia JP, Ruel M: An update on mechanical circulatory support for heart failure therapy. Current opinion in cardiology 2014;29:167-73. doi: 10.1097/HCO.0000000000000037. 3. Khazanie P, Hammill BG, Patel CB, et al.: Trends in the use and outcomes of ventricular assist devices among medicare beneficiaries, 2006 through 2011. Journal of the American College of Cardiology 2014;63:1395-404. doi: 10.1016/j.jacc.2013.12.020.

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4. Xie A, Phan K, Yan TD: Durability of continuous-flow left ventricular assist devices: a systematic review. Annals of cardiothoracic surgery 2014;3:547-56. doi: 10.3978/j.issn.2225-319X.2014.11.01. 5. Riebandt J, Haberl T, Mahr S, et al.: Preoperative patient optimization using extracorporeal life support improves outcomes of INTERMACS Level I patients receiving a permanent ventricular assist device. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 2014;46:486-92; discussion 92. doi: 10.1093/ejcts/ezu093. 6. Aaronson KD, Slaughter MS, Miller LW, et al.: Use of an intrapericardial, continuousflow, centrifugal pump in patients awaiting heart transplantation. Circulation 2012;125:3191-200. doi: 10.1161/CIRCULATIONAHA.111.058412.

7. Miller LW, Pagani FD, Russell SD, et al.: Use of a continuous-flow device in patients awaiting heart transplantation. The New England journal of medicine 2007;357:885-96. doi: 10.1056/NEJMoa067758 8. Slaughter MS, Rogers JG, Milano CA, et al.: Advanced heart failure treated with continuous-flow left ventricular assist device. The New England journal of medicine 2009;361:2241-51. doi: 10.1056/NEJMoa0909938 9. Slaughter MS, Naka Y, John R, et al.: Post-operative heparin may not be required for transitioning patients with a HeartMate II left ventricular assist system to long-term warfarin therapy. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2010;29:616-24. doi: 10.1016/j.healun.2010.02.003.

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10. Starling RC, Moazami N, Silvestry SC, et al.: Unexpected abrupt increase in left ventricular assist device thrombosis. The New England journal of medicine 2014;370:3340. doi: 10.1056/NEJMoa1313385. 11. Teuteberg JJ, Stewart GC, Jessup M, et al.: Implant strategies change over time and impact outcomes: insights from the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support). JACC Heart failure 2013;1:369-78. doi: 10.1016/j.jchf.2013.05.006. 12. Halbreiner MS, Soltesz E, Starling R, Moazami N: Current practice in patient selecting for long-term mechanical circulatory support. Current heart failure reports 2015;12:120-9. doi: 10.1007/s11897-014-0243-3.

13. Tsiouris A, Morgan JA, Nemeh HW, et al.: Does elective or emergent operative status influence outcomes in patients undergoing implantation of left ventricular assist devices? The heart surgery forum 2014;17:E64-72. doi: 10.1532/HSF98.2013298. 14. Trivedi JR, Cheng A, Singh R, Williams ML, Slaughter MS: Survival on the heart transplant waiting list: impact of continuous flow left ventricular assist device as bridge to transplant. The Annals of thoracic surgery 2014;98:830-4. doi: 10.1016/j.athoracsur.2014.05.019. 15. Moazami N, Fukamachi K, Kobayashi M, et al.: Axial and centrifugal continuousflow rotary pumps: a translation from pump mechanics to clinical practice. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2013;32:1-11. doi: 10.1016/j.healun.2012.10.001.

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16. Salamonsen RF, Mason DG, Ayre PJ: Response of rotary blood pumps to changes in preload and afterload at a fixed speed setting are unphysiological when compared with the natural heart. Artificial organs 2011;35:E47-53. doi: 10.1111/j.15251594.2010.01168.x. 17. Hayward CS, Salamonsen R, Keogh AM, et al.: Effect of alteration in pump speed on pump output and left ventricular filling with continuous-flow left ventricular assist device. ASAIO journal 2011;57:495-500. doi: 10.1097/MAT.0b013e318233b112. 18. Lampert BC, Eckert C, Weaver S, et al.: Blood pressure control in continuous flow left ventricular assist devices: efficacy and impact on adverse events. The Annals of thoracic surgery 2014;97:139-46. doi: 10.1016/j.athoracsur.2013.07.069.

19. Kirklin JK, Naftel DC, Kormos RL, et al.: Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) analysis of pump thrombosis in the HeartMate II left ventricular assist device. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 2014;33:1222. doi: 10.1016/j.healun.2013.11.001. 20. Stulak JM, Deo S, Schirger J, et al.: Preoperative atrial fibrillation increases risk of thromboembolic events after left ventricular assist device implantation. The Annals of thoracic surgery 2013;96:2161-7. doi: 10.1016/j.athoracsur.2013.07.004. 21. Boyle AJ, Russell SD, Teuteberg JJ, et al.: Low thromboembolism and pump thrombosis with the HeartMate II left ventricular assist device: analysis of outpatient anticoagulation. The Journal of heart and lung transplantation : the official publication of the

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International Society for Heart Transplantation 2009;28:881-7. doi: 10.1016/j.healun.2009.05.018. 22. Boyle AJ, Jorde UP, Sun B, et al.: Pre-operative risk factors of bleeding and stroke during left ventricular assist device support: an analysis of more than 900 HeartMate II outpatients. Journal of the American College of Cardiology 2014;63:880-8. doi: 10.1016/j.jacc.2013.08.1656. 23. Sorabella RA, Yerebakan H, Walters R, et al.: Comparison of outcomes after heart replacement therapy in patients over 65 years old. The Annals of thoracic surgery 2015;99:582-8. doi: 10.1016/j.athoracsur.2014.08.044.

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Figure 1. Survival Comparison. Kaplan-Meier survival comparison between periods. No survival difference was observed between cohorts (p=0.955). Period 1=full line, Period 2=dashed line, Period 3=dotted line. Figure 2. Freedom from Adverse Events. Kaplan-Meier comparison evaluating freedom from adverse events between periods. Later period (period 3) was associated with an increased risk of adverse events overtime (p=0.002). Period 1=full line, Period 2=dashed line, Period 3=dotted line. Figure 3. Freedom from Neurological Events. Kaplan-Meier comparison evaluating freedom from neurological events between periods. Later period (period 3) was associated with an increased risk of neurological events overtime (p=0.02). Period 1=full line, Period 2=dashed line, Period 3=dotted line. Figure 4. Freedom from Gastrointestinal Bleeding. Kaplan-Meier comparison evaluating freedom from gastrointestinal bleeding between periods. Later period (period 3) was associated with an increased risk of bleeding (p=0.006). Period 1=full line, Period 2=dashed line, Period 3=dotted line. Figure 5. Freedom from Pump Thrombus. Kaplan-Meier comparison evaluating freedom from pump thrombus between periods. Second period (period 2) was associated with an increased risk of pump thrombus overtime (p=0.019). Period 1=full line, Period 2=dashed line, Period 3=dotted line.

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Table 1. Patient/Period Characteristics. Comparison of preoperative patient characteristics between periods studied.

Age (years), (median[IQR])

All

Period 1

Period 2

Period 3

n=1,064

n=134

n=543

n=387

59 [50,

59 [51, 68]

59 [50,

59 [50,

66]

64]

65]

P value 0.27

Gender (male %)

80

78

78

83

0.23

HF etiology (ischemic %)

53

47

53

54

0.71

HeartMate II (%)

78

100

88

57

<0.001

Redo Sternotomy (%)

30

39

31

25

0.006

81 [61,

97 [80,

80 [61,

77 [57,

<0.001

110]

118]

108]

106]

Pre-op IABP (%)

42

36

50

32

<0.001

Pre-op AF (%)

36

27

36

40

0.03

Diabetes (%)

36

38

36

36

0.86

Hypertension (%)

55

48

55

58

0.14

Creatinine (mg/dl),

1.3 [1,

1.4 [1.1,

1.3 [1,

1.3 [1,

0.06

1.6]

1.7]

1.6]

1.5]

Bypass time (min), (median[IQR])

(median[IQR])

AF: atrial fibrillation, HF: heart failure, IABP: intra-aortic balloon pump.

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Table 2. Clinical Outcomes by Periods. Cumulative adverse events and mortality comparing all 3 periods (not adjusted for follow-up time). P value

All

Period 1

Period 2

Period 3

n=1,064

n=134

n=543

n=387

Median follow-up (y)

1.0

0.9

1.6

0.6

<0.001

Any AE (%)

43

48

45

39

0.13

Pump Thrombus OR

13

7

17

10

0.002

GI Bleeding (%)

19

17

18

20

0.61

Driveline Infection (%)

10

18

13

5

<0.001

Neurologic Event (%)

16

14

17

14

0.42

Death (%)

27

35

31

17

<0.001

Hemolysis (%)

GI: gastrointestinal, AE: adverse event.

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Table 3. Multivariable Analyses. Evaluating association of pre-determined variables with mortality and adverse events. Mortality

HR (95% CI)

Adverse Events

P-

HR (95% CI)

P-value

value 0.53

Period

0.002

2 vs. 1

0.89 (0.6, 1.34)

1.07 (0.77, 1.48)

3 vs. 1

1.08 (0.66, 1.77)

1.6 (1.11, 2.3)

HVAD vs. HMII

1.19 (0.82, 1.73)

0.35

0.93 (0.72, 1.21)

0.60

Age (per 10y increase)

1.31 (1.15, 1.49)

<0.001

1.08 (0.99, 1.18)

0.10

Female vs. Male

1.18 (0.85, 1.65)

0.31

1.25 (0.97, 1.6)

0.08

Ischemic etiology

0.98 (0.73, 1.31)

0.88

1.48 (1.19, 1.83)

<0.001

INTERMACS

0.59

0.008

1 vs. ≥ 4

1.79 (1.17, 2.74)

0.92 (0.64, 1.33)

2 vs. ≥ 4

1.09 (0.74, 1.62)

1.04 (0.78, 1.39)

3 vs. ≥ 4

0.91 (0.64, 1.31)

1.13 (0.88, 1.46)

HMII: HeartMate II, HVAD: HeartWare Ventricular Assist System

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Figure 1.

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Figure 2.

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Figure 3.

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Figure 4.

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Figure 5.

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