Author + information
- Received November 15, 2017
- Revision received April 25, 2018
- Accepted May 3, 2018
- Published online July 11, 2018.
- Carmelo A. Milano, MDa,∗ (, )
- Joseph G. Rogers, MDa,
- Antone J. Tatooles, MDb,
- Geetha Bhat, PhD, MDb,
- Mark S. Slaughter, MDc,
- Emma J. Birks, MB, BS, PhDc,
- Nahush A. Mokadam, MDd,
- Claudius Mahr, MDd,
- Jeffrey S. Miller, MDe,
- David W. Markham, MD, MSce,
- Valluvan Jeevanandam, MDf,
- Nir Uriel, MD, MScf,
- Keith D. Aaronson, MD, MSg,
- Thomas A. Vassiliades, MDh,
- Francis D. Pagani, MD, PhDg,
- for the ENDURANCE Investigators
- aDepartments of Surgery and Medicine, Duke University School of Medicine, Durham, North Carolina
- bCenter for Heart Transplant and Assist Devices, Advocate Christ Medical Center, Oak Lawn, Illinois
- cCardiovascular and Thoracic Surgery and Department of Cardiovascular Medicine, University of Louisville, Louisville, Kentucky
- dDivisions of Cardiothoracic Surgery and Cardiology, University of Washington, Seattle, Washington
- eDepartments of Cardiac Surgery and Medicine, St. Joseph’s Hospital of Atlanta, Atlanta, Georgia
- fHeart and Vascular Center, University of Chicago Medicine, Chicago, Illinois
- gDivisions of Cardiovascular Medicine and Cardiothoracic Surgery, University of Michigan, Ann Arbor, Michigan
- hDepartment of Clinical and Medical Affairs, Medtronic (formerly HeartWare), Framingham, Massachusetts
- ↵∗Address for correspondence:
Dr. Carmelo A. Milano, Duke University School of Medicine, 4532 Hospital South–Blue Zone, Durham, North Carolina 27710.
Objectives The aim of this study was to prospectively evaluate the impact of blood pressure management on stroke rates in patients receiving the HeartWare HVAD System.
Background The ENDURANCE trial demonstrated noninferiority of the HeartWare HVAD System versus control (HeartMate II) in patients with advanced heart failure ineligible for heart transplantation. However, stroke was more common in HVAD subjects. Post hoc analyses demonstrated increased mean arterial blood pressure as a significant independent risk factor for stroke.
Methods The ENDURANCE Supplemental Trial was a prospective, multicenter evaluation of 465 patients with advanced heart failure ineligible for transplantation, randomized 2:1 to HVAD (n = 308) or control (n = 157). The primary endpoint was the 12-month incidence of transient ischemic attack or stroke with residual deficit 24 weeks post-event. Secondary endpoints included the composite of freedom from death, disabling stroke, and need for device replacement or urgent transplantation, as well as comparisons of stroke or transient ischemic attack rates in HVAD cohorts in ENDURANCE Supplemental and ENDURANCE.
Results The enhanced blood pressure protocol significantly reduced mean arterial blood pressure. The primary endpoint was not achieved (14.7% with HVAD vs. 12.1% with control, noninferiority [margin 6%] p = 0.14). However, the secondary composite endpoint demonstrated superiority of HVAD (76.1%) versus control (66.9%) (p = 0.04). The incidence of stroke in HVAD subjects was reduced 24.2% in ENDURANCE Supplemental compared with ENDURANCE (p = 0.10), and hemorrhagic cerebrovascular accident was reduced by 50.5% (p = 0.02).
Conclusions The ENDURANCE Supplemental Trial failed to demonstrate noninferiority of HVAD versus control regarding the pre-specified primary endpoint. However, the trial confirmed that BP management is associated with reduced stroke rates in HVAD subjects. HVAD subjects, relative to control subjects, more commonly achieved the composite endpoint (freedom from death, disabling stroke, and device replacement or urgent transplantation). (A Clinical Trial to Evaluate the HeartWare™ Ventricular Assist System [ENDURANCE SUPPLEMENTAL TRIAL] [DT2]; NCT01966458)
Heart failure is one of the leading causes of death in the developed world and is characterized by limitations in survival despite treatment with guideline-directed medical therapies (1). Projections indicate that the prevalence of heart failure will increase by 46% from 2012 to 2030 (2). Patients with heart failure progress to advanced stages and require cardiac transplantation or implantation of durable left ventricular assist devices (LVADs) to extend survival and improve quality of life and functional status (1). As the number of suitable heart donors and patient comorbidities place restrictions on the feasibility of cardiac transplantation, implantation of durable LVADs has emerged as the most frequently applied surgical treatment for end-stage heart failure as either a bridge to transplantation or permanent therapy (i.e., destination therapy) (3,4). Considerable data have documented improvements in survival, functional status and quality of life offered by destination therapy (5–7).
We previously reported the outcomes of the ENDURANCE trial, a prospective, multicenter, randomized controlled trial evaluating the use of the HVAD LVAD (HeartWare, Miami Lakes, Florida) compared with control (HeartMate II, a U.S. Food and Drug Administration–approved LVAD for destination therapy, Abbott, Abbott Park, Illinois) for destination therapy in 445 patients with advanced heart failure not eligible for cardiac transplantation (8). ENDURANCE demonstrated noninferiority of the HVAD compared with control in survival at 2 years free from disabling stroke and alive on the originally implanted device. Although the rate of device exchange was lower with the HVAD, the rate of stroke for the HVAD cohort was significantly greater than the rate for the control device, with the greatest difference seen in the rate of hemorrhagic events. Retrospective multivariable analyses of the data from the HVAD pivotal trial for bridge-to-transplantation indication (9,10) determined that elevated blood pressure was a highly significant, independent risk factor for stroke in patients on HVAD support (11). This observation was corroborated in a post hoc multivariable analysis of data from ENDURANCE (completed by the sponsor but not yet published). It was also observed in ENDURANCE that most strokes occurred early, in the first 6 months post-implantation. The ENDURANCE Supplemental Trial was designed to prospectively determine effectiveness of a blood pressure management strategy to reduce neurological injury in patients receiving the HVAD System. The data from the ENDURANCE trial and the Supplemental Trial data presented here led to Food and Drug Administration approval in September 2017 for the HVAD System as destination therapy in patients with advanced heart failure.
The ENDURANCE Supplemental Trial was a prospective, randomized controlled, unblinded, multicenter trial in patients with chronic American Heart Association stage D/New York Heart Association (NYHA) functional class IIIB or IV heart failure in whom optimal medical management was unsuccessful and who were deemed ineligible for transplantation. A total of 465 subjects enrolled at 47 centers were randomly assigned in a 2:1 ratio to receive either the study device (HeartWare HVAD System) (12) or control (HeartMate II). After implantation, device performance, laboratory data, and medications were recorded until hospital discharge and at follow-up visits scheduled at 3, 6, and 12 months. Functional capacity and quality-of-life measurements were performed at 3, 6, and 12 months. All HVAD subjects received oral anticoagulation with a target international normalized ratio of 2.0 to 3.0 and antiplatelet therapy (recommended starting dose of aspirin 325 mg/day). Management of patients who received the control device was at the discretion of their providers and by the device-specific instructions for use.
The primary endpoint was the incidence of neurological injury (defined as any stroke with a modified Rankin scale [mRS] score >0 at 24 weeks post-stroke or any transient ischemic attack [TIA] or spinal cord infarct) at 12 months, including only time on the originally implanted LVAD. Strokes with mRS scores of 0 at 24 weeks (n = 13 for HVAD, n = 5 for control) were not included in the primary endpoint of neurological injury. The composite secondary efficacy endpoint was freedom from death, disabling stroke (mRS score ≥4), and device malfunctions or failures requiring exchange, explantation, or urgent transplantation over 1 year from implantation, including only time on the originally implanted LVAD. Additional endpoints also included rates for adverse events, which were classified according to the Interagency Registry for Mechanically Assisted Circulatory Support definitions and were adjudicated by an independent clinical events committee (13). Additionally, a pre-specified secondary endpoint analysis called for a comparison of the stroke or TIA rate for the HVAD subjects in the ENDURANCE Supplemental Trial against a performance goal of 17.7%, which was based on the lower bound of the confidence interval in the sintered cohort of the ENDURANCE trial.
A post hoc hierarchical analysis of all randomized and implanted subjects in the study was performed as part of the secondary composite endpoint analysis. Transplantation, recovery, and device exchange were treated as terminal events, meaning that any neurological event (stroke or TIA) or death that occurred after those events was not counted, and death was always counted as the failing event in the binary-components analysis (i.e., subjects were only counted once as a failure, and death was considered the worst-case failure event in subjects with multiple events). For subjects with multiple events other than death, only the first event was counted.
Primary and secondary endpoints as well as adverse events were adjudicated by an independent clinical events committee. A data and safety monitoring board monitored and reviewed study compliance, adverse events, and outcomes. The study was conducted in compliance with Food and Drug Administration regulations for good clinical practice and approved by each clinical site’s Institutional Review Board. All subjects or their authorized representatives provided informed consent.
Changes in quality of life were measured using the Kansas City Cardiomyopathy Questionnaire, a disease-specific, 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity, and recent change), social function, self-efficacy, knowledge, and quality of life, and the EuroQoL EQ-5D-5L, an assessment of general well-being.
Changes in functional status were measured using NYHA classification and the 6-min walk test. NYHA class was assessed by a qualified person at the clinical site not directly involved with this clinical trial. The 6-min walk test was conducted by the site staff according to the American Thoracic Society’s guidelines for the 6-min walk test (14).
Blood pressure management protocol
Following discharge from the index hospitalization, all HVAD subjects were required to adhere to a blood pressure management protocol in addition to receiving standard of care. Prior to discharge, subjects and caregivers were trained to measure blood pressures and record values in a diary. Subjects with a palpable pulse used a Terumo Elemano (model ESH5503, Terumo, Somerset, New Jersey) automated blood pressure cuff. Subjects without a palpable pulse were trained on the use of a Doppler and manual cuff to obtain an opening pressure. In the latter case, the opening pressure was assumed to be 5 mm Hg higher (a correction factor) than the mean arterial blood pressure. Subjects were to record their blood pressure twice per day for at least the first 3 months following discharge and to continue this routine after the first 3 months until blood pressure consistently remained within the recommended range. The recommended blood pressure range was defined as mean arterial pressure (MAP) ≤85 mm Hg for the automated cuff method and an opening pressure ≤90 mm Hg for the Doppler cuff method.
Subject compliance was assessed weekly during the initial 3 months, after which the investigator determined if the subject’s blood pressure was stable or unstable. If the blood pressure was determined to be unstable, the subject continued the blood pressure monitoring for an additional 3 months, with reassessment for stability. Subjects with 4 consecutive blood pressure measurements outside the target range were instructed to contact the study site, with the expectation that antihypertensive therapy would be adjusted. Compliance was assessed via review of diaries by the study site and the sponsor.
Management of blood pressure in subjects receiving the control device was not standardized by study protocol. The manufacturer’s instructions for use for the control device allows treatment of post-implantation hypertension at the discretion of the physician and notes that maintaining MAP at <90 mm Hg should be adequate (15). Also, the current International Society for Heart & Lung Transplantation guidelines for patients receiving mechanical circulatory support recommend blood pressure control, specifically maintaining blood pressure at <85 mm Hg, as a standard of care in these patients (16).
The difference in the percentage of patients meeting the primary endpoint between the HVAD and control devices was tested using the Farrington-Manning asymptotic test of noninferiority with a noninferiority margin of 6%. The confidence interval was reported using the pre-specified exact method, using SAS code (SAS Institute, Cary, North Carolina) to perform the exact methods. However, this method was found to be too conservative, so an alternative method, the δ-projected Z statistic without restricted search for the nuisance parameter, is also presented (17).
The composite secondary endpoint was tested using the Farrington-Manning asymptomatic test of noninferiority with a noninferiority margin of 15%. Because noninferiority was statistically significant, superiority testing was performed without alpha penalty. Analyses of the primary and secondary endpoints were conducted on the modified intention-to-treat subjects who did not exit prior to an event. A post hoc comparison of the stroke or TIA rates in the HVAD subjects between the 2 studies was also performed using the chi-square test.
For blood pressure analysis, 5 mm Hg was subtracted from the Doppler opening pressure values to estimate the MAP measurement. Comparison of groups’ mean MAPs was done using 2-sample Student’s t tests. Post-transplantation values were not included in the analysis.
The Fisher exact test was used to compare the rates of adverse events between the treatment and control cohorts. Survival analysis was performed using Kaplan-Meier methods. Patients were censored from analysis at the time of original device explantation. A p value < 0.05 was considered to indicate statistical significance. P values were not adjusted for multiple testing.
Between October 2013 and August 2015, 494 subjects were screened at 48 sites in the United States (Figure 1). There were 19 screen failures, resulting in randomization of 475 subjects in a 2:1 fashion, study device to control. Ten subjects did not undergo implantation, resulting in a modified intention-to-treat population of 465 subjects (n = 308 HVAD, n = 157 control) from 47 sites. All subjects underwent implantation of the devices to which they were randomized.
The baseline characteristics of the 2 groups were similar (Table 1). Study and control cohorts did not differ with respect to severity of illness or treatments at the time of enrollment. International normalized ratio was measured monthly post-implantation, and the percentage of HVAD subjects within the international normalized ratio target range of 2.0 to 3.0 ranged between 49% and 62% during the 12-month follow-up period, while the percentage of control subjects ranged from 47% to 61%. Additionally, after adjustment for multiple comparison, there were no statistically significant differences in the percentage in the target range between HVAD and control at any time point during the follow-up period. A comparison of baseline characteristics between the HVAD cohort in the ENDURANCE Supplemental Trial and the ENDURANCE trial revealed no statistically significant differences among any of the demographics or medical history, with the exception of a significantly larger mean body mass index in the ENDURANCE Supplemental patients receiving the HVAD compared with those in the ENDURANCE trial (28.2 vs. 27.2 kg/m2; p = 0.03) and a significantly greater history of hypertension in those patients in the ENDURANCE Supplemental Trial (75.0% vs. 65.5%; p = 0.01). Interestingly, these 2 parameters could have biased against success in a trial targeting blood pressure management.
Subjects receiving the HVAD and management with the blood pressure management protocol had lower MAP compared with subjects receiving the control device without protocol-directed management of blood pressure (Figure 2A). Additionally, the mean MAP was significantly reduced at all post-implantation time points in subjects receiving the HVAD in the ENDURANCE Supplemental Trial compared with the ENDURANCE trial. However, there was also a reduction in the mean blood pressure of the control device when comparing ENDURANCE with ENDURANCE Supplemental (Figure 2A), although the reductions was not statistically significant. An analysis of the proportion of subjects meeting the target MAPs was also similar over time for HVAD and control, although HVAD subjects had nominally better target adherence in the post-discharge periods than at 6 and 12 months (Figure 2B). A comparison of the percentage of subjects with strokes between 3 and 12 months between HVAD and control subjects by those who were outside of the target blood pressure range at 3 months showed no significant difference between the 2 cohorts (7.8% [6 of 77] vs. 6.7% [4 of 60], respectively; p > 0.99), although the number of strokes in each group was small. Additionally, the mean MAP in patients with strokes (averaging MAPs up to the day prior to a stroke) were similar in the HVAD and control groups (80.7 mm Hg vs. 78.1 mm Hg).
Neurological injury as defined for the primary endpoint occurred in 14.7% of the HVAD cohort and 12.1% of the control cohort (Figure 3). The primary endpoint as defined in this study was not achieved, with an upper limit of the confidence interval (pre-specified method) of 10.7%, which was above the pre-specified noninferiority margin of 6% (p = 0.14). A more reliable, but post hoc, confidence limit method produced an upper confidence bound of 7.9% (17).
An analysis of the composite secondary endpoint of freedom from death, disabling stroke, and device malfunction or failure requiring exchange, explantation, or urgent transplantation (the primary outcome measure used in most clinical trials of LVAD therapy as well as from the ENDURANCE trial but measured at 1 year) demonstrated noninferiority of the HVAD group compared with control (76.1% vs. 66.9%; p < 0.0001). A subsequent test of superiority showed the HVAD to be significantly better than control (superiority p = 0.04). A Kaplan-Meier representation of the results is presented in Figure 4.
Although the mortality rate was similar between HVAD and control (16.9% HVAD, 17.8% control), a higher percentage of control subjects experienced disabling (mRS score ≥4) strokes (1.6% vs. 3.2%) and device exchange (3.2% vs. 10.2%) as their worst event. Strokes with mRS scores <4 were more common in the HVAD group (9.1% vs. 5.7%) (Figure 5A).
The comparison of the rate of strokes between HVAD (16.9%) and control (14.6%) was not statistically significantly different (p = 0.60). There was also no significant difference between ischemic cerebrovascular accident (13.0% vs. 7.6%) and HCVA (5.2% vs. 7.0%) for HVAD versus control, respectively. However, a significantly greater percentage of subjects experienced TIAs in the HVAD group versus control (4.2% vs. 0.6%, respectively; p = 0.04). The overall level of disability post-stroke was proportionately lower in the HVAD group compared with control (Figure 5B).
The secondary endpoint of incidence of stroke or TIA in patients receiving the HVAD was pre-specified to be compared with a 17.7% performance goal and did not pass (p = 0.74). However, the incidence of stroke was reduced by 24.2% in the ENDURANCE Supplemental Trial compared with the HVAD cohort of the ENDURANCE trial, although superiority was not shown (chi-square superiority p = 0.10). However, an analysis of the overall strokes in HVAD patients in ENDURANCE compared with ENDURANCE Supplemental revealed an improvement of the neurological event profile in general, and hemorrhagic strokes in particular were statistically significantly reduced by 50.5% (p = 0.02) (Table 2). The overall stroke rates for the control device were not significantly different between the control arms in the 2 trials, including the rate of disabling strokes, which occurred in 4.7% of patients (7 of 149) in the ENDURANCE trial and 6.4% of those (10 of 157) enrolled in the ENDURANCE Supplemental Trial at 12 months.
Adverse event rates for major bleeding, cardiac arrhythmias, renal dysfunction, and infections, including percutaneous driveline infections, were similar between HVAD and control subjects (Table 3). TIAs were more frequent in the HVAD cohort, while hemolysis, pump replacement, and exchange due to pump thrombus were all significantly higher in the control cohort. Additionally, freedom from any pump thrombus event through 1 year was significantly greater for subjects receiving the HVAD, 91.3%, compared with 81.6% for those receiving the control (log-rank p = 0.0013).
Although the overall rate of device malfunctions was similar between the 2 cohorts, there were differences in the types of malfunctions. In the HVAD cohort, 19.6% of the device malfunctions were related to battery problems or electric faults, whereas 26.2% were due to controller faults and another 26.2% of the total malfunctions to suspected or confirmed pump thrombus events. In the control group, there were no battery-related malfunctions, 23.4% of the total malfunctions were related to controller faults, and 57.4% of the total device malfunctions consisted of pump thrombosis.
Overall quality-of-life scores (Table 4) were similarly significantly improved at 12 months compared with baseline in both HVAD and control subjects. Functional capacity, as measured by NYHA classification improvements and increase in 6-min walk distance, were comparably improved in both cohorts. Although data were somewhat incomplete (51.9% of HVAD and 43.3% of control subjects had paired data), improvements of ≥100 m in the 6-min walk total distance were similarly achieved by 47.5% of the subjects in the HVAD group and 51.5% of the subjects in the control group.
Previous analyses of data from the ADVANCE and ENDURANCE trials suggested that increased MAP is an independent predictor of stroke among patients supported with the HVAD (11). In the ENDURANCE Supplemental Trial, a blood pressure algorithm, most often using a Doppler/cuff method, was applied to subjects receiving the HVAD to measure MAP. Application of this protocol successfully lowered MAP in the HVAD cohort relative to the control cohort (managed according to the standard of care). The absolute difference in MAPs was small, on the order of 4 to 5 mm Hg, but was observed at all time points throughout the trial. This small difference may be clinically important compared with other studies of blood pressure treatment (18,19).
Although the difference in neurological injury for the primary endpoint between the HVAD cohort and control was only 2.6%, this failed to achieve the pre-specified test of noninferiority, which called for a 6% noninferiority margin. It is important to note that although TIAs, which do not represent persistent injury, were included in the definition of neurological injury for the primary endpoint, the primary endpoint did not include strokes with mRS scores of 0 at the 24-week follow-up point (fully recovered strokes with no residual deficit).
Although the primary endpoint was not met, examination of the totality of data from this trial suggests that the HVAD cohort managed according to this algorithm experienced a significant decrease in the rate of stroke. The total stroke rate as captured in the summary of adverse events demonstrates no statistical difference in rates for any stroke, ischemic stroke, and hemorrhagic stroke for the HVAD cohort versus control. Although not statistically significant, the rate of hemorrhagic stroke was less for the HVAD cohort versus control, representing an improvement from the original ENDURANCE trial, which showed a 2- to 3-fold increased stroke rate for HVAD patients compared with control. Similarly, the 2.6% higher rate of neurological injury for the HVAD group in the primary endpoint is much improved from the differences seen in the ENDURANCE trial for stroke rate or TIA. Finally, the rates of stroke and TIA for the HVAD cohort in the ENDURANCE Supplemental Trial were all meaningfully lower than those for the HVAD cohort in the original ENDURANCE trial. The improvement included a 50.5% reduction for hemorrhagic events in the ENDURANCE Supplemental Trial versus the ENDURANCE trial, which is consistent with the therapy focused on blood pressure reduction. Therefore, the examination of all data in this trial would suggest a meaningful association between reduced MAP for the HVAD patients and reduced risk for stroke events.
Previous studies in non-LVAD patients have shown an association between reduced stroke and better blood pressure management (20). Therefore, the reduced rate of hemorrhagic stroke for the HVAD patients in this trial may have been anticipated. There also appears to be a beneficial effect with regard to ischemic stroke. The exact mechanism for this is unclear. One theory is that reduced MAP results in reduced afterload for the LVAD pump, which translates into greater pump flow and better washing of the entire left heart and LVAD pump. This could reduce stasis and result in less thrombus formation at different sites. A greater reduction in afterload could also promote greater native left ventricular ejection and intermittent opening of the aortic valve, which has been demonstrated to reduce areas of blood flow stagnation in the left ventricle (21).
We also examined the conventional composite outcome of survival free from death, disabling stroke (mRS score ≥4), or need for device replacement or urgent transplantation. This endpoint is a convention used in trials to assess LVAD outcomes and was used in the ENDURANCE trial (8) as well as in the recently published MOMENTUM trial (22). At 1 year, the HVAD group was superior to the control group at achieving this endpoint. This difference is due mainly to greater need for pump replacement because of thrombosis observed in the control group. One limitation for this composite endpoint is that all 3 types of events that constitute it are not equal. For example, death is a greater failure than need for device replacement. To examine this more carefully, the rates of different events are presented in hierarchical severity (i.e., death first) (see Figure 4).
Improved blood pressure management was not mandated for the control cohort in this trial. Clinical trial design rules do not allow alterations in the standard of care in a control population. Therefore, it is unknown whether improved blood pressure management would have resulted in any impact on the stroke rate for the control cohort. However, the MAPs of patients with stroke events in both cohorts were similar, and conversely the incidence of neurological events was similar in the HVAD and control cohorts that did not have adequately controlled blood pressure.
HVAD patients were not randomized to receive the blood pressure management protocol; rather, outcomes were compared with results from the ENDURANCE trial. The blood pressure measures in the ENDURANCE trial were not collected with the same frequency or methodology as in the ENDURANCE Supplemental Trial, and the analysis was retrospective. Other changes may have occurred in the device or patient management that may account for the reduced rates of stroke.
Additionally, elements of the ENDURANCE Supplemental Trial design contributed to limitations of the results. First, the primary endpoint excluded patients who experienced strokes but went on to have complete recovery (mRS score = 0) at 24 weeks, while including patients who experienced TIAs. In retrospect, it might have been more appropriate to include or exclude both. Second, sample-size calculations for the primary endpoint used lower power (80%) and a small noninferiority margin (6%), underestimated the event rate, and assumed a superior rate in the HVAD group compared with control subjects, which could have led to the nonsignificant result of the primary endpoint. Finally, no adjustments were made to p values reported, so multiple comparisons should be taken into account when interpreting p values.
The ENDURANCE Supplemental Trial failed to demonstrate noninferiority of the HVAD versus control with respect to the primary endpoint; there was a higher incidence of neurological injury for the HVAD versus control. However, the trial confirmed that blood pressure management was associated with a reduced risk for stroke in HVAD subjects. Additionally, with regard to the composite endpoint of survival free from disabling stroke and need for device exchange or urgent transplantation or death, the HVAD System was superior to the control. Therefore, the HVAD is a reasonable alternative and may be superior to the HeartMate II for some patients, as there were fewer thrombi requiring device exchange, and the majority of strokes were not disabling. This study also provides support for the existing International Society for Heart & Lung Transplantation recommendations for blood pressure management in patients with mechanical circulatory support (16), perhaps further defining that blood pressure be monitored twice daily for at least the first 3 months post-implantation to ensure appropriate blood pressure control. Finally, these results support the use of the HVAD as a safe and effective system for patients ineligible for cardiac transplantation.
COMPETENCY IN MEDICAL KNOWLEDGE: For clinicians, this study has demonstrated that careful attention to blood pressure management may lead to lower rates of strokes in patients supported with the HVAD System, thus improving overall outcomes for patients with advanced heart failure ineligible for transplantation.
TRANSLATIONAL OUTLOOK: For investigators, these data have prospectively validated the preliminary data found through a post hoc analysis of clinical trial data, which demonstrated through a multivariable analysis that elevated blood pressure is significant risk factor for stroke in patients with advanced heart failure implanted with LVADs. This study is an example of the utility and value of data-mining efforts and post hoc analyses of clinical trial data.
The authors acknowledge Mary V. Jacoski, MS, of Medtronic for assistance in the analysis and preparation of the manuscript, and Jeffrey Cerkvenik, also of Medtronic, for statistical support.
This study was supported by Medtronic (formerly HeartWare). HeartWare (now Medtronic) sponsored this clinical trial and partnered with us in this analysis, but the authors had access to all the data and provided critical review, writing, and content control. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. John R. Teerlink, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- hemorrhagic cerebrovascular accident
- hazard ratio
- improved blood pressure management
- left ventricular assist device
- mean arterial pressure
- modified Rankin scale
- New York Heart Association
- transient ischemic attack
- Received November 15, 2017.
- Revision received April 25, 2018.
- Accepted May 3, 2018.
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