Classic Studies in MCS: The ADVANCE Trial

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Colin McCloskey
Colin McCloskey
EM Intensivist at University Hospitals Cleveland Medical Center

The Pre-brief

Mechanical circulatory support (MCS) is an established treatment modality for end stage heart failure. This is a series walking through the classic papers that advanced the field. You can find a discussion of the REMATCH trial, which demonstrated improved survival using a first generation left ventricular assist device (LVAD) compared to medical therapy. ADVANCE tested the efficacy of a new, smaller LVAD compared to the commercially available LVADs at the time for patients awaiting heart transplant.

See below for an incredible infographic by Sharleen Yuan. Other images by Rahel Gizaw.

Let’s Deep Dive This Thing

Introduction: The first generation LVAD design used in the REMATCH trial was a pusher-plate blood pump that generated pulsatile flow. Experience with this design brought concerns due to both the large size of the LVAD and its limited durability. The probability of device failure at 2 years was 35% in the REMATCH trial1. Pagani and colleagues described the use of a novel second generation LVAD design, one with a continuous-flow rotary pump with axial flow2. This device was smaller and promised improved reliability due to simplification of the pumping mechanism. Used as bridge to transplant, this continuous axial flow device showed improved actuarial survival at one year compared to pulsatile devices (73% vs 53%). Further, only 4% of patients receiving the continue flow device required LVAD replacement, and none of these replacements was due to pump failure. These pumps were implanted within the abdominal wall or peritoneal cavity. A third generation LVAD pump is a bearing-less, centrifugal flow design. It was even smaller than the second-generation axial flow pumps and was implanted directly into the left ventricle. The ADVANCE study prospectively compared these third generation centrifugal flow pumps to the second generation axial flow model.

Figure 1: Schema of an axial flow LVAD. This pump required creation of a “pump pocket” inferior to the heart.

What Did They Do?

Aaronson and colleagues conducted a multicenter, prospective trial of a continuous-flow centrifugal LVAD compared to a contemporaneous control group of commercially-approved axial-flow LVADs. This study was designed by the maker of the novel LVAD, Heartware (Medtronic). Subjects were adults with NYHA Class IV heart failure who were listed as UNOS Status 1A or 1B for cardiac transplantation. Notable exclusion criteria included need for mechanical circulatory support beyond an intra-aortic balloon pump, recent myocardial infarction, severe right ventricular failure, or any suggestion of developing multiorgan system failure.

Subjects in the intervention arm received the Heartware HVAD, an implantable continuous-flow pump with centrifugal design. This pump is surgically placed in the pericardial space and the inflow cannula is within the left ventricle. The impeller is the only moving part of the pump, suspended by magnetic and hydrodynamic forces. See Figure 2.

Figure 2: Schema of a centrifugal flow LVAD. This is placed adjacent to the pericardium, without need for creation of a “pump pocket”.

Control subjects were identified from the Interagency Registry for Mechanical Assisted Circulatory Support (INTERMACS). The patients were also bridge to transplant that had a commercially approved axial LVAD implanted during the study period.  

The primary outcome was a composite of survival from original LVAD implantation for 180 days or survival to explantation to receive a heart transplant or recovery before 180 days. Secondary outcomes of note were overall survival, serious adverse events, and quality of life. 

This was a non-inferiority study, with a prespecified 15% margin between the intervention cohort and the registry-matched control cohort.

What Did They Find?

140 patients were enrolled in the novel centrifugal flow LVAD arm, compared to 497 from INTERMACS who had an axial flow device. The cohorts were well matched at baseline, with a glaring exception being the control cohort had more INTERMACS 1 profiles, connoting a greater severity of illness. 

In an intention-to-treat analysis, 90.7% of the centrifugal flow LVAD patients and 90.1% of the INTERMACS axial flow patients met the primary outcome. This finding fell within the boundaries of non-inferiority.


Centrifugal Flow LVAD

Axial Flow LVAD

P Value for Noninferiority Hypothesis

Primary Outcome

90.7 % (127/140)

90.1% (448/497)

P < 0.001

Table 1: Primary outcome: survival at 180 days with LVAD or survival to explantation or transplant prior to 180 days

Secondary outcomes regarding quality of life showed a statistically significant improvement in 6 minute walk distance, EQ-5D Visual analog scale, and Kansas City Cardiomyopathy Questionnaire scores. This was compared to a baseline established pre-implantation of the centrifugal LVAD, and not a comparison between the case and control arms. 

Adverse events were mostly similar between the novel centrifugal flow LVAD and its axial flow predecessor. Of note, this comparison is between two different trials and not between the intervention group and controls of ADVANCE. The big difference favoring the centrifugal device was less bleeding that required surgery. It is opined by the authors that the smaller surgical dissection involved for the intrapericardial pump drove this reduction.

Adverse Event

Centrifugal Flow LVAD

Axial Flow LVAD*

Bleeding Requiring Surgery

14% (20/140)




11% (16/140)



Right Heart Failure

16% (23/140)



Renal Failure

9% (12/140)








Device Replacement





Table 2: Secondary safety outcomes. incidence at 180 days. *This is not a direct comparison from this trial but contrasted against incidence data from Pagani, Francis D., et al. “Extended mechanical circulatory support with a continuous-flow rotary left ventricular assist device.” Journal of the American College of Cardiology 54.4 (2009): 312-321.

The authors conclude that a continuous-flow, centrifugal pump implanted directly into the left ventricle and positioned in the pericardial space was noninferior to contemporary axial flow, peritoneally positioned LVADs.


This is not a randomized control trial, but rather a cohort study with a comparator arm derived from a registry. Thus, important confounders in baseline characteristics may have led to imbalance favoring the outcome. Also, given the comparison to a registry, selection bias can exist as it is unknown the rationale for device implantation in the comparator arm. Further, there were a larger number of INTERMACS 1 and 2 patients in the control group, marking a sicker cohort. This imbalance would favor the intervention arm. The authors, however, provide a detailed INTERMACS outcome analysis in the supplement which argues that this baseline imbalance is not concerning, given that the primary outcome was consistent across INTERMACS profiles. Lastly, adverse event rates cannot be directly compared between this device and predecessors since it was not a trial. These differences should be considered solely hypothesis-generating.

The Debrief

The third generation, continuous flow, centrifugal pump is non-inferior to its continuous flow axial forebears. This laid the groundwork for two randomized control trials comparing the designs, Momentum 34 and Endurance5.


  1. Rose, Eric A., et al. “Long-term use of a left ventricular assist device for end-stage heart failure.” New England Journal of Medicine 345.20 (2001): 1435-1443.
  2. Pagani, Francis D., et al. “Extended mechanical circulatory support with a continuous-flow rotary left ventricular assist device.” Journal of the American College of Cardiology 54.4 (2009): 312-321.
  3. Aaronson, Keith D., et al. “Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation.” Circulation 125.25 (2012): 3191-3200.
  4. Mehra, Mandeep R., et al. “A fully magnetically levitated left ventricular assist device.” New England Journal of Medicine 380.17 (2019): 1618-1627.
  5. Rogers, Joseph G., et al. “Intrapericardial left ventricular assist device for advanced heart failure.” New England Journal of Medicine 376.5 (2017): 451-460.


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