Clinical and In Vitro Evidence that LVAD-Induced Von Willebrand Factor Degradation May Alter Angiogenesis
Contributor: Darien Allen
GI bleeds in continuous-flow left ventricular assist device (CF-LVAD) patients are an increasing problem. Bartoli et al posit a two-hit hypothesis to explain the increased risk of mucosal bleeds in this population:
Hit 1: CF-LVAD-induced shear stress activates von Willebrand factor (VWF) multimers leading to enzymatic and mechanical degradation into variably sized fragments and acquired VWF deficiency. CF-LVAD induced VWF deficiency reduces VWF-collagen and VWF-platelet binding resulting in increased risk of mucosal bleeding.
Hit 2: Higher circulating concentrations of VWF fragments lead to altered angiogenesis and likely contribute to the development of angiodysplasia.
Early right ventricular assist device utilization in patients undergoing continuous-flow left ventricular assist device implantation: Insight from INTERMACS
Contributor: Steven Stroud
Frustrated by limited, single small center risk scores for RV failure? Kiernan and colleagues analyzed the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) to identify factors associated with RV failure following continuous flow left ventricular assist device (CF-LVAD) support.
Old drug… new trick? Treatment with sildenafil may prevent device thrombosis and ischemic stroke in LVAD patients.
Contributor: Chris Sobowale
Bleeding and thrombosis account for almost half of adverse events in patients with CF-LVADs.
Saeed et al analyzed 144 HeartMate II (HMII) CF-LVAD patients in a single center, retrospective study. Patients in the sildenafil groups were on sildenafil for pulmonary hypertension or right ventricular dysfunction for at least 30 days after discharge from CF-LVAD implant. Patients were divided into four groups:
- Low level hemolysis not on sildenafil (n=31)
- Low level hemolysis on sildenafil (n= 16)
- No low level hemolysis not on sildenafil n= (76)
- No low level hemolysis on sildenafil (n=21)
Contributor: Steven Stroud
Status 1A heart transplant candidates are critically-ill patients requiring mechanical circulatory support (MCS) or high-dose / multiple inotrope therapy to maintain perfusion. Status 1A candidates are listed as highest priority, and are thus more likely to receive a heart transplant. In 2006, a significant change occurred in the Organ Procurement and Transplantation Network (OPTN) criteria with the intent of increase geographic sharing. Following the update, organs were shared within a 500-mile radius as opposed to offers first being made to all candidates (Status 1A, 1B and 2) within local organ procurement organization.
Parker and colleagues investigated whether this policy change affected clinical practice patterns in care of patients listed for heart transplant. The bottom line: following the policy change transplanted patients were more likely to be on low dose inotropes.
Using the Scientific Registry of Transplant Recipients (SRTR) a comparison was made between heart transplant candidates pre (7/2000-7/11/2006) and post (7/12/2006-7/2015) geographic sharing.Status 1A candidates had the following values analyzed: hemodynamic data, MCS type, inotrope type(s) and doses.Between 2000 and 2006, the number of 1A candidates declined from 656 (22% of total candidates) to 452 (18%). However, from 2006-2015, 965 (26%) candidates were Status 1A. The same trend is seen in 1B candidates as well. Not surprisingly, Status 2 candidates steadily declined from 2000-2015 (1,673, 55% to 1,038, 28%).
Among Status 1A candidates, the inotrope subgroup (candidates without MCS) decreased in the pre-sharing era (256, 11% to 174, 8%), but significantly increased in the post-sharing era (381, 18% in 2015, p<0.001). Specifically, multiple-inotrope therapy increased substantially, with 153 more multiple-inotrope 1A candidates in 2015 compared to 2005 (p<0.001). The mean dose of inotropes within the multiple-inotrope subgroup was lower in the post-sharing era compared to the pre-sharing era (dobutamine dose decreased 49%, dopamine dose decreased 55%, and milrinone dose decreased 29%, p<0.001). Interestingly, the cardiac index slightly increased (2.17 to 2.25 L/min/m2, p=0.044).
The single, high-dose inotrope 1A subgroup had relatively stable dosing of milrinone (p=0.063) and a decrease of dobutamine by 4%, p<0.005. Of note, milrinone was used more frequently in the post-sharing era, with a 10% increase in frequency, p<0.001.
The waitlist survival of 1A candidates also increased in the post-sharing era. In the pre-sharing era, 1A candidates had a 130% higher chance of dying, while in the post-sharing era 1A candidates had a 33% higher chance of dying in comparison to Status 2 candidates. This shift represents a 62% risk reduction in death (comparing the last three years of pre-sharing with 7/12/2006-12/31/2010).
No study is perfect. Not all advanced heart failure patients are included in the SRTR, and although hemodynamic data was provided, there may be other factors not listed contributing to the use of multiple inotropes. Improvements in heart failure medical therapy may also contribute to improved waitlist survival of 1A candidates.
Worth noting, there were 220 more CF-LVAD 1A candidates in 2015 compared to 2005 (p<0.001), which certainly contributed to the growing number of 1A candidates as well.
In a heartbeat… The use of multiple inotropes to shift patients to 1A status contributed to excess 1A transplant candidates in the post-geographic sharing era (7/12/2006-7/2015). Changes in policy that require clear hemodynamic rationale for candidate urgency may help stratify transplant candidates more appropriately.
Bonus Points: December 2016 Proposal for six-status allocation system