Low Adoption Rates of Sacubitril/Valsartan Use in the US
Contributor: Nick Hawkes
Sacubitril/valsartan reduces morbidity and mortality in patients with HFrEF, so why has the adoption of this therapy in the outpatient setting been so slow?
Oxidative state of cGMP-dependent protein kinase determines the efficacy of sildenafil vs direct guanylate cyclase activators in pressure-overload HF
Contributor: Elise Vo
Precision therapy for HF is on the horizon. Activating cyclic guanosine monophosphate (cGMP)-dependent protein kinase-1α (PKG1α), results in vasodilation and prevents cardiac remodeling — a good thing. There are two ways to activate PKG1a: 1) directly soluble guanylate cyclase (sGC) activators and 2) indirectly by PDE5 inhibition. So, do these two methods of targeting PKG1α work equally well? Nakamura et al used a TAC murine model to demonstrate that the oxidative state of PKG1α determines whether or not sildenafil is efficacious in preventing pathologic remodeling in pressure-overload HF.
Slow Adoption and Low Adherence of Sacubitril/Valsartan for HFrEF
Contributor: Nick Hawkes
PARADIGM – HF demonstrated that Sacubitril/Valsartan reduces morbidity and mortality in patients with HFrEF compared to ACE-I/ARB therapy, so why is its adoption in the real world delayed?
Sangaralingham et al. accessed data from OptumLabs Data Warehouse, a large database of de-identified medical and pharmacy claims. Among patients identified based on systolic HF ICD codes, those prescribed sacubitril/valsartan were compared to those who were not. Patient variables included health plan, age, gender, race, region, comorbidities, other prescription medications, and provider specialty. Additionally the costs, out-of-pocket (OOP) and to the health plan, were captured.
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)
Multiple inotrope use at lower doses led to excess 1A candidates in the post-geographic sharing era
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.
Study Link: Trends in the Use of Inotropes to List Adult Heart Transplant Candidates at Status 1A
Bonus Points: December 2016 Proposal for six-status allocation system