The prevalence of heart failure continues to rise and treatment options become more complex as patients progress toward end-stage disease.¹ While heart transplantation is the treatment of choice, there is a shortage of available organs and some patients are not transplant candidates. Some are too ill to undergo the long transplant surgery, while others have antibodies that preclude finding a compatible organ. In addition, comorbidities such as pulmonary hypertension, kidney disease, and obesity can prevent patients from receiving a transplant. Brian Houston, MD, Assistant Professor of Medicine in the Division of Cardiology at the Medical University of South Carolina (MUSC) explains, “In advanced heart failure, patients are highly symptomatic and have a high chance of dying from their heart failure despite being on the best medical therapies. These patients are running out of options.”

In recent years, improved mechanical circulatory support devices have become available that can significantly extend the lives of heart failure patients.^2,3 Houston says, “The best study comparing optimal medical therapy with an LVAD (left ventricular assist device) finds that three out of four–about 75% of patients with end-stage heart failure –on medical therapy only are dead at one year, but 90% of those who get an LVAD are alive at one year.” This substantial survival benefit and improved quality-of-life mean that most (about 90%) end-stage heart failure patients receive an LVAD whether or not they are put on the transplant waiting list.⁴“Just like with cell phones, there’s a big difference between the newer and older generations of these devices. The LVADs in the 1980s and ‘90s pumped blood like a bellows and the patient had a pulse. Now we have continuous flow devices that use an impeller to push blood through the body at a constant speed. Most of these patients don’t have a pulse you can feel unless the heart is still strong enough to pump through the LVAD,” says Houston.

The therapeutic utility of an LVAD varies by patient. For some, the device is implanted as a bridge-to-transplant, stabilizing them while they wait for a suitable heart. For those who are not transplant candidates, the LVAD may be a final therapeutic option. Others, who may have had contra-indications for transplant (e.g., pulmonary hypertension or obesity), may improve enough after receiving an LVAD  to become eligible. Despite the substantial benefits, however, continuous flow LVADs are also associated with significant morbidity including gastrointestinal bleeding (GIB) which is estimated to occur in 15-40% of LVAD patients.^5,6 “They’re not perfect by any means. LVADs can have a lot of complications–most commonly gastro-intestinal bleeding,” says Houston. “These bleeds are really tough. The patient usually has to spend a lot of days in the hospital and we have to stop their blood thinners which raises the risk for clots and stroke. They also need blood transfusions which increase the risk for developing antibodies and potentially reduce their ability to receive a transplant.”

Researchers have long worked to better understand the mechanisms behind the increased GIB risk in patients with LVADs which cannot be explained by anti-coagulant therapy alone. For example, arteriovenous malformations (AVMs; abnormally dilated connections between the arteries and veins) are known to account for as many as 50% of all GIBs via enhanced angiogenesis.^7,8 Although the exact mechanism that causes AVMs is unknown, angiogenesis appears to be up-regulated and transforming growth factor (TGF)-b levels are higher after a continuous flow LVAD is placed.⁹ The thinking is that this may up-regulate vascular endothelial growth factor (VEGF) and initiate angiogenesis and AVM formation. Other proposed causes of GIB in these patients include acquired von Willebrand disease and impaired platelet aggregation.¹⁰

In an important breakthrough, a team of MUSC researchers recently confirmed that angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin receptor blocker (ARB) medications are associated with a dose-dependent reduction of major GIBs and AVM-related GIB events in patients with continuous flow LVADs.¹¹ Houston explains, “It’s been an interesting journey. I came up with this hypothesis when I was a cardiology fellow in Baltimore at Johns Hopkins. We thought these medications had some incidental effects that inhibited certain vascular growth factor pathways– angiopoietin II and VEGF (vascular endothelial growth factor). We studied our LVAD patients there and saw fewer bleeds in those who got ACE inhibitors and ARBs.¹² At the same time, the group here at MUSC led by Dr. Walt Uber was looking at this too. When I came here, we studied it in this patient population and saw the same thing."

The MUSC study followed 111 continuous flow LVAD patients for a mean of 2.1+1.4 years. Over half, 67% (n=74) of these patients received an ACEi and/or ARB within 30 days of LVAD placement while 33% (n=37) did not. Data show that patients who received an ACEi and/or ARB had a 57% lower risk of developing a major GIB (adjusted hazard ratio [aHR]: 0.43; 95% confidence interval [CI]: 0.19 to 0.97; p=0.042; iAUC=0.81) and a 63% reduction in risk of AVM-related GIB (aHR: 0.37; 95% CI: 0.16 to 0.84; p=0.017; iAUC=0.77) with no difference in overall survival.¹³

"I was pleasantly surprised. It’s always nice to watch a hypothesis come to fruition because you have a lot of ideas that don’t work out," says Houston. "Two years ago, I was at an international conference where one session featured a panel discussion about whether heart failure patients should get ACE inhibitor and ARB therapy. These findings start to put that debate to bed. In terms of preventing GIB, the answer is 'yes'–even though we still don’t know whether these medications impact heart failure outcomes. That’s a big deal because bleeds are a major source of morbidity in our patients," says Houston. In addition, the study establishes that the therapeutic dose to reduce GIB is quite low. "A 5mg dose of these medications is very low–so low, in fact, that it may not help with their heart failure. We aren’t sure because we haven’t studied a large enough group to know what the heart failure outcomes are. But, what we do now know is that it does reduce GIB risk."

--Kat Hendrix

 

Resources 

1. Benjamin EJ, et al. Heart disease and stroke statistics - 2017 update: A report from the American Heart Association. Circulation. 2017;135:e146–603.
2. Pagani FD. Continuous-flow rotary left ventricular assist devices with "3rd generation" design. Semin Thorac Cardiovasc Surg. 2008;20:255-63.
3. Ibid.
4. Pozzi M, et al. Long-term continuous-flow left ventricular assist devices (LVAD) as bridge to heart transplantation. J Thorac Dis. 2015;7(3):532-542.
5. Eckman PM, et al. Bleeding and thrombosis in patients with continuous-flow ventricular assist devices. Circulation. 2012;125:3038–47.
6. Stern DR, et al. Increased incidence of gastrointestinal bleeding following implantation of the HeartMate II LVAD. J Card Surg. 2012;25:352–6.
7. Demirozu ZT, et al. Arteriovenous malformation and gastrointestinal bleeding in patients with Heartmate II left ventricular assist device. J Heart Lung Transplant. 2011;30:849–53.
8. Aggarwal A, Pant R, Kumar S, et al. Incidence and management of gastrointestinal bleeding with continuous flow assist devices. Ann Thoracic Surg. 2012;93:1534–9.
9. Converse MP, et al. Effect of Angiotensin II Inhibitors on Gastrointestinal Bleeding in Patients with Left Ventricular Assist Devices. JACC. 2019;73(14):1769-78.
10. Klovaite J. Severely impaired von Willebrand’s factor-dependent platelet aggregation in patients with a continuous-flow left ventricular assist device. J Am Coll Cardiol. 2009;53:2162–7.
11. Converse MP, et al. Effect of Angiotensin II Inhibitors on Gastrointestinal Bleeding in Patients with Left Ventricular Assist Devices. JACC. 2019;73(14):1769-78.
12. Houston BA, et al. Angiotensin II antagonism is associated with reduced risk for gastrointestinal bleeding to due arteriovenous malformations in patients with left ventricular assist devices. J Heart Lung Transplant. 2016;36:380–5.
13. Converse MP, et al. Effect of Angiotensin II Inhibitors on Gastrointestinal Bleeding in Patients with Left Ventricular Assist Devices. JACC. 2019;73(14):1769-78.