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Invited Commentary

Pumps and The New Pills

Birks, Emma J.; Kolodziej, Andrew

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doi: 10.1097/MAT.0000000000001142
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Treatment with durable left ventricular assist devices (LVADs), which have been shown to improve quality of life as well as survival,1 have transformed the treatment of patients with advanced heart failure (HF).

However, the complication, comorbidity, and readmission rates of patients on LVAD support remain high. Optimization of the medical management of patients on LVADs is likely to significantly help this.

Ideally, most patients with an LVAD have no need for diuretics as the HF is theoretically corrected, however many patients on LVADs remain on regular loop diuretics and studies show that half of LVAD patients still have unoptimized hemodynamics.2 The abnormal hemodynamics may be multifactorial and often are divided into left- and right-sided etiologies. Unloading of the left ventricle can be optimized by incremental increases in LVAD speed which can be used to attempt to optimize hemodynamics. Optimization of hemodynamics following LVAD implantation is also associated with reduced HF readmission.3 Although unloading of the left ventricle reduces the afterload on the right heart and the central venous pressure, these patients often have septal shift to the left with the pump which can worsen right ventricular (RV) hemodynamics along with already poor RV function that is often worsened by LVAD implant surgery (the associated cardiopulmonary bypass, protamine, etc.) and the increased cardiac output returning to the RV creating increased work the RV has to do. Hence the RV hemodynamics are often difficult to optimize.

The 2013 ISHLT MCS Guidelines recommend loop diuretics such as furosemide, torsemide, and bumetanide for the management of fluid overload or RV dysfunction in patients with an LVAD.4 However the goal should be to give patients the minimal necessary diuretic therapy in each clinic visit after implantation because diuretic therapy has never shown mortality benefits in LVAD patients, and overdiuresis could cause adverse effects such as acute kidney injury, metabolic alkalosis, electrolyte imbalances, and hypotension.5

Fluid overload is still a cause of readmission in LVAD patients, usually mostly due to right-sided failure and Kido et al.6 reported more than half of LVAD patients to be still on loop diuretics 2 years after LVAD implantation. They also showed the length of initial hospitalization after LVAD implant was significantly associated with furosemide equivalent dose at both 1 and 3 months post-implant suggesting volume overload (likely from RV failure) significantly affects the index LVAD length of stay. Furthermore, diuretic resistance is common in LVAD patients due to long-term loop diuretic exposure and these advanced HF patients often having cardiorenal syndrome and concomitant chronic kidney disease. Loop diuretic resistance is associated with further volume overload and loop diuretics are known to increase neurohormonal activation and have been demonstrated to worsen renal function and induce hyponatremia.5

Tolvaptan is an effective therapy for HF patients with symptomatic congestion and hyponatremia.7 However the efficacy of its use in patients with continuous-flow LVADs has not previously been reported.

In this issue of the ASAIO Journal, Fujino et al.8 report an interesting retrospective review of patients on LVAD support taking Tolvaptan at their institution in an attempt to assess its clinical efficacy and safety in LVAD patients. Of 217 consecutive LVAD patients, tolvaptan was used in 20 patients (9%) for a mean of 4 days. They matched each patient in the tolvaptan group with two patients in the non-tolvaptan group by age, gender, and serum sodium before LVAD implantation. They found urine volume significantly increased from 2,623 ± 1,109 ml/day to 4,308 ± 1,432 ml/day during tolvaptan therapy (P < 0.001) and serum sodium increased from 127 ± 3 to 133 ± 3 mEq/L (P < 0.001). Body-weight significantly decreased following tolvaptan therapy (99 ± 30 to 97 ± 30 kg) and the diuretic dose requirement decreased although not significantly.

None of the patients developed hypernatremia or hypovolemia requiring volume resuscitation during tolvaptan therapy and the serum creatinine remained unchanged. The 90-day overall survival was the same in both the tolvaptan group and the propensity score-matched non-tolvaptan group (P = 0.918) and survival free of HF readmissions was also comparable (P = 0.751).

Tolvaptan is an arginine vasopressin Type 2 antagonist approved since 2009 for hypervolemic and euvolemic hyponatremia which has demonstrated efficacy in acutely decompensated HF patients.7 The use of tolvaptan has been studied as an adjunct to diuretic therapy in chronic systolic HF patients with a HF hospitalization. It caused improvement in congestive symptoms and ameliorated hyponatremia in the efficacy of vasopressin antagonism in HF outcome study with Tolvaptan trial.9 Tolvaptan therapy increased weight loss during hospitalization but had no effect on long-term mortality or HF hospitalizations.

Tolvaptan increases the excretion of free water, thus stabilizing the hemodynamic state and correcting hyponatremia. Adding tolvaptan to conventional diuretic therapy can decrease the dose of loop diuretics and prevent worsening renal function during decongestion. Those with LVADs have been lacking this data and the authors of this analysis show in this albeit small, retrospective and single-center study that the short-term use of tolvaptan following LVAD implantation is a safe and effective therapy to augment diuresis and improve hyponatremia. Their analysis performed on a small cohort of patients showed not only a favorable safety profile but also consistent diuresis and improvement in hyponatremia. Similar to the Tolvaptan studies in HF patients, this analysis showed no effect on long-term survival or HF readmissions.7,9

Hyponatremia is an electrolyte disorder commonly encountered in clinical practice, and dilutional hyponatremia is the most common form of the disorder which is often worsened in advanced HF due to the increased excretion of sodium by diuretics. HF patients with resultant low cardiac output often also have hyponatremia with high levels of plasma ADH.10 In most patients, LVAD cardiac replacement therapy reverses serum sodium levels and is associated with dramatic decreases in plasma ADH levels with the marked changes in ADH levels being attributable to the correction of low cardiac output. However, some continue to have issues with volume overload and some with hyponatremia. It is hard to know how many patients on LVAD support, with restored cardiac output, will need addition of Tolvaptan, but it will likely be very useful for a subset who mainly have RV failure and subsequent diuretic-resistant volume overload.

Interestingly Fujino et al.8 showed improvement of some of the right-sided parameters on echocardiography in those who had Tolvaptan in this study. The echocardiographic parameters showed right-sided chamber size to decrease in the patients who had Tolvaptan with the RV end-diastolic area and right atrial volume as well as inferior vena cava diameter being significantly decreased. The left ventricular end-diastolic diameter and left atrial volume did not significantly decrease with tolvaptan therapy. However, the improvement in right-sided echocardiographic function in combination with the volume reduction seen is interesting and likely requires further study. A study of the hemodynamic effects of tolvaptan in HF patients also showed a reduction in RA pressure.11 Right-sided failure after LVAD implantation is a common clinical problem with limited therapeutic options and most of its management is by augmented diuresis which can be very difficult to achieve once RV failure is present so this signal of RV improvement with better volume unloading is potentially clinically useful although there was no invasive evaluation in this study to determine true improvement in those parameters.

The dosage response of tolvaptan cannot really be established in this small study and the results cannot be extrapolated to long-term tolvaptan use.

Hence this small but useful study demonstrated effective diuresis with Tolvaptan and improvement of hyponatremia in LVAD patients without significant adverse effects. Tolvaptan use could be useful to reduce length of stay due to volume overload by augmenting the diuresis and correcting hyponatremia. However this is a retrospective analysis in a small population from a single-center and a larger multi-center study is needed to verify its findings or ideally a randomized, prospective study.

The use of neurohormonal blockade in LVAD patients is gaining increasing importance and emphasis. Recent single-center studies have shown angiotensin converting enzyme (ACE)converting enzyme (ACE) inhibitors to improve B-type natriuretic peptide, New York Heart Association Class, 6-minute walk distance, reverse remodeling parameters12 and improved mortality13 in LVAD patients. A recent retrospective study of 307 LVAD patients at two institutions14 showed treatment with angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) was an independent factor associated with decreased mortality post-LVAD, their use being associated with a reduction in mortality risk by 47%.

A very large recent INTERMACs cohort analysis15 of 12,144 LVAD patients also strongly supports the use of neurohormonal blocking (NHB) agents in patients receiving LVAD support. Those receiving any NHB medication at 6 months had a better 4 year survival compared with those not receiving NHB (56.0% vs. 43.9%) and the use of NHB was also associated with a significantly higher Kansas City Cardiomyopathy Questionnaire score and a significantly longer 6-minute walk test at 2 years. Use of any NHB was associated with significantly improved survival compared with medical regimens without NHB 4 years postimplant (59.3% vs. 50.4%). Patients receiving triple therapy with an ACE inhibitor or angiotensin receptor blocker, ß-blocker, and mineralocorticoid antagonist had the lowest hazard of death (hazard ratio 0.34) compared with patients in other groups and the lowest N terminal pro–B-type and creatinine. There may also be other benefits as ACE-I and digoxin have also been shown to reduce the rate of gastrointestinal bleeding in LVAD patients.16

A protocol that used very high doses of neurohormonal blockade along with beta-blockade and aldosterone antagonism in combination with optimized LVAD unloading and regular testing of underlying myocardial function was able to produce high rates of myocardial recovery allowing explantation of the device.17 This uses the LVAD as a platform to give very high doses of these drugs and the high doses of neurohormonal blockade given likely significantly contributed to the high rates of recovery seen.

Neprilysin inhibition with sacubitril/valsartan increases the levels of vasoactive peptides, thereby counteracting the neurohormonal activation in patients with HF.18 The “Prospective Comparison of angiotensin receptor neprilysin inhibitor with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure” (PARADIGM-HF) trial demonstrated that among stable patients with symptomatic HFrEF, treatment with the neprilysin–angiotensin receptor inhibitor sacubitril/valsartan, versus placebo, was associated with a 20% relative risk reduction in cardiovascular mortality or HF hospitalization.18 Hence this drug could theoretically offer great benefit in LVAD patients, however, so far its use in this patient population has been anecdotal and not reported.

In this issue of the ASAIO Journal Sharma et al.19 conducted a small retrospective analysis to evaluate sacubitril/valsartan in patients with durable LVADs. This appears to be the first analysis utilizing ARNI in patients with continuous-flow LVADs.

It comes from Stanford University who use sacubitril/valsartan for resistant hypertension among patients with LVADs, so these authors performed a retrospective chart review of patients with LVADs over a 2.5 year period and identified five patients who were on sacubitril/valsartan for a median of 166 days for hypertension (mean arterial pressure (MAP) ≥90 mm Hg) unresponsive to three or more antihypertensive medications. All patients were receiving ACE inhibitors/angiotensin receptor blockers before sacubitril/valsartan initiation.

One of these patients discontinued sacubitril/valsartan early within 1 month (at day 6) due to symptomatic postural hypotension. Of the other patients remaining on sacubitril/valsartan, there was a significant decline in median MAP from baseline to one month (94 vs. 74 mm Hg; P = 0.003). The median dose achieved was 49 of 51 mg orally twice daily. By the end of their follow-up, an additional two patients had discontinued sacubitril/valsartan: one because of postural symptomatic hypotension (at day 68) and one because of AKI in the context of an LVAD thrombosis.

In the PARADIGM-HF trial, hypotension was the most common adverse event noted in patients randomized to sacubitril/valsartan.18 In this study by Sharma et al., the effect was more profound, with a reduction in 18 mm Hg in median MAP between baseline and 1 month of follow-up compared to a mean difference of −2.7 mm Hg between sacubitril/valsartan and placebo in the PARADIGM-HF trial (although the very small sample size could be significantly affecting this). Hence it seems that hypotension could be a potential problem with this drug in patients with continuous-flow pumps, likely due to only having a mean pressure and the effect on the HQ curves.

There was no evidence of AKI, hyperkalemia, or other adverse events associated with sacubitril/valsartan over the short-term period in this study. Both patients who experience postural hypotension were also concomitantly prescribed beta-blockers

Control of MAP in LVAD patients is critical to minimize adverse cardiovascular events, such as stroke. Sacubitril/valsartan is likely to play a role in the management of refractory hypertension in LVAD patients where its hypotensive effect would be useful, however, this study suggests it should be given carefully in selected patients with careful monitoring. Currently, it seems that there is insufficient evidence regarding safety and efficacy of sacubitril/valsartan to recommend the widespread use of this therapy in LVAD patients. Adequately powered prospective studies with longer-term results are needed to determine the tolerability and potential improvement of other outcomes associated with the use of sacubitril/valsartan among patients with LVADs.

In the studies which showed high recovery rates using aggressive neurohormonal and beta-blockade in combination with an aldosterone antagonist and optimal unloading together with regular testing of underlying function, an ACE plus an Angiotensin II inhibitor was given. The theory was that LVAD support could be used to allow the patient to tolerate both. Hence although the PARADIGM trial showed the benefit of salcubittri/valsartan over an ACE it is not known whether it would be more beneficial to give sacubitril/valsartan than an ACE plus an ARB to promote recovery in this population, but should be studied.

Both of these interesting analyses, despite being retrospective and utilizing a small cohort of patients, provide useful information on the safety, tolerability and efficacy profile of recently established medical therapy in patients with systolic HF, in those with implanted continuous-flow LVADs.


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heart-assist devices; heart failure; LVAD; loop diuretics

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