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231
15. Banares R, Nevens F, Larsen FS, Jalan R, Albillos A, Dollinger M, Saliba F, Sauerbruch T, Klammt S, Ockenga J, Pares A, Wendon J, Bru¨nnler T, Kramer L, Mathurin P, de la Mata M, Gasbarrini A, Mu¨llhaupt B, Wilmer A, Laleman W, Eefsen M, Sen S, Zipprich A, Tenorio T, Pavesi M, Schmidt HH, Mitzner S, Williams R, Arroyo V; RELIEF study group: Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology 57(3):1153–1162, 2013
13. Zheng Z, Li X, Li Z, Ma X: Artificial and bioartificial liver support systems for acute and acute-on-chronic hepatic failure: a meta-analysis and meta-regression. Exp Ther Med 6(4):929–936, 2013 14. Kribben A, Gerken G, Haag S, Herget-Rosenthal S, Treichel U, Betz C, Sarrazin C, Hoste E, van Vlierberghe H, Escorsell A, Hafer C, Schreiner O, Galle PR, Mancini E, Caraceni P, Karvellas CJ, Salmhoffer H, Knotek M, Gines P, Kozik-Jaromin J, Rifai K; the Helios Study Group: Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure. Gastroenterology 142(4):782–789 e783, 2012
Do Any Patients with Acute Decompensated Heart Failure and Acute Cardio-Renal Syndrome Benefit from Ultrafiltration? Jeffrey M. Turner* and Jeffrey M. Testani*† *Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, and †Program of Applied Translational Research, Yale University School of Medicine, New Haven, Connecticut
The interaction between the heart and kidneys in acute decompensated heart failure (ADHF) is complex and incompletely understood (1,2). Commonly, the renal phenotype seen in “cardio-renal syndrome” is nearly identical to that observed in dehydration or acute blood loss, even with overt volume overload. This paradoxical response of the kidney is often explained with the difficult to test concept of “arterial underfilling.” Employing this concept, it follows that fluid removal in such a patient may worsen arterial underfilling and thus lead to worsening kidney function (3). However, in addition to a maladaptive neurohormonal response to “arterial underfilling” there also appears to be direct adverse effects from “venous overfilling,” with negative renal effects ascribed to increased renal venous and intrabdominal pressure (4–7). Furthermore, the effect of reduction in “venous overfilling” on “arterial underfilling” is unpredictable, and often times, reduction in severely elevated filling pressures leads to improved ventricular interactions and valvular regurgitation with a resultant augmentation of cardiac output. This observation is often incorrectly ascribed to the phenomenon of diuresing a patient off the descending limb of Starling curve (8). Perhaps as a result of the above complexities, fluid removal in ADHF can lead to either an improvement or worsening in kidney function. Interestingly, kidney function improvement
appears to be as common if not more common as worsening in this setting (9–11). An additional confounding factor is that the main approach to fluid removal in patients with ADHF is the loop diuretic. This is problematic in that a primary mechanism by which the kidneys sense tubular sodium delivery is dependent on flux through the sodium-potassium-2 chloride (NKCC2) transporter, which is directly antagonized by loop diuretics (12). As a result, the kidneys perceive diminished tubular sodium delivery with loop diuretic therapy, resulting in additional neurohormonal activation and often a reduction in glomerular filtration rate (13–16). Furthermore, development of diuretic resistance is common in patients with ADHF (17–20). In part, due to the adverse effects of loop diuretics and their suboptimal effectiveness, ultrafiltration (UF) was proposed as a superior method for fluid removal in ADHF. It is generally accepted that volume overload that is unresponsive to medical therapy is an indication for initiation for renal replacement therapy (RRT), providing a precedent for this approach. Notably, early data in highly selected patients yielded very promising results (21–23). However, two relatively large, multicenter trials provide what at first glance appear to be conflicting data. In the Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) trial, patients undergoing UF had superior weight loss, similar changes in serum creatinine, but a substantial reduction in rehospitalization compared to those treated with intravenous (IV) diuretics (9). However, the recently published Cardio-Renal Rescue Study in Acute Decompensated Heart Failure (CARRESSHF) trial showed no difference in weight loss, a higher rate of worsening renal function, and no
Address correspondence to: Jeffrey Turner, MD, Section of Nephrology, Yale School of Medicine, Boardman Building 114, 330 Cedar Street, New Haven CT 06510, Tel.: (203) 785-4184; Fax: (203) 785-7068, or e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 3 (May–June) 2014 pp. 231–233 DOI: 10.1111/sdi.12221 © 2014 Wiley Periodicals, Inc. 231
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difference in outcomes, including hospitalization, with UF (10). How do we reconcile the seemingly contradictory results, and what if any definitive conclusions can we now draw about the role of UF in ADHF? When interpreting the results of UNLOAD and CARRESS-HF, it’s important to appreciate the differences in their study design, limitations, and era when they were published. UNLOAD randomized patients to UF vs. usual care and demonstrated clear superiority of UF. Importantly, this study was the first large randomized trial following the glowing results of earlier physiologically oriented studies. Some of these studies demonstrated that UF had significant advantage over diuretics in reducing filling pressures, neurohormonal levels, and various functional parameters, benefits that appeared to persist for months (23). As a consequence, the results of UNLOAD, particularly the improvement in rehospitalization, were met with great enthusiasm. The major criticism was that UNLOAD did not prove that UF was a superior method for fluid removal; an alternative explanation was that more complete decongestion in the UF arm drove the results and that more aggressive diuretic therapy in the usual care arm would have produced similar results. It should be pointed out, however, that even if the above is true, the results of UNLOAD remain valid: UF was superior to the usual care provided in the UNLOAD population and may very well be superior to the usual care provided in actual clinical practice. CARRESS-HF was published in 2012 and designed to address some of the criticisms of UNLOAD. This study ensured that an aggressive diuretic strategy was employed in the medical therapy group. Patients receiving IV diuretics had dose adjustments made per a very aggressive predefined stepped pharmacologic protocol with a goal urine output of 3–5 l/day. This strategy proved to be extremely effective and on average patients in the medical arm were a remarkable ~11 pounds lighter by their third day of treatment. While there were clear measures to ensure optimal diuresis in the medical therapy group, to the contrary, there were no such measures in place to ensure optimal volume removal in the UF group. Importantly, there was on average a delay of 8 hours from randomization to initiation of UF, and the duration of UF was only 40 out of the 96 planned hours prior to the primary endpoint assessment with only 50% of the patients in the UF group having therapy discontinued because the “best possible fluid volume was reached.” Importantly, 9% of patients included in the intention to treat analysis for UF never actually received UF and 30% of subjects received intravenous diuretics before the 96 hour primary endpoint analysis took place. As such, when interpreting the results of CARRESS-HF, it is important to remember this was a trial comparing remarkably well done medical therapy to what appears to have been marginally applied UF.
Thus, two questions emerge from CARRESS-HF: (i) Although fluid loss and rehospitalization was similar to a very well done stepped pharmacologic approach, would UF have been superior to a usual care control group? (ii) Would a more effectively applied UF strategy have been superior over the stepped pharmacologic strategy? These are important considerations since the message many have taken away from CARRESS-HF is not that we should be using the stepped pharmacologic protocol, or that we should be doing a better job when we perform UF, rather, it has been that UF is not useful. CARRESS-HF, unlike UNLOAD, required patients to meet AKI criteria (defined as a ≥0.3 mg/ dl rise serum creatinine) for inclusion into the trial. While the intention of this measure was to study the effects of UF in a more homogeneous group of patients with “cardio-renal syndrome”, we have no idea what it did to the interpretability of the study findings and it clearly made it more difficult to directly compare to UNLOAD. While there are many paths to an increase in serum creatinine in patients with ADHF, a common one is via a reduction in intravascular volume (24–27). Including patients with AKI from intravascular volume contraction is worrisome since these patients may further worsen their kidney function with rapid fluid removal by UF. It has been well established that despite the potent natriuretic effects of loop diuretics, the kidney retains the ability to limit natriuresis in response to physiologic perturbations (28). For example, simply assuming an upright vs. supine posture during diuresis treatment can reduce natriuresis nearly by half (29). However, unlike the kidney, UF machines do not automatically reduce the rate of fluid removal. This is important as we know that hemoconcentration, which is direct evidence that the plasma refill rate has been exceeded is common in patients with ADHF and a rise in serum creatinine (24–27). As such, including patients with a ≥0.3 mg/dl increase in creatinine may have selected the very group in whom UF would cause further deterioration in kidney function with the fixed rate of fluid removal provided by this modality. Following the publication of CARRESS-HF, the sentiment of many is that the book has been closed on UF in ADHF. However, we would submit that the unique design of CARRESS-HF raises more questions than providing answers. Furthermore, we believe that the utility of UF probably resides somewhere in the middle between the post-UNLOAD/ pre-CARRESS-HF view that UF was the next panacea to the post-CARRESS-HF sentiment that UF is worthless. It is our opinion that there is probably great value for UF in the properly selected patient. Unfortunately, the only thing that is clear at this point is that it is completely unclear who this appropriate patient is. However, a few facts are worth noting: (i) congestion is the major therapeutic target in ADHF (ii) diuretic resistance limiting fluid removal is common (iii) a functioning UF circuit can always 232
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remove fluid. Although UF may not offer “cardiorenal rescue”, its unimpeded fluid removal will, in the wrong patient, cause hypotension and worsening AKI. In fact, data are accumulating that if patients are truly diuretic refractory, outcomes are dismal with UF (30). Mechanical fluid removal with UF may not be much different than mechanical circulatory support with left ventricular assist devices (LVADs). Just as UF machines will remove fluid, LVAD will pump blood. However, in order for this ‘pumping of blood’ to translate into improved patient outcomes the correct patient needs to be selected. Prior to LVAD implantation, a patient selection process is undertaken to determine which patients are too sick, which are too healthy, and to assess whether the patient’s heart failure phenotype will benefit from an LVAD. These common sense lessons likely need to be applied to UF. The next phase of research in this area should focus not on if UF is superior to diuretics, but rather to determine in which patients is UF superior. Thus, we are currently unable to definitively answer the question “Do any patients with acute decompensated heart failure and acute cardio-renal syndrome benefit from ultrafiltration?” Hopefully, in time we can identify patients with a phenotype who may garner benefit from the UF device. For now, we will “take our best stab” in choosing patients for UF—likely “cardio-renal” patients who are volume overloaded and diuretic resistant, without a need for dialysis-associated clearance.
233
10. Testani JM, McCauley BD, Kimmel SE, Shannon RP: Characteristics of patients with improvement or worsening in renal function during treatment of acute decompensated heart failure. Am J Cardiol 106:1763–1769, 2010 11. Dupont M, Mullens W, Finucan M, Taylor DO, Starling RC, Tang WH: Determinants of dynamic changes in serum creatinine in acute decompensated heart failure: the importance of blood pressure reduction during treatment. Eur J Heart Fail 15:433–440, 2013 12. Brenner BM, Rector FC: Brenner & Rector’s the Kidney. Philadelphia: Saunders Elsevier, 2008 13. Lindenfeld J, Schrier RW: Blood urea nitrogen a marker for adverse effects of loop diuretics? J Am Coll Cardiol 58:383–385, 2011 14. Chen HH, Redfield MM, Nordstrom LJ, Cataliotti A, Burnett JC Jr: Angiotensin ii at1 receptor antagonism prevents detrimental renal actions of acute diuretic therapy in human heart failure. Am J Physiol Renal Physiol 284:F1115–F1119, 2003 15. Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine TB, Cohn JN: Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis. Ann Intern Med 103:1–6, 1985 16. Gottlieb SS, Brater DC, Thomas I, Havranek E, Bourge R, Goldman S, Dyer F, Gomez M, Bennett D, Ticho B, Beckman E, Abraham WT: Bg9719 (cvt-124), an a1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation 105:1348–1353, 2002 17. Brater DC: Diuretic therapy. N Engl J Med 339:387–395, 1998 18. Vargo DL, Kramer WG, Black PK, Smith WB, Serpas T, Brater DC: Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure. Clin Pharmacol Ther 57:601–609, 1995 19. Brater DC, Chennavasin P, Seiwell R: Furosemide in patients with heart failure: shift in dose-response curves. Clin Pharmacol Ther 28:182–186, 1980 20. Testani JM, Brisco MA, Turner JM, Spatz ES, Bellumkonda L, Parikh CR, Tang WH: Loop diuretic efficiency: a metric of diuretic responsiveness with prognostic importance in acute decompensated heart failure. Circ Heart Fail 2013 Dec 30 [Epub ahead of print] 21. Marenzi G, Lauri G, Grazi M, Assanelli E, Campodonico J, Agostoni P: Circulatory response to fluid overload removal by extracorporeal ultrafiltration in refractory congestive heart failure. J Am Coll Cardiol 38:963–968, 2001 22. Guazzi MD, Agostoni P, Perego B, Lauri G, Salvioni A, Giraldi F, Matturri M, Guazzi M, Marenzi G: Apparent paradox of neurohumoral axis inhibition after body fluid volume depletion in patients with chronic congestive heart failure and water retention. Br Heart J 72:534–539, 1994 23. Agostoni P, Marenzi G, Lauri G, Perego G, Schianni M, Sganzerla P, Guazzi MD: Sustained improvement in functional capacity after removal of body fluid with isolated ultrafiltration in chronic cardiac insufficiency: failure of furosemide to provide the same result. Am J Med 96:191–199, 1994 24. Testani JM, Brisco MA, Chen J, McCauley BD, Parikh CR, Tang WH: Timing of hemoconcentration during treatment of acute decompensated heart failure and subsequent survival: importance of sustained decongestion. J Am Coll Cardiol 62(6):516–524, 2013 25. van der Meer P, Postmus D, Ponikowski P, Cleland JG, O’Connor CM, Cotter G, Metra M, Davison BA, Givertz MM, Mansoor GA, Teerlink JR, Massie BM, Hillege HL, Voors AA: The predictive value of short term changes in hemoglobin concentration in patients presenting with acute decompensated heart failure. J Am Coll Cardiol 61:1973–1981, 2013 26. Davila C, Reyentovich A, Katz SD: Clinical correlates of hemoconcentration during hospitalization for acute decompensated heart failure. J Card Fail 17:1018–1022, 2011 27. Testani JM, Chen J, McCauley BD, Kimmel SE, Shannon RP: Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival. Circulation 122:265–272, 2010 28. Ellison DH: Diuretic therapy and resistance in congestive heart failure. Cardiology 96:132–143, 2001 29. Galiwango PJ, McReynolds A, Ivanov J, Chan CT, Floras JS: Activity with ambulation attenuates diuretic responsiveness in chronic heart failure. J Card Fail 17:797–803, 2011 30. Patarroyo M, Wehbe E, Hanna M, Taylor DO, Starling RC, Demirjian S, Tang WH: Cardiorenal outcomes after slow continuous ultrafiltration therapy in refractory patients with advanced decompensated heart failure. J Am Coll Cardiol 60:1906–1912, 2012
References 1. Bock JS, Gottlieb SS: Cardiorenal syndrome: new perspectives. Circulation 121:2592–2600, 2010 2. Ronco C, Haapio M, House AA, Anavekar N, Bellomo R: Cardiorenal syndrome. J Am Coll Cardiol 52:1527–1539, 2008 3. Schrier RW, Ecder T: Gibbs memorial lecture. Unifying hypothesis of body fluid volume regulation: implications for cardiac failure and cirrhosis. Mt Sinai J Med 68:350–361, 2001 4. Mullens W, Abrahams Z, Francis GS, Sokos G, Taylor DO, Starling RC, Young JB, Tang WH: Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 53:589–596, 2009 5. Damman K, Navis G, Smilde TD, Voors AA, van der Bij W, van Veldhuisen DJ, Hillege HL: Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction. Eur J Heart Fail 9:872–878, 2007 6. Mullens W, Abrahams Z, Skouri HN, Francis GS, Taylor DO, Starling RC, Paganini E, Tang WH: Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol 51:300–306, 2008 7. Testani JM, Damman K: Venous congestion and renal function in heart failure.. It’s complicated. Eur J Heart Fail 15:599–601, 2013 8. Katz AM: The descending limb of the starling curve and the failing heart. Circulation 32:871–875, 1965 9. Testani JM, McCauley BD, Chen J, Coca SG, Cappola TP, Kimmel SE: Clinical characteristics and outcomes of patients with improvement in renal function during the treatment of decompensated heart failure. J Card Fail 17:993–1000, 2011
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15. Banares R, Nevens F, Larsen FS, Jalan R, Albillos A, Dollinger M, Saliba F, Sauerbruch T, Klammt S, Ockenga J, Pares A, Wendon J, Bru¨nnler T, Kramer L, Mathurin P, de la Mata M, Gasbarrini A, Mu¨llhaupt B, Wilmer A, Laleman W, Eefsen M, Sen S, Zipprich A, Tenorio T, Pavesi M, Schmidt HH, Mitzner S, Williams R, Arroyo V; RELIEF study group: Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial. Hepatology 57(3):1153–1162, 2013
13. Zheng Z, Li X, Li Z, Ma X: Artificial and bioartificial liver support systems for acute and acute-on-chronic hepatic failure: a meta-analysis and meta-regression. Exp Ther Med 6(4):929–936, 2013 14. Kribben A, Gerken G, Haag S, Herget-Rosenthal S, Treichel U, Betz C, Sarrazin C, Hoste E, van Vlierberghe H, Escorsell A, Hafer C, Schreiner O, Galle PR, Mancini E, Caraceni P, Karvellas CJ, Salmhoffer H, Knotek M, Gines P, Kozik-Jaromin J, Rifai K; the Helios Study Group: Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure. Gastroenterology 142(4):782–789 e783, 2012
Do Any Patients with Acute Decompensated Heart Failure and Acute Cardio-Renal Syndrome Benefit from Ultrafiltration? Jeffrey M. Turner* and Jeffrey M. Testani*† *Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, and †Program of Applied Translational Research, Yale University School of Medicine, New Haven, Connecticut
The interaction between the heart and kidneys in acute decompensated heart failure (ADHF) is complex and incompletely understood (1,2). Commonly, the renal phenotype seen in “cardio-renal syndrome” is nearly identical to that observed in dehydration or acute blood loss, even with overt volume overload. This paradoxical response of the kidney is often explained with the difficult to test concept of “arterial underfilling.” Employing this concept, it follows that fluid removal in such a patient may worsen arterial underfilling and thus lead to worsening kidney function (3). However, in addition to a maladaptive neurohormonal response to “arterial underfilling” there also appears to be direct adverse effects from “venous overfilling,” with negative renal effects ascribed to increased renal venous and intrabdominal pressure (4–7). Furthermore, the effect of reduction in “venous overfilling” on “arterial underfilling” is unpredictable, and often times, reduction in severely elevated filling pressures leads to improved ventricular interactions and valvular regurgitation with a resultant augmentation of cardiac output. This observation is often incorrectly ascribed to the phenomenon of diuresing a patient off the descending limb of Starling curve (8). Perhaps as a result of the above complexities, fluid removal in ADHF can lead to either an improvement or worsening in kidney function. Interestingly, kidney function improvement
appears to be as common if not more common as worsening in this setting (9–11). An additional confounding factor is that the main approach to fluid removal in patients with ADHF is the loop diuretic. This is problematic in that a primary mechanism by which the kidneys sense tubular sodium delivery is dependent on flux through the sodium-potassium-2 chloride (NKCC2) transporter, which is directly antagonized by loop diuretics (12). As a result, the kidneys perceive diminished tubular sodium delivery with loop diuretic therapy, resulting in additional neurohormonal activation and often a reduction in glomerular filtration rate (13–16). Furthermore, development of diuretic resistance is common in patients with ADHF (17–20). In part, due to the adverse effects of loop diuretics and their suboptimal effectiveness, ultrafiltration (UF) was proposed as a superior method for fluid removal in ADHF. It is generally accepted that volume overload that is unresponsive to medical therapy is an indication for initiation for renal replacement therapy (RRT), providing a precedent for this approach. Notably, early data in highly selected patients yielded very promising results (21–23). However, two relatively large, multicenter trials provide what at first glance appear to be conflicting data. In the Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) trial, patients undergoing UF had superior weight loss, similar changes in serum creatinine, but a substantial reduction in rehospitalization compared to those treated with intravenous (IV) diuretics (9). However, the recently published Cardio-Renal Rescue Study in Acute Decompensated Heart Failure (CARRESSHF) trial showed no difference in weight loss, a higher rate of worsening renal function, and no
Address correspondence to: Jeffrey Turner, MD, Section of Nephrology, Yale School of Medicine, Boardman Building 114, 330 Cedar Street, New Haven CT 06510, Tel.: (203) 785-4184; Fax: (203) 785-7068, or e-mail: [email protected]. Seminars in Dialysis—Vol 27, No 3 (May–June) 2014 pp. 231–233 DOI: 10.1111/sdi.12221 © 2014 Wiley Periodicals, Inc. 231
232
Turner and Testani
difference in outcomes, including hospitalization, with UF (10). How do we reconcile the seemingly contradictory results, and what if any definitive conclusions can we now draw about the role of UF in ADHF? When interpreting the results of UNLOAD and CARRESS-HF, it’s important to appreciate the differences in their study design, limitations, and era when they were published. UNLOAD randomized patients to UF vs. usual care and demonstrated clear superiority of UF. Importantly, this study was the first large randomized trial following the glowing results of earlier physiologically oriented studies. Some of these studies demonstrated that UF had significant advantage over diuretics in reducing filling pressures, neurohormonal levels, and various functional parameters, benefits that appeared to persist for months (23). As a consequence, the results of UNLOAD, particularly the improvement in rehospitalization, were met with great enthusiasm. The major criticism was that UNLOAD did not prove that UF was a superior method for fluid removal; an alternative explanation was that more complete decongestion in the UF arm drove the results and that more aggressive diuretic therapy in the usual care arm would have produced similar results. It should be pointed out, however, that even if the above is true, the results of UNLOAD remain valid: UF was superior to the usual care provided in the UNLOAD population and may very well be superior to the usual care provided in actual clinical practice. CARRESS-HF was published in 2012 and designed to address some of the criticisms of UNLOAD. This study ensured that an aggressive diuretic strategy was employed in the medical therapy group. Patients receiving IV diuretics had dose adjustments made per a very aggressive predefined stepped pharmacologic protocol with a goal urine output of 3–5 l/day. This strategy proved to be extremely effective and on average patients in the medical arm were a remarkable ~11 pounds lighter by their third day of treatment. While there were clear measures to ensure optimal diuresis in the medical therapy group, to the contrary, there were no such measures in place to ensure optimal volume removal in the UF group. Importantly, there was on average a delay of 8 hours from randomization to initiation of UF, and the duration of UF was only 40 out of the 96 planned hours prior to the primary endpoint assessment with only 50% of the patients in the UF group having therapy discontinued because the “best possible fluid volume was reached.” Importantly, 9% of patients included in the intention to treat analysis for UF never actually received UF and 30% of subjects received intravenous diuretics before the 96 hour primary endpoint analysis took place. As such, when interpreting the results of CARRESS-HF, it is important to remember this was a trial comparing remarkably well done medical therapy to what appears to have been marginally applied UF.
Thus, two questions emerge from CARRESS-HF: (i) Although fluid loss and rehospitalization was similar to a very well done stepped pharmacologic approach, would UF have been superior to a usual care control group? (ii) Would a more effectively applied UF strategy have been superior over the stepped pharmacologic strategy? These are important considerations since the message many have taken away from CARRESS-HF is not that we should be using the stepped pharmacologic protocol, or that we should be doing a better job when we perform UF, rather, it has been that UF is not useful. CARRESS-HF, unlike UNLOAD, required patients to meet AKI criteria (defined as a ≥0.3 mg/ dl rise serum creatinine) for inclusion into the trial. While the intention of this measure was to study the effects of UF in a more homogeneous group of patients with “cardio-renal syndrome”, we have no idea what it did to the interpretability of the study findings and it clearly made it more difficult to directly compare to UNLOAD. While there are many paths to an increase in serum creatinine in patients with ADHF, a common one is via a reduction in intravascular volume (24–27). Including patients with AKI from intravascular volume contraction is worrisome since these patients may further worsen their kidney function with rapid fluid removal by UF. It has been well established that despite the potent natriuretic effects of loop diuretics, the kidney retains the ability to limit natriuresis in response to physiologic perturbations (28). For example, simply assuming an upright vs. supine posture during diuresis treatment can reduce natriuresis nearly by half (29). However, unlike the kidney, UF machines do not automatically reduce the rate of fluid removal. This is important as we know that hemoconcentration, which is direct evidence that the plasma refill rate has been exceeded is common in patients with ADHF and a rise in serum creatinine (24–27). As such, including patients with a ≥0.3 mg/dl increase in creatinine may have selected the very group in whom UF would cause further deterioration in kidney function with the fixed rate of fluid removal provided by this modality. Following the publication of CARRESS-HF, the sentiment of many is that the book has been closed on UF in ADHF. However, we would submit that the unique design of CARRESS-HF raises more questions than providing answers. Furthermore, we believe that the utility of UF probably resides somewhere in the middle between the post-UNLOAD/ pre-CARRESS-HF view that UF was the next panacea to the post-CARRESS-HF sentiment that UF is worthless. It is our opinion that there is probably great value for UF in the properly selected patient. Unfortunately, the only thing that is clear at this point is that it is completely unclear who this appropriate patient is. However, a few facts are worth noting: (i) congestion is the major therapeutic target in ADHF (ii) diuretic resistance limiting fluid removal is common (iii) a functioning UF circuit can always 232
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remove fluid. Although UF may not offer “cardiorenal rescue”, its unimpeded fluid removal will, in the wrong patient, cause hypotension and worsening AKI. In fact, data are accumulating that if patients are truly diuretic refractory, outcomes are dismal with UF (30). Mechanical fluid removal with UF may not be much different than mechanical circulatory support with left ventricular assist devices (LVADs). Just as UF machines will remove fluid, LVAD will pump blood. However, in order for this ‘pumping of blood’ to translate into improved patient outcomes the correct patient needs to be selected. Prior to LVAD implantation, a patient selection process is undertaken to determine which patients are too sick, which are too healthy, and to assess whether the patient’s heart failure phenotype will benefit from an LVAD. These common sense lessons likely need to be applied to UF. The next phase of research in this area should focus not on if UF is superior to diuretics, but rather to determine in which patients is UF superior. Thus, we are currently unable to definitively answer the question “Do any patients with acute decompensated heart failure and acute cardio-renal syndrome benefit from ultrafiltration?” Hopefully, in time we can identify patients with a phenotype who may garner benefit from the UF device. For now, we will “take our best stab” in choosing patients for UF—likely “cardio-renal” patients who are volume overloaded and diuretic resistant, without a need for dialysis-associated clearance.
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