Better Late Than Never: The True Results of CARRESS-HF

This article refers to ‘Comparison of ultrafiltration to pharmacological decongestion in heart failure: a per-protocol analysis of CARRESS-HF’ by J.L. Grodin et al., published in this issue on pages 1148–1156. Grodin and colleagues are admirable for their courage to examine and present, albeit with a 5-year delay, the per-protocol analysis of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) in this issue of the Journal.1 With the inclusion only of subjects who received their randomized treatment, the authors found that ultrafiltration (UF) was associated with higher cumulative fluid loss, net fluid loss and relative reduction in weight compared to stepped pharmacological therapy (SPT). The UF group had higher serum creatinine (sCr) and blood urea nitrogen by 72 h.1 Grodin and colleagues deserve heartfelt congratulations for using the term ‘increase in sCr’ to describe their findings, rather than worsening renal function (WRF) or acute kidney injury (AKI). Unfortunately, the assumption that ‘increased sCr’, WRF and ‘AKI’ are merely different names of the same pathological entity, still pervades the cardiorenal literature.2 An increasing number of publications, however, suggest that transient increases in sCr may not represent renal tubular damage and instead signify a haemodynamically-driven reduction in glomerular filtration rate, indicative of effective decongestion which portends improved outcomes.3 Indeed, a recent analysis from the Low Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure with Renal Dysfunction (ROSE-AHF) trial, in which all patients received aggressive diuresis regardless of randomization, showed that increases in either sCr or markers of tubular damage were not only poorly correlated with each other and with diuretic effect, but may have contributed to premature cessation of decongestive therapies.4 Indeed, the data from ROSE-AHF revealed that increases in neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-D-glucosaminidase (NAG) and kidney injury molecule-1 (KIM-1) were paradoxically associated with improved survival. These findings lend strong support to the results of previous studies suggesting that fluid overload is a ‘greater evil’ than some degree of renal tubular injury.2, 4, 5 It follows that the foremost aim of therapy to improve outcomes of fluid overloaded heart failure patients must be to achieve effective decongestion. This essential goal was not achieved in CARRESS-HF where, as stated in the trial primary manuscript: ‘The rate of clinical decongestion at 96 h was low in the two treatment groups (9% with pharmacological therapy and 10% with ultrafiltration, P=0.83)’. The reader should reflect upon this astonishing result of the CARRESS-HF trial: 90% of the study subjects had unresolved congestion at the time of evaluation of the primary endpoint.6 This fact debunks the commonly held belief that an important contribution of CARRESS-HF is the formulation of an optimal diuretic strategy for fluid overloaded heart failure patients. However, it remains difficult to discern whether the inability to achieve adequate decongestion was due to intrinsic ineffectiveness of the CARRESS-HF SPT strategy or to inadequate adherence of the investigators to the study protocol. In contrast, the causes for the poor performance of UF, which could be surmised in CARRESS-HF intention-to-treat analysis, are laid bare by the per-protocol analysis of Grodin and colleagues in this issue of the Journal. The reader should carefully examine Figure 1, which displays the daily evolution of the CARRESS-HF population. At 96 h, the time of evaluation of the primary endpoint, compared to the SPT arm, in which 76/94 (80%) remained on treatment, only 30/94 (32%) subjects were still undergoing UF. For 28/64 patients (43%) no longer on UF by 96 h, the reason for therapy discontinuation is described in the Figure as ‘MD Decision’. Because such choice is separate from the other listed causes of therapy discontinuation, including achievement of optimal volume status, haemodynamic instability, evidence of volume depletion, increased sCr, filter clotting and vascular access failure, the suspicion arises that UF was prematurely terminated either for convenience, lack of familiarity with the therapy, or both.1 Disconcerting is also the unprecedented incidence of filter clotting which occurred in 23/64 (36%) patients no longer on UF at 96 h. The estimated UF rates were 83 [46–109] mL/h; 140 [83–178] mL/h; 107 [32–178] mL/h; and 70 [21–115] mL/h for each sequential 24 h period from baseline to 96 h, respectively. Low UF rates, such as those reported by Grodin and colleagues, should indeed reduce, rather than increase, filter clotting by decreasing filtration fraction.7 Therefore, the most plausible cause of the high incidence of filter clotting was the use of excessively low blood flows which, in contrast to slow UF rates, augment the risk of haemofilter clotting by increasing the filtration fraction. Furthermore, the risk of this event increases over time due to the haemoconcentration induced by fluid removal itself.7 Between randomization and primary endpoint evaluation, UF was terminated in 10/64 (16%) because of hypotension or evidence of volume depletion. Notably, UF rates at 48 and 72 h were higher than those used at 24 h. This fact alone suggests disregard of the physiological principles of fluid shift between the interstitium and the vascular space described by Starling.8 As fluid is removed from the intravascular space, the rate of vascular refilling with fluid present in the interstitial space [plasma refill rate (PRR)] decreases and the risk of intravascular volume depletion increases.8 Therefore, once an initial UF rate is chosen, it should remain the same or decrease, so that PRR can keep pace with the rate of fluid removal, and intravascular volume depletion is avoided.2 In the Ultrafiltration Versus Intravenous Diuretics in Decompensated Heart Failure (UNLOAD), Continuous Ultrafiltration for Congestive Heart Failure (CUORE) and Aquapheresis versus Intravenous Diuretics and Hospitalization for Heart Failure (AVOID-HF) trials, compared to pharmacological therapy, UF, used at rates higher than those reported for CARRESS-HF, achieved better decongestion without greater increases in sCr.9-11 This apparent paradox can be explained by the following consideration: in CARRESS HF, by protocol, UF rates were not tailored to individual patients' ‘baseline’ renal function, vital signs, and urine output; therefore the very low average UF rates reported by Grodin and colleagues may be misleading as they might not reflect either lingering congestion in the subjects who might have needed more fluid extraction or overzealous fluid removal in individuals at higher risk of hypovolaemia.1, 6 The finding of an increased risk of hyponatraemia in the UF arm, already reported by Kitai et al.,12 is also quite puzzling. The authors' explanations for this unexpected finding, which are identical in both manuscripts, do not seem convincing. One hypothesis is that ‘depletional’ hyponatraemia occurs because of efficient removal of sodium by UF. With 5-6 L of ultrafiltrate (containing 140 mmol/L of sodium), the maximum amount of sodium that can be removed is approximately 800 mmol. By 96 h, a hospitalized patient on a strict low sodium diet of 100 mmol/day (2.4 g/day), can regain 400 mmol of sodium or half the amount removed by UF. This fact does not support the hypothesis of ‘depletional’ hyponatraemia.13 Moreover, there is evidence that when UF therapy causes intravascular volume depletion, the resulting decrease in urinary sodium may partially offset the advantage of iso-osmotic fluid removal by UF vs. generation of hypotonic urine by loop diuretics.13 The other hypothesis proposed by the authors to explain the lower serum sodium in the UF group at 48 h is that free water refill exceeds the rate of sodium shift towards intravascular space. Since water follows sodium in most known clinical scenarios, this hypothesis is unfounded. A more plausible explanation is that in some cases (e.g. when UF rate significantly exceeds PRR) the unintentional intravascular volume depletion stimulates renin secretion. This, in turn, may heighten production of angiotensin, which is a potent trigger of thirst and, consequently, may lead to increased free water intake. Indeed, Grodin and colleagues found that, compared to the SPT group, UF patients had a higher plasma renin activity by 96 h. However, the interpretation of this finding is not straightforward. One would expect that heightened renin activity would be associated with increased plasma aldosterone levels, which did not occur in CARRESS-HF. Furthermore, the significance of renin and aldosterone levels cannot be accurately estimated in heart failure patients due to use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and mineralocorticoid receptor antagonists as background therapy.14 With awareness of the inherent limitations of any per-protocol analysis, the results of the study presented by Grodin and colleagues differ significantly from those of the intention-to-treat analysis and corroborate the key findings of UNLOAD, AVOID-HF and CUORE trials that demonstrated more effective decongestion with UF than with pharmacological therapies.9-11 However, in contrast to UNLOAD, AVOID-HF and CUORE, that consistently showed greater reductions in heart failure events in the UF compared to the diuretic arm, the per-protocol analysis of CARRESS-HF showed no differences in 60-day outcomes between the UF and pharmacological arms.1, 9-11 This finding is hardly surprising, because 90% of the CARRESS-HF population was not adequately decongested when the primary endpoint was evaluated. Mounting evidence demonstrates that unresolved congestion is the principal driver of poor outcomes.2, 3, 5 Hopefully, the Peripheral Ultrafiltration for the Relief from Congestion in Heart Failure (PURE-HF) trial (NCT03161158), which is randomizing approximately 900 fluid overloaded heart failure patients to either UF plus low-dose intravenous diuretics or high-dose diuretic therapy alone, will further elucidate the impact of UF on outcomes such as heart failure events and mortality. Conflict of interest: M.R.C. served as principal investigator for the AVOID-HF trial; has received research support through her institution for the AVOID-HF trial; consultant for Axon Therapies and CHF Solutions Inc. A.K. is a consultant for CHF Solutions Inc.