ULTRAFILTRAZIONE EXTRACORPOREA NELLA SINDROME CARDIORENALE ACUTA (Lo Studio CARRESS-HF)

1. ULTRAFILTRAZIONE EXTRACORPOREA NELLA SINDROME CARDIORENALE ACUTA(Lo Studio CARRESS-HF) Aurelio Limido UO Nefrologia e Dialisi AO Fatebenefratelli e Oftalmico Milano

2. 2012;367 24 december:2296-304.

3. The acute cardiorenal syndrome (type 1) is defined as worsening renal function in patients with acute decompensated heart failure. It occurs in 25 to 33% of patients with acute decompensated heart failure and is associated with poor outcomes. Multiple processes contribute to the development of the acute cardiorenal syndrome, including extrarenal hemodynamic changes, neurohormonal activation, intrarenal microvascular and cellular dysregulation, and oxidative stress. In some cases, intravenous diuretics, which are often administered in patients with acute decompensated heart failure, may directly contribute to worsening renal function. The use of diuretics to treat persistent congestion after the onset of worsening renal function may lead to further kidney injury.

4. Current treatment guidelines state that ultrafiltration is a reasonable approach in patients with congestion that is not responding to medical therapy (class IIa, level of evidence B). Potential advantages of ultrafiltration include greater control over the rate and volume of fluid removal, greater net loss of sodium, and less neurohormonal activation. However, little is known about the safety and efficacy of ultrafiltration as compared with pharmacologic therapy in patients with acute decompensated heart failure complicated by acute cardiorenal syndrome and persistent congestion.

5. Methods We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days.

6. Patients who were hospitalized with acute decompensated heart failure as the primary diagnosis were eligible for enrollment. There was no exclusion criterion that was based on ejection fraction. All patients had worsened renal function (increase in the serum creatinine level of at least 0.3 mg per deciliter) within 12 weeks before or 10 days after the index admission for heart failure. All patients were required to have at least two of the following conditions at the time of randomization: at least 2+ peripheral edema, jugular venous pressure greater than 10 cm of water, or pulmonary edema or pleural effusion on chest radiography. Patients with a serum creatinine level of more than 3.5 mg per deciliter at the time of admission and those receiving intravenous vasodilators or inotropic agents were excluded from the study.

7. For patients assigned to ultrafiltration therapy, loop diuretics were to be discontinued for the duration of the ultrafiltration intervention. Ultrafiltration was performed at a fluid-removal rate of 200 ml per hour. For patients assigned to stepped pharmacologic therapy, intravenous diuretics were used to manage signs and symptoms of congestion. Investigators were encouraged to decrease doses, increase doses, or continue current doses of diuretics as necessary to maintain a urine output of 3 to 5 liters per day.

9. Results Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P = 0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was −0.04±0.53 mg per deciliter in the pharmacologic therapy group, as compared with +0.23±0.70 mg per deciliter in the ultrafiltration group (P = 0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg and 5.7±3.9 kg, respectively; P = 0.58).

11. Conclusions In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches.

12. Our study has several limitations. First, although the trial was randomized, the treatment assignments were not blinded, and biases on the part of study investigators may have affected the duration or relative intensity of ultrafiltration and pharmacologic therapy. Second, the safest and most effective rates of fluid removal, the duration of therapy, and the conditions for termination of ultrafiltration are unknown. Finally, the results of the strategies tested here may not apply to other patient populations with acute decompensated heart failure, such as patients with less severe cardiorenal syndrome.

13. NEJM 367; 24 december 13, 2012 (Editorial Comment) CARRESS-HF illustrates overall dismal outcomes in patients with acute cardiorenal syndrome. Regardless of treatment strategy … more than a third of the patients died or were readmitted to the hospital for acute decompensated heart failure within 60 days, despite substantial overall weight loss. We simply do not know whether a rise in serum creatinine level during treatment represents desired effects of hemoconcentration (when therapy is efficacious) or undesired deterioration of renal function (when therapy is ineffective). In fact, transient changes in serum creatinine levels during therapy for acute decompensated heart failure may not necessarily reflect substantial underlying renal injury or adverse longterm consequences. The effect of therapy on the bivariate primary end point of change in weight and change in serum creatinine level may be dependent on the rate at which congestion is being relieved. It is conceivable that a slower but steady ultrafiltration rate may help maintain an adequate plasma refill rate. This may result in longer duration of ultrafiltration and greater volume removal without inducing azotemia.

14. NEJM 368;12 march 21, 2013 Ultrafiltration presumably should be restricted to patients with impairment of renal function, cardiac function, or both that is more severe than the impairment in patients involved in the current trial. Furthermore, it is unclear at first sight why renal function should be different at 96 hours only when serum creatinine concentrations are used as a marker of renal function, but not when the level of cystatin C or the glomerular filtration rate are used. How can this discrepancy be explained? Jenny Haas, M.D. Bernhard K. Krämer, M.D. Urs Benck, M.D.

15. NEJM 368;12 march 21, 2013 Given the bivariate primary end point that entailed the serum creatinine level for the comparison of ultrafiltration with pharmacologic therapy … this trial could not have had different results. In the ultrafiltration group, most of the fluid removal was achieved with ultrafiltration, which implied that less fluid was eliminated by the kidney through glomerular filtration. By contrast, in the pharmacologic-therapy group, the excess fluid was eliminated exclusively through the kidney. Since, according to the manufacturer, creatinine is not removed with the ultrafiltration procedure used in the study, it could be anticipated that a smaller amount of creatinine was excreted through glomerular filtration and tubular secretion. Gian Paolo Rossi, M.D. Antonio Piccoli, M.D., D.Sc. Lorenzo A. Cal, M.D., Ph.D.

16. NEJM 368;12 march 21, 2013 As manufacturers of the Aquadex FlexFlow ultrafiltration system, we would like to highlight some points. First, the study population in this trial had more advanced disease than that which is indicated for this therapy. Second, ultrafiltration was performed at a fluid removal rate of 200 ml per hour, which may have been inappropriate for this patient population. Third, rates of intravascular volume refill were not monitored. Juan Bosch, M.D. Luis A. Rios-Nogales Garces, M.D., Ph.D.

17. NEJM 368;12 march 21, 2013 Transient increases in the creatinine level may not portend a poor prognosis. Whereas doses of diuretics were adjusted in the pharmacologic-therapy group, the ultrafiltration rate was uniformly 200 ml per hour, which may be excessive … in patients with low blood pressure or right ventricular dysfunction. In contemporary ultrafiltration devices, hematocrit sensors estimate blood volume so that the capillary refill time is not exceeded and hypovolemia is prevented. A total of 12% of patients in the pharmacologic-therapy group received inotropic agents, which are prohibited in ultrafiltration; this may have attenuated hypotension-related worsening renal function. A total of 23% of patients in the ultrafiltration group crossed over to alternative therapy, and 39% received intravenous diuretics before the 96-hour assessment, which may have contributed to worsening renal function. Maria Rosa Costanzo, Gregg C. Fonarow, Gerasimos S. Filippatos, M.D.

20. NEJM 368;12 march 21, 2013 (Reply) The diversity of responses to the results of our trial highlights the uncertainty in clinical practice for patients with acute decompensated heart failure and kidney disease. Haas et al. recommend that ultrafiltration be reserved for patients with more advanced kidney disease or cardiac dysfunction, whereas Bosch and RN Garces suggest that the patients in our trial had disease that was more advanced than the disease stage for which ultrafiltration is recommended. Both Haas et al. and Rossi et al. question the use of the serum creatinine level to assess renal function. We selected change in the creatinine level as a key component of the primary end point in our trial because it is one of the few measures routinely used ... . Bosch and RN Garces, and Costanzo et al., raise important issues related to the application of ultrafiltration in our trial. We acknowledge that the ideal rate of fluid removal, supportive medical therapy, monitoring measures, and the conditions used to determine the best time for discontinuing acute decongestive therapies for ultrafiltration are unknown.

21. 2013;62(3):453-456

22. 2013;62(3):453-456 As shown in CARRESS-HF, when diuretic dosages are titrated effectively and in a timely manner that uses a continuous infusion of loop diuretics and adds distal-acting diuretics, it is possible in many patients to remove an amount of fluid similar to ultrafiltration. At the present time, we can recommend ultrafiltration only in patients with ADHF who are unable to achieve decongestion with a rational stepped-up diuretic regimen and usual hemodynamic care. Because readmission and mortality rates remain high for patients with ADHF and cardiorenal syndrome, further studies are needed to guide clinicians in the use of diuretics and ultrafiltration. In order to improve care, we need methods that optimize active monitoring of congestion and the hemodynamic and kidney responses to treatment that go beyond measurement of body weight and SCr Benjamin J. Freda, DO Jaya Mallidi, MD Gregory L. Braden, MD Baystate Medical Center Springfield, Massachusetts

23. Open questions remain. First, is UF really justified in congested patients who still have daily urine output greater than 2.5-3 L during medical therapy, as in the CARRESSHF study? On the basis of the available data, the answer is probably no … Second, is there a threshold level of renal dysfunction beyond which UF should not be used? Albeit definite clinical evidence is limited, most of the trials excluded patients with sCr values exceeding 3 mg/dL. Quite obviously, UF is not indicated in the presence of metabolic derangements (azotemia, hyperkalemia, metabolic acidosis) requiring different techniques of RRT. Third, how could the fluid removal rate by UF be optimized in order to match the capillary refilling rate in individual patients? Despite the availability of infrared hemoglobinometry to estimate relative blood volume decrease in modern UF devices, clinical experience in the nephrology field suggests that this approach does not invariably obviate hemodynamic instability during extracorporeal procedures.

24. On the whole, the available evidence suggests that clinicians should adopt a very selective and targeted approach to performing UF in patients with ADHF – e.g., as emergency treatment in the presence of acute pulmonary edema with respiratory failure in oliguric ADHF, or when congestion is really unresponsive to maximal and appropriate diuretic treatment. Along the same line of reasoning, UF is not indicated as an alternative strategy to diuretic therapy.