CARRESS-HF

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Bart BA, et al. "Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome". The New England Journal of Medicine. 2012. 367(24):2296-2304.
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Clinical Question

In patients with acute decompensated heart failure and cardiorenal syndrome, does ultrafiltration improve volume removal, renal function, and reduce HF complications when compared to medical therapy?

Bottom Line

In patients with acute decompensated HF and cardiorenal syndrome, ultrafiltration is associated with more adverse events, worsening renal function, and no change in weight when compared to medical therapy.

Major Points

Diuretics are the mainstay of therapy for acute decompensated heart failure (ADHF), but their use is associated with electrolyte abnormalities and renal dysfunction, that have led investigators to study other methods of volume removal in ADHF.[1][2] FDA-approved ultrafiltration (UF) devices, similar to dialysis machines, allow direct removal of isotonic fluid directly from the bloodstream. This therapy has been thought by some to be the preferred method for volume removal in ADHF based on small trials.[1] The first large trial comparing UF to diuretic therapy in ADHF was UNLOAD (2007)[3], which demonstrated improved weight loss and fewer readmissions with UF, although there was no difference in serum creatinine or length of stay when compared to standard diuretic therapy. Despite the promising results in UNLOAD, the role of UF in ADHF complicated by cardiorenal syndrome was unclear until CARRESS-HF.

The 2012 Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial randomized 188 patients with ADHF and worsening renal function to UF or an aggressive stepped diuretic therapy. At 4 days, there was a significant increase in creatinine in the UF group without a significant change in weight or symptoms between the two groups, compared to medical therapy. UF was associated with higher rates of adverse events.

There are several reasons to account for the conflicting results of CARRESS-HF and UNLOAD. The patient populations were different, in large part because CARRESS-HF studied patients with renal impairment from the cardiorenal syndrome. Additionally, the rigid, protocol-driven, higher-dose diuretic strategy of CARRESS-HF may have been more appropriate than the more conservative strategy in UNLOAD. Of note, the effectiveness and safety of high-dose diuretics in ADHF was previously demonstrated in DOSE (2011).[4]

Guidelines

AHA/ACCF Heart Failure Guidelines (2013, adapted)[5]

  • UF may be considered for those with obvious volume overload to improve symptoms of congestion and reduce weight from fluid (class IIb, level B)
  • UF may be considered for patients with congestion not responding to medical therapy (class IIb, level C)

Design

  • Multicenter, prospective, randomized, open-label comparative trial
  • N=188 patients with decompensated acute heart failure and worsening renal function
    • Ultrafiltration (n=94)
    • Stepped pharmacologic therapy (n=94)
  • Setting: 22 centers in the US and Canada
  • Enrollment: 2008-2012
  • Follow-up: 60 days
  • Analysis: Intention-to-treat
  • Primary outcome: Change in serum creatinine level and change in weight (bivariate)

Population

Inclusion Criteria

  • Hospitalization for acute HF
  • Increase in serum creatinine ≥0.3 mg/dL
  • ≥2 of the following:
    • 2+ peripheral edema
    • JVD ≥10 cmH2O
    • CXR with pulmonary edema or pleural effusion

Exclusion Criteria

  • Creatinine >3.5 mg/dL
  • Vasodilator or inotrope therapy

Baseline Characteristics

From the ultrafiltration group.

  • Demographics: Age 69 years, male 78%, white race 77%
  • Baseline health data: Weight 207 lb, EF 30%
  • PMH: a-fib or a-flutter 57%, ischemic HF 51%, DM 65%
  • Medications: ACE-inhibitor/ARB 55%, beta-blocker 79%, aldosterone antagonist 22%, furosemide or equivalent 91%
  • HF hospitalization in prior year: 79%
  • Laboratory results:
    • BUN: 48.7 mg/dL
    • Creatinine: 1.90 mg/dL (median increase of 0.43 mg/dL from baseline)
    • NT-proBNP: 5,013 pg/mL

Interventions

  • Randomization to one of two groups
    • Ultrafiltration: Discontinuation of loop diuretics and use of an ultrafiltration device with fluid removal of 200 mL/hr
      • Ionotropes or vasodilators were used as rescue therapy only
    • Pharmacologic: Protocol-driven[6] titration of IV diuretics to clinical status and evidence of volume status, though clinicians were encouraged to achieve UOP of 3-5 L/day
      • Ionotropes and vasodilators were used in those unable to attain the UOP if no contraindications due to BP, EF, and right HF at 48 hours

Outcomes

Comparisons are ultrafiltration vs. medical therapy.

Primary Outcome

Change in serum creatinine level and change in weight at day 4 (bivariate)
Creatinine change: +0.23 vs. -0.04 mg/dL (P=0.003)
Weight loss: -5.7 vs. -5.5 kg (P=0.58)

Secondary Outcomes

All-cause mortality at 60 days
17% vs. 13% (P=0.47)
Weight loss and renal improvement
Day 4: 17% vs. 21% (P=0.62)
Day 7: 16% vs. 21% (P=0.52)
Changes in laboratory values, functional measurements, and subjective measurements at 4 days
Sodium: -2.3 vs. 0.0 mmol/L (P<0.001)
Hgb: -0.01 vs. +0.38 g/dL (P=0.002)
NT-proBNP: -814 vs. -979 pg/mL (P=0.30)
Cystatin C: +0.22 vs. +0.14 mg/L (P=0.37)
BUN: +12.54 vs. +5.68 mg/dL (P=0.02)
GFR: +0.93 vs. +1.67 (P=0.66)
Global well-being scale: 13.7 vs. 22.8 (P=0.33)
Dyspnea assessment scale: 16.5 vs. 20.5 (P=0.57)
Decongestion: 10% vs. 9% (P=0.83)
Worsening condition or crossover at 7 days
23% vs. 18% (P=0.45)
Change in furosemide equivalent dose at 7 days
-20.6 vs. +2.2 mg/day (P=0.18)

Adverse Events

Any
72% vs. 57% (P=0.03)
Heart failure: 33% vs. 30%
Renal failure: 6% vs. 5%
Anemia or thrombocytopenia: 9% vs. 5%
Sepsis, bacteremia, or cellulitis: 9% vs. 4%

Criticisms

  • Open label
  • Unclear what is the safest method by which to perform ultrafiltration
  • Cannot generalize the results to less severe HF or patients without cardiorenal syndrome
  • The inclusion criteria may have been too generous and the negative outcomes may not have resulted in a benefit as a result (Note: The manufacturer argues the opposite in the same publication)[7]
  • Creatinine level is an imprecise measurement of kidney function, especially since ultrafiltration does not filter the blood like hemodialysis[7]
  • The rate of fluid removal may have been too rapid[7]
  • High crossover[7]

Funding

The National Heart, Lung, and Blood Institute

Further Reading

  1. 1.0 1.1 Bart BA. "Treatment of Congestion in Congestive Heart Failure: Ultrafiltration Is the Only Rational Initial Treatment of Volume Overload in Decompensated Heart Failure." Circulation: Heart Failure. 2009. 2(5):499-504.
  2. Shin JT and Dec GW. "Ultrafiltration Should Not Replace Diuretics for the Initial Treatment of Acute Decompensated Heart Failure." Circulation: Heart Failure 2009. 2:505-511.
  3. Costanzo MR, et al. "Ultrafiltration versus intravenous diuretics for patients hospitalized for acute decompensated heart failure." Journal of the American College of Cardiology. 2007. 49(6):675-683.
  4. Felker GM, et al. "Diuretic strategies in patients with acute decompensated heart failure." The New England Journal of Medicine 2011. 364(9):797-805.
  5. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.
  6. Supplementary appendix with stepped pharmacologic algorithm
  7. 7.0 7.1 7.2 7.3 NEJM letters to the editor