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Furosemide-induced high urine output combined with a hydration monitoring and infusion system helps prevent contrast-induced nephropathy (CIN) in patients with chronic kidney disease (CKD) undergoing coronary procedures, according to a randomized study published in the January 2012 issue of JACC: Cardiovascular Interventions. The prophylactic strategy also results in fewer in-hospital complications.

For the single-center MYTHOS trial, investigators led by Giancarlo Marenzi, MD, of the University of Milan (Milan, Italy), randomized 170 patients with moderate to severe CKD scheduled for coronary angiography to furosemide with matched hydration (n = 87) or standard intravenous (IV) isotonic saline hydration (n = 83).

In the former group, following an initial 250-mL IV bolus of isotonic saline, hydration was automatically adjusted to precisely replace urine output using the RenalGuard System (PLC Medical Systems, Milford, MA), which is approved in Europe but not the United States. When the urine output rate exceeded 300 mL/hour, patients underwent coronary intervention. Balanced hydration was maintained throughout the procedure and for 4 hours afterward.

Furosemide/RenalGuard Lowers CIN by a Third

The total duration of furosemide/RenalGuard treatment was 6 ± 1 hours with a cumulative hydration volume of 3,995 ± 1,401 mL, compared with a hydration duration of 25 ± 2 hours and a hydration volume of 1,742 ± 290 mL in the control group. Thus, a twofold higher IV hydration rate and a slightly higher urine output rate were obtained in a fourfold shorter time in the treatment group compared with the control group.

After the procedure, furosemide/RenalGuard patients were more than one-third less likely to develop CIN than controls. However, while the treatment had a major impact on urgent patients, the positive effect on elective patients did not reach statistical significance (table 1).

Table 1. Incidence of CIN by Indication

The furosemide/RenalGuard group also had lower rates of in-hospital morbidity (table 2).

Table 2. Postprocedural Complications

 
In the per-protocol analysis, the combined incidence of CIN and major adverse events was 13% for the furosemide/RenalGuard group vs. 40% for the control group (P < 0.001), reflecting a 68% reduction in risk (adjusted RR 0.32; 95% CI 0.15-0.67; P = 0.003).

No significant complications were associated with use of furosemide and matched hydration, although 4 patients developed asymptomatic hypokalemia that was reversed with potassium supplementation.

‘A New Concept’ for Prevention

The authors say that “a new concept is emerging for CIN prevention, similar to conventional hemofiltration: Hydration volume should be commensurate to patient risk, and high-risk patients likely require a high-volume (~1 L/hr) of controlled hydration.”

The positive results with the furosemide/RenalGuard approach were driven by the therapy’s effect on NSTEMI patients undergoing urgent angiography, the investigators observe. “This is a high-risk group of patients who are less likely to receive CIN prophylaxis, and in whom several factors . . . may further increase the risk of renal injury,” Dr. Marenzi and colleagues write. “It is possible that these patients may benefit the most from this strategy, not only in terms of contrast toxicity prevention, but also in terms of overall kidney protection from acute injury.” On the other hand, the cost-benefit ratio in elective patients “needs further investigation,” they add.

Worthy of a Larger Trial

In a telephone interview with TCTMD, Hitinder S. Gurm, MD, of the University of Michigan Medical School (Ann Arbor, MI), said that overall “this study showed pretty impressive results, and [the strategy] definitely merits a larger study.”

In fact, a multicenter pivotal US trial is just beginning enrollment, Roxana Mehran, MD, of Mount Sinai Medical Center (New York, NY), told TCTMD in a telephone interview. It will include at least twice as many patients as MYTHOS and will use a very similar protocol, she reported.

“Whatever we can do to bring our patients into a euvolemic and nondehydrated state is how we’re going to preserve kidney function,” explained Dr. Mehran, a PI for the new trial. “I think [this approach] is one of the most important contributions to this effort that’s been made over the years. Pretty much every other [strategy] hasn’t worked.”

 The efficacy of the treatment appears to depend on achieving optimal urinary flow, Dr. Gurm indicated. “In this study they have gotten very good [urinary] outputs,” he commented. “I wish I could say that we are able to do that routinely in all our patients. I would be a little cautious about that, though, because in some of the earlier studies that was not the case.”

At the same time, the very high urine output maintained in these patients is potentially problematic, Dr. Mehran acknowledged. “But so far in the initial studies this did not seem to be an important issue. We’re going to see as we move ahead.”

Dr. Gurm noted that pulmonary edema is a risk anytime forced diuresis is used. “In this study, the control group had more pulmonary edema than the forced hydration group, but in some of the prior work it was the other way around, so I think we need to be worried about that,” he said.

Start by Reducing Exposure

Although this protective strategy against contrast toxicity appears promising, Dr. Gurm stressed that more attention should be paid to limiting contrast exposure in the first place. “The contrast volumes in this study are high,” he said. “The first rule should be to minimize the amount of contrast. We recently found that if you keep the ratio of contrast volume to GFR below 3, the risk of complications is very low.”

Nonetheless, he called the trial “a good proof of concept. But I’d like to see a larger trial because it’s hard to change therapy based on a 170-patient trial, especially for something that is common and where other trials have suggested there may be the possibility of harm,” he cautioned.

Looking ahead to results from the upcoming US study, Dr. Mehran noted that “if we can save patients from acute kidney injury by use of this new technology, I think we will be doing a great service to our patients.”

Study Details

Patients’ mean age was 73 ± 7 years and the mean eGFR was 39 ± 10 mL/min/1.73 m². Baseline characteristics of the 2 groups were comparable except for a lower serum potassium concentration in the furosemide group. In particular, CIN risk factors and calculated risk score also were similar.

A nonionic, low-osmolality contrast agent (iomeprol) was used for all patients. CIN was defined as at least a 25% or 0.5 mg/dL increase in serum creatinine over baseline.

 

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Source:
Marenzi G, Ferrari C, Marana I, et al. Prevention of contrast nephropathy by furosemide with matched hydration: The MYTHOS (Induced Diuresis with Matched Hydration Compared to Standard Hydration for Contrast Induced Nephropathy Prevention) trial. J Am Coll Cardiol Intv. 2012;5:90-97.

 

 

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