Swapping recombinant tissue plasminogen activator (rt-PA) for heparin once a week as a dialysis catheter locking solution significantly reduced the incidence of catheter malfunction and bacteremia in a blinded, randomized trial. The trial results were published in the New England Journal of Medicine (2011;364:303-312).
“With the use of rt-PA once a week at a low dose—just a milligram per lumen—we were actually able to reduce the rates of catheter malfunction by twofold—by 50%—and the rates of bacteremia or bloodstream infections by two-thirds,” said lead author Brenda Hemmelgarn, MD, PhD, Associate Professor at the University of Calgary, in a phone interview.
Despite efforts to reduce their use, central venous catheters continue to be the mode of vascular access for most patients on hemodialysis.
Arteriovenous (AV) fistulas are the preferred method of access, but they need to mature for weeks or months before they're ready for use. Synthetic grafts fall right in the middle of the order of preference. While they don't require the maturation time of a fistula, they carry a higher risk of infection than that access type.
“In patients who require central venous catheters for dialysis access, there can be a number of complications with the catheter,” Dr. Hemmelgarn said. “In fact, up to 50 percent of them will malfunction within one year, and there are high rates of bloodstream infections as well.
“Currently, we use rt-PA as a treatment when there is a malfunction, so what we postulated was that perhaps if we use this medication at a lower dose as a preventative strategy, we might be able to prevent some of these complications from happening.”
‘Really Well-Conducted Study’
The trial, which was funded by Hoffmann–La Roche, included 225 patients from 11 Canadian sites who were on long-term hemodialysis and had a central venous catheter inserted within two weeks of recruitment.
The patients were randomly assigned to a catheter-locking regimen with heparin (5,000 U/mL) three times a week (115 patients) or with rt-PA (1 mg in each lumen) swapped for heparin once a week and heparin used the remaining two times (110 patients).
Participants were followed for six months after randomization, and treatment assignments were concealed from patients, investigators, and trial personnel. The primary outcome was catheter malfunction, and the secondary outcome was catheter-related bacteremia.
In the rt-PA group, 22 patients reached the primary outcome (20.0%), compared with 40 in the heparin group (34.8%). Catheter-related bacteremia occurred in five patients in the rt-PA group (4.5%) and 15 patients in the heparin group (13.0%).
At the same time, rt-PA did not increase the risk for adverse events: 70.0% of patients in the rt-PA group and 68.7% of patients in the heparin group had an adverse event, and serious adverse events were reported in 23 patients receiving rt-PA (20.9%) and 34 patients receiving heparin only (29.6%). Those in the rt-PA group did not have a higher frequency or severity of bleeding events.
“I thought it was a really well-conducted study,” said Micah R. Chan MD, MPH, Assistant Professor of Nephrology at the University of Wisconsin School of Medicine and Public Health and an interventional nephrologist, in a phone interview.
“It showed significant improvement in catheter patency over six months in the t-PA versus the heparin group, and also an over threefold difference in catheter-related bacteremia.
“I think it's gratifying to see level-one evidence in this field of hemodialysis vascular access because there is a paucity of literature, and I think the authors took the time and the effort in recruiting as many patients as they could, so I thought it was a very well-conducted study.”
Early Versus Late Dysfunction
While the results may be practice-changing, there need to be trials of the cost-effectiveness of rt-PA before the agent is routinely used in this way, Dr. Chan said.
“As a preventive measure, this is one of the first trials with a large number of patients that shows it possibly could be used. I think there have to be more trials to really use t-PA across the board.”
Such trials should examine the use of citrate and lower-dose heparin (1,000 U/mL) as catheter-locking solutions, he said.
Dr. Chan also made the distinction between early and late catheter dysfunction.
“As an interventionalist, we do see both early and late dysfunction,” he said. “Early dysfunction typically can be caused by mechanical causes from the catheter, but most of the time thrombotic occlusion, and t-PA is very useful in this situation. In late dysfunction—we see it time and time again—large fibrin sheaths, and t-PA doesn't work as well in those cases.”
Catheter Malfunction Defined
Michael Allon, MD, Professor of Medicine in the Division of Nephrology at the University of Alabama at Birmingham, also praised the conduct of the study.
“I think it's a wonderfully designed and executed study, and the main issue is: What is the interpretation of the results, and what does that mean in terms of the future care for hemodialysis patients with catheters?”
In terms of the interpretation of the primary outcome, the point in question is the definition of catheter malfunction, Dr. Allon said.
In the trial, catheter malfunction was defined as the first occurrence of any of the following after attempts to reestablish patency:
* Peak blood flow of 200 mL/min or less for 30 minutes during a dialysis treatment.
* Mean blood flow of 250 mL/min or less during two consecutive dialysis treatments.
* Inability to initiate dialysis due to inadequate blood flow.
Patients who met the definition were followed for up to three months or until the catheter was removed, with a median follow-up spanning 11.5 dialysis sessions in the rt-PA group and 10.0 dialysis sessions in the heparin group.
During this follow-up time, only one of 22 patients with catheter malfunction in the rt-PA group (4.5%) and three of 40 patients with catheter malfunction in the heparin group (7.5%) had to have their catheter removed because of malfunction, Dr. Allon noted.
“So the question in my mind is: What is the more clinically meaningful endpoint?” he said. “Is it that in one dialysis or two dialysis sessions you had a suboptimal blood flow, or is it whether you actually had to replace the catheter?
“In my mind, the more clinically meaningful endpoint is that you had to replace the catheter. Most of the time, either with simple conservative measures or instillation of t-PA, the flow was restored, and fewer than 10 percent of the patients who achieved the endpoint of malfunction actually had to have the catheter replaced.
“Obviously t-PA is a fairly expensive drug, and the question that I would pose is, rather than instilling t-PA three times a week in an attempt to prevent the malfunction, would it be more cost-effective to just use standard heparin and then only to instill t-PA in those situations where the catheter malfunction developed despite the heparin instillation?”
In the trial, the catheters that met the definition for malfunction continued to work poorly, though, Dr. Hemmelgarn noted.
“We chose the definition after long discussion with our steering committee and chose catheter malfunction as defined by published guidelines; the hemodialysis guidelines actually define catheter malfunction in this manner based on blood flow.
“The optimal outcome obviously would be removal of the catheter, but we were concerned that we wouldn't be able to enroll some patients because some investigators might not want to wait until the catheter was removed in order to have their subjects in the study.
“Also, we followed the patients after their catheter malfunction based on this definition to see what happened, and a number of them had repeated episodes of malfunction with high use of rt-PA, so we felt confident that it was a valid definition of malfunction because the line continued to work poorly.”
Dr. Hemmelgarn and colleagues conducted a preliminary cost-effectiveness analysis of the use of rt-PA.
For each patient who received six months of therapy, the mean costs, in Canadian dollars, were $1,794 for rt-PA and $195 for heparin. The costs of managing complications associated with catheter malfunction and catheter-related bacteremia were $156 per patient for rt-PA and $582 per patient for heparin. The incremental cost, then, of rt-PA versus heparin was $1,173 per patient or $13,956 per episode of catheter-related bacteremia prevented.
A full economic evaluation for the trial is not complete, as administrative data on the cost of hospitalizations were not yet available.
“I think there's going to need to be an open dialogue among nephrologists and among the dialysis providers and certainly among the insurers, which is primarily CMS [Centers for Medicare & Medicaid Services], about this,” Dr. Allon said.
The new End-Stage Renal Disease Prospective Payment System, which went into effect Jan. 1, adds another layer of complexity to this cost equation. Under the new system, each dialysis treatment is reimbursed with a single payment that covers all dialysis services, as opposed to the old system, which paid a composite rate for a defined set of items and services while reimbursing certain drugs, laboratory tests, and other services separately.
“There's no way that I can see that dialysis providers are going to dialyze all these patients at a loss in order to give the t-PA instillation once a week,” Dr. Allon said.
The full cost-effectiveness analysis will be an important factor as programs consider the results of the trial and what the implications should be, Dr. Hemmelgarn noted.
“I think it's going to have to be evaluated on a program-by-program basis,” she said.
‘Pivotal and Landmark Study’
The trial provides preliminary findings while setting the stage for more prospective randomized trials, Dr. Chan said.
“This was a pivotal study and a landmark study in our field, and I think it really will get a lot of people's attention.
“However, I think the most important factor and research area that we can look at is how to decrease catheters, especially here in the US—strategies such as specific multidisciplinary vascular access teams, early referral process to nephrologists, venous mapping surveillance, and looking at possibly more PD [peritoneal dialysis] and more PD as a bridge to AV fistula versus catheters.
“I think there's a lot of opportunity to look at how we can decrease catheters, and I think that's an area that needs to be studied more as well.” •