Recombinant tissue plasminogen activator reduces incidence of catheter malfunction and bacteremia

Hemmelgarn B, Moist L, Lok C, et al. Prevention of dialysis catheter malfunction with recombinant tissue plasminogen activator. N Engl J Med. 2011;364:303-312. Malfunctioning and infected hemodialysis catheters increase morbidity, mortality, and the cost of care of hemodialysis patients. More than 50% to 70% of hemodialysis catheters will be expected to fail within the first year, with half to two-thirds of these failures attributable to catheter thrombosis.1 Heparin has been shown to be superior to saline as a locking solution in preventing catheter malfunction. Only one study, however, has previously evaluated recombinant tissue plasminogen activator (rt-PA) as a locking solution for primary prevention of catheter failure rather than as a treatment of existing/suspected thrombosis. In addition, line-related sepsis constitutes up to 75% of deaths from infection among this population,2 and infection risk increases in the presence of partial or complete thrombosis.3 In this month's literature watch, we review a study by Hemmelgarn and colleagues designed to evaluate whether rt-PA administered once weekly as locking solution in substitution for the scheduled dose of heparin is superior to the current customary care of locking catheters with heparin only after each dialysis session, in preventing catheter malfunction (primary outcome) and infection (secondary outcome). The ideal study design to investigate whether one intervention is superior to another is a randomized clinical trial (RCT) with masked allocation and determination of outcomes. The study by Hemmelgarn and colleagues represents a well-designed RCT with random allocation of the patients and full masking (blinding) of group assignment, in which the investigators evaluate whether a protocol including 1 mg of rt-PA as a locking solution used once a week in place of 5,000 U of heparin is superior to heparin alone in preventing catheter malfunction and bacteremia. Participants were recruited from 11 Canadian hemodialysis centers within 2 weeks of a newly inserted hemodialysis catheter. Patients were excluded from the study if their catheters at baseline failed to function adequately, defined as a blood flow of at least 300 mL/min during the dialysis sessions immediately prior to randomization. Masked random treatment allocation in a 1:1 ratio was performed centrally with the use of a permuted-block design stratified according to center and catheter status (first ever catheter for patient or not). Catheter malfunction and catheter-related bacteremia episodes by pre-defined criteria were documented. Analysis of outcomes was conducted on an intention-to-treat basis. Additionally, a cost assessment of maintaining future catheter patency was conducted. Although the study was originally designed for an enrollment of 340 patients to ensure 80% power to detect approximately a 34% reduction in the incidence of catheter malfunction with rt-PA once weekly, due to lower than expected enrollment, only 225 patients were enrolled. Despite a smaller size, the study did show a significant reduction in the primary outcome because of a higher than expected baseline risk and higher than expected risk reduction with treatment. The strengths of the study included masked allocation, pre-defined inclusion and exclusion criteria, and clinically relevant pre-defined primary and secondary outcomes. Additionally, there were no significant differences in baseline characteristics of both groups, indicating the success of the blocked stratified randomization schema used. Finally, the study had excellent follow-up with robust ascertainment of the outcomes. The single limitation of this study (smaller than expected study size) does not invalidate the overall findings but does reduce the precision of the final estimates of effect size or benefit. The current study by Hemmelgarn and colleagues demonstrates that the use of rt-PA as a locking solution for central venous catheters in place of heparin for one out of every three hemodialysis sessions decreases significantly the incidence of hemodialysis catheter malfunction and bacteremia. Hemmelgarn and colleagues demonstrated a reduction in events of hemodialysis catheter malfunction of 14.8%. If this reflects the true absolute risk reduction, than a number needed to treat (NNT) of seven patients to prevent one catheter malfunction episode can be expected. Similarly, locking hemodialysis catheters once weekly with rt-PA reduced episodes of catheter-related bacteremia by 0.97 episodes per 1,000 patient days, resulting in an NNT of approximately three patients treated for 1 year to prevent one episode of bacteremia. Several clinically important questions are not addressed by this robust RCT. Most importantly, this study does not determine whether additional benefit or risk can be obtained with larger or more frequent rt-PA doses.4 If infection risk is reduced, a reduction in mortality might also be anticipated. The current study was insufficiently powered and of insufficient duration to determine whether the reduced incidence of the primary or secondary outcomes resulted in improved survival. There were five deaths among patients receiving customary care and three in the experimental rt-PA group. There was no difference between the groups in total or in serious adverse events. Adverse events were experienced by 70% versus 68.7% of patients in the rt-PA and heparin-only groups, respectively. Significant intracranial bleeding episodes were observed in the customary care (heparin-only) group only. The authors also explored to some degree the cost differences of the two strategies and noted that for an incremental cost for rt-PA of $13,956 (Canadian dollars) one would expect to prevent one episode of catheter-related bacteremia. This apparent benefit did not include considerations of substantial potential improvements in patient quality of life, and it is likely that when expressed in terms of patient-centered outcomes such as QOL, the intervention might be even more clearly cost effective. This study does not address whether similar benefits might be obtained with other catheter locking solutions.5 As long as a substantial number of patients begins hemodialysis with a catheter for hemodialysis access, complications attributable to the catheters will remain significant. The current study provides compelling evidence that a strategy using once weekly rt-PA in place of heparin as a locking solution, which should reduce partial and/or total catheter thrombosis, will result in improved catheter function and reduced risk of infection. Although this strategy is likely to result in a favorable cost effectiveness, the costs of rt-PA will largely be borne by the dialysis units, the benefits will accrue almost entirely to the patient, and therefore, it should be anticipated that there will be additional disincentives for the adoption of this potentially beneficial therapy in an era of bundled payments for dialysis. Evans RW, Applegate WH, Briscoe DM, et al. Cost-related imunosuppressive medication non-adherence among kidney transplant recipients. Clin J Am Soc Nephrol. 2010;5:2323-2328. The most cost-effective, long-term treatment modality in ESRD patients is kidney transplantation; however, it is a commonly expressed view that loss of insurance coverage of immunosuppressive medications post transplantation is a serious issue for many recipients and an important source of immunosuppression medication non-adherence and allograft loss. Currently, Medicare covers 80% of the immunosuppressive medication cost until 36 months post transplantation, with extension to lifetime coverage in those who are eligible based on age or disability.6, 7 Nonetheless, many patients are unable to afford the expensive immunosuppressive medications, resulting in unplanned discontinuation of immunosuppression therapy and in premature and potentially avoidable allograft loss. Estimations of the negative economic impact due to non-adherence for immunosuppressive therapy (from all etiologies) in kidney transplantations are above 100 million dollars annually.8 The question of lifetime coverage has thus been raised.9 There are limited national data rigorously obtained on cost-related immunosuppressive medication non-adherence and transplant kidney loss to inform the debate on the magnitude of any potential benefit from an expansion of Medicare immunosuppression therapy coverage. Given the relatively short time required for the emergence of the consequences of non-adherence, the ideal study design to determine the potential harmful impact of insurance coverage on adherence to immunosuppression medications in transplant recipients is either an RCT of expanded coverage compared with current coverage or an inception cohort of all transplant recipients followed forward from the time of potential Medicare coverage loss (3 years) for a specified duration of follow-up. A robustly conducted cohort study should have careful ascertainment of allograft loss and of non-adherence to medications and the motivations for such non-adherence, whereby the latter are determined as unbiasedly as possible. In a cohort study these might be determined respectively by pill-counts or questionnaire and by surveying members of the cohort directly regarding their motivations. The cohort study design is typically more feasible and would allow for a detailed description of multiple risk factors for non-adherence to medications and the natural history of allograft survival unique to transplant recipients. The current study by Evans and colleagues seeks to fill in some of the missing data to support the benefits of expanding coverage by determining the impact of loss of Medicare coverage on adherence. Specifically, the authors state that “whereas the economic implications of graft loss have been well-documented, virtually no nationally representative contemporary data have been available to characterize the prevalence of immunosuppressive medication-related problems that kidney-transplant recipients experience. Consequently, the efforts of legislators to expand Medicare coverage for immunosuppressive medications have remained unpersuasive.” We “undertook a brief descriptive survey of transplant centers in hopes of establishing the scope and magnitude of the problem.” In the current study, Evans and colleagues report the results of a survey, conducted in collaboration by the American Society of Transplantation, the United Network for Organ Sharing (UNOS), and the North American Pediatric Renal Trials and Collaborative Studies group. The survey consisted of 12 closed-end questions distributed to all 254 UNOS-approved transplant centers in the United States, with multiple persons providing input in each center. Ninety-nine percent of the centers responded to the survey. Seventy percent of programs report that they believe that more than 20% of their patients have difficulties in paying for medications, and 43% of programs reported that more than 10% of patients were not taking their medications due to cost. Overall, 68% of centers reported deaths and graft losses directly associated with cost-related immunosuppression non-adherence. This published report, however, does not provide actual center-specific data on non-adherence, allograft loss, or death, nor does it specify the time period represented by the data or whether inability to pay/cost was the leading cause or only a contributing cause of non-adherence. It is uncertain whether patients were queried directly about their medication adherence and any motivation for non-adherence. A particular strength of this cross-sectional survey is its large size and nearly complete participation of all 254 UNOS-approved kidney transplant centers in the United States. Participation in this survey was likely increased due to the simplicity of the questions. It is, however, uncertain whether the data were collected in a uniform manner in each center, as it does not appear that instructions were provided to those filling out the surveys, and it is likely that some misinterpretation of the survey questions occurred. This is best exemplified by the very wide range of responses listed in Table 1, where it is clear that some programs report non-adherence rates of > 40% for their transplant patients when it is likely that they were reporting rates of cost concern amongs those with non-adherence. Thus, the results of the survey reflect, most directly, transplant center attitudes about the problem of non-adherence due to cost. These data represent a description of current opinions about the impact of inability to pay for immunosuppressive medication on long-term kidney transplantation outcomes. This survey is a first step in revealing the national scope of this problem. Additional studies will be required to quantify the individual, societal, and economic impact of non-adherence due to inability to pay. Improved Survival for Dialysis Patients With Congestive Heart Failure Treated With the Combination of an ACE Inhibitor Plus an Angiotensin Receptor Blocker: Results of a Randomized Clinical Trial Cice G, Di Benedetto A, D'Isa S, et al. Effects of telmisartan added to angiotensin-converting enzyme inhibitors on mortality and morbidity in hemodialysis patients with chronic heart failure. J Am Coll Cardiol. 2010;56:1701-1708. ACE inhibitors (ACEIs) have been a cornerstone of therapy for patients with left ventricular (LV) dysfunction for nearly two decades. In these populations, the ACEIs have been shown to improve cardiac performance, relieve symptoms, decrease hospitalizations, and prolong survival. The angiotensin II receptor blockers (ARBs) have been shown to have similar effects to the ACEIs in improving hemodynamic variables and cardiac function. The possibility that combination therapy with both classes of drug (dual renin-antiotensin-aldosterone system [RAAS] blockade) could offer benefits beyond those seen with either of the agents alone has been proposed.10 Recently published results from a large RCT, however, failed to demonstrate a survival or a renal survival benefit for proteinuric chronic kidney disease patients not on dialysis treated with an ACEI/ARB combination when compared with customary care with ACEI or ARB monotherapy.11, 12 Although dual therapy appears to provide some benefit to individuals with advanced congestive heart failure (CHF), whether dual RAAS blockade might benefit patients with CHF on dialysis has not been determined with the current studies. It remains to be demonstrated that dual RAAS blockade in ESRD patients is effective in improving patient-centered outcomes and is safe when compared with RAAS blockade with a single agent. In the current Italian study by Cice and coworkers, 351 hemodialysis patients who were receiving a stable dose of an ACEI with clinically significant CHF despite ACEI (New York Heart association [NYHA] functional class II and III) and ejection fraction ≤ 40% were randomized to telmisartan or placebo added to their current ACEI-containing therapy. Cice and co-workers report on the results of a 3-year randomized double-blind, placebo-controlled, multicenter trial. Participants were recruited from 30 clinics of a single large Italian dialysis provider network from January 1999 to January 2003. All study participants were on ACEI therapy, which was individually optimized and unchanged for more than 30 days prior to study enrollment. The use of other conventional heart failure treatments, including beta-blockers (carvedilol) and digitalis, was permitted. All patients were dialyzed four times per week. Of the population, 92.2% of the patients had an arteriovenous (AV) fistula. Plasma potassium levels were checked in all patients at the beginning of each dialysis treatment. All patients received telmisartan (20 mg/d) for a 2-week run-in phase to determine whether they were intolerant to small doses of the drug. Of the 351 enrolled patients, 19 patients (5.4%) did not complete the run-in phase. The final population of 332 ESRD patients was randomized to telmisartan (n = 165) or placebo (n = 167) administered in addition to their ACEI therapy (enalapril or ramipril)/CHF therapy (60.3% and 61.6% of telmisartan and placebo participants, respectively, were taking carvedilol) and titrated to a final target dose of 80 mg/d. The target dose of 80 mg/d was reached in 76% of the telmisartan group. The primary outcomes were all-cause mortality, cardiovascular death, and hospital admission for management of worsening CHF. Pre-specific secondary outcomes included acute non-fatal myocardial infarction, combined end point (cardiovascular mortality in addition to acute non-fatal myocardial infarction), cardiovascular hospital admission, non-fatal stroke, coronary revascularization, and permanent premature treatment withdrawals. At the time of randomization, approximately two-thirds of the patients (66.5%) were NYHA functional class II, and one-third (33.5%) were NYHA functional class III. There were no significant differences between the two groups in baseline characteristics. During the 3-year follow up, telmisartan significantly reduced all cause of mortality (n = 58, 35% vs. n = 91, 54.4%; p < 0.001), cardiovascular death (n = 50, 30.3% vs. n = 73, 43.7%, p < 0.001), and CHF hospital admissions (n = 56, 33.9% vs. n = 92, 55.1%). These changes translate into a mean absolute risk difference for all-cause mortality of 19.6% or an NNT with the addition of telmisartin of five patients for 3 years to save one life, an NNT of eight patients for 3 years to prevent one cardiovascular death, and an NNT of five patients for 3 years to prevent one additional CHF hospitalization. Furthermore, patients treated with telmisartan demonstrated a significantly greater probability of improvements in NYHA functional class (37.4% vs. 32.6%), of clinically significant reductions in both baseline systolic and diastolic blood pressure, and in LV diameter and improvements in left ventricular ejection fraction (LVEF). The number of non-fatal MIs, unknown cause of death, and non-cardiovascular deaths did not significantly differ between the two groups. The survival benefit appeared to be attributable largely to the decrease in deaths classified as due to a cardiovascular cause. Furthermore, the rate of adverse events was higher in the telmisartin group, but this increased rate was attributable to an increased rate of hypotension. There was no increased rate of hyperkalemia observed in the telmisartin group compared with control and no increase in adverse events or drug intolerance in participants who were concurrently on beta-blockers. The authors concluded that the addition of telmisartan (titrated up to 80 mg, as tolerated) to standard heart failure medications in hemodialysis patients with CHF and an LVEF ≤ 40% was safe and significantly decreased the risk of all-cause and cardiovascular death or hospitalization for de-compensated CHF. This study is one of the first to demonstrate that the addition of an ARB, specifically telmisartan, to regimens including various combinations of ACEIs, digitalis, and beta-blockers is beneficial and safe in ESRD hemodialysis patients with CHF. Randomization was performed centrally. The authors do not indicate whether a blocked randomization technique was used to minimize the potential for a center effect, so this potential source of error cannot be entirely excluded; however, the final groups were well balanced in terms of baseline characteristics, and therefore it is less likely that a center effect is present. Group allocation was masked, and analysis was performed in an intention-to-treat manner. It is likely that blinding was not entirely possible during the conduct of the study. It is therefore important that the authors pre-defined the outcomes and more importantly, that the primary outcome of overall mortality is largely independent of observer bias in studies with minimal drop-out rates. The drop-out rate was low compared with that of other studies in ESRD patients and the size of the benefit sufficiently large that it is also unlikely that any potential differential drop-outs would have changed the direction of the benefit measured. The study was powered to 90% (a more conservative assumption than customary), for an effect size of 10% and a drop-out rate of 5%. Forty percent more patients than required were recruited so that despite a slightly higher than expected drop-out rate, the study was more than sufficiently powered for the primary outcomes. The limitations of the study include the potential effect of duration of prior ACEIs on outcomes. Furthermore, the study population may not be fully representative of the population on hemodialysis in the United States. Patients in this study were younger, more were dialyzed via an AV fistula, and all patients received hemodialysis four times weekly. Patients with more advanced cardiovascular disease and CHF, including those with NYHA functional class IV, were not included in the study, so application of the results to this population must be performed with some uncertainty. It is possible that the lower blood pressure values reached in the telmisartan group might play a role in the observed improvements in morbidity and mortality rather than a more intense inhibition of activated RAAS. This former possibility can only be excluded with results from a study with an active blood pressure-lowering control. Given recent findings that lowering blood pressure excessively might have an unfavorable impact on survival for some hemodialysis patients, it is more likely that the benefits observed in the current study were due to RAAS blockade and not simply to lowering of blood pressure. This study demonstrated that the addition of telmisartan to standard heart failure medications in hemodialysis patients with CHF and LVEF ≤ 40% decreases the risk of all-cause and cardiovascular death as well as hospital stay for CHF decompensation. The population in this study is a highly selected group of dialysis patients with heart failure in an advanced NYHA functional class that exhibits a very high mortality and morbidity rate despite standard CHF treatment. The results from this study offer clinicians an opportunity to achieve further improvements in the poor prognosis of ESRD with CHF. The results are also consistent with the results from the Val-HeFT and CHARM studies, which demonstrated that valsartan and candesartan were generally well tolerated and significantly reduced cardiovascular deaths and hospital admissions for heart failure without ESRD.13, 14 The current study extends these findings to patients with ESRD. The risk of hypotension might limit the use of dual RAAS blockade therapy in some hemodialysis patients. The current study does not address whether the beneficial effect of telmisartan could be achieved with doses lower than the 80 mg dose used in this study or in patients with less severe or more severe cardiac disease than in this study population. Additionally, since all of the study participants were dialyzed four times per week, it is possible that the benefits and safety (including the absence of hyperkalemia) of this therapeutic approach require more intense dialysis than that which is currently customary in the United States.

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