Bradley S. Dixon

Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial.

CONTEXT The arteriovenous fistula is the preferred type of vascular access for hemodialysis because of lower thrombosis and infection rates and lower health care expenditures compared with synthetic grafts or central venous catheters. Early failure of fistulas due to thrombosis or inadequate maturation is a barrier to increasing the prevalence of fistulas among patients treated with hemodialysis. Small, inconclusive trials have suggested that antiplatelet agents may reduce thrombosis of new fistulas. OBJECTIVE To determine whether clopidogrel reduces early failure of hemodialysis fistulas. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled trial conducted at 9 US centers composed of academic and community nephrology practices in 2003-2007. Eight hundred seventy-seven participants with end-stage renal disease or advanced chronic kidney disease were followed up until 150 to 180 days after fistula creation or 30 days after initiation of dialysis, whichever occurred later. INTERVENTION Participants were randomly assigned to receive clopidogrel (300-mg loading dose followed by daily dose of 75 mg; n = 441) or placebo (n = 436) for 6 weeks starting within 1 day after fistula creation. MAIN OUTCOME MEASURES The primary outcome was fistula thrombosis, determined by physical examination at 6 weeks. The secondary outcome was failure of the fistula to become suitable for dialysis. Suitability was defined as use of the fistula at a dialysis machine blood pump rate of 300 mL/min or more during 8 of 12 dialysis sessions. RESULTS Enrollment was stopped after 877 participants were randomized based on a stopping rule for intervention efficacy. Fistula thrombosis occurred in 53 (12.2%) participants assigned to clopidogrel compared with 84 (19.5%) participants assigned to placebo (relative risk, 0.63; 95% confidence interval, 0.46-0.97; P = .018). Failure to attain suitability for dialysis did not differ between the clopidogrel and placebo groups (61.8% vs 59.5%, respectively; relative risk, 1.05; 95% confidence interval, 0.94-1.17; P = .40). CONCLUSION Clopidogrel reduces the frequency of early thrombosis of new arteriovenous fistulas but does not increase the proportion of fistulas that become suitable for dialysis. Trial Registration clinicaltrials.gov Identifier: NCT00067119.

Effect of Dipyridamole plus Aspirin on Hemodialysis Graft Patency

BACKGROUND Arteriovenous graft stenosis leading to thrombosis is a major cause of complications in patients undergoing hemodialysis. Procedural interventions may restore patency but are costly. Although there is no proven pharmacologic therapy, dipyridamole may be promising because of its known vascular antiproliferative activity. METHODS We conducted a randomized, double-blind, placebo-controlled trial of extended-release dipyridamole, at a dose of 200 mg, and aspirin, at a dose of 25 mg, given twice daily after the placement of a new arteriovenous graft until the primary outcome, loss of primary unassisted patency (i.e., patency without thrombosis or requirement for intervention), was reached. Secondary outcomes were cumulative graft failure and death. Primary and secondary outcomes were analyzed with the use of a Cox proportional-hazards regression with adjustment for prespecified covariates. RESULTS At 13 centers in the United States, 649 patients were randomly assigned to receive dipyridamole plus aspirin (321 patients) or placebo (328 patients) over a period of 4.5 years, with 6 additional months of follow-up. The incidence of primary unassisted patency at 1 year was 23% (95% confidence interval [CI], 18 to 28) in the placebo group and 28% (95% CI, 23 to 34) in the dipyridamole-aspirin group, an absolute difference of 5 percentage points. Treatment with dipyridamole plus aspirin significantly prolonged the duration of primary unassisted patency (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P=0.03) and inhibited stenosis. The incidences of cumulative graft failure, death, the composite of graft failure or death, and serious adverse events (including bleeding) did not differ significantly between study groups. CONCLUSIONS Treatment with dipyridamole plus aspirin had a significant but modest effect in reducing the risk of stenosis and improving the duration of primary unassisted patency of newly created grafts. (ClinicalTrials.gov number, NCT00067119.)

Design of the Dialysis Access Consortium (DAC) clopidogrel prevention of early AV fistula thrombosis trial

Background The Dialysis Access Consortium (DAC) was developed to investigate interventions to improve hemodialysis vascular access outcomes. The autogenous arteriovenous fistula created by direct connection of native artery to vein is the recommended vascular access for hemodialysis. However, it fails frequently due to clotting after surgery. Purpose The DAC Early AV Fistula Thrombosis Trial tests the hypothesis that clopidogrel can prevent early fistula failure and increase the number of fistulas that ultimately become usable for hemodialysis access. This is one of two initial and concurrent trials being performed by the DAC. The companion trial investigates pharmacologic approaches to prevent venous stenosis leading to AV graft failure. Methods This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1284 patients over four years. Patients undergoing creation of a new native arteriovenous (AV) fistula are randomized to treatment with clopidogrel or placebo for six weeks following fistula creation surgery. The primary outcome is fistula patency at six weeks. The major secondary outcome is fistula suitability for dialysis. Results This paper examines key aspects of this study that have broad relevance to trial design including: 1) the selection of an intermediate event as the primary outcome, 2) timing of the intervention to balance efficacy and safety concerns, 3) ethical considerations arising from required modifications of concomitant drug therapy, and 4) choosing an efficacy or effectiveness evaluation of the intervention. Conclusions This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent early AV fistula failure and promote more usable fistulas for hemodialysis. The methodologic challenges identified and addressed during the development of this trial should help to inform the design of future vascular access trials, and are relevant to clinical trials addressing a wide range of questions.

A multi-center, dose-escalation study of human type I pancreatic elastase (PRT-201) administered after arteriovenous fistula creation

Purpose To explore the safety and efficacy of PRT-201. Methods Randomized, double-blind, placebo-controlled, single-dose escalation study of PRT-201 (0.0033 to 9 mg) applied after arteriovenous fistula (AVF) creation. Participants were followed for one year. The primary outcome measure was safety. Efficacy measures were the proportion with intra-operative increases in AVF outflow vein diameter or blood flow ≥25% (primary), changes in outflow vein diameter and blood flow, AVF maturation and lumen stenosis by ultrasound criteria and AVF patency. Results The adverse events in the PRT-201 group (n=45) were similar to those in the placebo group (n=21). There were no differences in the proportion with ≥25% increase in vein diameter or blood flow, successful maturation or lumen stenosis. There was no statistically significant difference in primary patency between the dose groups (placebo n=21, Low Dose n=16, Medium Dose n=17 and High Dose n=12). In a subgroup analysis that excluded three participants with early surgical failures, the hazard ratio (HR) for primary patency loss of Low Dose compared with placebo was 0.38 (95% CI 0.10-1.41, P=0.15). In a Cox model, Low Dose (HR 0.27, 95% CI 0.04-0.79, P=0.09), white race (HR 0.17, 95% CI 0.03-0.79, P=0.02), and age <65 years (HR 0.25, CI 0.05-1.15, P=0.08) were associated (P<0.10) with a decreased risk of primary patency loss. Conclusions PRT-201 was not different from placebo for safety or efficacy measures. There was a suggestion for improved AVF primary patency with Low Dose PRT-201 that is now being studied in a larger clinical trial.

Human type I pancreatic elastase treatment of arteriovenous fistulas in patients with chronic kidney disease

OBJECTIVE This study explored the safety and efficacy of recombinant type I pancreatic elastase (PRT-201) topically applied once to the external surface of an arteriovenous fistula. METHODS This was a randomized, double-blind, placebo-controlled trial. Adults with kidney disease undergoing creation of a radiocephalic fistula (RCF) or brachiocephalic fistula were randomized to treatment with placebo (n = 51), PRT-201 at 10 μg (n = 51), or PRT-201 at 30 μg (n = 49). The primary efficacy measure was unassisted primary patency (PP) over 1 year. Secondary efficacy measures were secondary patency (SP), unassisted maturation by ultrasound interrogation, use for hemodialysis, and hemodynamically significant lumen stenosis. RESULTS Median PP was 224 days for placebo and >365 days for the PRT-201 groups. At 1 year, 45%, 54%, and 53% of placebo, 10-μg, and 30-μg patients retained PP. The risk of PP loss was nonsignificantly reduced for 10 μg (hazard ratio [HR], 0.69; P = .19) and 30 μg (HR, 0.67; P = .17) vs placebo. In the subset (44% of patients) with a RCF, the median PP was 125 days for placebo and >365 days for the PRT-201 groups. At 1 year, 31%, 50%, and 63% of placebo, 10-μg, and 30-μg RCFs retained PP. The risk of RCF PP loss was nonsignificantly reduced by 10 μg (HR, 0.59; P = .18) and significantly reduced by 30 μg (HR, 0.37; P = .02) vs placebo. At 1 year, 77%, 81%, and 83% of placebo, 10-μg, and 30-μg patients retained SP. The risk of SP loss was nonsignificantly reduced for 10 μg (HR, 0.79; P = .61) and 30 μg (HR, 0.76; P = .55) vs placebo. In the subset with RCFs, 65%, 82%, and 90% of placebo, 10-μg, and 30-μg patients retained SP at 1 year. The risk of RCF SP loss was nonsignificantly reduced for 10 μg (HR, 0.45; P = .19) and 30 μg (HR, 0.27; P = .08) vs placebo. At month 3, 67%, 87% (P = .03), and 92% (P < .01) of the placebo, 10-μg, and 30-μg group fistulas had unassisted maturation by ultrasound interrogation. At month 3 in the subset with an RCF, 47%, 74% (P = .17), and 93% (P < .01) of placebo, 10-μg, and 30-μg group fistulas had unassisted maturation by ultrasound interrogation. Adverse event reports were not meaningfully different between groups. CONCLUSIONS PRT-201 appeared safe. The primary efficacy end point was not met. However, both PRT-201 doses were associated with improved unassisted maturation. The 30-μg dose was associated with increased PP in the subset with RCF.

Renal Substance P–Containing Neurons and Substance P Receptors Impaired in Hypertension

In normotensive rats, increased renal pelvic pressure stimulates the release of prostaglandin E and substance P, which in turn leads to an increase in afferent renal nerve activity (ARNA) and a contralateral natriuresis, a contralateral inhibitory renorenal reflex. In spontaneously hypertensive rats (SHR), increasing renal pelvic pressure failed to increase afferent renal nerve activity. The inhibitory nature of renorenal reflexes indicates that impaired renorenal reflexes could contribute to increased sodium retention in SHR. Phorbol esters, known to activate protein kinase C, increase afferent renal nerve activity in Wistar-Kyoto rats (WKY) but not in SHR. We examined the mechanisms involved in the impaired responses to renal sensory receptor activation in SHR. The phorbol ester 4beta-phorbol 12,13-dibutyrate increased renal pelvic protein kinase C activity similarly in SHR and WKY. Increasing renal pelvic pressure increased afferent renal nerve activity in WKY (27+/-2%) but not in SHR. Renal pelvic release of prostaglandin E increased similarly in WKY and SHR, from 0.8+/-0.1 to 2.0+/-0.4 ng/min and 0.7+/-0.1 to 1.4+/-0.2 ng/min. Renal pelvic release of substance P was greater (P<.01) in WKY, from 16.3+/-3.8 to 41.8+/-7.4 pg/min, than in SHR, from 9.9+/-1.7 to 17.0+/-3.2 pg/min. In WKY, renal pelvic administration of substance P at 0.8, 4, and 20 microg/mL increased ARNA 382+/-69, 750+/-233, and 783+/-124% second (area under the curve of afferent renal nerve activity versus time). In SHR, substance P at 0.8 to 20 microg/mL failed to increase ARNA. These findings demonstrate that the impaired afferent renal nerve activity response to increased renal pelvic pressure is related to decreased release of substance P and/or impaired activation of substance P receptors.

Design of the Dialysis Access Consortium (DAC) Aggrenox prevention of access stenosis trial

Background Surgically created arteriovenous (AV) grafts are the most common type of hemodialysis vascular access in the United States, but fail frequently due to the development of venous stenosis. The Dialysis Access Consortium (DAC) Aggrenox Prevention of Access Stenosis Trial tests the hypothesis that Aggrenox (containing dipyridamole and aspirin) can prevent stenosis and prolong survival of arteriovenous grafts. Methods This is a multicenter, randomized, double-blind, placebo-controlled trial that will enroll 1056 subjects over four years with one-half year follow-up. Subjects undergoing placement of a new AV graft for hemodialysis are randomized to treatment with Aggrenox or placebo immediately following access surgery. The primary outcome is primary unassisted patency defined as the time from access placement until thrombosis or an access procedure carried out to maintain or restore patency. The major secondary outcome is cumulative access patency. Monthly access flow monitoring is incorporated in the study design to enhance detection of a hemodynamically significant access stenosis before it leads to thrombosis. Results This paper describes the key issues in trial design, broadly including: 1) ethical issues surrounding the study of a clinical procedure that, although common, is no longer the clinical intervention of choice; 2) acceptable risk (bleeding) from the primary intervention; 3) inclusion of subjects already receiving a portion of the study intervention; 4) inclusion of subjects with incident rather than prevalent qualifying clinical conditions; 5) timing of the study intervention to balance safety and efficacy concerns; and 6) the selection of primary and secondary study endpoints. Conclusions This is the first, large, multicenter trial evaluating a pharmacologic approach to prevent AV graft stenosis and failure, an important and costly problem in this patient population. Numerous design issues were addressed in implementing the trial and these will form a roadmap for future trials in this area.

Use of Aspirin Associates with Longer Primary Patency of Hemodialysis Grafts

Extended-release dipyridamole plus low-dose aspirin (ERDP/ASA) prolongs primary unassisted graft patency of newly created hemodialysis arteriovenous grafts, but the individual contributions of each component are unknown. Here, we analyzed whether use of aspirin at baseline associated with primary unassisted graft patency among participants in a randomized trial that compared ERDP/ASA and placebo in newly created grafts. We used Cox proportional hazards regression, adjusting for prespecified baseline comorbidities and covariates. Of all participants, 43% reported use of aspirin at baseline; of these, 82% remained on nonstudy aspirin (i.e., excluding ERDP/ASA) at 1 year. After 1 year of follow-up, the incidence of primary unassisted patency among participants using aspirin at baseline was 30% (95% CI: 24 to 35%) and among those not using aspirin was 23% (95% CI: 18 to 27%). Use of aspirin at baseline associated with a dose-dependent prolongation of primary unassisted graft patency that approached statistical significance (adjusted HR, 0.83; 95% CI: 0.68 to 1.01; P=0.06). Use of aspirin at baseline did not associate with prolongation of cumulative graft patency or participant survival. In conclusion, use of aspirin associates with a trend toward longer primary unassisted patency of newly placed hemodialysis grafts similar to that observed for ERDP/ASA.

The Bradykinin B2 Receptor Is a Delayed Early Response Gene for Platelet-derived Growth Factor in Arterial Smooth Muscle Cells

Bradykinin and platelet-derived growth factor (PDGF) are inflammatory mediators important in the response to vascular injury. Based upon the known effect of oncogenic Ras to increase bradykinin receptor expression and the ability of PDGF to stimulate Ras, we examined whether PDGF regulates bradykinin B2 receptor expression in cultured arterial smooth muscle cells. Treatment with PDGF (AB and BB, but not AA) produced a dose- and time-dependent increase in both mRNA (6-7-fold increase at 2-4 h) and cell surface receptors (2-4-fold at 6-12 h) for the B2 receptor. There was a 60-min delay between exposure to PDGF and the initial increase in B2 receptor mRNA. Transcriptional inhibitors, actinomycin D or 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole, completely blocked the increase in B2 receptor mRNA when added up to 60 min after stimulation with PDGF. However, protein synthesis was not required, as treatment with cycloheximide did not block but rather superinduced the PDGF-induced increase in B2 receptor mRNA. Comparison with the immediate early response gene c-fos demonstrated that the increase in B2 receptor mRNA was similarly inhibited by the tyrosine kinase inhibitor, tyrphostin, as well as staurosporine. However, stimulation of c-fos was slightly more sensitive to genistein, while the B2 receptor mRNA was more sensitive to inhibition by the protein kinase C inhibitor, calphostin C. The increase in cell surface B2 receptors were functionally coupled to an increase in phosphoinositide-specific phospholipase C, and the effects of PDGF were selective as there was no increase in either angiotensin II- or arginine vasopressin-induced inositol phosphate formation or intracellular calcium release. Taken together, these results demonstrate that the B2 receptor is a delayed early response gene for PDGF in vascular smooth muscle cells.

Interaction between growth factors and kinins in arterial smooth muscle cells.

Bradykinin receptors are present on vascular smooth muscle cells; however, the regulation and biological function of these receptors is unclear. To address these questions the interaction between growth factors and kinins in cultured arterial smooth muscle cells has been examined. Based upon the data a hypothesis is presented that platelet-derived growth factor (PDGF) upregulates cell surface bradykinin B2 receptors on arterial smooth muscle cells. The biological effect of the increase in B2 receptors is currently unclear but under certain conditions they may enhance mitogenesis. These mitogenic effects however, are strongly opposed by the effects of bradykinin acting via a B1-type of receptor which mediates potent inhibition of growth factor-induced mitogenesis.