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Comparison of N-acetylcysteine and fenoldopam for preventing contrast-induced nephropathy (CAFCIN)
International Journal of Cardiology 109 (2006) 322 – 328 www.elsevier.com/locate/ijcard
Comparison of N-acetylcysteine and fenoldopam for preventing contrast-induced nephropathy (CAFCIN) Tien M.H. Ng *, Scott W. Shurmur, Mary Silver, Lindsay R. Nissen, Edward L. O’Leary, Richard S. Rigmaiden, Mike Cieciorka, Laura L. Porter, Beata A. Ineck, Mary E. Kline, Susan E. Puumala Departments of Pharmacy Practice, Internal Medicine, and Preventive and Societal Medicine, University of Nebraska Medical Center, 986045 Nebraska Medical Center, Omaha, Nebraska, 68198-6045, USA Received 13 April 2005; accepted 10 June 2005 Available online 22 July 2005
Abstract Background: N-acetylcysteine and fenoldopam are commonly prescribed for prevention of contrast mediated nephropathy, however, comparative superiority of either agent is unknown. Methods: In a prospective, randomized, parallel-group trial, adult cardiac catheterization patients at the university and veterans’ hospitals with pre-existing stable renal insufficiency were randomized to N-acetylcysteine 600 mg orally twice daily for 4 doses or fenoldopam 0.1 mcg/kg/min intravenously for a minimum of 8 h. All patients received intravenous hydration with normal saline (5% dextrose in normal saline for diabetics on insulin). Randomization was stratified for diabetes. The primary endpoint was mean change in Scr at 72 h. Secondary endpoint was the incidence of contrast-induced nephropathy (25% increase above baseline Scr or absolute increase of 0.5 mg/dL). Results: Study termination occurred after ninety-five patients (mean age 68 T 10 years, female 25%, diabetic 42%, mean baseline Scr 1.5 T 0.4 mg/dL) were randomized, with 84 completing follow-up (44 N-acetylcysteine, 40 fenoldopam). Overall, there were no significant differences in mean change in Scr at 72 h (N-acetylcysteine 0.20 T 0.72 vs. fenoldopam 0.08 T 0.48 mg/dL, p = 0.4) or incidence of contrast-induced nephropathy (N-acetylcysteine 5 vs fenoldopam 8, p = 0.4). No differences were detected in subgroup analyses for diabetes, baseline Scr >1.7 or 2.0 mg/dL, gender, age >70 years, or contrast volume > 150 mL. Results were similar after multivariate adjustment for diabetes, contrast volume, heart failure and gender. Conclusions: Our randomized comparison failed to demonstrate a significant difference in the abilities of N-acetylcysteine and fenoldopam to prevent the decline in renal function or the incidence of contrast-induced nephropathy during cardiac catheterization. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Angiography; Nephropathy; Clinical trials; N-acetylcysteine; Fenoldopam
1. Introduction Contrast induced nephropathy can be defined as an acute impairment of renal function occurring 24 to 48 h and up to five days after the administration of radiographic contrast dye [1 – 3]. The reported incidence of contrast-induced * Corresponding author. Department of Pharmacy, University of Southern California, School of Pharmacy, Los Angeles, CA 90033, USA. Tel.: +1 323 442 1840; fax: +1 323 442 1681. E-mail address: [email protected] (T.M.H. Ng). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.06.038
nephropathy varies between 4 and 70%, and its development has been linked to significant morbidity and mortality [1,3 – 7]. Contrast material exerts multiple effects on renal physiology that can contribute to impaired renal function, including vasoconstrictive decreases in renal perfusion and oxidative renal damage. Multiple potentially renoprotective therapies have been used with few demonstrating consistent benefit. Forced diuresis with furosemide and mannitol, as well as agents which improve renal perfusion through vasodilation, such as dopamine, calcium channel blockers, aminophylline, atrial
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natriuretic peptide and endothelin antagonists, have all failed to demonstrate an appreciable effect on preventing contrast-induced nephropathy when compared to simple saline hydration alone [4– 9]. N-acetylcysteine, which exerts both antioxidant and vasodilatory effects, was shown in various animal studies of ischemic renal failure to maintain glomerular filtration rate, and speed-up the recovery from renal failure [10 – 13]. Although, human epidemiologic and small clinical trials of N-acetylcysteine have yielded mixed results, it was the first therapy to demonstrate added efficacy for renoprotection in addition to hydration in a prospective, randomized study [14]. As a consequence of a lack of alternative therapies, N-acetylcysteine has been almost universally adopted for the prevention of contrast-induced nephropathy in ‘‘high-risk’’ individuals. Stimulation of dopaminergic receptors has long been known to exert potentially beneficial effects in the maintenance of renal function. Stimulation of renal mesenteric dopamine-1 receptors increases glomerular filtration rate, renal blood flow and sodium excretion [15]. Fenoldopam, a dopamine-1 selective agonist, has been shown to prevent radiocontrast material induced declines in glomerular filtration rate and renal blood flow in several animal and human studies [16 – 20]. Preliminary clinical evidence supports the renoprotective efficacy of fenoldopam administered at a rate of 0.1 mcg/kg/min for 6 h, initiated immediately prior to cardiac catheterization [21 – 25]. At the launch of this study, no trials had been published evaluating the comparative efficacy of these two agents for prevention of contrast-induced renal impairment. The randomized Comparison of N-acetylcysteine and Fenoldopam for the prevention of Contrast-Induced Nephropathy (CAFCIN) study was undertaken to directly compare the relative efficacy of oral N-acetylcysteine to intravenous fenoldopam for the prophylaxis of contrast-induced nephropathy in patients undergoing cardiac catheterization. In light of the results of CONTRAST [43] which demonstrated no renoprotective effect of fenoldopam, our study was terminated early. We report our results at the time of study termination.
2. Materials and methods 2.1. Patient population Adult inpatients and outpatients scheduled for cardiac catheterization at the University of Nebraska Medical Center and the Omaha Veterans’ Administration Hospital were eligible for inclusion. Male or female patients, 19 years or older, who met the pre-specified criteria for ‘‘higher-risk’’ for the development of contrast-induced nephropathy were eligible for inclusion after documentation of informed consent. Patients were considered ‘‘higher-risk’’ if they had pre-existing renal disease defined as baseline serum creatinine > 1.2 mg/dL. Diabetic patients were included
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under the same criteria. Patients were also required to have stable renal function at entry (no change in serum creatinine greater than T 0.1 mg/dL over two assessments prior to catheterization). Patients were excluded if they were already experiencing acute renal failure/insufficiency prior to catheterization, were deemed to required both N-acetylcysteine and fenoldopam for prophylaxis by the primary service, had a history of renal transplantation, were receiving N-acetylcysteine or fenoldopam for another indication, had a known contraindication or hypersensitivity to N-acetylcysteine or fenoldopam, or were pregnant. The study was approved by the University of Nebraska Medical Center institutional review board and the Omaha Veterans’ Administration regulatory committee. 2.2. Study design The study was a prospective, randomized, parallel-group trial comparing the efficacy of oral N-acetylcysteine and intravenous fenoldopam for prophylaxis of contrast-induced nephropathy in patients undergoing cardiac catheterization. Computer generated 6-block randomization lists were used to assign treatment regimens and included stratification for the presence or absence of diabetes. Patients were randomized to receive one of two prophylactic regimens: 1) Nacetylcysteine 600 mg given orally twice daily for a total of 4 doses, with the first dose given 1 day prior to the scheduled catheterization or 2) Fenoldopam 0.1 mcg/kg/min intravenously, initiated 1 – 2 h pre-catheterization and continued for 6 h post-catheterization. On the day prior to the catheterization, patients randomized to receive Nacetylcysteine began therapy, with a minimum of 3 doses prior to the catheterization and the fourth dose postprocedure. Times of administration were recorded. On the day of the catheterization, patients randomized to fenoldopam were initiated on an intravenous infusion. Fenoldopam was initiated at 0.1 mcg/kg/min. Systolic blood pressure was maintained above 120 mmHg. Times of initiation and termination of fenoldopam infusion were recorded. Patients scheduled for cardiac catheterization were screened for history or presence of renal insufficiency, and other inclusion and exclusion criteria. Patients on metformin had the medication held at least one day prior to the catheterization. Once written informed consent was obtained, the patients were randomized to one of the two treatment arms. All randomized patients had serum chemistries and vitals assessed at baseline and daily from 1 day prior to the catheterization to 72 h after the catheterization procedure. Patients discharged from the hospital prior to the 72 h blood draw were asked to return for a final serum creatinine determination on the third day post-catheterization. All patients received concomitant infusions of normal saline (or 5% dextrose in normal saline in diabetics on insulin) at a rate of 1 mL/kg/h beginning 1 –2 h prior to catheterization and continuing for 6 – 12 h. The exact duration of the intravenous hydration was left to the
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discretion of each patient_s attending physician. All other catheterization procedures remained unchanged from the standard institutional practice. Only non-ionic, low or isoosmolar contrast dyes were used during the catheterizations. Time of contrast material infusion during the catheterization, contrast type, and volume of contrast material infused were recorded. 2.3. Statistical analysis To demonstrate a difference of 0.2 mg/dL (standard deviation 0.4 mg/dL) in the primary endpoint of mean change of serum creatinine from baseline between Nacetylcysteine and fenoldopam at 72 h, with 80% power and a = 0.05, 128 patients (64 in each group) were required. Anticipating 10% of patients to be protocol violations or subjects lost to follow-up, 140 subjects were to be randomized. The primary endpoint was the mean change in serum creatinine from day 0 prior to catheterization to 72 h postcatheterization. For subjects missing the 72-h measure, a last observation carried forward algorithm was used to impute the missing data. Results were analyzed on an intent-to-treat basis. The distributions of changes in serum creatinine were compared between the treatment groups using an independent two-sample t-test (a non-parametric Wilcoxon rank-sum test was used for the subgroup analyses described below). The secondary endpoint was the incidence of contrastinduced nephropathy defined as any increase (day 1, 2, or 3) in serum creatinine above 25% of the day 0 measure or an increase of 0.50 mg/L above the day 0 measure. The probability of contrast-induced nephropathy was compared between the treatment groups using Fisher’s exact test. The primary and secondary endpoints were compared between the treatment groups within subgroups defined by diabetes status (diabetic/non-diabetic), day 0 serum creatinine (> 1.7 mg/dL, > 2.0 mg/dL), gender (male/female), age (> 70 years), and volume of contrast (> 150 mL, > 200 mL). The primary and secondary endpoint distributions were compared between the treatment groups using linear (change in serum creatinine) and logistic (indication of contrast-induced nephropathy) regression while adjusting for the possible confounding effects of day 0 serum creatinine, age, gender, weight, chronic heart failure, diabetes, and volume of contrast. Relationship of fenoldopam dose and duration to mean change in serum creatinine were determined and reported as a Spearman Rank Correlation Coefficient.
3. Results 3.1. Patient population At the time of study termination (see Discussion), a total of 95 patients scheduled for cardiac catheterization were
randomized, with 84 (44 N-acetylcysteine, 40 fenoldopam) completing the cardiac catheterization and study laboratory follow-up. Two patients did not have cardiac catheterizations performed, one patient received both N-acetylcysteine and fenoldopam, and 8 patients did not have any follow-up blood chemistries. Baseline patient demographics are summarized in Table 1. Overall, 25% of patients were female, 42% were diabetics, and 28% had diagnosed systolic heart failure. More patients randomized to fenoldopam were female, had experienced a previous myocardial infarction, and had documented coronary artery disease. Fenoldopam patients were more commonly on amiodarone, but less frequently on diuretics. The two treatment groups were otherwise matched for age, concomitant cardiovascular diseases and chronic cardiac medications. Baseline renal function was not statistically different between groups, although the absolute mean baseline serum creatinine value was slightly higher in the fenoldopam treated patients (N-acetylcysteine 1.46 T 0.38 vs fenoldopam 1.53 T 0.37 mg/dL, p = 0.4). There was also no difference in the average contrast volume administered (N-acetylcysteine 172.15 T 18.95 vs fenoldopam 164.42 T 85.01 mL, p = 0.6) during the catheterizations.
Table 1 Baseline patient characteristics
N Age (years) Weight (kg) Female (%) Diabetes (%) CHF (%) HTN (%) CAD (%) Previous MI (%) AF (%) Medications (%) ACEI/ARB Amiodarone Antiplatelet Beta-blocker CCB Digoxin Diuretic Lipid lowering Nitrate Spironolactone Day 0 Scr (mg/dL) Contrast volume (mL) Contrast type (%) Omnipaque Visipaque Both Hexabrix
N-acetylcysteine
Fenoldopam
All patients
48 67 T 10 89.3 T 19.0 18.8 43.8 25.0 77.1 75.0 29.2 16.7
47 69 T 11 91.1 T 24.7 29.8 40.4 31.9 83.0 85.1 42.6 16.3
95 68 T 10 90.2 T 21.9 24.8 42.1 28.4 80.0 80.0 35.8 16.5
77.1 2.1 81.2 85.4 31.2 10.4 58.3 66.7 43.8 2.1 1.46 T 0.38 172.2 T 73.2
74.5 12.8 78.7 83.0 29.8 8.5 44.7 57.5 40.4 8.5 1.53 T 0.37 164.4 T 85.0
75.8 7.4 80.0 84.2 30.5 9.5 51.6 62.1 42.1 5.6 1.50 T 0.37 167.8 T 78.6
27.4 4.2 17.9 2.1
27.4 8.4 10.5 2.1
54.8 12.6 28.4 4.2
Mean T standard deviation. ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; AF = atrial fibrillation; CAD = coronary artery disease; CCB = calcium channel blocker; CHF = chronic heart failure; HTN = hypertension; MI = myocardial infarction; Scr = serum creatinine.
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Table 3 Subgroup analyses of mean change in serum creatinine over 72 h
3.2. Univariate comparison of N-acetylcysteine and fenoldopam
N-acetylcysteine
The vast majority of the 84 patients included in the analyses had their follow-up serum creatinine 48 or 72 h (19% and 75%, respectively) after completion of their cardiac catheterization. The remaining 6% had their last follow-up serum creatinine 24 h post-catheterization. There was no significant difference in the primary endpoint of mean change in serum creatinine over the 72 h (Nacetylcysteine 0.20 T 0.72 vs. fenoldopam 0.08 T 0.48 mg/ dL, p = 0.4) or the secondary endpoint of incidence of contrast-induced nephropathy (N-acetylcysteine 11.4 vs. fenoldopam 20.0%, p = 0.4) between the two treatment groups. Results are summarized in Table 2.
Diabetics Non-diabetics Baseline Scr <1.7 Baseline Scr 1.7 Baseline Scr <2.0 Baseline Scr 2.0 Male Female Age <70 years Age 70 years Contrast <150 mL Contrast 150 mL Contrast <200 mL Contrast 200 mL
0.44 T 1.12 0.04 T 0.17 0.19 T 0.80 0.23 T 0.32 0.20 T 0.75 0.20 T 0.10 0.22 T 0.78 0.03 T 0.10 0.33 T 0.98 0.05 T 0.13 0.12 T 0.38 0.26 T 0.92 0.12 T 0.35 0.33 T 1.12
Fenoldopam 0.23 T 0.65 0.01 T 0.34 0.05 T 0.23 0.13 T 0.82 0.02 T 0.25 0.27 T 0.91 0.12 T 0.50 0.03 T 0.41 0.02 T 0.20 0.11 T 0.61 0.01 T 0.32 0.19 T 0.62 0.01 T 0.29 0.31 T 0.84
p-value 0.5 0.3 0.8 0.1 0.2 0.5 0.4 0.6 0.4 0.3 0.4 0.5 0.3 0.8
Mean T standard deviation (mg/dL).
3.3. Subgroup analyses 3.5. Adverse effects No significant differences were found in any subgroup analysis for mean change in serum creatinine over 72 h (Table 3). Comparison of the mean change in serum creatinine in diabetics (N-acetylcysteine 0.44 T 1.12 vs. fenoldopam 0.23 T 0.65 mg/dL, p = 0.5) or non-diabetics (N-acetylcysteine 0.04 T 0.17 vs. fenoldopam 0.01 T 0.34, p = 0.3) demonstrated no differences between treatments, although the overall average increase in serum creatinine tended to be higher in diabetic patients (diabetics 0.36 T 0.91 vs non-diabetics 0.05 T 0.32 mg/dL, p = 0.07). The effects of the two therapies were also comparable in subgroups based on baseline serum creatinines above 1.7 and 2 mg/dL, gender, age greater than 70 years, and contrast volume equal or greater than 150 and 200 mL. There were also no differences in the incidence of contrast-induced nephropathy based on the same subgroup analyses. There was no significant correlation between duration of fenoldopam infusion (r = 0.159, p = 0.3258) and mean change in serum creatinine. 3.4. Multivariate analyses Adjustment for the possible confounding effects of diabetes status, contrast volume, heart failure, and gender produced similar results. No difference was detected for mean change in serum creatinine ( p = 0.7) and no association was found between the odds of contrast-induced nephropathy and treatment assignment ( p = 0.3). Table 2 Comparative effects on serum creatinine and incidence of contrast-induced nephropathy
N Mean change in Scr over 72 h CIN, n (%)
N-acetylcysteine
Fenoldopam
p-value
44 0.20 T 0.72 5 (11.4)
40 0.08 T 0.48 8 (20.0)
0.4 0.4
Mean T standard deviation (mg/dL). CIN = contrast-induced nephropathy.
No significant adverse effects were reported in either treatment group. Therapy did not have to be discontinued in any patient during the course of the study.
4. Discussion In this prospective, randomized, head-to-head comparison of oral N-acetylcysteine and intravenous fenoldopam, there were no significant differences between the two regimens in their abilities to prevent changes in renal function after contrast media exposure, and in the number of patients who went on to develop contrast-induced nephropathy or oliguria. This apparent similarity in efficacy was also consistent regardless of diabetic status, gender, baseline renal function, age or contrast load. Our findings are consistent with the one other study that directly compared these two therapies using similar doses to our study. In the prospective, randomized, three-arm study by Allaqaband et al., fenoldopam 0.1 mcg/kg/min for 4 h pre- and post-catheterization (plus hydration), N-acetylcysteine 600 mg every 12 h for four doses (plus hydration), and 0.45% saline at 1 mL/kg/h, were evaluated in 123 patients undergoing cardiac catheterization using low-osmolar nonionic contrast media [26]. Baseline serum creatinine was approximately 2 mg/dL across the study population. There were no significant differences between all three treatment regimens in the incidence of radiocontrast-induced nephropathy or absolute change in serum creatinine at 48 h. Although the severity of underlying renal insufficiency at baseline was greater than in our study, subgroup analysis of our patients with serum creatinines greater than 2 mg/dL also revealed no differences. Lack of differences based on diabetic status were also in agreement with our findings. Despite N-acetylcysteine and fenoldopam having distinct mechanisms of action, no difference in efficacy could be detected. Several reasons could be postulated for the null
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findings. First, it is possible that no difference exists between these two therapies as a result of failure of either agent to be renoprotective. Apart from intravenous hydration and the use of low-osmolar, non-ionic contrast media, no pharmacologic therapy has consistently demonstrated an ability to reduce the incidence of nephropathy after exposure to radiocontrast dye. This includes the two therapies compared in this study. Although generally positive, results with N-acetylcysteine have been mixed. Several observational and prospective, randomized studies have shown N-acetylcysteine attenuates increases in serum creatinine after radiologic procedures or reduces the incidence of contrast-induced nephropathy [14,27 –31]. These studies used doses of 600 mg twice daily for a total of 4 doses. Intravenous hydration with either 0.9% or 0.45% saline was standard [14]. In agreement with our data, the effect was independent of degree of renal insufficiency or volume of contrast administration. In contrast, no renoprotective effect has been shown in several other observational and prospective studies [26,32 –35]. In these negative studies, there was also no apparent trend for a benefit. The N-acetylcysteine and hydration regimens were similar between positive and negative studies. Comparison of the studies is difficult since patient populations, baseline renal function and length of follow-up varied. The most significant limitation of all the studies was the sample size, thus confidence intervals were wide regardless of whether the study demonstrated a beneficial or neutral effect. Several meta-analyses and systematic reviews have been conducted with similarly discordant findings [36 – 40]. More recently, it has been proposed that higher doses may be required for a renoprotective effect. Double-dose N-acetylcysteine (1200 mg twice daily) has been found to be more effective than standard dose N-acetylcysteine (600 mg twice daily) [41] or intravenous fenoldopam [42] in two randomized studies. Initially, data with fenoldopam also appeared promising. In healthy volunteers and in hypertensive patients with chronic renal insufficiency, fenoldopam has been shown to increase renal blood flow, glomerular filtration rate, creatinine clearance, urine output and fractional sodium excretion [17 – 20]. Several early clinical experiences with similar fenoldopam regimens as used in our study also supported a renoprotective effect [21 –23]. A recent cohort study of 46 consecutive patients with pre-existing renal disease (serum creatinine greater than 1.7 mg/dL for nondiabetics and 1.5 for diabetics), the fenoldopam group experienced smaller increases in serum creatinine (16% vs. 118% control) and lower rates of radiocontrast nephropathy, also defined by an increase of at least 25% in baseline serum creatinine at 48 h (13% vs. 38% control) [24]. However, recent publication of two randomized, placebo-controlled trials have cast serious doubt over fenoldopam’s renoprotective efficacy against contrast-induced nephropathy. The first is the previously described study by Allaqaband et al. which found no difference in the incidence
of contrast-induced nephropathy between patients prophylaxed with 0.45% saline or those receiving 0.45% saline and fenoldopam [26]. More recently, the results of a multicenter, randomized study evaluating fenoldopam 0.05– 0.1 mcg/kg/min compared to placebo in 315 patients undergoing invasive cardiac procedure were published [43]. All patients received standard intravenous hydration with 0.45% saline at a rate of 1– 1.5 mL/kg/h. Fenoldopam was initiated 1 h prior to the procedure and continued for 12 h after. Mean baseline serum creatinine was approximately 1.8 mg/dL in both groups. Fenoldopam was not associated with any reduction in the incidence of contrast-induced nephropathy (defined as an increase of 25% above baseline) compared to the placebo at 48 or 96 h. Results were similar in subgroups based on diabetic status, baseline serum creatinine above 2 mg/dL, N-acetylcysteine use prior to the procedure, contrast volume greater than 150 mL or volume of pre-contrast hydration. There was also no difference in the index hospitalization length of stay. In summary, lack of efficacy remains a potential explanation for failure to demonstrate a difference in efficacy. A second consideration for the lack of a difference concerns the probable mechanisms mediating contrastinduced renal damage. Contrast material exerts multiple effects on renal physiology that can contribute to impaired renal function. They can be broadly classified as: interference of renal perfusion, direct nephrotoxicity, altered glomerular permeability, intraluminal renal obstruction and immunologic mechanisms [2]. Renal blood flow is diminished acutely after exposure to contrast media secondary to vasoconstriction involving both the renin-angiotensin and vasopressin systems. Diminished renal perfusion not only reduces glomerular filtration, but also contributes to renal medullary hypoxia [2]. This hypoxic state has been implicated in the generation of free radicals that could further impair renal vasodilation through inactivation of nitric oxide and may also cause direct renal damage. Nacetylcysteine is purported to act as a free radical scavenger, with some effect on renal blood flow [10,11]. Fenoldopam is a selective dopaminergic-1 receptor agonist that significantly increases renal blood flow. How likely would a therapy with one or two specific mechanisms of action modulate a pathophysiologic response with multiple contributing mechanisms? The efficacy of augmenting renal blood flow is questionable since a myriad of renal vasodilating therapies have all universally failed to prevent the development of contrast-induced nephropathy [4 –9]. Complex disease mechanisms may not respond to targeted therapies. For instance, inflammation is linked to the pathophysiology of both sepsis and chronic heart failure, however, anti-tumor necrosis factor therapies have failed to alter the clinical course of either disease [44]. Third, the failure to demonstrate a difference may also have been a consequence of the decision to terminate our study prior to completing enrollment of our targeted 140 subjects. The decision to terminate the study was based on
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ethical considerations and slowing enrollment owing to accumulating evidence that fenoldopam, and possibly Nacetylcysteine at standard doses, may not be renoprotective. As a result, the power to detect a difference in mean change in serum creatinine was lower than anticipated. Although no statistical difference in serum creatinine change was detected, the absolute mean change favored fenoldopam. However, this favorable trend did not translate into fewer episodes of contrast-induced nephropathy. It is unknown whether a smaller, statistically significant difference in serum creatinine would have translated into a reduction in contrast-induced nephropathy. Independent of our results, the clinical relevance of an arbitrarily set definition for contrast-induced nephropathy has continued to be questioned since it is unknown whether changes in serum creatinine predict the development of oliguria or anuria [45].
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the combination may be more effective than monotherapy with either agent. In conclusion, our randomized comparison failed to demonstrate a difference in the abilities of oral N-acetylcysteine and intravenous fenoldopam to prevent declines in renal function or the incidence of contrast-induced nephropathy after contrast dye administration during cardiac catheterization in mildly renal insufficient patients.
Acknowledgements The investigators would like to thank Shaina Walker (Pearson) for help in data entry, and Steve Nissen and the cardiology fellows at the University of Nebraska Medical Center, especially Wilson Ginete and Scott Chapman, for their efforts in recruiting patients for the study.
4.1. Limitations Due to early termination of the study, as described above, the power of this study to demonstrate a statistically significant difference in the mean change in serum creatinine and more importantly, a difference in the incidence of contrast-induced nephropathy was reduced. It cannot be ruled out that continued enrollment may have revealed a difference in efficacy. It is also important to note that the failure to demonstrate a significant difference in this study does not equate to equivalency of the two therapies, as our study was not designed to test equivalence. The level of renal insufficiency, as reflected in the mean baseline serum creatinine in the two groups, was also lower than anticipated. The study was designed to be comparable with the Tepel study that lead to widespread acceptance of N-acetylcysteine for prophylaxis [14]. Although the exact reasons for our low baseline serum creatinine are not clear, it should be noted that our institution favors combination prophylactic therapy with both N-acetylcysteine and fenoldopam for patients with baseline serum creatinines above 2.0 mg/dL. As a consequence, the overall incidence of contrast-induced nephropathy was 16%. The low number of events may have precluded a proper assessment of whether one agent was more renoprotective than the other independent of mean serum creatinine changes. This explanation may not be as likely since several recent studies, including our own, have not found baseline renal function to be a determinant of contrast-induced nephropathy. There are also several therapeutic questions that our study was not designed to answer. This study included no placebo arm. It was felt during the design stages, that there was sufficient evidence that N-acetylcysteine was effective in providing renal protection and it would be unethical to deny therapy to one-third of the study subjects. As detailed above, there is some question as to whether these two agents truly reduce the incidence of contrast-induced nephropathy. This study does not provide any answers to that question. There also remains the question of whether
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[16] Barkis G, Lass N, Glock D. Renal hemodynamics in radiocontrast medium-induced renal dysfunction: a role for dopamine-1 receptors. Kidney Int 1999;56:206 – 10. [17] Harvey J, Worth D, Brown J, Lee M. The effect of oral fenoldopam (SKF 82526-J), a peripheral dopamine receptor agonist, on blood pressure and renal function in normal man. Br J Clin Pharmacol 1985; 19:21 – 7. [18] Murphy M, McCoy C, Weber R, Frederickson E, Douglas F, Goldberg L. Augmentation of renal blood flow and sodium excretion in hypertensive patients during blood pressure reduction by intravenous administration of the dopamine 1 agonist fenoldopam. Circulation 1987;76:1312 – 8. [19] Andres A, Garcia-Robles R, Alcazar J, et al. Diuretic and natriuretic properties of fenoldopam in chronic renal failure. J Hypertens Suppl 1989;7:S326 – 7. [20] White W, Halley S. Comparative renal effects of intravenous administration of fenoldopam mesylate and sodium nitroprusside in patients with severe hypertension. Arch Int Med 1989;149:870 – 4. [21] Kini A, Mitre M, Kamran M, Duffy M, Reich D, Sharma S. Preliminary experience with fenoldopam, a new renal vasodilator, in reducing radio contrast nephropathy during percutaneous coronary intervention. Am J Cardiol 2000;86:1i. [22] Morales P, Hayes J, Bailey S. Contrast-induced nephropathy: fenoldopam, a new agent to decrease acute renal insufficiency. Am J Cardiol 2000;86:1i. [23] Hunter D. Fenoldopam: a dopamine type 1 receptor agonist in the prevention of renal injury associated with the administration of intravascular contrast. J Vasc Interv Radiol 2000;11:396 – 9. [24] Madyoon H, Croushore L, Weaver D, Mathur V. Use of fenoldopam to prevent radiocontrast nephropathy in high-risk patients. Catheter Cardiovasc Interv 2001;53:341 – 5. [25] Tumin J, Marbur V. Prophylactic efficacy of fenoldopam in radiocontrast nephropathy (RCN): a randomized, double-blind, placebocontrolled trial. J Vasc Interv Radiol 2000;11:175 – 6. [26] Allaqaband S, Tumuluri R, Malik A, et al. Prospective, randomized study of N-acetylcysteine, fenoldopam, and saline for prevention of radiocontrast-induced nephropathy. Cathet Cardiovasc Interv 2002;57: 279 – 83. [27] Kay J, Chow W, Chan T, et al. Acetylcysteine for prevention of acute deterioration of renal function following elective coronary angiography and intervention. JAMA 2003;289:553 – 8. [28] Diaz-Sandoval L, Kosowsky B, Losordo D. Acetylcysteine to prevent angiography-related renal tissue damage (The APART Trial). Am J Cardiol 2002;89:356 – 8. [29] Shyu K, Cheng J, Kuan P. Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol 2002;40:1383 – 8. [30] Mouhayar E, Tadros G, Akinwande A, Campbell B, Blankenship J, Illiadis E. Prevention of contrast-induced renal dysfunction with acetylcysteine in patients undergoing coronary angiography. J Am Coll Cardiol 2002;39:5A suppl.
[31] Adamian M, Moussa I, Mehran R. The role of mucomyst administration prior to percutaneous interventions on renal function in patients with chronic renal failure. J Am Coll Cardiol 2002;39:5A suppl. [32] Durham J, Caputo C, Dokko J. A randomized controlled trial of Nacetylcysteine to prevent contrast nephropathy in cardiac angiography. Kidney Int 2002;62:2202 – 7. [33] Briguori C, Manganelli F, Scarpato P. Acetylcysteine and contrast agent-associated nephrotoxicity. J Am Coll Cardiol 2002;40:298 – 303. [34] Boccalandro F, Ahmad M, Sdringola S, Baptista E, Smalling R. Oral acetylcysteine does not prevent contrast induced nephropathy in patients with chronic renal insufficiency undergoing cardiac catheterization. Circulation 2002;106:II-691 suppl. [35] Kahlon J, Moser L, Rosman H, Nordstrom C, Zafar A, Khairullah Q. Effectiveness of N-acetylcysteine for the prevention of radiocontrastinduced nephropathy: is the jury still out? Circulation 2002;106:II-691 suppl. [36] Birck R, Krzossok S, Markowetz F, Schnulle P, van der Woude F, Braun C. Acetylcysteine for prevention of contrast nephropathy: metaanalysis. Lancet 2003;362:598 – 603. [37] Isenbarger D, Kent S, O’Malley P. Meta-analysis of randomized clinical trials on the usefulness of acetylcysteine for prevention of contrast nephropathy. Am J Cardiol 2003;92:1454 – 8. [38] Kshirsagar A, Poole C, Mottl A, et al. N-acetylcysteine for the prevention of radiocontrast induced nephropathy: a meta-analysis of prospective controlled trials. J Am Soc Nephrol 2004;15:761 – 9. [39] Goldenberg I, Schechter M, Matetzky S, et al. Oral acetylcysteine as an adjunct to saline hydration for the prevention of contrast-induced nephropathy following coronary angiography. A randomized controlled trial and review of the current literature. Eur Heart J 2004; 25:212 – 8. [40] Alonso A, Lau J, Jaber B, Weintraub A, Sarnak M. Prevention of radiocontrast nephropathy with N-acetylcysteine in patients with chronic kidney disease: a meta-analysis of randomized, controlled trials. Am J Kidney Dis 2004;43:1 – 9. [41] Briguori C, Colombo A, Violante A, et al. Standard vs. double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity. Eur Heart J 2004;25:206 – 11. [42] Briguori C, Colombo A, Airoldi F, et al. N-acetylcysteine versus fenoldopam mesylate to prevent contrast agent-associated nephrotoxicity. J Am Coll Cardiol 2004;44:762 – 5. [43] Stone G, McCullough P, Tumulin J, et al. Fenoldopam mesylate for the prevention of contrast-induced nephropathy—a randomized controlled trial. JAMA 2003;290:2284 – 91. [44] Mann D, McMurray J, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure—results of the randomized etanercept worldwide evaluation (RENEWAL). Circulation 2004;109: r76 – 84. [45] Kellum J. A drug to prevent renal failure? Lancet 2003;362:589 – 90.
Comparison of N-acetylcysteine and fenoldopam for preventing contrast-induced nephropathy (CAFCIN) Tien M.H. Ng *, Scott W. Shurmur, Mary Silver, Lindsay R. Nissen, Edward L. O’Leary, Richard S. Rigmaiden, Mike Cieciorka, Laura L. Porter, Beata A. Ineck, Mary E. Kline, Susan E. Puumala Departments of Pharmacy Practice, Internal Medicine, and Preventive and Societal Medicine, University of Nebraska Medical Center, 986045 Nebraska Medical Center, Omaha, Nebraska, 68198-6045, USA Received 13 April 2005; accepted 10 June 2005 Available online 22 July 2005
Abstract Background: N-acetylcysteine and fenoldopam are commonly prescribed for prevention of contrast mediated nephropathy, however, comparative superiority of either agent is unknown. Methods: In a prospective, randomized, parallel-group trial, adult cardiac catheterization patients at the university and veterans’ hospitals with pre-existing stable renal insufficiency were randomized to N-acetylcysteine 600 mg orally twice daily for 4 doses or fenoldopam 0.1 mcg/kg/min intravenously for a minimum of 8 h. All patients received intravenous hydration with normal saline (5% dextrose in normal saline for diabetics on insulin). Randomization was stratified for diabetes. The primary endpoint was mean change in Scr at 72 h. Secondary endpoint was the incidence of contrast-induced nephropathy (25% increase above baseline Scr or absolute increase of 0.5 mg/dL). Results: Study termination occurred after ninety-five patients (mean age 68 T 10 years, female 25%, diabetic 42%, mean baseline Scr 1.5 T 0.4 mg/dL) were randomized, with 84 completing follow-up (44 N-acetylcysteine, 40 fenoldopam). Overall, there were no significant differences in mean change in Scr at 72 h (N-acetylcysteine 0.20 T 0.72 vs. fenoldopam 0.08 T 0.48 mg/dL, p = 0.4) or incidence of contrast-induced nephropathy (N-acetylcysteine 5 vs fenoldopam 8, p = 0.4). No differences were detected in subgroup analyses for diabetes, baseline Scr >1.7 or 2.0 mg/dL, gender, age >70 years, or contrast volume > 150 mL. Results were similar after multivariate adjustment for diabetes, contrast volume, heart failure and gender. Conclusions: Our randomized comparison failed to demonstrate a significant difference in the abilities of N-acetylcysteine and fenoldopam to prevent the decline in renal function or the incidence of contrast-induced nephropathy during cardiac catheterization. D 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Angiography; Nephropathy; Clinical trials; N-acetylcysteine; Fenoldopam
1. Introduction Contrast induced nephropathy can be defined as an acute impairment of renal function occurring 24 to 48 h and up to five days after the administration of radiographic contrast dye [1 – 3]. The reported incidence of contrast-induced * Corresponding author. Department of Pharmacy, University of Southern California, School of Pharmacy, Los Angeles, CA 90033, USA. Tel.: +1 323 442 1840; fax: +1 323 442 1681. E-mail address: [email protected] (T.M.H. Ng). 0167-5273/$ - see front matter D 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2005.06.038
nephropathy varies between 4 and 70%, and its development has been linked to significant morbidity and mortality [1,3 – 7]. Contrast material exerts multiple effects on renal physiology that can contribute to impaired renal function, including vasoconstrictive decreases in renal perfusion and oxidative renal damage. Multiple potentially renoprotective therapies have been used with few demonstrating consistent benefit. Forced diuresis with furosemide and mannitol, as well as agents which improve renal perfusion through vasodilation, such as dopamine, calcium channel blockers, aminophylline, atrial
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natriuretic peptide and endothelin antagonists, have all failed to demonstrate an appreciable effect on preventing contrast-induced nephropathy when compared to simple saline hydration alone [4– 9]. N-acetylcysteine, which exerts both antioxidant and vasodilatory effects, was shown in various animal studies of ischemic renal failure to maintain glomerular filtration rate, and speed-up the recovery from renal failure [10 – 13]. Although, human epidemiologic and small clinical trials of N-acetylcysteine have yielded mixed results, it was the first therapy to demonstrate added efficacy for renoprotection in addition to hydration in a prospective, randomized study [14]. As a consequence of a lack of alternative therapies, N-acetylcysteine has been almost universally adopted for the prevention of contrast-induced nephropathy in ‘‘high-risk’’ individuals. Stimulation of dopaminergic receptors has long been known to exert potentially beneficial effects in the maintenance of renal function. Stimulation of renal mesenteric dopamine-1 receptors increases glomerular filtration rate, renal blood flow and sodium excretion [15]. Fenoldopam, a dopamine-1 selective agonist, has been shown to prevent radiocontrast material induced declines in glomerular filtration rate and renal blood flow in several animal and human studies [16 – 20]. Preliminary clinical evidence supports the renoprotective efficacy of fenoldopam administered at a rate of 0.1 mcg/kg/min for 6 h, initiated immediately prior to cardiac catheterization [21 – 25]. At the launch of this study, no trials had been published evaluating the comparative efficacy of these two agents for prevention of contrast-induced renal impairment. The randomized Comparison of N-acetylcysteine and Fenoldopam for the prevention of Contrast-Induced Nephropathy (CAFCIN) study was undertaken to directly compare the relative efficacy of oral N-acetylcysteine to intravenous fenoldopam for the prophylaxis of contrast-induced nephropathy in patients undergoing cardiac catheterization. In light of the results of CONTRAST [43] which demonstrated no renoprotective effect of fenoldopam, our study was terminated early. We report our results at the time of study termination.
2. Materials and methods 2.1. Patient population Adult inpatients and outpatients scheduled for cardiac catheterization at the University of Nebraska Medical Center and the Omaha Veterans’ Administration Hospital were eligible for inclusion. Male or female patients, 19 years or older, who met the pre-specified criteria for ‘‘higher-risk’’ for the development of contrast-induced nephropathy were eligible for inclusion after documentation of informed consent. Patients were considered ‘‘higher-risk’’ if they had pre-existing renal disease defined as baseline serum creatinine > 1.2 mg/dL. Diabetic patients were included
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under the same criteria. Patients were also required to have stable renal function at entry (no change in serum creatinine greater than T 0.1 mg/dL over two assessments prior to catheterization). Patients were excluded if they were already experiencing acute renal failure/insufficiency prior to catheterization, were deemed to required both N-acetylcysteine and fenoldopam for prophylaxis by the primary service, had a history of renal transplantation, were receiving N-acetylcysteine or fenoldopam for another indication, had a known contraindication or hypersensitivity to N-acetylcysteine or fenoldopam, or were pregnant. The study was approved by the University of Nebraska Medical Center institutional review board and the Omaha Veterans’ Administration regulatory committee. 2.2. Study design The study was a prospective, randomized, parallel-group trial comparing the efficacy of oral N-acetylcysteine and intravenous fenoldopam for prophylaxis of contrast-induced nephropathy in patients undergoing cardiac catheterization. Computer generated 6-block randomization lists were used to assign treatment regimens and included stratification for the presence or absence of diabetes. Patients were randomized to receive one of two prophylactic regimens: 1) Nacetylcysteine 600 mg given orally twice daily for a total of 4 doses, with the first dose given 1 day prior to the scheduled catheterization or 2) Fenoldopam 0.1 mcg/kg/min intravenously, initiated 1 – 2 h pre-catheterization and continued for 6 h post-catheterization. On the day prior to the catheterization, patients randomized to receive Nacetylcysteine began therapy, with a minimum of 3 doses prior to the catheterization and the fourth dose postprocedure. Times of administration were recorded. On the day of the catheterization, patients randomized to fenoldopam were initiated on an intravenous infusion. Fenoldopam was initiated at 0.1 mcg/kg/min. Systolic blood pressure was maintained above 120 mmHg. Times of initiation and termination of fenoldopam infusion were recorded. Patients scheduled for cardiac catheterization were screened for history or presence of renal insufficiency, and other inclusion and exclusion criteria. Patients on metformin had the medication held at least one day prior to the catheterization. Once written informed consent was obtained, the patients were randomized to one of the two treatment arms. All randomized patients had serum chemistries and vitals assessed at baseline and daily from 1 day prior to the catheterization to 72 h after the catheterization procedure. Patients discharged from the hospital prior to the 72 h blood draw were asked to return for a final serum creatinine determination on the third day post-catheterization. All patients received concomitant infusions of normal saline (or 5% dextrose in normal saline in diabetics on insulin) at a rate of 1 mL/kg/h beginning 1 –2 h prior to catheterization and continuing for 6 – 12 h. The exact duration of the intravenous hydration was left to the
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discretion of each patient_s attending physician. All other catheterization procedures remained unchanged from the standard institutional practice. Only non-ionic, low or isoosmolar contrast dyes were used during the catheterizations. Time of contrast material infusion during the catheterization, contrast type, and volume of contrast material infused were recorded. 2.3. Statistical analysis To demonstrate a difference of 0.2 mg/dL (standard deviation 0.4 mg/dL) in the primary endpoint of mean change of serum creatinine from baseline between Nacetylcysteine and fenoldopam at 72 h, with 80% power and a = 0.05, 128 patients (64 in each group) were required. Anticipating 10% of patients to be protocol violations or subjects lost to follow-up, 140 subjects were to be randomized. The primary endpoint was the mean change in serum creatinine from day 0 prior to catheterization to 72 h postcatheterization. For subjects missing the 72-h measure, a last observation carried forward algorithm was used to impute the missing data. Results were analyzed on an intent-to-treat basis. The distributions of changes in serum creatinine were compared between the treatment groups using an independent two-sample t-test (a non-parametric Wilcoxon rank-sum test was used for the subgroup analyses described below). The secondary endpoint was the incidence of contrastinduced nephropathy defined as any increase (day 1, 2, or 3) in serum creatinine above 25% of the day 0 measure or an increase of 0.50 mg/L above the day 0 measure. The probability of contrast-induced nephropathy was compared between the treatment groups using Fisher’s exact test. The primary and secondary endpoints were compared between the treatment groups within subgroups defined by diabetes status (diabetic/non-diabetic), day 0 serum creatinine (> 1.7 mg/dL, > 2.0 mg/dL), gender (male/female), age (> 70 years), and volume of contrast (> 150 mL, > 200 mL). The primary and secondary endpoint distributions were compared between the treatment groups using linear (change in serum creatinine) and logistic (indication of contrast-induced nephropathy) regression while adjusting for the possible confounding effects of day 0 serum creatinine, age, gender, weight, chronic heart failure, diabetes, and volume of contrast. Relationship of fenoldopam dose and duration to mean change in serum creatinine were determined and reported as a Spearman Rank Correlation Coefficient.
3. Results 3.1. Patient population At the time of study termination (see Discussion), a total of 95 patients scheduled for cardiac catheterization were
randomized, with 84 (44 N-acetylcysteine, 40 fenoldopam) completing the cardiac catheterization and study laboratory follow-up. Two patients did not have cardiac catheterizations performed, one patient received both N-acetylcysteine and fenoldopam, and 8 patients did not have any follow-up blood chemistries. Baseline patient demographics are summarized in Table 1. Overall, 25% of patients were female, 42% were diabetics, and 28% had diagnosed systolic heart failure. More patients randomized to fenoldopam were female, had experienced a previous myocardial infarction, and had documented coronary artery disease. Fenoldopam patients were more commonly on amiodarone, but less frequently on diuretics. The two treatment groups were otherwise matched for age, concomitant cardiovascular diseases and chronic cardiac medications. Baseline renal function was not statistically different between groups, although the absolute mean baseline serum creatinine value was slightly higher in the fenoldopam treated patients (N-acetylcysteine 1.46 T 0.38 vs fenoldopam 1.53 T 0.37 mg/dL, p = 0.4). There was also no difference in the average contrast volume administered (N-acetylcysteine 172.15 T 18.95 vs fenoldopam 164.42 T 85.01 mL, p = 0.6) during the catheterizations.
Table 1 Baseline patient characteristics
N Age (years) Weight (kg) Female (%) Diabetes (%) CHF (%) HTN (%) CAD (%) Previous MI (%) AF (%) Medications (%) ACEI/ARB Amiodarone Antiplatelet Beta-blocker CCB Digoxin Diuretic Lipid lowering Nitrate Spironolactone Day 0 Scr (mg/dL) Contrast volume (mL) Contrast type (%) Omnipaque Visipaque Both Hexabrix
N-acetylcysteine
Fenoldopam
All patients
48 67 T 10 89.3 T 19.0 18.8 43.8 25.0 77.1 75.0 29.2 16.7
47 69 T 11 91.1 T 24.7 29.8 40.4 31.9 83.0 85.1 42.6 16.3
95 68 T 10 90.2 T 21.9 24.8 42.1 28.4 80.0 80.0 35.8 16.5
77.1 2.1 81.2 85.4 31.2 10.4 58.3 66.7 43.8 2.1 1.46 T 0.38 172.2 T 73.2
74.5 12.8 78.7 83.0 29.8 8.5 44.7 57.5 40.4 8.5 1.53 T 0.37 164.4 T 85.0
75.8 7.4 80.0 84.2 30.5 9.5 51.6 62.1 42.1 5.6 1.50 T 0.37 167.8 T 78.6
27.4 4.2 17.9 2.1
27.4 8.4 10.5 2.1
54.8 12.6 28.4 4.2
Mean T standard deviation. ACEI = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; AF = atrial fibrillation; CAD = coronary artery disease; CCB = calcium channel blocker; CHF = chronic heart failure; HTN = hypertension; MI = myocardial infarction; Scr = serum creatinine.
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Table 3 Subgroup analyses of mean change in serum creatinine over 72 h
3.2. Univariate comparison of N-acetylcysteine and fenoldopam
N-acetylcysteine
The vast majority of the 84 patients included in the analyses had their follow-up serum creatinine 48 or 72 h (19% and 75%, respectively) after completion of their cardiac catheterization. The remaining 6% had their last follow-up serum creatinine 24 h post-catheterization. There was no significant difference in the primary endpoint of mean change in serum creatinine over the 72 h (Nacetylcysteine 0.20 T 0.72 vs. fenoldopam 0.08 T 0.48 mg/ dL, p = 0.4) or the secondary endpoint of incidence of contrast-induced nephropathy (N-acetylcysteine 11.4 vs. fenoldopam 20.0%, p = 0.4) between the two treatment groups. Results are summarized in Table 2.
Diabetics Non-diabetics Baseline Scr <1.7 Baseline Scr 1.7 Baseline Scr <2.0 Baseline Scr 2.0 Male Female Age <70 years Age 70 years Contrast <150 mL Contrast 150 mL Contrast <200 mL Contrast 200 mL
0.44 T 1.12 0.04 T 0.17 0.19 T 0.80 0.23 T 0.32 0.20 T 0.75 0.20 T 0.10 0.22 T 0.78 0.03 T 0.10 0.33 T 0.98 0.05 T 0.13 0.12 T 0.38 0.26 T 0.92 0.12 T 0.35 0.33 T 1.12
Fenoldopam 0.23 T 0.65 0.01 T 0.34 0.05 T 0.23 0.13 T 0.82 0.02 T 0.25 0.27 T 0.91 0.12 T 0.50 0.03 T 0.41 0.02 T 0.20 0.11 T 0.61 0.01 T 0.32 0.19 T 0.62 0.01 T 0.29 0.31 T 0.84
p-value 0.5 0.3 0.8 0.1 0.2 0.5 0.4 0.6 0.4 0.3 0.4 0.5 0.3 0.8
Mean T standard deviation (mg/dL).
3.3. Subgroup analyses 3.5. Adverse effects No significant differences were found in any subgroup analysis for mean change in serum creatinine over 72 h (Table 3). Comparison of the mean change in serum creatinine in diabetics (N-acetylcysteine 0.44 T 1.12 vs. fenoldopam 0.23 T 0.65 mg/dL, p = 0.5) or non-diabetics (N-acetylcysteine 0.04 T 0.17 vs. fenoldopam 0.01 T 0.34, p = 0.3) demonstrated no differences between treatments, although the overall average increase in serum creatinine tended to be higher in diabetic patients (diabetics 0.36 T 0.91 vs non-diabetics 0.05 T 0.32 mg/dL, p = 0.07). The effects of the two therapies were also comparable in subgroups based on baseline serum creatinines above 1.7 and 2 mg/dL, gender, age greater than 70 years, and contrast volume equal or greater than 150 and 200 mL. There were also no differences in the incidence of contrast-induced nephropathy based on the same subgroup analyses. There was no significant correlation between duration of fenoldopam infusion (r = 0.159, p = 0.3258) and mean change in serum creatinine. 3.4. Multivariate analyses Adjustment for the possible confounding effects of diabetes status, contrast volume, heart failure, and gender produced similar results. No difference was detected for mean change in serum creatinine ( p = 0.7) and no association was found between the odds of contrast-induced nephropathy and treatment assignment ( p = 0.3). Table 2 Comparative effects on serum creatinine and incidence of contrast-induced nephropathy
N Mean change in Scr over 72 h CIN, n (%)
N-acetylcysteine
Fenoldopam
p-value
44 0.20 T 0.72 5 (11.4)
40 0.08 T 0.48 8 (20.0)
0.4 0.4
Mean T standard deviation (mg/dL). CIN = contrast-induced nephropathy.
No significant adverse effects were reported in either treatment group. Therapy did not have to be discontinued in any patient during the course of the study.
4. Discussion In this prospective, randomized, head-to-head comparison of oral N-acetylcysteine and intravenous fenoldopam, there were no significant differences between the two regimens in their abilities to prevent changes in renal function after contrast media exposure, and in the number of patients who went on to develop contrast-induced nephropathy or oliguria. This apparent similarity in efficacy was also consistent regardless of diabetic status, gender, baseline renal function, age or contrast load. Our findings are consistent with the one other study that directly compared these two therapies using similar doses to our study. In the prospective, randomized, three-arm study by Allaqaband et al., fenoldopam 0.1 mcg/kg/min for 4 h pre- and post-catheterization (plus hydration), N-acetylcysteine 600 mg every 12 h for four doses (plus hydration), and 0.45% saline at 1 mL/kg/h, were evaluated in 123 patients undergoing cardiac catheterization using low-osmolar nonionic contrast media [26]. Baseline serum creatinine was approximately 2 mg/dL across the study population. There were no significant differences between all three treatment regimens in the incidence of radiocontrast-induced nephropathy or absolute change in serum creatinine at 48 h. Although the severity of underlying renal insufficiency at baseline was greater than in our study, subgroup analysis of our patients with serum creatinines greater than 2 mg/dL also revealed no differences. Lack of differences based on diabetic status were also in agreement with our findings. Despite N-acetylcysteine and fenoldopam having distinct mechanisms of action, no difference in efficacy could be detected. Several reasons could be postulated for the null
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findings. First, it is possible that no difference exists between these two therapies as a result of failure of either agent to be renoprotective. Apart from intravenous hydration and the use of low-osmolar, non-ionic contrast media, no pharmacologic therapy has consistently demonstrated an ability to reduce the incidence of nephropathy after exposure to radiocontrast dye. This includes the two therapies compared in this study. Although generally positive, results with N-acetylcysteine have been mixed. Several observational and prospective, randomized studies have shown N-acetylcysteine attenuates increases in serum creatinine after radiologic procedures or reduces the incidence of contrast-induced nephropathy [14,27 –31]. These studies used doses of 600 mg twice daily for a total of 4 doses. Intravenous hydration with either 0.9% or 0.45% saline was standard [14]. In agreement with our data, the effect was independent of degree of renal insufficiency or volume of contrast administration. In contrast, no renoprotective effect has been shown in several other observational and prospective studies [26,32 –35]. In these negative studies, there was also no apparent trend for a benefit. The N-acetylcysteine and hydration regimens were similar between positive and negative studies. Comparison of the studies is difficult since patient populations, baseline renal function and length of follow-up varied. The most significant limitation of all the studies was the sample size, thus confidence intervals were wide regardless of whether the study demonstrated a beneficial or neutral effect. Several meta-analyses and systematic reviews have been conducted with similarly discordant findings [36 – 40]. More recently, it has been proposed that higher doses may be required for a renoprotective effect. Double-dose N-acetylcysteine (1200 mg twice daily) has been found to be more effective than standard dose N-acetylcysteine (600 mg twice daily) [41] or intravenous fenoldopam [42] in two randomized studies. Initially, data with fenoldopam also appeared promising. In healthy volunteers and in hypertensive patients with chronic renal insufficiency, fenoldopam has been shown to increase renal blood flow, glomerular filtration rate, creatinine clearance, urine output and fractional sodium excretion [17 – 20]. Several early clinical experiences with similar fenoldopam regimens as used in our study also supported a renoprotective effect [21 –23]. A recent cohort study of 46 consecutive patients with pre-existing renal disease (serum creatinine greater than 1.7 mg/dL for nondiabetics and 1.5 for diabetics), the fenoldopam group experienced smaller increases in serum creatinine (16% vs. 118% control) and lower rates of radiocontrast nephropathy, also defined by an increase of at least 25% in baseline serum creatinine at 48 h (13% vs. 38% control) [24]. However, recent publication of two randomized, placebo-controlled trials have cast serious doubt over fenoldopam’s renoprotective efficacy against contrast-induced nephropathy. The first is the previously described study by Allaqaband et al. which found no difference in the incidence
of contrast-induced nephropathy between patients prophylaxed with 0.45% saline or those receiving 0.45% saline and fenoldopam [26]. More recently, the results of a multicenter, randomized study evaluating fenoldopam 0.05– 0.1 mcg/kg/min compared to placebo in 315 patients undergoing invasive cardiac procedure were published [43]. All patients received standard intravenous hydration with 0.45% saline at a rate of 1– 1.5 mL/kg/h. Fenoldopam was initiated 1 h prior to the procedure and continued for 12 h after. Mean baseline serum creatinine was approximately 1.8 mg/dL in both groups. Fenoldopam was not associated with any reduction in the incidence of contrast-induced nephropathy (defined as an increase of 25% above baseline) compared to the placebo at 48 or 96 h. Results were similar in subgroups based on diabetic status, baseline serum creatinine above 2 mg/dL, N-acetylcysteine use prior to the procedure, contrast volume greater than 150 mL or volume of pre-contrast hydration. There was also no difference in the index hospitalization length of stay. In summary, lack of efficacy remains a potential explanation for failure to demonstrate a difference in efficacy. A second consideration for the lack of a difference concerns the probable mechanisms mediating contrastinduced renal damage. Contrast material exerts multiple effects on renal physiology that can contribute to impaired renal function. They can be broadly classified as: interference of renal perfusion, direct nephrotoxicity, altered glomerular permeability, intraluminal renal obstruction and immunologic mechanisms [2]. Renal blood flow is diminished acutely after exposure to contrast media secondary to vasoconstriction involving both the renin-angiotensin and vasopressin systems. Diminished renal perfusion not only reduces glomerular filtration, but also contributes to renal medullary hypoxia [2]. This hypoxic state has been implicated in the generation of free radicals that could further impair renal vasodilation through inactivation of nitric oxide and may also cause direct renal damage. Nacetylcysteine is purported to act as a free radical scavenger, with some effect on renal blood flow [10,11]. Fenoldopam is a selective dopaminergic-1 receptor agonist that significantly increases renal blood flow. How likely would a therapy with one or two specific mechanisms of action modulate a pathophysiologic response with multiple contributing mechanisms? The efficacy of augmenting renal blood flow is questionable since a myriad of renal vasodilating therapies have all universally failed to prevent the development of contrast-induced nephropathy [4 –9]. Complex disease mechanisms may not respond to targeted therapies. For instance, inflammation is linked to the pathophysiology of both sepsis and chronic heart failure, however, anti-tumor necrosis factor therapies have failed to alter the clinical course of either disease [44]. Third, the failure to demonstrate a difference may also have been a consequence of the decision to terminate our study prior to completing enrollment of our targeted 140 subjects. The decision to terminate the study was based on
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ethical considerations and slowing enrollment owing to accumulating evidence that fenoldopam, and possibly Nacetylcysteine at standard doses, may not be renoprotective. As a result, the power to detect a difference in mean change in serum creatinine was lower than anticipated. Although no statistical difference in serum creatinine change was detected, the absolute mean change favored fenoldopam. However, this favorable trend did not translate into fewer episodes of contrast-induced nephropathy. It is unknown whether a smaller, statistically significant difference in serum creatinine would have translated into a reduction in contrast-induced nephropathy. Independent of our results, the clinical relevance of an arbitrarily set definition for contrast-induced nephropathy has continued to be questioned since it is unknown whether changes in serum creatinine predict the development of oliguria or anuria [45].
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the combination may be more effective than monotherapy with either agent. In conclusion, our randomized comparison failed to demonstrate a difference in the abilities of oral N-acetylcysteine and intravenous fenoldopam to prevent declines in renal function or the incidence of contrast-induced nephropathy after contrast dye administration during cardiac catheterization in mildly renal insufficient patients.
Acknowledgements The investigators would like to thank Shaina Walker (Pearson) for help in data entry, and Steve Nissen and the cardiology fellows at the University of Nebraska Medical Center, especially Wilson Ginete and Scott Chapman, for their efforts in recruiting patients for the study.
4.1. Limitations Due to early termination of the study, as described above, the power of this study to demonstrate a statistically significant difference in the mean change in serum creatinine and more importantly, a difference in the incidence of contrast-induced nephropathy was reduced. It cannot be ruled out that continued enrollment may have revealed a difference in efficacy. It is also important to note that the failure to demonstrate a significant difference in this study does not equate to equivalency of the two therapies, as our study was not designed to test equivalence. The level of renal insufficiency, as reflected in the mean baseline serum creatinine in the two groups, was also lower than anticipated. The study was designed to be comparable with the Tepel study that lead to widespread acceptance of N-acetylcysteine for prophylaxis [14]. Although the exact reasons for our low baseline serum creatinine are not clear, it should be noted that our institution favors combination prophylactic therapy with both N-acetylcysteine and fenoldopam for patients with baseline serum creatinines above 2.0 mg/dL. As a consequence, the overall incidence of contrast-induced nephropathy was 16%. The low number of events may have precluded a proper assessment of whether one agent was more renoprotective than the other independent of mean serum creatinine changes. This explanation may not be as likely since several recent studies, including our own, have not found baseline renal function to be a determinant of contrast-induced nephropathy. There are also several therapeutic questions that our study was not designed to answer. This study included no placebo arm. It was felt during the design stages, that there was sufficient evidence that N-acetylcysteine was effective in providing renal protection and it would be unethical to deny therapy to one-third of the study subjects. As detailed above, there is some question as to whether these two agents truly reduce the incidence of contrast-induced nephropathy. This study does not provide any answers to that question. There also remains the question of whether
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