RACE611 CLINICAL EPIDEMIOLOGY AND EVIDENCE-BASED … · Critical appraisal for therapeutic study Appraising an article about therapy Scenario (Appendix 4) You went home to visit your

RACE611 CLINICAL EPIDEMIOLOGY AND EVIDENCE-BASED MEDICINE

Theraputic study

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REFERENCES

1. Fletcher RH, Fletcher SW, Wagner EH. Clinical Epidemiology. The Essentials. 4th Ed. Baltimore: Lippincott Williams & Wilkins, 2005:125-46. 2. Haynes RB, Sackett DL, Guyatt GH, Tugwell P. Clinical epidemiology. How to do clinical

practice research, 3rd Ed. Philadephia: Lippincott Williams & Wilkins, 2006:59-243. 3. Heneghan C, Badenoch D. Evidence-based medicine toolkit. 2nd Ed. Massachusetts:

Blackwell Publishing, 2006:50-8. 4. Levine M, Haslan D, Walter S, et al. Harm. Guyatt G, Rennie D. Users’ guides to the medical

literature. Essentials of evidence-based clinical practice. Chicago: AMA Press, 2002:81-120.

Critical appraisal for therapeutic study Appraising an article about therapy

Scenario (Appendix 4)

You went home to visit your 60-year old mother. She had no history of coronary heart

disease, cerebrovascular disease, or other chronic illness. She just returned from visiting her

younger brother who had no history of any chronic illness but his doctor prescribed aspirin to him.

She asks you whether she should received aspirin to prevent “heart attacks”

Unsure if there was any protective effects, you promise yourself that you will check the

medical literature before your next visit.

After going through MEDLINE, you find an article entitled, A Randomized Trial of Low-Dose

Aspirin in Primary Prevention of Cardiovascular Disease in Woman, which seemed like the best

article that would help answer your question.

A. Read the article and critically appraise its validity using Appraisal form for an Article on

Therapy. Discuss the rationale for each criterion.

B. After appraising study validity, decide if you want to go on and read the rest of the article.

C. What would you advise your mother on your next visit?

A. What is your clinical question? P: I: C: O:

B. What are your search term? C. Read the article and critically appraise its validity using the Appraisal Guides for an Article

on therapy (Appendix 1). D. Appraise the results of the study, discussing the rationale for each in worksheet for therapy

study (Appendix 2). E. Create critical appraisal topic (CAT) from this study (Appendix 3).

READING: 1. Haynes RB, Sackett DL, Guyatt GH, Tugwell P. Clinical epidemiology. How to do clinical practice research, 3rd Ed. Philadephia: Lippincott Williams & Wilkins, 2006:59-243. 2. Levine M, Haslan D, Walter S, et al. Harm. Guyatt G, Rennie D. Users’ guides to the medical literature. Essentials of evidence-based clinical practice. Chicago: AMA Press, 2002:81-120.

Assignments

Appendix (include articles assign for reading)

Appendix 1: Guideline for Critical Appraisal on Therapeutic study

Levine M, Haslan D, Walter S, et al. Harm. Guyatt G, Rennie D. Users’ guides to the medical literature. Essentials of evidence-based clinical practice. Chicago: AMA Press, 2002: 81-120.

THERAPY

EBM Elective CEU

USERS’ GUIDES FOR AN ARTICLE ABOUT THERAPY Are the results valid? Did experimental and control groups begin the study with a similar prognosis? • Were patients randomized? • Was randomization concealed (blinded or masked)? • Were patients analyzed in the groups to which they were randomized? • Were patients in the treatment and control groups similar with respect to known prognostic factor?

Did experimental and control groups retain a similar prognosis after the study started? • Were patients aware of group allocation? • Were clinicians aware of group allocation? • Were outcome assessors aware of group allocation? • Was follow-up complete?

What are the results? • How large was the treatment effect? • How precise was the estimate of the treatment effect?

How can I apply the results to patient care? • Were the study patients similar to the patient in my practice? • Were all clinically important outcomes considered? • Are the likely treatment benefits worth the potential harm and costs

What was the results?

EBM ElectiveCEU

ESTIMATING THE SIZE OF THE TREATMENT EFFECT Outcome

+ - Treated (Y) Control (X)

a b Risk of Outcome: Y = a/(a + b) X = c/(c + d)

c d

Relative Risk, or Risk Ratio (RR), is the ratio of risk in the treated group (Y) to the risk in the control group (X): RR = Y/X

Relative Risk Reduction (RRR) is the percent reduction in risk in the treated group(Y) compared to controls (X):

RRR = 1- RR = 1 – Y/X x 100% or RRR = [(X – Y)/X] x 100%

Absolute Risk Reduction (ARR) is the difference in risk between control group (X) and the treated group (Y): ARR = X – Y

Number Needed to Treat (NNT) is the inverse of the ARR: NNT = 1/ARR = 1/(X – Y)

Please look for future tools and EBM information at the Users’ Guides Web site, www.usersguides.org

Appendix 2: Therapeutic worksheet

A. Are the results valid?

1. Did experimental and control groups begin the study with a similar prognosis?

* Were patients randomized?

* Was randomization concealed (blinded or masked)?

* Were patients analyzed in the groups to which they were randomized?

* Were patients in the treatment and control groups similar with respect to known prognostic factor?

2. Did experimental and control groups retain a similar prognosis after the study started?

* Were patients aware of group allocation?

* Were clinicians aware of group allocation?

* Were outcome assessors aware of group allocation?

* Was follow-up complete?

B. What are the results?

* How large was the treatment effect?

* How precise was the estimate of the treatment effect?

C. How can I apply the results to patient care?

* Were the study patients similar to the patient in my practice?

* Were all clinically important outcomes considered?

* Are the likely treatment benefits worth the potential harm and costs?

Appendix 3: Critical appraisal topic (CAT) for therapeutic study Clinical Question:

Citation:

A. Study Characteristics: 1. Patients included – 2. Interventions Compared – 3. Outcomes Monitored – B. Validity Criteria: 1. Were patients randomized? 2. Was randomization concealed? 3. Were patients analyzed in the groups to which they were randomized? 4. Were patients in treatment and control groups similar at baseline? 5. Were patients aware of group allocation? 6. Were clinicians aware of group allocation? 7. Were outcome assessors aware of group allocation? 8. Was follow-up complete?

C. Results [choose appropriate tables(s)]: Outcome Rc Rt RR RRR ARR NNT P

1. 2. 3.

Outcome Mean (c) Mean (t) Mean diff. P 1. 2. 3.

D. Applicability: 1. Are the study patients similar to the patients in my practice? 2. Were all clinically relevant outcomes reported? 3. Are the likely treatment benefits worth the harm and costs? Author’s Conclusion: Reviewer’s Conclusion: Reviewer: Date:

Appendix Reading article

Acetylcysteine In Diabetes (AID): A randomized studyof acetylcysteine for the prevention of contrastnephropathy in diabeticsLouis C. Coyle, DO, Antonio Rodriguez, MD, Robert E. Jeschke, MD, Anabela Simon-Lee, MD,Kevin C. Abbott, MD, MPH, and Allen J. Taylor, MD Washington, DC

Background Patients with diabetes mellitus (DM) are at increased risk of contrast-associated nephropathyirrespective of their baseline creatinine (Cr). We tested the efficacy of N-acetylcysteine (NAC) relative to hydration inunselected patients (irrespective of baseline Cr) with DM.

Methods We conducted a randomized open-label study comparing hydration alone (combined oral and rapidintravenous hydration, n = 69) to NAC plus hydration (similar hydration protocol plus NAC 600 mg BID � 4 doses, n = 68)in diabetic patients (mean age 65 F 10 years, 65% men) undergoing elective coronary angiography. The primary end pointwas the mean change in serum Cr measured up to 96 hours postangiography.

Results Baseline Cr was 1.14 F 0.43 mg/dL (Cr z1.3 mg/dL in 37 subjects). Baseline characteristics includingblood urea nitrogen, Cr, and contrast volume were similar between the 2 groups. The mean Cr change in the NAC groupwas 0.14 F 0.47 versus 0.08 F 0.11 mg/dL in the hydration only group ( P = NS). Contrast-associated nephropathy,defined as a z0.5 mg/dL increase in Cr, was significantly more common in the NAC group, 9.2% versus 1.4%, P = .043.Similar results were found in the subgroup of participants with either an increased baseline serum Cr (z1.3 mg/dL) or inthose receiving high contrast volumes (N100 mL).

Conclusions N-Acetylcysteine provides no benefit over an aggressive hydration protocol in patients with DMundergoing coronary angiography. (Am Heart J 2006;151:1032.e921032.e12.)

Individuals with diabetes mellitus (DM) are at in-

creased risk for contrast-associated nephropathy

(CAN) 1,2 and thereby constitute an appropriate target

population for efforts at prevention of this important

complication with substantial associated morbidity and

mortality risk.2 Preventative therapies primarily include

limitation of contrast exposure, administration of fluid,

and selection of low osmolality, nonionic contrast

media.3 However, because these measures provide

incomplete protection from CAN, interest has emerged

in a number of adjunctive short-term pharmacothera-

pies. Among these, N-acetylcysteine (NAC) has been of

considerable interest after an initial report by Tepel et al4

showed a reduction in the increase in serum creatinine

(Cr) with NAC compared with hydration alone. After

this, a number of small studies have been conducted,

which have been quantitatively summarized by several

different meta-analyses,5 - 8 with the summary risk ratio

suggesting that NAC may be modestly effective in

preventing contrast-associated increases in serum Cr. In

general, these studies have been conducted in individ-

uals with preexisting renal insufficiency.

The purpose of this study is to extend our understand-

ing of the potential of NAC to prevent CAN to unselected

patients with DM, regardless of their level of serum Cr.

MethodsThis study was a randomized, open-label, single center trial

approved by the Department of Clinical Investigation of Walter

Reed Army Medical Center, Washington, DC, and funded by

the clinical care provided under the Army Medical Department

of the Department of Defense. Between April 2001 and

December 2002, 169 potential subjects were identified, of

whom 137 provided consent for the study and entered the

intervention. Eligible patients were men and women older than

18 years with a diagnosis of DM scheduled to undergo coronary

angiography. Exclusion criteria were the need for emergency

From the Cardiology Service, Walter Reed Army Medical Center, Washington, DC.

The opinions or assertions herein are the private views of the authors and are not to be

construed as reflecting the views of the United States Army, United States Navy, or the

Department of Defense.

Submitted May 24, 2005; accepted February 5, 2006.

Reprint requests: Allen J. Taylor, MD, Chief, Cardiology Service, Walter Reed Army

Medical Center, 6900 Georgia Ave, NW, Building 2, Room 3L28, Washington, DC

20307-5001.

E-mail: [email protected]

0002-8703/$ - see front matter

n 2006, Published by Mosby, Inc.

doi:10.1016/j.ahj.2006.02.002

procedures, anticipated inability to complete the hydration

protocol, or a history of CAN. Baseline serum Cr was measured

during the precatheterization evaluation, and glomerular

filtration rate was calculated using the Modification of Diet in

Renal Disease Study Group equation.9

Randomization and end pointsPatients were randomized in a 1:1 fashion using a random

number generator with concealment of allocation to either

hydration only (control arm) or hydration plus NAC (inter-

vention arm). This was an open-label study because of the

inability to blind the intervention (administration of NAC) due

to its unique taste. All participants received an oral prehydra-

tion protocol consisting of 1 L of clear fluids over the 10 hours

before angiography. At the initiation of the coronary angio-

graphic procedure, intravenous hydration (0.45N saline) at a

rate of 300 mL/h for 6 hours was begun in the catheterization

laboratory. Patients received a 1-L bottle and instructed to drink

the full contents of clear liquids over the 10 hours before

coronary angiography. Intravenous and oral fluids administered

either during or after the procedure were tracked by study

personnel. Patients assigned to the NAC arm received NAC

600 mg every 12 hours by mouth for 2 doses before and

2 doses after angiography. All patients underwent invasive

coronary angiographic procedures with the selection and

volume of contrast at the discretion of the operator. The pre-

specified primary end point was the maximal change in serum

Cr between 48 and 96 hours after angiography. The prespe-

cified secondary end point was the proportion of participants

with contrast associated nephropathy (CAN) defined as an

increase in serum Cr of z0.5 mg/dL.

Statistical analysisAssuming a baseline Cr of 1.4 F 0.6 mg/dL, for an a of .05

and power of 0.80, a sample size of 65 per group was required

to detect a mean difference in the change in serum Cr of

0.3 mg/dL, similar to the effect size by Tepel et al.4 A secondary

end point was the proportion of participants with CAN,

although the trial was not powered to the secondary end point.

Comparisons of baseline characteristics and end point data

between the 2 study groups were performed using a t test for

independent continuous variables and a v2 test for categorical

variables. Normality of the data was tested with a 1-sample

Kolmogorov-Smirnov test. Data are presented as mean F SD. A

2-tailed P value of V.05 was considered significant.

ResultsThe characteristics of the 137 participants are shown

in Table I, demonstrating even allocation of baseline

characteristics and medications between the 2 study

groups. There was no significant difference between the

2 groups for any measured baseline variables including

Cr, calculated glomerular filtration rate, blood pressure

or left ventricular end-diastolic pressure. The hydration

and contrast results are shown in Table II. The NAC

group received slightly more preprocedural fluids and

slightly less contrast (88 F 61 vs 98 F 65 mL, P = .34),

but these differences were not statistically significant.

Most of the patients in each group received nonionic

low-osmolar contrast. Nonionic contrast was adminis-

tered in 73.8% of NAC subjects compared with 68.1%

of hydration subjects (P = NS). Low or isoosmolar

contrast was administered to 86.2% of NAC subjects

compared with 81.2% of hydration subjects (P = NS).

The observed changes in Cr were unrelated to the

type of contrast (nonionic or low osmolar) admin-

istered. Specifically, the changes in serum for those

administered high- versus low-osmolar contrast (0.10 F0.15 vs 0.12 F 0.33 mg/dL, P = .80) or ionic versus

nonionic contrast (0.07 F 0.15 vs 0.13 F 0.35 mg/dL,

P = .27) were similar.

Table I. Baseline characteristics of the 137 study patients

Hydration,N = 69

Hydration +NAC, N = 68

Male, n (%) 47 (68.1) 42 (61.8)Age, mean F SD 63.3 F 9.2 y 66.7 F 10 yHypertension, n (%) 60 (87.0) 62 (91.2)Congestive

heart failure, n (%)8 (11.6) 8 (11.8)

DM, n (%) 69 (100%) 68 (100%)Medications n (%)

Angiotensin-convertingenzyme inhibitor

45 (65.2) 45 (66.2)

Insulin 18 (26.1) 18 (26.5)Oral agent 35 (50.7) 29 (42.6)Metformin 31 (41.9) 39 (42.6)Thiazolidinedione 7 (10.1) 5 (7.4)

Angiography indication, n (%)Angina/chest pain 42 (60.9) 44 (64.7)Recent acutecoronary syndrome

5 (7.2) 6 (8.9)

Others 22 (31.9) 18 (26.5)

Table II. Procedural variables

Hydration,N = 69

Hydration +NAC, N = 65 P

Baseline Cr (mg/dL)Mean 1.10 F .44 1.16 F .38 .31Cr range 0.5-2.4 0.7-3.1

Baseline glomerularfiltration rate(mL/kg per minute)

76 F 23 70 F 20 .13

Systolic blood pressure(mm Hg)

149 F 25 150 F 30 .82

Diastolic blood pressure(mm Hg)

75 F 15 74 F 12 .67

Left ventricular end-diastolicpressure (mm Hg)

20 F 9 18 F 8 .36

Preangiogramhydration (mL)

1172 F 760 1288 F 6323 .34

Postangiogramhydration (mL)

1971 F 479 1989 F 628 .15

Contrast volume (mL) 98 F 65 88 F 61 .34

American Heart Journal

May 20061032.e10 Coyle et al

There was no difference between the 2 groups for the

primary end point. The mean maximal change in serum

Cr measured 48 to 96 hours after angiography in the

hydration group was 0.08F 0.11 and 0.15F 0.42 mg/dL

in the NAC group (nonparametric P = .80) (Figure 1).

For the secondary end point of the proportion of

individuals with CAN, 1 (1.4%) of 69 participants in the

hydration only group developed CAN compared with

6 (9.2%) of 65 in the NAC group (P = .043) (Figure 2).

Among the 7 subjects who developed CAN, the mean

contrast administration was significantly higher (143 F57 vs 91 F 63 mL, P = .033), but their pre- and

postangiography hydration volumes were similar to the

other study subjects. The calculated glomerular filtration

rate decreased slightly in both groups (hydration �5.3 F8.5 vs NAC �5.5 F 11.8 mL/kg per minute, P = .91).

Nonprespecified subgroup analyses were performed

on questions of interest that emerged from the primary

data analysis. Among participants receiving greater

than 100 mL of contrast, the change in serum Cr was

similar in the hydration (0.11 F 0.12 mg/dL, n = 35)

and NAC groups (0.24 F 0.61 mg/dL, n = 29, P = .25).

Among participants with baseline Cr z1.3 mg/dL, the

change in serum Cr was similar in the hydration

(0.12 F 0.16 mg/dL, n = 18) and NAC groups (0.29 F0.72 mg/dL, n = 19, P = .34). We also performed

exploratory logistic regression to test the relationships

among CAN, baseline Cr, and volume of contrast

administration. In this analysis, CAN was predicted by

the volume of contrast administration (OR 1.015/mL

contrast, 95% CI 1.002-1.027, P = .022) and treatment

with NAC (OR 9.36, 95% CI 0.97-9.2, P = .053).

No study-related adverse events were noted from the

NAC or the hydration protocol.

DiscussionThe potential of NAC to reduce the risk of CAN has

been a topic of intense, recent interest, manifested by

the number of small randomized controlled studies on

this topic.5-8 This is likely, in part, due to the absence of

effective adjunctive pharmacotherapies for this impor-

tant angiographic complication. However, it seems likely

that the potential for benefit from NAC and the absence

of data indicating potential harm also have contributed

to interest in NAC before definitive demonstration of

meaningful clinical benefit on the incidence of CAN and

its attendant morbidity and mortality. The present study,

the first to show potential harm of this pharmacother-

apy, and the emerging literature on the confounding

effects of NAC on serum Cr levels10 lead us to question

the application of NAC for the prevention of CAN.

Multiple small randomized controlled clinical trials

have been conducted, with many, but not all of them,

showing positive results when outcomes were measured

as the change in serum Cr or the occurrence of CAN.

Multiple meta-analyses of this topic have been

reported5-8 and, in general, have suggested that the

evidence to date shows a modest benefit of NAC on

CAN. However, the degree of instability in these

analyses and the potential for publication bias within the

literature are notable. In the most recent meta-analysis

by Pannu et al,8 the absence of any small trials with

Figure 1

Bar graph showing the maximal change in serum Cr 48 to 96 hoursafter contrast administration among diabetic subjects in the AID studytreated with either hydration alone or hydration and NAC.

Figure 2

Box plot showing the distribution of values in the maximal change inserum Cr 48 to 96 hours after contrast administration amongdiabetic subjects in the AID study treated with either hydration aloneor hydration and NAC.

American Heart Journal

Volume 151, Number 5Coyle et al 1032.e11

negative results was noted, indicating possible publica-

tion bias. Of further concern was a high degree of

quantitative instability in the analysis such that the

addition of a single negative trial of only 50 participants

could meaningful alter the quantitative analysis.

Of further concern is the absence of a demonstrated

biologic mechanism for NAC as an effective treatment

of pharmacoprophylaxis of CAN. Proposed mechanistic

theories include several basic and animal investiga-

tions postulating antioxidant or vasodilator effects of

NAC. However, recent evidence indicates that any

observed changes in Cr after NAC administration may

simply be confounded by the independent effect of

NAC on Cr measurement. An intriguing study by

Hoffmann et al10 showed that, in the absence of contrast

administration in subjects with normal Cr, NAC may

decrease serum Cr with no effect on glomerular

filtration rate, as measured by serum cystatin levels.

Thus, it appears that NAC may interfere with the

measurement of serum creatinine leading to the con-

clusion that studies showing a benefit of NAC after

contrast administration are confounded.

The present study, showing no effect of NAC on the

pharmacoprophylaxis of CAN, confirms the negative

results of other small randomized controlled trials on

this topic and is the first to suggest that this intervention,

applied broadly to patients with DM irrespective of

serum Cr level, could even be harmful. In light of the

data published to date on NAC, an alternative interpre-

tation of our study is that our adverse finding with

respect to CAN is a chance finding (a type I error)

among the many small trials that have been conducted.

Thus, we recommend that the primary interpretation of

our study be from the perspective of the primary end

point, with our negative results demonstrating no

benefit of NAC. Within this interpretation of our data,

several limitations are notable. First, the data presented

here are applicable to unselected patients with DM in

which the control group was treated with an aggressive

oral and intravenous pre- and posthydration strategy. As

previously shown by our group, this hydration strategy

is safe in appropriately selected patients, and its

effectiveness is similar to intravenous hydration alone.11

In comparison, prior studies of NAC have typically used

standard hydration of 1 mL/kg per minute, an amount

that may be insufficient for maximal protection from

contrast nephrotoxicity.12,13 This study focused upon

treatment of a high-risk group, patients with DM,

although most had a normal level of serum Cr. Lastly, it

should be noted that the intravenous infusion protocol

in this study used 0.45N saline; whether similar results

would be found using normal saline is unclear.

Based upon the discordant results of many small

clinical trials, and the potential that any Cr change

observed in the setting of NAC may be unrelated to

changes in glomerular filtration rate, we believe at this

time that it is premature to apply NAC in pharmaco-

prophylaxis of CAN. Other potential pharmacotherapies

such as intravenous administration of serum bicarbon-

ate14 or vitamin C15 are under study for this indication,

and ultimately, a sufficiently powered randomized

clinical trial is required. Until then, proper hydration,

limitation of contrast volume, and contrast selection

should be the primary methods to prevent CAN.

References1. Lautin EM, Freeman NJ, Schoenfeld AH, et al. Radiocontrast-

associated renal dysfunction: incidence and risk factors. AJR Am JRoentgenol 1991;157:49 -58.

2. McCullough PA, Wolyn R, Rocher LL, et al. Acute renal failure aftercoronary intervention: incidence, risk factors, and relationship tomortality. Am J Med 1997;103:368-75.

3. Maeder M, Klein M, Fehr T, et al. Contrast nephropathy: reviewfocusing on prevention. J Am Coll Cardiol 2004;44:1763 -71.

4. Tepel M, van der GM, Schwarzfeld C, et al. Prevention ofradiographic-contrast-agent–induced reductions in renal function byacetylcysteine. [see comments]. N Engl J Med 2000;343:180 -4.

5. Alonso A, Lau J, Jaber BL, et al. Prevention of radiocontrastnephropathy with N-acetylcysteine in patients with chronic kidneydisease: a meta-analysis of randomized, controlled trials. Am JKidney Dis 2004;43:1 -9.

6. Birck R, Krzossok S, Markowetz F, et al. Acetylcysteine forprevention of contrast nephropathy: meta-analysis. Lancet 2003;362:598 -603.

7. Isenbarger DW, Kent SM, O’Malley PG. Meta-analysis of random-ized clinical trials on the usefulness of acetylcysteine for prevention ofcontrast nephropathy. Am J Cardiol 2003;92:1454-8.

8. Pannu N, Manns B, Lee H, et al. Systematic review of the impactof N-acetylcysteine on contrast nephropathy. Kidney Int 2004;65:1366 -74.

9. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method toestimate glomerular filtration rate from serum creatinine: a newprediction equation. Modification of Diet in Renal Disease StudyGroup. Ann Intern Med 1999;130:461 -70.

10. Hoffmann U, Fischereder M, Kruger B, et al. The value ofN-acetylcysteine in the prevention of radiocontrast agent-inducednephropathy seems questionable. J Am Soc Nephrol 2004;15:407 -10.

11. Taylor AJ, Hotchkiss D, Morse RW, et al. PREPARED: Preparation forAngiography in Renal Dysfunction: a randomized trial of inpatientvs outpatient hydration protocols for cardiac catheterization inmild-to-moderate renal dysfunction. Chest 1998;114:1570-4.

12. Bader BD, Berger ED, Heede MB, et al. What is the best hydrationregimen to prevent contrast media–induced nephrotoxicity?Clin Nephrol 2004;62:1 -7.

13. Baker CS, Wragg A, Kumar S, et al. A rapid protocol for theprevention of contrast-induced renal dysfunction: the RAPPID study.J Am Coll Cardiol 2003;41:2114 -8.

14. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast-induced nephropathy with sodium bicarbonate: a randomizedcontrolled trial. JAMA 2004;291:2328 -34.

15. Spargias K, Alexopoulos E, Kyrzopoulos S, et al. Ascorbic acidprevents contrast-mediated nephropathy in patients with renaldysfunction undergoing coronary angiography or intervention.Circulation 2004;110:2837 -42.

American Heart Journal

May 20061032.e12 Coyle et al