ACE inhibitors and angiotensin receptor blockers: To hold or not to hold for IV contrast?

Contrast-induced nephrotoxicity is a significant complication that occurs in patients receiving iodinated contrast media for coronary angiography.

The incidence of contrast-induced nephrotoxicity (CIN) reported in the literature varies depending on the definition and the risk factors of the patient population but ranges from 3% to 15%. The definition of CIN can be based on the percent decrease in renal function (25% to 50%) or increase in serum creatinine (0.3 mg/dL-1 mg/dL). The possible implications of CIN include increased mortality; morbidity (need for dialysis, late CV events after percutaneous coronary intervention, vascular complications and bleeding requiring transfusion); increased length of hospital stay; and costs. Risk factors for CIN include: chronic kidney disease (CKD); diabetes; advanced age; congestive HF; concurrent nephrotoxic agents; hypovolemia; and the amount and type of contrast media.

Lindsay Justin

Danielle M. Blais

Multiple interventions have been studied to decrease the incidence of CIN, some of which include utilization of lower osmolar agents, hydration with or without sodium bicarbonate, N-acetylcysteine, withholding nephrotoxic medications, dialysis, fenoldopam and dopamine. ACE inhibitors or angiotensin II receptor blockers (ARBs) are recommended in high-risk patients, including those who are post-MI or have diabetes or congestive HF; however, there is controversy regarding their concurrent use with contrast media and risk for CIN. Here, we review the evidence for and against continuing ACE inhibitors or ARBs in patients who will receive contrast media for CV procedures.

Evidence for potential link

Dangas and colleagues performed a prospective cohort study of 7,230 patients (n=1,980 with CKD, n=5,250 without CKD) to determine predictors of CIN in patients undergoing a PCI. CKD was defined as an estimated glomerular filtration rate of less than 60 mL/minute/1.73m². CIN was defined as an increase of at least 25% (or ≥0.5 mg/dL) in preprocedural serum creatinine at 48 hours after the procedure. Those excluded from the study were patients with an acute STEMI within 48 hours, cardiogenic shock and baseline CKD requiring dialysis. Patients with a serum creatinine of more than 1.5 mg/dL received 0.45% normal saline at 1 mL/kg/hour for 12 to 24 hours before and after catheterization. All other patients received hydration before and after their PCI, and ACE inhibitors were not held before PCI.

There was no information on other nephrotoxic medications that the patients may have received. Thirty-one percent of the patients with CKD treated with an ACE inhibitor pre-catheterization developed CIN vs. 32.9% who did not (P=.02). Of the patients treated with an ACE inhibitor pre-catheterization who did not have CKD, 28.4% developed CIN vs. 24.5% who did not (P=.01). In a multivariate regression model that included preprocedural medications, taking an ACE inhibitor was associated with a lower risk of CIN in patients with baseline CKD.

In a prospective cohort study, Cirit and colleagues evaluated the incidence of CIN in patients at least 65 years of age with mild to moderate renal insufficiency requiring non-emergent cardiac catheterization. Of the 230 patients included in the study, only 108 patients were receiving an ACE inhibitor before catheterization. CIN was defined as an increase in serum creatinine of at least 25% more than the baseline value within 48 hours after the PCI. Patients were included in the ACE inhibitor group if they received an ACE inhibitor within 2 months of the procedure. Those excluded from the study were patients with an acute MI; cardiogenic shock; sepsis; known acute renal failure; baseline CKD requiring dialysis; those who received nephrotoxic agents within 3 days of the procedure (eg, contrast dye; aminoglycosides; amphotericin B, NSAIDs and cisplatin); ARBs; and renal protective drugs (N-acetylcysteine or sodium bicarbonate).

All patients received normal saline 2 mL/kg/hour 6 hours before and after catheterization. The incidence of CIN in the ACE inhibitor group was 15.6% vs. 5.8% in the non-ACE inhibitor group (P=.015). After PCI, the absolute change in eGFR was significantly lower (P=.001) and the absolute change in serum creatinine was significantly higher (P<.001) in the ACE inhibitor group. This study concluded that in elderly patients, chronic use of ACE inhibitors before contrast does not prevent the development of CIN and, in fact, increased incidence of CIN.

Rosenstock and colleagues conducted a prospective randomized controlled trial in stage III-IV CKD patients who were receiving ACE inhibitors or an ARB for at least 1 month before angiography. Patients were randomly assigned to discontinuation of ACE inhibitors or ARBs (n=113) or continuation (n=107), although in the continuation group, the dose of ACE inhibitors or ARB was held on the morning of the procedure and for 24 hours afterward. The researchers also included a control group of patients who were ACE inhibitor- or ARB-naive (n=61).

The primary outcome was the incidence of CIN, defined as either a 0.5 mg/dL or a 25% increase in serum creatinine from baseline within 24 to 72 hours of angiography. Those excluded from the study were patients with a STEMI within 2 weeks, NYHA Class IV HF, acute renal failure before the procedure, serum potassium level of more than 5 mEq/L, angiography in the last month, eGFR of less than 15 mL/minute/1.73m², systolic blood pressure of less than 90 mm Hg or more than 180 mm Hg, combination ACE inhibitors and ARB therapy, or those receiving an ACE inhibitors or ARB within 24 hours before randomization.

Other therapies for renal protection were left to the discretion of the physician, including N-acetylcysteine and IV fluids. Metformin and diuretics were held for all patients. Results indicated no difference in post-procedure serum creatinine, eGFR and incident CIN comparing the three groups, and the authors concluded that it is not necessary to advise CKD stage III-IV patients to hold their ACE inhibitors and ARBs before angiography, although it may be advisable to hold these medications for patients with hyperkalemia or hypotension. Limitations of this study include that serum creatinine was only measured 24 hours after the angiography, unless clinically indicated, and increases in serum creatinine can occur up to 72 hours after the procedure.

Lastly, Hölscher and colleagues conducted a prospective trial in patients with a baseline serum creatinine between 1.5 mg/dL and 3.5 mg/dL, requiring an elective left heart catheterization to determine the incidence of CIN. CIN was defined as an increase in serum creatinine of 0.5 mg/dL or more within 72 hours after PCI. Those excluded from the study include patients with a MI or receiving contrast media within 7 days, NYHA Class IV HF, transplant and monoclonal gammopathy. ACE inhibitors in the preprocedural regimen were identified as a significant independent predictor for development of CIN within 72 hours, increasing the risk more than sixfold and leading the authors to conclude that ACE inhibitors should be discontinued before administration of contrast media.

Conclusions

The data regarding the temporary discontinuation of ACE inhibitors in patients receiving contrast media are conflicting, whereas the data regarding ARBs are very limited. Patients who develop CIN have increased morbidity, mortality, length of hospital stay and associated costs. Therefore, if there is a potential to prevent CIN by temporarily discontinuing ACE inhibitors in high-risk patients, it would seem that the potential benefits appear to outweigh the risks of short-term ACE inhibitor discontinuation.

Lindsay Justin, PharmD, MS, is a specialty practice resident in the Health-System Pharmacy Administration at The Ohio State University Medical Center, Columbus. Danielle M. Blais, PharmD, BCPS, is a cardiology specialty pharmacist at The Ohio State University Medical Center.

Rhonda M. Cooper-DeHoff, PharmD, MS, is Cardiology Today’s Pharmacology Consult column editor and a member of the CHD and Prevention section of the Cardiology Today Editorial Board. Dr. Cooper-DeHoff is associate professor, department of pharmacotherapy and translational research, College of Pharmacy, and Division of Cardiovascular Medicine, College of Medicine, University of Florida, Gainesville.

For more information:

• Cirit M. Nephron Clin Pract. 2006;104:c20-c27.
• Dangas G. Am J Cardiol. 2005;95:13-19.
• Hölscher B. Can J Cardiol. 2008;24:845-850.
• Rosenstock JL. Int Urol Nephrol. 2008;40:749-755.

Disclosures: Drs. Blais, DeHoff and Justin report no relevant financial disclosures.