Angiotensin converting enzyme inhibitors / angiotensin receptor blockers and contrast induced nephropathy in patients receiving cardiac catheterization: results from the CAPTAIN trial

CAPTAIN trial: study design A randomized study of holding angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) versus continuing ACEI/ARB prior to cardiac catheterization in patients with chronic kidney disease Patients on ACEI/ARB and scheduled for cardiac cath ≥24hrs from enrolment with chronic kidney disease (CKD)* RANDOMIZED Continue ACEI/ARB Hold ACEI/ARB Hold 24 hrs before and 96 hrs after procedure All patients receive peri-procedural intravenous hydration and N-acetylcystine Follow-up: between 48-96 hours post-procedure Primary Outcome: Acute kidney injury (AKI)** Secondary Outcome: Rise in serum creatinine post procedure *CKD: Cr >= 150umol/L within 3 months before cardiac catheterization and/or documented Cr >= 132umol/L within 1 week before cardiac catheterization ** AKI: absolute rise in serum creatinine of ≥ 44umol/L from baseline and/or a relative rise in serum creatinine of ≥ 25% compared with baseline measured at 48-96 hours post cardiac catheterization 2 2

Selected baseline characteristics Variable CONTINUE (N=102) HOLD (N=106) P-value Demographic characteristics Age (mean, SD) 72.4 (8.4 ) 73.2 (9.1 ) 0.5600 Gender (% Female) 27 (26.5 ) 28 (26.4 ) 1.0000 Medical history (%) Diabetes mellitus 57 (55.9 ) 55 (51.9 ) 0.5806 Hypertension 96 (94.1 ) 93 (87.7 ) 0.1488 Congestive heart failure 12 (11.8 ) 17 (16.0 ) 0.4266 Ejection fraction (median, %) 50.0 (42.0 ,55.0 ) 50.0 (35.0 ,55.0 ) 0.2023 Medications prior to cardiac catheterization (%) Aspirin 80.4 77.4 0.6145 COX II inhibitors 1.0 0.4904 Other NSAIDS 5.9 2.8 0.3250 Loop diuretics 26.5 34.0 0.2910 Thiazide diuretics 17.6 14.2 0.5704 Beta Blockers 59.8 67.9 0.2494 Spironolactone 2.0 5.7 0.2802 Statins 78.4 75.5 0.6258 ACEI/ARB 100.0 0.9999 Baseline characteristics were well balanced between the two groups. Note, high rates of diabetes were noted which were similar in both groups although there was a trend towards higher rates of insulin used to treat diabetics in the continue ACEI/ARB group (24.5%. vs. 14.2%, p=0.08). All patients were on an ACEI/ARB (ACEI [72.1%] or ARB [27.9%]) prior to randomization

Catheterization characteristics Pre-catheterization During catheterization Variable CONTINUE (N=102) HOLD (N=106) P-value Hydration Intravenous hydration (%) 100 99.1 0.9888 Rate of IV hydration (cc/hr mean, SD) 264.1 (103.9 ) 278.2 (113.5 ) 0.3530 Duration of IV hydration (hrs, mean, SD) 1.5 (0.9 ) 1.5 (1.0 ) 0.8498 Laboratory tests Hemoglobin (g/dL, mean) 36.2 (46.9 ) 35.9 (48.4 ) 0.9601 Highest creatinine documented in last 3 mo. (umol/L, mean, SD) 160.4 (37.8 ) 158.1 (35.9 ) 0.6446 Pre-procedural creatinine within 1 wk of cath (umol/L, mean, SD) 151.3 (34.6 ) 148.3 (35.0 ) 0.5458 Creatinine level on day of Cath (umol/L, mean, SD) 143.3 (36.8 ) 140.1 (32.9 ) 0.5265 Variable CONTINUE (N=102) HOLD (N=106) P- value Visipaque 30.4 36.8 0.3288 Omnipaque 69.6 63.2   Contrast during procedure Contrast (mL, mean, SD) 122.9 (65.5 ) 109.8 (67.0 ) 0.1561 Hemodynamic measurements during procedure Blood pressure (systolic, mmHg, mean, SD) 134.8 (25.4 ) 140.7 (26.9 ) 0.1068 Blood pressure (diastolic, mmHg, mean, SD) 64.6 (14.6 ) 67.8 (15.8 ) 0.1385 SBP <90 mmHg for at least 5 min during procedure (%) 3 (2.9 ) 1 (0.3) 0.3619 Cardiac catheterization Left ventricular end-diastolic pressure (mmHg, mean, SD) 10.3 (5.2 ) 10.4 (5.6 ) 0.8637 PCI performed (%) 22.6 0.2057 Pre-catheterization characteristics showed patients were well hydrated with intravenous normal saline on average 1.5 hours before the procedure which was similar in both groups. Serum creatinine levels were elevated in keeping with renal insufficiency but were similar in the two groups During cardiac catheterization, similar volumes of radioactive contrast were used and invasive hemodynamics were comparable between both groups

Primary outcome Acute kidney injury HR 0.59; 95% CI 0.30-1.19; p=0.16 Incidence of AKI defined as an absolute rise in serum creatinine of ≥ 44umol/L from baseline and/or a relative rise in serum creatinine of ≥ 25% compared with baseline measured at 48-96 hours post cardiac catheterization

Secondary outcome Other outcome Variable CONTINUE (N=102) HOLD (N=106) Hazard Ratio (95% CI) P value Composite outcome* 4(3.92) 0.11(0.01,2.96) 0.0561 Death 1(0.98) 0.32(0.01,7.79) 0.4904 MI . NA CHF Ischemic stroke Dialysis Re-hospitalization 3(2.94) 0.14(0.01,2.63) 0.1162 P=0.03 *Composite of death, myocardial infarction, ischemic stroke, congestive heart failure, re-hospitalization or need for dialysis 72 hours post-procedure

Prespecified sub-group analyses Exploratory analysis 40 18.2 11.1 0.61[0.12,2.96] 159 18.4 10.8 0.59[0.27,1.28] 109 22.8 13.5 0.59[0.26,1.37] 90 12.2 8.2 0.67[0.19,2.33] 10.6 4.8 0.45[0.04,4.60] 74 19.4 7.0 0.36[0.10,1.33] 80 21.7 17.7 0.81[0.33,2.02] 208 10.9 0.59[0.30,1.19] Age <65Yr >=65Yr Diabetes Yes No Mehran risk score 0-5 6-10 >10 Total Event Rate (%) Patient# Continue Hold Risk Ratio (95% CI) Favours Hold Favours Continue 0.04 0.1 1 5 10 20 Modification of diet in renal disease formula Cockcroft-gault formula P=0.06 P=0.06 There was no significant heterogeneity in the primary outcome of AKI in subgroups stratified according to age or diabetes Reduction in renal function following cardiac catheterization seems to be attenuated with holding ACEI/ARB regardless of the measurement used for renal function. Change in Renal Function Following Cardiac Catheterization

Conclusion Our study showed that in patients with renal insufficiency requiring cardiac catheterization, holding ACEI/ARB did not differ from continuing ACEI/ARB in preventing acute kidney injury However, holding ACEI/ARB resulted in: Significantly lower rise in serum creatinine following coronary angiography Attenuation in renal function decline following angiography Improved clinical outcomes Large scale clinical trial is warranted However, we do believe a larger scale clinical trial is warranted to definitively address this issue.