Effect of ramipril on renal function in patients with intermittent claudication

ORIGINAL RESEARCH Effect of ramipril on renal function in patients with intermittent claudication Simon D Hobbs 1 Martin W Claridge 1 Antonius BM Wilmink 1 Donald J Adam 1 Mark E Thomas 2 Andrew W Bradbury 1 University Department of Vascular Surgery and 2 Department of Nephrology, Heart of England NHS Trust (Teaching), Birmingham, UK 1 Background: The Heart Outcomes Prevention Study (HOPE) demonstrated that ramipril resulted in a blood-pressure-independent 25% reduction in cardiovascular events in patients with peripheral arterial disease (PAD). Despite this, general practitioners and vascular surgeons remain reluctant to prescribe ACE inhibitors in this group of patients because of concerns about renal artery stenosis (RAS). We aimed to define the effect of ramipril on renal function in patients with intermittent claudication (IC). Methods and Results: Of 132 unselected patients with IC entering the study 78 (59%) were excluded due to: current ACE inhibitor use (38%), renal impairment (serum creatinine above normal range) (15%), known severe RAS (1%) or unwillingness to participate (5%). The remaining 54 patients were titrated to 10 mg ramipril and renal function was monitored at 1, 5, and 12 weeks. Treatment was discontinued during titration in 5 patients due to symptoms (3) or lack of compliance (2). In the remainder, median [IQR] serum creatinine increased (94 [85.8–103.3] to 98 [88.0–106.5] µmol/L, p ⱕ 0.001) and median [IQR] GFR decreased (71.5 [64.6–82.3] to 68.7 [59.8–74.7] mL/min per 1.73 m2, p ⱕ 0.001) between baseline and 5 weeks. These changes were not considered clinically significant. By 12 weeks these values had returned almost to baseline (Cr 95.5 [88.0–103.25] µmol/L, GFR 71.8 [65.3–77.4] mL/min). No patient had a serum creatinine rise ⬎30%. Conclusion: Most of patients with IC and a normal serum creatinine can be safely commenced on ramipril provided they are screened, titrated and monitored as described above. Studies in patients with borderline renal impairment (serum creatinine up to 30% above baseline) are on-going. Keywords: peripheral arterial disease, ramipril, renal function, intermittent claudication Introduction Correspondence: Andrew W Bradbury University Department of Vascular Surgery, Research Institute, Lincoln House, Birmingham Heartlands and Solihull NHS Trust (Teaching), Bordesley Green East, Birmingham, B9 5SS, UK Tel/fax +44 121 424 1633 Email . nhs.uk Best medical therapy (BMT) is the mainstay of treatment for patients with peripheral arterial disease (PAD) with endovascular or surgical intervention reserved for those who remain unacceptably symptomatic or have life and/or limb-threatening complications (Burns et al 2003). In addition to smoking cessation therapies, hypertension and diabetic control, and antiplatelet and lipid lowering medication, the publication of the Heart Outcomes Prevention Evaluation (HOPE) study has provided level 1 evidence to support the use of ramipril for secondary cardiac prevention in patients with PAD (The Heart Outcomes Prevention Evaluation Study Investigators 2000). The HOPE study recruited patients with a history of cardiovascular disease (including a cohort of 4051 (44%) patients with PAD) or a history of diabetes plus at least one other risk factor and randomized them to receive ramipril (titrated up to 10 mg) or placebo. At a mean follow-up of 4.5 years, ramipril significantly reduced the composite end-point (myocardial infarction, stroke, or death from cardiovascular causes) by 25%. This reduction in risk was at least as large as that observed for treatment with aspirin and lipid-lowering agents (Heart Protection Study Collaborative Group 2002; Vascular Health and Risk Management 2008:4(2) 471–475 471 © 2008 Hobbs et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Hobbs 130 Creatinine µmol/L 120 110 100 90 80 70 Baseline 1 Week 5 weeks 12 weeks Time point Figure 1 Boxplots of change in serum creatinine in response to initiation of ramipril. Patients are commenced on ramipril 2.5 mg for 1 week, increased to 5 mg for 3 weeks, and then maintained on 10 mg. Compared with baseline, 1 week p = 0.015, 5 weeks p ⱕ 0.001, 12 weeks p = 0.003, Wilcoxon signed ranks). Peripheral Arterial Diseases Antiplatelet Consensus Group 2003) and was independent of entry blood pressure. Although the HOPE study indicated that the benefits of ACE inhibition in patients with PAD outweigh the risks, vascular surgeons remain wary of the small risk of precipitating acute renal failure in patients with hemodynamically significant renal artery stenosis (RAS) (Pillay et al 2002). The aim of this study was to evaluate in detail for the first time, the effect of ramipril titration on renal function in a cohort of surgical PAD patients presenting with intermittent claudication, in the expectation that if safety could be demonstrated then this would change vascular surgeons’ practice. Patients and methods Local ethical approval was obtained and written informed consent was obtained from all patients. Patients, over the age of 55 years, attending the vascular surgical outpatient department of a large teaching hospital with a diagnosis intermittent claudication (IC) based on structured history (Leng and Fowkes 1992) and ankle brachial pressure index (ABPI) entered the study. Patients were excluded if they were 472 currently receiving an ACE inhibitor or angiotensin receptor blocker, had abnormal baseline renal function (serum creatinine ⬎120 µmol/L males, ⬎110 µmol/L females), a history of severe renal artery stenosis (RAS), or were unwilling to participate. Patients who fulfilled the entry criteria were commenced on ramipril (Tritace® titration pack, Aventis Pharma UK), starting at 2.5 mg for 1 week, increased to 5 mg for 3 weeks and then further increased to the maintenance dose of 10 mg. Renal function was monitored by means of a blood sample collected after 1, 5, and 12 weeks and glomerular filtration rate (adjusted to a body surface area of 1.73 m2) was estimated by means of the Modification of Diet in Renal Disease (MDRD) Equation 7 (Levey et al 1999). The MDRD equation 7 requires serum creatinine, urea, and albumin values and it factors for the patient’s age, sex, and race. It has largely superseded the Cockcroft-Gault equation, as it has improved accuracy and does not require knowledge of the patient’s weight (Nation Kidney Foundation 2007). Ramipril was to be discontinued if the patient’s serum creatinine rose greater than 30% from their baseline value or if serum potassium rose ⬎5.9 mmol/L, in line with our Vascular Health and Risk Management 2008:4(2) ACE inhibitors and intermittent claudication recently published treatment algorithm (Hobbs et al 2004). Ramipril was also discontinued if the subject encountered unacceptable side effects. Statistical analysis was performed using (...truncated)