Title: Multi-centre Randomized Controlled Trial of angiotensin converting enzyme inhibitor (ACEi) /angiotensin receptor blocker (ARB) - withdrawal in chronic kidney disease – STOP-ACEi-STUDY (SAS)
Funder: Medical Research Council

Abstract: Clinical studies have suggested that as chronic kidney disease (CKD) progresses, the number of filters (nephrons) in the kidney decreases causing the pressure in each filter to rise, leading to a vicious cycle of progressive damage of the surviving filters. RCTs showed that ACEi/ARBs, by blocking RAAS and specifically reducing this increase in filter pressure, slowed CKD progression over and above their effect on systemic BP. However, recent research, including an observational study by one of the applicants, has indicated in a subgroup of people with advanced progressive CKD (stages 4-5) there is stabilization or improvement of kidney function on discontinuing of ACEi/ARBs. If confirmed, this observation has profound clinical implications as trial evidence is lacking. We and others, in various cohorts of CKD patients, have shown that patients with more rapid progression of eGFR have worse outcomes. We therefore, propose an RCT to test the hypothesis that in patients with CKD stages 4 or 5, who are undergoing a progressive and sustained decline in kidney function, stopping ACEi/ARBs compared with continuing these treatments, leads to an improvement in kidney function with the potential for direct clinical benefit. We plan to randomize 410 patients with advanced (stages 4 or 5) progressive CKD to either continue their normal drug treatment or to stop ACEi/ARB. This will give 80% power (alpha=0.05) to detect a 5ml/min difference between arms (using SD=16ml/min, effect size=0.31) in estimated Glomerular Filtration Rate at 3 years (including 20% drop-out rate). This effect size is well below that reported in the index pilot study at one year. This change in GFR over the three year study period will therefore be a direct surrogate marker for future dialysis therapy and potential mortality for which there is substantial literature to support the relationship. There is excellent evidence to show acceptable accuracy of eGFR compared to gold standard measurements of kidney function (measured GFR (including Iohexol clearance).The results of such a study would then allow the design of a larger randomised study with mortality as the primary end-point. Patients will be recruited from at least 12 UK nephrology units at a rate of 2/month/centre. Data on laboratory (e.g. proteinuria), clinical (e.g. dialysis) and quality of life measures will be collected. The analysis will be by intention to treat, and according to a pre-specified analysis plan. The trial has been designed in collaboration with renal units with a strong track record in this type of research, an eminent cardiologist with huge experience in clinical trials, nurses, patient groups and the University of Birmingham Clinical Trials Unit (BCTU) and is supported by the UK Kidney Research Consortium (UKKRC) and British Renal Association CKD Clinical Studies Group (CSG). The trial will be managed by the BCTU, a UKCRC registered CTU which is already co-ordinating 4 on-going large-scale randomized trials in renal disease: ASTRAL; PEXIVAS, PREDNOS and GloMY. If this study confirms that renal function is stabilised or improved following the withdrawal of ACEi/ARBs, then the NHS would save substantial per person per year costs on drugs (£250), dialysis (~£30,000) and transplantation (£15,000 initial then £3,000 annually).


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL