A Randomised Open Label, Blinded End Point Trial to Compare the Effects of Spironolactone With Chlortalidone on LV Mass in Stage 3 Chronic Kidney Disease (SPIRO-CKD)

Background

1. Chronic kidney disease and cardiovascular disease CKD is a major but poorly recognised and under-treated risk factor for cardiovascular disease. It can be categorised in to 5 stages according to GFR and the presence of markers of kidney damage. Stage 3 CKD, the subject of this proposal, is defined by a glomerular filtration rate (GFR) of 30-59 ml/min/1.73m2. There is a graded inverse relationship between cardiovascular risk and GFR which is independent of age, sex and other risk factors. There is also a graded association between albuminuria and cardiovascular risk and in patients with both low GFR and albuminuria, risk is increased with a multiplicative association. While the cardiovascular risk of end stage CKD is extreme, in public health terms the burden resides in early stage (CKD stages 1-3) disease, which is more prevalent affecting almost 1 in 7 of the entire population, including approximately 4% of those aged 40-59 and more than 40% of those over 70 years. Thus, CKD is a potentially important risk factor for cardiovascular disease in the general population. Although the risks of myocardial infarction and other manifestations of coronary artery disease are increased in CKD, there is a much greater increase in the incidence of heart failure and sudden cardiac death in stages 3-5. This is almost certainly a reflection of the very high prevalence of myocardial disease; left ventricular hypertrophy (LVH) often accompanied by magnetic resonance imaging evidence of fibrosis is present in over 30% of patients with stage 2 (GFR 60-89) and stage 3 CKD and in 80% of patients at the start of renal replacement therapy. To date, the only prospective trial to examine the prognostic benefit of drug therapy in this high risk group is the recently presented SHARP trial. This showed a reduction in occlusive vascular events associated with LDL lowering with simvastatin and ezetimibe. The Birmingham CRIB-2 study (see below) published in 2010 provided evidence that mineralocorticoid receptor blockade with spironolactone exerts beneficial effects on intermediate end points of strong prognostic value including LV mass and arterial stiffness. That work provides the basis for this application.

Pathophysiology of myocardial and vascular disease in chronic kidney disease

The main pathological features of cardiovascular disease in CKD are:

1. Myocardial disease characterised by LVH and fibrosis accompanied by systolic and diastolic dysfunction.
2. Arterial wall thickening, stiffening and calcification (arteriosclerosis).
3. Coronary and peripheral artery atherosclerosis.

Although there is no doubt that patients with CKD are subject to accelerated atherosclerosis the major pathological features of the cardiovascular system in CKD are myocardial disease (so called uraemic cardiomyopathy) and arterial stiffening due to arteriosclerosis. As kidney function declines, a range of abnormalities occur that may exert adverse effects upon the cardiovascular system. Hypertension, chronic anaemia, oxidative stress, inflammation and activation of the renin-angiotensin-aldosterone (RAAS) and sympathetic nervous systems all appear to contribute to the development of atherosclerosis, arteriosclerosis and myocardial hypertrophy and fibrosis. 2. Aldosterone and Cardiovascular Disease The fundamental role of the RAAS in cardiovascular disease is apparent from the results of many large ACE inhibitor trials showing mortality benefit in patients with chronic heart failure and in those with, or at high risk of, coronary artery disease. These beneficial effects have been attributed to prevention of the multiple adverse effects of angiotensin II. Strong evidence suggests that aldosterone may also be an important mediator of cardiac and vascular damage in many disease states. In trials involving patients with chronic heart failure and heart failure complicating myocardial infarction, the addition of the MRBs - spironolactone (RALES) or eplerenone (EPHESUS and EMPHASIS ) - to standard therapy including ACE inhibition reduced mortality by up to 30%. Primary aldosteronism is associated with a greater LV mass and higher risk of adverse cardiovascular events than control hypertensive populations and in patients after myocardial infarction, plasma aldosterone concentration even within the normal range predicts an adverse prognosis. More recently, a study of subjects undergoing coronary angiography confirmed an independent association of plasma aldosterone levels with total and cardiovascular mortality.