Comparing the Effects of Spironolactone With Chlortalidone on LV Mass in Patients With CKD

In stage 3 chronic kidney disease (CKD) the risk of death due to cardiovascular causes is high and greatly exceeds the risk of progression to end stage renal failure. This high cardiovascular risk is predominantly due to sudden cardiac death and heart failure, manifestations of left ventricular hypertrophy and fibrosis. Aldosterone appears to play an important role in the causation of this myocardial disease both by direct inflammatory and fibrotic myocardial effects and via increased arterial stiffness due to hypertrophy, inflammation, and fibrosis within the media of large arteries. Levels of aldosterone are high in CKD despite sodium overload and treatment with angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) drugs due to the twin phenomena of aldosterone escape and breakthrough. In a previous British Heart Foundation funded study, Birmingham investigators showed that the addition of the mineralocorticoid receptor blocker (MRB) spironolactone to background therapy with ACE inhibitors or ARBs caused reductions in the prognostically important parameters of arterial stiffness and LV mass. Because spironolactone therapy was also associated with significant falls in arterial pressure it remains possible that these effects were mediated simply by blood pressure reduction. In this multi-centre, randomised controlled study, the effects of treatment with spironolactone on LV mass and arterial stiffness in patients with stage 3 CKD on established ACE or ARB therapy will be compared to those of chlortalidone, a control anti-hypertensive agent. Early stage chronic kidney disease is highly prevalent and new, cost effective treatment strategies are required to reduce cardiovascular risk. This study is designed to provide the rationale for a larger study of morbidity and mortality with MRB therapy in early stage 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.

The mechanisms of action of aldosterone include upregulation of Angiotensin 1 receptors and direct effects on fibroblast collagen synthesis as well as decreased matrix metallo-proteinase secretion. An anti-fibrotic effect of MRB therapy may be of major importance. After myocardial infarction, circulating markers of collagen turnover and fibrosis were reduced by MRB therapy and in the RALES study myocardial collagen turnover was significantly reduced by spironolactone and the fall in the marker of this index was related to the mortality benefit. In CKD stages 2 and 3, data from CRIB-2 showed that spironolactone improves myocardial diastolic function and collagen turnover. .

Use of MRBs in Patients with CKD Although some doubt remains about whether ACE inhibitors and ARBs are superior to other blood pressure lowering drugs in slowing the progression of CKD, they may provide marginal extra benefit and are widely recommended in national and international guidelines. Conversely, the traditional approach by nephrologists to MRB drugs has been to avoid their use because of the risk of azotaemia and hyperkalaemia. There are both theoretical and empirical reasons why this avoidance may be incorrect. Firstly, CKD is characterised by an abnormal combination of chronic sodium overload and high (unsuppressed) levels of circulating aldosterone; the normal relationship between circulating volume and aldosterone secretion appears to be altered (aldosterone escape). Secondly, in a large proportion of patients with CKD on standard treatment with ACE inhibitors or ARBs, there is aldosterone 'breakthrough' so that aldosterone levels are high despite inhibition of the system by prevention of angiotensin II formation or inhibition of angiotensin receptors. Thus patients with CKD are exposed to high levels of aldosterone despite standard treatment. The only other common disease state in which high aldosterone production continues to occur in the face of sodium overload is chronic heart failure in which MRB therapy is of major prognostic benefit reducing both adverse cardiovascular events and total mortality.

There is also accumulating evidence to suggest that the addition of MRBs to ACE inhibitors in CKD might have beneficial effects by slowing the otherwise progressive decline in renal function. Animal experiments have shown that aldosterone can mediate renal injury and that MRBs such as eplerenone effectively reduce this. MRBs remain effective in low aldosterone models of CKD probably reflecting the importance of local (paracrine) aldosterone synthesis. In humans, small studies have suggested that the addition of MRBs to ACE inhibitors or ARB reduces proteinuria and may slow the progression of renal disease. Thus, the widespread use of MRBs in CKD has been advocated and has even been termed 'renal aspirin'. Until the publication of the CRIB-2 trial however, little attention had been paid to the potentially beneficial effects of MRB therapy on the cardiovascular system in patients with CKD.

The CRIB-2 trial The Effect of Spironolactone on Left Ventricular Mass and Aortic Stiffness in Early-Stage Chronic Kidney Disease; a Randomised Controlled Trial In a placebo controlled double blind trial, 112 patients (mean age 54 years) with stage 2 and 3 CKD with good blood pressure control on established treatment with ACE inhibitors or ARBs were treated in an active run-in phase with spironolactone 25 mg once daily for 4 weeks and then randomised to continue spironolactone or to receive a matching placebo for a total of 40 weeks. LV mass (cardiac magnetic resonance) and arterial stiffness (pulse wave velocity/analysis, aortic distensibility) were measured before run in and after 40 weeks of treatment. Compared with placebo, the use of spironolactone resulted in large reductions in LV mass and arterial stiffness (pulse wave velocity, augmentation index and aortic distensibility). This trial has been well received and widely publicised. In a recent review, Pitt stated that "we can be cautiously optimistic that use of an MRB in addition to an ACE inhibitor or an ARB will reduce the mortality and morbidity associated with CKD, as well as prevent its progression to end-stage renal disease with all of its health-care and health-cost consequences". Thus, this old and inexpensive drug has the potential to reduce adverse cardiovascular events and mortality in early stage CKD, a risk factor that is now screened for routinely in primary care by measurement of eGFR in the United Kingdom population. In the CRIB-2 trial, systolic blood pressure was significantly reduced; spironolactone is well recognised as an effective anti-hypertensive agent for patients with hypertension, even when this is resistant to other drugs. It is therefore necessary to determine whether the improvements in arterial stiffness and LV mass that occurred with spironolactone were mediated by this effect. Furthermore, before a large scale clinical trial of spironolactone can be contemplated, it is necessary to demonstrate that spironolactone can be used safely in a multi-centre trial design with local monitoring of renal function and serum potassium. This study will provide the pilot data on efficacy (independent of blood pressure) and safety that are necessary to undertake a definitive phase III trial of the role of spironolactone in reducing cardiovascular morbidity and mortality in patients with early stage CKD.

Recruitment and sample size

The trial started recruitment in June 2014, and aimed to recruit 350 patients over a 2 year period. The study was originally planned to be complete by February 2017. The rate of recruitment however was much slower than anticipated and it became evident by November 2015 that it would take a further 2 years to reach this target. This period of time was greater than funding allowed and the decision was taken to change the study design.

The initial design of the study was to use a co-primary end point of change in LV mass and change in pulse wave velocity. A sample size of 350 patients was planned to give 90% power to detect a difference in PWV with a p value of 0.025 and \>90% power to detect a change in LV mass. When it became evident that was not achievable within the funded time frame the study was re-designed using the single end point of change in LV mass. With a p value of 0.05 and a power of 85%, it was calculated that 63 patients per group would be required. The sample size was calculated at 150 patients allowing for a 15% rate of missing data. This allowed a smaller sample size which was achievable within the funded time frame.

Eligibility Criteria:
Inclusion Criteria:

* Age \>18 years
* Chronic kidney disease stage 2 or 3 (eGFR 30-89 ml/min/1.73m2 by Modification of Diet in Renal Disease equation). eGFR must be within the last 12 months, on at least 2 occasions, at least 90 days apart.
* Well controlled blood pressure
* Established (\>6 weeks) on treatment with ACE inhibitors or ARBs
* Not pregnant or breast feeding
* Males of childbearing age will be required to use medically approved contraception during and for 6 weeks following the last dose of study treatment.

Exclusion Criteria:

* Diabetes mellitus
* Clinical evidence of hypovolaemia
* Recent (\< 6 months) acute myocardial infarction or other major adverse cardiovascular event (STEMI, NSTEMI, unstable angina, coronary revascularization, stroke, transient ischaemic attack)
* Known left ventricular systolic dysfunction ( ejection fraction \<50%) or severe valvular heart disease
* Active malignant disease with a life expectancy of \<5 years
* Previous hyperkalaemia (K+ \>6.0 mmol/l) without precipitating cause
* Serum K+ \>5.0 mmol/l at entry
* Serum sodium \<130 mmol/l at entry
* Atrial fibrillation on screening ECG
* Use of a thiazide or loop diuretic in the 6 weeks prior to enrolment
* Pregnant or breastfeeding
* Known alcohol or drug abuse
* Active chronic diarrhea
* Recent active gout (within 3 months)
* Acute kidney injury in previous 3 months
* Documented Addison's disease
* On treatment with fludrocortisone, co-trimoxazole and / or lithium therapy
* Combination treatment with ACE inhibitor and ARB
* Office blood pressure \<115 mmHg systolic or \<50 mmHg diastolic
* Office blood pressure uncontrolled and requiring urgent non trial treatment in the opinion of the investigator
* Unable to provide informed consent