Is Spironolactone Safe and Effective in the Treatment of Cardiovascular Disease in Mild Chronic Renal Failure?
Condition: Chronic Kidney Disease; Cardiovascular Disease
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Failure, Chronic; Cardiovascular Diseases
Study type: Interventional
Phase: Phase 2

Summary: 
      Patients with kidney failure have a poor survival rate that is due to a much higher than
      average rate of heart and vascular disease. The reason that kidney failure causes heart
      disease is unknown but recent research suggests that a hormone called aldosterone, which is
      increased in patients with kidney disease may damage the heart and blood vessels.

      The investigators propose, using a randomized blinded trial, to find out whether drugs that
      inhibit the actions of aldosterone have beneficial effects on the cardiovascular system in
      patients with kidney failure
    

Detailed description: 
      Cardiovascular disease leads to the death of over half of patients with chronic renal failure
      (CRF) but the causes of this 'vasculopathy' remain unknown. Aldosterone is present in the
      circulation of renal failure patients at high levels and is known to exert damaging effects
      upon the myocardium, vasculature and autonomic nervous system. Patients will be randomised to
      determine the effect of chronic treatment with an aldosterone receptor inhibitor on left
      ventricular mass, diastolic function, arterial stiffness and autonomic function. All of these
      endpoints are predictors of mortality so that the results of this study may yield information
      of prognostic value and provide the basis for a future mortality study.

      Premature cardiovascular disease is the leading cause of mortality in CRF accounting for
      approximately 60% of deaths. Across the age range, cardiovascular mortality is 10 and 20
      times greater than controls but in young patients the relative risk is extreme. Dialysis
      patients under the age of 45 have over 100 times the risk of cardiovascular death than the
      control population. An increased risk is also present in patients with mild renal impairment,
      which has been estimated to occur in approximately 8% of the population. Thus, renal
      dysfunction is a potentially important risk factor for coronary artery disease in the general
      population. This study builds upon previous and current BHF funded work by Dr Townend and
      colleagues in Birmingham (PG97/162 and PG02/153) which has resulted in a number of
      publications in the area of cardiovascular disease in renal failure but takes a new approach
      examining the potential role of aldosterone in renal 'vasculopathy'.

      Pathophysiology of myocardial and vascular disease in chronic renal failure:

      The main pathological features of the cardiovascular system of patients with renal failure
      are:

        1. LVH often accompanied by systolic and diastolic dysfunction.

        2. Arterial wall thickening, stiffening and calcification (arteriosclerosis).

        3. Coronary and peripheral artery atherosclerosis.

      The pathophysiology of cardiovascular disease in renal failure is poorly understood but as
      renal function declines, a range of abnormalities occur that may exert adverse effects upon
      the cardiovascular system. Hypertension, chronic anaemia and activation of the
      renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system all contribute to
      the development of myocardial hypertrophy and fibrosis. The same abnormalities may also lead
      to muscular hypertrophy and fibrosis of the arterial walls including the aorta. In
      combination with an increase in extracellular matrix, loss of elastic fibres and diffuse
      medial calcification, the arterial wall changes lead to arterial 'stiffening'. In addition to
      these adverse haemodynamic and structural changes, endothelial injury, the first
      physiological manifestation of atherosclerosis, occurs early in the course of renal failure.

      Hypertension, anaemia, chronic inflammation, an atherogenic lipid profile, diabetes and less
      certainly hyperhomocysteinaemia and abnormal calcium/phosphate metabolism are possible causes
      of endothelial injury and recent evidence suggests that to this list should now be added
      angiotensin II (ANG II) and aldosterone.

      Aldosterone and cardiovascular disease: The fundamental role of the RAAS in cardiovascular
      disease is apparent from the results of many large ACE inhibitor trials. In patients with
      chronic heart failure and in those with or at high risk of coronary artery disease, ACE
      inhibitors improve survival, functional status and hospitalisation. These beneficial effects
      have been attributed to prevention of the multiple adverse effects of ANG II. More recently,
      evidence has accumulated in support of an important role for aldosterone.

      The persistent elevation of ANG II and aldosterone concentrations during ACE inhibitor
      therapy is often termed 'escape'. Aldosterone secretion from the adrenal cortex persists in
      response to ANG II (produced by the non ACE enzymatic conversions of ANG I) and a rise in
      plasma potassium. Comparison of the effects of adding ANG II receptor blockers (ARB) and
      aldosterone receptor antagonists to ACE inhibitors in heart failure trials suggests that it
      is aldosterone escape that exerts the greater pathophysiological effects. In ValHeFT the
      addition of valsartan to ACE inhibitor therapy had no detectable effect on mortality. In both
      the RALES and EPHESUS trials however, mortality was significantly reduced by the addition of
      spironolactone (RALES) or eplerenone (EPHESUS) to standard therapy including ACE inhibitors.

      Aldosterone is synthesised in numerous tissues and mineralocorticoid receptors are present in
      the brain, heart and blood vessels as well as the kidney. In addition to its physiological
      role in the kidney aldosterone exerts several pathological actions on the cardiovascular
      system:

        1. Endothelial dysfunction: The administration of aldosterone and sodium to rats results in
           transmural coronary arterial inflammation with monocyte and macrophage infiltration and
           the expression of inflammatory markers such as COX-2, MCP-1 and VCAM-1. The
           administration of an aldosterone antagonist markedly reduced this inflammatory response.
           Although a similar response occurred with infusion of ANG II, this was in part dependent
           on aldosterone synthesis as it was reduced by adrenalectomy but restored by aldosterone
           infusion. In vitro, vascular endothelial fibrinolysis is inhibited by aldosterone as a
           result of an increase in plasminogen activator inhibitor (PAI-1). In humans, primary
           hyperaldosteronism is associated with endothelial dysfunction compared to normal and
           hypertensive controls. In patients with chronic heart failure, aldosterone receptor
           blockade with spironolactone results in significant improvement in endothelial dependent
           vasodilatation and vascular nitric oxide bioactivity.

        2. Myocardial and vascular hypertrophy and fibrosis: Aldosterone appears to cause
           myocardial and vascular injury independently of effects on blood pressure. Chronic
           aldosterone infusion and sodium loading resulted in myocardial fibrosis and ventricular
           hypertrophy in rats. Treatment with aldosterone receptor antagonists prevented aortic
           and myocardial fibrosis in rat models of hypertension even in the absence of blood
           pressure lowering. In addition, in aldosterone treated stroke-prone hypertensive rats,
           spironolactone exerted a powerful protective effect against the development of
           nephrosclerotic and cerebrovascular lesions. The mechanisms of action of aldosterone may
           include upregulation of AT1 receptors, direct effects on fibroblast collagen synthesis
           and possibly decreased matrix metallo-proteinase secretion. In humans, aldosterone
           concentrations have been correlated with mortality in chronic heart failure, with the
           severity of LVH in non-diabetic renal failure and hypertension and negatively with
           carotid artery compliance in hypertension. When added to ACE inhibitors, treatment with
           aldosterone receptor antagonists further reduces LVH in both hypertension and heart
           failure. Myocardial collagen turnover (a marker for fibrosis) was significantly reduced
           by spironolactone in the RALES study and the fall in the marker of this index was
           related to the mortality benefit.

        3. Autonomic dysfunction: Like heart failure, renal failure is characterised by autonomic
           dysfunction manifest by high resting sympathetic tone, impaired vagal control and
           reduced baroreflex sensitivity. The prognostic significance of autonomic dysfunction is
           not established for renal failure, but in chronic heart failure, the degree of
           dysfunction, measured by techniques such as heart rate variability, is a powerful and
           independent marker of prognosis. This evidence, coupled with the efficacy of
           beta-blocker therapy in heart failure, suggests that autonomic dysfunction can actively
           contribute to mortality and cardiovascular disease progression. Aldosterone appears to
           increase sympathetic and reduce cardiac vagal influence. The action of the sympathetic
           nervous system is increased as a result of reduced uptake of noradrenaline in the
           myocardium. A reduction in baroreflex sensitivity in response to aldosterone infusion
           has been demonstrated in both animals and man and in heart failure patients, an increase
           in heart rate variability occurred in response to aldosterone inhibition. We have
           recently shown that acute aldosterone receptor inhibition results in improved HRV
           markers of cardiac parasympathetic control in healthy subjects.

        4. Is the effect of aldosterone receptor blockade with spironolactone mediated by lowering
           arterial pressure? Spironolactone is now recognised as an effective anti-hypertensive
           agent for patients with hypertension, even when this is resistant to other drugs. It is
           therefore necessary to consider whether any improvements that do occur in measures such
           as arterial stiffness and LV mass after spironolactone might simply be due to this
           effect. Several lines of evidence suggest that the effects of aldosterone inhibition are
           independent of blood pressure. The work of Rocha et al. in experimental animals clearly
           showed that inhibition of myocardial and aortic fibrosis, nephrosclerotic and
           cerebrovascular lesions by aldosterone inhibition occurred in the absence of changes in
           blood pressure. In humans, in the RALES and EPHESUS studies, the mortality effects
           occurred in the absence of any fall in blood pressure. In patients with controlled
           hypertension and diabetic nephropathy, a group relevant to the work proposed in this
           application, high dose spironolactone treatment (100 mg per day) did not result in a
           fall in either systolic or diastolic blood pressure but did reduce albuminuria
           independently of blood pressure. Finally, Professor Struthers, a national authority on
           aldosterone and the cardiovascular system, has shown that in trials of spironolactone in
           severe heart failure and diabetes, no fall in blood pressure occurred with
           spironolactone suggesting that the beneficial action of spironolactone on endothelial
           function was not mediated by such an effect. (personal communication). Nevertheless, an
           effect mediated by a reduction in blood pressure cannot be excluded. In order to examine
           this hypothesis, we will examine the relationship between the magnitude of changes in
           end points and changes in blood pressure.

      The renin-angiotensin-aldosterone system in chronic renal failure: The importance of the RAAS
      in CRF is illustrated by the efficacy of ACE inhibitors in retarding the progression of
      diabetic and non-diabetic renal disease. The significance of ANG II mediated renal damage was
      shown by the finding that combined treatment with ACE inhibitors and ARBs further slows the
      progression of non-diabetic renal disease compared with either agent alone.

      Plasma aldosterone concentrations are increased in animal models of CRF as well as in
      patients with even mild renal impairment and several lines of evidence point to a major role
      of aldosterone in promoting progressive renal dysfunction. Observational studies in patients
      with primary hyperaldosteronism found the prevalence and degree of proteinuria to be greater
      than in patients with essential hypertension. Several experimental animal models are
      consistent with the concept that aldosterone can mediate renal injury. In patients with
      diabetic nephropathy and aldosterone escape despite ACE inhibitor therapy, aldosterone
      blockade significantly reduced proteinuria with no change in blood pressure. Little attention
      has been paid however, to the potentially beneficial effects of aldosterone antagonism on the
      cardiovascular system in renal failure. In a single, small uncontrolled study of 13 patients
      with diabetic nephropathy on established ACE inhibitor therapy, left ventricular mass index
      was significantly reduced after 24 weeks of treatment with spironolactone.

      Left ventricular hypertrophy and arterial stiffness as endpoints in studies in chronic renal
      failure:

      LVH: Up to 80% of patients have LVH at the start of dialysis. As with other patient groups,
      LVH is a powerful independent predictor of mortality in CRF and regression of LVH is
      associated with improved cardiac outcome.

      Arterial stiffness: Large conduit arteries buffer the changes in pressure resulting from
      intermittent ventricular ejection. Stiffening of the arteries (loss of arterial compliance)
      leads to increased systolic and pulse pressure; indeed arterial stiffness is the principal
      determinant of pulse pressure in patients with CRF. It is also closely associated with LVH
      and its progression over time. Recent prospective studies have demonstrated that measures of
      aortic stiffness, such as aortic pulse wave velocity (PWV), and augmentation of central
      aortic pressure by early wave reflections (AIx), are independent and powerful predictors of
      all-cause and cardiovascular mortality in patients on dialysis. Indeed, in a recent
      prospective study, lowering aortic PWV, mainly by use of an ACE-inhibitor, was associated
      with an improved survival in dialysis patients. This reduction in aortic PWV was associated
      with a parallel reduction in mean arterial and pulse pressure in survivors. In contrast, in
      those who died from cardiovascular events, although mean arterial pressure was lowered to the
      same extent as in survivors; neither pulse pressure nor aortic PWV was significantly modified
      by ACE inhibition. These findings suggest that arterial stiffness is not merely a marker of
      arterial damage but a potentially reversible factor contributing to mortality.

      In summary: Activation of the RAAS occurs early in the course of renal disease and both
      angiotensin and aldosterone are likely to be important factors in the pathogenesis of
      arterial stiffness, LVH and autonomic dysfunction. ACE inhibitors reduce arterial stiffness
      and LVH as well as the progression of renal dysfunction but levels of circulating aldosterone
      may remain high and the effects of aldosterone inhibition are unknown.
    

Intervention name(s): Spironolactone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): All patients receive a 4 week open labeled run in phase of 25mg spironolactone daily after which they are randomized to continue or receive matched placebo for 8 months.; matching placebo
Intervention MeSH terms: Spironolactone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Aldosterone; Spironolactone; Chronic Kidney Disease; Arterial Stiffness