The therapy of patients with chronic heart failure (HF) due to systolic left ventricular dysfunction (SLVD) continues to evolve. There is agreement that all patients with HF due to SLVD should be treated with an angiotensin converting enzyme inhibitor (ACE-I) and a beta-adrenergic receptor blocking agent (BB) unless contraindicated or not tolerated. The role of angiotensin receptor blocking agents (ARBs) is more problematical. ARBs in comparison with an ACE-I appear similar in effectiveness but, as yet, have not been shown to be statistically equivalent in patients with chronic HF. It is likely however, based upon the results of the Valsartan in Acute Myocardial Infarction Trial (VALIANT1) study in patients with HF or SLVD post myocardial infarction (MI), that when used at an effective dose, such as valsartan 160mg bid, they are equivalent. However, until further studies are available, ACE-I remains the strategy of choice to inhibit the effect of angiotensin II in patients with chronic HF due to SLVD. The situation with regard to adding an ARB to an ACE-I and a BB, is controversial. In Valsartan Heart Failure Trial (Val-HeFT2), the addition of valsartan to standard therapy, which could include an ACE-I and a BB, failed to improve cardiovascular mortality although it did reduce hospitalizations for HF. In contrast, in the CHARM-Added trial,3 the addition of candesartan resulted in a reduction in cardiovascular mortality as well as hospitalization for HF. Therefore, further study will be required to determine whether the benefits of candesartan seen in the CHARM-Added trial3 are unique to candesartan or are common to other ARBs such as valsartan and whether adding an ARB to an ACE-I and a BB in a patient with HF due to SLVD is beneficial. Increasing data suggests, however, that adding an aldosterone blocker (AB) to an ACE-I and a BB reduces total and cardiovascular mortality in patients with SLVD. Further data will be required before AB can be recommended in all patients with HF due to SLVD current guidelines both in the US and Europe, which recommend AB in patients with severe heart failure due to SLVD based upon the Randomized Aldactone Evaluation Study (RALES) trial.4
RALES4 evaluated the AB spironolactone at an initial dose of 25mg daily in over 1,600 patients with severe HF (New York Heart Association (NYHA) Class III-IV with a history of being in Class IV HF). Patients with a baseline serum potassium ÔëÑ5.0meq/L or a creatinine ÔëÑ2.5mg/dl were excluded. The study was prematurely stopped at a mean follow-up of two years when patients randomized to spironolactone were found to have a 30% reduction in all cause mortality in comparison with placebo. The reduction in death associated with spironolactone was attributed both to a reduction in sudden cardiac death (SCD) and death due to progressive HF. In addition, there was a 35% reduction in the incidence of hospitalization for HF. The beneficial effect of spironolactone on mortality was seen in both males and females - ischemic and non-ischemic ideologies of HF, whether or not patients were on an ACE-I and/or a BB.
Although the point estimate for benefit in those patients on a BB was greater, overall, the confidence levels were wide due to the fact that, at the time this study was carried out, the results of the large scale BB studies in patients with HF due to SLVD were not available and therefore only 10% to 11% of patients were on a BB. However, the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS)5 in patients with HF and SLVD post-MI showed a significant benefit of AB in patients on both an ACE-I or ARB and a BB.Although adding an AB to an ACE-I could potentially cause serious hyperkalemia (KÔëÑ6.0meq/l), there was no significant increase of serious hyperkalemia in RALES and no deaths were attributable to hyperkalemia in patients randomized to the AB. It should, however, be emphasized that patients with a baseline potassium ÔëÑ5.0meq/l and/or renal insufficiency (creatinine ÔëÑ2.5mg/dl) were excluded and that potassium was carefully monitored with adjustment of the dose of the study medicine to half if the potassium level reached 5.5meq/l and was discontinued if potassium was ÔëÑ6.0meq/l and there was no other cause for this finding (such as the use of a non-steroidal anti-inflammatory agent or a potassium supplement). There was, however, a significant increase in the incidence of gynecomastia and breast pain in males. Spironolactone, although an effective blocker of the mineralocorticoid receptor (MR), is not a specific blocker and down-regulates androgen while up-regulating progesterone receptors. Eplerenone, a more recent AB, is a more specific blocker of the MR with little effect on androgen or progesterone receptors and hence is not associated with the side-effects seen with spironolactone such as gynecomastia, breast pain, and impotence in males as well as menstrual irregularities and libido changes in premenstrual females.
Although AB was shown to be effective in reducing total mortality in patients with severe chronic HF due to SLVD in RALES4 there was initially a reluctance of some clinicians to accept these results since they were thought to be surprising and it was assumed that the production of aldosterone from the adrenal gland would be inhibited by an ACE-I since angiotensin II (ATII) was known to be a major stimulus for aldosterone production. However, the effectiveness of AB in reducing total mortality in patients with HF due to SLVD was confirmed by the results of EPHESUS5 in patients with SLVD and HF post-MI. Increasing evidence has shown that, while ATII is a major stimulus for aldosterone production both from the adrenal gland, and locally in the myocardium, other stimuli such as potassium may be as or more important under certain circumstances and that the production of aldosterone may escape ('aldosterone escapeÔÇÖ)6 the effect of ATII inhibition or blockade. In fact, ATII is not required for aldosterone production as evidenced by the finding that aldosterone can be produced from the adrenal gland in the angiotensinogen knockout mouse in which ATII is not present.7
While increased serum aldosterone levels have been shown to be predictive of mortality in patients with severe HF,8 the effectiveness of AB in reducing mortality does not appear to be predicted by serum aldosterone levels. The failure of serum aldosterone levels to predict the effectiveness of AB could be due to the fact that aldosterone may be produced in the myocardium independent of the adrenal gland and/or by the fact that MR may be activated by cortisol as well as by aldosterone. Cortisol has greater affinity for the MR than aldosterone. However, under normal circumstances, cortisol is transformed to corticosterone, by the enzyme 11betaHSD2, which cannot activate the MR. Recent data suggest that 11betaHSD2 activity can be down-regulated in patients with essential hypertension,9 suggesting that, under certain circumstances, cortisol rather than aldosterone may activate the MR. 11betaHSD2 is sensitive to increased oxidative stress and the production of reactive oxygen species (ROS), which in heart failure are increased. Regardless of whether the MR is activated by aldosterone or cortisol, AB with either spironolactone or eplerenone is effective in blocking MR activation and its consequences. MRs are present in the renal tubule, myocardium, endothelium, brain, kidney, as well as in sweat glands and the gastrointestinal tract.10;11 Activation of MR in the renal tubule results in sodium retention, potassium, and magnesium loss. MR activation, while important for volume regulation, has a number of other important effects. Increasing data suggests that activation of MR results in an increase in vascular NAD(P)H oxidase activity with a consequent increase in ROS.12 Angiotensin II has been shown to increase vascular NAD(P)H oxidase activity and ROS. Both angiotensin II and aldosterone activate the NFkappaB and AP-1 signaling pathways, which are important in vascular and myocardial inflammation and fibrosis.13 Both aldosterone and angiotensin II activate the epidermal growth factor receptor (EGFR), an important transcription factor for phosphorylation including ERK1/2 and JNK.14 While both aldosterone and ATII share common signaling pathways, their effects are not identical such that optimal effects on ventricular remodeling and fibrosis as well as several other pathophysiologic parameters are obtained when both are blocked. Many of the pathophysiologic effects of ATII, although not all (such as vasoconstriction and hypertension), attributed to ATII have been shown to be mediated through aldosterone or activation of the MR as evidenced by the ability of AB to negate the effects of ATII on vascular inflammation, fibrosis, and experimental atherosclerosis.
Aldosterone production is often, although as pointed out above not always, the result of ATII-induced ATI receptor activation. However, aldosterone may not only cause an increase in ATII production, but may augment the adverse effects of ATII-induced ATI receptor stimulation. Aldosterone has been shown to up-regulate tissue ACE activity15 and prevent ATII-induced down-regulation of the ATI receptor resulting in a vicious cycle.16 Aldosterone has also been shown to down-regulate AT2 receptor expression during experimental hindlimb ischemia.16 Since AT2 receptor stimulation is thought to result in the release of nitric oxide and bradykinin as well as to promote apoptosis, increased aldosterone levels would tend to exacerbate the effects of ATI receptor stimulation and AB to ameliorate these effects.
Aldosterone or activation of the MR due to its effects on ROS also has a number of other important consequences on the pathophysiology of HF and AB, and a number of beneficial effects in patients on an ACE-I.17 The effects of MR activation include: destruction of nitric oxide; endothelial dysfunction; activation of several vascular adhesion molecules including COX-2, MCP-1, ICAM, VCAM; perivascular inflammation of microvessels in the heart, kidney, and brain; myocardial hypertrophy and fibrosis; ventricular remodeling; renal fibrosis; decreased myocardial norepinephrine uptake; and decreased heart rate variability and baroreceptor function; as well as activation of central sympathetic neurons. These pathophysiologic changes in addition to sodium retention and potassium loss predispose to progressive HF and sudden cardiac death in patients with HF due to SLVD.The effects of MR activation with production of ROS and subsequent destruction of NO also have important effects on thrombosis and fibrinolysis as evidenced by the ability of AB to decrease platelet activation, decrease fibrinogen levels, and improve the ratio of PAI-1/tpa and hence fibrinolysis.
The effects of aldosterone on activation of the MR outlined above explain, in large part, the beneficial effects of AB seen in RALES4 and in EPHESUS.5 EPHESUS5 confirms the important role of aldosterone and activation of the MR in patients with SLVD and provides further evidence that ABs are effective in reducing total and cardiovascular mortality in patients with SLVD treated with an ACE-I or ARB and a BB.
In EPHESUS,5 over 6,600 patients with evidence of an acute myocardial infarction, SLVD (left ventricular ejection fraction 40%), and evidence of HF, except in patients with diabetes mellitus in whom only SLVD post-acute MI was required, were randomized to eplerenone 25mg daily or placebo. After one month, if there was no evidence of hyperkalemia (potassium (5.5meq/l)), the study medication was increased to 50mg a day. Patients were randomized between days three and 14 post-acute MI, mean 7.3 days and follow-up was planned until 1,032 deaths occurred. Of note, patients had a mean age of 64 years,were normotensive, with a mean left ventricular ejection fraction of 33%. It should, however, be noted that the left ventricular ejection fraction could be determined at any time from the onset of acute MI to randomization, such that many patients had recovered from ventricular stunning or hibernation and/or undergone coronary revascularization after determination of their left ventricular ejection fraction, suggesting that the mean left ventricular ejection fraction at the time of randomization could have been considerably higher than 33%. Relatively few patients, <15%, had a prior history of HF, approximately one-quarter had a prior history of myocardial infarction, one-third were diabetics, and two-thirds had a history of hypertension, although they were normotensive at the time of randomization post-acute MI. Also of importance was the fact that at baseline, over 85% of patients were on an ACE-I or ARB, the vast majority on an ACE-I, 75% were on a BB, slightly less than half underwent coronary reperfusion, and slightly less than half received a statin.
EPHESUS5 had two co-primary end-points - total mortality and cardiovascular mortality/cardiovascular hospitalization. Cardiovascular hospitalization included hospitalizations due to non-fatal acute MI non-fatal stroke, ventricular arrhythmias, and HF. Most of the statistical power in the study, 0.04, was allotted to the end-point of total mortality with 0.01 allotted to the end-point cardiovascular mortality/cardiovascular hospitalizations.
At a mean follow-up of 16 months, patients randomized to eplerenone were found to have a significant 15% reduction in all cause mortality and a significant 13% reduction in cardiovascular mortality/cardiovascular hospitalization. The most frequent cause of cardiovascular mortality was sudden cardiac death, which was reduced by 21%, and the most frequent cause of cardiovascular hospitalization was heart failure, which was reduced by 15% and episodes of heart failure by 22%.
There was no increase in sexually-related side-effects attesting to the selectivity of eplerenone for the MR. There was, however, a 1.6% absolute increase in the incidence of serious hyperkalemia (potassium (6.0meq/l). There were no deaths attributable to hyperkalemia in patients randomized to eplerenone and the number of patients dropping out of the study due to side-effects were similar to those patients randomized to placebo. Of interest is the fact that the incidence of hypokalemia (potassium <3.5meq/l) was almost twice that of serious hyperkalemia. Hypokalemia may be as great or a greater risk than hyperkalemia and predisposes both to death due to progressive HF as well as to sudden cardiac death.The incidence of hypokalemia was significantly reduced by AB, suggesting that net potassium homeostasis was altered favorably.
Implications of the Pathophysiology of Aldosterone and/or MR Activation and the Results of RALES and EPHESUS
The most immediate implication relates to the use of ABs in patients with HF due to SLVD. Patients with severe chronic HF due to SLVD should be treated with an AB as well as an ACE-I or ARB and a BB if tolerated. Similarly, patients with SLVD and evidence of HF post-MI should be given an AB early post-infarction in addition to an ACE-I or ARB and a BB if tolerated. Patients who do not tolerate an ACE-I,ARB, or BB because of hypotension should be given a trial of an AB since ABs, although effective in lowering blood pressure in hypertensive patients, do not appear to lower blood pressure in normotensive patients, and hence may be better tolerated than an ACE-I, ARB, or a BB in those patients who have borderline low blood pressure as a result of HF or acute MI. While automatic implantable cardiac defibrillators (AICDs) have been shown to be effective in preventing sudden cardiac death and reducing total mortality post-MI it should be emphasized that they are not effective in reducing total mortality when applied early post-infarction (between six and 40 days post-infarction) and when implanted 30 days after onset of infarction do not appear to reduce total mortality for over a year (DYNAMIT). In contrast, ABs appear to be effective in reducing sudden cardiac death and total mortality relatively early post-infarction and therefore can be viewed as an important bridge to prevent early mortality post-infarction in those with a low left ventricular ejection fraction (30% to 35%) to allow patients with persistent SLVD to obtain the long-term benefits of AICD implantation.18 Early use of an AB will likely prevent many patients from developing severe SLVD (left ventricular ejection fraction (30% to 35%)), hence the need for long-term AICD implantation. Similarly, in patients with chronic HF and SLVD, ABs may have an important additive effect with AICDs in reducing death due to progressive heart failure as well as sudden cardiac death.
Although there has not, as yet, been a large-scale mortality trial in patients with chronic HF and SLVD with mild HF (NYHA Class II), it is likely that ABs will also be effected in these individuals in preventing death due to progressive HF and sudden cardiac death as well as hospitalization for HF. Suggestive evidence for this comes from studies demonstrating the effect of ABs in improving left ventricular ejection fraction, heart rate variability, baroreceptor function, myocardial collagen formation, endothelial function, and exercise tolerance in patients with mild heart failure treated with an ACE-I and/or a BB. Proof of this hypothesis must, however, await confirmation by adequately powered large-scale prospective randomized studies.
ABs may also have an important role in HF associated with preserved systolic function. There is a good correlation between the extent of myocardial fibrosis, and diastolic myocardial function, as assessed by the echocardiographic E/A ratio and AB, have been to improve the E/A ratio. A large-scale randomized study is currently planned by the National Heart Lung and Blood Institute (NHLBI) to explore the role of the AB eplerenone in these patients.
ABs may also play an important role in the prevention of HF. AB has been shown to reduce left ventricular mass alone and in conjunction with an ACE-I in patients with essential hypertension and echocardiographic evidence of left ventricular hypertrophy.19 Essential hypertension and left ventricular hypertrophy are recognized as being important precursors of HF.ABs have also been shown to be of value in controlling blood pressure in patients resistant to blood pressure control with three or more antihypertensive agents at target doses, regardless of whether or not they had an increase in plasma or urinary aldosterone in relationship to renin. ABs will also be likely to be effective in preventing atherosclerosis and cardiovascular events in patients with known vascular disease and those with diabetes mellitus currently treated with an ACE-I on the basis of the Heart Outcome Prevention Evaluation Study (HOPE) study.20 In experimental studies ABs have been shown to prevent ATII-induced atherosclerosis and to reduce macrophage oxidized low-density lipoprotein-cholesterol levels.21
ABs may also have an important role in patients with end-stage renal vascular disease (ESRVD). Patients with ESRVD on either hemo or peritoneal dialysis have a relatively high mortality rate and incidence of cardiovascular events including myocardial infarction, stroke, and HF. Preliminary data suggest that ABs may be safe in these patients despite the presence of severe renal dysfunction at baseline.
A pilot study testing the safety and efficacy of eplerenone in patients with ESRVD is currently underway, and if short-term surrogate markers are favorably effected without a high incidence of serious hyperkalemia, one would predict that ABs will be effective in reducing total mortality and cardiovascular events in these patients. ABs may also have an important role in preventing ESRVD. Initial studies show that ABs alone and/or in conjunction with an ACE-I are effective in reducing the extent of albuminuria in patients with essential hypertension and those with diabetes mellitus.
ABs may also play an important role in postmenopausal women. Current hormone replacement therapy (HRT) has been shown to increase cardiovascular risk in postmenopausal women.22 Drospirenone 3mg is a potent progesterone which also has the equivalent of approximately 25mg of spironolactone.23-24 In conjunction with estradiol, it is currently being evaluated in postmenopausal women. Initial studies show that it significantly reduces blood pressure in hypertensive postmenopausal women when used alone and/or in conjunction with an ACE-I without a significant increase in serious hyperkalemia. Conventional HRT has not been shown to significantly lower blood pressure in hypertensive postmenopausal women. In view of the pathophysiologic mechanisms reviewed above, the results of RALES4, and EPHESUS5, it can be postulated that drospirenone/estradiol could have an important role in preventing the development of hypertension, atherosclerosis and cardiovascular events in postmenopausal women who require HRT for symptom relief.
Which AB Should be Used in Cardiovascular Therapy?
Both spironolactone and eplerenone are effective in blocking the effects of MR activation regardless of activation by aldosterone or cortisol. Spironolactone has been proven to reduce total mortality in patients with severe chronic HF due to SLVD at a mean dose of 26mg and eplerenone effective in reducing total mortality in patients with evidence of HF and SLVD post-acute MI at a mean dose of 53mg daily. One should, however, be cautious in extrapolating data for effectiveness of a therapeutic strategy in chronic HF to patients with acute MI and vice versa, although it is likely that both spironolactone and eplerenone would be effective in either indication. However, without direct comparative study, a definitive answer as to their relative effectiveness is not available, and it would be prudent to use each agent at its effective dose in its proven indication. It is clear from years of experience with spironolactone that it is often not tolerated because of sexually-related side-effects.
In view of this, eplerenone, which does not appear to have the sexually-related side-effects associated with spironolactone would be the AB of choice. A patient who discontinues spironolactone due to its sexually-related side-effects would be at risk of hospitalization for HF and death due to progressive HF or sudden cardiac death. Some clinicians have suggested that eplerenone be used only in those patients who do not tolerate spironolactone. It is, however, likely that this strategy will leave many patients exposed to increased cardiovascular risk for several months after they discontinue spironolactone before they are seen by their clinician and an attempt made to institute eplerenone. On the other hand, spironolactone is generic and consequently less expensive than eplerenone, and would therefore be recommended to obtain the benefits of ABs in patients who otherwise could not afford eplerenone.
In the future, drospirenone/estradiol might be the preferred aldosterone blocking strategy in postmenopausal women requiring HRT for symptom relief in order to prevent hypertension and its consequences. Large-scale prospective randomized studies will, however, be required to determine its net benefit/risk ratio and place in the therapy of postmenopausal women. Drospirenone/estradial is currently available both in the US and in Europe as a birth control strategy and has been used in many thousands of premenopausal women without a major risk of serious hyperkalemia or other aldosterone-blocking-related side-effects suggesting it will likely play an important role in the therapy of postmenopausal women. Drospirenone/estradiol is, however, not approved for use by the US Food and Drug Administration (FDA) for use in postmenopausal women, although it is available for HRT in several European countries.
In conclusion, activation of MRs in the renal tubule, endothelium, myocardium, kidney, and brain results in sodium retention, volume expansion, and, most importantly, an increase in ROS. AB prevents an increase in ROS, stimulation of various adhesion molecules and growth factors, sodium retention and its consequences including hypertension. The effectiveness of AB demonstrated in RALES4 and EPHESUS5 in reducing total mortality in patients with SLVD has important implications for these patients and, in the future, may have an even more important role in preventing cardiovascular mortality and cardiovascular events. It can be postulated that where we use an ACE-I or ARB today, we will use an ACEI and/or an ARB as well as an AB in the future. The next decade will provide the opportunity to test this hypothesis and if it is proven to extend the benefits of AB on mortality and cardiovascular events to an even larger number of patients. Ôûá