RATIONAL CLINICAL EVIDENCE AND EFFECT OF ANTI-ALDOSTERONE THERAPY.
Massimo Romano, Department of Clinical Medicine and Cardiovascular and Immunological Sciences,University Federico II of Naples.
Heart failure (IC) is a syndrome characterized by extreme severity in terms of mortality, quality of life and social costs. In the study of the Framingham 5-year survival rate of patients with congestive heart failure was less than 50%, the worst cancers in general (1). Obviously, the high mortality grows in NYHA class (60% at 1 year in III-IV) (2). Sudden death prevails in classes I-II and death from progressive heart failure in III-IV (3). The advent of drug therapy in ACE-inhibitors has led to enormous progress in the natural history of the JV. The addition of ACE inhibitor therapy with digitalis and diuretics is not only in preventing ventricular remodeling (4), a reduction in mortality in post-myocardial infarction and in patients with IC a mixed etiology (5-8), proportionately more evident in advanced NYHA classes with low ejection fraction (EF) (6) and a delayed transition from asymptomatic left ventricular dysfunction to congestive syndrome (9). Moreover, ACE inhibitors modestly improve the FE (10), their benefit on mortality tends to disappear after 2 years of treatment (7), do not demonstrate a positive effect on sudden death in patients with congestive heart failure (7), nor improveFE or 4 years to reduce mortality in patients with asymptomatic left ventricular dysfunction (9). In particular, the most severely compromised patients (NYHA IV) studied in the CONSENSUS I, receiving 40 mg of enalapril daily in addition to digitalis and diuretics showed a 27% reduction in mortality. Unfortunately, the mortality rate increased from 52% to 36% certainly not satisfactory despite the ACE inhibitor (6). On the other hand, patients with and without left ventricular dysfunction and congestive heart failure in NYHA class I-II showed a lack of benefit (0%) in mortality at 12 months (9).Why ACE-inhibitors, while showing a new era in the treatment of the CI could not be considered the ultimate solution? E 'known that the main drawbacks of therapy with these drugs are cough, hypotension and the onset of renal failure. In addition, there has to be considered progressive loss of effectiveness at a distance.This fact is evident from the observation that in SOLVD the combined risk of mortality and hospitalization was -40% and -27% after 12 months after 48 months (7).The production of angiotensin II is not only related to the enzyme ACE, but also a series of kinases that are activated to a level of various tissues and particularly in myocardial angiotensin II may be produced through non-ACE-dependent pathways and therefore not influenced by ACE inhibitors. A possible explanation for the loss of effectiveness of ACE inhibitors could be ascribed to the so-called phenomenon of 'escape "of aldosterone. This phenomenon was described in patients with hypertension (11). Despite the administration of captopril, at doses up to 600 mg / day was observed suppression of plasma levels of angiotensin II, aldosterone and the saliva in spite of increasing doses of captopril (11). This finding was confirmed in post-myocardial infarction with the use of the ACE inhibitor zofenopril (12). That the increase of aldosterone may play a role in the pathology of the CI shown by the observation that in severely compromised patients enrolled in the CONSENSUS-I, despite the high doses of enalapril administered, the patients who died showed higher values compared with aldosteronesurvivors (6). The phenomenon of 'escape' during therapy with ACE inhibitors and diuretics has been interpreted in various ways. It 'possible that the prolonged blockade of angiotensin converting enzyme, becomes the important role of other mechanisms of aldosterone biosynthesis, in particular the increase of ACTH, the levels of intracellular potassium and magnesium, l' endothelin. Also important is the role of tissue angiotensin in regulating the synthesis of mineralocorticoids in the adrenal cortex (13). Finally, we showed a extrasurrenalica production of aldosterone in the myocardium and blood vessels (14). There are numerous effects of aldosterone that can adversely affect the natural history of the JV. It induces the reabsorption of sodium and water in the distal renal tubule resulting in volume expansion resulting in extravascular volume overload with consequent deterioration of hemodynamic condition and further stimulate the renin-angiotensin-aldosterone system (SRAA). In addition, increased venous pressure, linked to the expansion of intravascular volume, contributes to the development of congestion and edema. Aldosterone induces vasoconstriction, increasing afterload, both for the increased responsiveness of the vessels vasoconstrictor effect of angiotensin II to the activity of receptors for aldosterone and the synthesis of mRNA encoding Key mineralocorticoid hormone biosynthesis in endothelial cells and smooth muscle cells of the pulmonary artery (15). Of particular clinical relevance is the effect of aldosterone to increase the urinary excretion of potassium and magnesium. Hypokalaemia el'ipomagnesemia, particularly in patients taking chronic diuretics, can cause atrial and ventricular arrhythmias and precipitate sudden death. And 'demonstrated the key role of aldosterone profibrotica activity in the myocardium (16-17) and vascular (18-19). Interstitial fibrosis, related to the activation of fibroblasts, induces a remodeling of the myocardium with impaired left ventricular function (16-17), while in the vessel wall increases its rigidity (18-19). In addition, aldosterone itself is involved in direct vascular damage (20), baroreceptor dysfunction (21) and prevents the 'uptake of norepinephrine by the myocardium (22-23). Not enough, it is known that the "clearance" impairment of the hormone is reduced in patients with congestive IC, implying that higher serum levels (24).
Spironolactone is an aldosterone antagonist (with mild diuretic action and in this role supplanted by loop diuretics), used in the past mainly as a potassium-sparing in patients treated with digitalis and diuretics. Some effects are independent of aldosterone antagonism. They could be related to the presence of a lactone ring and the steroid component of spironolactone. In fact they are shown: a positive inotropic effect, similar to that of digitalis, an increase of refractory period, a decrease in transmembrane efflux of potassium, an increase of action potential duration, which may explain the negative chronotropic effect of spironolactone (25). Its use had been gradually reduced both the fear of the possible deleterious effects on renal function and the risk of hyperkalemia in patients treated with ACE inhibitors is essential for the confidence that they were able to effectively monitor the SRAA. Clinical studies were used in conjunction with spironolactone and ACE inhibitors. In 124 patients in NYHA II-IV receiving spironolactone and captopril had shown an improvement of NYHA class in 72%, persistent in 3 years and a benefit Hospitalization (5 to 1.5 per year per patient). Six patients out of 124 for interrupting renal failure (26).A small study in patients with documented failure "refractory" to initori ACE, diuretics and water restriction that adding spironolactone compensated 80% of patients (27). Two studies documenting a reduction in ventricular arrhythmias in patients with NYHA II-III correlated with an increase during magnesemia adding spironolactone (22.28).
Massimo Romano, Department of Clinical Medicine and Cardiovascular and Immunological Sciences,University Federico II of Naples.
Heart failure (IC) is a syndrome characterized by extreme severity in terms of mortality, quality of life and social costs. In the study of the Framingham 5-year survival rate of patients with congestive heart failure was less than 50%, the worst cancers in general (1). Obviously, the high mortality grows in NYHA class (60% at 1 year in III-IV) (2). Sudden death prevails in classes I-II and death from progressive heart failure in III-IV (3). The advent of drug therapy in ACE-inhibitors has led to enormous progress in the natural history of the JV. The addition of ACE inhibitor therapy with digitalis and diuretics is not only in preventing ventricular remodeling (4), a reduction in mortality in post-myocardial infarction and in patients with IC a mixed etiology (5-8), proportionately more evident in advanced NYHA classes with low ejection fraction (EF) (6) and a delayed transition from asymptomatic left ventricular dysfunction to congestive syndrome (9). Moreover, ACE inhibitors modestly improve the FE (10), their benefit on mortality tends to disappear after 2 years of treatment (7), do not demonstrate a positive effect on sudden death in patients with congestive heart failure (7), nor improveFE or 4 years to reduce mortality in patients with asymptomatic left ventricular dysfunction (9). In particular, the most severely compromised patients (NYHA IV) studied in the CONSENSUS I, receiving 40 mg of enalapril daily in addition to digitalis and diuretics showed a 27% reduction in mortality. Unfortunately, the mortality rate increased from 52% to 36% certainly not satisfactory despite the ACE inhibitor (6). On the other hand, patients with and without left ventricular dysfunction and congestive heart failure in NYHA class I-II showed a lack of benefit (0%) in mortality at 12 months (9).Why ACE-inhibitors, while showing a new era in the treatment of the CI could not be considered the ultimate solution? E 'known that the main drawbacks of therapy with these drugs are cough, hypotension and the onset of renal failure. In addition, there has to be considered progressive loss of effectiveness at a distance.This fact is evident from the observation that in SOLVD the combined risk of mortality and hospitalization was -40% and -27% after 12 months after 48 months (7).The production of angiotensin II is not only related to the enzyme ACE, but also a series of kinases that are activated to a level of various tissues and particularly in myocardial angiotensin II may be produced through non-ACE-dependent pathways and therefore not influenced by ACE inhibitors. A possible explanation for the loss of effectiveness of ACE inhibitors could be ascribed to the so-called phenomenon of 'escape "of aldosterone. This phenomenon was described in patients with hypertension (11). Despite the administration of captopril, at doses up to 600 mg / day was observed suppression of plasma levels of angiotensin II, aldosterone and the saliva in spite of increasing doses of captopril (11). This finding was confirmed in post-myocardial infarction with the use of the ACE inhibitor zofenopril (12). That the increase of aldosterone may play a role in the pathology of the CI shown by the observation that in severely compromised patients enrolled in the CONSENSUS-I, despite the high doses of enalapril administered, the patients who died showed higher values compared with aldosteronesurvivors (6). The phenomenon of 'escape' during therapy with ACE inhibitors and diuretics has been interpreted in various ways. It 'possible that the prolonged blockade of angiotensin converting enzyme, becomes the important role of other mechanisms of aldosterone biosynthesis, in particular the increase of ACTH, the levels of intracellular potassium and magnesium, l' endothelin. Also important is the role of tissue angiotensin in regulating the synthesis of mineralocorticoids in the adrenal cortex (13). Finally, we showed a extrasurrenalica production of aldosterone in the myocardium and blood vessels (14). There are numerous effects of aldosterone that can adversely affect the natural history of the JV. It induces the reabsorption of sodium and water in the distal renal tubule resulting in volume expansion resulting in extravascular volume overload with consequent deterioration of hemodynamic condition and further stimulate the renin-angiotensin-aldosterone system (SRAA). In addition, increased venous pressure, linked to the expansion of intravascular volume, contributes to the development of congestion and edema. Aldosterone induces vasoconstriction, increasing afterload, both for the increased responsiveness of the vessels vasoconstrictor effect of angiotensin II to the activity of receptors for aldosterone and the synthesis of mRNA encoding Key mineralocorticoid hormone biosynthesis in endothelial cells and smooth muscle cells of the pulmonary artery (15). Of particular clinical relevance is the effect of aldosterone to increase the urinary excretion of potassium and magnesium. Hypokalaemia el'ipomagnesemia, particularly in patients taking chronic diuretics, can cause atrial and ventricular arrhythmias and precipitate sudden death. And 'demonstrated the key role of aldosterone profibrotica activity in the myocardium (16-17) and vascular (18-19). Interstitial fibrosis, related to the activation of fibroblasts, induces a remodeling of the myocardium with impaired left ventricular function (16-17), while in the vessel wall increases its rigidity (18-19). In addition, aldosterone itself is involved in direct vascular damage (20), baroreceptor dysfunction (21) and prevents the 'uptake of norepinephrine by the myocardium (22-23). Not enough, it is known that the "clearance" impairment of the hormone is reduced in patients with congestive IC, implying that higher serum levels (24).
Spironolactone is an aldosterone antagonist (with mild diuretic action and in this role supplanted by loop diuretics), used in the past mainly as a potassium-sparing in patients treated with digitalis and diuretics. Some effects are independent of aldosterone antagonism. They could be related to the presence of a lactone ring and the steroid component of spironolactone. In fact they are shown: a positive inotropic effect, similar to that of digitalis, an increase of refractory period, a decrease in transmembrane efflux of potassium, an increase of action potential duration, which may explain the negative chronotropic effect of spironolactone (25). Its use had been gradually reduced both the fear of the possible deleterious effects on renal function and the risk of hyperkalemia in patients treated with ACE inhibitors is essential for the confidence that they were able to effectively monitor the SRAA. Clinical studies were used in conjunction with spironolactone and ACE inhibitors. In 124 patients in NYHA II-IV receiving spironolactone and captopril had shown an improvement of NYHA class in 72%, persistent in 3 years and a benefit Hospitalization (5 to 1.5 per year per patient). Six patients out of 124 for interrupting renal failure (26).A small study in patients with documented failure "refractory" to initori ACE, diuretics and water restriction that adding spironolactone compensated 80% of patients (27). Two studies documenting a reduction in ventricular arrhythmias in patients with NYHA II-III correlated with an increase during magnesemia adding spironolactone (22.28).
The concern that adding spironolactone to ACE inhibitors and diuretics may induce hyperkalemia and renal failure was substantially lifted by the RALES pilot study that assessed the tolerability of increasing doses (25-100 mg) of spironolactone in 214 patients II NYHA-IV (29). The RALES study showed in 1663 patients with EF <35% in NYHA III-IV, all treated with ACE inhibitors and diuretics, with an average dose of 25 mg / day of spironolactone, a reduction of mortality by 30% 24 months, both died from sudden worsening of the JV (30). In addition, it noted a 35% reduction in hospitalizations due to an improvement in symptoms related to an improvement in NYHA class in 41%.Apart from a very unfortunate incidence of gynecomastia in 10% of the males there were substantial problems associated with hyperkalemia and renal failure (30). In addition, the positive effect of spironolactone was not related to a diuretic effect as the analysis of the "sodium retention score" showed no differences related to treatment. More positive data were dell'antialdosteronico beneficial effect in patients receiving beta-blocker. The dreaded hyperkalemia was observed in only 2% of patients vs 1% in those receiving placebo (30). Other observations support the data from the RALES. Spironolactone at a dose of 50 mg / day, in addition to ACE inhibitor-diuretic therapy, improves endothelial function, increases the activity of NO and inhibits the conversion of vascular angiotensin I to II heart failure in patients already treated with ACE inhibitors and diuretics in NYHA II-III (31). In patients with congestive IC high serum levels of markers of cardiac fibrosis are signs of a poor prognosis. They fall under treatment with spironolactone in particular in patients with the highest values and medically compromised (32). The plasma aldosterone is extracted from the myocardium of normal subjects and heart failure.Spironolactone inhibits the extraction of aldosterone in heart failure suggesting that the drug blocks the harmful effects of the hormone in patients (33). In addition, subjects in class II-III as well as the addition dell'antialdosteronico lead to an improvement of symptoms and FE induced a favorable balance simpatovagale calculated by analysis of heart rate variability (34).What to expect from treatment with antialdosteronici in patients in NYHA III-IV?Better control of hydro-saline retention, particularly in patients with hypotension and intolerant of high doses of ACE inhibitor and diuretics. In particular, it is extremely useful in clinical monitoring of urinary electrolytes (Na / K <1, indicative of activation of aldosterone). For our own clinical experience can reduce the dose of loop diuretic (which is often very acceptable to patients) due to the mild diuretic action of spironolactone and potentiating effect of natriuresis with its use at low doses (35). A protective effect against the deleterious effects of aldosterone in terms of myocardial fibrosis, which accelerates the race to the death for heart electrical activity is not homogeneous (QT dispersion), hypokalemia, hypomagnesemia simpatovagale imbalance, arrhythmias and risk of sudden death. It 'also know that I can get an additive effect with the beneficial effects of administration of beta-blockers that are already synergistic with ACE inhibitors (30). In addition, the best endothelial function and increased activity of NO may be beneficial in reducing vasoconstriction, and the post-load and probably improve exercise tolerance (36). What other patients may benefit dell'antialdosteronico? Data suggest that patients with endothelial dysfunction to atherosclerosis, hypertension and diastolic dysfunction linked to vascular and myocardial fibrosis may benefit in the long term. Without attention to the obvious risk of renal failure and hyperkalemia remains a significant problem the presence of antiandrogenic effects and gynecomastia. E 'reported that derivatives of spironolactone available in Europe, potassium canrenoate and canrenone can be administered at higher doses of spironolactone and reduced incidence of side effects.Basically what are the alternatives in addition dell'antialdosteronico? First the administration of high doses of ACE inhibitor. E 'is known that higher doses are more effective (37), if tolerated, which is not common in patients with congestive heart failure. Remains the fact that in one third of patients, however, there is evidence of "escape" of aldosterone and that the experience of the CONSENSUS-I showed an inverse relationship between plasma aldosterone and mortality in patients receiving 40 mg of enalapril (38). Another promising alternative is the use of inhibitors of angiotensin II in addition or as an alternative to ACE inhibitors. However apart from the significant cost-therapy (in absolute terms and in relation to the cost of the use of antialdosteronici) data show the following trials.These drugs rarely induce hypotension and renal failure, the symptoms are effective as an ACE inhibitor (39-40) and the combination effectively prevents ventricular remodeling (39).Moreover, while the antialdosteronico induces a significant improvement in mortality (30), in any large study of angiotensin II inhibitors reduce mortality compared with ACE inhibitors, alone or in addition (39-40) and in particular whether the two treatments and the association reduced sympathetic activation (39), plasma aldosterone decreases only adding candesartan enalapril (39) and only 17 weeks and goes back to 43 weeks.Finally it seems clear that inhibitors of angiotensin II is not expected a synergism with beta-blockers if not a negative interaction (40).REFERENCES1. 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