by Andre Garcia
Congestive Heart Failure (CHF) is a clinical syndrome corresponding to the inability of the heart to meet the metabolic requirements of the body at normal filling pressures. Although many times heart failure is mainly precipitated by left ventricular systolic dysfunction, it sometimes also can be secondary to diastolic dysfunction; or a combination of both. CHF is highly prevalent in the USA, Canada, Europe, Australia (corresponding to the "developed countries" as sometimes is told). Mortality, morbidity, direct and indirect costs; all remain being very high yet. The hemodynamic model of CHF has been largely abandoned and replaced by the concept of left ventricular remodeling; which indicates stretching and dilation with subsequent reduction in left ventricular function. Causes include: Coronary Artery Disease (CAD), Myocardial Infarction (MI), hypertension, valvular heart disease, diabetes, congenital heart defects, anemia, and alcoholism. Independently of the precipitating injury, neuro-hormonal mechanisms are activated and promote the remodeling process. These include the Renin-Angiotensin-Aldosterone System (RAAS) and the sympathetic nervous system. A rise in endothelin-1 production, resulting from dysfunctional endothelium, also occurs and contributes to vasoconstriction. Inflammatory markers and cytokines are increased, hence further exacerbating endothelial dysfunction (a "vicious cycle" thereby occurs). A rise in angiotensin II promotes apoptosis (programmed cell death), hypertrophy, and fibrosis. Angiotensin II also causes an increase in aldosterone secretion, which in return augments the harmful effects of angiotensin II on myocardium and promotes adverse remodeling.
Congestive Heart Failure (CHF) is a clinical syndrome corresponding to the inability of the heart to meet the metabolic requirements of the body at normal filling pressures. Although many times heart failure is mainly precipitated by left ventricular systolic dysfunction, it sometimes also can be secondary to diastolic dysfunction; or a combination of both. CHF is highly prevalent in the USA, Canada, Europe, Australia (corresponding to the "developed countries" as sometimes is told). Mortality, morbidity, direct and indirect costs; all remain being very high yet. The hemodynamic model of CHF has been largely abandoned and replaced by the concept of left ventricular remodeling; which indicates stretching and dilation with subsequent reduction in left ventricular function. Causes include: Coronary Artery Disease (CAD), Myocardial Infarction (MI), hypertension, valvular heart disease, diabetes, congenital heart defects, anemia, and alcoholism. Independently of the precipitating injury, neuro-hormonal mechanisms are activated and promote the remodeling process. These include the Renin-Angiotensin-Aldosterone System (RAAS) and the sympathetic nervous system. A rise in endothelin-1 production, resulting from dysfunctional endothelium, also occurs and contributes to vasoconstriction. Inflammatory markers and cytokines are increased, hence further exacerbating endothelial dysfunction (a "vicious cycle" thereby occurs). A rise in angiotensin II promotes apoptosis (programmed cell death), hypertrophy, and fibrosis. Angiotensin II also causes an increase in aldosterone secretion, which in return augments the harmful effects of angiotensin II on myocardium and promotes adverse remodeling.
Angiotensin-converting enzyme inhibitors (ACEi) were the first class of drugs proved to reduce mortality on patients with CHF. In 1987, NEJM (New England Journal of Medicine) published the results of CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study), showing that enalapril, used at 2.5 to 40mg per day dosage, on patients with severe (class 4) CHF, resulted in a 40% reduction in risk of death (versus placebo). Later, in 1991, NEJM, again, published a new study about enalapril on patients with severe CHF - it was the SOLVD (Studies of Left Ventricular Dysfunction). (Source: N Engl J Med 1991 Aug 1;325(5):293-302 PMID: 2057034, UI: 91278933) SOLVD was focused on the effect of enalapril on mortality and hospitalization in CHF patients with ejection fractions less than 35%. The reduction in risk of death was 22% (versus placebo). This 2 studies were the first giving some good hope in front of a very catastrophic and disastrous clinical picture (CHF) until then. Enalapril was the hero; the angel that saved lives! Next, many, many studies showed (thus confirming) the same idea - ACEi significantly reduced mortality on patients with severe CHF. This became, then, an (almost) unquestionable and irrefutable golden rule/pearl in the treatment of CHF.
Nowadays, about ACEi, we know as being Level of Evidence A: *) ACEi are recommended in all patients with CHF and left ventricular dysfunction unless a contraindication exists (ACC/AHA Guidelines). *) ACEi should be used in all patients with a history of MI and asymptomatic reduced left ventricular function irrespective of ejection fraction (ACC/AHA Guidelines).
ACEi, as name suggests, inhibit the angiotensin-converting enzyme, thereby blocking the conversion of angiotensin I to angiotensin II and bradykinin breakdown. However, since there are other angiotensin II generation pathways, even a total (100%) ACE blockade would not put angiotensin II levels on absolute zero. Here, angiotensin-receptor blockers (ARBs) can fit in.
ARBs bind to the type 1 angiotensin II (AT1) receptor and block it, what leads to plasma renin, angiotensin I, and angiotensin II increased levels. Blockade of the AT1 receptor will also result in the stimulation of the AT2 receptor (physiologically paradoxical), what will increase nitric oxide (NO) production and will trigger other molecular actions which mediate vasodilation; inhibition of fibrosis and of apoptosis (hence, less ventricular remodeling will happen; more time patient will be alive). Overall, ACEi are cheaper, older and better known than ARBs. However, ARBs tend to be better tolerated (less side effects; specially - less persistent cough and recurrent angioedema - very probably because bradykinin levels will not be raised). Many studies were then done, aiming to directly compare the efficacy and safety of the yet "newborns" (ARBs) versus their "bigger and older cousins" (ACEi). This would not be an easy task for ARB laboratory producers - ACEi had the "golden crown of king" - the only drug class (before Losartan, the first ARB on the market, on 1997) which until then had proved to reduce mortality on patients with CHF, do you remember? Well, ARBs proved to have an efficacy similar to ACEi in treatment of CHF and also for patients with non-complicated or complicated hypertension; MI; and diabetic nephropathy. Great, isn't it? The list of studies is enormous.
Sometimes you can find results different from what I have just said about ARBs efficacy and safety, but such studies were methodologically incorrect (or "less correct"), so it became consensual to use an ACEi as first option to antagonize angiotensin II (same efficacy, less price), and only switch to an ARB if patient cannot tolerate an ACEi due to its side effects (persistent cough is, by far, the side effect more frequently forcing patients to give up using an ACEi; but angioedema, although rarely, can kill, if it makes airway obstruction). This seems a prudent and intelligent strategy; I agree. But from present, I would like all doctors to think on a question - maybe now is the moment to begin researching a new plan - why not associate a lower-dose of an ACEi with a lower-dose of an ARB? It makes sense to suppose a better efficacy (by synergy) and less side effects (lower-dose of each one). Why not give a try on this hypothesis rather than continue repeating the same type of studies (ACEi versus ARB - who wins? - neither! - it's a draw! - surprised? - no! -I have already read it so many times!!)? Feel free to discuss your point of view about this! ;) Statistical and methodological analysis of Clinical Trials always is a supreme challenge for all MDs ;)
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