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Angiotensin II receptor antagonists
See also individual agents
General information
Inhibition of the renin–angiotensin system by ACE inhibitors has proved efficacious in the treatment of hypertension, cardiac failure, myocardial infarction, in secondary prevention after myocardial infarction, and for kidney protection in diabetic and non-diabetic nephropathy. The development of specific antagonists to subtype 1 of the angiotensin II receptor (AT1) has provided a new tool for inhibiting the renin–angiotensin system.
Experimental data and preliminary clinical experience have suggested that the efficacy of AT1 receptor antagonists in the treatment of hypertension is similar to that of ACE inhibitors. However, the two drug categories also have potential differences, because of their different mechanisms of action. Since they have an action that is exclusively targeted at angiotensin II, the AT1 receptor antagonists should lack the effects of ACE inhibitors that are mediated through the accumulation of bradykinin and other peptides. Furthermore, since a significant amount of angiotensin II can be generated by enzymes other than ACE, particularly the chymases, AT1 receptor antagonists achieve more complete blockade of the effects of angiotensin than ACE inhibitors do. Nevertheless, whether these differences are clinically important is still being investigated.
The first attempt at blocking the AT1 receptor with the peptide analogues of angiotensin II resulted in the discovery of saralasin, an antagonist that lacked oral activity and had partial agonist properties. Losartan was the first agent in the new class of orally active AT1 receptor antagonists. Other agents with different receptor affinities and binding kinetics, such as candesartan, eprosartan, irbesartan, losartan, tasosartan, telmisartan, and valsartan, have since become available [ ]. Variations in chemical structure may lead to marginal but potentially clinically significant differences in the time-effect profile. Non-competitive antagonists may have longer durations of action than competitive antagonists, because they bind irreversibly to angiotensin II receptors. There have been several reviews of this class of agents [ , ]. All have emphasized their remarkable tolerance profile. In double-blind, placebo-controlled trials, the type and frequency of reported adverse effects were consistently no different from placebo [ ].
The angiotensin II receptor antagonists are being considered for the treatment of diseases other than hypertension (heart failure with or without left ventricular systolic dysfunction, during and after acute myocardial infarction, diabetic nephropathy, other forms of glomerulopathy, re-stenosis after coronary angioplasty, and atherosclerosis).
General adverse effects and adverse reactions
The safety profile of angiotensin II receptor antagonists is so far remarkably good. Except for hypotension, virtually no dose-related adverse effects have been reported. Headache, dizziness, weakness, and fatigue are the most common adverse effects. There have been reports of raised liver enzymes [ ], cholestatic hepatitis [ ], and pancreatitis [ ] with losartan. Several cases of angioedema have been reported but no other obvious hypersensitivity reactions.
Drug studies
Comparative studies
The RESOLVD (Randomized Evaluation of Strategies for Left Ventricular Dysfunction) trial was a pilot study investigating the effects of candesartan, enalapril, and their combination on exercise tolerance, ventricular function, quality of life, neurohormone concentrations, and tolerability in congestive heart failure [ ]. Candesartan alone was as effective, safe, and well tolerated as enalapril. The combination of candesartan with enalapril was more beneficial in preventing left ventricular remodelling than either alone. Although the trial was not powered to assess effects on cardiovascular events, it was terminated prematurely because of a trend toward a greater number of events in the candesartan alone and combination groups compared with enalapril alone.
In the ELITE study losartan produced greater survival benefit in elderly patients with heart failure than captopril [ ]. ELITE II was performed in order to confirm this. It included 3152 patients aged 60 years and over with NYHA class II–IV heart failure and was powered to detect a clinically significant effect on all-cause mortality. Median follow up was 555 days. Losartan was not superior to captopril in improving survival; however, it was better tolerated. Significantly fewer patients taking losartan withdrew because of adverse effects, including effects attributed to the study drug, or because of cough. Fewer patients discontinued treatment because of adverse effects (10% versus 15%), including effects attributed to the study drug (3% versus 8%) or because of cough (0.4% versus 2.8%) [ ].
The results of SPICE (The Study of Patients Intolerant of Converting Enzyme Inhibitors) and of the previously published RESOLVD led to the design of the current CHARM trial, which is investigating the effect of candesartan in 6600 patients with heart failure in three different ways: versus an ACE inhibitor in patients with preserved left ventricular function; versus placebo in patients intolerant of ACE inhibitors; and in addition to ACE inhibitors in all other patients. While waiting for the results of this trial it is advisable to continue to use ACE inhibitors as the initial therapy for heart failure. In patients with documented intolerance of ACE inhibitors (which may represent 10–20% of patients with heart failure) angiotensin receptor antagonists may be useful as a substitute to block the renin–angiotensin–aldosterone system.
Placebo-controlled studies
SPICE was a smaller trial (270 patients, 12 weeks follow-up) which evaluated the use of candesartan versus placebo in patients with heart failure and a history of intolerance of ACE inhibitors (most commonly because of cough, symptomatic hypotension, or renal insufficiency). Titration to the highest dose of candesartan 16 mg was possible in 69% of the patients (84% in the placebo group). Death and cardiovascular events tended to be lower with candesartan [ ].
The results of another trial in heart failure with another angiotensin receptor antagonist (valsartan) are now available but are still to be published. In the VAL-HeFT (Valsartan in Heart Failure Trial) valsartan 160 mg bd was compared with placebo in 5010 patients with heart failure and left ventricular systolic dysfunction receiving optimal conventional therapy, including ACE inhibitors. The results showed a non-significant effect on mortality (19% on placebo, 20% on valsartan), but a highly significant effect on the primary endpoint of all-cause mortality and morbidity (32% on placebo, 29% on valsartan). A subgroup analysis suggested that the combination of valsartan, an ACE inhibitor, and a beta-blocker was not beneficial and might even be harmful, whereas the combination of valsartan and an ACE inhibitor caused a reduction of 45% [ ].
Organs and systems
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