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Published on 1 May 2005

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ARBs for the treatment of cardiovascular diseases

teaser

Steven G Chrysant
MD PhD
Clinical Professor of Medicine
University of Oklahoma
Director
Oklahoma Cardiovascular and Hypertension Center
Oklahoma City, OK
USA
E:schrysant@yahoo.com

Angiotensin II (Ang-II) exerts it deleterious effects on blood pressure and cardiovascular remodelling through the stimulation of type 1 (AT(1)) receptors.(1) Blockade of these receptors by the angiotensin-receptor blockers (ARBs) reverses the harmful effects of Ang-II.(1,2) The ARBs, introduced after the angiotensin-converting enzyme inhibitors (ACEIs) for the treatment of hypertension and cardiovascular diseases, were initially used as an alternative to ACEIs for patients who were intolerant to ACEIs. However, as more clinical experience has since been gained with ARBs, these drugs are currently used as first-line treatment for hypertension and cardiorenal diseases and, frequently, instead of ACEIs.

Mechanism of action
Ang-II is produced by the classical pathway through the action of the ACE and by the alternative pathways through the action of other enzymes, especially chymase. After its generation, Ang-II attaches itself to the AT(1)-receptor, through which it mediates its effects on peripheral vasoconstriction, aldosterone secretion, salt and water retention, sympathetic nervous system stimulation and cardiovascular remodelling. Ang-II also stimulates the AT(2)-receptors, the effects of which are opposite to those of AT(1)-receptors. ARBs exert their blood pressure-lowering and cardiovascular antiremodelling effects primarily through selective blockade of the Ang-II pathway at the AT(1)-receptor level, and also through the Ang-II-mediated stimulation of the unoccupied AT(2)-receptors, which enhances the action of ARBs. Based on their mechanism of action, ARBs should theoretically be superior to ACEIs because they block the action of all Ang-II generated through both classical and alternative pathways, whereas ACEIs interfere with the production of Ang-II only through the classical pathway. However, the antihypertensive effects of ARBs are not superior to those of ACEIs, although ARBs have a better side-effect profile (they do not cause cough, and the incidence of angio-oedema is much more rare). In addition, recent studies have shown that ARBs confer better stroke protection than ACEIs.(3) So far, seven ARBs have been approved in the USA for clinical use. These ARBs have been tested in the treatment of hypertension, heart failure, kidney failure and stroke in various short- and long-term prospective, randomised clinical trials, which provided considerable knowledge on their effectiveness and safety with respect to the treatment of hypertension, stroke, heart failure and diabetic nephropathy.

Several large prospective clinical outcomes studies have been carried out. In all these trials, additional drugs were given with the study drugs for optimal clinical results.(7–22)

Hypertension
Most clinical trials of short and long duration have shown that ARBs are as effective as other antihypertensive drugs for the treatment of hypertension but are better tolerated, with almost no side-effects observed. Their antihypertensive action is greatly enhanced by combination with a low-dose diuretic.(4–6) Drugs that interfere with the action of the renin–angiotensin–aldosterone system (RAAS), such as the ACEIs and ARBs, are particularly effective in preventing or reversing cardiovascular remodelling, and also in producing beneficial effects in addition to blood pressure-lowering. Such an additional benefit has been demonstrated in the LIFE (Losartan Intervention for Endpoint reduction in hypertension) and SYLVHIA (Swedish Irbesartan left Ventricular Hypertrophy Investigation versus Atenolol) studies, where left ventricular hypertrophy (LVH) regression was greater with the use of losartan and irbesartan than for atenolol for the same degree of blood pressure reduction.(7,8)

This difference was not demonstrated in the CATCH (Candesartan Assessment in the Treatment of Cardiac Hypertrophy) study, which used drugs that interfere with the action of RAAS (candesartan vs enalapril).(9)

Stroke
Several large outcomes studies have also shown that ARBs have a greater effect in stroke prevention than other drugs.(7,10–13) The protective effect of ARBs is even greater in older patients with isolated systolic hypertension.(11,12) The results of the VALUE (Valsartan Antihypertensive Long-term Use Evaluation) study were somewhat disappointing regarding the overall effects of valsartan on cardiovascular and stroke morbidity and mortality compared with those of amlodipine; this has been attributed to the delay in blood pressure reduction by valsartan compared with amlodipine.(14) However, this difference in clinical outcomes was greatly decreased and even reversed for stroke prevention by the end of the study, when the blood pressure difference was greatly decreased. The stroke protective effect of ARBs is possibly mediated through blockade of the AT(1) and simultaneous stimulation of the unoccupied AT(2)-receptors in the brain by free-floating Ang-II. The end-result is local vasodilatation and improvement in local brain ischaemia.(3)

Heart failure
ARBs have also been shown to be as effective as ACEIs in decreasing cardiovascular morbidity and mortality in patients with heart failure when added to standard background therapy.(15–19) Since these studies have not shown any superiority of ARBs over the ACEIs, the current consensus is that ACEIs should be the drugs of choice for the treatment of heart failure, and ARBs should be used only for ACEI-
intolerant patients. However, some studies have been criticised for not using doses of ARBs equipotent to those of ACEIs.(15–19)

Diabetic nephropathy
Type 2 diabetic hypertensive patients with diabetic nephropathy also seem to benefit from the use of ARBs.(20–23) In all these patients, ARBs significantly decreased the urinary protein excretion and delayed the progression of renal disease to endstage requiring haemodialysis. These renal protective effects of ARBs are observed in addition to the blood pressure-lowering effects.

Recent experimental studies have shown that some ARBs, such as telmisartan and irbesartan, have actions similar to those of peroxisome-proliferator-activated-receptors gamma (PPAR-gamma), which improve glucose metabolism and thus could have an independent effect in the control of diabetes mellitus. The American Diabetic Society has recommended that ARBs be the preferred choice for the treatment of diabetic hypertensive patients.(24)

References

  1. Am Heart J 1998;135:S21-30.
  2. J Hypertens 2003;21 Suppl 6:S3-7.
  3. Drugs Today 2004;40:791-801.
  4. J Hum Hypertens 2005;19:173-83.
  5. J Clin Hypertens 2004;6:445-51.
  6. Expert Opin Pharmacother 2004;5:657-67.
  7. Lancet 2002;359:995-1003.
  8. J Cardiovasc Pharmacol 2003;42:719-26.
  9. J Hypertens 2002;20:2293-300.
  10. J Hypertens 2003;21:875-86.
  11. JAMA 2002;288:1491-8.
  12. J Am Coll Cardiol 2004;44:1175-80.
  13. Schrader J. MOrbidity and mortality after Stroke – Eprosartan compared with Nitrendipine in secondary prevention (MOSES). Presented at the European Society of Cardiology 2004, Munich, Germany.
  14. Lancet 2004;363:2022-31.
  15. Lancet 2000;355:1582-7.
  16. N Engl J Med 2001;345:1667-75.
  17. Lancet 2003;362:759-66.
  18. N Engl J Med 2003;349:1893-906.
  19. Lancet 2002;360:752-60.
  20. Circulation 2002; 06:672-8.
  21. N Engl J Med 2001;345:851-60.
  22. N Engl J Med 2001;345:861-9.
  23. N Engl J Med 2001;385:870-8.
  24. Diabetes Care 2002; 25 Suppl 1:S85-9.


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