Indian Journal of Pharmacology Medknow Publications on behalf of Indian Pharmacological Society ISSN: 0253-7613 EISSN: 1998-3751 Vol. 38, Num. 4, 2006, pp. 296-298

Indian Journal of Pharmacology, Vol. 38, No. 4, July-August, 2006, pp. 296-298

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Gautam CS, Aditya S

Department of Pharmacology, GMCH, Chandigarh-160 031
Correspondence Address:Department of Pharmacology, GMCH, Chandigarh-160 031, suruchiaditya@rediffmail.com

Code Number: ph06082

Related article: ph06041, ph06081

In response to the queries raised about the topic, authors would like to highlight the following facts which may explain to some extent the irrationality behind the fixed dose combination of ACE inhibitors and ARBs.

• VALIANT Trial [1] (Valsartan in acute myocardial infarction) involved 14,703 high risk patients with evidence of acute heart failure, LV systolic dysfunction or both after MI randomized to valsartan, captopril and valsartan plus captopril. This trial failed to show any mortality benefit in the combined valsartan captopril group and was associated with increased rate of adverse events especially hypotension and renal related causes leading to permanent discontinuation of study treatment.
• The Valsartan Heart Failure Trial (VAL-HeFT)[2] a double-blind, placebo controlled trial with 5,010 patients that examined the effect of the ARB valsartan Vs placebo in patients on traditional therapy for heart failure (ACE inhibitors, diuretics, digoxin and beta blockers) also found no difference in all-cause mortality in the two groups.
• An interesting observation from Val-HeFT was that much of the benefit from ARB therapy was observed in those patients who were not on either ACE inhibitor or beta blocker. Only 7% of the patients were not on ACE inhibitors but these patients showed significant improvement with addition of valsartan.
• Further the question of "too much neurohumoral blockade" was raised as patients who were taking all three neurohumoral blockers (ACE inhibitors, ARBs and beta blockers) tended to have a negative outcome in this trial.
• Randomised Evaluation Of Strategies for Left Ventricular Dysfunction (RESOLVD) study compared candesartan and enalapril independently and in combination to examine the effects on congestive heart failure. This multicentre double blind, placebo controlled pilot study randomized 768 patients to candesartan, enalapril or a combination of both and was terminated prematurely after it showed no significant difference in clinical events among ACE inhibitor, ARB, and their combination despite a noticeable increase in the ejection fraction of patients in the combination group.[3]
• AT ₂ receptor stimulation occurs in combination therapy and is believed to be beneficial due to its vasodilatory and antiproliferative effects. However, recent observations have proposed that although AT ₂ receptor induced apoptosis or inhibition of growth which is good for diseased kidney or heart, it may not be true in every case. Expression of chemokine RANTES is transduced by AT ₂ receptors and this stimulated glomerular influx of macrophages/monocytes while AT ₂ receptor antagonist (PD 123177) attenuated the effect which showed angiotensin II can exert proinflammatroy effects through activation of AT ₂ receptors. It was also shown that angiotensin II can activate nuclear factor k B in vitro and in vivo through AT ₂ recptors.[4] Cell culture and animal studies have clearly demonstrated that activation of AT ₂ receptors could have important pathophysiological consequences.[5],[6] This profibrogenic effect completely blocked by AT ₂ receptor antagonist but not by losartan. The above observation show that it is unwise to predict clinical outcomes based on any one mechanism of action, especially with drugs that affect complex system.
• Theoretically, the price to be paid for combining an ACE inhibitor with an AT ₁ R antagonist will be the addition of side effects, especially those dependent on ACE inhibition (cough, angioneurotic edema),[7],[8] and the potential hazards of a complete RAAS blockage, especially in situations in which BP and renal function are renin dependent.[9],[10] If treatments that combine an ACE inhibitor and an ATIR antagonist are to become commonly used, it is important to be aware of any increased risk of functional renal insufficiency associated with this combination. There is undoubtedly an increased risk for some patients exposed to an intensified blockade of the RAS by high doses of a single-site blocker or combined usual doses of 2 RAAS blockers: elderly or salt-depleted patients, patients receiving cyclooxygenase inhibitors, patients with renal artery stenosis, and during anesthetic induction). The risk of hyperkalemia is also increased when baseline glomerular filtration rate is < 35 mL/min. In addition to surveillance of serum potassium levels, especially in patients with renal failure, the hematocrit should be monitored. A more complete and rigorous assessment of these risks is needed. It will require pharmacoepidemiological studies of a large number of diverse patients with hypertension, renal insufficiency, and CHF in general population.
• The biochemical cosequences of combination include accumulation of vasodilatory and natriuretic peptides such as angiotensin,[1],[2],[3],[4],[5],[6],[7] acetyl-seryl-aspartyl-lysyl-proline (ac SDKP), bradykinin etc.[11] The latter activates B2 receptors and releases NO, prostacyclin and other vasodilatory substances. Both the drugs act via NO and autocrine interaction among NO, kinins, prostaglandins, c-GMP and AT II receptors are involved leading to synergistic fall in blood pressure which may lead to reflex tachycardia.
• Antihypertensive therapy is a tailor made treatment which needs to be titrated over a period of time depending on the clinical response observed especially when multiple antihypertensives are being used. In such situations it is very difficult to titrate a dose with a fixed dose combination.

To conlude, authors would like to state that there is a need for critical choice of right dose[12] and dosing interval and further trials like result of much awaited ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) may help to define a clear status. Many lacunae exist and there is a need to prove a lot more, before it can be classified as rational. At best this combination may be categorized as controversial.

We genuinely appreciate the interest taken in the article and the queries, which gave us a platform to express our views about the controversial topic.

References

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