Therapeutics Letter 28 explores the role of angiotensin II receptor blockers in hypertension and congestive heart failure. Conclusions: Angiotensin receptor blockers act to modulate the renin angiotensin pathway at a different site compared to ACE inhibitors. There is suggestive evidence that angiotensin receptor blockers may not be as good at lowering blood pressure as ACE inhibitors. Because they are not associated with the intractable dry cough seen in some patients taking ACE inhibitors, angiotensin receptor blockers are indicated in patients who require an ACE inhibitor (see Therapeutics Letter 8) but who cannot tolerate it due to drug-induced dry cough.
Keywords:
Angiotensin Receptor Antagonists, Antihypertensive Agents, Heart Failure, HypertensionThere has been a rapid growth in members of this new class of drugs; at the present time four are being actively marketed in Canada:
Losartan (Cozaar®), Valsartan (Diovan®), Irbesartan (Avapro®), Candesartan (Atacand®).Indications: Hypertension is at present the only approved indication for these drugs in Canada.
Mechanism of Action: The final active messenger of the renin-angiotensin pathway is angiotensin II. Angiotensin II binds to AT1 receptors to cause vasoconstriction and fluid retention, both of which lead to an increase in blood pressure. The angiotensin II receptor blockers lower blood pressure by blocking the AT1
receptors. Therefore they have similar effects to angiotensin converting enzyme (ACE) inhibitors, which inhibit the synthesis of angiotensin II by ACE (see illustration). However, non-ACE pathways can produce some angiotensin II. ACE inhibitors also decrease bradykinin breakdown and this action could be involved in some of the beneficial and adverse effects of that class of drugs. Therefore, a potential for differential clinical effects exists for these two classes of drugs.
Pharmacokinetics: The four drugs differ in how they are handled in the body (see Table).
Angiotensin Receptor Blockers.
Evidence in hypertension: Angiotensin receptor blockers have not been studied in any randomised controlled trials (RCTs) measuring long-term health outcomes in patients with hypertension. ACE inhibitors have likewise not been compared to placebo in this clinical setting.1 Two recent RCTs have demonstrated that captopril is associated with similar total cardiovascular events as compared to thiazides and/or beta blockers (10,985 hypertensive patients)2 and as compared to atenolol (1,148 hypertensive patients with type 2 diabetes)3. In 3 RCTs involving patients with hypertension4 and diabetes and hypertension5,6 ACE inhibitors were associated with significantly fewer cardiovascular events than dihydropyridine calcium channel blockers (CCBs). Most likely these 3 trials reflect worse outcomes with dihydropyridine CCBs, consistent with previous evidence (Letter 16).
We are therefore limited to efficacy evidence of angiotensin receptor blockers on surrogate markers, mostly blood pressure. All members of this class of drugs have been shown in double blind randomised placebo controlled trials to lower blood pressure to a greater degree than placebo. We have done an extensive search of the literature and identified 17 RCTs where angiotensin receptor blockers have been compared to once daily ACE inhibitors in terms of their effect on blood pressure (see our Web site for a list of included and excluded trials). When systolic BPs from these trials are pooled (3238 patients) there is a statistically significant 2.0 mmHg (95%CI, 1.0–3.1; p < 0.01) greater reduction in systolic pressure by the ACE inhibitors as compared to angiotensin receptor blockers. The difference was still statistically significant for the comparison with losartan (N=1333) and valsartan (N=1524) alone, but not for irbesartan (N=220) and candesartan (N=161) alone. In most cases the blood pressure was measured approximately 24 hours after the dose. However, the difference was similar in trials where peak effect or 24 hr BP was measured. The cause of this consistent difference is not known. It is unlikely due to bias as the companies marketing the angiotensin receptor blockers funded most of the trials. It is most likely due to a difference in the mechanism of action, possibly involving bradykinin stimulation of vascular nitric oxide production (see illustration), however, a pharmacokinetic explanation cannot be ruled out.
There are 2 published RCTs demonstrating a significantly greater antihypertensive efficacy of irbesartan as compared to losartan.7,8 One published trial comparing 8 mg of candesartan with 50 mg losartan8 and one unpublished trial comparing 80 – 160 mg valsartan with 50 – 100 mg losartan showed no differences in blood pressure lowering efficacy.
Evidence in Congestive Heart Failure: There is one published RCT (722 patients in the ELITE trial) comparing losartan with captopril in patients over 65 with heart failure.10 The primary endpoint of the trial, persistent increase in creatinine, was the same in both groups (10.5%). The secondary endpoint, admissions with heart failure, was also the same in both groups (5.7%). There was an unexpected decrease in total mortality (p < 0.05), in the losartan group (4.8%) as compared to the captopril group (8.7%) (ARR = 3.9%, NNT = 26). A larger trial evaluating morbidity and mortality is required and is in progress.
Adverse effects: Adverse event rates for angiotensin receptor blockers were low and similar to placebo in the trials to date. In a meta-analysis of the comparative trials above, the incidence of dry cough was significantly lower with angiotensin receptor blockers, 1.0%, as compared to ACE inhibitors, 5.5%. Withdrawals due to adverse events were also significantly lower with angiotensin receptor blockers, 4.8%, than with ACE inhibitors, 7.9%. When patients with an ACE inhibitor cough were randomized to an angiotensin receptor blocker, a thiazide, or an ACE inhibitor, the cough resolved in 81%, 80% and 19%, of patients respectively.11,12
Rare serious adverse effects that have been reported with the clinical use of angiotensin receptor blockers include: hepatotoxicity, angioneurotic edema, and neuropsychiatric symptoms.
Precautions: As with ACE inhibitors, renal impairment is likely in susceptible individuals whose renal function depends on the renin angiotensin system: bilateral renal artery stenosis, renal artery stenosis in solitary kidney and severe congestive heart failure.
Contraindications: pregnancy.
Dose and Cost: See Table. The cost of all the available dosage forms in this class is similar. Halving tablets halves the cost (eg 4 mg candesartan). This is not possible for valsartan, which comes in capsules.
Conclusions: Angiotensin receptor blockers act to modulate the renin angiotensin pathway at a different site compared to ACE inhibitors. There is suggestive evidence that angiotensin receptor blockers may not be as good at lowering blood pressure as ACE inhibitors. Because they are not associated with the intractable dry cough seen in some patients taking ACE inhibitors, angiotensin receptor blockers are indicated in patients who require an ACE inhibitor (see Therapeutics Letter 8) but who cannot tolerate it due to drug-induced dry cough.
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This Letter contains an assessment and synthesis of published (and whenever possible peer-reviewed) publications up to March 1, 1999. We attempt to maintain the accuracy of the information in the Therapeutics Letter by extensive literature searches and verification by both the authors and the editorial board. In addition this Therapeutics Letter was submitted for review to 80 experts and primary care physicians in order to correct any identified shortcomings or inaccuracies and to ensure that the information is concise and relevant to clinicians.
See our Web site for the list of included and excluded trials in the meta-analysis.
The Therapeutics Initiative’s objectives are unbiased review and dissemination of therapeutic evidence. Our recommendations are intended to apply to most patients; exceptional patients require exceptional approaches. We are committed to evaluate the effectiveness of our educational activities using the Pharmacare/PharmaNet databases without identifying individual physicians, pharmacies or patients. The Therapeutics Initiative is funded by the BC Ministry of Health through a 5-year grant to the University of BC. The Therapeutics Initiative provides evidence based advice about drug therapy, and is not responsible for formulating or adjudicating provincial drug policies.
