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Therapeutics Letter, issue 28, January/February/March 1999

Angiotensin II Receptor Blockers

Their role in hypertension and congestive heart failure

There 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).

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 hypertension(4) and diabetes and hypertension(5),(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 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.

TABLE: Angiotensin Receptor Blockers

Angiotensin Blockers

Brand Name

Active metabolite

Major route of inactivation

Half-life (hrs)

Usual daily dose range (mg)

Daily cost range ($)
Losartan Cozaar®

Yes

Liver

5

25 – 100

1.14 – 1.14
Valsartan Diovan®

No

Liver

6

80 – 160

1.11 – 1.11
Irbesartan Avapro®

No

Liver

13

75 – 300

1.16 – 1.16

Candesartan Atacand®

Yes

Liver and renal

10

4 – 16

0.58 – 1.16

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 losartan(9) 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.

This Therapeutics 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 contained 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.

References:

  1. Wright JM, Lee CH, Chambers GK. A systematic review of the effectiveness and efficacy of anti-hypertensive therapies: Does the evidence assist in choosing a first-line drug? Can Med Assoc J 1999 (in press).
  2. Hansson L, Lindholm LH, Niskanen L et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 1999; 353:611-16 and p.604 Commentary: Which drug for hypertension?
  3. UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ 1998; 317:713-20.
  4. Study Group on Long-term Antihypertensive Therapy. A 12-month comparison of ACE inhibitor and CA antagonist therapy in mild to moderate essential hypertension - the GLANT Study. Hypertens Res 1995;18:235-244.
  5. Estacio, RO, Jeffers MS, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl J Med 1998;338:645-52.
  6. Tatti P, Phor M, ByingtonRP, Di Mauro P, Guarisco R, Strollo G, Strollo F. Outcome results of the fosinopirl versus amlodipine cardiovascular events randomized trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998;21:597-603.
  7. Kassler-Taub K, Littlejohn T, Elliott W, Ruddy T, Adler E. Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan, in mild to moderate hypertension. Am J Hypertens 1998;11:445-453.
  8. Oparil S, Guthrie R, Lewin AJ, Marbury T, Reilly MS et al. An elective-titration study of the comparative effectiveness of two angiotensin II receptor blockers, irbesartan and losartan. Clin Therap 1998:20:398-409.
  9. Andersson OK, Neldam S. The antihypertensive effect and tolerability of candesartan cilexetil, a new generation angiotensin II antagonist, in comparison with losartan. Blood Pressure 1998;7:53-59.
  10. Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ et al. Randomized trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of losartan in the elderly study, ELITE). Lancet 1997;349:747-52.
  11. Benz J, Oshrain C, Henry D et al. Valsartan, a new angiotensin II receptor antagonist: a double-blind study comparing the incidence of cough with lisinopril and hydrochlorothiazide. J Clin Pharmacol 1997;37:101-107.
  12. Chan P, Tomlinson B, Huang TY et al. Double-blind comparison of losartan, lisinopril, and metolazone in elderly hypertensive patients with previous angiotensin-converting enzyme inhibitor-induced cough. J Clin Pharmacol 1997;37:253-257.

 

Excluded Studies [reason for exclusion]

  1. Byyny RL et al. An inpatient trial of the safety and efficacy of losartan compared with placebo and enalapril in patients with essential hypertension. Cardiovascular drugs and therapy 1996; 10: 313-319. [five days treatment only]
  2. Critchley JAJH et al. A randomized, double-masked comparison of the antihypertensive efficacy and safety of combination therapy with losartan and hydrochlorothiazide versus captopril and hydrochlorothiazide in elderly and younger patients. Current Therapeutic Research 1996; 57(5): 392-406. [combination therapy, once daily captopril]
  3. Hortal L et al. Losartan versus ramipril in the treatment of postrenal transplant erythrocytosis. Transplantation Proceedings 1998; 30: 2127-2128. [no blood pressure data]
  4. Roca-Cusachs A, Oigman W, Lepe R et al. A randomized, double-blind comparison of the antihypertensive efficacy and safety of once-daily losartan compared to twice-daily captopril in mild to moderate essential hypertension. Acta Cardiologica 1997; 52(6): 495-506. [twice daily captopril]
  5. Franke H. Antihypertensive effects of candesartan cilexetil, enalapril and placebo. J Human Hypertens 1997; 11 Suppl 2: S61-S62. [no systolic pressures recorded]

Included Studies:

  1. Benz J, Oshrain C et al Valsartan, a new angiotensin II receptor antagonist: A double-blind study comparing the incidence of cough with lisiopril and hydrochlorothiazide. J Clin Pharmacol. 1997; 37: 101-107.
  2. Black HR, Graff A et al. Valsartan, a new angiotensin II antagonis for the treatment of Essential hypertension: efficacy, tolerability and safety compared to an angiotensin-converting enzyme inhibitor, lisinopril. Journal of Human Hypertension 1997; 11: 483-489.
  3. Bremner AD, Baur M et al. Valsartan: long term efficacy and tolerability compared to lisinopril in elderly patients with essential hypertension. Clin and Exper Hypertension 1997; 19(8): 1263-1285.
  4. Chan P, Tomlinson B et al. Double-blind comparison of losartan, lisiopril, and metolazone in elderly hypertensive patients with previous angiotensin-converting enzyme inhibitor-induced cough. J Clin Pharmacol 1997; 37: 253-257.
  5. Fogari R, Zoppi A, Corradi L et al. Comparative effects of lisinopril and losartan on insulin sensitivity in the treatment of non diabetic hypertensive patients. Br. J. Clin. Pharmacol. 1998; 46: 467-471.
  6. Fogari R, Zoppi A, Lazzari P et al. ACE inhibition but not angiotensin II antagonism reduces plasma fibrinogen and insulin resistance on overweight hypertensive patients. J Cardiovasc Pharmacol 1998; 32: 616-620.
  7. Gradman AH, Arcuri KE et al. A randomized, placebo-controlled, double-blind, parallel study of various doses of losartan potassium compared with enalapril maleate in patients with essential hypertension. Hypertension 1995; 25: 1345-1350.
  8. Holwerda NJ, Fogari R et al. Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy and safety compared with placebo and enalapril. Journal of Hypertension 1996, 14:1147-1151.
  9. Mallion JM, Boutelant S et al. Valsartan, a new angiotensin II antagonist; blood pressure reduction in essential hypertension compared with an angiotensin converting enzyme inhibitor, enalapril. Blood Pressure Monitoring 1997; 2: 179-184.
  10. Mimran A, Ruilope L Kerwin L et al. A randomised, double-blind comparison of the angiotensin II receptor antagonist, irbesartan, with the full dose range of enalapril for the treatment of mild-to-moderate hypertension. J Human Hypertension 1998; 12: 203-208.
  11. Nielsen S, Dollerup J, Nielsen B et al. Losartan reduces albuminuria in patients with essential hypertension. An enalapril controlled 3 month study. Nephrol Dial Transplant 1997; 12 Suppl 2: 19-23.
  12. Pechere-Bertschi A, Nussberger J et al. Renal response to the angiotensin II receptor subtype 1 antagonist irbesartan versus enalapril in hypertensive patients. J Hypertens 1998; 16: 385-393.
  13. Perico N, Spormann D Peruzzi E et al. Efficacy and tolerability of valsartan compared with lisinopril in patients with hypertension and renal insufficiency. Clin Drug Invest 1997; 14(4): 252-259.
  14. Ruff D, Gazdick LP, Berman R et al. Comparative effects of combination drug therapy regimens commencing with either losartan potassium, an angiotensin II receptor antagonist, or enalapril maleate for the treatment of severe hypertension. J Hypertens 1996; 14: 263-270.
  15. Tikkanen I, Omvik P and Jensen HAE. Comparison of the angiotensin II antagonist losartan with the angiotensin converting enzyme inhibitor enalapril in patients with essential hypertension. J Hypertens 1995; 13: 1343-1351.
  16. Townsend R, Haggert B, Liss C et al. Efficacy and tolerability of losartan versus enalapril alone or in combination with hydrochlorothiazide in patients with essential hypertension. Clin Therapeutics 1995; 17(5): 911-923.
  17. Zanchetti A, Omboni S and Di Biagio C Candesartan cilexetil and enalapril are of equivalent efficacy in patients with mild to moderate hypertension. J Human Hypertens 1997; 11 Suppl 2: S57-S59.

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