Basic Res Cardiol 93: Suppl. 2, 47 – 50 (1998)© Steinkopff Verlag 1998

M. J. Kendall Therapeutic advantages of AT1 blockers in hypertension

relatively inexpensive. Most impor-tantly it should reduce the risk of theadverse effects of high blood pressure,such as myocardial infarction, suddendeath, stroke, heart failure, renaldamage, and retinal changes.

Most antihypertensive drugs effec-tively reduce blood pressure, are avail-able as once daily preparations, and aresafe long-term. Unfortunately, mostantihypertensive drugs cause adverseeffects in some patients and for fewdrugs is there good evidence that theyprotect the heart, the brain, the kidney,and the eye? Reducing the effects of

Angiotensin II (using an ACEinhibitor) has been shown to reduce theincidence of coronary events, suddendeath, heart failure, renal damage, andfundal changes. AT1 blocking drugsoffer the same pharmacological advan-tages but also very good tolerability, inparticular no cough. Therefore, theyhave the potential to meet all thecriteria for an ideal antihypertensivedrug.

Key words Hypertension – ACEinhibitors – candesartan – AT1 blockers– therapy

M. J. Kendall (Y)Department of MedicineQueen Elizabeth HospitalBirmingham B15 2TH, EnglandE-mail: m.j.kendall@bham.ac.uk

Abstract Most antihypertensives haveadvantages and disadvantages. Theideal antihypertensive drug should beeffective in lowering blood pressure,well tolerated, safe in the long term,and easy to use. Ideally, it should be

Introduction

The Angiotensin II receptor blocking drugs which act pre-dominantly at the AT1 receptor (AT1 blockers) are the mostrecently developed major class of antihypertensive drugs.Doctors must now decide their role in the management ofpatients with hypertension. To make this decision in a logicaland scientific manner it would seem reasonable to try toanswer 3 questions:

E What do we aim to do when we treat hypertension, and canwe describe an ideal antihypertensive drug?

E What drugs are currently available to lower blood pressure,and what are the advantages and disadvantages of thesedrugs?

E What do we know of the new AT1 blockers, and are theybetter than some of the other antihypertensive drugs?

The ideal antihypertensive drug

Table 1 sets out some of the key requirements for an ideal anti-hypertensive drug. Most currently used antihypertensive drugsare effective, safe, and available as a once daily oral prepara-tion. Further, because they reduce blood pressure and becausehypertension is the major cause of stroke, they will probablyreduce the incidence of stroke. The relative costs of drugs areoutside the scope of this paper, will vary from country tocountry, and will be influenced by the passage of time and bymarketing pressures.

The two remaining requirements of the ideal antihyperten-sive drug are that it should be well tolerated, and most impor-tant it should reduce the risk of cardiovascular complications.Coronary artery disease (CAD) is the most common cause ofdeath in developed countries of the world, and it is the mostfrequent and most serious consequence of uncontrolled hyper-tension (10).

48 Basic Research in Cardiology, Vol. 93, Suppl. 2 (1998)© Steinkopff Verlag 1998

Antihypertensive drugs

The major classes of antihypertensive drugs are presented inTable 2. AT1 blockers act on the same system and may beexpected to have effects similar to the ACE inhibitors. Thesegroups will be considered separately. First the advantages ofthe other major antihypertensives will be considered briefly.

Thiazide diuretics are effective, well tolerated, and remark-ably cheap. They cause biochemical changes includingincreases in plasma cholesterol and glucose and a fall inplasma potassium. They reduce the risk of stroke (14) and havesome impact on coronary events in older patients’ (11) buthave not been shown to reduce the risk of sudden death (14)and may increase the risk (15).

Beta-blockers are contraindicated in certain patients andnon-selective beta-blockers are not well tolerated by somepatients. However, selective beta-blockers when given as asustained release preparation are relatively well tolerated (6).Beta-blockers are the group of antihypertensives for whichthere is most evidence in terms of reducing coronary risk andsudden death (7).

Alpha-blockers have a reputation for causing adverseeffects, though they are tolerated well by some patients. Theyhave very positive beneficial effects on plasma lipids but thereis no good evidence that this produces clinical benefits.

Calcium channel blockers, specifically dihydropyridines,tend to cause flushing, headaches, and ankle swelling. How-ever, they are very effective antihypertensive drugs, they donot cause metabolic adverse effects, and there are almost nocontraindications to their use. They have recently been shownto reduce stroke in elderly patients (16). These drugs have beenused very extensively worldwide in recent years, and felo-dipine has been the central treatment in the HOT study.

ACE inhibitors

ACE inhibitors have many of the features of the ideal antihy-pertensive. They are effective, well tolerated except that theycause hypotension, usually when treament is started, andcough in 10 % (2). They are safe except in these with renalartery stenosis. Most preparations can be given once daily. Afew patients have suffered severe adverse reactions withangio-neurotic edema.

Recent publications have highlighted the cardiac and vas-cular actions of ACE inhibitors (8, 20). They have a positiveimpact on myocardial oxygen supply and demand, ventricularpreload and afterload, left ventricular mass, and sympatheticstimulation. ACE inhibitors also have vascular actions, such asreduction of atheroma formation, cell proliferation in theendothelium, antiplatelet effects, and positive effects onendothelial and smooth muscle function. These results arepredominantly due to the reduction in the unwanted actions ofangiotensin II.

The documented clinical benefits of ACE inhibition areimpressive. ACE inhibitors reduce the incidence of coronaryevents, myocardial infarcts, and reinfarctions in heart failurestudies (4) and post infarct studies (12). Furthermore in at leasttwo studies, ACE inhibitors reduced the number of suddendeaths (5, 9). Their role in the treatment of heart failure is wellknown and well documented. They reduce mortality whenused prophylactically (19) and also when given to those withthe most severe heart failure (17).

In addition to the above, ACE inhibitors have been shownto reduce the rate of decline in renal function (18) and toreduce retinal damage in type I diabetes (3).

Table 1 The requirements of an ideal antihypertensive drug

It should be E EffectiveE Well ToleratedE Safe in Long-Term UseE Easy to Use

– Oral Therapy, once dailyE Not Expensive

Its use should reduce the risk of the vascular complications of Hyper-tension

E Cardiac – Myocardial Infarction– Sudden Death– Congestive Cardiac Failure

E Cerebrovascular – Stroke

E Renal– Progressive Renal Impairment

E Eyes– Hypertensive retinopathy

Table 2 Major classes of antihypertensive drugs

E Thiazide Diuretics

E Beta-Adrenoceptor Blocks Drugs (b-Blockers)– B1 Selective and Non-selective– Lipophilic and Hydrophilic

E Alpha-Adrenoceptor Blocking Drugs (Alpha-Blockers)

E Calcium channel blockers– Dihydropyridine – Nifedipine– Phenylalkalamine – Verapamil– Benzthiazepine – Diltiazem

E Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors)

E Angiotensin II Receptor Blockers Working at the AT1 Receptor (AT1Blockers)

M. J. Kendall 49Therapeutic advantages of AT1 blockers in hypertension

AT1 blocker

An antihypertensive drug having all the actions of the ACEinhibitors reducing the adverse cardiovascular complicationsof hypertension as effectively or more effectively than theACE inhibitors and doing so without causing any significantadverse effects would come close to being the ideal anti-hypertensive drug.

It will be some time before there is adequate data from goodlong-term clinical trials to demonstrate the impact of AT1blockers on the risk of myocardial infarction, sudden death,heart failure, and stroke. However, the results of the EliteStudy (13) which showed that patients with heart failure onLosartan (33–9.4 %) had a much lower mortality than patientson captopril (49–13.2 %) do suggest a very positive role forAT1 blockers.

Theoretically, one would anticipate that since most of theactions of ACE inhibtors are attributed to reduced stimulationof AT1 receptors, blockade of these receptors should producesimilar actions. Furthermore since AT1 blockers should proveto be more effective in reducing the effects of angiotensin IIand should therefore prove to be more effective cardioprotec-tive drugs.

The key clinical data currently available on the AT1 blocker,Candesartan, have been summarized in a supplement to theJournal of Human Hypertension 1997. Like other AT1 block-ers, this drug effectively lowers blood pressure for 24 h, andthe positive impact is maintained over months and years. Thereis a good response to 4, 8, and 16 mg; the effects are as goodas or better than standard doses of other antihypertensive drugssuch as enalapril, and it complements the antihypertensiveeffects of thiazide diuretic.

The particular merit of the AT1 blockers is that they seemto have no major biochemical adverse effect and they are welltolerated. Not only do they not cause cough or posturalhypotension but also adverse events seem to be no more

common after an AT1 blocker than after a placebo. Further-more, not only have several studies confirmed this observationbut it has also been demonstrated in the elderly.

The hope that AT1 blockers would achieve their therapeu-tic objectives without causing significant adverse effects hasobviously been realized. These groups of drugs appear to beremarkably well tolerated. Data for candesartan are presentedin Table 3 (Fig. 1) (1).

AT1 blockers – their therapeutic role

It is not easy to decide the place of a new drug in the manage-ment of a medical problem. New information is being obtainedand new data are being collected. At this time a good cardio-protective effect is a probability; good tolerability is a cer-tainty. Since the elderly are those who most need a drug thatis easy to take and well tolerated, these drugs should proveideal. Secondly, those patients for whom an ACE inhibitor

Table 3 Candesartan – most frequent adverse events

Placebo Candesartan Cilexetil4 mg 8 mg 16 mg

Headache 10.3 10.3 9.0 6.3Upper Respiratory Tract 3.8 4.9 5.2 5.6

InfectionBack Pain 0.9 2.9 3.8 2.9Dizziness 2.3 0.9 2.3 1.9Nausea 1.3 0.3 2.8 2.3Bronchitis 2.2 0.4 1.5 0.4Influenza-like symptoms 0.8 1.2 0.7 1.8Cough 1.1 1.1 0.8 3.0

Fig. 1 Total adverse events andwithdrawals due to adverse events(1)

50 Basic Research in Cardiology, Vol. 93, Suppl. 2 (1998)© Steinkopff Verlag 1998

would be chosen, such as diabetics or those with renal impair-ment, could be offered an AT1 blocker as a good alternative.Addressing the question the other way, one could ask whichhypertensives should not be given an AT1 blocker. Probablythose with renal artery stenosis who should probably be givencalcium channel blocker and those with coexisting anginamight benefit from a b-blocker or calcium channel blocker.

Many doctors will want to give themselves time to becomefamiliar with AT1 blockers and will not prescribe them,initially, as their first choice. However, for those who do nottolerate the first choice, whatever it is, they really ought totolerate an AT1 blocker; those who do not will not tolerate aplacebo.

1. Belcher G, Höbner R, George M, ElmfeldtD, Lunde H (1997) Candesartan cilexetil:Safety and tolerability in healthy volunteersand patients with hypertension. J HumanHypertens 11 (Suppl. 2): S85–S89

2. Brown MJ (1993) Angiotensin receptorblockers in essential hypertension. Lancet342: 1374–1375

3. Chaturvedi N, Sjolie Anne-K, StephensonJM, Abrahamian H, Keipes M, CastellarinA, Rogulja-Pepeonik Z, Fuller JH,EUCLID Study Group (1998) Effect oflisinopril on progression of retinopathy innormotensive people with type I diabetes.Lancet 351: 28–31

4. Cleland JGF (1994) The clinical course ofheart failure and its modification by ACEinhibitors: Insights from recent clinicaltrials. Europ Heart J 15: 125–130

5. Cleland JGF, Erhardt L, Murray G, HallAS, Ball SG, AIRE Study Investigators(1997) Effect of ramipril on morbidity andmode of death among survivors of acutemyocardial infarction with clinical evi-dence of heart failure. Europ Heart J 18:41–51

6. Kendall MJ (1997) Clinical relevance ofpharmacokinetic differences between Beta-Blockers. Am J Cardiol 80 (9B): 15J–19J

7. Kendall MJ, Lynch KP, Hjalmarson A,Kjekshus J (1995) b-Blockers and suddencardiac death. Ann Intern Med 123:358–367

8. Kendall M, McMurray J (1998) Cardiovas-cular disease, hypertension and angina. In:Kendall MJ, Horton RC (eds) PreventingCoronary Artery Disease. CardioprotectiveTherapeutics in Practice, 2nd edn. MartinDunitz, Singapore

9. Köber L, Torp-Pedersen C, Carlsen JE,Bagger H, Eliasen P, Lyngborg K, Tran-dolapril Cardiac Evaluation (TRACE)Study group, et al. (1995) A clinical trial of the Angiotensin-converting enzymeinhibitor trandolapril in patients with leftventricular dysfunction after myocardialinfarction. NEJM 333: 1670–1676

10. Meredith PA (1996) Implications of thelinks between hypertension and myocardialinfarction for choice of drug therapy inpatients with hypertension. Am Heart J 132:222–228

11. MRC Working Party (1992) MedicalResearch Council trial of treatment ofhypertension in older adults: Principalresults. BMJ 304: 405–412

12. Pfeffer MA, Braunwald E, Moy LA, BastaL, Brown EJ, Cuddy TE, Davis BR et al.(1992) Effect of captopril on mortality andmorbidity in patients with left ventriculardysfunction after myocardial infarction.NEJM 327: 669–677

13. Pitt B, Segal R, Martinez FA, Meurers G,Cowley AJ, Thomas I, Deedwania PC, NeyD, Snavely D, Chang PI, ELITE StudyInvestigators (1997) Randomised trial oflosartan versus captopril in patients over 65with heart failure (Evaluation of Losartanin the Elderly Study, ELITE). Lancet 349:747–752

14. SHEP Cooperative Research Group (1991)Prevention of stroke by antihypertensivedrug treatment in older persons with iso-lated systolic hypertension. JAMA 265:3255–3264

15. Siscovick DS, Raghunathan TE, Psaty BM(1994) Diuretic therapy for hypertensionand the risk of primary cardiac arrest.NEJM 330: 1852–1857

16. Staessen JA, Fagard R, Thijs L, Celis H,Arabidze G, Birkenhäger WH, Bulpitt C,Leeuw P, Dollery CT, Fletcher A, Forette F,Leonetti G, Nachev C, O’Brien E, Rosen-feld J, Rodicio JL, Tuomilehto J (1997)Randomised double-blind comparison ofplacebo and active treatment for olderpatients with isolated systolic hypertension.Lancet 350: 757–764

17. The Consensus Trial Group (1987) Effectof enalapril on mortality in severe conges-tive heart failure: results of the CooperativeNorth Scandinavian Enalapril SurvivalStudy (CONSENSUS). NEJM 316:1429–1435

18. The GISEN Group (1997) Randomisedplacebo-controlled trial of effect of ramiprilon decline in glomerular filtration rate andrisk of terminal renal failure in proteinuric,non-diabetic nephropathy. Lancet 349:1857–1863

19. The SOLVD Investigators (1992) Effect ofenalapril on mortality and development ofheart failure in asymptomatic patients withreduced left ventricular ejection fractionsand congestive heart failure. NEJM 327:685–691

20. Yusuf S, Pepine CJ, Garces C, Pouleur H,Salem D, Kostis J, Benedict C, RousseauM, Bourassa M, Pitt B (1992) Effect ofenalapril on myocardial infarction andunstable angina in patients with low ejec-tion fractions. Lancet 340: 1173–1178

References