LEADING ARTICLE Drug Safety 12 (2} 85-90. 1995 01 14-5916/95/00J2-oo85/S03.oo/0

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Low Dose Combination Antihypertensive Therapy Additional Efficacy Without Additional Adverse Effects?

Angus M. MacConnachie and Derek Maclean

Ninewells Hospital and Medical School, Dundee Teaching Hospitals NHS Trust, Dundee, Scotland

1. Changing Goals in the Treatment of Hypertension

Despite the fact that newer more potent antihyper­tensives have become available in recent years, cardiovascular morbidity and mortality remains unacceptably high in treated hypertensive patients compared with the normotensive population.[I] This frequent finding has prompted interest in the possi­bility that benefits are to be gained from achieving tighter control of hypertension by setting lower and narrower target blood pressure (BP) ranges than have hitherto been attempted. The strategy is some­what analogous to the modem treatment of diabetes mellitus in which strict glycaemic control is the key to the prevention of long term complications. Co­incidentally, regular and accurate assessment of BP control is now possible through the increasing application of continuous ambulatory BP monitor­ing and echocardiography. The current Hyperten­sion Optimal Treatment (HOT) study[2] is a large multicentre trial which seeks specifically to address the issue of tight control of BP as a means of reduc­ing end-organ damage and improving survival. Its findings, which are eagerly awaited, are expected within the next 2 years.

Since monotherapy of hypertension may be limited by an unacceptable level of drug adverse effects at dosages required to achieve the desired level of control, it is likely that the judicious use of antihypertensive combination therapy will in­creasingly playa key role in the optimisation of BP control in the future.

Many, but by no means all, adverse drug reac­tions (ADRs) are dose-related, being merely an ex­tension of a drug's pharmacological action (type A reactions). In the case of antihypertensive drug therapy (table I) such reactions are relatively com­mon and therefore predictable, while idiosyncratic (type B) ADRs, the occurrence of which cannot be readily predicted, rarely arise in practice. Since the hypotensive action is at least additive between drugs from different classes, there is considerable scope for individual drug dosage reduction when­ever combination therapy is used. Furthermore, the choice of a particular combination can often result in attenuation of a given adverse effect of one drug as a result of the pharmacological action of the other.

Therefore, any measure which reduces the dosage requirement of an antihypertensive while main­taining therapeutic efficacy, or otherwise limits the possibility of commonly encountered ADRs, will encourage good patient compliance and so improve long term control of hypertension.

2. The Case for Low Dose Antihypertensive Drug Therapy

2.1 Thiazide Diuretics

The case for low dose antihypertensive therapy is exemplified over the years by the thiazide diuret­ics, which remain among the most cost-effective antihypertensives, producing demonstrable benefit, particularly in reducing excess risk of stroke. 13,4]

86 MacConnachie & Maclean

Table I. Examples of dose-related (type A) and much rarer idiosyncratic (type B) adverse drug reactions associated with the common antihypertensive drugs

Drug group Type A (common) Type B (rare)

Diuretics Hyponatraemia Hypokalaemia Dehydration

Thrombocytopenia Pancreatitis Skin rashes Cholestasis Altered glucose tolerance

Urate retention Dyslipidaemia Impotence

~-Blockers Bradycardia Heart failure

Pneumonitis Pulmonary fibrosis Thrombocytopenia Arthropathy

Cold extremities Bronchospasm Impaired gluconeogenesis Dyslipidaemia Impotence

ACE inhibitors Renal failure Hyperkalaemia

Skin rash Hepatitis Alveolitis Cough

a-Blockers

Angio-oedema

Tachycardia Postural hypotension Oedema

Calcium antagonists Flushing Dizziness Tachycardia Oedema

Their hypotensive action is associated with an ex­trarenal mechanism which is thought to result in a chronic reduction in the sensitivity of the vascular endothelium to vasoconstrictor influences. This is generally manifested at dosages not normally as­sociated with a diuresis so that daily doses as low as cyclopenthiazidel5] 12Sllg, chlorthalidone[6] lSmg or bendroflumethiazide (bendrofluazide)[7] 1.2Smg can effectively lower elevated BP while minimising the risk of adverse biochemical effects.

2.2 P-Blockers

Similar considerations apply in the case of the ~-adrenoceptor antagonists (~-blockers). Their anti­hypertensive action, although not clearly under­stood, appears to be associated in the long term with some adaptation or down-regulation of neuro­humoral mechanisms which are active in patients with raised BP, and the hypotensive dose-response curve demonstrates a clear ceiling effect. Thus, it

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Skin rashes Fever Lymphadenopathy Hepatosplenomegaly

has long been apparent that a daily dose of, for example, atenolol SOmg is as effective as doses of lOOmg and even 200mg in reducing lying, standing and post-exercise BPs,l8] and that a daily dose as low as 2Smg is sufficient for some patients. On the other hand, acute effects including bradycardia and the various metabolic complications of ~-blockade might be expected to increase in proportion to drug dosage.

The highly cardioselective agent bisoprolol has even been reported to produce a beneficial shift in the lipid profile in very low dosage. When admin­istered in a dose of 2.Smg daily it reduced low den­sity lipoprotein (LDL) cholesterol in newly diag­nosed hypertensive patients, while remaining as effective as Smg in lowering elevated BP.[9]

2.3 ACE Inhibitors

ACE inhibitors are all licensed for use within narrow and clearly defined dose ranges. It was soon

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Low Dose Combination Antihypertensive Therapy

apparent following the introduction of captopril , the first clinically useful ACE inhibitor, that recommended dosages of 300 to 450mg daily were too high and were associated with frequent, often severe, adverse effects in the absence of any clinical gain over current dosages as low as 25 to 100mg daily.

2.4 Calcium Antagonists

The hypotensive effect of the dihydropyridines, the most active vasodilators of the calcium antag­onist series, appears to increase in relation to dose but once again only within a relatively narrow range above which adverse effects are commonly encountered. Amlodipine, used as monotherapy in a series of patients with mild to moderate hyper­tension, has shown increasing activity within the dose range of 2.5 to 10mg daily. However, more than half of the patients who responded to 10 mg/day showed an equally satisfactory response to 2.5 mg/day.IIO]

Early experience with nifedipine, the fore­runner of the dihydropyridines, demonstrated an increased incidence of flushing, tachycardia, diz­ziness and pedal oedema related to the high peak plasma concentrations produced by frequent dosing with conventional tablets and capsules. By smoothing out the plasma concentration profile, newer slow release preparations of nifedipine appear to be better tolerated yet remain effective antihypertensi ves.

2.5 (X-Blockers

The selective <XI-adrenergic blocking drugs (doxazosin, prazosin and terazosin) are something of an exception in that they do display an extended dose-response relationship. For example, the effec­tive daily dose range of doxazosin varies from as little as 2mg up to as much as 16mg. However, at doses in the higher range the relative selectivity for post-synaptic <XI-receptors diminishes, with a re­sultant increase in the risk of dose-related adverse effects. When used as sole antihypertensives these agents produce adverse effects in up to 40% of patients,111.12] including dizziness, orthostatic

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87

hypotension, headache, fatigue , palpitations and nausea.

3. Antihypertensive Drug Combinations

In the management of hypertension, the primary goal of therapy is to lower BP effectively while minimising the risk of dose-related adverse effects. Therefore, if monotherapy is ineffective in control­ling mild to moderately raised BP within the lower dosage range of a gi ven drug , rather than persisting with increasing doses, the use of a drug combina­tion is often the preferred option. This exploits the additive hypotensive effects of drugs from differ­ent classes or the marked potentiation which some combinations display. Thus, therapy for mild to moderate hypertension can be based on dual, or occasionally triple, therapy using drug combina­tions carefully selected from each of the major groups. The most recent guidelines of the World Health Organization/International Society on Hy­pertension (WHO/ISH),1 31 identify 5 basic groups of antihypertensives (see fig. 1 for examples from each of these groups and suggested low daily doses which may be tried initially).

What antihypertensive drug combinations might therefore be considered? While in practice almost any combination of drugs from the major groups can be used , a few selected options are available, some of which may have specific appli­cations.

3.1 ~-Blocker plus Thiazide Diuretic

That this is one of the most commonly tried drug combinations is reflected in the availability of sev­eral proprietary products combining one of the ~-blockers with a thiazide diuretic. Although di­uretics are not normally associated with reflex tachycardia, or ~-blockers with fluid retention , there is a possible gain in terms of attenuation by the ~-blocker of the tendency for the diuretic to increase plasma renin activity and occasionally produce hypokalaemia.

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88 MacConnachie & Maclean

ACE inhibitors, e.g Captopnl12.5mg bid Enalapril 5mg ad

!}-Blockers, e.g . • --------1 Atenolol 25mg od

WHOIISH 1993 Thiazide diuretics, e.g. Bendroflumethiazlde (bendrofluazide) 1.25mg od

Guidelines 1-----...

Calcium antagonists, e.g Amlodlplne 2.5mg ad Nlfedipine 10mg bid

eLt-Blockers, e.g. Doxazosin 2mg ad

Fig. 1. The principal antihypertensive drug groups in the World Health Organization/lnternational Society on Hypertension (WHO/ISH) guidelines, including examples from each and suggested minimum adult dosages in appropriate drug combinations. Abbreviations: od = daily; bid = twice daily.

3.2 ACE Inhibitor plus Diuretic

Activation of the renin-angiotensin system by diuretics probably underlies the marked increase in efficacy reported for such combinations. Thus

low dose captopril plus hydrochlorothiazide has proved effective and well tolerated in patients uncontrolled on diuretic alone.[14] Also, the addition

of a low dose of hydrochlorothiazide to Iisino­pril (a fixed combination product already exists) produced a significantly greater BP reduction than either agent used alone in a large multicentre trial in patients with mild to moderate hyperten­sion.[IS]

It is important to note, however, the profound

fall in BP which may follow the initiation of ACE inhibitor therapy. This is especially likely to oc­cur in chronically diuresed or salt-depleted individ­uals and it may therefore be necessary to withdraw any diuretic for 48 hours beforehand and com­mence with a low initial dose of ACE inhibitor. Patients should be monitored closely for several

hours after the first dose .

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3.3 ~-Blocker plus Calcium Antagonist

The combination of a dihydropyridine calcium antagonist with a P-blocker is regarded as one of the most effective measures for lowering elevated BP unresponsive to monotherapyJ I61 It may be particularly appropriate for patients with unstable angina but combination with either diltiazem or verapamil, both of which possess negative inotro­pic activity, should be avoided. Any tendency for nifedipine to cause reflex tachycardia is offset by concurrent P-blockade but there have been occa­sional reports of bradycardia and heart failure associ­ated with this combination. Nevertheless, low dosage acebutolol (100 mg/day) plus nifedipine (10 mg/day) appeared to be well tolerated and proved as effective as dosages of acebutolol up to 400 mg/day in patients with mean pretreatment BP of around l80/l05mm Hg.[171

3.4 ACE Inhibitor plus Calcium Antagonist

It is proposed that calcium antagonists enhance the hypotensive response to ACE inhibitors as a result of the weak diuretic activity they possess. Further, such combinations have a most favourable

Drug Safety 12 (2) 1995

Low Dose Combination Antihypertensive Therapy

influence on the lipid profile and may be consid­ered for patients with dyslipidaemia who have other coronary risk factors. A low daily dose of felodipine (Smg) plus enalapril (Smg) effectively achieved a target supine BP of 90mm Hg or less in 75% of a series of elderly hypertensive patients. IIS] This compared with only 69% and 56% of patients treated with felodipine 10 mg/day or enalapril 10 mg/day monotherapy, respectively. Also, the low dose combination regimen was better tolerated than either drug used alone and, in particular, the incidence of ankle oedema was substantially reduced.

3.5 f3-Blocker plus ACE Inhibitor

This combination would appear to have little advantage over monotherapy with either agent. Drugs of both groups interact with the renin-angiotensin­aldosterone system and the ~-blocker, by reducing kidney renin release, might be expected to attenu­ate the actions of an ACE inhibitor. Although a few early studies did suggest additional benefit from such combinations,[IY] more recent larger clinical trials have failed to confirm thisJ201 An exception arises in the treatment of hypertension following acute myocardial infarction, in which symptom­less left ventricular dysfunction may develop. The combination not only reduces the risk of sub­sequent arrhythmias but also reduces progressive ventricular dilatation and so improves exercise tol­erance.121.221

3.6 f3-Blocker plus a-Blocker

In practice such a combination is generally re­served for the treatment of more severe or resistant hypertension. In a retrospective analysis of prazosin prescribing in over 1000 patients treated in a hyper­tension clinic during a 3-year period, combination with one of the cardioselective or non-selective ~-blockers was used for patients with initial dias­tolic BPs of 100 to 120mm Hg in over one-half the number of cases, and diastolic pressures above 120mm Hg in a further one-third.r231

Labetalol, a combined a/~-blocker, has been available for many years but is not favoured for

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routine use as a result of the postural dizziness which it frequently causes due to attenuation of the reflex tachycardia which occurs in response to erect posture by ~-blockade.

4. Conclusion

The careful selection of first-line antihyperten­sive therapy using a variety of drug combinations might enable more precise control of hypertension at low dosage and in the absence of many dose-re­lated and often limiting adverse effects . Further support for such a strategy may be forthcoming in the aftermath of the HOT study if the benefits of strict BP control on outcome in terms of survival and end-organ damage are eventually demon­strated.

References I. Hansson L. Rationale for combination therapy. Br J Clin Phar­

macal 1987: 23 Suppl. I: 15-9 2. HOT Study Group. Hypertension optimal treatment study (the

HOT study ). Blood Press 1993; 2: 62-8 3. Dupont AG. The place of diuretics in the treatment of hyper ten­

sion: a historical reviewa l' classical experi ence over 30 years . Cardiovasc Drugs Ther 1993; 7 Suppl. I: 55-62

4. Swales JD. Pharmacolog ical treatment of hypertension. Lancet 1994: 344: 380-5

S. McVeigh G. Galloway D. Johnston D. The case for low dose diuretics in hypertens ion: comparison of low and conven­tional doses of cyclopenthiazide. BMJ 1988; 297: 95-8

6. Vardan S. Mchrotra KG. Mookherjee S. et al. Efficacy and re­duced metabolic side effects of a 15mg chlorthalidone formu ­lation in the treatment of mild hypertension. A multicenter study. JAMA 1987; 258 ; 484-8

7. Carl sen JE, Kober L. Torp-Pederson C, et al. Relation between dose of bendrotluazide. antihypertensive e ffect, and adverse biochemical effects. BMJ 1990: 300: 975-8

8. Petrie JC, Jeffers TA. Scott AK. et al. Dose and duration of response to ~-blocker s in the treatme nt of hypertension. Drugs 1983: 22 Suppl. 2: 26-9

9. Lithell H. Weiner L, Vessby B. et al. Effects of small doses of bioprolol on blood pressure and lipoprotein concentrations in hype rtensive pati ents. Eur J Clin Pharmaco l 1993; 44: 19-22

10. Frick MH. McGibney D, Tyler HM. A dose- response study of amlodipine in mild to moderate hypertension. J Intern Med 1989: 225; 101-5

II. Hayduk K. Scheider HT. Antihypertensive effects of doxazosin in systemic hypertension and comparison with terazosin. Am J Cardiol 1987: 59: 95G-98G

12. Grimm RH. A1phal -antagoni sts in the treatment of hyperten­s ion. Hypertens ion 1989: 13 Suppl. I: 1131-6

13. WHO/ISH Guidelines Subcommittee 1993. Guidelines for the management of mild hypertension: memorandum from WHO/ISH meeting. J Hypertens 1993; II: 905-18

14. Vlasses PH. Rotmen sc h HH. Swanson BN. et al. Low-dose captopril: its use in mild to moderate hypertension unre-

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sponsive to diuretic treatment. Arch Intern Med 1982; 142: 1098-101

15. Lang H. The results of a large multicentre study comparing low dose lisinopril-hydrochlorothiazide treatment with the monocomponents. J Human Hypertens 1991; 6 Suppl. 2: 73-6

16. Hansson L, Himmelmann A. Calcium antagonists in antihyper­tensive combination therapy. J Cardiovasc Pharmacol 1991: 18 Suppl. 10: 76-80

17. Lejeune P, Gunselmann W, Hoppe I, et a!. Effects of a fixed combination of low dose nifedipine and acebutolol on essen­tial hypertension: comparison with standard dose acebutolol. Clin Exp Hypertens 1985; 7: 1541-2

18. Morgan TO, Anderson A, Jones E. Comparison and interaction of low dose felodipine and enalapril in the treatment of essen­tial hypertension in elderly subjects. Am J Hypertens 1992; 5: 238-43

19. Pickering TG, Case DB, Sullivan PA, et a!. Comparison of an­tihypertensive and harmful effects of captopril and proprano­lol at rest and during exercise. Am J Cardiol 1982; 49: 1566-8

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MacConnachie & Maclean

20. Hannson L. Swedish lisinopril study group. Lisinopril com­bined with atenolol in the treatment of hypertension. J Car­diovasc Pharmacol 1991; 18: 457-61

21. Sharpe N, Murphy J, Smith H, et a!. Treatment of patients with symptomless left ventricular dysfunction after myocardial in­farction. Lancet 1988; I: 255-9

22. Pfeffer MA, Lamas GA, Vaughan DE, et a!. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988; 319: 80-6

23. Stokes GS, Raftos J, Lewis RG, et a!. Combined use of prazosin and beta-blockers in hypertension. J Cardiovasc Pharmacol 1982; 4 Suppl. I: 172-5

Correspondence and reprints: Angus M. MacConnachie, Tayside Drug Information Service, Ninewells Hospital and Medical School, Dundee DDl 9SY, Scotland.

Drug Safety 12 (2) 1995