Fixed -dose antihypertensive drug combinations may be useful if dual therapy is clinically indicated

Fixed-dose antihypertensive combinations have both proponents and opponents depending on the relative impor­tance attached to the potential advantages and disadvantages of these preparations (see table 1).

The 1993 World Health OrganizationlInternational Soci­ety of Hypertension guidelines for the management of mild hypertension note that ' ... preparations that combine two drugs in a single tablet or capsule may be appropriate for many hypertensive patients once the need and dose for con­stituent drugs have been established' P]

Recommendations made by the British Hypertension Society also suggest that drug combinations may be required in up to 50% of patients with mild hypertension, although these guidelines do not comment on the appropriateness of fixed-dose combinations)3]

The key to optimising the use of fixed-dose combination antihypertensive drugs is to understand which combinations represent logical partnerships, and which patients are most likely to benefit from them.

Rationale for combination preparations Improved patient compliance is suggested as a reason for

using fixed-dose combination preparations in hypertension guidelines, provided that both drugs are neededPA]

However, there do not appear to have been any trials specifically evaluating whether combination preparations improve patient compliance compared with taking the com­ponents individually, although logic suggests that they would improve the convenience of therapy.

What is apparent from clinical trials is that dosage fre­quency has an influence on patient compliance. Patient com­pliance with once- and twice-daily therapy appears to be comparable, but it is significantly reduced with thrice-daily dosage regimens)5,6]

Thus, the main impetus for combined therapy is not improved patient compliance but rather greater therapeu­tic efficacy or a reduced risk of adverse effects compared with mono therapy, which may be achieved as follows)I,3] 1 Drugs from different classes with complementary physio-

logical effects may have additive or synergistic blood pressure-lowering effects.

2 Reflex responses to a single drug may be counteracted by the addition of a second drug.

3 Prescribing 2 drugs at low dosages may avoid adverse effects that would occur if either agent were used in higher dosages as monotherapy. Examples of combinations that fulfil ~1 of these criteria

are shown in table 2. Concern that 24-hour blood pressure control may be

inadequate using once-daily fixed-dose combinations, be­cause of differences in drug pharmacokinetics, generally appears to be unfounded)I,IO-13]

Which patients will benefit? Guidelines for antihypertensive drug therapy generally

recommend either a thiazide diuretic or a ~-blocker as first-

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Table 1. Potential advantages and disadvantages of fixed-dose antihypertensive drug combinations! 1)

Potential advantages Convenient for both physician and patient Improved patient compliance Lower acquisition costs than individual components Potentiation of anti~ypertensive efficacy Reduced adverse effects

Potential disadvantages Lock of dosage Aexibility Pharmacokinetic 'mismatches' between component drugs Higher acquisition costs than individual components ar

monotherapy Drugs may have additive adverse effects

line therapy for mild hypertensionP-4] Some guidelines also include the ACE inhibitors, calcium channel blockers and <Xl-blockers as first-line agents)2,3]

Physicians are also encouraged to consider concomitant disorders when determining initial drug therapy, and age and ethnic group may also be important)14,15]

Whatever drug is deemed appropriate for initial therapy, it should first be tried as monotherapy at the lowest recom­mended dosagep,3] If this is ineffective but well tolerated, dosage escalation may be attempted)3] If the drug remains ineffective, an alternative agent is indicated)3]

Drugs that are only partially effective as monotherapy may be tried in combination with a second agent from a different class)3A] Only after adequate blood pressure con­trol has been achieved with combination therapy may a fixed-dose combination product be substituted for the indi­vidual components, and then only if the dosages are appro­priate. [2,3, 16]

Black patients appear to be particularly likely to require combination therapy. This is because hypertension tends to be more severe in this population, and also because Black patients are less likely than White patients to respond to monotherapy with ~-blockers or ACE inhibitors.[4]

Consider pharmacoeconomics also In developing countries with a majority of Black patients,

the acquisition costs of fixed-dose combinations may be of concern and may limit the usefulness of newer drugs such as ACE inhibitors)9]

In one trial, a fixed-dose combination of reserpine 0.125mg and hydroflumethiazide t 50mg was compared with a fixed-dose combination of atenolol 50mg plus chlorthalidone 12.5mg once-daily)91 The authors of this study considered the benefits of the reserpine/diuretic com­bination to be: • adequate antihypertensive efficacy using a low dosage of

reserpine that is unlikely to be associated with an increased risk of depression

• similar efficacy and tolerability compared with a ~­blocker/diuretic combination

• fewer reserpine/diuretic than ~-blocker/diuretic recipients require the dosage to be doubled for blood pressure control

• low acquisition costs «50% that of the alternative fixed­dose combination).

t Hydroflumethiazide has been withdrawn in Spain; in Germany, the only fixed dose combination of hydroflumethiazide and reserpine contains 50mg and O.05mg, respectively.

Vol. 5, No.8; May 1, 1995

9

Table 2. Examples of antihypertensive drugs that may logically be used in combination[l ,3,7·9]

Drugs Comments

Thiazide + potassium-sporing diuretic

Potassium-sporing diuretic prevents hypokalaemia ossociated with thiazides Rorely requiredo

~-Blocker + thiazide diuretic

Additive antihypertensive eHicacy ~-Blockers blunt the rise in plasma renin activity and tachycardia induced by diuretics Diuretics attenuate sodium retention induced by ~-blockers Both drug classes may cause impotence and have metabolic eHects that are undesirable in diabetes or dyslipidaemia Volume depletion without signiFicant vasodilatation may compromise peripheral perfusion in at-risk patients

ACE inhibitor + thiazide diuretic

Synergistic antihypertensive eHicacy ACE inhibitors attenuate the rise in plasma renin activity induced by diuretics ACE inhibitors attenuate thiazide-induced metabolic derangements such as hypokaleemia, hyperuricaemia and

hypercholesterolaemia Both drug classes are also useful in patients with heart failure

~-Blocker + dihydropyridine CCBb

Additive antihypertensive eHicacy ~·Blockers may attenuate tachycardia and SNS activation caused by CCBs CCBs prevent peripheral vasacanstrictian secondary to (X·adrenoceptor stimulation caused by ~-blockode Both drug classes are also useful in angina

ACE inhibitor + CCB

Additive antihypertensive eHicacy Reduced risk of adverse eFFects ACE inhibitors ottenuate activation of SNS and RAS by CCBs Negative sodium balance induced by CCBs enhances antihypertensive eFFect of ACE inhibitors

a -Blocker + ~-blocker

Additive antihypertensive eFFicacy a-Blocker attenuates vasoconstriction caused by j3-blocker

Reserpine + thiazide diuretic

Addi tive antihypertensive eHicacy Combination may allow use of lower reserpine dosages, with consequent reduction of adverse eHects compared with

reserpine monotherapy

a Consider potassium· sparing diuretics in patients receiving a thiazide or loop diuretic who have a plasma potassium level of < 3 or 3.2 mmol/L either before initiation of therapy or after .4 to 5 weeks of treatment. Patients at particular risk of hypokalaemia (e.g. those with hyperaldosteronism or psoriasis, or those taking digoxin or corticosteroids) may require potassium-sparing diuretics if plasma potassium levels are below 3.5 mmol/L b ~ -Blockers should not be combined with other CCBs such as the phenylolkylamines (e.g. verapomil) and benzothiazepines (e.g. diltiazem) becouse of the risk af inducing heart failure and conduction disorders. Abbreviations: CCB = calcium channel blocker; RAS = renin-angiotensin system; SNS = sympothetic nervous system.

References L Sica DA. Fixed-dose combination antihypertensive drugs. Do they have

a role in rational therapy? Drugs 1994; 48: 16-24 2. Guidelines sub-committee. 1993 guidelines for the management of

mild hypertension: memorandum from a World Health Organiza­tionlInternational Society of Hypertension meeting. J Hypertens 1993; II: 905-18

3. Sever P, Beevers G, Bulpitt C, et aL Management guidelines in essential hypertension: report of the second working party of the British Hy­pertension Society. BMJ 1993; 306: 983-7

4. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The fifth report of the Joint National Commit­tee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993; 153: 154-83

5. Kruse W, Rampmaier J, Ullrich G, et aL Patterns of drug compliance with medications to be taken once and twice daily assessed by continuous electronic monitoring in primary care. Int J Clin Pharmacol Ther 1994; 32: 452-7

6. Eisen SA, Miller OK, Woodward RS, et aL The effect of prescribed daily dose frequency on patient medication compliance. Arch Intern Med 1990; 150: 1881-4

7. Salient points regarding potassium homeostasis in cardiovascular disease. Drug Ther Perspect 199427 Jun; 3: 11-2

8. Robertson JIS. Guidelines for the treatment of hypertension: a critical re­view. Cardiovasc Drug Ther 1994; 8: 665-72

9. Maharaj B, ven der Byl K. Randomised double-blind comparative study of efficacy and safety of hydroflumethiazide and reser­pine and chlortalidone and atenolol in the treatment of mild to moderate hypertension in black patients. J Hum Hypertens 1993; 7: 447-50

VoL 5, No.8; May 1, 1995

10. Chrysant SG, The Lisinopril-Hydrochlorothiazide Group. Antihyper­tensive effectiveness of low-dose lisinopril-hydrochlorothiazide combination. A large multicenter study. Arch Intern Med 1994; 154: 737-43

11. Wilkinson R, Mansy S. A dose finding study of the combination of aten-0101 and nifedipine in hypertension. CUIT Med Res Opin 1990; 12: 108-13

12. Hort JF, Wilkins HM. Changes in blood pressure, serum potassium and electrolytes with a combination of triamterene and a low dose of chlorthalidone. CUIT Med Res Opin 1991; 12: 430-40

13. Valvo E, Bedogna V, Casagrande P. Ambulatory blood pressure meas­urement in assessing the antihypertensive effect of benazepril plus hydrochlorothiazide in a fixed combination. Clin Ther 1993; 15: 650-6

14. Treatment of hypertension in patients with concomitant disorders. Drug Ther Perspect 1994 Nov 14; 4(10): 8-11

15. Materson BJ, Reda OJ, Cushman WC, et aL Single-drug therapy for hy­pertension in men. A comparison of six antihypertensive agents with placebo. N Engl J Med 1993; 328: 914-21

16. British National Formulary No. 27. London: The Pharmaceutical Press, 1994; 67-82

17. Chrysant SG, Chappel C, Farnham OJ, et aL Antihypertensive and meta­bolic effects of single and combined atenolol regimens. J Clin Phar­macoI1992; 32: 61-5

18. Chrysant SG, Chrysant C, Trus J, et aL Antihypertensive effectiveness of amlodipine in combination with hydrochlorothiazide. Am J Hypertens 1989; 2: 537-41

19. Chrysant SG, Fox AAL, Stimpel M. Comparison ofmoexipril- a new ACE inhibitor - to verapamil-SR as add on therapy to low dose hy­drochlorothiazide in hypertensive patients. Am J Hypertens 1995 Apr; in press

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