For Rational

FEBRUARY 21, 1994

CONTENTS

New Drugs and Therapeutics

• Diltiazem: a useful 1 antihypertensive in the elderly

• Cladribine and pentostatin 4 improve the outlook in hairy cell leukaemia

• RSV immunoglobulin 8 reduces the severity of RSV infection in at-risk children

• Macrolides still first 8 choice in legionnaires' disease

• Pain is the key to diagnosis 11 and treatment of musculoskeletal disorders in the elderly

Drug Reactions and Interactions

• Extra caution required to 12 prevent anticholinergic adverse effects in the elderly

Drug Economics and Quality of Life

• Low-dosage epoetin: 14 pragmatism prevails

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D rug Selection and Use

VOLUME 3, NO.3

ISSN 1172-0360

Diltiazem: a useful antihypertensive in the elderly

DillHlJ'em appetm. to be a suitable alternutive antihYpc!rtensive patients wh n t1iuretic. are contnumhcuted or in those with concomitant

conditions ... uch u." angina pccltlrh and pcriphcml vascular t1"case. The t1rug ~IPPCtm. particularly useful u.s an alternative to t1iuretics in elderly Black pUlients.

Th role of diltia7em relative to that of other groups of ulternati\c lip,t-line antihypcrtensl~es hl1.' yet to bc deli ned in the elderly populatIOn. vatlable e\ idence suggest, thut diltiu/cm lowers blood pressure ut leu't 11., effectively." othcr drug . .

hoice (If drug muy. therefore. bc guided by the presence of cllntraindications and oncomitant onditionl>.

DiltlUl:cm is genemlly well tolerated. With the mllst common adverse effect, bemg those typical of a vasodilator. However. it should be avoided in patients with cardiac eondueti n disturbanccs and lert ventricular dysfunction ,ince it may cxacerbatc these conditions.

It is now accepted that treating hypertension, including isolated systolic hyper­tension, in elderly patients produces worthwhile reductions in morbidity and mortality. Indeed, the absolute benefit is greater in the elderly than in younger patients. I

The only drug classes that have been conclusively proven to reduce mortality associated with hypertension are diuretics and l3-blockers. The results of the recent l)K Medical Research Council trial suggest that diuretics are preferred in the elderly.2 In this trial, a combination of hydrochlorothiazide with arniloride reduced the risks of stroke, coronary events and all cardiovascular events compared with placebo, whereas atenolol did not.2

Agents such as the calcium antagonists, ACE inhibitors and a-blockers reduce blood pressure, but have not been proven to reduce mortality. Nonetheless, these agents are cited as alternative first-line drugs in recent guidelines issued by the World Health Organization (WHO)IInternational Society of Hypertension3 and the second working party of the British Hypertension Society,4 among others.5

Diltiazem was one of the first calcium antagonists to be introduced. Although it is perhaps regarded primarily as an antianginal agent, its antihypertensive efficacy has been studied specifically in elderly patients. Diltiazem is compared with other drugs used in the treatment of hypertension in the elderly in the Differential Features table.

Diltiazem Diltiazem is a benzothiazepine derivative calcium antagonist, the only repre­

sentative of this chemical class currently available. Accumulated data have established that diltiazem:

• is as effective as l3-blockers or other calcium antagonists in the prophylaxis of stable angina pectoris, and reduces symptoms in unstable and variant angina

• is as effective as other first-line options in mild to moderate hypertension

Drug & Therapy Pen.pective, Editor: Janel Ken l n \. lid t, Edlto : lut

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International Edit ri I B rd

Vol 3, No.3; Februory 21, 1994

• does not disrupt glucose or lipid homeostasis • terminates supraventricular tachycardia in 60 to 100% of

patients when administered intravenously • slows the ventricular response to atrial fibrillation or

flutter. 7

Data from the large Multicenter Diltiazem Postinfarction Trial indicate that the drug should not be used as secondary prevention of myocardial infarction in patients with evidence of left ventricular dysfunction, and particularly those with ejection fractions of <0.40.8,9 In these patients, diltiazem increases the risk of first recurrent cardiac events and late occurrence of congestive heart failure.

However, the drug may be of benefit in patients without left ventricular dysfunction. Diltiazem recipients without pul­monary congestion had lower I-year event rates following the index infarction (8%) than placebo recipients (11 %).8

Subset analysis of data from this trial also indicates that diltiazem may be beneficial in patients with non-Q wave infarction. During the first 6 months after the initial event, fewer reinfarctions occurred in patients receiving diltiazem (l.6%) than in those receiving placebo (I2%).(() However, beneficial effects of diltiazem did not extend into the second 6 months following non-Q wave infarction. to

In patients with hypertension, diltiazem 120 to 360 mg/day for 4 to 16 weeks has been shown to reduce left ventricular mass index by around 10%, without impairing cardiac function. II

Diltiazem in elderly hypertensives

Efficacy In randomised controlled trials involving elderly patients

with hypertension, diltiazem 60 to 360 mg/day has been at least as effective as: • atenolol 50 to 100 mg/day • enalapril 5 to 40 mg/day • hydrochlorothiazide/triamterene 25/50 mg/day and • hydrochlorothiazide 12.5 to 50 mg/day. II

One large trial compared the effects of sustained release diltiazem (120 to 360 mg/day in 2 divided doses) with those of 5 other antihypertensive agents and placebo.6

In this trial, responses were assessed according to treat­ment, age «60 or :;::60 years) and race (Black or White).

Response rates in the elderly patients are shown in the Differential Features table.

For older White patients, all of the drugs were similarly effective, with atenolol, diltiazem and captopril all producing response rates :;::60%. In the older Black patients, diltiazem and hydrochlorothiazide were both significantly more effective than the other treatments.6

Captopril was among the most effective agents in White patients, but performed poorly in both older and younger Black patients. Diltiazem appeared similarly effective in all patient groups, with the response rate dropping below 60% only in younger Whites (44%).

These results were obtained in men, and it may not be possible to extrapolate them to women.

However, results from a trial conducted in elderly women (average age 70 years) indicate that diltiazem controls hyper­tension at least as well as atenolol and enalapril in this popu­lation. 12 Patients received sustained release diltiazem 60 to I80mg twice daily, atenolol 50 to IOOmg once daily or enalapril 5 to 20mg once daily.

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Differential Features

Comparison of the features of diltiazem with those of other antihypertensive agents used in elderly patients with hypertension

Feature Diltiazem Atenolol Captopril Clonidine H¥drochlol'o- Prazosin thiazide

Drug closs Calcium j3-Blocker ACE inhibitor Centrolly octing Thiazide !'I-Blocker antagonist agent diuretic

Efficocy (%)0 64b 58b Blacks 33 20 45 38

Whiles 64< 68c 60< 58c 52 48

Concomitant conditionsd A$thma ./ x ./ NA ./ ./ Diabetes mellitus ./ .// ./ NA .// . ./ Dyslipidael'/lia ./ ? ./ NA ? ./ Gout ./ ./ ./ NA x ./ Heart failure ./I ./ NA ./ ./ Ischaemic heart disease ./ ./ ./ NA ./ ./ Peripheral vascular disease ./ .// .// NA ./ ./

Common/importont adverse Headache, Dyspnoea, Cough, rash, Dry mouth, Impotence, Postural effects Rushing, lethargy, blood sedation hypotension, ~out, postural

oedema, imldtence, dyscrasia" Raynau~h ~potension, drowsiness, heart block cod hyperkalaemio phenomenon, eectralyte headache

extremities, depression, disturbance bradycardia headache

a Efficacy evaluated with each agent as monotherapy in a randomised double-blind trial involving 746 elderly men.6 The efficacy rates shown oro the percentages of patients who achieved diastolic blood pressure values <90mm Hg during a 4- to 8-week titration phase and a diastolic blood pressure <95mm Hg after 1 year of maintenance treatment. b Dihiazem and hydrochlorothiazide were similarly effective, and both were significantly' more effective than the other drugs and placebo. c Atenolol, diltiozem, coplopril and clanidine were similarly effective, and all were significantly more effective than either hydrochlorothiazide or prazosin. d Use of drugs in concomitant conditions as listed far the drug classes of which the agents are representatives in the management guidelines for essential hypertension issued by the British Hypertension Society." Abbreviation and symbols: NA - not applicable (drug closs not rec~nised as initial therapy in the British Hypertension Society guidelines); ./ • suitable far use in potients wilh this condition; x - not suitable for use in potients with tliis condition; ./ /" - use with core in potients with this condition; ? - use in this condition remains controversial.

77, 63 and 67% of patients achieved blood pressure control after 16 weeks' treatment with diltiazem, atenolol and enalapril , respectively. 12

This trial also evaluated quality of life during treatment. No significant differences were found between treatments over the duration of the trial. 12

Tolerability

Diltiazem is generally well tolerated. The most common effects include headache, flushing, peripheral oedema and hypotension secondary to vasodilation. II Adverse effects, with the possible exception of orthostatic hypotension, do not appear to be more frequent in elderly patients than in their younger counterparts. I J

Reflex tachycardia appears to be less common with diltiazem than with the dihydropyridine calcium antagonists. 14

Constipation may occur with diltiazem, although this appears to be less common than with verapamil. Generally, lower dosages or increased dietary fibre will be sufficient to relieve constipation. 15

Because diltiazem prolongs atrioventricular conduction, it may produce heart block. The risk of this effect is increased in patients receiving concomitant j3-blocker therapy, and in those with other conduction abnormalities. Thus, the drug should be used with caution in combination with j3-blockers. It is contra­indicated in patients with sick sinus syndrome and second- or third-degree heart block in patients without functioning ven­tricular pacemakers. II

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As mentioned previously, diltiazem should be avoided in patients with evidence of left ventricular dysfunction.8.9,14

Diltiazem, like other calcium antagonists, is metabolised in the liver. \3 Hepatic blood flow decreases in the elderly, reducing clearance and increasing plasma concentrations, area under the plasma concentration-time curve and elimination half-life. 13

In addition, diltiazem has the potential to interact with other hepatic ally metabolised drugs. There is evidence of interac­tions between diltiazem and propranolol, digoxin, cyclosporin, cimetidine, carbamazepine, imipramine and anaesthetics. I I Thus, these combinations should be administered cautiously, with monitoring of both clinical status and; for digoxin, cyclo­sporin and carbamazepine, blood concentrations.

Dosage and administration For the treatment of hypertension, sustained release

preparations of diltiazem are preferred over standard preparations. 16

Oral dosages of 120 to 480 mg/day (usually administered twice-daily in sustained release formulations) are used. ll However, in Japan and Southeast Asia, dosages of 90 to 180 mg/day are the norm.?

Treatment should be initiated at low dosages and titrated against response. This is particularly important in the elderly who may be at increased risk of orthostatic hypotension. Reductions in hepatic function with aging, which reduce the clearance of diltiazem, also argue for lower initial dosages in the elderly.

Vol. J, No. J; February 21,1994

Adis Evaluation

Key points in the overall evaluation of diltiazem as an antihypertensive drug in elderly patients CLINICAL 8INI.ITS ____________ _

• At least as effective as alternative drugs in elderly patients with respect 10 blood pressure lowering

• Favourable or neutral effects on glucose and lipid metabolism

• Useful in patients with concomilont ischaemic heart disease, obstructive airways disease and peripheral vascular disease

POTINTIAL UMITATIONS __________ _

• Not proven 10 reduce mortality in controlled clinical trials

• Not suitable in patients with left ventricular dysfunction or cardiac conduction disturbances

• Higher acquisition costs than diuretics

Prescribing and formulary considerations Thiazide diuretics are generally considered to be the main­

stay of hypertension therapy in elderly patients. I These drugs have been proven to reduce mortality, have low acquisition costs and are generally well tolerated.

However, concern over the adverse effects of diuretics on lipids and individual variations in response mean that diuretics are not used uniformly as first-line therapy in older hyperten­sive patients. Moreover, they should not be used in patients with gout and other agents are preferred in diabetes mellitus. I

Calcium antagonists have been suggested as alternative first-line agents. Diltiazem has been shown to be an effective and well tolerated antihypertensive, suitable for consideration as an alternative to diuretics.

Diltiazem may be particularly suitable in:

• elderly Black patients in whom it appears more effective than other alternatives to diuretics6

• patients with angina pectoris, since the drug is effective in both angina and hypertension 7,11

• patients with hypertension and concomitant peripheral vas­cular disease or obstructive airways disease, in whom J3-blockers are not appropriate. I

• patients with diabetes mellitus and gout in whom diuretics are less suitable (although ACE inhibitors may be preferred in patients with diabetes). I Compared with other calcium antagonists, diltiazem is less

likely to cause tachycardia than the dihydropyridines, and less likely to cause conduction disturbances and constipation than verapamil.

The cautions and contraindications mentioned previously should also be considered, particularly the need to guard against heart block and exacerbation of left ventricular dys­function. However, combining diltiazem with J3-blockers may have better anti anginal efficacy than either drug alone, and may be used cautiously in some patients.7

a-Blockers may be preferred in elderly men with benign prostatic hypertrophy (see 'Finasteride: good tolerability but modest clinical benefit in BPH' Drugs & Therapy Perspectives 2: 1-4,30 Aug 1993). ACE inhibitors are favoured in patients with concomitant heart failure or diabetes mellitus. I

Vol 3, No. 3; February 21, 1994

References I. Beard K. et al. BM] 304: 412·416, 1992 2. MRC Working Party. BM] 304: 405-412,1992 3. Guidelines subcommittee of the WHO/ISH Mild Hypertension Liaison

Committee.] Hypertension 11 : 905·918,1993 4. Sever P, et al. BM] 306: 983·987, 1993 5. Swales ID, et al.] Hypertension II: 899·903, 1993 6. Materson Bl, et al. N Engl] Med 328: 914·921,1993 7. Buckley MM·T, et at. Drugs 39: 757·806, 1990 8. The Multicenter Diltiazem Postinfarction Trial Research Group. N Engl ]

Med 319: 385·392, 1988 9. Goldslein RE, el at. Circulation 83: 52·60,1991

10. Wong S·C, et al.] Am Coli Cardiol19: 1421·1425, 1992 II. Markham A, Brogden RN. Drugs Aging 3: 363·390, 1993 12. ApplegateWB, et al. Arch InternMed lSI: 1817· 1823, 1991 13. Kelly IG, et al. Clin Pharmacokinet22: 416·433,1992 14. Frishman WH. Am] Cardiol69: I7C·25C, 1992 15. Tijoa HI , Kaplan NM. ]AMA 264: 1015·1018,1990 16. Anon. British National Formulary 26: 83, 1993

Cladribine and pentostatin improve the outlook in hairy cell leukaemia

I"iiii;1 Either cladribine or pento~taLin is likely 10

become the lreaUnent of choice for patienL' with hairy cell leukaemia (HCL). Response rales and dUfillions are far greater than lhose achie cd with eilher interferon-a. or splenectomy.

Wilh regard to response rates. there is lillie 10 choose between these 2 dnlgs in HC at present. However, recovery from neutropenia. anaemia and thrombocytopenia is more rapid with cladribme than with pentostutin.ln addillon. nausea, vomiling and disturbance of liver function tests do nOl seem to occur with c1adribine at recommended dosages.

Only I course of cladribine is required 10 achieve response rutes similar (0 those after several pentoslatin infu. ions. How­ever. the current ladribine regimen requires a 7·day hospital slay, while penlostutin can be given on an outpalient basis. If a 5·day intermittent cladribine regimen proves as effective as Ihe 7·day continuous coursc. it may become rea.,ible to administer cladribine to outpatients.

If one of these ugents achieves responses that arc signifi­cantly more durable than those produced by the other, il will b<!c me the drug or chOice. In the meunllme, the slightly beth:r tolerability of c1adribinc may be an important ructor in choos­ing betwccn these 2 drugs.

Until recently, the best available treatment of hairy cell leukaemia (HCL) was interferon-a (IFNa) with or without splenectomy. Two new antimetabolites, pentostatin t and cladribine t , have drastically improved the outlook for patients with this condition.

HCL is a rare condition, accounting for about 2% of all adult leukaemias. 1 Splenectomy was the mainstay of treat­ment, with alkylating agents being administered to those patients with significant bone marrow involvement.2,3 More

t In Sweden, pentostatin is not registered, but can be obtained under special circumstances; pentostatin is not available in Denmark, Spain or Germany; c1adribine is not available in Denmark, Spain, France, the UK or Germany.

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