Correspondence
Single-Drug Therapy for Hypertension in Men
N Engl J Med 1993; 329:1043-1045September 30, 1993
- Article
To the Editor:
Materson and colleagues (April 1 issue)1 compared the effects of six different antihypertensive agents in patients with mild-to-moderate hypertension. Their findings contrast with the results of a similar study comparing five single agents with placebo: the Treatment of Mild Hypertension Study2. In that study, no differences were observed in diastolic blood pressure with the five drugs -- acebutolol, amlodipine, chlorthalidone, doxazosin, and enalapril. For systolic blood pressure, the only difference observed was that the diuretic agent (chlorthalidone) was more effective than the alpha-adrenoceptor antagonist (doxazosin) in reducing pressure.
The different findings of the two studies highlight the problems caused by trials that attempt to compare different antihypertensive agents. Most, if not all, of the observed differences relate to the study design and depend on the types of patients studied, the dose ranges chosen, and the relation between drug dosage and effect. As Materson et al. acknowledge, the patients they studied were not representative of hypertensive patients as a whole, since there were clear sex and racial biases. It is therefore important not to extrapolate these data to other populations. Also, the optimal dose ranges for most antihypertensive drugs have not been accurately defined3. To determine the lower level of the dose-response relation, it is necessary to include a dose that has substantially less effect than the maximal dose and is more effective than placebo; the study should preferably use a parallel dose design with placebo control. The authors have used the lowest starting doses available, but we still do not know whether doses lower than 12.5 mg in the case of hydrochlorothiazide and 25 mg in the case of atenolol lower blood pressure more than would placebo3. With the exception of the calcium antagonists, there is little evidence that there is an increasing effect with increasing doses of most antihypertensive agents3. In particular, there is little evidence from properly designed studies that a 50-mg dose of hydrochlorothiazide is more effective than a 25-mg dose,4 that a 100-mg dose of atenolol is more efficacious than a 50-mg dose,5,6 or that a 100-mg dose of captopril is more effective than lower doses3. Finally, the authors do not seem to have considered the different relations between drug dose and effect. Thiazide diuretics, beta-adrenoceptor antagonists, and probably most angiotensin-converting-enzyme inhibitors often do not achieve their maximal antihypertensive effect for several weeks3,5,6. It is therefore inappropriate to increase the dose at intervals of two weeks, before the maximal antihypertensive effect of the first dose is achieved. Calcium antagonists, in contrast, rapidly achieve their maximal effect, and the blood-pressure response is short-lived, so increasing the dose every two weeks is appropriate.
Given the study design, it was not surprising that diltiazem proved to be the most effective agent in lowering diastolic blood pressure. It has a rapid onset of action and a relatively steep dose-response relation.
6 ReferencesG. Dennis Johnston, M.D., Ph.D., F.R.C.P.
Queen's University of Belfast, Belfast BT9 7BL, Northern Ireland1
Materson BJ ,Reda DJ ,Cushman WC , et al. Single-drug therapy for hypertension in men -- a comparison of six antihypertensive agents with placebo. N Engl J Med 1993;328:914-921
Full Text | Web of Science | Medline2
The Treatment of Mild Hypertension Research Group
CrossRef | Web of Science | Medline3
Johnston GD . Dose-response relationships with antihypertensive drugs. Pharmacol Ther 1992;55:53-93
CrossRef | Web of Science | Medline4
Burris JF ,Weir MR ,Oparil S ,Weber M ,Cady WJ ,Stewart WH . An assessment of diltiazem and hydrochlorothiazide in hypertension: application of factorial trial design to a multicenter clinical trial of combination therapy. JAMA 1990;263:1507-1512
CrossRef | Web of Science | Medline5
Petrie JC ,Jeffers TA ,Scott AK ,Webster J . Dose and duration of response to beta-blockers in the treatment of hypertension. Drugs 1983;25:Suppl 2:26-29
CrossRef | Web of Science6
Douglas-Jones AP ,Cruickshank JM . Once-daily dosing with Atenolol in patients with mild or moderate hypertension. BMJ 1976;1:990-991
CrossRef | Web of Science | Medline
To the Editor:
Materson et al. found that high doses of single-drug regimens are ineffective in keeping diastolic blood pressure at or below 95 mm Hg, even in patients with hypertension that is mild to moderately severe. How long will the focus remain on ineffective, very expensive, single-drug regimens for treating the huge mass of such patients? An inexpensive triple-drug regimen of reserpine, chlorothiazide, and hydralazine was demonstrated1,2 to be highly effective in reducing the risk of absolute end points (morbidity and mortality). We now know much more about the interactions of antihypertensive-drug combinations with neuroendocrine mechanisms of blood-pressure support3,4. Diastolic blood pressure can usually be maintained below 90 mm Hg with relatively low doses of three drugs. In our prospective, long-term study of blood-pressure control involving many severely hypertensive patients,5 we kept diastolic blood pressure below 90 mm Hg in nearly all patients for years and below 80 mm Hg for several months in most patients.
5 ReferencesWilliam A. Pettinger, M.D.
Hing-Chung Lee, M.D., Ph.D.
Midwest Hypertension Research Center, Omaha, NE 68131-21971
Veterans Administration Cooperative Study Group on Antihypertensive Agents
CrossRef | Web of Science2
Veterans Administration Cooperative Study Group on Antihypertensive Agents
CrossRef | Web of Science3
Pettinger WA ,Mitchell HC . Renin release, saralasin and the vasodilator-beta-blocker drug interaction in man. N Engl J Med 1975;292:1214-1217
Full Text | Web of Science | Medline4
Lee HC ,Pettinger WA . Multidrug regimens in moderate & severe hypertension. Nebr Med J 1992;77:300-309
Medline5
Pettinger WA ,Lee HC ,Reisch J ,Mitchell HC . Long-term improvement in renal function after short-term strict blood pressure control in hypertensive nephrosclerosis. Hypertension 1989;13:766-772
Web of Science | Medline
To the Editor:
At about the time I received the April 1 issue of the Journal, I received a box from the “Cooperative Studies Program of the Medical Research Service of the Department of Veterans Affairs.” The box contained a “Study Results Summary” describing the study's results “in more detail than was possible in the original published paper.” The material was copyrighted by GEM Communications, Stamford, Connecticut, and supported by an “educational grant from Marion Merrell Dow.”
I am sure that if the data on the use of diltiazem as a single agent for hypertension had been less favorable, Marion Merrell Dow, sole purveyors of diltiazem, would not have supported this mailing. The mailing included an offer of up to 20 educational slides for physicians wanting to teach the results of this study to others.
One of our local pharmacies supplied me with the following data. The cost to the patient of a three-month supply (100 doses) of hydrochlorothiazide in a daily dose of 25 or 50 mg is $3.95. A three-month supply of slow-release diltiazem in a twice-daily dose of 60 mg costs $151.98, and the cost of a twice-daily dose of 120 mg is $223.98.
Surely, expense should be of more than passing consideration in the choice of agents whose clinical effects are approximately equal in most situations. Given the extreme difference in cost -- less than $16 a year as compared with more than $600 to $900 -- should not hydrochlorothiazide still be the first agent tried in almost all patients?
Marion Merrell Dow supplied without cost the diltiazem used in this study. The promotional value they derived from the results is probably incalculable. I object to receiving promotional material in an educational disguise.
Bernadine Z. Paulshock, M.D.
Medical Center of Delaware, Wilmington, DE 19801Author/Editor Response
The authors reply:
To the Editor: Dr. Johnston implies that our Veterans Affairs study and the Treatment of Mild Hypertension Study are directly comparable; they are not. The average base-line diastolic blood pressure in the patients in the latter study was 8.5 mm Hg lower than that in our patients; nonpharmacologic management reduced blood pressure a further 10.6/8.1 mm Hg in the placebo group. It is not surprising that no substantive long-term differences in drug efficacy were seen. Our study was designed to examine differences in drug effects in patients who were frankly hypertensive. No women were included in this trial because less than 2 percent of the patients in our population of veterans were women. Our study emphasizes that both age and race should be considered in drug selection. A heterogeneous group of hypertensive patients should not be viewed as if it were homogeneous. We tested a 12.5-mg dose of hydrochlorothiazide and a 25-mg dose of atenolol. These doses were lower than those in use in 1984, when the Treatment of Mild Hypertension Study was being planned. We did not seek to determine the lowest effective dose of each of the six drugs that were studied. We carefully considered the duration of our dose-titration intervals. A controlled clinical trial must be uniform; a blinding scheme that would have permitted a different dose-titration regimen for each drug would have been unnecessarily complex. The maximal two-month titration period should have allowed for the identification of the majority of potential responders to all drugs.
Drs. Pettinger and Lee are advocates of combining very low doses of multiple drugs for the treatment of even mild hypertension1. Although they find our therapeutic glass empty, we believe it to be 55 to 68 percent full at one year, according to intention-to-treat analysis, if age and race are considered in the selection of a single drug. Patients who do not respond can be treated with another single drug, or another drug (often a diuretic) can be added to the regimen. A triple-drug formulation may provide more medication than is required for most patients with mild hypertension. Low-dose reserpine plus chlorthalidone is an effective and inexpensive fixed-dose combination2.
Dr. Paulshock addresses an issue of great sensitivity and deep concern to us. None of the participating companies, including Marion Merrell Dow (which is not the sole purveyor of diltiazem), had an influence on or control over the trial. We carefully weighed the opportunity for wider dissemination of our study results against the risk of any inference of impropriety. An agreement between the Department of Veterans Affairs Cooperative Studies Program and GEM Communications stipulated that all materials would be edited and subject to final review by the study chairman and biostatistician. We attempted to generate documents, press releases, and media interviews that reflected the objectivity of the original paper. The response has been overwhelmingly positive. We believe that this opportunity to shorten the lag time betwen the publication of results and their incorporation into practice has been worthwhile3. Our study did not address cost; it is one important factor in the selection of medication, antihypertensive or otherwise.
3 ReferencesBarry J. Materson, M.D.
Veterans Affairs Medical Center, Miami, FL 33125Domenic J. Reda, M.S.
Veterans Affairs Medical Center, Hines, IL 60141William C. Cushman, M.D.
Veterans Affairs Medical Center, Memphis, TN 381041
Lee HC ,Pettinger WA . Multidrug regimens in moderate and severe hypertension. Nebr Med J 1992;77:300-309
Medline2
Participating Veterans Administration Medical Centers
CrossRef | Web of Science3
Steinbrook R ,Lo B . Informing physicians about promising new treatments for severe illnesses. JAMA 1990;263:2078-2082
CrossRef | Web of Science | Medline
Author/Editor Response
A spokesperson for Marion Merrell Dow replies:
To the Editor: The educational materials to which Dr. Paulshock refers were issued by the Department of Veterans Affairs. Marion Merrell Dow had no control over the editorial content of these materials. Naturally, the company was pleased with the results of the study, but we have supported many educational projects over the years and did not support this study simply because we thought the results might be favorable to our compound.
Dr. Paulshock is incorrect in saying that Marion Merrell Dow is the sole provider of diltiazem. Diltiazem is now available in generic form from several U.S. pharmaceutical manufacturers.
Marion Merrell Dow did provide the product used in the study without cost, as did all the pharmaceutical companies whose products were involved. This is a common practice and allows many studies that advance scientific knowledge to be performed that might otherwise not be performed. Because our company agreed to supply the product before the initiation of the study, we could not have had any foreknowledge of the results.
The study did not compare the chemical compounds for cost, only efficacy. Marion Merrell Dow does have a form of diltiazem, Cardizem CD, that can be administered once daily, and this form is generally less expensive than the form used in the study.
Charles F. Rouse, III, III
Marion Merrell Dow, Inc., Kansas City, MO 64114
