Massive Study Confirms That Inexpensive Water Pills (DIURETICS) Should Be Used First In Treating High Blood Pressure

The results of a very large clinical trial designed to give a definitive answer to the decades-old question of which of four commonly used families of high blood pressure medications should be prescribed first was published in the December 18, 2002 issue of the Journal of the American Medical Association. The answer is that the oldest drugs — known as the thiazide diuretics, or water pills — are superior in preventing one or more major forms of cardiovascular disease to the other families of drugs. And in this day of high and rising drug costs, there is an added benefit: the thiazides are far and away the cheapest of the drugs tested.

This clinical study, formally known as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT for short) involved 33,357 patients aged 55 years or older with high blood pressure and at least one other risk factor for coronary heart disease. This was the largest and longest trial of its kind, with patients being followed for four to eight years.

Taxpayers were the primary funding source for ALLHAT, through the National Institutes of Health’s National Heart, Lung, and Blood Institute. The pharmaceutical industry is loath to sponsor large clinical trials directly comparing drugs that measure medical outcomes important to patients, such as increased survival, because there are always some drug company losers. The industry determined long ago that they do not need science to sell drugs, only marketing, and the less objective comparative information that patients and physicians receive, the easier it is to sell drugs.

The four families of drugs studied in ALLHAT were: (1) the calcium channel blockers represented by the “blockbuster” amlodipine (NORVASC); (2) the angiotensin converting enzyme (ACE) inhibitors, represented by lisinopril (PRINIVIL, ZESTRIL); (3) the alpha-blocking drugs represented by doxazosin (CARDURA); and (4) the oldest family of all, the thiazide diuretics represented by chlorthalidone (HYGROTON). More complete lists of these families of drugs are given below.

Alpha-Blockers Compared to Chlorthalidone

The first loser in ALLHAT was Pfizer Inc. of New York City with its alpha-blocking drug doxazosin. The alpha-blocker part, or “arm,” of the ALLHAT study was halted prematurely in March 2000 by the National Institutes of Health when it became clear that it was less effective than the thiazide drug chlorthalidone in preventing the serious complications of high blood pressure (see Worst Pills, Best Pills News May 2000). Doxazosin users had 25 percent more dangerous cardiovascular events and were twice as likely to be hospitalized for congestive heart failure as patients on chlorthalidone.

The doxazosin group also had a poorer compliance record: only 75 percent were still on the drug or another alpha-blocker after four years, compared with 86 percent still taking chlorthalidone or another diuretic. Both drugs were similarly effective in preventing heart attacks and in reducing the risk of death from all causes.

Pfizer followed the common practice in the pharmaceutical industry when a drugmaker is faced with a negative result in a trial involving one of its products: trash the study. The company also scripted a strategy for sales personnel when speaking to physicians to minimize the negative effect of the ALLHAT results on doxazosin sales.

Other alpha-blockers on the market including doxazosin are prazosin (MINIPRESS), terazosin (HYTRIN) and tamsulosin (FLOMAX). The ALLHAT results apply to prazosin and terazosin when they are used to treat high blood pressure. Tamsulosin is approved by the Food and Drug Administration (FDA) only for treating enlarged prostate, also known as benign prostatic hyperplasia (BPH).

Calcium Channel Blockers Compared to Chlorthalidone

Unlike the prematurely terminated alpha-blocker arm just described, the portion of ALLHAT comparing the calcium channel blocker amlodipine to chlorthalidone went the full distance. The conclusion reached was that no statistical difference existed between the two in the major outcome being measured, the occurrence of death from coronary heart disease combined with nonfatal heart attacks. However, chlorthalidone (the “water pill”) was superior to amlodipine in preventing heart failure. The absolute difference in risk at the end of six years was 2.5 percent. This means that for every 40 patients treated with chlorthalidone for six years compared to amlodipine, one case of heart failure will be prevented.

Amlodipine belongs to a chemical sub-family of calcium channel blockers called dihydropyridines that includes, in addition to amlodipine, felodipine (PLENDIL), isradipine (DYNACIRC), nicardipine (CARDENE), nifedipine (PROCARDIA XL) and nisoldipine (SULAR). The ALLHAT results apply to all these calcium channel blockers when used to treat high blood pressure.

The calcium channel blockers verapamil (COVERA HS) and diltiazem (CARDIZEM, CARDIZEM CD) are not in the dihydropyridine sub-family and the ALLHAT results do not apply directly to them. However, in the absence of any compelling evidence that these drugs are equal to or superior to the thiazide diuretics, verapamil and diltiazem should not be used as the initial treatment for high blood pressure.

ACE Inhibitors Compared to Chlorthalidone

In the comparison between chlorthalidone and the ACE inhibitor lisinopril, the results were surprising. Those taking lisinopril had a 15 percent higher risk for stroke and a 10 percent higher risk of combined cardiovascular disease (CVD), defined in the study as coronary heart disease, stroke, treated angina (chest pain), heart failure and peripheral arterial disease. These percentages, known as the relative risk, were in comparison to those patients receiving chlorthalidone. The absolute risk difference after six years between the two drugs was 2.4 percent. This computes to one case of CVD for every 41 patients taking lisinopril rather than chlorthalidone after six years of treatment.

Chlorthalidone was also found superior to lisinopril in preventing a number of other adverse outcomes of high blood pressure such as heart failure.

Another speculation put to rest in this trial was that African-American patients should selectively be placed on the more expensive ACE inhibitors such as lisinopril because of a suspicion that hypertension in African-Americans might be due to a different physiological mechanism. This implausible speculation received no support in the ALLHAT trial where all “races,” genders and age groups responded similarly to the medications.

The results of the ALLHAT study apply to all ACE Inhibitors on the market. In addition to lisinopril, these include benazepril (LOTENSIN), captopril (CAPOTEN), enalapril (VASOTEC), fosinopril (MONOPRIL), moexipril (UNIVASC), quinapril (ACCUPRIL), ramipril (ALTACE), trandolapril (MAVIK) and perindopril (ACEON).

The Thiazide Diuretics

An editorial from the Johns Hopkins Medical School that accompanied ALLHAT in the Journal of the American Medical Association was forthright and the recommendations flowing from this study were clearly stated:

The ALLHAT results provide compelling evidence that thiazide diuretics should be the initial drug of choice for patients with hypertension, especially compared with those agents that were directly tested in this trial.

This recommendation is not news. Previous studies have consistently documented that diuretics substantially reduce the risk of stroke. However, the benefits of diuretic treatment on coronary heart disease were never as strong as they now are.

In the first edition of Worst Pills, Best Pills, published in 1988, we recommended the thiazide diuretic hydrochlorothiazide (HYDRODIURIL) as the drug that should be used first in the treatment of high blood pressure. In subsequent editions of Worst Pills, Best Pills, released in 1993 and 1999, we followed the national guidelines of the National Institutes of Health’s (NIH) National Heart, Lung and Blood Institute, which recommended that diuretics be used first. As was mentioned above, taxpayers through the NIH were the major sponsors of ALLHAT.

The results of ALLHAT apply to all members of the thiazide diuretic family of drugs, which includes, in addition to chlorthalidone, bendroflumethiazide (NATURETIN), benzthiazide (EXNA), chlorothiazide (DIURIL), hydrochlorothiazide (HYDRODIURIL), hydroflumethiazide (SALURON), methyclothiazide (ENDURON), polythiazide (RENESE) and trichlormethiazide (NAQUA).

A Problem Remains

A major problem remains from a public health perspective: How to change physicians’ prescribing habits so that thiazide diuretics do get prescribed first in the treatment of high blood pressure. To the credit of the ALLHAT investigators, there are plans to use the approximately 700 physicians who participated in the study to actively communicate the study’s results to their colleagues.

We wish them success. However, because history tends to repeat itself, the most likely result will be a small and brief downturn in sales of the new brand name blood pressure lowering drugs and an increase in prescriptions for thiazide diuretics before the industry ratchets up its promotional juggernaut and the new drugs again outsell the older, less expensive and more effective thiazides.

We are aware of only a few cases in the last forty years in which a physician prescribing habit was changed on a large scale. One involved the antibiotic chloramphenicol (CHLORMYCETIN) — which causes life-threatening bone marrow toxicity — being prescribed for trivial reasons such as the common cold. When the public finally had access to the same information about the toxicity of this drug as their doctors already had, the trivial prescribing of chloramphenicol was curtailed.

What You Can Do

If you are now being treated for high blood pressure and a thiazide diuretic is not part of your treatment, you should ask your doctor if your blood pressure drugs should be reviewed because of the results of this new, large and important study.