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Recent publications of the major findings of theAntihypertensive and Lipid-Lowering Treatment

to Prevent Heart Attack Trial (ALLHAT) have cap-tured the interest of the media and physicians world-wide.1 The results have important implications for thetreatment of hypertension.

Results of the ALLHAT study on blood pressure(BP) control rates appeared in the last issue of TheJournal of Clinical Hypertension and reported thatcareful attention to target BPs had resulted in goal BPin more than 60% of a population of patients (meanage, 67 years) that included 35% black patients and36% with diabetes.2 These results were obtaineddespite protocol limitations on how medications couldbe combined. The study sent a message to physiciansthat more patients can be treated to goal BPs; at pres-ent only about 30% of hypertensive patients in theUnited States are at goal levels. If more people aretreated to pressures of <140/90 mm Hg, fewer cardio-vascular (CV) events will occur.

The final ALLHAT results published last month1

concluded that, in this trial of more than 33,000 rela-tively high-risk hypertensive patients who were treatedover a 5 year period either with chlorthalidone, adiuretic, in doses of 12.5–25 mg/day; amlodipine, a cal-cium channel blocker (CCB), in doses of 2.5–10mg/day; or lisinopril, an angiotensin-converting en-zyme (ACE) inhibitor, in doses of 10–40 mg/day,patients receiving the diuretic experienced fewer over-all CV events than those on the other agents. Therewere no differences, however, in the primary outcomeof fatal or nonfatal coronary heart disease (CHD)events and no mortality difference, but there were somedifferences in outcome on selected end points. Forexample, patients on diuretics had a lower incidence ofheart failure and strokes than the group randomized to

lisinopril. This was especially true in black patients.The risk of hospitalized/fatal heart failure was not,however, statistically significant. The diuretics weremore effective in reducing the occurrence of hospital-ized/fatal heart failure in the amlodipine group.

CHOICE OF SECOND-STEP DRUGS: THIS COULD HAVE MADE A DIFFERENCEThere was some difference in achieved BPs in ALL-HAT among the three drugs tested. On average, sys-tolic BPs were 4 mm Hg lower with diuretics thanwith lisinopril in black subjects and 3 mm Hg lower inpatients 65 years or older. Overall, the systolic BP was2 mm Hg higher in the ACE inhibitor group comparedto the diuretic cohort. These results were not unex-pected given the demographics of the patients studied.Black subjects and the elderly generally experience agreater decrease in BP on diuretics compared to med-ications that block the renin-angiotensin-aldosteronesystem. The systolic BP was 0.8 mm Hg higher and thediastolic BP 0.8 mm Hg lower with amlodipine com-pared to chlorthalidone (these differences were signif-icant because of the large numbers of patients studied(chlorthalidone: 15,255; amlodipine: 9048; and lisino-pril: 9054). Again, these results are similar to thosenoted in other comparative studies.

In ALLHAT, the second drug that could be used inpatients who had not achieved goal BPs could not bea study drug. While patients on a diuretic could receivea β blocker, a logical second drug, subjects who didnot reach goal BP on the ACE inhibitor, lisinopril,could not by protocol receive a diuretic or a CCB—logical choices for a second drug. Some patients didreceive a combination ACE inhibitor/diuretic, butmost received other agents such as a β blocker, reser-pine, clonidine, or hydralazine. This sequence of care

E d i t o r i a l

Results of the ALLHAT Trial: Is the Debate About Initial AntihypertensiveDrug Therapy Over?

Marvin Moser, MDEditor in Chief

Results of the ALLHAT study have focused attention on the preferred approaches to the management of hypertension.Some of the conclusions of this trial have already been questioned. In this issue of The JCH, Marvin Moser, MD, andMichael A. Weber, MD, two of the senior editors, present their critiques of the ALLHAT results.

is not the usual one followed in practice and may havecontributed somewhat to the difference in outcome.For example, if a diuretic had been routinely added tothe ACE inhibitor, the difference in BPs betweengroups most probably would have been less; this com-bination usually reduces or eliminates any differencesin response to ACE inhibitors between black andwhite patients. It is also possible that any difference inoutcome, especially regarding the occurrence of heartfailure, between the ACE inhibitor and diuretic-basedtreatment groups would have been minimized or elim-inated. In addition, patients on a CCB could not begiven either a diuretic or an ACE inhibitor as a secondagent. As noted, despite this lack of more logical choic-es of second-step medications, a large number ofpatients achieved goal BP.

IS THIS THE END OF THE DIURETIC DEBATE?The ALLHAT results appear to have settled the debateabout the benefits or risks of diuretics in the manage-ment of hypertension.

For many years, physicians had argued that the useof diuretics had not reduced the occurrence of CHDevents to as great a degree as predicted by epidemiolog-ic data. They reasoned that the metabolic effects ofthese agents theoretically might actually increase therisk of CV disease and that diuretics might be “out-classed as initial therapy for hypertension.”3 Statementsin the literature describing these metabolic changesincluded: “The adverse effects of diuretics on uric acidmetabolism, serum potassium, plasma cholesterol, andtriglycerides may contribute to increases in the inci-dence of CHD, angina pectoris, myocardial infarction,and congestive heart failure...”4 or an even moreextreme comment, “Diuretics elevate blood sugar, causeovert diabetes, induce diabetic ketoacidosis, elevatetotal cholesterol and LDL-C [low-density lipoproteincholesterol], and reduce HDL-C [high-density lipopro-tein cholesterol], cause deterioration of renal functionand worsening of left ventricular hypertrophy. They arecontraindicated in patients with hyperglycemia, hyper-lipidemia, and coronary heart disease.”5 These state-ments were widely quoted in the literature. Yet, therewere abundant data from carefully conducted hyper-tensive treatment trials demonstrating the reduction ofCHD events when diuretics were used.6

These reports appeared to negate the “metabolicabnormalities” argument.7–11 In the clinical trialswhere diuretics were used as initial therapy or in com-bination with β blockers there was: 1) a reduction,not an increase, in CHD events; 2) cholesterol levelswere not significantly increased; 3) there was anincrease of only approximately 0.6% in new onsetdiabetes and the minimal blood glucose level increas-es were probably of limited clinical importance; and

4) the progression of renal disease and heart failurewas decreased, not increased, with diuretic use.

Prospective studies refuted the argument thathypokalemia, a not uncommon finding with high-dosediuretics, had resulted in serious ventricular arrhyth-mias12—a finding that had been reported by one ortwo researchers whose studies were poorly controlledor included only carefully selected patients.13,14

The so-called short fall in reduction of CHD events(16% compared with a predicted 20%–25%) with thedegree of BP lowering achieved in the diuretic and/orβ blocker-based trials (–12/–5 mm Hg treated com-pared to control) probably resulted from the fact thatthe clinical trials were of 3–5 years duration and theepidemiologic studies were longer than 10 years.15

There is some evidence that reducing BP to this degreeover longer periods of time improves outcome.16

There is also evidence from diuretic-based treatmenttrials17 in the elderly that CHD events can be reducedto levels close to those estimated by the longer-termobservational studies.

Despite the increasing number of hypertensiontreatment trials that demonstrated benefit with diuret-ics and the repeated recommendations of the JointNational Committee on Detection, Evaluation, andTreatment of High Blood Pressure for their use as ini-tial therapy,18,19 the use of these agents decreased in the1980s and 1990s. They were off the promotionalradar screen; they were off patent; newer drugs prom-ised more exciting results.20,21 With a decrease in theuse of diuretics, it was to be anticipated that therewould be increased numbers of resistant hypertensives.In fact, many physicians who worked as specialists inhypertension noticed an increase in their referrals of“resistant hypertension.” In several large clinics whereresistant hypertension was defined as BPs >160/100mm Hg on at least 2–3 medications, antihypertensivedrug resistance disappeared in almost 50% of patientswhen diuretic dosage was increased or diuretics wereadded to the treatment regimen. The message wasclear—diuretics are an important component of hyper-tension management.

The Systolic Hypertension in the ElderlyProgram (SHEP) study21 in 1991 described dra-matic decreases in strokes and CV events in the eld-erly on the regimen based on diuretics.17 Followingpublication of this trial, an editorial in The Lanceton November 23, 1991, attempted closure to the“metabolic abnormalities negate blood pressurelowering benefits” argument. “Results of the SHEPstudy should drive a stake through the heart ofsome fondly held hypotheses...Significant reduc-tion of 31% in nonfatal and fatal MIs in subjectswith abnormal ECGs argues against a thiazide-induced risk for coronary death.”

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In 1993 the role of diuretics was again defined basedon available data in a book chapter titled “DiureticsShould Continue To Be Preferred Initial Therapy inHypertension.”22 “There is increasing evidence thatdiuretics as initial monotherapy or in combination withother antihypertensive drugs are highly effective in notonly reducing blood pressure but in decreasing mor-bidity and mortality in hypertensive patients...Diureticsshould continue to be considered as a preferred med-ication in the management of hypertension.”

In the 1990s many physicians had concluded thatdiuretics might be acceptable therapy in uncomplicat-ed cases of hypertension but that other agents shouldbe preferred in patients with comorbid conditions. Theargument had persisted that diuretics might not beeffective or may not be one of the medications ofchoice in patients with left ventricular hypertrophy orin diabetics. But data had indicated that the use ofthese agents resulted in regression of left ventricularhypertrophy.23,24 Other data indicated that their use indiabetics reduced CV events.25 The ALLHAT resultsin high-risk elderly subjects indicate that diuretics arejust as effective in preventing CV events in diabeticsubjects as in nondiabetics. The use of these medica-tions should not be limited to low-risk patients.

The Swedish Trial in Old Patients with Hyper-tension-2 (STOP-2) study26 in 1999 reported nodifference in outcome among diuretics, ACE in-hibitors, and CCBs in elderly patients.

Thus, it should not have been a major surprisewhen the ALLHAT study reported that diuretics hadproved to be as effective, or even more so, in reducingsome clinical events than other agents tested.

THE ISSUE OF COST Cost should not be the major reason for selecting onemedication or procedure over another. However, iftwo treatments are equally effective, then the lessexpensive option should be chosen. This is certainlytrue in the management of hypertension.27,28 TheALLHAT investigators conclude that in view of theirfindings, cost should enter into the equation of choiceand diuretics, which are considerably less costly thanmost other antihypertensive agents, should be con-sidered as the first-step drug in treatment unless thereare contraindications to their use.

COMBINATION THERAPYIt is important to remember that there are many rea-sons to use medications in addition to a diuretic in themanagement of hypertension. First, fewer than 50% ofsubjects will achieve goal BP on diuretics as monother-apy. More than 50% of black and elderly patients doachieve goal BP levels, but a majority of hypertensivepatients, especially those with diabetes or evidence of

renal disease, will not respond to diuretic monotherapywith normotensive levels. On the other hand, clinicaltrial results, including ALLHAT, were not achievedwith the use of just one medication; more than 50% ofsubjects on any medication as monotherapy did notachieve goal BP levels. The recent trials describing benefits from treatment with ACE inhibitors orangiotensin receptor blockers (ARBs) were not trials ofmonotherapy.29–34 In most of these studies more than50%–60% of patients were receiving diuretics in addi-tion to study drugs. Improvement in outcomes,whether from heart or renal failure, usually resultedfrom the use of two or more medications with differentmechanisms of action. There are clearly advantages tousing more than one medication in the management ofhypertension. If two or more agents are used, one ofthem should logically be a diuretic.35

There are some physicians who, based on the ALL-HAT results, have begun to advise patients who arewell controlled on other agents, such as ACE inhibitorsor CCBs, to change their medication. Although it isclear that a diuretic should be part of a treatment regi-men in hypertensive individuals, this may not be thebest advice. If BPs are at levels >140/90 mm Hg, a smalldose of a diuretic should be added, but if BPs are wellcontrolled and the patient is feeling well, the decision tochange therapy should be left to the physician.

Data with the ACE inhibitors or ARBs from othertrials cannot be ignored. These medications (usuallywith a diuretic) are highly effective in slowing downprogression of renal disease and, importantly, prevent-ing new onset diabetes. There is also other evidence forthe use of drugs other than diuretics in the managementof hypertensive patients. For example, β blockers areeffective in lowering BP; they are the drugs of choice inpostmyocardial infarction patients and in angina, etc.

Thus, there is little doubt that ACE inhibitors,CCBs, β blockers, and ARBs will and should continueto be used as therapy for hypertension. ALLHAT didnot report that these drugs were ineffective; only thatthey may not be as, or more effective, in preventingCV events (especially heart failure) than a diuretic inan elderly population of relatively higher-risk patients.As noted, the demographics of the study population,as well as the drug choices for second-step therapy,may have influenced the recorded differences betweenthe ACE inhibitor and chlorthalidone groups.

A FINAL NOTE Physicians involved in the ALLHAT trial and theNational Heart, Lung, and Blood Institute should becongratulated on obtaining data that are of greatimportance for the management of hypertension.Publication of this trial has also put the managementof hypertension back on the radar screen of the media.

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There are no walkathons or telethons for hyperten-sion; it is not a disease that is frequently highlighted ontelevision or in newspapers. An important study likeALLHAT will help to alert the public to the problemsassociated with the management of hypertension andshould help to improve outcome. Widespread mediacoverage will help to gain the attention of the literallymillions of hypertensive patients who are either not ontreatment or who are inadequately treated.

The ALLHAT study is a landmark trial confirmingprevious data and clarifying some of the myths andmisconceptions that have been promulgated throughthe years.36 It should not be taken as just anotherstudy comparing different drugs; the results should bereviewed carefully and incorporated into the manage-ment of all patients with hypertension.

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3 Ames RP. The influence of non β-blocking drugs on the lipidprofile: are diuretics outclassed as initial therapy for hyperten-sion? Am Heart J. 1987;114:998–1006.

4 Zussman RM. Alternatives to traditional antihypertensive ther-apy [editorial]. Hypertens. 1986;8:837–842.

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6 Hebert P, Moser M, Mayer J, et al. Recent evidence of drugtherapy on mild to moderate hypertension and decreased risk ofcoronary heart disease. Arch Intern Med. 1993;153:578–581.

7 McInnes GT, Yeo WW, Ramsey LE, et al. Cardiotoxicity anddiuretics: much speculation, little substance. J Hypertens.1992;10:317–335.

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21 SHEP Cooperative Group. Prevention of stroke by antihyper-tensive drug treatment in older persons with isolated systolichypertension: final results of the Systolic Hypertension in theElderly Program (SHEP). JAMA. 1991;265:3255–3264.

22 Moser M. Diuretics should continue to be recommended as ini-tial therapy in the treatment of hypertension. In: Puschett JB,Greenberg A, eds. Diuretics IV: Chemistry, Pharmacology andClinical Applications. New York, NY: Exerpta Medica;1993:465–477.

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25 Moser M, Ross H. The treatment of hypertension in diabeticpatients. Diabetes Care. 1993;16:542–547.

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28 Moser M. Hypertension can be treated effectively withoutincreasing the cost of care. J Human Hypertens. 1996;10(suppl2):S33–S38.

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32 Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotectiveeffect of the angiotensin-receptor antagonist irbesartan inpatients with nephropathy due to type 2 diabetes (IDNT). NEngl J Med. 2001;345:851–860.

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34 Parving HH, Lennert H, Brochner-Mortensen J. The effect ofirbesartan on the development of diabetic nephropathy inpatients with type 2 diabetes. Irbesartan Microalbuminuria TypeII Diabetes in Hypertensive Patients (IRMA II). N Engl J Med.2001;345:870–878.

35 Moser M. Diuretics revisited—again. J Clin Hypertens.2001;3:136–138.

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