diuretics as monotherapy or as part of combination therapy for hypertension: an update

E x p e r t P a n e l D i s c u s s i o n

Diuretics as Monotherapy or as Part ofCombination Therapy for Hypertension:An Update

MarvinMoser,MD;DomenicSica,MD;WilliamCushman, MD;Ken Jamerson,MD

At a meeting of The American Society of Hypertension in May 2008, a panel was convened to discuss theuse of diuretics. Are they still preferred initial therapy, are they still the preferred agent to add in combina-tion therapy, and is there a difference between or among the diuretics that have been used in the clinicaltrials? The session was moderated by Marvin Moser, MD, of the Yale University School of Medicine,New Haven, CT. Participants included Domenic Sica, MD, Virginia Commonwealth University,Richmond, VA; William Cushman, MD, University of Tennessee, Memphis, TN; and Ken Jamerson, MD,University of Michigan, Ann Arbor, MI. J Clin Hypertens (Greenwich). 2008;10:726–734. ª2008 Le Jacq

DR MOSER: Bill, let’s start with you. There areabundant evidence-based data reporting that diure-tic-based treatments have significantly reduced theincidence of stroke, coronary heart disease, conges-tive heart failure, and progression of renal disease.Despite the availability of those data, the use ofdiuretics has consistently decreased since the 1970s,when the information became available, to the late1990s, when the Antihypertensive and Lipid-Low-ering Treatment to Prevent Heart Attack Trial(ALLHAT) was published. Explain ALLHAT to usand review some of the other data on results oftreatment with diuretics. Are diuretics alone orwith the addition of other drugs still acceptabletreatments? And does it make a difference whichdiuretic is given?

DR CUSHMAN: Starting with the VA Coopera-tive Study in the 1960s, there have been a numberof studies that were diuretic-based that showedconsistent benefits in reducing morbidity and mor-tality in hypertension. This was particularly true ofstrokes and heart failure but also of coronary heartdisease. Obviously, there were a variety of differentregimens that were used, but before the 1990s thenewer agents that we commonly use now as

add-on drugs were not available. By the 1990s, theprescription of thiazide-type diuretics had fallen toabout 20% of hypertensive patients despite the factthat at that time, the only outcome data thatwe had in hypertension trials were with thiazidediuretics and, less compellingly, with b-blockers.

DR MOSER: Why do you believe that diureticuse decreased when we had the VA CooperativeStudy, Hypertension Detection and Follow-UpProgram (HDFP), and the Systolic Hypertension inthe Elderly Program (SHEP), all of which werediuretic-based and all of which showed benefit?

DR CUSHMAN: Well, we know that the use ofdiuretics in high doses has biochemical effects interms of reducing potassium, increasing uric acid,and increasing glucose to some degree. All of thoseare relatively small effects unless you use very highdoses. It was also true that there was no longer thesame degree of marketing of diuretics when someof the newer drugs came along in the 1980s and1990s. In particular, angiotensin-converting enzyme(ACE) inhibitors and calcium channel blockers(CCBs), the new kids on the block in the 1980s,were heavily promoted. The theories behind theirpotential benefits were intriguing, and the potentialadverse effects of thiazides, and to some degreeb-blockers, were highlighted. There was a consis-tent decrease in use of thiazides despite that theredoi: 10.1111/j.1751-7176.2008.00010.x

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were no outcome data from hypertension clinicaltrials with those newer classes of drugs until thelate 1990s.

ALLHAT was designed in the early 1990s todetermine whether these newer classes of drugswere in fact superior to the thiazide-type diureticclass. ALLHAT was a randomized double-blindclinical trial designed to determine whether the inci-dence of fatal coronary heart disease or nonfatalmyocardial infarction (the primary outcome) andother cardiovascular outcomes was lower for high-risk hypertensive patients initially treated with aCCB (amlodipine 2.5–10 mg ⁄d), an ACE inhibitor(lisinopril 10–40 mg ⁄d), or an a-blocker (doxazosin2–8 mg ⁄d) compared with a thiazide-type diuretic(chlorthalidone 12.5–25 mg ⁄d). It showed thatchlorthalidone was at least as good as amlodipine orlisinopril for lowering blood pressure and preventingcardiovascular and renal end points. Chlorthalidonewas superior to all 3 other drugs in preventing heartfailure and superior to the ACE inhibitor anda-blocker in preventing stroke and combined cardio-vascular disease events; the stroke benefit over theACE inhibitor was only in African Americans. Thesefindings are largely consistent with those of otherrelevant trials and meta-analyses.

DR MOSER: Dom, how much of this change intreatment practices was a result of concern abouthypokalemia and possible ventricular arrhythmias?Hypokalemia was probably the finding that both-ered physicians the most. How much of that wasreal, and how much of it was dosage-related orspecific to the drugs that were used?

DR SICA: The hypokalemia was, without ques-tion, real and related to the high-dosages (50–100mg ⁄d) of either hydrochlorothiazide or chlorthali-done commonly used at that time. It took us sometime to adjust our thinking relative to diuretic dos-ing and to adopt a more low-dose strategy fordiuretic administration.

DR MOSER: Fifty to 100 mg of chlorthalidoneas well as hydrochlorothiazide?

DR SICA: Yes. Unfortunately, lessons learnedfrom high-dose therapy were ill advised. Webelieved that the electrolyte disturbances at the highdoses were so significant that we erred on the sideof extreme caution and began using ultralow doses,which then took away some of the blood pressure–lowering benefits of these drugs. We also movedaway from the use of chlorthalidone, which wasthe thiazide-type diuretic most extensively studiedfrom an outcomes viewpoint. In so doing, therewas a subtle shift to the belief that all thiazide-typediuretics were equal and that the outcomes results

would be the same whether hydrochlorothiazide orchlorthalidone was being used.

DR MOSER: So what’s the difference betweenthe two drugs?

DR SICA: Well, the belief has been that there’s aclass effect for thiazide-type diuretics, yet they arefairly different from one another and they may befundamentally different in their outcomes effects. Weknow that you can get a substantially greater bloodpressure reduction with one vs the other, that is,chlorthalidone compared with hydrochlorothiazide.

DR MOSER: Is that because of potency or dura-tion of action?

DR SICA: It’s an interesting phenomenon.Nobody quite knows, because when you have apharmacologic attribute for a compound, it’s toughto distinguish which attribute you can assign cau-sality to a positive effect. Chlorthalidone has a verylong duration of action. It is a true diuretic, com-pared with hydrochlorothiazide, in that there’s anet volume loss for blood pressure reduction, butwith thiazide-type diuretics there is vasodilation;however, chlorthalidone may have a little morestaying power than hydrochlorothiazide. Recentstudies with ambulatory blood pressure monitoringwould seem to suggest this. In the one study I amspeaking of, 50 mg of hydrochlorothiazide wascompared with 25 mg of chlorthalidone. The differ-ence was an overnight decrease in blood pressurewith chlorthalidone of several mm Hg or more.This, to me, was a pretty significant decrease innocturnal blood pressure and separates these twocompounds in a meaningful fashion.

That being said, what we’re left with is that wehave different drugs, different durations of action,and potentially different mechanisms of action. Butwe’re saddled with a belief that these two diureticsare equal. Many have promulgated this message,but I’ve got a strong belief that there’s a within-class distinction, an important intraclass difference.

DR MOSER: Do you think that some of theperceived problems with diuretics were that wewere using chlorthalidone in the clinical trials indosages that were high, with more hypokalemia?Did we frighten doctors away from using it?

DR SICA: I think we did. We did that withhydrochlorothiazide, too. I also believe that thefixed-dose combination products began to dominatebut none of them included chlorthalidone excepttwo: one with clonidine and another with atenolol.We just became more and more familiar with thehydrochlorothiazide-containing combinations, andwe all but forgot that a drug such as chlorthalidoneexisted.

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DR MOSER: I think you’re right; ‘‘HCTZ’’[hydrochlorothiazide] is also easier to write outthan ‘‘chlorthalidone.’’

DR SICA: It’s easier and doctors kind of grewup with it. The fixed-dose combination productswith ACE inhibitors only contained hydrochlorothi-azide, as is the case with the angiotensin receptorblocker fixed-dose combinations; thus, anyonebeing trained in the 1980s and 1990s was left withlittle choice but fixed-dose combinations containinghydrochlorothiazide. Unfortunately, this prescrip-tion practice was neglectful of the within-classdifferences among the thiazide-type diuretics.

DR MOSER: Ken, the thiazides, whether chlor-thalidone in clinical trials or hydrochlorothiazideby perception, had all these positive study findingsthat showed reduction of cardiovascular events toan extent that hadn’t been proven with anythingelse. But there were some other problems withthiazides besides hypokalemia that bothered people.There were some effects on lipids and on glucose.Are those important problems with the doses weuse now, or have they been overemphasized?

DR JAMERSON: I think that the possible meta-bolic effects resulted in clinicians’ seeing patientsmore often for blood tests. But there may be animportant problem that we’re missing to explainwhy the usage of diuretics decreased. Workingadults who take them have to urinate frequently,and it may interrupt their lives. If one can havesimilar blood pressure control without having to dothis, why should he or she continue with a diuretic?This may be a very important limitation. So thelower the dose went, the smaller the metaboliceffect, but the urge to have to stop and urinate wasstill there to some extent.

Quite frankly, heretofore I thought that whetherthe diuretic was a thiazide-like hydrochlorothiazideor chlorthalidone, the primary mechanism forreducing cardiovascular disease was lowering bloodpressure. There has not been a great deal of infor-mation about effects of these agents other thanlowering blood pressure and thereby reducingcardiovascular risk.

So whether hydrochlorothiazide or chlorthali-done was used, if blood pressure was reduced andthe patient tolerated it, you typically thought yourjob was done well.

DR MOSER: We could argue that pointbecause, in fact, if you lower the blood pressureand you reduce stroke, coronary disease, and heartfailure, that may be all that has to be done.Another point is that in studies that have beenblinded and controlled the tolerability of diuretics

turns out to be just as good or better than otherdrugs, despite the perceptions of some physicians.With chlorthalidone, for example, you may havean increase in urination for several hours, and thenit becomes less obvious over 48 to 72 hours. It is,of course, true that in some men with prostate dis-ease this can be annoying. But with the dosages weuse, 12.5 or 25 mg ⁄d, this is not a major problemin the majority of patients.

DR JAMERSON: I think you’re right, but if youlook long term, particularly in clinical trials inwhich you’re going to follow patients for 4 to 5years, the biggest occurrence of complaints wouldbe in the first 3 months. If people stay on therapyfor 3 months, the odds are that they will stick it outfor the duration of the trial. In trials, you do haveextra resources; you have nurses and others toencourage the patient. But to the primary practi-tioner who has to take care of colds and lots ofother issues, it may be a little tougher to get patientsto stay with a medication for that initial 3 months,so it is important to achieve blood pressure controlwithout too many adverse effects. So I think that asnewer drugs like the ACE inhibitors came alongand could lower blood pressure equally, there waslittle reason to put up with adverse effects, notnecessarily with diuretics but with any medications.

DR MOSER: We can argue that, too, because I’mnot sure that any of the newer drugs by themselveswill lower blood pressure in as high a percentage ofpatients as seen in many of the clinical trials. WithACE inhibitors, for example, or with angiotensinreceptor blockers, more than 60% of people requirea diuretic to lower the blood pressures to goal levels.

DR JAMERSON: The best data I recall suggestthat, especially in the African American population,the drugs that work best are CCBs. But they toohave adverse effects, and CCB-based treatmentresults in more episodes of heart failure than ACEinhibitor- or diuretic-based treatment.

DR MOSER: Bill, do you want to comment ontolerability?

DR CUSHMAN: I will say that in any blindedstudies, even short-term studies, you virtually neversee increased urination as an adverse effect. I thinka lot of people have that perception and if theythink they are going to have a side effect, theyoften experience it. But we’ve not seen frequent uri-nation as a deterrent to therapy in even short-termrandomized, controlled, blinded studies. And overand over again, I’ve never seen it in any of theregistration-blinded studies.

DR JAMERSON: We never ask, so we don’t seeit either.


DR SICA: I rarely see it. A thiazide diuretic, atthe dosage we now use, is not a potent diuretic. Itsaction is short-lived.

What does happen, though, when you talk toenough patients is that in anticipation of a diuresis,they increase their fluid intake and urine output thenmatches intake, thus, the origin of their urinatingmore. This, of course, is not true of patents withheart failure, in whom diuresis can be profuse. Wealso see this belief in more urination with a diureticwith spironolactone. The spironolactone is givenexclusively for blood pressure control, but as soon asthe word diuretic is seen on the product brochure, apatient often becomes concerned about increased fre-quency of urination. I agree that there’s a perceptualissue, but anticipatory intake is also very important.

DR MOSER: I think that a valuable point tomake is the problem with nonblinded studies. Forexample, most of the studies with b-blockers arenonblinded. If people know they’re on a b-blockerand have read the package insert, they get coldhands and are certain that it was because of theb-blocker. It could be freezing cold weather, butthey stop the medication anyway. Similarly, if youget a cough and know that it may be a result of anACE inhibitor, the drug will be stopped—even ifyou obviously have a cold. Dom, comment verybriefly on the sequence of physiologic changes thatoccur over the first 4 to 6 weeks when you give adiuretic. Obviously, if the drugs continued to act asa diuretic and the patient kept losing fluid, he or shewould look like a shriveled up prune in 3 or 4 days.

DR SICA: There are 3 phases in the response todiuretics. The acute phase is marked by a modestincrease in sodium excretion. There is a small vol-ume change during this time period, and the initialdrop in blood pressure seems to relate to thisvolume change.

DR MOSER: So plasma volume decreases?DR SICA: Yes, and cardiac output also tempo-

rarily decreases. Thereafter, there is a transitionalphase during which there’s an accommodation tothe diuretic action of these drugs. This process hasbeen termed the braking phenomenon. The mecha-nistic basis for this is poorly worked out. This isbut one of several factors that return plasma vol-ume back toward pretreatment values. This gain influid volume is also shared by the extracellular andinterstitial fluid compartments. During this phase ofthe response to a thiazide-type diuretic, there’sprobably a resetting of vascular tone that somehave held relates to a change in both sodiumand calcium content in the vessel wall. As thistissue-leaching effect ensues, there is a gradual

vasodilatation. There’s something about salt andwater depletion that sets the stage for the vessels todilate over the long term (Figure).

If you have a high salt intake at the time of ini-tial diuretic activity, it seems to blunt the short-and long-term positive blood pressure–loweringeffects. Of interest, there have been studies in whichdiuretics have been infused directly into the bra-chial arteries and downstream vasodilator effectshave been assessed. These studies have shown littleif any direct vascular effects.

DR MOSER: So on balance after about 4 to 6weeks, the cardiac output is back to normal andplasma volume may still not be quite back to pre-treatment levels. So that’s why the renin angioten-sin system is more active. But blood pressure andvascular resistance are reduced.

DR SICA: With most antihypertensive patients,with a few exceptions, there is a dose-response rela-tionship that’s timed on a 24-hour basis. We give adrug, obtain measurable blood levels, get thedesired effect often equating with the blood level,and then do the same thing the following day withthe next dose. A diuretic’s vasodilating actionsmay, to a certain degree, persist despite misseddoses once a steady state has been reached; thus,

After about 4 to 6 weeks of treatment, BP remains be-low pretreatment levels, cardiac output has returned tonormal, and vascular resistance is reduced, but plasmavolume remains slightly below pretreatment levels, Re-sistance and BP return to pretreatment levels when thediuretic is stopped.

Abbreviations: , drug therapy BP, blood pressure; PV,plasma volume; TPR, total peripheral resistance; CO,cardiac output; PRA, plasma-renin activity.

stopped

TRPTPR

PRATime

PV

BP

COCO

No

Modified from Tarazi et al.Circulation. 1970;41;709-717.

Figure. Hemodynamic effects of chlorothiazide in ahypertensive patient.


there is a residual effect that seems to be presentupon missing a dose or in some instances discon-tinuing therapy. Unfortunately, this persistence ofeffect upon discontinuation of a thiazide-type diure-tic is poorly studied, particularly as it relates tohead-to-head comparison with other nondiureticantihypertensive drug classes. It is interesting thatover the years a common clinical practice in theelderly has emerged, which is to give a thiazide-type diuretic, but 3 to 4 times a week to ‘‘lessen’’net weekly diuresis. At least anecdotally there doesnot appear to be much loss of antihypertensiveeffect when such an approach is used.

DR MOSER: The ALLHAT study, which wasblinded and randomized and included 42,000people, should be reemphasized. A diuretic-basedregimen was compared with an ACE inhibitor orCCB-based treatment program. CCBs and ACEinhibitors are clearly effective, very useful antihyper-tensive agents, and their use with other drugs hasresulted in reduction in cardiovascular events. Ken,what’s your take on this study, which was designedto determine whether chlorthalidone—in this case inmodest dosages, 12.5 to 25 mg ⁄d—was as effectivein reducing cardiovascular events as an ACE inhibi-tor or CCB? In subsets of patients—in diabetics, dif-ferent racial groups, heart failure patients, andangina patients—the diuretic-based treatment wasjust as effective as treatment based on an ACEinhibitor or CCB. In fact, there was less heart failurewith a diuretic than with a CCB and fewer strokeswith the diuretic when compared with the ACEinhibitor, especially in African Americans.

DR JAMERSON: ALLHAT is clearly one of thelargest head-to-head trials, and you summarized itquite well. The intent was to compare the diureticwith newer drugs. Within the study design of ALL-HAT, the newer agents did not prove themselves tobe better. Groups were titrated to a target bloodpressure and add-on therapy was used, but theadd-on therapy may not have been appropriate.For example, if you give a diuretic and add ab-blocker, if blood pressure can be reduced to goal,that seems appropriate, but if a CCB doesn’t work,an ACE inhibitor probably should be added, andthis was not allowed by the protocol. Instead, ab-blocker was added.

DR MOSER: In other words, if the diureticwas ineffective, you could add a b-blocker, whichis logical.

DR JAMERSON: Right.DR MOSER: But if an ACE inhibitor was inef-

fective, you couldn’t add a CCB or a diureticbecause of the study design.

DR JAMERSON: Right. But about 25% of thepatients did receive diuretics in the ACE inhibitorand CCB groups. It did answer some questions, butin terms of how physicians manage patients, itdidn’t answer all the questions.

DR MOSER: And yet, we talk about the adversemetabolic effects of diuretics and b-blockers, espe-cially when combined; in ALLHAT, in which 30%of patients receiving a diuretic also got a b-blocker,new-onset diabetes was more common, but the out-come data are as good or better than with other regi-mens, whether you look at coronary disease, angina,or heart failure. How do we explain that?

DR JAMERSON: The regimen looks good forlowering blood pressure. But, if I had my choice, toachieve the same blood pressure control withouthaving abnormal metabolic milieu or tipping youover to diabetes, I would prefer to have the bloodpressure control without the diabetes. Even thoughyou tell me that mathematically it doesn’t matter,it’s my body, they’re my numbers, and I don’t wantit. I think it’s more logical and reasonable to notgive patients metabolic aberrations. Why would youwant to do it, why would you want a diuretic and ab-blocker if there’s equal efficacy with a methodthat won’t give you these metabolic aberrations?

DR MOSER: I agree with some of that, but themetabolic changes were small and did not appearto be clinically relevant. But I agree, a diuretic as abase plus an ACE inhibitor, an angiotensin receptorblocker, or a CCB makes a lot of sense in terms ofgood blood pressure control and potentially fewermetabolic changes than with a b-blocker. Bill, inALLHAT there was about a 3.5% increase in new-onset diabetes with diuretic-based therapy, com-pared with the ACE inhibitor–based regimen, andyet outcome was not affected at all in terms ofpatients with pretreatment impaired glucose toler-ance or diabetes. Describe the extent to whichglucose levels changed. Was it 2, 3, or 10 mg ⁄dL?

DR CUSHMAN: Well, I agree with Ken that ifyou had two drugs that did the same thing in termsof blood pressure lowering or outcomes, yet the useof one of them either resulted in adverse events orcaused significant metabolic abnormalities, thenobviously you wouldn’t use that one. I think that’sone good reason not to use b-blockers routinely,because they do not have any advantage on out-comes in hypertension. As a matter of fact, theyfairly consistently—not always, but fairly consis-tently–underperform, yet they have metaboliceffects particularly on glucose and triglycerides.However, if a drug is more effective at preventingmajor cardiovascular events despite having some


metabolic changes, as is true for the diuretic, thenthat agent should be used in preference.

DR MOSER: So if you had had your choice inALLHAT, it might have been an ACE inhibitorplus a diuretic or a CCB plus a diuretic?

DR CUSHMAN: Right, although in 1992 whenALLHAT was done—we have to remember, that’san awfully long time ago—there were just no out-come data at all with CCBs, ACE inhibitors, ora-blockers. So the very large group of experiencedinvestigators who put the study together felt that weshould not mix up the groups and just routinely addsomething else. Even in practice, adding the drugsthat we added, b-blockers and clonidine, was verycommonly done. We tried to encourage the morefrequent use of reserpine, since it is better toleratedthan clonidine, is long-acting, and had been used inmany other studies as a second agent. I would addthat the investigators did not have a strong bias asto which regimen would be proven best in ALL-HAT. As a matter of fact, if you had polled us, Ithink most of us would have guessed that the ACEinhibitor–based program probably would have wonthe day in terms of outcomes. And it did not.

DR MOSER: If you had to design that studytoday, would you use a diuretic first and then addan ACE inhibitor, an angiotensin receptor blocker,or even a CCB if goal blood pressures were notachieved?

DR CUSHMAN: Well, you wouldn’t design thesame study. It confounds a study too much to rou-tinely add the other study drugs being compared,so you really have to ask a different question. Oneof the considerations is to look at various combina-tions, just as the Avoiding Cardiovascular EventsThrough Combination Therapy in Patients LivingWith Systolic Hypertension (ACCOMPLISH) studylooked at two different combinations. But inALLHAT, the metabolic effects like hypokalemiawere fairly trivial and were fairly easy to treat. Asa matter of fact, if we could have routinely usedpotassium-sparing drugs, it would have been evenless of an issue. The glucose difference betweenchlorthalidone and the ACE inhibitor was about 5mg ⁄dL. As you know, some studies with ACEinhibitors show a benefit on glucose, but somedon’t. The Diabetes Reduction Assessment WithRamipril and Rosiglitazone Medication (DREAM)did not suggest a benefit with the ACE inhibitor,which may have surprised some people. The differ-ence in ALLHAT’s blood glucose levels correspondsto only a 0.1% to 0.2% difference in hemoglobinA1c. By comparison, the Action to Control Cardio-vascular Risk in Diabetes (ACCORD) study was

powered for a 1.5% difference in hemoglobin A1c

with more than 10,000 participants to detectwhether there was a significant cardiovascularbenefit in reducing hemoglobin A1c.

DR MOSER: Could you tell us what theACCORD study is?

DR CUSHMAN: Sure. The ACCORD study is alarge National Heart, Lung, and Blood Institutestudy comparing the effects on cardiovascularevents of a hemoglobin A1c goal of <6% comparedwith 7% to 7.9%. We now know from 3 majortrials, including ACCORD, that there is no benefitin reducing cardiovascular events even by reducinghemoglobin A1c by >1%. Much smaller differencesin glucose seen sometimes with antihypertensiveagents would not be expected to have an importanteffect on outcomes.

DR MOSER: And these possible metabolicchanges don’t worry you?

DR CUSHMAN: They don’t worry me if the drugyou’re using is superior. So, for example, if you’reusing a b-blocker post–myocardial infarction, whichwe know improves survival, I would not worryabout a small difference in glucose or triglyceridesfrom the b-blocker. Similarly, in hypertension, if thediuretic did not have the advantages that were seenin ALLHAT and other studies in terms of heart fail-ure and stroke and overall cardiovascular events,then I would not favor it. But certainly with these rel-atively small metabolic differences, I am not con-cerned. In the VA Cooperative Single-Drug TherapyStudy, for example, we looked very carefully at lipidsover a 1- to 2-year period and reported that the thia-zide had no significant effect on lipids or lipopro-teins. It did have an effect on glucose, just as we’veseen in other studies, but we’ve already discussed thenet benefits of the thiazide on outcomes.

Now, to step back 16 years after ALLHAT wasstarted and look at all the data that we have on howeffective various drugs are in lowering event rates,clearly our best data are with thiazide-type diuretics,ACE inhibitors, angiotensin receptor blockers, andCCBs. And the CCBs look much better than whatwas thought to be the case 10 years ago.

DR MOSER: We will be asking Dom about spe-cific combinations and Ken about the ACCOM-PLISH study, but first, Bill, did you think that thedifference in outcome—especially with stroke andheart failure being more common with the ACEinhibitor than with the diuretic or heart failurebeing more common with the CCB when comparedwith the diuretic—was due to a blood pressure dif-ference? In stroke especially, in the black cohort,which was about 30% of the total group, there


was a big difference in blood pressure between theACE inhibitor and diuretic. Is it the blood pressuredifference, or was there perhaps some specific effectof the diuretic?

DR CUSHMAN: We carefully measured officeblood pressure and tried to retrain people, butthat’s never perfect. Based on these blood pressures,the CCB and the diuretic were virtually identical interms of blood pressure change, a mm Hg here orthere, one way or the other.

There is no way, therefore, that the difference inheart failure, either clinically or statistically, can beattributed that to these blood pressure differences.

DR MOSER: Why does the diuretic appear tobe better?

DR CUSHMAN: You can’t say from a clinicaltrial mechanistically why things work, but I thinkthat we’ve seen such persistent benefits of diureticsin preventing heart failure, on average about a50% reduction compared with placebo, that itdoesn’t surprise me that something else that hasnever come close to that would do worse. I don’tbelieve that the CCB caused heart failure; it justdidn’t reduce it as much as the diuretic.

DR MOSER: Do you think it may result from aslight degree of volume depletion over time?

DR CUSHMAN: I think an appropriately dosedthiazide diuretic has an effect that would be likeputting somebody on a very low–sodium diet.Otherwise, the CCB and the diuretic were similar.In addition, in the non–African American popula-tion in ALLHAT, there was no difference in bloodpressure change between the ACE inhibitor and thediuretic, but there was about 15% to 20% moreheart failure with the ACE inhibitor whencompared with the diuretic-based treatment.

DR MOSER: How did you reconcile this?Blocking the renin system should help to preventheart failure, yet the ACE inhibitor did not turnout to be the most effective drug.

DR CUSHMAN: Right. If you look at studies likethe Valsartan Antihypertensive Long-Term Use Eva-luation (VALUE) and ALLHAT and you comparethe ACE inhibitor or angiotensin receptor blocker toamlodipine in both studies, the curves look very sim-ilar. You have no difference in heart failure for thefirst 2 to 3 years, and then beyond that you see somebenefit of the ACE inhibitor or the angiotensin recep-tor blocker over amlodipine. In ALLHAT the differ-ence was significant, but in VALUE the differencedid not achieve significance, perhaps because a diu-retic was added frequently in both groups. I thinkthere is probably a different effect mechanistically;again, we can’t prove mechanisms from clinical

trials, but it appears that something is different,because of the immediate benefit of the diuretic onheart failure. There was less than half the incidenceof heart failure with the diuretic compared with theother drugs within the first 6 to 12 months. And sothere was an immediate effect with the diuretic. Itwas very dramatic and it persisted.

DR MOSER: And this was true in people whohad angina, who had ischemic heart disease, whohad diabetes, etc?

DR CUSHMAN: The heart failure differenceswere seen in every subgroup.

DR MOSER: Dom, what about combinationtherapy, that’s the buzzword of the 2000s; every-body’s doing it and we all recognize that at least halfof our patients, especially with stage 2 hypertensionor worse, are going to need ‡2 drugs to control bloodpressure. Should we start patients on 2 drugs sepa-rately or in combinations? Which patients? Should itbe hydrochlorothiazide, chlorthalidone, indapamide,or some other thiazide that we should use as part ofthe therapy? What’s your present take on this?

DR SICA: Well, I think the Seventh Report ofthe Joint National Committee on Prevention,Detection, Evaluation, and Treatment of HighBlood Pressure guidelines were fairly progressive inrecommending that 2 drugs be started at the incep-tion of therapy if blood pressure was >20 ⁄10 mmHg above goal.

DR MOSER: In other words, 160 ⁄100 mm Hgfor most people.

DR SICA: Yes, 160 ⁄100 for nondiabetics, with-out chronic kidney disease, but if you do that com-putation, it means that at 150 ⁄90 mmHg in adiabetic patient, you’re already 20 ⁄10 mm Hgabove goal. The 2-drug therapy paradigm has beenthere for some time for many clinicians. Manydrugs have a fixed ability to reduce blood pressurewith a systolic blood pressure decrease of maybe10 to 15 mm Hg on average. Because of this aspectof blood pressure–lowering response to most mono-therapies, physicians should really become morefamiliar with 2-drug combinations, either given asindividual therapies or as a fixed-dose combination.

DR MOSER: Are we at a place now where wemight wish to question the present recommenda-tions for combination therapy? Should a thiazidebe one of the components, whether it’s a thiazideACE inhibitor, a thiazide angiotensin receptorblocker, or even a thiazide CCB? Or do we nowhave data that say that perhaps these are not theideal combinations for most people?

DR SICA: I would say that we have to reexam-ine past beliefs to try to understand the role of


renin-angiotensin system (RAS) blockade combinedwith a CCB compared with a diuretic and an ACEinhibitor. We do not have the answers to that ques-tion. I’d personally reserve my judgment. Weshould discuss the ACCOMPLISH study beforeyou try to answer this question.

DR MOSER: All right, Ken. What is theACCOMPLISH study?

DR JAMERSON: ACCOMPLISH compared 2different fixed-dose combinations with 2 differentclasses of drugs. In all, 11,464 individuals wererandomized to one of two strategies, a diuretic andRAS inhibitor or a CCB and an RAS inhibitor.

DR MOSER: Was the study blinded?DR JAMERSON: Yes. In ACCOMPLISH, the

RAS inhibitor was a foundation of therapy, with adiuretic or the CCB on top. The study was stoppedearly when it was clear that one strategy wassuperior to the other. Ultimately, if you werereceiving a combination of a CCB with an ACEinhibitor, there was 20% superiority comparedwith receiving an RAS inhibitor plus a diuretic.

DR MOSER: Was the primary outcome differ-ent, or are these different secondary outcomes?

DR JAMERSON: This was a primary outcomecomposed of several composite measures. The com-posite measures were cardiovascular death, heartattack, stroke, hospitalization for unstable angina,coronary revascularization procedures to preventmyocardial infarction and bypass, and resuscitationfrom sudden death.

DR MOSER: And in both regimens, were bloodpressures reduced equally? The diuretic ⁄RAS inhibi-tor when compared with the RAS inhibitor ⁄CCB?

DR JAMERSON: About as equal as we can getin a clinical trial. There was a 0.7-mm Hg differencein systolic blood pressure between the two arms.

DR MOSER: So your and the ACCOMPLISHinvestigators’ conclusions were that the combina-tion of an RAS inhibitor and a CCB was superiorto an RAS inhibitor plus a diuretic. Bill, you’vestudied the ACCOMPLISH trial; would you liketo comment?

DR CUSHMAN: I’m on the steering committeeeven though I didn’t help design the study, but Ithink the results are clear and they’re consistent,even if you take out the revascularizations.

DR JAMERSON: I think one thing that’s clearis that the amlodipine, a CCB, and benazepril oran ACE inhibitor combination is a good regimen.

DR MOSER: What dose of hydrochlorothiazidedid they use in that study?

DR JAMERSON: The dose of hydrochlorothiazidewas 12.5 to 25 mg.

DR MOSER: So 25 mg was the maximum?DR JAMERSON: Right, and clearly that’s

what’s been used; that’s what almost all combina-tions in recent years have contained.

DR MOSER: Is that a reasonable and effectivedose?

DR CUSHMAN: I think it’s too little, but wedon’t know for sure. If you consider chlorthalidoneat 12.5 or 25 mg as being effective for loweringblood pressure, the dose of 25 mg of hydrochloro-thiazide may be too small.

DR MOSER: Do you think that if they’d used alarger dose, a better blood pressure reduction wouldhave been noted with the diuretic ⁄RAS inhibitor?

DR CUSHMAN: There may have been a betterblood pressure reduction, but as we discussed, wecan’t attribute the benefits in ALLHAT to bloodpressure change alone.

DR MOSER: So that may be something elsethat might have occurred in the ALLHAT pati-ents to account for the better response to thediuretic?

DR CUSHMAN: You know, we have indirectdata showing that a low-dose diuretic may notwork very well. Let’s look at the Anglo-Scandina-vian Cardiac Outcomes Trial (ASCOT), in which aCCB ⁄ACE inhibitor improved secondary outcomesmore than a b-blocker ⁄diuretic regimen. In thattrial, the dose of bendroflumethiazide was one-fourth to one-half of what had been used in previ-ous outcome studies, although a great part of theoutcome difference could have been a result ofusing a b-blocker first. In the recent Action inDiabetes and Vascular Disease (ADVANCE) trial,a very small dose of indapamide was used, muchsmaller than what was used in the PerindoprilProtection Against Recurrent Stroke Study (PRO-GRESS), a study of an ACE inhibitor and diureticin poststroke patients in which recurrent stroke wasreduced by the combination. In ADVANCE, theyhad much less reduction in cardiovascular events.The ACE inhibitor was also used in a lower dosethan a full dose, and there was only about a 9%reduction in cardiovascular events in a diabeticpopulation. So, to me, there’s some suggestion andevidence now from several trials that we have to becareful in terms of underdosing any medication,especially diuretics.

DR MOSER: Do you think ACCOMPLISHmay have underdosed the diuretic?

DR CUSHMAN: Relative to older studies, it is alower dose, but clearly we have to do other stud-ies. We do not have studies of chlorthalidone incombination with an ACE inhibitor or a CCB.


DR MOSER: Also, Ken, why wasn’t heart fail-ure considered an end point in the ACCOMPLISHstudy?

DR JAMERSON: The dose of diuretics in previ-ous trials has been primarily driven by the need tocontrol blood pressure. Heretofore, there has notbeen significant discussion of diuretics possessingunique attributes that confer benefit beyond lower-ing the blood pressure alone. The introduction ofan argument suggesting that the dose of diureticcould influence cardiovascular outcomes can neitherbe substantiated nor negated by current trials. Theissue of paramount importance regarding theACCOMPLISH dosing of diuretics is that it cap-tures the dosing strategy of more than 80% ofprescribing clinicians and therefore has direct impli-cations for millions of hypertensive patients. Theresults provide compelling evidence that the diureticdose that the vast majority of patients receive (incombination with benazepril) is inferior to the com-bination of amlodipine and benazepril.

DR MOSER: Last comment, Dom, and thenI’ll summarize.

DR SICA: I don’t know that it was the lowerdose per se, because even if chlorthalidone wassubstituted in ACCOMPLISH, you still would havegotten to the same blood pressures as were recorded.You would not have had blood pressure differencesper se. You might have had a blood pressure differ-ence overnight with chlorthalidone that you maynot have had with hydrochlorothiazide. There wereno data about blood pressures at night. We knowthat chlorthalidone works for a longer portion ofthe 24-hour dose interval. The blood pressure differ-ences at night may have made the difference.

DR JAMERSON: I just wanted to point out thatthere’s an academic question here. Perhaps whatmost clinicians are using is not the right diuretic,and academically maybe it should have been chlor-thalidone in ACCOMPLISH. But there’s a messagehere that if you’re using combination tablets thatare available, there is one that’s superior to theother, and it turns out that the ACE inhibitor with12.5 to 25 mg of hydrochlorothiazide may not bethe way to go.

DR CUSHMAN: I think there should be astrong message not to abandon diuretic use butclearly not to use doses that have not been provenbeneficial in trials. In terms of blood pressure differ-ences, one thing we have seen repeatedly is that ifone regimen starts out more effective in loweringblood pressure, even if you titrate or add otherdrugs, it remains the superior regimen, usually both

for blood pressure efficacy and for outcomes.Because of therapeutic inertia even among verygood investigators, you never completely overcomethe early difference in blood pressure. We have seenthat now in every single trial in which there’s evena small difference in blood pressure.

DR MOSER: Let me summarize. Diuretics havebeen in use since 1957, and we probably have moreaccumulated data on these drugs than any otherantihypertensive drug. We have excellent outcomedata in the young, the elderly, diabetics, and nondi-abetics that these are effective as monotherapy insome studies and in combination with other medi-cations in reducing not just stroke and heart failurebut coronary heart disease events and progressionto renal failure.

The question is, do we continue to use hydro-chlorothiazide, which is the drug that most physi-cians have become accustomed to? This may bebecause when we were using other diuretics, suchas chlorthalidone, we were giving dosages of 50,100, or even 200 mg ⁄d. A great deal of hypokale-mia occurred and people were concerned about it.Should we begin to use more chlorthalidone indoses of 12.5 or 25 mg, which we think are equiva-lent to about 25 or 37.5 mg of hydrochlorothia-zide? This is the agent used in the clinical trials inthe United States with good results and with alonger duration of action than hydrochlorothiazide.

Another question is this: We’ve all gotten usedto using a thiazide plus an RAS inhibitor, a thiazideand a b-blocker, or a thiazide and CCB as therapyin a large number of cases, and the results of treat-ment have been good. But now these combinationshave been challenged by the results of a large ran-domized blinded study that suggest that a combina-tion of an RAS inhibitor and a CCB may indeed bemore effective in preventing events than a thiazide(hydrochlorothiazide) ⁄RAS combination.

These results should be considered when weadvocate therapeutic interventions. We should alsoconsider that if the diuretic had been given in largerdoses or a different diuretic was used, the resultsmight have been different. At present, this questioncannot be answered.

Disclosure: This expert panel discussion was supported byTakeda Pharmaceuticals North America, Inc., including anhonorarium for each author for time and effort spentparticipating in the discussion and/or reviewing the transcriptfor important intellectual content before publication. Theauthors maintained full control of the discussion and theresulting content of this article; Takeda PharmaceuticalsNorth America, Inc., had no input in the choice of topic,speakers, or content.


diuretics as monotherapy or as part of combination therapy for hypertension: an update

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