does it matter how hypertension is controlled 2009

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n engl j med 359;23 www.nejm.org december 4, 2008 2485

women that abortion may increase their risk ofdepression and suicide is exactly that false andmisleading.

The South Dakota law should alarm physi-cians and the public. If states are permitted tomandate ideological speech about abortion, whatis to stop them from doing the same for end-of-

life decisions, contraception, stem-cell therapies,vaccination, or any procedure or treatment thatdoes not conform to the political ideology ofthe statehouse? The doctorpatient relationshipis predicated on a foundation of trust. Doctorshave an ethical responsibility to provide theirpatients with accurate medical information. Butcan a patient trust any interaction with his orher physician knowing that the physicians verywords have been mandated by the state? Patientsshould not accept, and our profession should notallow, physicians to become a mouthpiece of state-

sponsored ideology.The amendment stating that Congress shall

make no law . . . abridging the freedom ofspeech was the f irst amendment to the Consti-

tution for a reason: It is the bedrock principle ofour democracy. The South Dakota script lawis an affront to the First Amendment rights ofphysicians and an embarrassment to the peopleof South Dakota. Although the law is currentlyin force, the merits of a challenge to its consti-tutionality will soon be addressed by Judge Karen

Schreier of the Federal District Court of SouthDakota. To preserve the integrity of the doctorpatient relationship, which is fundamental tothe practice of medicine, this law should be sum-marily overturned.

This article (10.1056/NEJMe0809669) was published at www.nejm.org on November 19, 2008.

Lazzarini Z. South Dakotas abortion script threatening1.the physicianpatient relationship. N Engl J Med 2008;359:2189-91.

HB 1166, 2005 Leg., 80th Sess. (S.D. 2005).2.Wooley v. Maynard. 430 U.S. 705, 713 (1977).3.Planned Parenthood v. Casey. 505 U.S. 833 (1992).4.

Post R. Informed consent to abortion: a First Amendment5.analysis of compelled physician speech. Univ Ill Law Rev 2007;April 12:939-90.Copyright 2008 Massachusetts Medical Society.

Does It Matter How Hypertension Is Controlled?Aram V. Chobanian, M.D.

Hypertension is one of the most important riskfactors for cardiovascular and renal diseases. Cur-rently, approximately 73 million adults in the Unit-ed States and approximately 1 billion adults world-wide have hypertension, and the prevalence isincreasing.1 Many clinical trials have examined theeffects of antihypertensive drugs. Studies compar-ing the effects of antihypertensive medicationswith those of placebo have shown consistently thatlowering blood pressure is associated with majorreductions in the incidence of coronary events,strokes, and congestive heart failure.2 These ben-efits have been observed irrespective of age, sex,

severity of the hypertension, presence or absenceof associated risk factors or concomitant diseases,or class of antihypertensive drug used. However,the results of trials comparing the effects of differ-ent antihypertensive drugs or drug regimens havenot been as consistent.

The initial findings from a new drug compar-ison study, the Avoiding Cardiovascular Eventsthrough Combination Therapy in Patients Livingwith Systolic Hypertension (ACCOMPLISH) tri-

al (ClinicalTrials.gov number, NCT00170950),are reported in this issue of the Journal.3 TheACCOMPLISH trial was a randomized, double-blind, industry-sponsored study involving subjectswith hypertension that examined the effects oncardiovascular outcomes of treatment with theangiotensin-convertingenzyme (ACE) inhibitorbenazepril combined with either the calcium-channel blocker amlodipine or the diuretic hydro-chlorothiazide. Somewhat surprisingly, as com-pared with the benazeprilhydrochlorothiazidegroup, the group that was treated with benazepriland amlodipine had a relative risk reduction of

approximately 20%, and an absolute risk reductionof 2.2%, in the primary end point, a compositeof illness and death from cardiovascular causes.The secondary end point of death from cardiovas-cular causes and nonfatal myocardial infarctionand stroke showed a similar benefit.

The ACCOMPLISH study population was athigh risk for cardiovascular diseases. The averageage at entry was 68 years, and participants witha history of ischemic heart disease, peripheral vas-

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cular disease, stroke, left ventricular hypertrophy,or diabetes (which was present in 60% of the sub-jects) were included. Because the study design didnot include a drug washout period, data on pre-treatment blood-pressure levels were unavailable.However, most subjects probably had relatively se-vere hypertension; at study entry, 38% were re-

ceiving three or more antihypertensive drugs, yetonly 37% had blood-pressure levels less than140/90 mm Hg.

Most previous comparison trials have failed toshow significant differences in the primary out-comes as long as equivalent decreases in bloodpressure were achieved with the different drugregimens. Selected examples include the SwedishTrial in Old Patients with Hypertension-2 (STOP-2)trial, a study that examined treatment with diuret-ics and beta-blockers as compared with treatmentwith ACE inhibitors and calcium-channel block-

ers in elderly subjects with hypertension4; the In-ternational Verapamil-Trandolapril Study (INVEST)(NCT00133692), a trial in which a regimen ofverapamil with or without trandolapril was com-pared with a regimen of atenolol with or with-out hydrochlorothiazide among patients withhypertension and coronary heart disease5; andthe Antihypertensive and Lipid-Lowering Treat-ment to Prevent Heart Attack Trial (ALLHAT)(NCT00000542), which compared chlorthalidone,lisinopril, and amlodipine therapies.6 In none ofthese trials did the primary outcomes differ be-tween regimens. In the Anglo-Scandinavian Car-diac Outcomes Trial (ASCOT), which comparedtreatment with the combination of amlodipineand perindopril with treatment with the combi-nation of atenolol and bendroflumethiazide, theprimary outcome of fatal coronary heart diseaseand nonfatal myocardial infarction also did notdiffer significantly between the two treatmentgroups; the composite secondary outcomes, whichincluded stroke, were less favorable in the atenololbendroflumethiazide group, which also had aver-

age blood-pressure levels that were approximately3 mm Hg systolic and 2 mm Hg diastolic higherthan those of subjects in the amlodipineperin-dopril group.7 In contrast, in the Losartan Inter-vention for Endpoint Reduction in Hypertension(LIFE) study (NCT00338260), the primary cardio-vascular outcomes (particularly stroke) with treat-ment with the angiotensin-receptor blocker losar-tan were better than those with atenolol therapy,even though there were similar reductions in blood

pressure in the two groups.8 In the Second Aus-tralian National Blood Pressure Study, ACE-inhib-itor therapy was associated with a somewhat lowerincidence of cardiovascular events than thiazide-based treatment, although the benefit was ob-served only in men.9

No previous outcome trial has compared treat-

ment with a combination of an ACE inhibitor anda calcium-channel blocker with treatment with thecombination of an ACE inhibitor and a thiazide-type diuretic. ALLHAT compared chlorthalidonetherapy with amlodipine therapy, though not incombination with an ACE inhibitor. The chlorthal-idone dose used in ALLHAT and the hydrochlo-rothiazide dose used in the ACCOMPLISH trialwere both in a range of 12.5 to 25.0 mg per day.Chlorthalidone is estimated to have double the po-tency of hydrochlorothiazide and a much longerduration of effect in this dose range. A recent

study used 24-hour ambulatory blood-pressuremeasurements to study the effects of chlorthali-done (25 mg per day) as compared with hydro-chlorothiazide (50 mg per day).10 Although blood-pressure levels measured during the daytime inthe clinicians office were similar, blood-pressurelevels measured during the nighttime, and 24-houraverage blood pressures, were considerably lowerwith chlorthalidone than with hydrochlorothia-zide. The reported blood-pressure levels measuredin the clinicians office in the ACCOMPLISH trialwere also relatively similar in the two treatmentgroups, but the possibility exists that the relativelylow dose of hydrochlorothiazide used (averag-ing 19 mg per day) did not provide 24-hourblood-pressure control that was as effective asthat provided by the benazeprilamlodipine reg-imen. Ambulatory blood-pressure measurementswere apparently included in the design of theACCOMPLISH trial,11 and the data, if available,could address this issue in the future.

Experimental evidence has suggested that ACEinhibitors and calcium-channel blockers can have

vasoprotective effects. These agents have beenshown to inhibit atherosclerosis in various animalmodels with hypercholesterolemia and to improveendothelium-dependent vasodilatation in isolatedarteries and in patients with vascular disease.12,13Diuretics do not share these properties. Howev-er, the clinical relevance of these findings is un-certain.

Are the results from the ACCOMPLISH trialapplicable to the general population with hyper-





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tension? As noted above, the study participantswere older and had relatively severe hypertensionand a high prevalence of cardiovascular diseaseand diabetes. Although this group of subjectsclearly does not mirror the broader populationwith hypertension, the same criticism can be ap-plied to the other trials as well. Treatment recom-

mendations should be based on the total avail-able evidence rather than on the results of anysingle trial.

The seventh report of the Joint National Com-mittee on Prevention, Detection, Evaluation, andTreatment of High Blood Pressure, published in2003, included a strong preference for thiazide-type diuretics as the initial therapy for most pa-tients with hypertension in the absence of com-pelling indications for specific drugs.14 However,it is time to reexamine these recommendations.The results from the many recent studies, includ-

ing the ACCOMPLISH trial, when considered to-gether, suggest that greater flexibility is now in-dicated in the choice of the initial drug. In myopinion, each of the major classes (diuretics, ACEinhibitors, calcium-channel blockers, angiotensin-receptor blockers, and, to a lesser extent, beta-blockers) appears reasonable as first-line therapy.The choice of a drug should depend on criteriasuch as compelling indications or contraindica-tions, coexisting conditions, adverse effects, race,and the clinicians experience. Nevertheless, in-creased flexibility in choice should not negate theimportance of diuretics, which have been a cor-nerstone of antihypertensive therapy for the past50 years. The data from the ACCOMPLISH trialalso should not diminish the value of treatmentwith the combination of an ACE inhibitor and adiuretic, a combination that effectively lowersblood pressure and that was recently shown toproduce major reductions in mortality and mor-bidity in the very old.15

Many excellent medications are available tocontrol hypertension. These drugs have acceptable

side-effect and adverse-event profiles, and manyare now available in generic versions, making costless of an issue in the selection of a drug. Mostpatients with hypertension will require two ormore drugs to control their hypertension, andcombination drug formulations may also be use-ful. Although specific benefits may be providedby a given drug or drug combination, the evidenceis overwhelming that the most important aspectof treatment is to reduce blood pressure to goal

levels. How this is achieved is less important.Unfortunately, despite the remarkable progressin therapy, blood pressure remains inadequatelycontrolled in almost two thirds of patients withhypertension in the United States. We must dobetter.

Dr. Chobanian reports serving as chair for the seventh report

of the Joint National Committee, which developed guidelines forthe management of hypertension, and receiving a lecture feefrom Bristol-Myers Squibb of Mexico. No other potential conflictof interest relevant to this article was reported.

From the Department of Medicine, Boston University School ofMedicine, and the Boston University Medical Center, Boston.

Heart disease stroke stat istics: 2008 update at-a-glance. Dal-1.las: American Heart Association, 2008. (Accessed November 13,2008, at http://www.americanheart.org/downloadable/heart/1200082005246HS_Stats%202008.final.pdf.)

Turnbull F, Neal B, Algert C, et al. Effects of different blood2.pressure-lowering regimens on major cardiovascular events inindividuals with and without diabetes mellitus: results of pro-spectively designed overviews of randomized trials. Arch Intern

Med 2005;165:1410-9.Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus3.

amlodipine or hydrochlorothiazide for hypertension in high-riskpatients. N Engl J Med 2008;359:2417-28.

Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial4.of old and new antihypertensive drugs in elderly patients: car-diovascular mortality and morbidity the Swedish Trial in OldPatients with Hypertension-2 study. Lancet 1999;354:1751-6.

Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calci-5.um antagonist vs a non-calcium antagonist hypertension treat-ment strategy for patients with coronary artery disease: the In-ternational Verapamil-Trandolapril Study (INVEST): a randomizedcontrolled trial. JAMA 2003;290:2805-16.

Major outcomes in high-risk hypertensive patients ran-6.domized to angiotensin-converting enzyme inhibitor or calci-um channel blocker vs diuretic: the Antihypertensive and Lip-id-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).JAMA 2002;288:2981-97. [Errata, JAMA 2003;289:178, 2004;291:2196.]

Dahlf B, Sever PS, Poulter NR, et al. Prevention of cardio-7.vascular events with an antihypertensive regimen of amlodipineadding perindopril as required versus atenolol adding bendro-flumethiazide as required, in the Anglo-Scandinavian CardiacOutcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA):a multicentre randomised controlled tria l. Lancet 2005;366:895-906.

Dahlf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular8.morbidity and mortality in the Losartan Intervention For End-point reduction in hypertension study (LIFE): a randomised trialagainst atenolol. Lancet 2002;359:995-1003.

Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes9.

with angiotensin-convertingenzyme inhibitors and diureticsfor hypertension in the elderly. N Engl J Med 2003;348:583-92.Ernst ME, Carter BL, Goerdt CJ, et al. Comparative antihy-10.

pertensive effects of hydrochlorothiazide and chlorthalidone onambulatory and office blood pressure. Hypertension 2006;47:352-8.

Jamerson KA, Bakris GL, Wun CC, et al. Rat ionale and de-11.sign of the Avoiding Cardiovascular events through COMbina-tion therapy in Patients LIving with Systolic Hypertension(ACCOMPLISH) trial: the first randomized controlled trial tocompare the clinical outcome effects of first-line combinationtherapies in hypertension. Am J Hypertens 2004;17:793-801.

Chobanian AV, Haudenschild CC, Nickerson C, Drago R. An-12.





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tiatherogenic effect of captopril in the Watanabe heritable hy-perlipidemic rabbit. Hypertension 1990;15:327-31.

Lscher TF, Wenzel RR, Moreau P, Takase H. Vascular protec-13.tive effects of ACE inhibitors and calcium antagonists: theoreticalbasis for a combination therapy in hypertension and other car-diovascular diseases. Cardiovasc Drugs Ther 1995;Suppl 3:509-23.

Chobanian AV, Bakris GL, Black HR, et al. The Seventh14.

Report of the Joint National Committee on Prevention, Detec-tion, Evaluation, and Treatment of High Blood Pressure: theJNC 7 report. JAMA 2003;289:2560-72. [Erratum, JAMA 2003;290:197.]

Beckett NS, Peters R, Fletcher AE, et al. Treatment of hyper-15.tension in patients 80 years of age or older. N Engl J Med 2008;358:1887-98.Copyright 2008 Massachusetts Medical Society.

Chronic Hepatitis B New Goals, New TreatmentChing-Lung Lai, M.D., and Man-Fung Yuen, M.D.

The hepatitis B virus (HBV) causes chronic in-fection in approximately 400 million people inthe world. Most carriers of chronic HBV, includingAsians, Africans, and a proportion of persons inMediterranean countries, acquire the infection atbirth or within the first 1 to 2 years after birth.1

It is estimated that 50% of male carriers and14% of female carriers will eventually die of thecomplications of cirrhosis and hepatocellular car-cinoma.2

The criteria and end points for the treatmentof chronic HBV infection should be reevaluatedin light of three important recent findings. First,more than 70% of patients with complicationsof cirrhosis and hepatocellular carcinoma arenegative for the hepatitis B e antigen (HBeAg).3Therefore, although the disease may become qui-escent in some patients after HBeAg seroconver-sion, the disease can progress, and most dis-ease-related deaths occur in these patients. Evenwith clearance of the hepatitis B surface antigen(HBsAg), there is no decrease in the risk of hep-atocellular carcinoma if the HBsAg is lost in pa-tients after the age of 50 years.4

Second, an elevated HBV DNA level of morethan 2000 IU per milliliter (104 copies per mil-liliter) is a strong independent predictor of therisk of complications of cirrhosis and hepatocel-lular carcinoma.5,6 Prolonged, effective suppres-

sion of HBV DNA has been shown to decrease therisk of the development of cirrhosis and hepato-cellular carcinoma.7,8

Finally, as is the case in chronic hepatitis Cinfection, patients with chronic HBV infection whohave alanine aminotransferase levels that arenear the upper limit of the normal range are ata significantly higher risk for complications ofcirrhosis and hepatocellular carcinoma than pa-

tients with alanine aminotransferase levels thatare less than half the upper limit of the normalrange.3 The highest risk of complications of cir-rhosis and hepatocellular carcinoma occurs in pa-tients with alanine aminotransferase levels thatare one to two times the upper limit of the nor-

mal range.The implications for the treatment of chronic

HBV infection are that, other than the tradition-al end point of HBeAg seroconversion alone, amore important aim is the sustained suppressionof HBV DNA to very low levels, preferably to be-low the detection limit of sensitive polymerase-chain-reaction (PCR) assays.1 The alanine amino-transferase level should also ideally be lower thanhalf the upper limit of the normal range.

The first licensed agent for the treatment ofchronic HBV infection was the conventional formof interferon alfa, which acts mainly throughimmunomodulation and has the advantage ofbeing given over a fixed period of time, althoughthis is partly because of its often severe side ef-fects. However, the majority of patients still havelevels of HBV DNA that are detectable by meansof PCR assays after treatment, and most studiesshow no decrease in the occurrence of hepato-cellular carcinoma on long-term follow-up.9,10The short-term efficacy of pegylated interferon(peginterferon), licensed in 2005, is almost iden-

tical to that of conventional interferon. Data onits long-term effects on the development of cirrho-sis and hepatocellular carcinoma have not yet beenpublished.

Lamivudine, a nucleoside analogue, was licensedin 1998. Nucleoside and nucleotide analogues sup-press HBV replication through inhibition of thereverse-transcriptase and DNA polymerase activi-ties. During the past decade, four other nucleo-




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