editorials

women that abortion may increase their risk of depression and suicide is exactly that false and misleading. The South Dakota law should alarm physicians and the public. If states are permitted to mandate ideological speech about abortion, what is to stop them from doing the same for end-oflife decisions, contraception, stem-cell therapies, vaccination, or any procedure or treatment that does not conform to the political ideology of the statehouse? The doctorpatient relationship is predicated on a foundation of trust. Doctors have an ethical responsibility to provide their patients with accurate medical information. But can a patient trust any interaction with his or her physician knowing that the physicians very words have been mandated by the state? Patients should not accept, and our profession should not allow, physicians to become a mouthpiece of statesponsored ideology. The amendment stating that Congress shall make no law . . . abridging the freedom of speech was the first amendment to the Consti-

tution for a reason: It is the bedrock principle of our democracy. The South Dakota script law is an affront to the First Amendment rights of physicians and an embarrassment to the people of South Dakota. Although the law is currently in force, the merits of a challenge to its constitutionality will soon be addressed by Judge Karen Schreier of the Federal District Court of South Dakota. To preserve the integrity of the doctor patient relationship, which is fundamental to the practice of medicine, this law should be summarily overturned.
This article (10.1056/NEJMe0809669) was published at www. nejm.org on November 19, 2008.
1. Lazzarini Z. South Dakotas abortion script threatening

the physicianpatient relationship. N Engl J Med 2008;359: 2189-91. 2. HB 1166, 2005 Leg., 80th Sess. (S.D. 2005). 3. Wooley v. Maynard. 430 U.S. 705, 713 (1977). 4. Planned Parenthood v. Casey. 505 U.S. 833 (1992). 5. Post R. Informed consent to abortion: a First Amendment 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 risk factors for cardiovascular and renal diseases. Currently, approximately 73 million adults in the United States and approximately 1 billion adults worldwide have hypertension, and the prevalence is increasing.1 Many clinical trials have examined the effects of antihypertensive drugs. Studies comparing the effects of antihypertensive medications with those of placebo have shown consistently that lowering blood pressure is associated with major reductions in the incidence of coronary events, strokes, and congestive heart failure.2 These benefits have been observed irrespective of age, sex, severity of the hypertension, presence or absence of associated risk factors or concomitant diseases, or class of antihypertensive drug used. However, the results of trials comparing the effects of different antihypertensive drugs or drug regimens have not been as consistent. The initial findings from a new drug comparison study, the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial (ClinicalTrials.gov number, NCT00170950), are reported in this issue of the Journal.3 The ACCOMPLISH trial was a randomized, doubleblind, industry-sponsored study involving subjects with hypertension that examined the effects on cardiovascular outcomes of treatment with the angiotensin-convertingenzyme (ACE) inhibitor benazepril combined with either the calciumchannel blocker amlodipine or the diuretic hydrochlorothiazide. Somewhat surprisingly, as compared with the benazeprilhydrochlorothiazide group, the group that was treated with benazepril and amlodipine had a relative risk reduction of approximately 20%, and an absolute risk reduction of 2.2%, in the primary end point, a composite of illness and death from cardiovascular causes. The secondary end point of death from cardiovascular causes and nonfatal myocardial infarction and stroke showed a similar benefit. The ACCOMPLISH study population was at high risk for cardiovascular diseases. The average age at entry was 68 years, and participants with a history of ischemic heart disease, peripheral vas2485

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cular disease, stroke, left ventricular hypertrophy, or diabetes (which was present in 60% of the subjects) were included. Because the study design did not include a drug washout period, data on pretreatment blood-pressure levels were unavailable. However, most subjects probably had relatively severe hypertension; at study entry, 38% were receiving three or more antihypertensive drugs, yet only 37% had blood-pressure levels less than 140/90 mm Hg. Most previous comparison trials have failed to show significant differences in the primary outcomes as long as equivalent decreases in blood pressure were achieved with the different drug regimens. Selected examples include the Swedish Trial in Old Patients with Hypertension-2 (STOP-2) trial, a study that examined treatment with diuretics and beta-blockers as compared with treatment with ACE inhibitors and calcium-channel blockers in elderly subjects with hypertension4; the International Verapamil-Trandolapril Study (INVEST) (NCT00133692), a trial in which a regimen of verapamil with or without trandolapril was compared with a regimen of atenolol with or without hydrochlorothiazide among patients with hypertension and coronary heart disease5; and the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) (NCT00000542), which compared chlorthalidone, lisinopril, and amlodipine therapies.6 In none of these trials did the primary outcomes differ between regimens. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), which compared treatment with the combination of amlodipine and perindopril with treatment with the combination of atenolol and bendroflumethiazide, the primary outcome of fatal coronary heart disease and nonfatal myocardial infarction also did not differ significantly between the two treatment groups; the composite secondary outcomes, which included stroke, were less favorable in the atenolol bendroflumethiazide group, which also had average blood-pressure levels that were approximately 3 mm Hg systolic and 2 mm Hg diastolic higher than those of subjects in the amlodipineperindopril group.7 In contrast, in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study (NCT00338260), the primary cardiovascular outcomes (particularly stroke) with treatment with the angiotensin-receptor blocker losartan were better than those with atenolol therapy, even though there were similar reductions in blood
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pressure in the two groups.8 In the Second Australian National Blood Pressure Study, ACE-inhibitor therapy was associated with a somewhat lower incidence of cardiovascular events than thiazidebased treatment, although the benefit was observed only in men.9 No previous outcome trial has compared treatment with a combination of an ACE inhibitor and a calcium-channel blocker with treatment with the combination of an ACE inhibitor and a thiazidetype diuretic. ALLHAT compared chlorthalidone therapy with amlodipine therapy, though not in combination with an ACE inhibitor. The chlorthalidone dose used in ALLHAT and the hydrochlorothiazide dose used in the ACCOMPLISH trial were both in a range of 12.5 to 25.0 mg per day. Chlorthalidone is estimated to have double the potency of hydrochlorothiazide and a much longer duration of effect in this dose range. A recent study used 24-hour ambulatory blood-pressure measurements to study the effects of chlorthalidone (25 mg per day) as compared with hydrochlorothiazide (50 mg per day).10 Although bloodpressure levels measured during the daytime in the clinicians office were similar, blood-pressure levels measured during the nighttime, and 24-hour average blood pressures, were considerably lower with chlorthalidone than with hydrochlorothiazide. The reported blood-pressure levels measured in the clinicians office in the ACCOMPLISH trial were also relatively similar in the two treatment groups, but the possibility exists that the relatively low dose of hydrochlorothiazide used (averaging 19 mg per day) did not provide 24-hour blood-pressure control that was as effective as that provided by the benazeprilamlodipine regimen. Ambulatory blood-pressure measurements were apparently included in the design of the ACCOMPLISH trial,11 and the data, if available, could address this issue in the future. Experimental evidence has suggested that ACE inhibitors and calcium-channel blockers can have vasoprotective effects. These agents have been shown to inhibit atherosclerosis in various animal models with hypercholesterolemia and to improve endothelium-dependent vasodilatation in isolated arteries and in patients with vascular disease.12,13 Diuretics do not share these properties. However, the clinical relevance of these findings is uncertain. Are the results from the ACCOMPLISH trial applicable to the general population with hyper-

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editorials

tension? As noted above, the study participants were older and had relatively severe hypertension and a high prevalence of cardiovascular disease and diabetes. Although this group of subjects clearly does not mirror the broader population with hypertension, the same criticism can be applied to the other trials as well. Treatment recommendations should be based on the total available evidence rather than on the results of any single trial. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, published in 2003, included a strong preference for thiazidetype diuretics as the initial therapy for most patients with hypertension in the absence of compelling indications for specific drugs.14 However, it is time to reexamine these recommendations. The results from the many recent studies, including the ACCOMPLISH trial, when considered together, suggest that greater flexibility is now indicated in the choice of the initial drug. In my opinion, each of the major classes (diuretics, ACE inhibitors, calcium-channel blockers, angiotensinreceptor blockers, and, to a lesser extent, betablockers) appears reasonable as first-line therapy. The choice of a drug should depend on criteria such as compelling indications or contraindications, coexisting conditions, adverse effects, race, and the clinicians experience. Nevertheless, increased flexibility in choice should not negate the importance of diuretics, which have been a cornerstone of antihypertensive therapy for the past 50 years. The data from the ACCOMPLISH trial also should not diminish the value of treatment with the combination of an ACE inhibitor and a diuretic, a combination that effectively lowers blood pressure and that was recently shown to produce major reductions in mortality and morbidity in the very old.15 Many excellent medications are available to control hypertension. These drugs have acceptable side-effect and adverse-event profiles, and many are now available in generic versions, making cost less of an issue in the selection of a drug. Most patients with hypertension will require two or more drugs to control their hypertension, and combination drug formulations may also be useful. Although specific benefits may be provided by a given drug or drug combination, the evidence is overwhelming that the most important aspect of treatment is to reduce blood pressure to goal

levels. How this is achieved is less important. Unfortunately, despite the remarkable progress in therapy, blood pressure remains inadequately controlled in almost two thirds of patients with hypertension in the United States. We must do better.

Dr. Chobanian reports serving as chair for the seventh report of the Joint National Committee, which developed guidelines for the management of hypertension, and receiving a lecture fee from Bristol-Myers Squibb of Mexico. No other potential conflict of interest relevant to this article was reported. From the Department of Medicine, Boston University School of Medicine, and the Boston University Medical Center, Boston.

1. Heart disease stroke statistics: 2008 update at-a-glance. Dal-

las: American Heart Association, 2008. (Accessed November 13, 2008, at http://www.americanheart.org/downloadable/heart/ 1200082005246HS_Stats%202008.final.pdf.) 2. Turnbull F, Neal B, Algert C, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med 2005;165:1410-9. 3. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417-28. 4. Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999;354:1751-6. 5. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease: the International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA 2003;290:2805-16. 6. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-97. [Errata, JAMA 2003;289:178, 2004;291: 2196.] 7. Dahlf B, Sever PS, Poulter NR, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005;366:895906. 8. Dahlf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995-1003. 9. Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-convertingenzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med 2003;348:583-92. 10. Ernst ME, Carter BL, Goerdt CJ, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension 2006;47: 352-8. 11. Jamerson KA, Bakris GL, Wun CC, et al. Rationale and design of the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial: the first randomized controlled trial to compare the clinical outcome effects of first-line combination therapies in hypertension. Am J Hypertens 2004;17:793-801. 12. Chobanian AV, Haudenschild CC, Nickerson C, Drago R. An-

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tiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit. Hypertension 1990;15:327-31. 13. Lscher TF, Wenzel RR, Moreau P, Takase H. Vascular protective effects of ACE inhibitors and calcium antagonists: theoretical basis for a combination therapy in hypertension and other cardiovascular diseases. Cardiovasc Drugs Ther 1995;Suppl 3: 509-23. 14. Chobanian AV, Bakris GL, Black HR, et al. The Seventh

Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-72. [Erratum, JAMA 2003; 290:197.] 15. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension 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 Treatment

Ching-Lung Lai, M.D., and Man-Fung Yuen, M.D. The hepatitis B virus (HBV) causes chronic infection in approximately 400 million people in the world. Most carriers of chronic HBV, including Asians, Africans, and a proportion of persons in Mediterranean countries, acquire the infection at birth or within the first 1 to 2 years after birth.1 It is estimated that 50% of male carriers and 14% of female carriers will eventually die of the complications of cirrhosis and hepatocellular carcinoma.2 The criteria and end points for the treatment of chronic HBV infection should be reevaluated in light of three important recent findings. First, more than 70% of patients with complications of cirrhosis and hepatocellular carcinoma are negative for the hepatitis B e antigen (HBeAg).3 Therefore, although the disease may become quiescent in some patients after HBeAg seroconversion, the disease can progress, and most disease-related deaths occur in these patients. Even with clearance of the hepatitis B surface antigen (HBsAg), there is no decrease in the risk of hepatocellular carcinoma if the HBsAg is lost in patients after the age of 50 years.4 Second, an elevated HBV DNA level of more than 2000 IU per milliliter (104 copies per milliliter) is a strong independent predictor of the risk of complications of cirrhosis and hepatocellular carcinoma.5,6 Prolonged, effective suppression of HBV DNA has been shown to decrease the risk of the development of cirrhosis and hepatocellular carcinoma.7,8 Finally, as is the case in chronic hepatitis C infection, patients with chronic HBV infection who have alanine aminotransferase levels that are near the upper limit of the normal range are at a significantly higher risk for complications of cirrhosis and hepatocellular carcinoma than patients with alanine aminotransferase levels that are less than half the upper limit of the normal range.3 The highest risk of complications of cirrhosis and hepatocellular carcinoma occurs in patients with alanine aminotransferase levels that are one to two times the upper limit of the normal range. The implications for the treatment of chronic HBV infection are that, other than the traditional end point of HBeAg seroconversion alone, a more important aim is the sustained suppression of HBV DNA to very low levels, preferably to below the detection limit of sensitive polymerasechain-reaction (PCR) assays.1 The alanine amino transferase level should also ideally be lower than half the upper limit of the normal range. The first licensed agent for the treatment of chronic HBV infection was the conventional form of interferon alfa, which acts mainly through immunomodulation and has the advantage of being given over a fixed period of time, although this is partly because of its often severe side effects. However, the majority of patients still have levels of HBV DNA that are detectable by means of PCR assays after treatment, and most studies show no decrease in the occurrence of hepatocellular carcinoma on long-term follow-up.9,10 The short-term efficacy of pegylated interferon (peginterferon), licensed in 2005, is almost identical to that of conventional interferon. Data on its long-term effects on the development of cirrhosis and hepatocellular carcinoma have not yet been published. Lamivudine, a nucleoside analogue, was licensed in 1998. Nucleoside and nucleotide analogues suppress HBV replication through inhibition of the reverse-transcriptase and DNA polymerase activities. During the past decade, four other nucleo-

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