Analysis of Recent Papers in Hypertension.
Jan Basile, MD, Section Editor

To compare the effect of newer therapies with diuretics on the risk of coronary heart disease (CHD) in hypertensive patients, the National Heart, Lung, and Blood Institute sponsored The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The largest randomized, double-blind, active-controlled hypertension trial ever performed, ALLHAT was designed to determine whether the occurrence of fatal CHD or nonfatal myocardial infarction (primary outcome) in high-risk patients with hypertension is lower when treated with a representative dihydropyridine calcium channel blocker (CCB) (amlodipine), a representative angiotensin-converting enzyme (ACE) inhibitor (lisinopril), or a representative α blocker (doxazosin), each compared with a representative long-acting thiazide diuretic (chlorthalidone). Discussions of this trial have been published in the November/December 2002 and January/February 2003 issues of The Journal of Clinical Hypertension. Recruitment occurred between 1994 and 1998, with data collection ending in March of 2002. The range of follow-up was from 3 years 8 months to 8 years 1 month (mean, 4.9 years). The study recruited 42,418 men and women from 623 centers in the United States, Canada, Puerto Rico, and the US Virgin Islands. About 7000 US veterans participated through 69 Department of Veterans Affairs clinics. Eligible participants were aged 55 years or older with at least one additional coronary risk factor. The risk factors included previous myocardial infarction or stroke (at least 6 months previously), electrocardiographically or echocardiographically measured left ventricular hypertrophy, history of type 2 diabetes, current cigarette smoking, high-density HDL cholesterol <35 mg/dL (<0.91 mmol/L), or documentation of other atherosclerotic cardiovascular disease (CVD). Those with a history of symptomatic heart failure and/or known left ventricular ejection fraction <35% were excluded. On entry, participants had stage 1 or stage 2 hypertension (blood pressures, 140–180/90–110 mm Hg), regardless of treatment status. More than 90% of patients were on one or two blood pressure-lowering agents that were stopped before entry into the study. No washout period was required. Participants underwent medical checkups and blood pressure evaluation at 1, 3, 6, 9, and 12 months after entry into the study and every 4 months thereafter. The doxazosin arm of the trial was stopped 2 years earlier because of a two-fold greater risk of clinical heart failure in the doxazosin group compared with those on chlorthalidone. The results of the 33,357 participants remaining in the other three arms were presented in this final report. 15,255 patients were randomized to chlorthalidone, 12.5–25 mg once a day; 9048 received amlodipine, 2.5–10 mg once a day; and 9054 were given lisinopril 10–40 mg once a day. If the participant did not achieve the goal blood pressure of <140/90 mm Hg after uptitration to the highest dose of the step 1 randomization, nonstudy open-label drugs were added. Step 2 drugs that could be added included atenolol (25–100 mg/day), clonidine (0.1–0.3 mg twice a day), or reserpine (0.05–0.2 mg/day); the only step 3 agent was hydralazine (25–100 mg twice a day). Nonpharmacologic therapy was recommended to all participants according to national guidelines. Study drugs, i.e., a diuretic, CCB, or ACE inhibitor could not be added as a second step medication. In addition to the study's primary end point of preventing fatal CHD and nonfatal myocardial infarction, four major prespecified secondary outcomes were included; all-cause mortality, fatal and nonfatal stroke, combined CHD (the primary outcome, coronary revascularization, hospitalized angina), and combined CVD (combined CHD, stroke, other treated angina, heart failure [fatal, hospitalized, or treated nonhospitalized] and peripheral arterial disease). Additional prespecified secondary outcomes included cancer, incident electrocardiographic left ventricular hypertrophy, end-stage renal disease (dialysis, renal transplant, or death), and the slope of the reciprocal of longitudinal serum creatinine measurements. Changes in estimated glomerular filtration rate were examined post hoc. Two major safety outcomes, angioedema and hospitalization for gastrointestinal bleeding, were also prespecified. Amlodipine and lisinopril were both compared with chlorthalidone. No comparison was valid between amlodipine and lisinopril. Baseline risk factors were nearly identically distributed in the three treatment groups. The mean age was 67 years; 47% were women, 35% were black, 19% were Hispanic, 22% were smokers, 36% were diabetic, and 25% had preexisting CHD. Mean seated blood pressure on entry (usually on some antihypertensive medications) was 146/84 mm Hg in all three groups, and was 134/75,135/74, and 136/75 mm Hg in the chlorthalidone, amlodipine, and lisinopril groups, respectively, at 5 year follow-up. Compared with chlorthalidone, systolic blood pressure (SBP) was significantly higher in the amlodipine group (1 mm Hg) and the lisinopril group (2 mm Hg) whereas diastolic blood pressure was lower in the amlodipine group (1 mm Hg). At the initial visit, 27% were at or below the blood pressure goal of <140/90 mm Hg; blood pressure control at 5 years improved to 68%, 66%, and 61% below goal for the chlorthalidone, amlodipine, and lisinopril groups, respectively. Adherence to therapy from years 1–5 fell from 87% to 80% for chlorthalidone, 88% to 80% for amlodipine, and dropped from 82% to 73% for lisinopril. Only the lisinopril group was less compared with chlorthalidone. About 41% of the patients on chlorthalidone, 40% of the patients on amlodipine, and 43% of the patients on lisinopril required the addition of a second- or third-line agent at the 5-year mark to control their hypertension. The mean number of drugs used to control blood pressure at the conclusion of the study was two. Mean serum cholesterol level at baseline was 216 mg/dL for all three groups. Total cholesterol at 4 years was 1–2 mg/dL higher in the chlorthalidone compared with the amlodipine and lisinopril groups. Serum potassium was 0.3–0.4 mmol/L lower on chlorthalidone compared with amlodipine and lisinopril with 7% of those on chlorthalidone more likely to have a serum potassium <3.5 mmol/L. Fasting glucose was 3 mg/dL higher in the chlorthalidone than in the amlodipine group and 5 mg/dL higher than in the lisinopril group. Among nondiabetic participants, the incidence of fasting glucose >126 mg/dL at 4 years was 1.8% higher in the chlorthalidone than amlodipine group, and 3.5% higher in the chlorthalidone than the lisinopril group. The estimated glomerular filtration rate decreased by 7–8 units at 4 years in the chlorthalidone and lisinopril groups, but decreased by only 3 units on amlodipine. A total of 2956 patients reached a primary outcome and there was no difference among the groups. Neither amlodipine nor lisinopril was superior to chlorthalidone in preventing major coronary events or improving overall survival. For both the primary and secondary outcomes, there was no difference between the amlodipine and chlorthalidone groups, although those randomized to chlorthalidone had a significant 38% reduction in the risk of heart failure. This was consistent among all the prespecified subgroups including men and women, blacks and nonblacks, those older or younger than age 65, and those with and without diabetes. Amlodipine was not associated with an excess in gastrointestinal bleeding or cancer death compared with chlorthalidone. In comparing chlorthalidone and lisinopril, those on chlorthalidone had a 15% reduction in the risk of stroke with a mean 2 mm Hg lower SBP. In blacks, which had a 4 mm Hg reduction in SBP on chlorthalidone compared with lisinopril, a 40% reduction in stroke risk occurred. The risk of heart failure was reduced by 19% in those on chlorthalidone compared with lisinopril. There were no differences in other secondary outcomes including peripheral arterial disease, cancer incidence, or death and all-cause mortality. There were no differences in the risk of end-stage renal disease, or glomerular filtration rate, between the lisinopril and chlorthalidone groups. Angioedema, a rare adverse event, occurred more often in the lisinopril group (0.4%), especially in blacks. Thiazide-type diuretics (TTDs) were unsurpassed in reducing clinical events and lowering blood pressure and were as well tolerated as CCB and ACE inhibitor therapy in ALLHAT. They are recommended as initial therapy in hypertension. To effectively control blood pressure, additional agents will be necessary.—The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. 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;288:2981–2997. Hypertension currently affects 50 million people in the United States. For those without hypertension who are 55–65 years of age, the lifetime probability of developing hypertension is 90%. Forty percent of the overall cost of $37 billion for hypertension is for drug therapy, currently taken by 24 million people. Early clinical trials with older and less expensive blood pressure-lowering agents have consistently documented that TTD therapy substantially reduced the risk of stroke and CHD events. Trials with newer, more expensive agents have recently documented that ACE inhibitor and CCB therapy reduces cardiovascular events in those with hypertension without the potential adverse metabolic consequences that might occur with diuretic therapy. Fueled by industry promotion, practitioners began to perceive these newer agents as more beneficial than the older, less expensive diuretic despite the fact that no clinical trial had ever shown superiority of any agent over a diuretic. Accordingly, between 1982–1992 the number of patients treated with diuretics fell from 56% to 27%, at an added cost of $3 billion while ACE inhibitor and dihydropyridine CCB agents continued to remain the most widely prescribed antihypertensive drugs. The previously reported doxazosin arm of ALL-HAT was stopped prematurely because there was a two-fold greater risk of clinical heart failure in the doxazosin group compared with chlorthalidone. These results suggested that an α blocker should not be used as first-line therapy for hypertension. The results of ALLHAT came somewhat as a surprise to some members of the medical community: TTD therapy was unsurpassed for reducing clinical events, for lowering blood pressure, for preventing clinical heart failure, and for tolerability. Low-dose diuretic therapy as initial therapy was equivalent to both the ACE inhibitor and CCB for the primary end point of nonfatal heart attack and CHD death, and there was no end point for which the newer agents were more beneficial. As diuretics remain significantly less costly, they should be thought of as initial therapy in all high-risk patients with hypertension. One of the major strengths of the study lies in its inclusion of large numbers of women (47%) and blacks (35%), as well as a high proportion of diabetics (36%), smokers (22%), and patients with existing cardiovascular disease (47%). These are the very groups that have been underrepresented in previous hypertension studies. None of these subgroups achieved less benefit from diuretic therapy. The diuretic was unsurpassed even in those with diabetes. While the Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of Hypertension (JNC VI) in 1997 strongly suggested the use of an ACE inhibitor in the diabetic with proteinuria, and either an ACE inhibitor, diuretic, calcium antagonist, or an α blocker in the diabetic without evidence of clinical nephropathy, the results of ALLHAT should allow the next JNC report to recommend a TTD as the preferred initial agent in those with type 2 diabetes unless there is a clear indication (renal insufficiency, albuminuria) to use another agent (i.e., ACE inhibitor, angiotensin-receptor blocker). Although some data have suggested that a dihydropyridine CCB was associated with an increased risk of cancer and gastrointestinal bleeding, there was no excess in gastrointestinal bleeding or cancer death with amlodipine compared with the other drugs. However, chlorthalidone was associated with a 38% reduction in the risk of clinical heart failure compared with amlodipine. Significant differences were observed in the one third of participants who were black when comparing lisinopril vs. chlorthalidone. Overall, patients on the ACE inhibitor had a 15% higher risk of stroke than those on the diuretic. Among blacks, however, the risk of stroke was 40% higher in the lisinopril group, with the TTD having a more favorable effect on both combined CVD and stroke. In addition, lisinopril was less effective in lowering SBP in blacks. This is consistent with other reports showing less blood pressure reduction in black participants on an ACE inhibitor. The prevalence of hypokalemia (serum potassium+ <3.5 mEq/L) and new-onset diabetes (fasting glucose >126 mg/dL) occurred more often in the chlorthalidone group. These metabolic effects did not translate into more cardiovascular events or into higher all-cause mortality compared with the other two groups. Potassium levels need to be monitored and, when necessary, supplements given as occurred throughout the trial. One of the strongest messages of ALLHAT may not be as much about the TTD as initial therapy but that blood pressure control rates can be improved and more than one drug will usually be required to do so. The number of patients with hypertension in the United States who have their blood pressure controlled to <140/90 mm Hg currently remains at 27% despite the availability of effective antihypertensive therapy. By following a fixed protocol, with most participants requiring two antihypertensive agents, two of every three ALLHAT participants were controlled to <140/90 mm Hg (final blood pressure, 135/75 mm Hg) whereas only 30% of those in ALLHAT on single-agent therapy achieved the same blood pressure reduction. This is an important clinical message! Blood pressure can be controlled in the office setting but will usually require more than one agent. ALLHAT was performed in a variety of practice settings, including urban and rural, private and academic, large and small, reflecting the “real world” situation of clinical practice faced by practitioners every day. The “volunteer effect” may have contributed to the excellent control rates achieved. Hypertension is a labor-intensive disease. One cannot just tell the patient what to do and expect blood pressure to become controlled. Incorporating strategies used during ALLHAT will improve blood pressure control. ACE inhibitor and CCB agents remain the most widely prescribed antihypertensive drugs, with up to 70% of patients prescribed one or the other as monotherapy. As TTDs were unsurpassed in reducing clinical events, lowering blood pressure, and were as well tolerated as CCB and ACE inhibitor therapy, they are recommended as initial therapy in hypertension. It is time to implement the ALLHAT results. For the patient who cannot tolerate a diuretic (gout, hypokalemia, sulfur sensitivity), therapy can be started with an ACE inhibitor, CCB (either dihydropyridine or nondihydropyridine type), β blocker, or angiotensin receptor blocker, as these medications have been shown to have CVD benefits compared with each other or to placebo. One drug will not control blood pressure effectively and multiple-agent therapy will almost always be necessary. As the current director of the National Heart, Lung, and Blood Institute of the National Institutes of Health, Dr. Claude Lenfant, recently stated, in the November/December 2002 issue of The Journal of Clinical Hypertension, “When the control rates among the general population approach those achieved in ALLHAT, it will be time to celebrate.” Let's not pop the champagne cork quite yet, but hope there will be future times for celebration. The National High Blood Pressure Education Program (NHBPEP) Working Group Report on The Primary Prevention of Hypertension provides a continuing opportunity to prevent and reduce the economic consequences of managing hypertension. This was first released in 1993 and incorporated into the 1997 Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). This latest document used a MEDLINE search of the scientific literature through 2001 to update the previous recommendations. The new guidelines continue to emphasize two complementary strategies to prevent hypertension; a population-based strategy as well as an individually targeted approach for those at high risk of developing hypertension. These high-risk groups include people with high-normal blood pressure (systolic blood pressure 130–139 mm Hg and/or diastolic blood pressure 85–89 mm Hg, who are older, with a family history of hypertension, of African American ancestry, overweight or obese, living a sedentary lifestyle, or those consuming a diet high in salt, low in potassium, or high in alcohol consumption. Four recommendations continue to be emphasized: engaging in as for at least on most alcohol to no more that 1 of for men (i.e., 24 of of or 2 of and one that for women or and reducing to no more than 1 of The new guidelines emphasize both potassium and of a diet in and as well as high in as used in the to Hypertension trial. While the evidence is in the the same to prevent hypertension should be to and in and Additional with less include calcium and The use of and supplements in the of hypertension cannot be from clinical trial High blood pressure remains one of the most important and risk factors for cardiovascular disease. The and industry need to to and improved for the the that the potential benefits from a to prevent hypertension remains an important national National High Blood Pressure Education Primary of clinical and from the National High Blood Pressure Education JAMA. The of hypertension remains an important About million currently have a blood pressure mm additional or million have high-normal blood pressure mm Two million new people hypertension each The for preventing hypertension are The recommendations from the of the on the of hypertension could not have at a more three of which is for through the of to remains at an in the prevalence of continue to to the of hypertension as than ever have a in their lifetime risk of developing hypertension. may to prevent hypertension without the need for drug therapy. The and and including and and reducing the of and reduced blood pressure more effectively than either a control diet or one only in and Although the for the benefit on blood pressure reduction are an effect among may quite the favorable effect on blood pressure reduction. the diet not been widely in clinical including and have recently been to in blood pressure reduction as well as favorable and and have been associated with a reduction in echocardiographically measured left ventricular They have also been associated with a reduction of peripheral the of hypertension. The of and been shown to to an in as measured by lower fasting and glucose and While the the clinical of in the treatment of hypertension, there is more evidence for preventing hypertension through than ever It is time to to and people to a and national require the industry to more for and to become a of family The use of group and may to the over their significant in will not as one of the for in the United States. It is three times more in women than and for and The and are estimated to be between and billion agents for treatment of have either or are tolerated for have examined the of antihypertensive agents to reduce the of Although a study the angiotensin-converting enzyme (ACE) inhibitor lisinopril to be an effective treatment for the patient with it is associated with both and angioedema that may its No previous study examined the effect of an angiotensin receptor blocker as a a randomized, double-blind, study patients aged years who were in an for with or without month for at least one year before a period to the of each patient was treated in two treatment by a patients were given mg while the other received and after the washout period were over to the other The primary end point was the number of with secondary end included with with with level of of of of of and on the Study an after 12 of therapy the mean number of with was reduced from with to with secondary end were reduced as well there was no difference between the groups on the of Overall, 40% more on had at least a reduction in the number of with events were between the and groups. The to effective with a to placebo. are to these treatment of with an angiotensin receptor JAMA. may occur in people with and without hypertension. nondihydropyridine calcium channel and regardless of the of hypertension, are often used as first-line The Sixth Report of the Joint National Committee for the Prevention, Detection, Evaluation, and Treatment of Hypertension recommended either a β blocker or a nondihydropyridine calcium channel blocker for treatment of the hypertensive patient with although the of effects may their have examined the of antihypertensive agents to reduce the of The same group of in the study previously a reduction in the of in women treated with the ACE inhibitor lisinopril, for a that in up to of patients, ACE are well tolerated and even in the In the the baseline blood pressure of the participants is not as in the study with lisinopril, the reduced the mean number of with a and reduced the need for The of is but both the ACE inhibitor and reduce the effects of angiotensin and as a representative to be effective in the therapy of It reduces blood pressure in who are and is as well tolerated as a placebo. Although are necessary, it should be added to the of agents used in the treatment of with a history of

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