Does It Matter How Hypertension Is Controlled?

Moral of the story: The ACCOMPLISH trial showed new outcomes data that is not consistent with previous data, where there were no differences in benefit received as long as the drop in blood pressure was equivalent. It can't hurt to follow the results of the new data, so I would go with that.

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 [ClinicalTrials.gov] ), are reported in this issue of the Journal.³ The ACCOMPLISH trial was a randomized, double-blind, industry-sponsored study involving subjects with hypertension that examined the effects on cardiovascular outcomes of treatment with the angiotensin-converting–enzyme (ACE) inhibitor benazepril combined with either the calcium-channel blocker amlodipine or the diuretic hydrochlorothiazide. Somewhat surprisingly, as compared with the benazepril–hydrochlorothiazide 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 vascular 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 [ClinicalTrials.gov] ), 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 [ClinicalTrials.gov] ), 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 amlodipine–perindopril group.⁷ In contrast, in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study (NCT00338260 [ClinicalTrials.gov] ), 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 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 thiazide-based 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 thiazide-type 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 blood-pressure levels measured during the daytime in the clinician's 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 clinician's 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 benazepril–amlodipine 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 hypertension? 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 thiazide-type 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, angiotensin-receptor blockers, and, to a lesser extent, beta-blockers) 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 clinician's 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.

Source Information

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

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