Disclosures

Linda Brookes, MSc
The results of ALLHAT (the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial)[1] have, as expected, received much attention. Their implications for antihypertensive treatment, not least in the context of the recently released Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines,[2] have been widely discussed. Following the major press coverage of the trial, it should now be well known that the ALLHAT investigators concluded that thiazide-type diuretics are unsurpassed in tolerability and in their effects on lowering blood pressure and reducing cardiovascular complications. The investigators also concluded that their benefits as first-line therapy apply to nearly all patients with hypertension. On the basis of the study, the ALLHAT investigators made the following recommendations:

1. Thiazide-type diuretics should be the drug of choice for initial therapy of hypertension.
2. For the patients who cannot take a thiazide-type diuretic (which should be an unusual circumstance), calcium channel blockers (CCBs) and ACE inhibitors may be considered.
3. In black hypertensive patients, whose major risk is for a cardiovascular disease event, thiazide-type diuretics (or CCBs in those who cannot take a diuretic) are recommended over ACE inhibitors.
4. Some hypertensive patients require more than 1 drug. Diuretics should generally be part of the antihypertensive regimen.
5. Lifestyle advice should be provided.

At the 2003 American Society of Hypertension meeting in New York, NY, Curt D Furberg, MD, who was chair of the ALLHAT steering committee, reviewed how the ALLHAT recommendations are already translating into clinical practice in the United States.

Benefit in All Subgroups

ALLHAT prespecified a number of subgroups: gender, age (< 65 or >/= 65 years), ethnicity, diabetes, and comorbidity. No evidence of any inconsistency of the benefits of diuretics was found among them, Dr. Furberg reported. Importantly, in the black cohort, lisinopril was less effective in lowering blood pressure than chlorthalidone (by 4 mm Hg) and was associated with an increased risk of combined cardiovascular disease and stroke. Some of this could be explained by the difference in blood pressure lowering, but it is difficult to determine how much of it was dependent on the difference in blood pressure lowering and how much was dependent on other drug actions, Dr. Furberg noted. It was reassuring that in the nonblack cohort, lisinopril was similar to chlorthalidone, with a only slight excess in heart failure, he added.

Diuretic Class Effect?

In ALLHAT, the thiazide-type diuretic used was chlorthalidone, a drug rarely prescribed in the United States nowadays. A question of particular interest, therefore, was whether the ALLHAT observations with chlorthalidone could be extrapolated to other thiazide-type diuretics. Dr. Furberg believes that they can, on the basis of evidence from the literature. He pointed to a large number of placebo-controlled trials with different diuretics that showed very similar significant reductions in mortality or morbidity with different diuretics (Table 1).
Table 1. Benefits of Thiazide-Type Diuretics in Clinical Trials

Australian = the Australian Therapeutic Trial in Mild Hypertension; EPWHE = European Working Party on High blood pressure in the Elderly; HDFP = Hypertension Detection and Follow-up Program; MRC = Medical Research Council hypertension trial; MRC-O = MRC trial of treatment of hypertension in older adults; Oslo = the Oslo study; PATS = Post-stroke Antihypertensive Treatment Study; PROGRESS = Perindopril Protection against Recurrent Stroke Study; SHEP = Systolic Hypertension in the Elderly Program; STOP = Swedish Trial in Old Patients with Hypertension; VA = Veterans Administration Co-operative Study on Antihypertensive Treatment
According to Dr. Furberg, these independent trial findings support the view that all of the thiazide-type diuretics tested are beneficial.

The ALLHAT results indicated that all thiazide-type diuretics should be considered for almost all patients with hypertension, including untreated patients, inadequately controlled patients on nondiuretic agent(s), and controlled patients on nondiuretic agents, unless a compelling indication exists for using another agent. Whether a patient who is controlled on a nondiuretic should be switched to a diuretic should be a matter of clinical judgment, Dr. Furberg added.

Second-line Therapy

As demonstrated in ALLHAT and other studies, a large proportion of antihypertensive patients require additional drugs for blood pressure control. ALLHAT did not directly compare second-line drugs, however, so the optimal type of add-on agent cannot be deduced from this trial. Dr. Furberg called for large trials to compare different classes of agents added to diuretics, to define the optimal step-up drugs. Thiazide-type diuretics, in low to moderate dose, should be the treatment control group of all future comparative trials in patients with hypertension, he believes.

Dr. Furberg would like to see a second trial, ALLHAT II, which he proposes would be a double-blind, randomized clinical trial focusing on a similar population to that of ALLHAT, but not controlled on a moderate dose of diuretic. Patients would be randomized to a representative of 4 drug classes: ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and CCBs. The outcomes would be all major cardiovascular outcomes, including heart failure, and it is Dr. Furberg's dream that this study should be independent of industry sponsorship.

Fixed Combinations

Dr. Furberg favors the traditional step-up approach as used in ALLHAT and other studies, starting with a diuretic and adding other drugs, rather then using fixed dose combinations.
Although fixed combinations have been widely discussed, they are not cheap (Table 2), Dr. Furberg cautioned, whereas generics can save patients money.

Table 2. Annual Cost of Fixed Dose Combination Agents[3]

Cost
Drug costs in the last year of ALLHAT were high, Dr. Furberg reported (Table 3), and physicians must be sensitive to the fact that drug costs are an important consideration for patients, he noted.

Table 3. ALLHAT: Drug Costs to Patients (United States, 2002)[3]

*Excludes licensing fee.
?Available as of third quarter of 2002.
The costs to society can vary widely (Table 4). Diuretics are the least expensive drugs for treating hypertension, and expensive drugs in most cases offer no added value, Dr. Furberg declared. Translating the ALLHAT findings into practice will reduce the financial cost of antihypertensive drugs, he believes.

Table 4. Drug Costs to Society

*Price of largest-selling drug/class (2002).
In millions.

Drug Sales

A question that has been asked by many is whether the ALLHAT results have influenced sales of antihypertensive drugs. Dr. Furberg reported that since the publication of the ALLHAT report, sales of thiazide-type diuretics have increased, there has been no change in sales of loop diuretics, and sales of chlorthalidone, which is hardly ever used in the United States, have also remain unchanged. Prescriptions of hydrochlorothiazide (HCTZ) have increased from about 800,000 per month to over 1 million per month, an approximate 20% increase, over this short period of time. Sales of lisinopril, branded and generic combined, have increased steadily, but may now have reached a plateau. Amlodipine sales remained unchanged. Dr. Furberg announced that data for April 2003 show that HCTZ has now overtaken amlodipine in terms of number of prescriptions.

Spreading the Word About ALLHAT

The ALLHAT investigators believe that it is important to disseminate information about ALLHAT and its findings. A total of 34 papers will follow the publication of the original report in JAMA. Media coverage and presentations at major national meetings are planned, and an ALLHAT Web site (http://www.allhat.org) has been set up. Workshops with ALLHAT investigators will be given at 623 sites, and interaction with formulary committees and academic detailing will be used to spread the word about ALLHAT, Dr. Furberg announced.