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The Pharmaceutical Journal
Vol 270 No 7230 p4
4 January 2003

Related websites
JAMA (jama.ama-assn.org)

Thiazide diuretics preferred in ALLHAT as first step in treating hypertension ...

Thiazide-type diuretics should be the preferred choice for first-line treatment in patients with hypertension, researchers recommend, following the publication of a major trial comparing different classes of antihypertensive therapy. The researchers say that thiazides are unsurpassed in lowering blood pressure and reducing clinical events and are better tolerated and less expensive than other classes.

This recommendation echoes the British National Formulary, which states that a thiazide is first-line treatment for hypertension unless there is a contraindication or a specific indication for another drug (September 2002).

Jon Silcock, research practitioner at the University of Leeds, told The Journal that the study confirmed the role of thiazide diuretics as first-line treatments for hypertension. "However, the diuretic chosen for this trial (chlortalidone) is not widely used in clinical practice in the United Kingdom, the steps used to achieve goal blood pressure involve some additional agents that are obsolete, patients with known heart failure were excluded and there was no beta-blocker arm.

"Integration of these findings into clinical practice and guidelines will require careful consideration of class effects and therapy combinations." He added that the good news for drug budget holders was that the cheapest agent had been shown to be the most effective one.

In the Antihypertensive and Lipid-lowering Treatment to prevent Heart Attack Trial (ALLHAT), researchers compared chlortalidone (Hygroton) with lisinopril (Zestril) and amlodipine (Istin). Neither lisinopril nor amlodipine was found to be superior to chlortalidone in preventing coronary deaths or increasing survival (JAMA 2002;288:2981). Another study arm using the alpha-blocker doxazosin (Cardura) was stopped in 2000 after doxazosin was found to be less effective than chlortalidone (PJ, 25 March 2000, p460).

In an accompanying editorial (ibid, p3039) Dr Lawrence Appel, Johns Hopkins University, Baltimore, comments: "The results of ALLHAT are robust, unambiguous and generalisable, especially to the broad population of patients with stage 1 or 2 hypertension." He says that the results provide definitive data on selecting the best initial therapy and compelling evidence that thiazide diuretics should be the initial drug of choice for patients with hypertension, especially compared with the two drugs used in the study. The results will have greatest impact on those with newly diagnosed hypertension.

Results from the ALLHAT study

In the Antihypertensive and Lipid-lowering Treatment to prevent Heart Attack Trial (ALLHAT), researchers determined whether treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowered the incidence of coronary heart disease (CHD) events compared with treatment with a diuretic. They randomly assigned 33,357 subjects aged 55 years or older with hypertension and at least one other CHD risk factor to receive chlortalidone 12.5mg to 25mg (n=15,255), amlodipine 2.5mg to 10mg (n=9,048) or lisinopril 10mg to 40mg (n=9,054) daily for planned follow-up of four to eight years.

The researchers found that neither of the comparator drugs was superior to the diuretics in preventing major coronary events or in increasing survival. Chlortalidone was better than amlodipine (by about 25 per cent) in preventing heart failure, although it did not differ from amlodipine in overall cardiovascular disease prevention. Chlortalidone was superior to lisinopril in lowering blood pressure and in preventing cardiovascular events — stroke, heart failure, angina and coronary revascularisation. However, no significant differences in CHD and stroke rates were found between chlortalidone and amlodipine.

The researchers say that chlortalidone was better tolerated than the other agents in the trial. However, angioedema occurred four times more often in those assigned chlortalidone. Cholesterol levels, the prevalence of hypokalaemia and new diabetes were all higher in the chlortalidone group than the other groups at two and four years of follow up. They say: "Overall, these metabolic differences did not translate into more cardiovasular events or into higher all-cause mortality in the chlortalidone group compared with the other two groups."

The researchers comment that the although the results apply directly to chlortalidone, amlodipine and lisinopril, they may also broadly apply to the drug classes used in the study. They conclude: "Although diuretics already play a key role in most antihypertensive treatment recommendations, the findings of ALLHAT should be carefully evaluated ... and be widely applied in patient care."

... while moderate lipid lowering adds little benefit

Moderate reductions in lipid levels using pravastatin (Lipostat), carried out as part of the ALLHAT trial comparing different antihypertensives, failed to show reductions in mortality compared with usual care.

In the lipid-lowering trial arm of the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT), 10,335 patients, drawn from the 42,418 participants initially entered in the main ALLHAT trial (see above), were randomised to receive either 40mg pravastatin daily or usual care on an open-label basis. In order to be randomised for this arm they had to have at least one additional cardiovascular risk factor and a low-density lipoprotein cholesterol (LDL-C) level of between 3.1 and 4.9mmol/L (2.6 to 3.3mmol/L for patients with known heart disease). The trial started in 1994 and after an average of 4.8 years of follow-up, there was no significant difference in all-cause mortality between the two groups (relative risk 0.99, 95 per cent confidence interval 0.89–1.11) with six-year mortality rates of 14.9 per cent for pravastatin versus 15.3 per cent with usual care. Coronary heart disease event rates were slightly lower in the pravastatin group but not significantly so (relative risk 0.91, 0.75–1.09).

Reductions in LDL-C of 28 per cent in the pravastatin group and 11 per cent in the usual care group were seen in a random sample of patients after four years' treatment. The ALLHAT trial co-ordinators say that these "modest reductions", and the subsequent results of the trial, show the need for adequate reductions of LDL-C levels in clinical practice (JAMA 2002;288:2998).

In an accompanying editorial (ibid, p3042), Dr Richard Pasternak, division of cardiology, Massachusetts General Hospital, Boston, says that, to some extent, the ALLHAT-LLT trial was overtaken by events. Shortly after it started the Scandinavian Simvastatin Survival Study (4S) showed benefits of statins in high-risk CHD patients. By the end of the ALLHAT-LLT over a quarter of the usual care group were taking statins and only 70 per cent of the pravastatin group were still taking 40mg daily, reducing the difference between them. Rather than showing that statins do not work, Dr Pasternak suggests that statins may be less effective in the primary care setting in which they were used in ALLHAT-LLT. One of the main lessons of the trial is the need to increase patients' compliance with treatment in routine practice, he concludes. "This is not a small challenge."