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The ASCOT trial enrolled over 19,000 patients with hypertension and at least three other risk factors. Risk factors included male gender and age, as well as other traditional risk factors.

Patients had been randomised to the calcium channel blocker amlodipine or to atenolol. If hypertension was not controlled with the initial drug, the amlodipine group could be treated with the ace-inhibitor peridopril and the beta-blocker group could also be treated with a thiazide diuretic.

The vast majority were on combination therapy, hence the investigators claim that the trial can be regarded as a comparison of amlodipine with peridopril vs atenolol with a thiazide diuretic.

The trial was stopped early because of a sixteen percent reduction in all cause mortality.

There was a non-significant ten percent reduction in the primary endpoint of non-fatal MI and fatal coronary heart disease. It is speculated that had the trial continued this difference would have reached statistical significance.

There was a significant twenty-three percent reduction in stroke and twenty-four percent reduction in cardiovascular mortality. We will await the publication of the full results, taking particular note of any differences in blood pressure between the two groups, differences that could potentially account for the better outcome in the amlodipine/peridopril group.

The ALLHAT trial had compared a number of different strategies. The results were interpreted as showing all classes of drug (including ace-inhibitors) were equivalent and that thiazides were recommended as initial drug therapy for all patients. The trial design, result and interpretation provoked considerable debate and disagreement.

The LIFE study enrolled hypertensives with left ventricular hypertrophy on ECG- the group assigned to therapy based on the angiotension blocker losartan had fewer strokes than the group assigned therapy based on the beta-blocker atenolol. There was no difference between the groups in occurence of cardiovascular mortality or myocardial infarction. An Echo substudy of the LIFE trial showed greater regression of LVH in the losaratan group than in the atenolol group. The investigators report that the benefits of losartan based therapy could not be explained by any differences in blood pressure between the groups but that a third of the benefit might be due to the greater reduction in left ventricular hypertrophy.

The Australian ANBP2 trial found that ace-inhibitor therapy was superior to thiazide diuretics, but other trials using ACE-inhibitors had not found such benefits.

The HOPE and EUROPA trials had found additional benefits from routine use of ace-inhibitor therapy in patients with atherosclerotic disease.

An increased incidence of diabetes was seen in the diuretic arm of the ALLHAT. An increased incidence of diabetes was also seen in the atenolol/thiazide diuretic group of the ASCOT trial. More new onset diabetes was also seen in the LIFE trial with atenolol based therapy compared with losartan based therapy.

A review of recent hypertension trials published in the Journal of the American College of Cardiology (2005;45:813-27) referred to meta-analysis of hypertension trials. These meta-analysis were done prior to the reporting of the findings of the ASCOT hypertension trial. The meta-analysis were dominated by the findings of the large ALLHAT trial. This meta-analysis found a non-significant trend towards less fatal and fatal myocardial infarction with ACE-inhibitor based therapy compared to beta-blocker/thiazide diuretic therapy. Conversely, the meta-analysis also found a non-significant trend of less stroke with a beta-blocker/thiazide based therapy compared with an ACE-inhibitor based therapy.

Undoubtedly, debate will continue, and some of the findings may be incorporated into guidelines. Until this occurs, the following conclusions may be worth considering:

In low risk patients treatment with thiazides and beta-blockers as first line agents seems to be appropriate.
In higher risk patients (multiple risk factors, LVH on ECG or echo, known atherosclerotic disease), we should consider very early use of ace-inhibitors or angiotensin blockers and calcium channel blockers such as amlodipine (as in the ASCOT trial), as part of multi-agent therapy.
Some high risk patients, such as those with previous infarction or heart failure, clearly obtain benefit from betablocker therapy. However, in the absence of strong indicators for use of beta-blockers, we may continue to wonder if beta-blockers are potentially less effective than other agents.
We would like to see data on use of beta-blockers combined with agents such as ace-inhibitors compared with ace-inhibitors and other non-beta-blocker drug combinations before we would even think of abandoning beta-blocker therapy for hypertension. When high risk patients are treated with beta-blockers, we may wish to ensure concomitant usage of an ace-inhibitor (this probably occurs often anyway since multi-agent therapy is commonly required to control hypertension well).
In those at risk of developing diabetes, one might avoid the use of thiazide diuretics, or alternatively be prepared to stop the drug if there is any evidence for impaired glucose tolerance.

These conclusions may not be currently supported by any updates of major hypertension guidelines. One would expect prolonged deliberation before any major guidelines recommend use of more expensive agents as first line therapy for a common condition such as hypertension. Nevertheless, practitioners always have to consider how to implement new knowledge before major guidelines are updated, and this requirement extends to all fields. With the passage of time additional information usually becomes available to clarrify the situation.

Hitesh Patel, Cardiologist
1st May, 2005

Hypertension

Hypertension Trials- ASCOT

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