The Thrombosis Prevention Trial (TPT)1
and the Hypertension Optimal Treatment (HOT) Study2
seem to show important differences in the risk-benefit ratio for aspirin. In TPT, 2540 patients were randomised to receive aspirin 75 mg in a controlled-release preparation or placebo. All patients were male with average age of 57·7 years (range 45—69). They were selected because they formed the top 20% of a cardiovascular risk-score distribution. None had had a myocardial infarction (MI) before. Systolic blood pressure on entry to the trial was 139 mm Hg. Median follow-up was 6·8 years.
In the HOT Study, 18 790 patients were randomised to receive soluble aspirin 75 mg daily or placebo in addition to treatment with felodipine to establish the relation between achieved blood pressure and cardiovascular events. 53% of the patients were male. The average age was 61·5 years (range 50—80), 1·5% had had an MI previously, blood pressure on entry to the trial was 170/105 mm Hg, and average follow up was 3·8 years.
The baseline risk of myocardial infarction and stroke in the two trial populations differed. Within the two placebo groups, the rate of MI was higher, whereas the rate of stroke was higher in the HOT study. The risk of major gastrointestinal (GI) bleeding on placebo was low in both trials but seemed to be higher in the HOT study: two patients had major bleeds during roughly 8000 placebo years of follow-up in TPT against 37 episodes of major bleeding in about 36 000 placebo years of follow-up in HOT. Aspirin was shown to prevent heart attacks and increase the risk of major GI bleeds in both trials with the following risks and benefits: 45 MIs were saved by aspirin in the HOT study at a cost of 40 major GI bleeds during about 36 000 years of aspirin treatment follow-up. By contrast, there were only four major GI bleeds for 29 MIs saved in the TPT during about 8000 years of aspirin treatment follow-up. Reassuringly, neither study showed an increase in the overall risk of stroke (table
Cardiovascular events and major GI bleeds in the TPT trial and HOT study
Why should there be such a difference in the risk-benefit ratio for serious GI bleeding? A controlled release preparation of aspirin was used in TPT, whereas soluble aspirin was used in HOT. The relative risk of aspirin for bleeding was similar in the two studies, however, in keeping with the conclusions of a review that gastric blood loss is not reduced by enteric-coated or modified-release preparations.3
A second possibility is that the excess haemorrhage in the HOT study resulted from use of the calcium-channel blocker,4
although recent work in this area suggests that this possibility is unlikely.5
The methods of recording side-effects may be relevant: major GI bleeding was defined as fatal or life-threatening haemorrhage requiring transfusion and/or surgery in TPT, but no definition was given in HOT. Pending clarification of this point, our interpretation of the data in these two trials is that the complications of aspirin may partly offset the benefits in hypertensives, who are at greater risk of stroke than MI, but that aspirin may be safer among patients who have other risks for vascular disease such as hyperlipidaemia, in whom the risks of MI are higher. We should be interested to hear the views of the authors of the TPT and the HOT study.