Drug combinations and all cause mortality in heart disease

Editor—The study reported by Hippisley-Cox and Coupland leads to much generalisation.¹ Firstly, I am concerned that the data on angiotensin converting enzyme (ACE) inhibitors, contradict convention. Secondly, without actual data in front of me, I have to guess at the meaning of the ACE inhibitor data.

As the EUROPA, PROGRESS, ANBP, PEACE, TRACE, SAVE, and HOPE studies have shown, there is a great disparity in efficacy of ACE inhibitors. As Doulton et al say in their review of ACE inhibitor and angiotensin receptor blocker trials, the ACE inhibitor trials were described as mostly using submaximal doses or a once daily dose of shorter acting ACE inhibitors.² It has long been known that the more efficacious trials of ACE inhibitors used a large dose, as the perindopril investigators found out in PROGRESS and EUROPA. The trandalopril investigators also saw this disparity in PEACE and TRACE. What were the ACE inhibitor doses in the trial reported by Hippisley-Cox and Coupland?

Another consideration is the order in which these drugs were given. If a β blocker is given first the drop in blood pressure will, for the most part, urge clinicians to give a lower dose of ACE inhibitor subsequently. These are submaximal doses.²

I cannot reach the conclusions that Hippisley-Cox and Coupland came to, without a better understanding of the raw data.

Then, there is the concept of equality in ACE inhibitors. Although a larger dose is good, does it still have the same effect as another ACE inhibitor might have? The MITRA-plus trial serves as an example here. This indicates the possibility of another disparity.