That actually goes back a fair way. We had been thinking of the role of ACE inhibitors for quite some time. They were developed initially for resistant hypertension in the early 1980s, and they were used at frightfully high doses and created a great deal of side effects. Later on, we found out that you didn't need such high doses. The first breakthrough came with a trial from Sweden showing reduced mortality in class IV heart failure—those are in extremely symptomatic people—which was published around 1985 or 1986. Then we were designing a study of another ACE inhibitor on people with heart failure and we showed it reduced mortality. What was unexpected was that the treatment also reduced myocardial infarction, and there was no theory or experimental data to explain why such a thing might happen at that time. When we reported it in the Lancet in the early 1990s, many people, including most regulatory bodies, were skeptical about it. I felt it was likely to be real, however. Not only had our trial shown it, but also a couple of other studies had hinted at it. So that led to the establishment of this HOPE Study—Heart Outcomes Prevention Evaluation Study—with the specific aim of testing whether treatment with ramipril in people who aren't hypertensive would get a reduction in myocardial infarction, strokes, and death. That was a new concept. What it was suggesting was that the renin-angiotensin system, the system blocked by ACE inhibitors, has an important role in protecting the vascular wall. So we were deriving a new concept from one set of clinical studies, and then testing it in the HOPE Study.

  So what exactly was HOPE?

It had 9,200 people. It tested vitamin E as well as an ACE inhibitor, ramipril. It involved 19 countries, 267 hospitals, and followed those 9,200 people for an average of 4.5 years. And we found a clear benefit of ramipril in reducing myocardial infarction, strokes, and death. We had an accompanying paper, published side-by-side, showing that vitamin E had no benefit. It was just as important a finding, but it doesn’t get cited as much because it wasn't a positive trial.

  While the paper has been cited heavily, did the HOPE results have an impact on clinical treatment, as well?

This had a huge effect, at least locally. In Canada, we have information showing that the use of ramipril has increased six-fold in the two years or so since we've published. First, ramipril is an easy drug to use. Second, it's not particularly expensive. Third, our trials showed not only a very clear effect in reducing myocardial infarction, strokes, and death, but we also saw a reduction in heart failure, in diabetes, in the need for revascularization procedures, and in further kidney damage. The effects were on multiple organs and they were clearly demonstrated. Thus the agent can be and is used pretty widely.

  Do you know what the mechanism of action is on myocardial infarctions and strokes?

There seem to be many mechanisms involved. One, it is obviously blocking the renin-angiotensin system. When you do that, you lower the level of a hormone called angiotensin II. If that level is high, it constricts blood vessels, makes them thicker, and this might also tend to make arteriosclerotic plaques rupture. But you can reduce it by using ACE inhibitors. Obviously it lowers blood vessels, and that's helpful as well. It allows the heart to pump less hard. And there's a direct effect in preventing arteriosclerosis, which is one of the new things that we discovered in the trial. I don’t think that point is fully understood yet. This is a case where the clinical research is ahead of the basic science.

  Are you continuing with research into ACE inhibitors?

Yes. One of the unexpected findings of the HOPE trial was that ramipril prevented diabetes in non-diabetic patients. That was not totally expected, but when you search the literature you find enough hints to make you believe that the effect might be real. Now we're running a study, called DREAM, where we're looking at whether ramipril will indeed prevent diabetes in people who are pre-diabetic. We should have some results in three or four years. Secondly, we think we can block the renin-angiotensin system at several levels. We are using a complementary approach to the ACE inhibitors and blocking the receptor for angiotensin II with an angiotensin receptor blocker. Now we're doing a fairly large study comparing ACE inhibitors verses an angiotensin II blocker verses a combination. Our expectation is that the combination may be better than either one alone. That study is recruiting patients and will also take a few years to finish.

  Are you satisfied with the pace of research in your field?

That’s a very tough question. I think in Western countries, we are probably making progress as fast as humanly possible, given the fact that you can't just rush into research—you need time for reflection, thought, and analysis. Having said that, in developing countries, where the majority of the disease burden is, the amount of research done into the problems there is woefully inadequate. You could estimate that 90% of the disease burden is in developing countries and less than 1% of the research is done in these countries. So if the question is how can we make the biggest impact on health in the future? I think the answer is more investment—not only in money but also in capacity building—in these developing countries. And by capacity developing, I mean, you can't just go and do research in these countries; you also have to train people, set up teams and facilities, and build the necessary infrastructure. There is lot to be done.

  What were the greatest challenges in performing and presenting your research?

With every major study, because they involve a lot of resources, a lot of people, a lot of centers, one challenge is simply raising the necessary funds for the study. For instance, HOPE was funded by 14 sources—some from government, some from industry, some from charitable organizations. And then, obviously, you need to deal with bureaucratic and regulatory issues in 19 countries, 267 hospitals, etc. Those were the obstacles. We had no problem getting the paper published, simply because the results were very impressive.

  What message do you think the public should take away from your research?