An Expert Interview With Michel White, MD
The 2003 European Society of Cardiology Annual Congress took place in Vienna, Austria, August 28 - September 3, and Medscape has been publishing news reports, session coverage, and faculty summaries, beginning during the meeting and continuing in the days following. To bring another perspective to these reports, we have interviewed two Canadian thought leaders to get a nationally focused interpretation of some of the most interesting new information presented and discussed at this year's ESC Congress.

For one of our interviews, we spoke with Michel White, MD, Director of the Heart Failure Research Programme at the Montreal Heart Institute and Associate Professor of Medicine at the University of Montreal in Montreal, Canada. About 50% of his practice is involved with research.

Medscape: Dr. White, what do you believe were the main highlights of this year's ESC meeting?

Dr. White: One of my main research interests is the pharmacology of angiotensin II in patients with heart failure. The highlight of the ESC Hotline session was the presentation of the results of the Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Research into angiotensin II in heart failure has been ongoing for the past 15 years, but interest in angiotensin receptor blockers (ARBs) really started when the results of the Evaluation of Losartan in The Elderly study (ELITE) were reported, suggesting that an ARB might be more effective in heart failure than an angiotensin-converting enzyme (ACE) inhibitor. The ELITE results were interesting, but actually too good to be true. Although the design of ELITE II, reported in 2000, was based on these results, this study failed to confirm the findings of ELITE. So there were some concerns about the use of ARBs compared with ACE inhibitors in patients with symptomatic congestive heart failure.

Medscape: Up until this congress, there were a lot of questions about ARBs. What was your feeling about ARBs in heart failure? Did it reflect the feeling in Canada in general?

Dr. White: ELITE II put a big cloud over the question of ARBs in heart failure, because it compared losartan vs captopril and found that neither was better or worse, so it was a little confusing. After ELITE II, however, we felt that it was appropriate to use ARBs in patients who had side effects such as cough with ACE inhibitors. The Valsartan HEart Failure Trial (Val-HeFT) showed us that if a patient has problems with ACE inhibitors, high-dose ARBs can be as effective. Although they were not directly compared in Val-HeFT, in the 366 patients who were intolerant to ACE inhibitors, the benefits of the ARB were sound. It was quite important and very encouraging.

So ELITE II and Val-HeFT told us that it was probably more than acceptable to give an ARB if a patient cannot tolerate ACE inhibitors. Val-HeFT also told us that if you add an ARB to an ACE inhibitor, patients may be less likely to be admitted to hospital, although mortality is not different. In addition, if you give a beta-blocker and an ACE inhibitor, there is no point in using high-dose valsartan, because these patients are already fully suppressed. So the CHARM program continued, but people had lost faith to a large extent in combination therapy with ARBs and this success was the biggest surprise of the CHARM trial and also a pleasant one.

Medscape: Did you regard all ARBs as equivalent before CHARM?

Dr. White: Before CHARM I might have regarded them as equivalent, but we may now conclude that they may not be equivalent. Before CHARM I thought that there might be a class effect, although I am always extremely meticulous when I say that, because a drug is much more complicated than we realize. We assume that once the receptor is blocked, that is the end of the story, but a medication may block a receptor, and in addition all the crosstalk with other receptors might be more important than we think. That is why I do not really like to say there was a class effect.

Medscape: Did Val-HeFT results change your practice?

Dr. White: Val-HeFT did change my practice, first, because if patients had any side effects with ACE inhibitors I was much more comfortable using valsartan than losartan. I was not so comfortable with candesartan, because following the Randomized Evaluation of Strategies for Left Ventricular Dysfunction Pilot Study (RESOLVD), there were misunderstandings and there was a lot of confusion surrounding candesartan.

Second, I was comfortable using valsartan on top of ACE inhibitors if patients were unable to tolerate a beta-blocker and they still presented with advanced symptoms. If I saw a patient with NYHA class II heart failure who was extremely stable, with no recent deterioration, I did not see the point of adding valsartan, because the patient was doing well even if he was unable to tolerate a beta-blocker. In patients hospitalized for heart failure or NYHA class III patients with advanced symptoms who still had a good blood pressure level, or patients with other problems such as microalbuminuria or proteinuria, I was more comfortable adding valsartan.

Medscape: Did the US Food and Drug Administration decision about valsartan have any influence on practice in Canada?

Dr. White: Physicians had already started to use valsartan as an alternative based on the Val-HeFT data, so the FDA point of view reinforced this. The fact that the FDA turned down the indications for add-on therapy, however, had a small impact. It did trigger some doubt.

Medscape: Canada enrolled the second highest number of patients in CHARM. How did that come about?

Dr. White: I think that despite the results of the Val-HeFT trial, many people were interested in that field. They believed that we needed more data and CHARM was a good platform for that, because about 50% of patients enrolled were on a beta-blocker, although it would have been nice to have about 80% to 90% to answer this question definitively.

Medscape: Were there any doubts about some of the components of the CHARM program, such as the CHARM-Added trial, where patients were already on a lot of therapy?

Dr. White: Yes. Before I heard the CHARM results, I thought that the trial might show benefit, but I had doubts about the component studies individually because the number of patients on each arm was not large. I was expecting to see significant benefit with candesartan in CHARM-Alternative and in CHARM-Preserved. I was not surprised that there was not much difference in the patients with preserved systolic function, however, because this group was more heterogeneous and healthier. The results of CHARM-Added, however, were a surprise. The achievement of a significant reduction in cardiovascular death and hospitalization was a big surprise. For me, cardiovascular death is a more interesting death than total death, because total death includes cancer, gastrointestinal bleed, sepsis, and renal failure, for example. This is background noise. So cardiovascular death gives you a better picture about the true cardioprotective effect of this molecule. I was not expecting to see such a big difference with triple therapy, based on that in Val-HeFT.

Medscape: Is it correct that the population in the CHARM-Preserved trial represents about 50% of heart failure patients?

Dr. White: Above the age of 65 years, that is correct.

Medscape: So how should they be treated now?

Dr. White: For me, if a patient has any indication of angiotensin II modulation and the patient has heart failure with preserved systolic function, I will use candesartan. I will seek reasons to give these patients candesartan, and I will select candesartan as opposed to an ACE inhibitor in this group, because we do not have such strong data with ACE inhibitors at the moment.

Medscape: What would you be looking for in these patients to give them candesartan?

Dr. White: Many of these patients have hypertension. Hypertensive heart disease is actually quite an important cause of heart failure. A lot of the patients in CHARM had type 2 diabetes and we know that ARBs are extremely good for treating proteinuria in type 2 diabetes. Even coronary artery disease may be an indication for candesartan, because I believe that ACE inhibitors and ARBs act the same at the level of the cardiomyocytes, the brain, and the kidney vessels. So I will seek reasons to give these patients angiotensin II-modulating agents.

Medscape: What else would you give these patients?

Dr. White: If you have a patient with coronary artery disease and hypertensive heart disease, we have good data with ramipril in the Heart Outcomes Prevention Evaluation study (HOPE) and we just got some good data at this congress from the European trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) in less sick patients. So if patients present with shortness of breath and they have evidence of heart failure with preserved systolic function, you may think about candesartan. If they have coronary artery disease and congestive heart failure with preserved systolic function and no other problem, you may give an ACE inhibitor. If they do present with diabetes, hypertension, and heart failure with preserved LV function, you should use candesartan based on the CHARM data.

Alternatively, if you are ACE intolerant, or have preserved systolic function, it is not going to matter too much if you have NYHA class II, III, or IV disease. You should receive candesartan based on these data. If it is an add-on, then we have to consider what we are going to do; this is the challenge. This is where I think the impact will differ between south and north of the border, because I think physicians in the United States will use more combinations of ACE inhibition and candesartan. Physicians tend to be a bit more conservative in Canada.

So in my mind the perfect patient for candesartan will be one with NYHA class III or IV, any evidence of worsening heart failure, and also with recent hospitalization for heart failure, within 3-6 months. This is my feeling, it is not evidence based, but it is the way physicians may decide to work on a day-to-day basis.

Medscape: Sometimes the point is made that this will be about the eighth drug that heart failure patients will be taking. Are people in Canada less likely to take so many drugs?

Dr. White: Canada is very much like the United States in this respect. However, I think that this dual suppression will make a larger impact in Quebec than the rest of Canada, where we are more like Europeans in practice. We already know that Quebec has the highest use of ARBs in Canada.

Medscape: Is adding the ARB inhibitor sometimes a problem?

Dr. White: Yes, but there is a way to avoid that. For example, if you want to add an ARB inhibitor because a patient has more advanced symptoms but the blood pressure is low, the patient should take the ACE inhibitor in the morning and the ARB at a different time. Then you avoid a lot of the problems with too-aggressive suppression and orthostatic hypotension when patients first stand up in the morning. But CHARM also showed that candesartan is an extremely well-tolerated medication. Blood pressure did not fall very much, and although there was a slight increase in hypotension and renal dysfunction, the patients were on a dose of 25 mg of candesartan, which is a high dose.

Medscape: It has been suggested that the high dose of candesartan might be the main reason for the CHARM results.

Dr. White: The mean dose of valsartan in Val-HeFT was 267 mg. This is a high dose as well. So I think as far as the dose is concerned, I would say that both Val-HeFT and CHARM were probably equivalent.

What is interesting is, maybe the drug is different, maybe there is something else. I am not sure to what degree, but if you look at the data from the Study on Cognition and PRognosis in the Elderly (SCOPE) trial and the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) trial, they show that candesartan is associated with cerebrovascular protection in the high-risk patient. So the effect at the microvasculature appears to be quite important, and maybe because the drug is lipophilic it stays in the system and works better at the level of microvessels. That is a hypothesis. I do not think that would be a major factor, but I do believe that evidence from the trials with candesartan shows that there is some activity at the microvessels level and/or maybe the pulmonary vasculature.

Medscape: One of the problems with the ACE inhibitor trials was that although they showed an effect, it was a problem to convince doctors to dose them up high enough to be effective. Is this a problem with the ARBs?

Dr. White: That is going to be another challenge. You must try what has been shown to be effective dosage, but if the patient is doing well on a lower dose and there are side effects with a higher dose, you should not increase the dose.

Medscape: There were quite a lot of discontinuations in each of the component trials.

Dr. White: They were not discouraging. You have to reassure physicians that candesartan is actually potent at 8 mg/day, not try to convince them always to use a high dose. I think that would be a strategic mistake. I think I would try to increase the use of this compound in triple therapy in the sickest patient. Unlike Val-HeFT, there was a lot of Canadian participation in CHARM, so I assume that the impact on the Canadian perspective will be much bigger than Val-HeFT. HOPE was another trial that had a big impact in Canada.

Medscape: In both CHARM and HOPE, there was an effect of preventing new-onset diabetes.

Dr. White: The prevention of new-onset diabetes is extremely important. In RESOLVD, 43% of our patients with heart failure had either diabetes or impaired glucose tolerance. This problem is huge and it is getting worse because the population is aging and we see more and more diabetes. In 2025 it will be double what it is now.

The CHARM data showed that angiotensin II-modulating agents work at the cellular level to reduce the development of diabetes. This is interesting, because the patients with preserved systolic function were older and probably more at risk to develop diabetes. The reduction in CHARM was as good as that seen in HOPE.

Another very interesting point is that in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, there was a significant 25% decrease in new-onset diabetes with losartan compared with atenolol. Critics of LIFE asserted that it might be that atenolol increased the rate of new-onset diabetes in this study and thus losartan had no effect. CHARM, however, has confirmed that this class of medications really does prevent the development of diabetes. There was some beta-blocker use in CHARM, but these patients had been treated for some time beforehand, so this had nothing to do with the drug they received before, I believe. This is important.

Medscape: How do you see the future effect of the CHARM results?

Dr. White: CHARM is very important, because based on these data, physicians will be more inclined to use candesartan to treat hypertensive patients who are more at risk to develop heart failure.

Medscape: You said you might be inclined to use the ARB as an antihypertensive agent in a high-risk patient who might be going on to heart failure. How do you assess that?

Dr. White: I would categorize them as older patients, patients with diabetes, and patients with hypertension. It is not clear evidence, but overall I think we will use more candesartan to treat hypertension, because we know that it protects the heart in the large proportion of patients with heart failure.

I think that the situation with ARBs will be very interesting over the next few months in the United States and in Canada, with the results of the Valsartan in Acute Myocardial Infarction trial (VALIANT) due in November. After that the only major ARB trial still ongoing will be the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) comparing amlodipine and valsartan. This is a very exciting time with regard to ARBs. We will have to address many interesting questions.