More CHARM: Candesartan in HF
More CHARM: Candesartan in HF
Thu, 02 Oct 2003 22:00:00
Las Vegas, NV - Heart failure specialists here again heard previously published results from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trials, showing benefit with candesartan (Atacand, AstraZeneca) in a broad range of heart failure patients, along with some additional analyses. As the voluminous data sink in, the response from doctors has been generally positive, CHARM researchers say, although some physicians still don't necessarily agree with the suggestion from these results that their patients will require both an ACE inhibitor and an angiotensin receptor blocker (ARB).
The results were presented as part of a late-breaking clinical trials session here at the 2003 Heart Failure Society of America Scientific Sessions and were published as four separate papers in the September 6, 2003 issue of The Lancet.,,,
"Candesartan saves lives and reduces hospitalizations for heart failure, particularly when the ejection fraction is less than 40%," said Dr James B Young (Cleveland Clinic Foundation, OH) who presented the results on behalf of the CHARM investigators. "Candesartan is effective and safe on top of optimal standard therapy with ACE inhibitors, beta blockers, and spironolactone," he added, and reduced heart failure hospitalization "irrespective of the presence of diastolic dysfunction, irrespective of the LVEF."
CHARM Alternative: A point of general agreement
Perhaps not surprisingly, results of the Alternative trial were the point of most general agreement among heart failure specialists polled by heartwire. All saw this as providing the evidence on which to base the use of an ARB among patients not able to tolerate an ACE inhibitor.
"I think the most important part of the study was that for ACE-intolerant patients, it seems that ARBs give you much the same benefit," said Dr Harlan M Krumholz (Yale University, New Haven, CT). "Most of us have thought that for a long time, and most of us, when patients were intolerant to ACE inhibitors, switched them over to ARBs, and this gives us an evidence base to say that. Of all the parts of the trial, it was the biggest benefit and the lowest number needed to treat and the biggest difference between placebo and candesartan."
Dr Marvin A Konstam (Boston, MA) called the CHARM trial, "extremely important," providing "a wealth of data" across the various subtrials. "We see very clearly that ARBs work against placebo in patients with low ejection fraction who are not on an ACE inhibitor, and that point is brought home with the CHARM trial more than any other trial that we have previously had," he said.
I have no problem in substituting an ARB for an ACE in an appropriate patient today because I think the efficacy is at least comparable.
Dr Jay Cohn (University of Minnesota, MN), principal investigator of Val-HeFT, said the CHARM results "confirm the impressions we got from the Val-HeFT trial, that an ARB is an effective alternative to an ACE inhibitor in patients who don't tolerate an ACE inhibitor.
"I think we still live by the guidelines that suggest that ACE inhibitors are still the preferred drug, because they've stood the test of time," Cohn added, but "I have no problem in substituting an ARB for an ACE in an appropriate patient today because I think the efficacy is at least comparable."
CHARM Preserved
Results of the CHARM Preserved trial provided evidence on a population not much studied in heart failure, those with preserved LV function (LVEF >40%). "We just have not had any good guidance at all about how to treat those patients, and CHARM unequivocally shows substantial reduction in heart failure hospitalizations when candesartan is used, and there's a lot of evidence taken in totality, that other events in heart failure are also reduced when the ejection fraction is preserved," Young told heartwire. "When we take these findings into the context of results of the two parallel CHARM trials with low EF, we believe that physicians should consider candesartan irrespective of the ejection fraction," he told doctors here.
Konstam agreed that these results represent a positive step. "They're not quite as impressive as [the other arms], but perhaps that's because of the difficulty in recruiting that population into the study," he said. "But I believe that even in that population, it advances the notion that in patients with heart failure, a nondilated ventricle, and a relatively preserved ejection fraction that there is a role for angiotensin receptor blockade."
John McMurray (Western Infirmary, Glasgow, Scotland), a CHARM investigator, told heartwire that in his view "all patients with heart failure can benefit from candesartan, especially those with reduced LV function." For those with preserved function, "there is nothing to lose by trying candesartan, and there is no alternative, so I think doctors are going to use it in this population. I'm going to use it."
There is nothing to lose by trying candesartan, and there is no alternative, so I think doctors are going to use it in this population. I'm going to use it.
The main treatment effect in this group was a reduction in hospitalizations, he noted, and while these patients tend to have a lower mortality, they do have multiple hospitalizations. "By using candesartan, we could save a lot of money."
Krumholz, however, points out that using the end point of readmissions is "kind of a tricky thing," because there is a lot of variation in who gets readmitted for heart failure, sometimes driven by nonmedical reasons, such as the availability of beds. More effective methods of preventing readmissions may also exist. At their institution, for example, disease management programscombining patient education with close supervision of patient treatment and lifestyle factorswere shown to reduce hospitalizations by 40%.
While the evidence is strong for those intolerant of ACE inhibitors, he pointed out that results in the other arms were much more "modest." "I'm sure they'll do cost-effectiveness, because even modest reductions in readmission are going to be economically attractive, because readmissions cost so much, but I'm not as impressed," Krumholz said. "I'm probably going to watch the debate and think about it and read the articles, but I'm not going to think of it as mandatory. I wouldn't consider it a quality indicator right now, that if you're not doing it, it's poor quality care."
I wouldn't consider it a quality indicator right now.
Dr Bertram Pitt (University of Michigan, Ann Arbor) called results in the preserved function group the "least impressive" finding of an otherwise very impressive trial. "I think we still need a lot more information there, and many more trials." A new NIH-sponsored trial will soon begin looking at aldosterone blockade in these patients, he noted.
CHARM Added: There's the rub
Most difficult for physicians to agree on was the idea that they must now consider adding yet another drug to the treatment of patients who are already takingand for some, paying forup to 10 drugs for heart failure and/or other comorbidities.
During the presentation here, the session moderator asked Young about this issue. He replied that clinical-trial evolution has been such that new drugs have been added on top of other drugs. In the SOLVD trial, enalapril was added to digoxin and a diuretic; the CIBIS II trial added a beta blocker to the mix, and now CHARM adds an ARB, he pointed out.
We've shown a stair-step incremental decrease [in each of these trials] and that, as a clinician, to get these outcomes, is what we're going to have to do.
"We've shown a stair-step incremental decrease [in each of these trials] and that, as clinicians, to get these outcomes, is what we're going to have to do. We're going to have to take our patients and add these medications on top of one another."
The CHARM data suggest, though, that this can be done safely and confirms the safety of using an ACE inhibitor, beta blocker, and an ARB together, contrary to a signal of harm seen in the Val-HeFT trial in a subgroup of patients on all three drugs.
However, of this potential risk, Cohn said, "We had long determined that the interaction in Val-HeFT was the play of chance and that the benefit of an ARB on top of an ACE inhibitor was still apparent, although more modest." In CHARM, he said, "there seems to be no interaction that would raise concern about using that triple therapy in the appropriate population, so I think that CHARM has helped to establish the safety of that combination."
Integrating data with beliefs
Asked how he would use this new information in practice, McMurray said that for a new heart failure patient, he intends to continue to use an ACE inhibitor and diuretic as first-line treatment. "I would then add in a beta blocker and if the patient remains symptomatic or is slightly hypertensive, I would then add an ARB,? he said.
Another CHARM investigator, Dr Karl Swedberg (Sahlgrenska University Hospital/Ostra, Göteborg, Sweden) told heartwire that, "In symptomatic patients like the ones we had in the trial, I will start adding this because I know there are important clinical benefits. The key is that it's symptomatic patientsthese patients were sicker than in the other arms, so they have failed on the treatment they are on."
One starts by dissecting and accepts what falls into one's beliefs.
Swedberg said he felt the reception of these data within the community had been positive, but the novel trial design looking at many faces of heart failure means that "physicians start by dissecting it, instead of looking into the overall aspects, which is common. One starts by dissecting and accepts what falls into one's beliefs."
The beta-blocker story was a good illustration of positive results met with some resistance, he added. In this case, "I think the discussion will be, is it really worthwhile approaching all these patients with another tablet? We'll seeit's a long journey to understand and accept a new aspect, but I think we have convincing data when they're taken in."
ARB or aldosterone blockade?
Other experts believe that despite the positive CHARM results, using all three agents is not a given, and they say an ARB might not be their next step after ACE inhibitors and beta blockers in patients who continue to be symptomatic. Instead, several doctors said they might rather choose an aldosterone blocker.
Dr Milton Packer (Columbia University, New York and University of Texas, Southwestern, Dallas) is one of these. He told heartwire that in his view the CHARM data do put ARBs forward as a potential third step in addressing the neurohormonal cascade in heart failure. "The question is what should be the next step? Should it be an angiotensin receptor blocker, or should it be an aldosterone blocker?" Packer said. Because no head-to-head comparison is currently available, he added, doctors will need to look at the combined data on the two classes of agents and decide for themselves.
Which would he choose? "From what I can tell, the data on aldosterone blockers are more convincing with respect to mortality," with a similar safety profile, he said. "I guess my own sense would be to lean toward aldosterone blockers ahead of angiotensin receptor blockers."
I'm not quite sure that we know that adding on an ARB to an ACE inhibitor, beta blocker, and aldosterone blocker is really going to do very much.
Konstam raised the same issue. "If I have a patient on an ACE inhibitor and a beta blocker, and I am motivated to add on, either because of data or because the patient is not doing well, I think the next drug, based on the results of RALES and EPHESUS, in which there is clear-cut suggested benefit in terms of survival, I think one has to consider an aldosterone blocker," he said.
He acknowledged that 16% to 17% of the population in CHARM was also on an aldosterone blocker, and there was no treatment interaction in that subgroup suggesting less benefit from the ARB but said, "I'm not quite sure that we know that adding on an ARB to an ACE inhibitor, beta blocker, and an aldosterone blocker is really going to do very much. That's the main quandary that I'm seeing for clinicians because of an increasing interest in adding on aldosterone blockade."
Perhaps not surprisingly, Pitt, who was principal investigator of both the RALES and EPHESUS trials, which established aldosterone blockade as beneficial in heart failure, was also in this camp. In his view, data in the CHARM Added trial were "not quite as striking as one would have liked," he said, although he noted that in patients with progressive failure, using the ARB would be "reasonable." However, he said, "I think there may be other strategies, and we hope that an aldosterone blocking strategy will be even better in that situation, but what we have to do is prove that."
VALIANT: More information to come
Dr Eric J Velazquez (Duke University Medical Center, Durham, NC) told heartwire that the CHARM data "nicely set up" upcoming results from the Valsartan in Acute Myocardial Infarction Trial (VALIANT), which is assessing the ARB valsartan in comparison and in combination with the ACE inhibitor captopril in post-MI patients with heart failure or LV dysfunction.
"I think the key component to VALIANT is that it's large, with an end point of all-cause mortality," Velazquez, a VALIANT investigator, told heartwire. In that trial, "2800-plus patients died, more than any of the populations that were studied in the three arms of CHARM, so in terms of breadth, it's much larger, it's a different population, and [valsartan] is going head to head against the combination, so it's definitive and kind of puts everything together."
The VALIANT results will be presented at the American Heart Association Scientific Sessions 2003, coming up in November.
Las Vegas, NV - Heart failure specialists here again heard previously published results from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trials, showing benefit with candesartan (Atacand, AstraZeneca) in a broad range of heart failure patients, along with some additional analyses. As the voluminous data sink in, the response from doctors has been generally positive, CHARM researchers say, although some physicians still don't necessarily agree with the suggestion from these results that their patients will require both an ACE inhibitor and an angiotensin receptor blocker (ARB).
The results were presented as part of a late-breaking clinical trials session here at the 2003 Heart Failure Society of America Scientific Sessions and were published as four separate papers in the September 6, 2003 issue of The Lancet.,,,
"Candesartan saves lives and reduces hospitalizations for heart failure, particularly when the ejection fraction is less than 40%," said Dr James B Young (Cleveland Clinic Foundation, OH) who presented the results on behalf of the CHARM investigators. "Candesartan is effective and safe on top of optimal standard therapy with ACE inhibitors, beta blockers, and spironolactone," he added, and reduced heart failure hospitalization "irrespective of the presence of diastolic dysfunction, irrespective of the LVEF."
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CHARM Alternative: A point of general agreement
Perhaps not surprisingly, results of the Alternative trial were the point of most general agreement among heart failure specialists polled by heartwire. All saw this as providing the evidence on which to base the use of an ARB among patients not able to tolerate an ACE inhibitor.
"I think the most important part of the study was that for ACE-intolerant patients, it seems that ARBs give you much the same benefit," said Dr Harlan M Krumholz (Yale University, New Haven, CT). "Most of us have thought that for a long time, and most of us, when patients were intolerant to ACE inhibitors, switched them over to ARBs, and this gives us an evidence base to say that. Of all the parts of the trial, it was the biggest benefit and the lowest number needed to treat and the biggest difference between placebo and candesartan."
Dr Marvin A Konstam (Boston, MA) called the CHARM trial, "extremely important," providing "a wealth of data" across the various subtrials. "We see very clearly that ARBs work against placebo in patients with low ejection fraction who are not on an ACE inhibitor, and that point is brought home with the CHARM trial more than any other trial that we have previously had," he said.
I have no problem in substituting an ARB for an ACE in an appropriate patient today because I think the efficacy is at least comparable.
Dr Jay Cohn (University of Minnesota, MN), principal investigator of Val-HeFT, said the CHARM results "confirm the impressions we got from the Val-HeFT trial, that an ARB is an effective alternative to an ACE inhibitor in patients who don't tolerate an ACE inhibitor.
"I think we still live by the guidelines that suggest that ACE inhibitors are still the preferred drug, because they've stood the test of time," Cohn added, but "I have no problem in substituting an ARB for an ACE in an appropriate patient today because I think the efficacy is at least comparable."
CHARM Preserved
Results of the CHARM Preserved trial provided evidence on a population not much studied in heart failure, those with preserved LV function (LVEF >40%). "We just have not had any good guidance at all about how to treat those patients, and CHARM unequivocally shows substantial reduction in heart failure hospitalizations when candesartan is used, and there's a lot of evidence taken in totality, that other events in heart failure are also reduced when the ejection fraction is preserved," Young told heartwire. "When we take these findings into the context of results of the two parallel CHARM trials with low EF, we believe that physicians should consider candesartan irrespective of the ejection fraction," he told doctors here.
Konstam agreed that these results represent a positive step. "They're not quite as impressive as [the other arms], but perhaps that's because of the difficulty in recruiting that population into the study," he said. "But I believe that even in that population, it advances the notion that in patients with heart failure, a nondilated ventricle, and a relatively preserved ejection fraction that there is a role for angiotensin receptor blockade."
John McMurray (Western Infirmary, Glasgow, Scotland), a CHARM investigator, told heartwire that in his view "all patients with heart failure can benefit from candesartan, especially those with reduced LV function." For those with preserved function, "there is nothing to lose by trying candesartan, and there is no alternative, so I think doctors are going to use it in this population. I'm going to use it."
There is nothing to lose by trying candesartan, and there is no alternative, so I think doctors are going to use it in this population. I'm going to use it.
The main treatment effect in this group was a reduction in hospitalizations, he noted, and while these patients tend to have a lower mortality, they do have multiple hospitalizations. "By using candesartan, we could save a lot of money."
Krumholz, however, points out that using the end point of readmissions is "kind of a tricky thing," because there is a lot of variation in who gets readmitted for heart failure, sometimes driven by nonmedical reasons, such as the availability of beds. More effective methods of preventing readmissions may also exist. At their institution, for example, disease management programscombining patient education with close supervision of patient treatment and lifestyle factorswere shown to reduce hospitalizations by 40%.
While the evidence is strong for those intolerant of ACE inhibitors, he pointed out that results in the other arms were much more "modest." "I'm sure they'll do cost-effectiveness, because even modest reductions in readmission are going to be economically attractive, because readmissions cost so much, but I'm not as impressed," Krumholz said. "I'm probably going to watch the debate and think about it and read the articles, but I'm not going to think of it as mandatory. I wouldn't consider it a quality indicator right now, that if you're not doing it, it's poor quality care."
I wouldn't consider it a quality indicator right now.
Dr Bertram Pitt (University of Michigan, Ann Arbor) called results in the preserved function group the "least impressive" finding of an otherwise very impressive trial. "I think we still need a lot more information there, and many more trials." A new NIH-sponsored trial will soon begin looking at aldosterone blockade in these patients, he noted.
CHARM Added: There's the rub
Most difficult for physicians to agree on was the idea that they must now consider adding yet another drug to the treatment of patients who are already takingand for some, paying forup to 10 drugs for heart failure and/or other comorbidities.
During the presentation here, the session moderator asked Young about this issue. He replied that clinical-trial evolution has been such that new drugs have been added on top of other drugs. In the SOLVD trial, enalapril was added to digoxin and a diuretic; the CIBIS II trial added a beta blocker to the mix, and now CHARM adds an ARB, he pointed out.
We've shown a stair-step incremental decrease [in each of these trials] and that, as a clinician, to get these outcomes, is what we're going to have to do.
"We've shown a stair-step incremental decrease [in each of these trials] and that, as clinicians, to get these outcomes, is what we're going to have to do. We're going to have to take our patients and add these medications on top of one another."
The CHARM data suggest, though, that this can be done safely and confirms the safety of using an ACE inhibitor, beta blocker, and an ARB together, contrary to a signal of harm seen in the Val-HeFT trial in a subgroup of patients on all three drugs.
However, of this potential risk, Cohn said, "We had long determined that the interaction in Val-HeFT was the play of chance and that the benefit of an ARB on top of an ACE inhibitor was still apparent, although more modest." In CHARM, he said, "there seems to be no interaction that would raise concern about using that triple therapy in the appropriate population, so I think that CHARM has helped to establish the safety of that combination."
Integrating data with beliefs
Asked how he would use this new information in practice, McMurray said that for a new heart failure patient, he intends to continue to use an ACE inhibitor and diuretic as first-line treatment. "I would then add in a beta blocker and if the patient remains symptomatic or is slightly hypertensive, I would then add an ARB,? he said.
Another CHARM investigator, Dr Karl Swedberg (Sahlgrenska University Hospital/Ostra, Göteborg, Sweden) told heartwire that, "In symptomatic patients like the ones we had in the trial, I will start adding this because I know there are important clinical benefits. The key is that it's symptomatic patientsthese patients were sicker than in the other arms, so they have failed on the treatment they are on."
One starts by dissecting and accepts what falls into one's beliefs.
Swedberg said he felt the reception of these data within the community had been positive, but the novel trial design looking at many faces of heart failure means that "physicians start by dissecting it, instead of looking into the overall aspects, which is common. One starts by dissecting and accepts what falls into one's beliefs."
The beta-blocker story was a good illustration of positive results met with some resistance, he added. In this case, "I think the discussion will be, is it really worthwhile approaching all these patients with another tablet? We'll seeit's a long journey to understand and accept a new aspect, but I think we have convincing data when they're taken in."
ARB or aldosterone blockade?
Other experts believe that despite the positive CHARM results, using all three agents is not a given, and they say an ARB might not be their next step after ACE inhibitors and beta blockers in patients who continue to be symptomatic. Instead, several doctors said they might rather choose an aldosterone blocker.
Dr Milton Packer (Columbia University, New York and University of Texas, Southwestern, Dallas) is one of these. He told heartwire that in his view the CHARM data do put ARBs forward as a potential third step in addressing the neurohormonal cascade in heart failure. "The question is what should be the next step? Should it be an angiotensin receptor blocker, or should it be an aldosterone blocker?" Packer said. Because no head-to-head comparison is currently available, he added, doctors will need to look at the combined data on the two classes of agents and decide for themselves.
Which would he choose? "From what I can tell, the data on aldosterone blockers are more convincing with respect to mortality," with a similar safety profile, he said. "I guess my own sense would be to lean toward aldosterone blockers ahead of angiotensin receptor blockers."
I'm not quite sure that we know that adding on an ARB to an ACE inhibitor, beta blocker, and aldosterone blocker is really going to do very much.
Konstam raised the same issue. "If I have a patient on an ACE inhibitor and a beta blocker, and I am motivated to add on, either because of data or because the patient is not doing well, I think the next drug, based on the results of RALES and EPHESUS, in which there is clear-cut suggested benefit in terms of survival, I think one has to consider an aldosterone blocker," he said.
He acknowledged that 16% to 17% of the population in CHARM was also on an aldosterone blocker, and there was no treatment interaction in that subgroup suggesting less benefit from the ARB but said, "I'm not quite sure that we know that adding on an ARB to an ACE inhibitor, beta blocker, and an aldosterone blocker is really going to do very much. That's the main quandary that I'm seeing for clinicians because of an increasing interest in adding on aldosterone blockade."
Perhaps not surprisingly, Pitt, who was principal investigator of both the RALES and EPHESUS trials, which established aldosterone blockade as beneficial in heart failure, was also in this camp. In his view, data in the CHARM Added trial were "not quite as striking as one would have liked," he said, although he noted that in patients with progressive failure, using the ARB would be "reasonable." However, he said, "I think there may be other strategies, and we hope that an aldosterone blocking strategy will be even better in that situation, but what we have to do is prove that."
VALIANT: More information to come
Dr Eric J Velazquez (Duke University Medical Center, Durham, NC) told heartwire that the CHARM data "nicely set up" upcoming results from the Valsartan in Acute Myocardial Infarction Trial (VALIANT), which is assessing the ARB valsartan in comparison and in combination with the ACE inhibitor captopril in post-MI patients with heart failure or LV dysfunction.
"I think the key component to VALIANT is that it's large, with an end point of all-cause mortality," Velazquez, a VALIANT investigator, told heartwire. In that trial, "2800-plus patients died, more than any of the populations that were studied in the three arms of CHARM, so in terms of breadth, it's much larger, it's a different population, and [valsartan] is going head to head against the combination, so it's definitive and kind of puts everything together."
The VALIANT results will be presented at the American Heart Association Scientific Sessions 2003, coming up in November.
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