Candesartan Approved For Heart Failure Tx

The recent approval of candesartan for a heart failure indication reflects the key findings of one of the three international trials comparing candesartan with placebo in patients with heart failure.

In February, the Food and Drug Administration approved the angiotensin receptor blocker (ARB) for treating patients with heart failure (New York Heart Association class II or IV and a left ventricular ejection fraction [LVEF] of 40% or less), “to reduce the risk of death from cardiovascular causes and to reduce hospitalizations for heart failure.” In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative trial, the risk of cardiovascular death or hospitalization for heart failure, the primary end point, was reduced by 23% among those on candesartan after a median follow-up of 34 months, compared with those on placebo—a highly statistically significant effect.

This trial, one of three in the CHARM program, enrolled 2,028 patients with symptomatic heart failure and an LVEF less than or equal to 40%, who were on standard heart failure treatments but were intolerant of ACE inhibitors. At baseline, 85% were on diuretics, 46% on digoxin, 55% on β-blockers, and 24% on spironolactone. There were 334 events in the 1,013 patients on candesartan, vs. 406 events in the 1,015 on placebo.

Supporting the approval of this indication, according to the FDA, were the results of CHARM-Added, which enrolled more than 2,500 patients with NYHA class II-IV heart failure and LVEFs at or below 40% who were on an ACE inhibitor. In this trial, adding candesartan to standard treatment, including a β-blocker, reduced the risk of cardiovascular mortality by 15%, compared with placebo, and significantly improved in heart failure symptoms, as assessed by NYHA functional class.

An approval for use in heart failure patients on ACE inhibitors is likely to follow. (See accompanying story.)

Candesartan, marketed as Atacand by AstraZeneca Pharmaceuticals LP, is the second ARB approved for heart failure; the first was Diovan (valsartan), approved in 2002 for a narrower indication, NYHA class II-IV heart failure in people who cannot tolerate ACE inhibitors. Candesartan was approved for hypertension in 1998.

Using candesartan for these indications will provide an important new tool for treating heart failure, said Christopher Granger, M.D., CHARM-Alternative's principal investigator, in an interview.

In the CHARM program, 4% of those on candesartan had to stop treatment with the drug because of hypotension, versus 2% of those on placebo. Hyperkalemia leading to discontinuation occurred in 2.4% of those on candesartan, versus 0.6% of those on placebo.

The recommended starting dosage is 4 mg/day, with a target dosage of 32 mg once daily, achieved by doubling the dose approximately every 2 weeks, as tolerated, according to the package insert.

Patients need to be monitored closely when the drug is being titrated because some will develop renal insufficiency, hyperkalemia, or hypotension during titration, side effects expected with any drug that affects the renal angiotensin system, said Dr. Granger, who is director of the cardiac care unit at Duke University, Durham, N.C. In the CHARM trials, it was recommended that investigators check serum potassium and creatinine approximately 2 weeks after dose titration.

Dr. Granger was on the executive committee for CHARM and was a consultant to AstraZeneca for this FDA approval and for the meeting of the FDA's cardiovascular and renal drugs advisory committee.

The recent approval of candesartan for a heart failure indication reflects the key findings of one of the three international trials comparing candesartan with placebo in patients with heart failure.

In February, the Food and Drug Administration approved the angiotensin receptor blocker (ARB) for treating patients with heart failure (New York Heart Association class II or IV and a left ventricular ejection fraction [LVEF] of 40% or less), “to reduce the risk of death from cardiovascular causes and to reduce hospitalizations for heart failure.” In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative trial, the risk of cardiovascular death or hospitalization for heart failure, the primary end point, was reduced by 23% among those on candesartan after a median follow-up of 34 months, compared with those on placebo—a highly statistically significant effect.

This trial, one of three in the CHARM program, enrolled 2,028 patients with symptomatic heart failure and an LVEF less than or equal to 40%, who were on standard heart failure treatments but were intolerant of ACE inhibitors. At baseline, 85% were on diuretics, 46% on digoxin, 55% on β-blockers, and 24% on spironolactone. There were 334 events in the 1,013 patients on candesartan, vs. 406 events in the 1,015 on placebo.

Supporting the approval of this indication, according to the FDA, were the results of CHARM-Added, which enrolled more than 2,500 patients with NYHA class II-IV heart failure and LVEFs at or below 40% who were on an ACE inhibitor. In this trial, adding candesartan to standard treatment, including a β-blocker, reduced the risk of cardiovascular mortality by 15%, compared with placebo, and significantly improved in heart failure symptoms, as assessed by NYHA functional class.

An approval for use in heart failure patients on ACE inhibitors is likely to follow. (See accompanying story.)

Candesartan, marketed as Atacand by AstraZeneca Pharmaceuticals LP, is the second ARB approved for heart failure; the first was Diovan (valsartan), approved in 2002 for a narrower indication, NYHA class II-IV heart failure in people who cannot tolerate ACE inhibitors. Candesartan was approved for hypertension in 1998.

Using candesartan for these indications will provide an important new tool for treating heart failure, said Christopher Granger, M.D., CHARM-Alternative's principal investigator, in an interview.

In the CHARM program, 4% of those on candesartan had to stop treatment with the drug because of hypotension, versus 2% of those on placebo. Hyperkalemia leading to discontinuation occurred in 2.4% of those on candesartan, versus 0.6% of those on placebo.

The recommended starting dosage is 4 mg/day, with a target dosage of 32 mg once daily, achieved by doubling the dose approximately every 2 weeks, as tolerated, according to the package insert.

Patients need to be monitored closely when the drug is being titrated because some will develop renal insufficiency, hyperkalemia, or hypotension during titration, side effects expected with any drug that affects the renal angiotensin system, said Dr. Granger, who is director of the cardiac care unit at Duke University, Durham, N.C. In the CHARM trials, it was recommended that investigators check serum potassium and creatinine approximately 2 weeks after dose titration.

Dr. Granger was on the executive committee for CHARM and was a consultant to AstraZeneca for this FDA approval and for the meeting of the FDA's cardiovascular and renal drugs advisory committee.

The recent approval of candesartan for a heart failure indication reflects the key findings of one of the three international trials comparing candesartan with placebo in patients with heart failure.

In February, the Food and Drug Administration approved the angiotensin receptor blocker (ARB) for treating patients with heart failure (New York Heart Association class II or IV and a left ventricular ejection fraction [LVEF] of 40% or less), “to reduce the risk of death from cardiovascular causes and to reduce hospitalizations for heart failure.” In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative trial, the risk of cardiovascular death or hospitalization for heart failure, the primary end point, was reduced by 23% among those on candesartan after a median follow-up of 34 months, compared with those on placebo—a highly statistically significant effect.

This trial, one of three in the CHARM program, enrolled 2,028 patients with symptomatic heart failure and an LVEF less than or equal to 40%, who were on standard heart failure treatments but were intolerant of ACE inhibitors. At baseline, 85% were on diuretics, 46% on digoxin, 55% on β-blockers, and 24% on spironolactone. There were 334 events in the 1,013 patients on candesartan, vs. 406 events in the 1,015 on placebo.

Supporting the approval of this indication, according to the FDA, were the results of CHARM-Added, which enrolled more than 2,500 patients with NYHA class II-IV heart failure and LVEFs at or below 40% who were on an ACE inhibitor. In this trial, adding candesartan to standard treatment, including a β-blocker, reduced the risk of cardiovascular mortality by 15%, compared with placebo, and significantly improved in heart failure symptoms, as assessed by NYHA functional class.

An approval for use in heart failure patients on ACE inhibitors is likely to follow. (See accompanying story.)

Candesartan, marketed as Atacand by AstraZeneca Pharmaceuticals LP, is the second ARB approved for heart failure; the first was Diovan (valsartan), approved in 2002 for a narrower indication, NYHA class II-IV heart failure in people who cannot tolerate ACE inhibitors. Candesartan was approved for hypertension in 1998.

Using candesartan for these indications will provide an important new tool for treating heart failure, said Christopher Granger, M.D., CHARM-Alternative's principal investigator, in an interview.

In the CHARM program, 4% of those on candesartan had to stop treatment with the drug because of hypotension, versus 2% of those on placebo. Hyperkalemia leading to discontinuation occurred in 2.4% of those on candesartan, versus 0.6% of those on placebo.

The recommended starting dosage is 4 mg/day, with a target dosage of 32 mg once daily, achieved by doubling the dose approximately every 2 weeks, as tolerated, according to the package insert.

Patients need to be monitored closely when the drug is being titrated because some will develop renal insufficiency, hyperkalemia, or hypotension during titration, side effects expected with any drug that affects the renal angiotensin system, said Dr. Granger, who is director of the cardiac care unit at Duke University, Durham, N.C. In the CHARM trials, it was recommended that investigators check serum potassium and creatinine approximately 2 weeks after dose titration.

Dr. Granger was on the executive committee for CHARM and was a consultant to AstraZeneca for this FDA approval and for the meeting of the FDA's cardiovascular and renal drugs advisory committee.