User login
ESTES PARK, COLO. – Introducing five evidence-based interventions in patients with heart failure with reduced ejection fraction would dramatically cut admissions for heart failure, according to Dr. JoAnn Lindenfeld, vice president of the Heart Failure Society of America.
Here are the five interventions: recognizing when to switch from furosemide to another oral loop diuretic with far better bioavailability; up-titrating beta-blocker therapy to the maximum recommended dose as quickly as possible; adding a low-dose aldosterone antagonist to the treatment regimen; prescribing digoxin in symptomatic patients with a low ejection fraction; and identifying and treating iron deficiency, Dr. Lindenfeld said at a conference on internal medicine sponsored by the University of Colorado.
• Loop diuretics: Furosemide, everybody’s favorite low-cost loop diuretic, turns out to have an enormously variable oral bioavailability, ranging from 10% to 90% from patient to patient. It also varies substantially from day to day within the same individual. In contrast, torsemide (Demadex) and bumetanide (Bumex) have a consistently high oral bioavailability of roughly 90%. They are useful alternatives in poorly compensated heart failure patients.
"When your patient says they’re not diuresing and you’re pretty sure they’re taking their drugs, or if they’ve had more than one recent admission for heart failure and they’re having trouble with congestion and fluid retention, think about switching to bumetanide or torsemide," said Dr. Lindenfeld, professor of medicine and medical director of the heart transplant program at the university.
"In my own practice, when I have a patient admitted for acute decompensated heart failure with congestion and I don’t find another reversible cause, I will usually switch them," noted Dr. Lindenfeld, who also is codirector of the university’s Center for Women’s Health Research.
In a classic study, 234 patients hospitalized for acute decompensated heart failure were randomized at discharge to torsemide or furosemide in equivalent doses. The torsemide group subsequently had a 52% lower rate of heart failure hospitalization (Am. J. Med. 2001;111:513-21).
Bumetanide is now a pretty inexpensive drug, Dr. Lindenfeld noted. In making the switch, remember that 40 mg of furosemide is equivalent to 1 mg of bumetanide or 20 mg of torsemide.
• Beta-blocker up-titration: Beta-blocker and angiotensin-converting enzyme* (ACE) inhibitor therapy both have a class IA recommendation in heart failure. But what’s the best way to juggle the timing of dual dose increases?
"None of the guidelines says how to manage up-titration, but I strongly believe that once you have somebody on a reasonable dose of an ACE inhibitor – say, 5 mg of lisinopril or the equivalent – then you should go to the beta-blocker and up-titrate it to its maximum," she said. "Then later, come back to the ACE inhibitor and get the patient on the maximum dose of that."
The rationale for this approach is based on a comparison of the outcomes of the landmark beta-blocker trials versus ATLAS, a 3,104-patient trial conducted in the pre-beta-blocker era in which patients were randomized to low-dose lisinopril at 2.5-5 mg/day or high-dose therapy at 32.5-35 mg/day to determine which was better. After 4 years of follow-up, the high-dose group showed a 24% reduction in the risk of heart failure hospitalizations, but no significant advantage in terms of all-cause mortality (Circulation 1999;100:2312-8).
Contrast those results with the outcomes of the major clinical trials for carvedilol, metoprolol, and bisoprolol, each of which featured up-titration to the target dose within 8 weeks whenever possible. All three studies were halted within less than a year because of a roughly 35% reduction in mortality, compared with placebo. And that mortality benefit became apparent at 3 months.
"These are huge reductions in mortality," Dr. Lindenfeld noted. "You don’t want to have a patient come back every 4 weeks to up-titrate their ACE inhibitor for 5 months and miss the opportunity to get the patient on an effective dose of a beta-blocker, when the lifesaving benefit begins so early."
The recommended maximum doses in heart failure patients are carvedilol (Coreg) at 25 mg twice daily, or 50 mg twice daily for patients weighing more than 85 kg; 200 mg/day for extended-release metoprolol (Toprol XL); and 10 mg/day for bisoprolol (Zebeta). The three beta-blockers are similar in their efficacy for treating heart failure, Dr. Lindenfeld said. However, bisoprolol has the fewest pulmonary effects and is thus the best choice in patients with chronic obstructive pulmonary disease (COPD), even though it lacks a specific Food and Drug Administration (FDA)-approved indication for heart failure, she continued.
• Aldosterone antagonists: In terms of mortality benefit, the randomized trial data show that the aldosterone antagonists are nearly as good as beta-blockers. Yet they remain widely underutilized in the United States, according to Dr. Lindenfeld.
Indeed, three major randomized trials showed roughly a 25% reduction in total mortality, compared with placebo, in patients on standard background therapy including a beta-blocker and ACE inhibitor, along with a 20% decrease in risk of sudden cardiac death. The doses used were spironolactone at 12.5-25 mg/day or eplerenone (Inspra) at 25-50 mg/day.
An intriguing retrospective analysis conducted in close to 7,000 patients with heart failure following an acute myocardial infarction concluded that getting the aldosterone antagonist onboard early in that situation is key. Patients who started on the drug less than 7 days post MI had a 29% reduction in total mortality and a 47% decrease in sudden cardiac death, compared with those started on day 7 or later (Eur. J. Heart Fail. 2009;11:1099-1105). That benefit is believed to be the result of early left ventricular remodeling.
A definitive European prospective, randomized trial looking at the impact of starting an aldosterone antagonist within 7 days after acute MI is due to be presented later this year. The inside word is the results are highly favorable, she noted.
Hyperkalemia is a legitimate concern when prescribing an aldosterone antagonist. These agents should be avoided in a patient who has a creatinine level above 2.5 mg/dL or an estimated glomerular filtration rate below 30 mL/min per 1.73 m2, or if other potassium-sparing drugs are onboard. Potassium levels should be checked after the first 3-7 days of therapy, again at 1 month, and then every 3 months, as well as anytime a patient becomes dehydrated.
• Digoxin: In the classic digoxin trial involving close to 7,000 patients, heart failure hospitalization was a prospectively defined endpoint. In patients with a left ventricular ejection fraction of 25%-45%, hospital admission for heart failure was reduced by 26% in patients assigned to digoxin. In those whose ejection fraction was less than 25%, the reduction in hospitalization was 39%.
"So don’t forget that digoxin is still a good drug in patients with low ejection fraction or who have substantial symptoms," Dr. Lindenfeld said. "If we had a drug approved today that didn’t change mortality but reduced hospital admissions by 39%, we’d all be giving it – and we’d be paying a lot for it."
• Role of iron deficiency in heart failure: A new European study is illuminating on this score: Among a cohort of 1,506 patients with chronic heart failure, fully 50% were determined to have iron deficiency, as defined by a ferritin level less than 100 mcg/L, or a ferritin level of 100-299 mcg/L with a transferring saturation lower than 20%. In a multivariate regression analysis, iron deficiency was a strong independent predictor for mortality, associated with a 42% increased risk (Am. Heart J. 2013;165:575-82).
"I think if you restricted the study to hospitalized heart failure patients, the iron deficiency rate would be even higher. It’s just appalling how many people we send home iron deficient without iron replacement therapy," Dr. Lindenfeld asserted.
She noted that in the European FAIR-HF trial involving 459 hospitalized iron-deficient heart failure patients randomized at discharge to intravenous iron corrective and maintenance therapy or to a matching placebo, the iron replacement group demonstrated significant improvement in quality of life and exercise capacity. The benefits were seen regardless of whether a patient’s baseline hemoglobin was high or low.
In addition, the rate of the combined endpoint of first hospitalization for worsening heart failure or death was 7.5% in the iron recipients, compared with 13.9% in placebo-treated controls – a difference that didn’t achieve statistical significance because the study was underpowered to evaluated that endpoint (N. Engl. J. Med. 2009;36:2436-48).
"Iron replacement is a distinct advantage for these patients, so you should be looking for iron deficiency. You probably don’t need to use IV iron, but if your patient is in the hospital anyway, IV iron is pretty benign and will get him iron-repleted almost immediately," Dr. Lindenfeld continued.
Before sending iron-deficient patients home on oral iron, make sure they can absorb it. Many older individuals can’t. Indeed, among patients hospitalized at the University of Colorado heart failure service, only 13% can actually absorb oral iron, she explained.
A simple way to tell is to draw a serum iron level, give the patient an iron tablet, and check the serum iron level again in 1-3 hours. It should roughly double, Dr. Lindenfeld explained.
Dr. Lindenfeld reported serving as a consultant for Medtronic, St. Jude, and other companies.
*Correction, 8/12/2013: An earlier version of this story misstated the meaning of ACE.
The five-point checklist as noted represents a reliable strategy for ensuring we apply evidence to our clinical practice. I would emphasize the following points:
•Pharmacodynamic issues such bioavailability of loop diuretics are often not well known, and the use of Bumex (bumetanide) can have a meaningful impact on those refractory to furosemide.
 |
| Dr. Hiren Shah |
•Up-titration to maximum beta-blockade prior to doing the same with ACE inhibitors is strongly supported by current evidence but not always done in clinical practice.
•Early use of aldosterone antagonists post MI is critical, but in those with chronic HF, it should still be restricted to patients with New York Heart Association (NYHA) class II HF and left ventricular ejection fraction (LVEF) less than or equal to 30% or class III to IV HF and EF less than or equal to 35%.
In addition, aldosterone antagonist therapy should be continued following hospital discharge only in patients who can be carefully monitored for hyperkalemia. Similarly, one should be aware of the occurrence of adverse drug reactions when using digoxin, owing to its narrow therapeutic index requiring serum level monitoring.
•Finally, the most overlooked aspect of HF management on this list is the importance of correcting iron-deficiency anemia, which occurs mainly through chronic renal insufficiency in HF patients.
We also now know that the anemia itself can worsen cardiac function, both because it causes cardiac stress through tachycardia and increased stroke volume, and because it can cause a reduced renal blood flow and fluid retention, adding further stress to the heart. Therefore, it is critical to correct the iron deficiency to break the vicious circle wherein CHF causes anemia, and the anemia causes more CHF, and both damage the kidneys, worsening the anemia and the CHF further.
We should all aim for the preferred strategy of intravenous iron for our hospitalized patients and then convert to oral iron, noting the absorption issues that should be evaluated prior to discharge. Of course, any new iron-deficiency anemia should still be worked up considering other causes such as GI losses.
Dr. Hiren Shah is an assistant professor of medicine in the Feinberg School of Medicine, Northwestern University, Chicago, and a medical director of the Medicine and Cardiac Telemetry Hospitalist Unit at Northwestern Memorial Hospital in Chicago.
The five-point checklist as noted represents a reliable strategy for ensuring we apply evidence to our clinical practice. I would emphasize the following points:
•Pharmacodynamic issues such bioavailability of loop diuretics are often not well known, and the use of Bumex (bumetanide) can have a meaningful impact on those refractory to furosemide.
|
| Dr. Hiren Shah |
•Up-titration to maximum beta-blockade prior to doing the same with ACE inhibitors is strongly supported by current evidence but not always done in clinical practice.
•Early use of aldosterone antagonists post MI is critical, but in those with chronic HF, it should still be restricted to patients with New York Heart Association (NYHA) class II HF and left ventricular ejection fraction (LVEF) less than or equal to 30% or class III to IV HF and EF less than or equal to 35%.
In addition, aldosterone antagonist therapy should be continued following hospital discharge only in patients who can be carefully monitored for hyperkalemia. Similarly, one should be aware of the occurrence of adverse drug reactions when using digoxin, owing to its narrow therapeutic index requiring serum level monitoring.
•Finally, the most overlooked aspect of HF management on this list is the importance of correcting iron-deficiency anemia, which occurs mainly through chronic renal insufficiency in HF patients.
We also now know that the anemia itself can worsen cardiac function, both because it causes cardiac stress through tachycardia and increased stroke volume, and because it can cause a reduced renal blood flow and fluid retention, adding further stress to the heart. Therefore, it is critical to correct the iron deficiency to break the vicious circle wherein CHF causes anemia, and the anemia causes more CHF, and both damage the kidneys, worsening the anemia and the CHF further.
We should all aim for the preferred strategy of intravenous iron for our hospitalized patients and then convert to oral iron, noting the absorption issues that should be evaluated prior to discharge. Of course, any new iron-deficiency anemia should still be worked up considering other causes such as GI losses.
Dr. Hiren Shah is an assistant professor of medicine in the Feinberg School of Medicine, Northwestern University, Chicago, and a medical director of the Medicine and Cardiac Telemetry Hospitalist Unit at Northwestern Memorial Hospital in Chicago.
The five-point checklist as noted represents a reliable strategy for ensuring we apply evidence to our clinical practice. I would emphasize the following points:
•Pharmacodynamic issues such bioavailability of loop diuretics are often not well known, and the use of Bumex (bumetanide) can have a meaningful impact on those refractory to furosemide.
|
| Dr. Hiren Shah |
•Up-titration to maximum beta-blockade prior to doing the same with ACE inhibitors is strongly supported by current evidence but not always done in clinical practice.
•Early use of aldosterone antagonists post MI is critical, but in those with chronic HF, it should still be restricted to patients with New York Heart Association (NYHA) class II HF and left ventricular ejection fraction (LVEF) less than or equal to 30% or class III to IV HF and EF less than or equal to 35%.
In addition, aldosterone antagonist therapy should be continued following hospital discharge only in patients who can be carefully monitored for hyperkalemia. Similarly, one should be aware of the occurrence of adverse drug reactions when using digoxin, owing to its narrow therapeutic index requiring serum level monitoring.
•Finally, the most overlooked aspect of HF management on this list is the importance of correcting iron-deficiency anemia, which occurs mainly through chronic renal insufficiency in HF patients.
We also now know that the anemia itself can worsen cardiac function, both because it causes cardiac stress through tachycardia and increased stroke volume, and because it can cause a reduced renal blood flow and fluid retention, adding further stress to the heart. Therefore, it is critical to correct the iron deficiency to break the vicious circle wherein CHF causes anemia, and the anemia causes more CHF, and both damage the kidneys, worsening the anemia and the CHF further.
We should all aim for the preferred strategy of intravenous iron for our hospitalized patients and then convert to oral iron, noting the absorption issues that should be evaluated prior to discharge. Of course, any new iron-deficiency anemia should still be worked up considering other causes such as GI losses.
Dr. Hiren Shah is an assistant professor of medicine in the Feinberg School of Medicine, Northwestern University, Chicago, and a medical director of the Medicine and Cardiac Telemetry Hospitalist Unit at Northwestern Memorial Hospital in Chicago.
ESTES PARK, COLO. – Introducing five evidence-based interventions in patients with heart failure with reduced ejection fraction would dramatically cut admissions for heart failure, according to Dr. JoAnn Lindenfeld, vice president of the Heart Failure Society of America.
Here are the five interventions: recognizing when to switch from furosemide to another oral loop diuretic with far better bioavailability; up-titrating beta-blocker therapy to the maximum recommended dose as quickly as possible; adding a low-dose aldosterone antagonist to the treatment regimen; prescribing digoxin in symptomatic patients with a low ejection fraction; and identifying and treating iron deficiency, Dr. Lindenfeld said at a conference on internal medicine sponsored by the University of Colorado.
• Loop diuretics: Furosemide, everybody’s favorite low-cost loop diuretic, turns out to have an enormously variable oral bioavailability, ranging from 10% to 90% from patient to patient. It also varies substantially from day to day within the same individual. In contrast, torsemide (Demadex) and bumetanide (Bumex) have a consistently high oral bioavailability of roughly 90%. They are useful alternatives in poorly compensated heart failure patients.
"When your patient says they’re not diuresing and you’re pretty sure they’re taking their drugs, or if they’ve had more than one recent admission for heart failure and they’re having trouble with congestion and fluid retention, think about switching to bumetanide or torsemide," said Dr. Lindenfeld, professor of medicine and medical director of the heart transplant program at the university.
"In my own practice, when I have a patient admitted for acute decompensated heart failure with congestion and I don’t find another reversible cause, I will usually switch them," noted Dr. Lindenfeld, who also is codirector of the university’s Center for Women’s Health Research.
In a classic study, 234 patients hospitalized for acute decompensated heart failure were randomized at discharge to torsemide or furosemide in equivalent doses. The torsemide group subsequently had a 52% lower rate of heart failure hospitalization (Am. J. Med. 2001;111:513-21).
Bumetanide is now a pretty inexpensive drug, Dr. Lindenfeld noted. In making the switch, remember that 40 mg of furosemide is equivalent to 1 mg of bumetanide or 20 mg of torsemide.
• Beta-blocker up-titration: Beta-blocker and angiotensin-converting enzyme* (ACE) inhibitor therapy both have a class IA recommendation in heart failure. But what’s the best way to juggle the timing of dual dose increases?
"None of the guidelines says how to manage up-titration, but I strongly believe that once you have somebody on a reasonable dose of an ACE inhibitor – say, 5 mg of lisinopril or the equivalent – then you should go to the beta-blocker and up-titrate it to its maximum," she said. "Then later, come back to the ACE inhibitor and get the patient on the maximum dose of that."
The rationale for this approach is based on a comparison of the outcomes of the landmark beta-blocker trials versus ATLAS, a 3,104-patient trial conducted in the pre-beta-blocker era in which patients were randomized to low-dose lisinopril at 2.5-5 mg/day or high-dose therapy at 32.5-35 mg/day to determine which was better. After 4 years of follow-up, the high-dose group showed a 24% reduction in the risk of heart failure hospitalizations, but no significant advantage in terms of all-cause mortality (Circulation 1999;100:2312-8).
Contrast those results with the outcomes of the major clinical trials for carvedilol, metoprolol, and bisoprolol, each of which featured up-titration to the target dose within 8 weeks whenever possible. All three studies were halted within less than a year because of a roughly 35% reduction in mortality, compared with placebo. And that mortality benefit became apparent at 3 months.
"These are huge reductions in mortality," Dr. Lindenfeld noted. "You don’t want to have a patient come back every 4 weeks to up-titrate their ACE inhibitor for 5 months and miss the opportunity to get the patient on an effective dose of a beta-blocker, when the lifesaving benefit begins so early."
The recommended maximum doses in heart failure patients are carvedilol (Coreg) at 25 mg twice daily, or 50 mg twice daily for patients weighing more than 85 kg; 200 mg/day for extended-release metoprolol (Toprol XL); and 10 mg/day for bisoprolol (Zebeta). The three beta-blockers are similar in their efficacy for treating heart failure, Dr. Lindenfeld said. However, bisoprolol has the fewest pulmonary effects and is thus the best choice in patients with chronic obstructive pulmonary disease (COPD), even though it lacks a specific Food and Drug Administration (FDA)-approved indication for heart failure, she continued.
• Aldosterone antagonists: In terms of mortality benefit, the randomized trial data show that the aldosterone antagonists are nearly as good as beta-blockers. Yet they remain widely underutilized in the United States, according to Dr. Lindenfeld.
Indeed, three major randomized trials showed roughly a 25% reduction in total mortality, compared with placebo, in patients on standard background therapy including a beta-blocker and ACE inhibitor, along with a 20% decrease in risk of sudden cardiac death. The doses used were spironolactone at 12.5-25 mg/day or eplerenone (Inspra) at 25-50 mg/day.
An intriguing retrospective analysis conducted in close to 7,000 patients with heart failure following an acute myocardial infarction concluded that getting the aldosterone antagonist onboard early in that situation is key. Patients who started on the drug less than 7 days post MI had a 29% reduction in total mortality and a 47% decrease in sudden cardiac death, compared with those started on day 7 or later (Eur. J. Heart Fail. 2009;11:1099-1105). That benefit is believed to be the result of early left ventricular remodeling.
A definitive European prospective, randomized trial looking at the impact of starting an aldosterone antagonist within 7 days after acute MI is due to be presented later this year. The inside word is the results are highly favorable, she noted.
Hyperkalemia is a legitimate concern when prescribing an aldosterone antagonist. These agents should be avoided in a patient who has a creatinine level above 2.5 mg/dL or an estimated glomerular filtration rate below 30 mL/min per 1.73 m2, or if other potassium-sparing drugs are onboard. Potassium levels should be checked after the first 3-7 days of therapy, again at 1 month, and then every 3 months, as well as anytime a patient becomes dehydrated.
• Digoxin: In the classic digoxin trial involving close to 7,000 patients, heart failure hospitalization was a prospectively defined endpoint. In patients with a left ventricular ejection fraction of 25%-45%, hospital admission for heart failure was reduced by 26% in patients assigned to digoxin. In those whose ejection fraction was less than 25%, the reduction in hospitalization was 39%.
"So don’t forget that digoxin is still a good drug in patients with low ejection fraction or who have substantial symptoms," Dr. Lindenfeld said. "If we had a drug approved today that didn’t change mortality but reduced hospital admissions by 39%, we’d all be giving it – and we’d be paying a lot for it."
• Role of iron deficiency in heart failure: A new European study is illuminating on this score: Among a cohort of 1,506 patients with chronic heart failure, fully 50% were determined to have iron deficiency, as defined by a ferritin level less than 100 mcg/L, or a ferritin level of 100-299 mcg/L with a transferring saturation lower than 20%. In a multivariate regression analysis, iron deficiency was a strong independent predictor for mortality, associated with a 42% increased risk (Am. Heart J. 2013;165:575-82).
"I think if you restricted the study to hospitalized heart failure patients, the iron deficiency rate would be even higher. It’s just appalling how many people we send home iron deficient without iron replacement therapy," Dr. Lindenfeld asserted.
She noted that in the European FAIR-HF trial involving 459 hospitalized iron-deficient heart failure patients randomized at discharge to intravenous iron corrective and maintenance therapy or to a matching placebo, the iron replacement group demonstrated significant improvement in quality of life and exercise capacity. The benefits were seen regardless of whether a patient’s baseline hemoglobin was high or low.
In addition, the rate of the combined endpoint of first hospitalization for worsening heart failure or death was 7.5% in the iron recipients, compared with 13.9% in placebo-treated controls – a difference that didn’t achieve statistical significance because the study was underpowered to evaluated that endpoint (N. Engl. J. Med. 2009;36:2436-48).
"Iron replacement is a distinct advantage for these patients, so you should be looking for iron deficiency. You probably don’t need to use IV iron, but if your patient is in the hospital anyway, IV iron is pretty benign and will get him iron-repleted almost immediately," Dr. Lindenfeld continued.
Before sending iron-deficient patients home on oral iron, make sure they can absorb it. Many older individuals can’t. Indeed, among patients hospitalized at the University of Colorado heart failure service, only 13% can actually absorb oral iron, she explained.
A simple way to tell is to draw a serum iron level, give the patient an iron tablet, and check the serum iron level again in 1-3 hours. It should roughly double, Dr. Lindenfeld explained.
Dr. Lindenfeld reported serving as a consultant for Medtronic, St. Jude, and other companies.
*Correction, 8/12/2013: An earlier version of this story misstated the meaning of ACE.
ESTES PARK, COLO. – Introducing five evidence-based interventions in patients with heart failure with reduced ejection fraction would dramatically cut admissions for heart failure, according to Dr. JoAnn Lindenfeld, vice president of the Heart Failure Society of America.
Here are the five interventions: recognizing when to switch from furosemide to another oral loop diuretic with far better bioavailability; up-titrating beta-blocker therapy to the maximum recommended dose as quickly as possible; adding a low-dose aldosterone antagonist to the treatment regimen; prescribing digoxin in symptomatic patients with a low ejection fraction; and identifying and treating iron deficiency, Dr. Lindenfeld said at a conference on internal medicine sponsored by the University of Colorado.
• Loop diuretics: Furosemide, everybody’s favorite low-cost loop diuretic, turns out to have an enormously variable oral bioavailability, ranging from 10% to 90% from patient to patient. It also varies substantially from day to day within the same individual. In contrast, torsemide (Demadex) and bumetanide (Bumex) have a consistently high oral bioavailability of roughly 90%. They are useful alternatives in poorly compensated heart failure patients.
"When your patient says they’re not diuresing and you’re pretty sure they’re taking their drugs, or if they’ve had more than one recent admission for heart failure and they’re having trouble with congestion and fluid retention, think about switching to bumetanide or torsemide," said Dr. Lindenfeld, professor of medicine and medical director of the heart transplant program at the university.
"In my own practice, when I have a patient admitted for acute decompensated heart failure with congestion and I don’t find another reversible cause, I will usually switch them," noted Dr. Lindenfeld, who also is codirector of the university’s Center for Women’s Health Research.
In a classic study, 234 patients hospitalized for acute decompensated heart failure were randomized at discharge to torsemide or furosemide in equivalent doses. The torsemide group subsequently had a 52% lower rate of heart failure hospitalization (Am. J. Med. 2001;111:513-21).
Bumetanide is now a pretty inexpensive drug, Dr. Lindenfeld noted. In making the switch, remember that 40 mg of furosemide is equivalent to 1 mg of bumetanide or 20 mg of torsemide.
• Beta-blocker up-titration: Beta-blocker and angiotensin-converting enzyme* (ACE) inhibitor therapy both have a class IA recommendation in heart failure. But what’s the best way to juggle the timing of dual dose increases?
"None of the guidelines says how to manage up-titration, but I strongly believe that once you have somebody on a reasonable dose of an ACE inhibitor – say, 5 mg of lisinopril or the equivalent – then you should go to the beta-blocker and up-titrate it to its maximum," she said. "Then later, come back to the ACE inhibitor and get the patient on the maximum dose of that."
The rationale for this approach is based on a comparison of the outcomes of the landmark beta-blocker trials versus ATLAS, a 3,104-patient trial conducted in the pre-beta-blocker era in which patients were randomized to low-dose lisinopril at 2.5-5 mg/day or high-dose therapy at 32.5-35 mg/day to determine which was better. After 4 years of follow-up, the high-dose group showed a 24% reduction in the risk of heart failure hospitalizations, but no significant advantage in terms of all-cause mortality (Circulation 1999;100:2312-8).
Contrast those results with the outcomes of the major clinical trials for carvedilol, metoprolol, and bisoprolol, each of which featured up-titration to the target dose within 8 weeks whenever possible. All three studies were halted within less than a year because of a roughly 35% reduction in mortality, compared with placebo. And that mortality benefit became apparent at 3 months.
"These are huge reductions in mortality," Dr. Lindenfeld noted. "You don’t want to have a patient come back every 4 weeks to up-titrate their ACE inhibitor for 5 months and miss the opportunity to get the patient on an effective dose of a beta-blocker, when the lifesaving benefit begins so early."
The recommended maximum doses in heart failure patients are carvedilol (Coreg) at 25 mg twice daily, or 50 mg twice daily for patients weighing more than 85 kg; 200 mg/day for extended-release metoprolol (Toprol XL); and 10 mg/day for bisoprolol (Zebeta). The three beta-blockers are similar in their efficacy for treating heart failure, Dr. Lindenfeld said. However, bisoprolol has the fewest pulmonary effects and is thus the best choice in patients with chronic obstructive pulmonary disease (COPD), even though it lacks a specific Food and Drug Administration (FDA)-approved indication for heart failure, she continued.
• Aldosterone antagonists: In terms of mortality benefit, the randomized trial data show that the aldosterone antagonists are nearly as good as beta-blockers. Yet they remain widely underutilized in the United States, according to Dr. Lindenfeld.
Indeed, three major randomized trials showed roughly a 25% reduction in total mortality, compared with placebo, in patients on standard background therapy including a beta-blocker and ACE inhibitor, along with a 20% decrease in risk of sudden cardiac death. The doses used were spironolactone at 12.5-25 mg/day or eplerenone (Inspra) at 25-50 mg/day.
An intriguing retrospective analysis conducted in close to 7,000 patients with heart failure following an acute myocardial infarction concluded that getting the aldosterone antagonist onboard early in that situation is key. Patients who started on the drug less than 7 days post MI had a 29% reduction in total mortality and a 47% decrease in sudden cardiac death, compared with those started on day 7 or later (Eur. J. Heart Fail. 2009;11:1099-1105). That benefit is believed to be the result of early left ventricular remodeling.
A definitive European prospective, randomized trial looking at the impact of starting an aldosterone antagonist within 7 days after acute MI is due to be presented later this year. The inside word is the results are highly favorable, she noted.
Hyperkalemia is a legitimate concern when prescribing an aldosterone antagonist. These agents should be avoided in a patient who has a creatinine level above 2.5 mg/dL or an estimated glomerular filtration rate below 30 mL/min per 1.73 m2, or if other potassium-sparing drugs are onboard. Potassium levels should be checked after the first 3-7 days of therapy, again at 1 month, and then every 3 months, as well as anytime a patient becomes dehydrated.
• Digoxin: In the classic digoxin trial involving close to 7,000 patients, heart failure hospitalization was a prospectively defined endpoint. In patients with a left ventricular ejection fraction of 25%-45%, hospital admission for heart failure was reduced by 26% in patients assigned to digoxin. In those whose ejection fraction was less than 25%, the reduction in hospitalization was 39%.
"So don’t forget that digoxin is still a good drug in patients with low ejection fraction or who have substantial symptoms," Dr. Lindenfeld said. "If we had a drug approved today that didn’t change mortality but reduced hospital admissions by 39%, we’d all be giving it – and we’d be paying a lot for it."
• Role of iron deficiency in heart failure: A new European study is illuminating on this score: Among a cohort of 1,506 patients with chronic heart failure, fully 50% were determined to have iron deficiency, as defined by a ferritin level less than 100 mcg/L, or a ferritin level of 100-299 mcg/L with a transferring saturation lower than 20%. In a multivariate regression analysis, iron deficiency was a strong independent predictor for mortality, associated with a 42% increased risk (Am. Heart J. 2013;165:575-82).
"I think if you restricted the study to hospitalized heart failure patients, the iron deficiency rate would be even higher. It’s just appalling how many people we send home iron deficient without iron replacement therapy," Dr. Lindenfeld asserted.
She noted that in the European FAIR-HF trial involving 459 hospitalized iron-deficient heart failure patients randomized at discharge to intravenous iron corrective and maintenance therapy or to a matching placebo, the iron replacement group demonstrated significant improvement in quality of life and exercise capacity. The benefits were seen regardless of whether a patient’s baseline hemoglobin was high or low.
In addition, the rate of the combined endpoint of first hospitalization for worsening heart failure or death was 7.5% in the iron recipients, compared with 13.9% in placebo-treated controls – a difference that didn’t achieve statistical significance because the study was underpowered to evaluated that endpoint (N. Engl. J. Med. 2009;36:2436-48).
"Iron replacement is a distinct advantage for these patients, so you should be looking for iron deficiency. You probably don’t need to use IV iron, but if your patient is in the hospital anyway, IV iron is pretty benign and will get him iron-repleted almost immediately," Dr. Lindenfeld continued.
Before sending iron-deficient patients home on oral iron, make sure they can absorb it. Many older individuals can’t. Indeed, among patients hospitalized at the University of Colorado heart failure service, only 13% can actually absorb oral iron, she explained.
A simple way to tell is to draw a serum iron level, give the patient an iron tablet, and check the serum iron level again in 1-3 hours. It should roughly double, Dr. Lindenfeld explained.
Dr. Lindenfeld reported serving as a consultant for Medtronic, St. Jude, and other companies.
*Correction, 8/12/2013: An earlier version of this story misstated the meaning of ACE.
EXPERT ANALYSIS FROM THE ANNUAL INTERNAL MEDICINE PROGRAM
