Heart Failure Drug Pipeline Full of Promising Newcomers

VANCOUVER, B.C. — The recent big therapeutic successes in heart failure have come from implantable electrophysiologic devices—cardiac resynchronization therapy, implantable cardioverter defibrillators—and surgical advances, such as ventricular reduction procedures.

Although attempts to develop new drugs have proved largely disappointing of late, that may be about to change, Robert E. Hobbs, M.D., said at a meeting sponsored by the International Academy of Cardiology.

Many heart failure drugs are working their way through the developmental process. Dr. Hobbs chose to highlight half a dozen, each having a different and novel mechanism of action.

Each of these drugs has shown promise in clinical trials, and each addresses a different hypothesis about the nature of worsening heart failure. And these six interesting drugs constitute only a portion of what's in the pipeline, added Dr. Hobbs of the Cleveland Clinic Foundation.

▸ A xanthine oxidase inhibitor. Oxypurinol, an analogue of allopurinol, inhibits xanthine oxidase, the enzyme that produces uric acid, as well as harmful oxygen free radicals. Xanthine oxidase is upregulated in heart failure. By inhibiting this enzyme, oxypurinol has been shown to improve myocardial energetics and endothelial function.

The Oxypurinol Therapy for Congestive Heart Failure (OPT-CHF) trial is a recently completed 400-patient phase II/III randomized double-blind trial. The data are now being analyzed and are due to be presented this fall at the annual meeting of the American Heart Association.

▸ A unique inotropic agent. Levosimendan's mechanism of action differs from that of other inotropes, such as dobutamine and milrinone. It binds to cardiac troponin C. Levosimendan is categorized as a calcium-sensitizing agent because it enhances myocardial contractility without increasing intracellular calcium concentrations. The drug also acts as a vasodilator through activation of potassium channels. Moreover, it's a weak phosphodiesterase inhibitor as well.

Levosimendan's hemodynamic effects include an increase in cardiac index along with systemic and coronary vasodilation. In heart failure patients, levosimendan reduces elevated intracardiac pressures without increasing myocardial oxygen consumption. Unlike other inotropes, it has low arrhythmic potential, Dr. Hobbs stressed. The drug is approved for use in more than 30 countries as a treatment for patients with decompensated heart failure in need of inotropic support. But not in the United States.

“In the United States, they're reinventing the wheel and taking the drug through repeats of the clinical trials,” the cardiologist said. “I can't believe I'm still talking about levosimendan 10 years later. I was involved in clinical trials of the oral formulation a decade ago.”

What's under study today, however, is the intravenous version of levosimendan. The 800-patient phase-III Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy (REVIVE) trial is due to be presented in November at the AHA meeting.

▸ A thyroid hormone analogue. Roughly 30% of patients with advanced heart failure have low T₃ and normal TSH. Giving T₃ to patients with heart failure confers multiple cardiovascular benefits, including positive inotropic effects, improved diastolic relaxation, and stimulation of alpha-myosin heavy chain gene expression. But it also causes tachycardia, largely negating the improved cardiac performance.

Treatment with 3,5-diiodothyropropionic acid (DITPA), a T₃ analogue, offers similar cardiovascular benefits—but without the tachycardia. A 40-center, 34-week randomized trial is underway in 150 patients with class III/IV heart failure, low ejection fraction, low T₃, and normal TSH. Participants are assigned to one of two doses of DITPA or placebo.

▸ An atrial natriuretic peptide. Carperitide, a synthetic atrial natriuretic peptide, is an intravenous vasodilator approved for use in acutely decompensated heart failure in Japan for a decade. Its multiple effects are similar to those of nesiritide (Natrecor), recombinant brain natriuretic peptide.

An ongoing U.S. clinical trial is aimed at determining the safety and efficacy of seven different doses of carperitide in 158 patients.

▸ Adenosine receptor antagonists. These agents cause afferent arteriolar dilatation. They promote diuresis while preserving renal function and maintaining glomerular filtration rate. One agent—known at this point only as KW-3902—is the subject of an ongoing clinical trial in 200 hospitalized heart failure patients with impaired renal function. It's a 4-day treatment study with 30-day follow-up. “These agents look promising, but it's early,” Dr. Hobbs commented.

▸ Vasopressin antagonists. Nicknamed “super diuretics,” these drugs cause profound diuresis without disrupting electrolytes. The target of these drugs—vasopressin—is synthesized by the hypothalamus in response to baroreceptor and osmotic stimuli. It causes vasoconstriction and sodium and water retention.

Two vasopressin antagonists, or “vaptans,” have been tested in clinical trials: conivaptan and tolvaptan. Ongoing is the large multinational phase III Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST). Results are probably several years off, according to Dr. Hobbs.

Udho Thadani, M.D., commented that heart failure patients already have a rather full plate just with today's standard medications, which include a b-blocker, an ACE inhibitor or angiotensin receptor blocker, an aldosterone blocker such as spironolactone, and digoxin.

If even a few of the drugs with novel mechanisms of action that are in the developmental pipeline eventually find their way into routine clinical practice on top of today's standard therapy, compliance issues will become a much more prominent concern, predicted Dr. Thadani, professor emeritus of medicine at the University of Oklahoma, Oklahoma City.

VANCOUVER, B.C. — The recent big therapeutic successes in heart failure have come from implantable electrophysiologic devices—cardiac resynchronization therapy, implantable cardioverter defibrillators—and surgical advances, such as ventricular reduction procedures.

Although attempts to develop new drugs have proved largely disappointing of late, that may be about to change, Robert E. Hobbs, M.D., said at a meeting sponsored by the International Academy of Cardiology.

Many heart failure drugs are working their way through the developmental process. Dr. Hobbs chose to highlight half a dozen, each having a different and novel mechanism of action.

Each of these drugs has shown promise in clinical trials, and each addresses a different hypothesis about the nature of worsening heart failure. And these six interesting drugs constitute only a portion of what's in the pipeline, added Dr. Hobbs of the Cleveland Clinic Foundation.

▸ A xanthine oxidase inhibitor. Oxypurinol, an analogue of allopurinol, inhibits xanthine oxidase, the enzyme that produces uric acid, as well as harmful oxygen free radicals. Xanthine oxidase is upregulated in heart failure. By inhibiting this enzyme, oxypurinol has been shown to improve myocardial energetics and endothelial function.

The Oxypurinol Therapy for Congestive Heart Failure (OPT-CHF) trial is a recently completed 400-patient phase II/III randomized double-blind trial. The data are now being analyzed and are due to be presented this fall at the annual meeting of the American Heart Association.

▸ A unique inotropic agent. Levosimendan's mechanism of action differs from that of other inotropes, such as dobutamine and milrinone. It binds to cardiac troponin C. Levosimendan is categorized as a calcium-sensitizing agent because it enhances myocardial contractility without increasing intracellular calcium concentrations. The drug also acts as a vasodilator through activation of potassium channels. Moreover, it's a weak phosphodiesterase inhibitor as well.

Levosimendan's hemodynamic effects include an increase in cardiac index along with systemic and coronary vasodilation. In heart failure patients, levosimendan reduces elevated intracardiac pressures without increasing myocardial oxygen consumption. Unlike other inotropes, it has low arrhythmic potential, Dr. Hobbs stressed. The drug is approved for use in more than 30 countries as a treatment for patients with decompensated heart failure in need of inotropic support. But not in the United States.

“In the United States, they're reinventing the wheel and taking the drug through repeats of the clinical trials,” the cardiologist said. “I can't believe I'm still talking about levosimendan 10 years later. I was involved in clinical trials of the oral formulation a decade ago.”

What's under study today, however, is the intravenous version of levosimendan. The 800-patient phase-III Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy (REVIVE) trial is due to be presented in November at the AHA meeting.

▸ A thyroid hormone analogue. Roughly 30% of patients with advanced heart failure have low T₃ and normal TSH. Giving T₃ to patients with heart failure confers multiple cardiovascular benefits, including positive inotropic effects, improved diastolic relaxation, and stimulation of alpha-myosin heavy chain gene expression. But it also causes tachycardia, largely negating the improved cardiac performance.

Treatment with 3,5-diiodothyropropionic acid (DITPA), a T₃ analogue, offers similar cardiovascular benefits—but without the tachycardia. A 40-center, 34-week randomized trial is underway in 150 patients with class III/IV heart failure, low ejection fraction, low T₃, and normal TSH. Participants are assigned to one of two doses of DITPA or placebo.

▸ An atrial natriuretic peptide. Carperitide, a synthetic atrial natriuretic peptide, is an intravenous vasodilator approved for use in acutely decompensated heart failure in Japan for a decade. Its multiple effects are similar to those of nesiritide (Natrecor), recombinant brain natriuretic peptide.

An ongoing U.S. clinical trial is aimed at determining the safety and efficacy of seven different doses of carperitide in 158 patients.

▸ Adenosine receptor antagonists. These agents cause afferent arteriolar dilatation. They promote diuresis while preserving renal function and maintaining glomerular filtration rate. One agent—known at this point only as KW-3902—is the subject of an ongoing clinical trial in 200 hospitalized heart failure patients with impaired renal function. It's a 4-day treatment study with 30-day follow-up. “These agents look promising, but it's early,” Dr. Hobbs commented.

▸ Vasopressin antagonists. Nicknamed “super diuretics,” these drugs cause profound diuresis without disrupting electrolytes. The target of these drugs—vasopressin—is synthesized by the hypothalamus in response to baroreceptor and osmotic stimuli. It causes vasoconstriction and sodium and water retention.

Two vasopressin antagonists, or “vaptans,” have been tested in clinical trials: conivaptan and tolvaptan. Ongoing is the large multinational phase III Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST). Results are probably several years off, according to Dr. Hobbs.

Udho Thadani, M.D., commented that heart failure patients already have a rather full plate just with today's standard medications, which include a b-blocker, an ACE inhibitor or angiotensin receptor blocker, an aldosterone blocker such as spironolactone, and digoxin.

If even a few of the drugs with novel mechanisms of action that are in the developmental pipeline eventually find their way into routine clinical practice on top of today's standard therapy, compliance issues will become a much more prominent concern, predicted Dr. Thadani, professor emeritus of medicine at the University of Oklahoma, Oklahoma City.

VANCOUVER, B.C. — The recent big therapeutic successes in heart failure have come from implantable electrophysiologic devices—cardiac resynchronization therapy, implantable cardioverter defibrillators—and surgical advances, such as ventricular reduction procedures.

Although attempts to develop new drugs have proved largely disappointing of late, that may be about to change, Robert E. Hobbs, M.D., said at a meeting sponsored by the International Academy of Cardiology.

Many heart failure drugs are working their way through the developmental process. Dr. Hobbs chose to highlight half a dozen, each having a different and novel mechanism of action.

Each of these drugs has shown promise in clinical trials, and each addresses a different hypothesis about the nature of worsening heart failure. And these six interesting drugs constitute only a portion of what's in the pipeline, added Dr. Hobbs of the Cleveland Clinic Foundation.

▸ A xanthine oxidase inhibitor. Oxypurinol, an analogue of allopurinol, inhibits xanthine oxidase, the enzyme that produces uric acid, as well as harmful oxygen free radicals. Xanthine oxidase is upregulated in heart failure. By inhibiting this enzyme, oxypurinol has been shown to improve myocardial energetics and endothelial function.

The Oxypurinol Therapy for Congestive Heart Failure (OPT-CHF) trial is a recently completed 400-patient phase II/III randomized double-blind trial. The data are now being analyzed and are due to be presented this fall at the annual meeting of the American Heart Association.

▸ A unique inotropic agent. Levosimendan's mechanism of action differs from that of other inotropes, such as dobutamine and milrinone. It binds to cardiac troponin C. Levosimendan is categorized as a calcium-sensitizing agent because it enhances myocardial contractility without increasing intracellular calcium concentrations. The drug also acts as a vasodilator through activation of potassium channels. Moreover, it's a weak phosphodiesterase inhibitor as well.

Levosimendan's hemodynamic effects include an increase in cardiac index along with systemic and coronary vasodilation. In heart failure patients, levosimendan reduces elevated intracardiac pressures without increasing myocardial oxygen consumption. Unlike other inotropes, it has low arrhythmic potential, Dr. Hobbs stressed. The drug is approved for use in more than 30 countries as a treatment for patients with decompensated heart failure in need of inotropic support. But not in the United States.

“In the United States, they're reinventing the wheel and taking the drug through repeats of the clinical trials,” the cardiologist said. “I can't believe I'm still talking about levosimendan 10 years later. I was involved in clinical trials of the oral formulation a decade ago.”

What's under study today, however, is the intravenous version of levosimendan. The 800-patient phase-III Randomized Multicenter Evaluation of Intravenous Levosimendan Efficacy (REVIVE) trial is due to be presented in November at the AHA meeting.

▸ A thyroid hormone analogue. Roughly 30% of patients with advanced heart failure have low T₃ and normal TSH. Giving T₃ to patients with heart failure confers multiple cardiovascular benefits, including positive inotropic effects, improved diastolic relaxation, and stimulation of alpha-myosin heavy chain gene expression. But it also causes tachycardia, largely negating the improved cardiac performance.

Treatment with 3,5-diiodothyropropionic acid (DITPA), a T₃ analogue, offers similar cardiovascular benefits—but without the tachycardia. A 40-center, 34-week randomized trial is underway in 150 patients with class III/IV heart failure, low ejection fraction, low T₃, and normal TSH. Participants are assigned to one of two doses of DITPA or placebo.

▸ An atrial natriuretic peptide. Carperitide, a synthetic atrial natriuretic peptide, is an intravenous vasodilator approved for use in acutely decompensated heart failure in Japan for a decade. Its multiple effects are similar to those of nesiritide (Natrecor), recombinant brain natriuretic peptide.

An ongoing U.S. clinical trial is aimed at determining the safety and efficacy of seven different doses of carperitide in 158 patients.

▸ Adenosine receptor antagonists. These agents cause afferent arteriolar dilatation. They promote diuresis while preserving renal function and maintaining glomerular filtration rate. One agent—known at this point only as KW-3902—is the subject of an ongoing clinical trial in 200 hospitalized heart failure patients with impaired renal function. It's a 4-day treatment study with 30-day follow-up. “These agents look promising, but it's early,” Dr. Hobbs commented.

▸ Vasopressin antagonists. Nicknamed “super diuretics,” these drugs cause profound diuresis without disrupting electrolytes. The target of these drugs—vasopressin—is synthesized by the hypothalamus in response to baroreceptor and osmotic stimuli. It causes vasoconstriction and sodium and water retention.

Two vasopressin antagonists, or “vaptans,” have been tested in clinical trials: conivaptan and tolvaptan. Ongoing is the large multinational phase III Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST). Results are probably several years off, according to Dr. Hobbs.

Udho Thadani, M.D., commented that heart failure patients already have a rather full plate just with today's standard medications, which include a b-blocker, an ACE inhibitor or angiotensin receptor blocker, an aldosterone blocker such as spironolactone, and digoxin.

If even a few of the drugs with novel mechanisms of action that are in the developmental pipeline eventually find their way into routine clinical practice on top of today's standard therapy, compliance issues will become a much more prominent concern, predicted Dr. Thadani, professor emeritus of medicine at the University of Oklahoma, Oklahoma City.