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The Pump House

Future improvements for heart failure patients will come from revolutionary treatments

Heart failure (HF) is a complex problem resulting from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill or eject blood adequately. In such a case, the heart is unable to supply sufficient blood flow, and therefore oxygen, to peripheral tissues and organs.

Due to the heart's weakened pumping ability, fluid retention also occurs as blood backs up in the vessels around the lungs, causing seepage into the lungs, which results in fatigue and shortness of breath (dyspnoea). Everyday activities, such as walking, carrying groceries or climbing stairs, can become very difficult; if left untreated, heart function progressively deteriorates leading to acute HF and also possibly death.

HF clearly has a significant impact on a patient's quality of life, but it is also a major public health concern affecting an estimated four to five million people in the United States (US) and 10 million people in countries throughout Europe. It is one of the most important causes of mortality and morbidity, with one-year mortality figures ranging from 50-60 per cent for patients diagnosed with severe failure, 15-30 per cent in mild to moderate failure, and about 10 per cent in mild or asymptomatic failure.

However, the combination of an ageing population and improved survival rates following acute myocardial infarction is leading to a rapid increase in the number of patients living with chronic heart failure and, concomitantly, increased numbers of patients hospitalised for decompensated heart failure.

HF can be subdivided into either systolic or diastolic categories. Systolic failure is linked to reduced cardiac contractility, whereas diastolic heart failure results in impaired cardiac relaxation and abnormal ventricular filling. The most common cause of HF is left ventricular systolic dysfunction, occurring in 60 per cent of HF patients.

Conditions leading to left ventricular systolic dysfunction include idiopathic dilated cardiomyopathy, valvular heart disease, hypertensive heart disease, toxin-induced cardiomyopathies, and congenital heart disease.

Diastolic left ventricular dysfunction is usually related to chronic hypertension or ischaemic heart disease. Inadequate organ perfusion ends in multiple systemic neurohormonal pathway activation, compensating initially by redistributing blood flow to vital organs, but later exacerbating symptoms, leading to deterioration and progression to chronic HF if left untreated. Consequently, the aim of HF intervention is to treat the underlying cause of the condition, improve symptoms and quality of life, provide stabilisation and improvement of cardiac haemodynamics, and thereby lead to improved long-term outcomes and prognosis.

Which HF model?
Cornerstone therapies used to treat HF include angiotensin-converting enzyme (ACE) inhibitors, aldosterone receptor blockers, angiotensin II receptor blockers, beta-blockers and diuretics, plus cardiac glycosides, as well as selective aldosterone receptor antagonists.

Until the early 1990s, the prevailing hypothesis for treatment was based, in large part, on a haemodynamic understanding of heart failure with an emphasis on abnormally increased loading conditions, both preload and afterload. Introducing ACE inhibitors, however, led to the first major reductions in morbidity and mortality due to HF. Consequently, targeting the renin-angiotensin-aldosterone system drew attention away from a haemodynamic model and directed it towards a neurohormonal treatment model targeting the sympathetic nervous system.

The realisation that a perturbed neurohormonal environment is central to the progression of left ventricular dysfunction - the neurohormonal hypothesis - has now become the platform for the majority of current pharmacological interventions in heart failure.

Support for the neurohormonal hypothesis was provided by the striking benefit of low-dose aldosterone blockade observed in the Randomised Aldactone Evaluation Study (RALES) trial. Treatment with spironolactone (Aldactone), an aldosterone antagonist, resulted in almost 35 per cent improvement in the risk of death in patients with advanced heart failure already treated with ACE inhibitor therapy.

However, concerns have been raised that too much neurohormonal blockade may not be a good strategy. The Valsartan (Diovan) Heart Failure Trial (Val-HeFT) suggested that a combination of ACE inhibitors, beta-blockers, and angiotensin receptor antagonists was less helpful and associated with more cardiovascular events than ACE inhibitors and beta-blockers alone.

New avenues
HF therapies have advanced greatly over the last 10 to 15 years, leading to a significant improvement in the management of patients with the disorder. However, it has been suggested that perhaps a nadir in the reduction of mortality by pharmacological agents has been reached, and future reductions will now likely come from new biological or genomic targets.

Examples of newer drug classes and treatment approaches include: synthetic natriuretic peptides, arginine vasopressin antagonists, erythropoietin therapy and stem cell therapy.

Ularitide
Ularitide is a synthetic form of urodilatin, a naturally occurring human natriuretic peptide involved in the regulation of blood pressure and the excretion of water and sodium from the kidneys.

Urodilatin is produced in the kidney and excreted into the urine, and thus exists naturally in low levels in the systemic blood circulation. When injected into the blood, ularitide appears to cause diuresis (urine output) and natriuresis (sodium excretion), as well as vasodilation. Currently in phase II development with PDL BioPharma for the treatment of acute decompensated HF, ularitide has shown promising results in a recent multicentre, double-blind trial involving 221 patients randomised equally to receive placebo or Ularitide at doses of 7.5, 15, or 30ng/kg/ min as a 24-hour intravenous infusion.

The SIRIUS (Safety and efficacy of an Intravenous placebo-controlled Randomised Infusion of Ularitide in a prospective double-blind Study) II trial showed ularitide to reduce pulmonary capillary wedge pressure significantly and improved dyspnoea score, which were the primary endpoints, in all three dose groups compared with placebo.

Vasopressin 2 antagonist
Tolvaptan, the lead compound from a series of vasopressin 2 antagonists from Otsuka, increases net fluid volume loss in heart failure without adversely affecting electrolytes and renal function. In a double-blind, randomised ACTIV in CHF trial (Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart failure) involving 319 patients with congestive HF, the primary endpoint for the in-hospital phase, which was a change in bodyweight at 24 hours, showed a significant decrease in patients receiving tolvaptan. It also reduced 60-day mortality significantly in patients with severe congestion and tended to decrease mortality in those with elevated blood urea nitrogen. However, the incidence of adverse events, such as thirst, dry mouth and polyuria tended to be higher in tolvaptan, compared with placebo recipients. Lixivaptan, an oral, nonpeptide, selective arginine vasopressin 2 receptor antagonist, under development by Cardiokine, has also showed promising results in a recent US-based multicentre, randomised trial.

Darbepoietin alfa
Anaemia is highly prevalent in patients with chronic HF and is associated with poor clinical outcomes.

Multiple mechanisms contribute to it, of which one is a subnormal compensatory rise in endogenous erythropoietin. There is evidence to support early correction of anaemia with subcutaneous erythropoietin and intravenous iron in patients with HF improves shortness of breath and fatigue, cardiac function, renal function and exercise capacity, reducing the need for hospitalisation and improving quality of life.

In a recent double-blind, randomized trial, Kirin-Amgen's darbepoietin alfa [Aranesp, Nespo], a hyperglycosylated version of a recombinant human erythropoietin, demonstrated significantly improved haemoglobin levels and patient symptoms.

Furthermore, quality of life measures were also improved significantly after approximately four months of treatment.

Stem cell therapy
Stem cells are those at an early stage of maturation and can develop into specific types of cell, such as heart muscle cells. The infusion of such cells into a patient's heart may provide a means of 'replacing' damaged cardiac cells with new, functional cells.

The double-blind, REPAIR-AMI (Reinfusion of Enriched Progenitor cells And Infarct Remodelling in Acute Myocardial Infarction) proof-of-concept study investigated the efficacy of intracoronary infusion of bone marrow-derived progenitor cells for the treatment of acute ST-segment elevation infarction. The primary endpoint of the study was the change from baseline in left ventricular ejection fraction (LVEF) four months after treatment. Some 204 patients were randomized to receive bone marrow-derived progenitor cells, or placebo.

Four months after treatment, stem cell recipients demonstrated significantly greater improvements from baseline in LVEF, compared with placebo recipients. Similarly, beneficial effects were seen in patients receiving bone marrow mononuclear stem cells, which were drawn from their marrow approximately four hours before the procedure. In these patients with end-stage HF, four months of treatment resulted in significantly fewer HF symptoms and angina pectoris, and their hearts demonstrated a superior ability to pump blood, compared with untreated patients. While HF is a major cause of morbidity and mortality in the general population, recent advances in combination therapies, coupled with the development of novel therapeutic agents, offer a brighter future.

The author
The author is Sarah Lount of Adis International,using information derived from Adis Clinical Trials Insight and R&D Insight. For more information on Adis services, call Camille Scot-Smith on 020 7981 0733

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2nd September 2008

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