Clinical trials update from the Heart Failure Society of America meeting: FIX-CHF-4, selective cardiac myosin activator and OPT-CHF

1.1. Presented by Martin Borggrefe from University of Heidelberg, Germany

The concept of applying an electrical stimulus during the absolute refractory period to the failing heart to enhance contractility has existed for many years, 1 but the FIX programme is the first to try to demonstrate that this technology can be used on a large scale, to improve symptoms, cardiac function and outcomes in patients with heart failure.

The technique involves implanting a pacing-type device, known as cardiac contractility modulation or CCM, with a sensing lead in the right atrium and two right ventricular leads that deliver relatively large amplitude electrical stimuli during the absolute refractory period of the myocardium. Since the stimulus occurs during the absolute refractory period, it does not cause another contraction but is reported to improve cardiac contractility. The mechanism of effect is thought to be due to improved cardiac myocyte calcium handling but other potential mechanisms of action have not been discounted, such as stimulation of cardiac nerves which could enhance sympathetic activation. The power output required can rapidly drain existing generators. Accordingly, in the clinical studies conducted so far, the device has been turned on for only 4 h per day. However, short-term cardiac support during the day could still have important benefits. Preliminary studies have been encouraging 123 and randomised controlled studies in heart failure patients are now required. Two studies of CCM therapy were reported at this meeting.

In a randomised, double-blind pilot study to assess the safety and efficacy of CCM therapy, 49 patients with NYHA class III heart failure refractory to medical treatment, and with normal QRS width were implanted with a CCM and randomly assigned to have the device switched on or off for 6 months. There were some baseline imbalances between the treatment groups for LVEF and peak VO₂, which make interpretation of the results difficult. Although the study showed some interesting trends, due to the small number of patients none of these achieved statistical significance 4.

FIX-CHF-4 was a randomised, double-blind, cross-over study in 129 patients to evaluate the use of CCM therapy in medically refractory NYHA class II-III heart failure. Patients were randomised to having the device switched on or off for the first 12 weeks and then crossed over for the second 12 week period. The primary endpoints were exercise tolerance and quality of life measured by the Minnesota Living With Heart Failure Questionnaire. During the first 12 week period, both groups showed a similar increase in exercise tolerance, suggesting a strong placebo effect. However, following the cross-over, the group in whom the devices were switched on showed further improvements in exercise tolerance compared to the patients in whom the device was switched off. Thus, at 24 weeks there was a significant difference in peak oxygen consumption between the groups (1.25 ml/kg/min; p=0.02). Quality of life scores showed a similar pattern, with a significant difference between groups at 24 weeks (p=0.03). These data show that in those patients in whom therapy can be implanted and who survive 12 weeks (there were 3 none procedural deaths), there may be an advantage to a CCM device. Clearly, confirmatory data are required.

Another study of CCM therapy, FIX-CHF-5, which is an open, randomised study to evaluate the safety and efficacy of CCM therapy over a 1 year treatment period in 420 patients with NYHA class III-IV heart failure, is currently ongoing and aims to complete in April 2007.

2.1. Presented by John R Teerlink from University of California, San Francisco, USA

An agent with an inotropic effect that does not increase energy demands or cytosolic calcium might be valuable for the treatment of acute or chronic heart failure. Cardiac myosin activators are designer molecules that increase myofibril ATPase activity, thereby altering the function of myosin so that the sarcomere can increase force generation without consuming more energy in the form of ATP. Data from experimental models have demonstrated improvements in cardiac function, suggesting that the cardiac myosin activator CK-1827452 may be beneficial for the treatment of human heart failure 5,6.

The results of the first study in healthy volunteers, which were presented at this meeting, support the safety of administration of a 6 h infusion of CK-1827452. The maximum tolerated dose was 0.5 mg/kg/h. Interestingly, these agents appear to increase the duration of systole rather than the rate of increase in systolic pressure, which contrasts with conventional inotropic agents.

In light of these data, the first trials in patients with heart failure are due to start shortly.

3.1. Presented by Joshua M Hare from John Hopkins University, Baltimore, USA

The synthesis of uric acid generates free radicals and thus oxidative stress, which may cause cardiovascular damage and contribute to the progression of heart failure. Hyperuricaemia is associated with a worse prognosis amongst patients with heart failure. Hyperuricaemia may just be a marker of patients with more advanced heart failure and declining renal function, could reflect the rate of synthesis of uric acid and therefore oxidative stress or could even be beneficial, since uric acid itself is an anti-oxidant 7. Clearly, intervention studies are required to clarify whether uric acid levels should be reduced, ignored or elevated further. Many patients with heart failure receive treatment with the xanthine oxidase inhibitor, allopurinol, and there is some evidence that this agent can improve vascular function and symptoms 8,9. Accumulated evidence suggests a role for the xanthine oxidase metabolic pathway in the pathophysiology of heart failure 10. The aim of the OPT-CHF study was therefore to evaluate the effect of the novel xanthine oxidase inhibitor oxypurinol in patients with heart failure.

In OPT-CHF, 405 patients with NYHA class III-IV heart failure and LVEF ≤40% were randomly assigned to double-blind treatment with either oxypurinol (600 mg/day) or placebo, for 24 weeks. The primary endpoint was a composite and was used to define outcome as improved, unchanged or worse. Although there was a significant reduction in uric acid levels in the oxypurinol group compared to placebo, this did not translate into a therapeutic benefit (Table 1). There was no reported difference in the composite endpoint between the two treatment groups (p=0.357) and an adverse trend on cardiovascular death or hospitalisation for heart failure (p=0.055). In a subgroup analysis of patients with elevated serum uric acid levels at baseline, there was an indication of a beneficial effect for oxypurinol. This post-hoc analysis suggests that a trial of urate reduction specifically in those patients with a high urate might be the next step.