CardioFit™ in treating congestive heart failure

The INOVATE-HF trial and the CardioFit device represent exciting developments in the management of autonomic imbalance in heart failure

Congestive heart failure is a clinical syndrome characterised by the failure of the heart to function as a pump to meet the body’s demands for circulation. This can be caused by damage to the heart muscle or ischaemia from coronary artery disease, genetic abnormalities in the heart muscle, such as in idiopathic (dilated) cardiomyopathy, in addition to other causes including heart rhythm disturbances, valvular heart disease, hypertension, infection, toxic and metabolic factors. The disease progression is characterised by early signs of ventricular remodelling, subsequent symptomatic and functional disability, and eventual multi-organ failure. Symptoms of fluid retention with breathlessness and leg swelling are common in addition to lethargy and fatigue. 

Heart failure is common in the Western world with a high prevalence and steadily rising incidence. The major reasons contributing to the increasing incidence in this part of the world include: better treatment of cardiovascular disease such as myocardial infarction, which keep more people alive, but with impaired heart muscle function; and an ageing population – the average age of the heart failure patient in the community is approximately 75 years. Average prevalence of heart failure is 2–2.5% overall, increasing to >10% in octogenarians. Up to 14 million people in Europe have heart failure. The average incidence of heart failure is 15/1000 inhabitants in people ≥55 years, but increases significantly in the elderly. The economic implication of such a pandemic is therefore high, with the cost of hospitalisation and mortality rates surpassing that of most forms of cancer.(1–3)

Beta-blockers and ACE-inhibitors are historically established as the cornerstone in heart failure treatment. The optimal pharmacological treatment coupled with the use of devices such as implantable cardioverter-defibrillators (ICD) and/or cardiac resynchronisation therapy (CRT) has improved both morbidity and mortality of heart failure. In spite of such advancement in therapy, the prognosis remains poor. Approximately 30–40% of subjects with advanced disease, and 5–10% with mild disease, die within five-to-ten years.(1–3)

The autonomic nervous system controls many aspects of normal body function. There are two branches to the system: sympathetic, which is responsible for the ‘flight and fight’ response and parasympathetic, which provides the opposite effects. A tight interaction between the two branches is responsible for the fine-tuning of many organ functions, including the heart, and to respond to body needs. The vagus nerve provides the key parasympathetic input into the heart. A disturbance of this ‘yin–yang’ balance is present in heart failure whereby there is overdrive of the sympathetic system and withdrawal of the parasympathetic system. This constellation has been linked to worse prognosis in patients with heart failure. Beta-blockers have been the main pharmacological tool to suppress the sympathetic overdrive in heart failure, but there has been lack of a clinical therapy to stimulate the opposing (parasympathetic) arm of the autonomic nervous system. That is, until until now. The CardioFit™ device is a novel vagus nerve stimulator developed by BioControl Medical (Yehud, Israel) that is set to change the scene. 

Prior to the arrival of this new technology, vagus nerve stimulation in animal models of heart failure has pertinently demonstrated favourable outcomes. In a rat model of heart failure, the animals that underwent vagal stimulation had a significant decrease in LV end-diastolic pressure and an increase in LV contractility in comparison with controls.(4) More importantly, vagal stimulation significantly increased survival rates at 140 days. Similar data were obtained in other animal models5 with improved survival rates, lower plasma norepinephrine levels and less increase in plasma angiotensin II levels, leading to the conclusion that vagal stimulation suppressed neurohormonal activation in heart failure, thereby improving the survival rates.

Sudden cardiac death is a common mode of mortality in heart failure as a result of ventricular arrhythmias, which is encouraged by the sympathetic overdrive in the syndrome. Our group has previously shown that sympathetic stimulation provokes, whereas vagus nerve stimulation protects, the heart against malignant ventricular arrhythmias. The results to date suggest that the effects of vagus nerve stimulation are mediated over and above antagonising the detrimental effects of sympathetic activity but that there is a direct anti-arrhythmic effect from vagus nerve stimulation that could involve a multitude of downstream molecular mechanisms.(6,7)

The CardioFit™ device (Figure 1) is an implantable neurostimulator capable of delivering low current electrical pulses, with adjustable parameters, to stimulate the vagus nerve. The stimulator is capable of sensing the heart rate via a unipolar lead placed in the right ventricle. Stimulation is delivered at a fixed delay (70ms) from ventricular activation (R wave on the ECG) with a bradycardia limit set at 55 beats/min. The stimulation lead is a 45-cm multipolar lead with multiple contacts indicated for cathodic induction of action potentials in the vagus nerve. The lead ends with a cuff that is surgically placed around the right cervical vagus nerve (Figure 2). The cuff is available in various internal diameters for optimal adjustment but shares the same external diameter and length.

During the development of the CardioFit™ device, its function has been characterised in animal heart failure models produced by coronary microembolisation.(7,8) In the treatment group, the CardioFit device was activated, with feedback on-demand heart rate control set to reduce basal heart rate by 10%. Left ventricular ejection fraction (LVEF), end-diastolic volume (EDV) and end-systolic volume (ESV) were measured from ventriculograms before and three months after therapy and compared with the treatment group and controls in which the stimulator was not activated. It was shown that the control animals had ventricular dilatation with increases in EDV and ESV as well as a decrease in LVEF, while treatment with CardioFit™ resulted in increase in LVEF and reduced LVEDV and ESV. 

Vagus nerve stimulation attenuated progressive LV remodelling as evident by evaluation of replacement and interstitial fibrosis. These effects were also investigated in the presence of background beta-blocker therapy where there was a greater increase in LVEF in the group with combined vagal stimulation and beta blocker compared with beta blocker alone. These findings suggest that beta bloakers and VNS may exert synergistic effects on the systolic function of the failing LV via different mechanisms of action.

The first human study with the CardioFit device was reported by Schwartz and colleagues in eight patients with advanced heart failure.9 At six-month follow up, there was a significant improvement in New York Heart Association (NYHA) class, Minnesota quality of life (QoL), left ventricular end-systolic volume, and a favourable non-significant trend toward reduction in end-diastolic volume. Following this favourable initial result, a multicentre pilot study was then carried out, enrolling 32 patients in Germany, Italy, The Netherlands and Serbia.(10)

All subjects were assessed as being NYHA class II–IV with reduced LV function. The mean age of the subjects was 56 years. The baseline data included on average: LVEF 22.1±7.7%, QoL score (per MLHFQ) of 51±19 and six-minute walk test of 388±97 metres. A total of 66% of the patients improved in their NYHA functional class from baseline to six months while the others remained unchanged. In addition, there were significant improvements in QoL (p<0.01), six-minute walk tests (from 411± 76 metres to 471±111 metres), LVEF (from 22±7 to 29±85%), and LV systolic volumes (p=0.02). These improvements were maintained at one year. Seven patients underwent replacement of the device without any complication. No device interaction was detected with concomitant devices such as an ICD.

With the backing of the promising preclinical and clinical pilot data, a randomised study was started in April 2012. The INOVATE-HF (Increase of Vagal Tone in Heart Failure) trial is designed to investigate the safety and efficacy of the CardioFit™ implantable electrical stimulation device for the treatment of patients with heart failure and LV dysfunction. This is a multi-centre, prospective, randomised controlled clinical trial with the aim of enrolling 650 patients with a follow-up period of 5.5 years from approximately 80 clinical sites globally (US 60, Europe 20).

The subjects consist of patients with LV systolic dysfunction (EF≤40%) with functional NYHA class III who have failed to achieve symptom relief despite optimal medical heart failure management as per applicable guidelines. The patients are randomised on a three-to-two basis with implantation of the CardioFit™ device or ongoing prescription heart failure drug therapy. The primary efficacy endpoint is time to first occurrence of unplanned heart failure hospitalisation or all-cause mortality. The primary safety endpoints are system- and device-related complications within 90 days of implantation and non-inferiority to prescription drug therapy beyond 90 days. Secondary endpoints include the rate of unplanned heart failure hospitalisation as well as the change from baseline to 12 months in heart failure symptoms as well as functional and structural cardiovascular status.

Our centre at Leicester, UK was the first site in the UK to enrol patients in INOVATE-HF. The first operation was successfully carried out at the University Hospitals of Leicester, Glenfield Hospital on 23 August 2012. Recruitment is ongoing. 

The INOVATE-HF trial represents an exciting development in the management of autonomic imbalance in heart failure. If the concept of vagus nerve stimulation translates into proven clinical benefits, the CardioFit™ device can be a potentially powerful and important addition to current pharmacological and device therapy for heart failure.

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