Vagal nerve stimulation for heart failure: new pieces to the puzzle?

Heart failure (HF) remains an important public health problem, which is increasing in incidence and prevalence.1 In the USA and many European countries, HF is the most common reason for hospitalizing adult patients. This ‘epidemic’ of HF has occurred despite important advances in pharmacological and device-based therapies over the past 25 years. However, the pace of new therapies has declined significantly. For instance, the recent PARADIGM-HF study2 identified the first new class of drugs for the treatment of heart failure with a reduced ejection fraction (HFrEF) in over a decade. Moreover, there are still no established pharmacological therapies for the treatment of heart failure with a preserved ejection fraction (HFpEF). Similarly, the guidelines for implantable cardioverter-defibrillator (ICD) use for primary prevention in HF have changed little over the past decade. In general, the guidelines for use of CRT have become more focused rather than expanding, with the exception of CRT for heart block patients with mild LV dysfunction.

Given the increasing burden of HF and the lack of new indications with conventional therapies, there has been renewed interest in finding innovative treatments.3 Device therapy to achieve autonomic modulation is one such area that has garnered significant interest. The pathophysiological basis for such therapies is well established as autonomic imbalance is an important aspect of HFrEF.4-6 There have been many approaches in development to modulate autonomic activity, including vagus nerve stimulation (VNS), spinal cord stimulation, baroreceptor activation, and renal artery denervation. These areas of investigation are at different levels of development, but share many of the same issues and questions for clinical investigation. Specifically, what is the appropriate trial design? How do we determine that autonomic modulation is occurring? What are appropriate clinical endpoints for device trials when it is hard to achieve adequate blinding? How is the delivery of therapy optimized?

The questions raised by these new innovative therapies are similar to those raised with more conventional treatment modalities. The lessons learned from drug and cardiac rhythm device trials are very instructive in this regard. Pharmacological studies showed that the concept of a class effect of drugs may be an oversimplification. For instance, not all beta-blockers are equally effective. There may even be differences in the clinical efficacy of different formulations of the same agent, as shown in the comparison of metoprolol succinate and tartrate. In addition, dose is important to achieve the full effect of the drug.

Studies of cardiac rhythm devices have identified other issues for studying HF therapies. For pharmacological studies, the prospective, double-blind, randomized, placebo-controlled trial design is the accepted gold standard. However, this is not always possible or appropriate for device trials.7 For instance, a therapy may cause symptoms, such as phrenic nerve stimulation with CRT, so that blinding is violated. There are ethical and regulatory issues with the use of implanted but inactivated devices for long-term studies. This is due in part to the fact that acute and long-term risks of an implanted device are much greater, even if inactivated, compared with a placebo drug. Some other factors which impact ICD or CRT outcomes include the intensity of therapy, programming of devices, and stimulation location. Interestingly, all of the above noted effects were observed in therapies already established and shown to reduce mortality. In some ways it is fortuitous that this was the case. It is speculated that if dual-chamber ICDs had been available for early primary prevention studies and programmed to nominal settings, then the benefit of this therapy would never have been established for primary prevention of sudden cardiac death.

Given the number of factors that affect outcomes with established therapies and the uncertainties of optimal trial design, it should not be surprising that novel therapies could have inconsistent results in early clinical trials. The two best studied device therapies for autonomic modulation are spinal cord stimulation and VNS.

Animal studies of thoracic spinal cord stimulation suggested a potential benefit of this treatment in HF,8 and a small open-label pilot study of nine HF patients also showed an improvement in functional status in most patients.9 In contrast to these encouraging results are the data of the recently presented DEFEAT-HF study.10 This was a single-blind, randomized study of 66 patients which showed no improvement in LV end-systolic volume index (primary endpoint) measured by echocardiography or clinical symptoms. In addition to trial size and design, other important differences between these studies should be noted. Specifically, in DEFEAT-HF, only one spinal cord segment was stimulated as opposed to multiple segments in the pilot trial and animal studies. In addition, there was a shorter duration of active stimulation over the course of the day. SCS HEART and TAME-HF are two additional ongoing studies that should provide further insight into the benefit of spinal cord stimulation in systolic heart failure.

Vagus nerve stimulation is an example of a new application of an established technique. The safety and efficacy of VNS for the treatment of epilepsy and depression are well established.11 With regard to the effect in HF, pre-clinical studies demonstrated the benefit of VNS to improve LV function and reduce mortality in a variety of animal models.4-6 These studies have demonstrated the pleiotropic effects of this therapy. In addition to lowering heart rate, VNS reduces inflammation, inhibits sympathetic activity, and modulates nitric oxide levels in cardiac myocytes.4

Based on the encouraging results of pre-clinical investigations, a number of clinical studies of VNS were initiated, as summarized in Table 1. DeFerrari et al. reported a multicentre, non-randomized study of 32 patients who were implanted with the Cardiofit system produced by BioControl Medical.12 VNS improved quality of life and LV systolic function, which has been maintained over long-term follow-up in an extension phase of the study. Moreover, the system was found to be safe and tolerated. These encouraging results have led to several other studies, two of which were recently presented in September 2014 at the European Society of Cardiology Meeting in Barcelona.

NECTAR-HF was a prospective, double-blinded, randomized control study that enrolled 96 patients with NYHA class II–III functional status and LVEF ≤35% and evaluated right-sided VNS produced by the Boston Scientific system.13 It failed to demonstrate an improvement in LV end-systolic diameter at 6 months, the primary endpoint of the trial. However, there was a significant improvement in quality of life, and the safety of the system was confirmed.

ANTHEM-HF was a prospective, open-label study of 60 patients randomized to right- or left-sided VNS (Cyberonics) for 6 months.14 Both right- and left-sided VNS significantly improved echocardiographic measures of reverse remodelling (LVEF and LV end-systolic diameter) compared with baseline, but there was no control group, i.e. all patients received VNS. VNS was shown to be safe and well tolerated.

How do we interpret the findings of these studies? All three studies were small, and the results may simply reflect statistical anomalies of underpowered trials. The double-blind design of NECTAR-HF should reduce the impact of a ‘placebo effect’ which can lead to improved outcomes independent of the therapy. However, blinding is difficult as patients can often sense vagal stimulation during device titration, as noted in the NECTAR-HF results. Follow-up was only 6 months in both of these trials, which may have precluded observing more long-term benefit. There are also important differences in the stimulation current achieved with these different systems. The lowest current was delivered in NECTAR-HF, which may have been insufficient to activate efferent vagal cardiac B fibres, whereas the higher stimulation current that was achieved with Cardiofit or ANTHEM-HF trials might explain the better results.

The INOVATE-HF study should help address many of the uncertainties regarding the role of VNS for adjunctive therapy in the treatment of HFrEF.15 This is the first trial with sufficiently long follow-up and HF events as an endpoint; further, this trial will increase the number of patients implanted with VNS more than four-fold. At least 650 patients will be randomized in INOVATE-HF and they will be followed for at least 2 years. The primary endpoint is the time to first HF hospitalization or death from any cause. One of the potential advantages of the VNS system used in INOVATE-HF is that it is capable of delivering more current while limiting side effects due to a novel electrode design. Thus, this should be the first clinical trial appropriately powered to test the hypothesis that device-based autonomic modulation can impact the ‘hard’ clinical outcomes associated with HF hospitalization and mortality. At the time of writing (the end of 2014), >550 patients have been enrolled in INOVATE-HF, but, until this trial is completed, ongoing studies should provide more data to help our understanding of the role of various modalities for device-based treatment of HF.

Conflict of interest: All authors are consultants to BioControl Medical and members of the Steering Committee of INOVATE-HF.