Cardiac Microcurrent Therapy Raises Eyebrows in Heart Failure

PHOENIX — Cardiac microcurrent (C-MIC) therapy may have great promise in heart failure (HF) — almost “too good to be true,” according to early studies.

With accruing evidence, C-MIC therapy met more objective criteria for success and showed that it could work in its new iteration as a subcutaneous rather than surgical implant, according to presentations here at the Heart Failure Society of America (HFSA) annual meeting.

In a post hoc analysis of the C-MIC II trial, 6-month results still favored C-MIC over controls when cardiopulmonary exercise test (CPET) analysis was repeated using a blinded core lab:

• Absolute peak VO2: 208.7 with C-MIC vs 7.3 mL/min with non-implanted controls (P=0.079)
• Peak metabolic equivalents (METs): 1.0 vs 0.1 (P=0.021)
• Percent-predicted peak VO2: 13.8% vs 0.5% (P=0.021)

Weight-adjusted peak VO2 also improved with a +2.70 mL/min/kg change, reported Dragana Kosevic, MD, of Cardiovascular Institute Dedinje in Belgrade, Serbia.

“Objective CPET findings support the functional benefits observed in C-MIC II,” she told the audience. “Larger randomized studies should confirm these findings.”

C-MIC II: Microcurrents Established Through Epicardial Implant

HFSA session discussant John Teerlink, MD, of San Francisco Veterans Affairs Health Care System and UCSF Medical Center, remarked on the “incredible” (in the literal sense) magnitude of benefit reported in C-MIC II. He cited the suspiciously high +2.70 improvement in weight-adjusted peak VO2 in particular.

“I am highly skeptical of the magnitude of the benefit that you folks are showing, but I remain actually very enthusiastic about moving this forward,” Teerlink said.

“Yes, it is too good to be true, to be honest,” Kosevic responded. “That’s why we need more. We need shell randomized studies and more patients and more centers involved.”

Surgical C-MIC therapy was developed to address myocardial alterations in electrical fields, which have been associated with myocardial edema that can act as a substrate for left ventricular dysfunction. C-MIC is believed to work by shifting activated fibroblasts toward a less fibrogenic state, producing less myocardial stiffness and improving ventricular structure and function.

The C-MIC II trial had shown benefits at 6 months of C-MIC in patients with refractory, non-ischemic heart failure with reduced ejection fraction (HFrEF). Based on 65 randomized patients, surgical epicardial implant of the C-MIC system was associated with improved left ventricular ejection fraction (LVEF), symptoms, functional capacity, and quality of life compared with controls — though peak VO2 only trended toward benefit without reaching statistical significance.

The CPET re-analysis thus provides some confirmation of C-MIC II, which originally relied on site-reported CPET values sans central CPET adjudication and which left room for problems with heterogeneous acquisition and bias.

The re-analysis population included 42 people (mean age about 62 years, over 70% men, LVEF 30%).

C-MIC III: Green Light for Pivot to Subcutaneous Approach

The next major item on the agenda will be development of the C-MIC implant under a subcutaneous approach.

During the same HFSA session, Stefan Simovic, MD, of the University of Kragujevac in Serbia reported initial evidence that C-MIC therapy could be delivered by a more accessible approach to a sicker population. With subcutaneous C-MIC, the generator and lead are placed subcutaneously, lead position is confirmed via fluoroscopy, and the procedure is performed by an electrophysiologist in the cath lab with the patient under moderate sedation.

Matching 10 patients who got a subcutaneous implant (in the C-MIC III first-in-human study) and 10 peers with a surgical implant (from C-MIC II), Simovic’s group showed comparable improvements in LVEF, 6-minute walking distance, and Kansas City Cardiomyopathy Questionnaire (KCCQ) quality-of-life scores as compared with another 10 matched controls from C-MIC II.

These findings add to the momentum from C-MIC III’s 6-month results, reported earlier this year, that had suggested improved LVEF (by 6 points), 6-minute walking distance (by 90 m), and quality of life (KCCQ up 30 points), all significant improvements from baseline.

The first-in-human study is far from conclusive, however, given its 10-person sample.

C-MIC II, while randomized, also had major limitations, having just several dozen patients enrolled and relying on an open-label design. What’s more, only five out of seven sites participated in the CPET re-analysis.

Patients chosen for the matched analysis of C-MIC II versus C-MIC III were 67 years old on average across groups. Despite matching, the C-MIC III patients still had more advanced disease at baseline, with lower ejection fractions and greater end-diastolic and end-systolic dilation.

C-MIC IV: Upcoming Sham-Controlled Trial and Questions of Safety

There is thus great interest in whether C-MIC can perform well in its next large test, the C-MIC IV sham-controlled crossover trial.

This study will include 60 people with LVEF in the 20%-40% range, and it will include people with non-ischemic and ischemic HF, all getting the subcutaneous device, according to Simovic. This expands the patient pool from C-MIC II and III, which had excluded people with previously implanted devices or ischemic cardiomyopathy.

Looking forward, Teerlink raised concerns about interference from existing implants, including implantable cardioverter-defibrillators (ICDs), cardiac resynchronization therapy, baroreflex activation therapy, cardiac contractility modulation, and coronary stents. “I mean, if somebody has coronary stents, do you actually electrically induce currents in those with this microcurrent probe?”

“We still do not have data on interference,” Simovic acknowledged. “We are afraid of interference, especially with the ICD lead.”

He added that observations of complications among C-MIC II surgical implants showed improvement with C-MIC III’s subcutaneous approach. Even so, the latter did result in infection.

“As you know, in devices, the thing that we are most afraid of are infections, and we did encounter one infection with the subcutaneous implant system. However, I have to note that looking from the empirical point of view, so not scientifical point of view, the explanation of the [subcutaneous C-MIC] system was much easier,” Simovic said.