VIENNA — An implanted device therapy for heart failure (HF) that seemed to improve both functional and clinical outcomes in randomized trials and a registry study was widely seen as both promising and a bit mysterious at two recent subspecialty meetings.
Patients implanted with the Optimizer (Impulse Dynamics) pulse-generator and endocardial-lead system in the studies showed significant improvements in exercise capacity, 6-minute walk test (6MWT), symptoms, and quality-of-life measures as well as fewer HF hospitalizations and longer survival.
The treatment, long in development and dubbed cardiac contractility modulation (CCM), is seen by its proponents as a possible strategy for some patients with HF who have few other options.
Studies have included patients with HF and a "mid-range" left ventricular ejection fraction (LVEF) of 25% to 45%, who were still in at least NYHA class III despite optimal meds. Importantly, they had QRS durations less than 130 msec, too narrow to be suitable for cardiac resynchronization therapy (CRT).
"These patients aren't yet sick enough to be considered end-stage heart failure, to be candidates for transplantation or LVAD [left-ventricular assist device]. On the other hand, they're not in class I or class II and not doing well enough for either the patient or the clinician to be satisfied," said William T. Abraham, MD, Ohio State University, Columbus.
The combined randomized-trial and registry experience also suggests that CCM's effect on functional and clinical outcomes applies to patients with LVEF in the 35% to 45% range and may even be more pronounced in that subgroup.
CCM "promises to fill a very large unmet need in the management of heart failure," Abraham told theheart.org | Medscape Cardiology.
Improved Clinical Outcomes in Context
The therapy consists of repeated daily intervals of electrical myocardial stimulation by the implanted generator. The stimulation doesn't engage cardiac rhythm but is believed to affect myocardial biochemistry, first near the stimulation site and more broadly over time, in a way that eventually seems to improve global contractile function.
The treatment was associated with a 3-year mortality about three fourths the predicted rate, and HF hospitalizations at 2 years were cut by about 75% in data from 140 patients with narrow QRS and LVEF of 25% to 35% in the European registry CCM-REG.
The clinical benefits were preceded by significant, sustained improvements in LVEF, symptoms, and quality-of-life measures, said Gerd Hasenfuss, MD, Heart Center Göttingen, Germany, presenting the registry findings here at European Society of Cardiology Heart Failure (ESC-HF) 2018.
A few weeks earlier, Abraham had presented data from a randomized trial of CCM or no CCM along with optimal medical therapy (OMT) for 24 weeks in 160 patients similar to those in the European registry: narrow QRS intervals, LVEF of 25% to 45%, and NYHA class III or ambulatory class IV.
His presentation of the FIX-HF-5C study in May at the Heart Rhythm Society (HRS) 2018 Scientific Sessions in Boston, Massachusetts, showed significant treatment benefits for peak VO2, change in NYHA class, and quality-of-life scores.
"CCM is a unique alternative in the narrow-QRS population of patients," Abraham said. The CCM-treated patients showed a peak VO2 response that was 0.84 mL/kg/min better than in controls. "That's very comparable to what we see with CRT in the wide-QRS population, where average improvement in peak VO2 is about 0.9 mL/kg/min."
Also, about twice as many patients on CCM compared with controls improved by at least one NYHA class during the 24-week study, he noted. And they showed an 11-point improvement on the Minnesota Living With Heart Failure Questionnaire (MLWHFQ). "Again, very comparable to what's seen with CRT."
Current best medical therapy for HF, including β-blockers and angiotensin-converting enzyme inhibitors, seem to improve MLWHFQ scores by only 4 to 5 points, Abraham said, "so the magnitude of benefit here is really quite robust."
The European registry and FIX-HF-5C showed heightened responses in patients with LVEF of 35% to 45% compared with either the 25%-to-35% subgroup or the entire 25%-to-45% cohort.
FIX-HF-5C was published May 10 to coincide with presentation of the trial at the HRS sessions by Abraham, who is lead author. He said the trial has been submitted for a promised priority review of the device for possible US Food and Drug Administration approval. It is already approved in Europe, India, Brazil, and a few other countries.
New Addition to the Armamentarium?
The trial, Abraham said, "now establishes CCM as a new addition to our armamentarium for the treatment of these class III and ambulatory class IV patients with narrow QRS complexes."
Others at the two meetings weren't so firmly convinced, even as they seemed hopeful CCM would work as claimed.
The trial "I think certainly makes a good case for going ahead with the device," Jagmeet P. Singh, MD, DPhil, Massachusetts General Hospital, Boston, told theheart.org | Medscape Cardiology.
"I think in a narrow-QRS patient population with this intermediate ejection fraction who have their quality of life significantly impacted — if you have a device therapy option that actually moves the needle for that — I would certainly think that it has a role," said Singh, who is an electrophysiologist.
HF specialist Andrew L. Clark, University of Hull, Kingston-Upon-Hull, United Kingdom, seemed guardedly enthusiastic about the treatment's potential. As invited discussant after the Hasenfuss presentation, he seemed delighted that an implant therapy may improve quality life in such a "very sick population" unsuitable for CRT.
Directing his comment at Hasenfuss, Clark said, "I think this is a fantastically exciting thing, but you've shown me something that I don't feel I understand, and I always find that slightly alarming."
Citing the aphorism "Extraordinary claims require extraordinary evidence," Clark said, "I think we have to interpret some of these results with not scepticism, exactly, but with a degree of caution."
After Abraham's presentation of FIX-HF-5C, discussant Lynne Warner Stevenson, MD, Brigham and Women's Hospital, Boston, also seemed puzzled by the treatment's mechanism of action.
"For me, anyway, it's a little hard to understand the concept," she said. How CRT works seems more straightforward, she noted, but "I don't yet really understand the CCM effects."
Nor is the electrical stimulation's dose-response effect clear from the available research, which has used different daily stimulation times, Stevenson pointed out. And more needs to be learned about which patients are most likely to benefit from the device therapy.
CCM has been long compared to CRT as another HF device therapy using a pulse generator and leads, but the similarities go beyond the technology, Abraham said in an interview.
"It turns out that CCM, CRT, and β-blockers in treating heart failure share something in common — they all have favorable effects on myocardial gene expression."
In HF, "the heart moves toward a fetal program of gene expression, a state of less contractility" in which proteins important to intracellular calcium handling are downregulated, he said. "β-Blockers, CRT, and CCM move it back toward the more adult profile of gene expression, which favors improved contractility."
CRT's mechanism of effect at first seem intuitive, but "it's not just simple resynchronization of the ventricles. There are biological effects on the heart that lead to improved contractility, and CCM has been demonstrated to do all of that."
The molecular changes start within a few centimeters of the pulse-delivery site on the right side of the intraventricular septum and gradually spread across the myocardium, according to Impulse Dynamics marketing literature.
Guided by atrial and ventricular-septal sensing leads, pulse delivery is timed to the absolute refractory period of ventricular contraction so that it doesn't trigger a new action potential, the company says.
"We asked these same questions early-on with CRT: Is there a proarrhythmic effect or is there some downside? The answer is no, we don't see any increase in arrhythmia or anything else that would mitigate some of the improvements in functional status that we see with CCM," Abraham said.
Results of FIX-HF-5C
At 24 weeks after the start of randomized therapy, the 74 patients undergoing CCM on top of OMT showed a significant rise in peak VO2 averaging 0.836 mL/kg/min compared with the 86 patients receiving OMT only, whereas the groups had been about equal at baseline.
The CCM group showed a mean 11.7-point advantage in improvement on the MLWHFQ (P < .001). Fully 81% of CCM-treated patients but 42% of controls showed at least a one-step improvement in NYHA functional class (P < .001), and the 6MWT distance increase averaged 43 m and 9.3 m, respectively (P = .0093).
Among patients with LVEF of 35% to 45%, the CCM group showed a mean 1.76-mL/kg/min peak VO2 advantage over controls (P = .009) and a 15-point better response on the MLWHFQ (P = .003). NYHA functional class improved by at least one step in 71% and 51%, respectively (P = .012).
The composite rate of cardiovascular death and HF hospitalizations was marginally significantly lower in the CCM group: 2.9% vs 10.8% for controls (P = .048).
Clinical Outcomes in CCM-REG
The CCM-REG registry included 145 patients treated with CCM at 31 sites across Europe. The cohort resembled the FIX-HF-5C population in that they had a narrow QRS and LVEF of 25% to 45%; they were followed for 2 years for hospitalizations and 3 years for mortality.
Table 1. Two-Year Cardiovascular and HF Hospitalization Rates Before vs After Registry Enrollment in CCM-REG
|Endpoints||Events per Patient-Year Before Enrollment||Events per Patient-Year After Enrollment|
|LVEF 25% to ≤45%||0.96||0.26|
|LVEF 35% to 45%||0.82||0.16|
|LVEF 25% to ≤45%||0.24||0.09|
|LVEF 35% to ≤45%||0.40||0.08|
|HF or CV hospitalization|
|LVEF 25% to ≤45%||1.20||0.35|
|LVEF 35% to ≤45%||1.23||0.24|
|P < .0001 for all postenrollment vs pre-enrollment event rates. CV = cardiovascular.|
Significant improvements in HF and cardiovascular hospitalizations were accompanied by significantly better survival for the CCM patients compared with predicted survival based on two validated risk-prediction models.
Table 2. Three-Year Survival Rates in the CCM-REG Cohort Compared With Two Risk Prediction Models, by LVEF Range
Soft vs Hard Endpoints
Some observers have cited the randomized trial's focus on exercise capacity and other functional measures as a limitation because of their "softness" as endpoints compared with mortality or even hospitalization. Abraham sees that focus as a strength.
"I would say perhaps we have come full circle in heart failure. CRT was initially approved on the basis of improvements in the 6-min hall walk, quality-of-life scores, and NYHA class ranking. And then we entered a period of about a decade or so where the focus shifted to morbidity and mortality," Abraham said.
"And finally we came back to appreciate the importance of these patient-centered endpoints." The harder endpoints may seem more important to researchers, "but if you ask clinicians in practice or patients what's most important, they want to feel better and perform more activities of daily living and have improved quality of life."
Singh said CCM seems promising for the subset of patients explored in the studies, but he's hesitant to embrace functional endpoints over mortality and morbidity events.
"As an electrophysiologist, I'm still not completely comfortable with the peak VO2 argument. I think that is still something that needs to be explored. Most of us still hang our hats on heart failure hospitalizations and mortality and harder endpoints."
The limitations of softer endpoints may be most noticeable in trials without placebo controls. Although the FIX-HF-5C trialists used blinded endpoint adjudication and other measures in an effort to limit bias, a sham control arm to blind patients to their treatment assignment would have been preferable, Clark observed.
"When you've been told by somebody that you've got a very exciting, very new, very expensive piece of equipment being implanted into you, I think it is possible it may influence how you perform on the treadmill," he said.
"And it may influence how you behave should you become unwell and decide whether or not to present yourself to the doctor or get yourself admitted to the hospital."
FIX-HF-5C was supported by grants from Impulse Dynamics, for which Abraham discloses serving as a consultant; disclosures for the other authors are in the report. Hasenfuss discloses consulting or receiving honoraria for lectures from Corvia, Servier, Impulse Dynamics, Novartis, and Vifor Pharma and honoraria for lectures from AstraZeneca and Berlin Chemie. Singh discloses receiving grants or compensation for services from Abbott, Biotronik, Boston Scientific, EBR Systems, Medtronic, Impulse Dynamics USA, and LivaNova. Clark has reported no relevant conflicts. Stevenson has disclosed receiving research grants from Novartis, consulting or serving on an advisory board for Abbott and travel expenses or meals from Novartis and St Jude Medical.
European Society of Cardiology Heart Failure (ESC-HF) 2018. Late breaking trial III - Innovative and device therapy. Presented May 28, 2018.
Heart Rhythm Society (HRS) 2018 Scientific Sessions. Late-Breaking Clinical Trials. B-LBCT01. Presented May 10, 2018.
JACC: Heart Failure. Published May 10, 2018. Full text
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