FDA Approval Based on the results of the pivotal FIX-HF-5C trial The FDA approved<unk>  therapy for use in the United States on March 21, 2019. FDA Indication The FDA approved the OPTIMIZER Smart System, which delivers<unk>  therapy, as indicated to improve 6-minute hall walk distance, quality of life, and functional status of NYHA Class III heart failure patients who remain symptomatic despite guideline directed medical therapy, who are in normal sinus rhythm, are not indicated for<unk>  Resynchronization Therapy, and have a left ventricular ejection fraction ranging from 25% to 45%. CE Mark Based on the results of clinical trials,<unk>  devices are approved and available for clinical use in all European Union countries and in Australia, Turkey, India and Hong Kong, as well as in other countries that recognize CE marking for medical devices. CE Indication Schematic representation of normal sinus rhythm as seen on an ECG. The QRS complex is shown in the center.Based on the approval of<unk>  devices, the therapy is a treatment option for patients that are at least 18 years old who suffer from heart failure symptoms due to left ventricular systolic dysfunction (LVSD) despite adequate medical treatment. Further clinical research are under way to identify which patient group within the scope of the device approval benefits most from<unk>  treatment. Criteria for the classification of patients with left ventricular systolic heart failure include the severity of the disease based on functional parameters (NYHA classification), the average percentage of blood volume ejected by the left ventricle with each heart beat (left ventricular ejection fraction or LVEF) and the duration of the QRS complex seen in the electrocardiogram (ECG). Most clinical studies on<unk>  therapy have involved heart failure patients who were classified initially as NYHA Class II, III or IV and had a normal QRS duration (QRS duration ≤ 120 ms). The efficacy of<unk>  on patients in an earlier stage of heart failure has not yet been studied. A subsequent evaluation study (subgroup analysis) has already suggested a particular patient group that responds exceptionally well to<unk>  therapy. The patients were characterized by a disease severity of NYHA class III and a left ventricular ejection fraction of ≥ 25%. Although studies on<unk>  therapy have focused on patients with a normal QRS duration (i.e. ≤ 120 ms), it is possible to use the therapy in patients who meet the treatment indication but who do not have a normal QRS duration. A preliminary study has previously shown that<unk>  may be safe and effective in such patients who have not responded to<unk>  resynchronization therapy (CRT). Therapeutic gap<unk>  resynchronization therapy (CRT; also known as biventricular pacing) has proven to be an effective treatment in heart failure. However, CRT is generally recommended exclusively for patients with a preserved sinus rhythm and a prolonged QRS complex (≥ 120 ms) who also suffer from left bundle branch block (LBBB), or for patients without left bundle branch block but who have a preserved sinus rhythm and a QRS complex with a width of ≥ 150 ms. However, only 30-40% of all heart failure patients show such a prolonged QRS complex, and therefore the 60-70% of patients who have a normal QRS complex cannot be treated with CRT. In addition, around 30% of the patients eligible for CRT treatment do not respond to CRT. Until recently, the only other available device-based treatment was the left ventricular assist device (LVAD). LVAD therapy is indicated in patients with severe illness and is associated with several hours of surgery (involving a cardiopulmonary bypass). It is usually considered as a therapy providing a “bridge to transplant” for heart failure patients classified as NYHA class IV, and is intended to support heart function until a heart transplant is received. Current research results suggest that the therapeutic gap described above could now be closed by the<unk>  therapy. Additionally, a long-term study showed that the<unk>  was able to stop the common and prognostically unfavorable long-term prolongation of QRS duration in heart failure patients. This result was interpreted as signaling the safety of the treatment and as an indicator that patients could benefit from<unk>  therapy in the long term. If the QRS-stabilizing effect were to be confirmed in further studies, the<unk>  would become the first device-based treatment for heart failure with the potential to halt QRS prolongation, a factor associated with a poor prognosis. Recommendations The guidelines issued by the European Society of Cardiology (ESC) in 2016, mention<unk>  therapy as a therapy option to be considered in selected group of patients with HF. Mostly these guidelines are endorsed by national<unk>  societies in individual countries within the European Union. Efficacy<unk>  has proven to be effective and safe in randomized controlled trials involving several hundred patients. The nature and extent of the effect of<unk>  have been the subject of numerous investigations. Although various individual publications, as well as one of two meta-analyses, have presented the efficacy and significant potential of<unk>  in the treatment of heart failure, medical evaluation of the therapy efficacy is not yet complete. Scientists point out, however, that this was also the case for CRT therapy when it was first introduced, advocating the provision of<unk>  to suitable patients before further studies are completed. To date (February 2015), there are at least two meta-analyses studying the efficacy of<unk>  therapy on heart failure, a large number of review articles (e.g.) and at least two survey articles on device-based treatments of advanced heart failure which address<unk> . Furthermore, there are more than 70 individual publications focusing specifically on<unk>  therapy. Further randomized controlled trials studying the effect of<unk>  on the progression of heart failure have been initiated and are currently (as of Feb 2015) recruiting patients. Meta-analyses Giallauria et al. evaluated the three randomized controlled trials (RCTs) currently available on<unk>  as a treatment for heart failure patients. The three trials included a total of 641 patients and assessed the effect of<unk>  either in comparison to a sham treatment or in comparison to the best medical treatment. In contrast to an earlier meta-analysis by Kwong et al. the study did not evaluate the data based on summarized results alone, but on the basis of the individual data sets of the 641 enrolled patients. The study concluded that<unk>  significantly improved important markers of<unk>  performance. These included the maximal oxygen uptake (peak VO2 or pVO2 – measured by ventilatory parameters during a cardiopulmonary exercise test), which is indicative of improved survival, and the 6-minute walk test. The quality of life of participating patients, measured by the Minnesota Living with Heart Failure Questionnaire (MLWHFQ), also improved significantly. However, both meta-analyses demanded additional and larger randomized controlled trials in order to evaluate the effect of the therapy more precisely. Giallauria et al. describe the success of<unk>  and the further potential of the therapy. Particular emphasis is given to the possibility that<unk>  therapy may close the therapeutic gap in heart failure treatment if previous study outcomes are confirmed. Long-Term Survival Studies As of February 2015, the effect of<unk>  therapy on the long-term mortality rates of heart failure patients has not been studied in a randomized controlled trial. Some preliminary single-center studies have been reported though. Kuschyk et al. evaluated the long-term efficacy and survival of patients with<unk> . Their analysis included 81 patients with a disease severity of NYHA class II, III or IV and a mean follow-up of around 3 years. The analysis compared the observed mortality rate with the prediction of the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) model which is based on the records of over 39,000 heart failure patients. Unlike a previous long-term outcome study of<unk> , this study was not limited by a widely heterogeneous group of patients. Following long-term observation, the study concluded that<unk>  improved quality of life, exercise tolerance, NYHA class, left ventricular ejection fraction (LVEF) and brain natriuretic peptide (BNP) levels. Mortality rates were significantly lower than predicted at year 1, and lower than predicted but not statistically significant at year 3. General Heart failure is a chronic disease that usually progresses gradually. The rate of progression and the degree of symptoms of the disease varies between different patients.<unk>  therapy aims to treat heart failure through a medium- to long-term treatment, over the course of weeks and months. According to large implanting clinics, after the implantation wound is healed, the lifestyle of a patient is not restricted by the implanted device. Leisure, travel (by car, train, ship or plane), hobbies and sex life will not
Cardiac contractility modulation
Vascular recruitment
Isolytic muscle contraction
Neural facilitation
Local blood flow regulation
Vasodilation
Vasoconstriction
Cardioprotection