Pacemaker Induced Transient Dyssynchrony for Treating Heart Failure (PITA-HF): Feasibility, Safety, and Tolerability
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 8
- 试验地点
- 2
- 主要终点
- Feasibility as assessed by percent ventricular capture through Holter monitoring
研究概览
简要总结
Heart failure affects over 25 million people worldwide and nearly 7 million adults in the United States alone. Nearly 25% of patients with heart failure have worsened disease burden from dyssynchronous ventricular contraction due to abnormal electrical impulse propagation. These patients may benefit from cardiac resynchronization therapy (CRT) where contraction between the ventricles is coordinated by simultaneous electrical stimulation of the right and left ventricles. In animal models, CRT changes molecular and cellular biology by improving myofilament function, ion channel regulation, beta-receptor signaling, and overall mitochondrial energetics. In randomized clinical outcomes trials, the use of CRT further reduced the incidence of heart failure events and improved overall mortality. However, nearly 75% of patients with heart failure have synchronous ventricular contraction and therefore do not qualify for CRT. CRT profoundly alters underlying molecular and cellular biology as a result of the transition from dyssynchronous to resynchronized contraction, enhancing myocyte function and adrenergic responsiveness. The investigators previously hypothesized CRT-like benefits could be achieved in otherwise synchronous heart failure by purposely inducing dyssynchrony for several hours each day and then reversing this for the remainder of the time. The investigators termed this pacemaker induced transient dyssynchrony, or PITA, and tested its impact in a canine dilated cardiomyopathy model. Following several weeks of rapid atrial pacing to induce heart failure in the animals, the investigators compared implementing 4-weeks of PITA - consisting of dyssynchronous rapid right ventricular pacing for 6 hours each night and atrial pacing for the remaining time - to animals that always received rapid atrial pacing. The fast rate is used to generate a heart failure phenotype. PITA improved chamber dilation, increased beta-adrenergic responsiveness and contractile function, and improved myofiber structure compared to heart failure canine controls. While first tested in an intact conscious translational model, no study has yet investigated PITA in humans. This pilot research protocol tests the feasibility, safety, and tolerability of PITA in humans with dilated cardiomyopathy. The study will leverage pre-existing Medtronic (Mounds View, MN) pacemaker/defibrillators implanted in dilated cardiomyopathy patients based on current clinical guidelines. If successful, this study will allow for a larger, first-in-human study to assess indexes of left ventricular function in dilated cardiomyopathy patients with PITA.
详细描述
Over 25 million people worldwide are affected by heart failure. In the United States alone, nearly 7 million adults have heart failure with a prevalence of ~3% of adults over 18 years old. Therapy is directed at the underlying cause of heart failure and stratified by ejection fraction. In patients with heart failure with reduced ejection fraction (HFrEF), standard guideline-directed medical therapy consists, at minimum, of maximally tolerated beta blockade and angiotension converting enzyme (ACE) inhibitor or angiotension receptor blockade (ARB) therapy. Additive therapies may include further neurohormonal blockade with spironolactone or eplerenone, with symptomatic management anchoring on lifestyle modifications and diuretics.
Antiarrhythmic devices are commonly employed in HFrEF patients. Patients with ischemic heart disease and an ejection fraction below 35% are recommended for internal cardiac defibrillators (ICD) as primary prevention, and those who have experienced episodes of sudden cardiac arrest or syncope related to ventricular arrhythmia are candidates for ICDs as secondary prevention. Individuals with non-ischemic HFrEF are recommended for secondary prevention ICD implantation.
Another device therapy is cardiac resynchronization therapy (CRT) used in HFrEF patients with underlying delayed electromechanical conduction delay. With differences in regional electrical propagation as with left bundle branch blocks or intraventricular conduction delays, the left ventricular free wall and septum (left and right sides) contract in a discoordinate manner, reducing overall pump efficiency and mechanoenergetic performance. CRT employs pacing of the left ventricular lateral wall and right ventricular septum simultaneously, recoordinating electromechanical activation to improve ventricular function.
The investigators previously showed that while CRT improves chamber-level mechanoenergetics, it also results in profound molecular and myocyte changes that are often global in nature and underlie functional improvement. In a dilated cardiomyopathy canine model (rapid pacing for 6 weeks), CRT improves myofilament function, ion channel regulation, beta-receptor signaling, and mitochondrial function and energetics. Several of these features have been examined in human endocardial biopsies following CRT supporting the appearance of these features in patients.
Furthermore, in large-scale, randomized trials, CRT improved cardiovascular outcomes. The MIRACLE trial randomized 453 patients to CRT with EF <35% and QRS >130 ms to CRT vs control and found significant improvements in clinical endpoints of six minute walk distance, functional class, quality of life, and ejection fraction. The COMPANION trial randomized 1,520 patients with advanced heart failure and intraventricular conduction delays to standard medical therapy, CRT-P (pacemaker only), or CRT-D (defibrillator). In both CRT groups, there were significant reductions in the primary endpoint of time to death or hospitalization, with relative reductions of 34% and 40% respectively. The MADIT-CRT trial randomized 1,820 patients with ejection fraction <30% and QRS duration of >130 milliseconds with New York Heart Association class I or II symptoms to CRT-D or ICD therapy alone. In the CRT-D group, a significant reduction in the primary endpoint of death from any cause or nonfatal heart failure event was observed. Interestingly, the Echo CRT trial randomized 809 patients with ejection fraction <35%, QRS <130 milliseconds, and New York Heart Association class III or IV heart failure with echocardiographic evidence of left ventricular dyssynchrony to CRT vs dual chamber pacemaker. Unlike MADIT-CRT, there was no significant differences in the primary endpoint of death or first hospitalization for worsening heart failure between the groups prompting the trial to terminate early, suggesting that the benefit from CRT is contingent upon high baseline level of ventricular dyssynchrony. Based on MADIT-CRT and other large-scale trials, CRT is now recommended as per the recent American College of Cardiology/American Heart Association heart failure guidelines as Class I indication in patients with (1) New York Heart Association (NYHA) Class III or IV symptoms despite optimal heart failure therapy with left ventricular ejection fraction (LVEF) <35% and prolonged QRS duration or (2) NYHA Class I, II, or III symptoms with LVEF <50% on optimal heart failure therapy with expected high percentage of ventricular pacing.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Device Feasibility
- 盲法
- None
盲法说明
This is a feasibility, safety, and tolerability pilot trial that is double-blinded. To the extent that is possible, the outcome variable collection and analysis will be fully blinded. Only the device nurse responsible for programming ICDs and investigators responsible for performing physical examinations will know specifics of patient protocol (ie which patients will have PITA and when) and will be unblinded; all other investigators and patients will be blinded. Subjects meeting inclusion criteria and not any exclusion criteria (see below) will have PITA on for Weeks 0-8 and PITA off for Weeks 8-12. This design provides assessment of feasibility, tolerability and safety of PITA over a 2 month timepoint and the decay effect of PITA for an additional month once turned off.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patient ≥18 years of age
- •Ejection fraction of <40% by noninvasive testing (TTE, nuclear stress, cardiac MRI) within 6 months of study enrollment
- •Presence of Medtronic device (single chamber ICD or dual chamber ICD) with Sleep Function feature (Models: Evera, Maximo II, Virtuoso II, Secura, Protecta)
- •Low pacing burden, defined as <5% RV pacing in the prior month as determined by baseline device interrogation (prior to Week 0)
- •Narrow QRS complex (<100 milliseconds) on baseline ECG without any pacing or with atrial pacing only
- •No evidence of incomplete bundle branch block or intraventricular conduction delay, defined as QRS 100-120 milliseconds with: a. S wave in V1 with broad R waves in I, aVL, and V6 b. RSR' in v1 with terminal S waves in I, aVL, and V6 c. not meeting patterns in a or b but with QRS complex 100-120 milliseconds
- •No indications for CRT-D upgrade at time of enrollment
- •Followed by a physician for treatment of heart failure
- •Currently receiving guideline-directed medical therapy for HFrEF
- •No changes in diuretic over the past 30 days
- •Willingness to provide informed consent
- •Negative pregnancy test in a female of child bearing potential
排除标准
- •Age <18 years
- •Ejection fraction >40% by noninvasive testing in the preceding 12 months
- •Acute coronary syndrome within 4 weeks as defined by electrocardiographic (ECG) ST-segment depression or prominent T-wave inversion and/or positive biomarkers of necrosis (e.g., troponin) in the absence of ST-segment elevation and in an appropriate clinical setting (chest discomfort or anginal equivalent)
- •Hospital admission for acute decompensated heart failure in the prior 30 days
- •Non-Medtronic implanted device or Medtronic device lacking Sleep Function, or Medtronic pacemaker without ICD
- •High pacing burden defined as >5% right ventricular pacing in the preceding month based on interrogation
- •Meets indication for CRT-D upgrade at the time of enrollment
- •Not currently on guideline-directed therapy or non-compliant with medical therapy, assessed through patient interview and review of medical charts
- •Non-compliant with medical visits defined as >3 missed clinical visits in the prior year
- •NYHA Class IV symptoms at time of enrollment
- •Hemodynamically significant arrhythmias including supraventricular tachycardias not responsive to rate control therapies or resulting in hemodynamic instability, sustained ventricular tachycardia (defined as >30 seconds of VT), or defibrillator shock within 4 weeks
- •Cardiac arrest within the prior 6 months
- •Coronary artery bypass graft (CABG) or percutaneous coronary intervention (PCI) within the prior 3 months, or recent coronary angiogram with plans for CABG or PCI (unrevascularized disease)
- •Presence of durable mechanical hemodynamic support (left ventricular assist device)
- •Actively listed for cardiac transplantation, prior history of cardiac transplantation or undergoing evaluation for cardiac transplantation
- •Actively listed for any other organ transplantation or undergoing evaluation for any other organ transplantation
- •Planned surgical intervention in the next 1 year
- •History of persistent, permanent, or long-standing atrial fibrillation
- •Terminal illness (other than HF) with expected survival of less than 1 year
- •Other end-organ, permanent dysfunction including severe chronic obstructive pulmonary disease (COPD) by Gold's criteria or severe pulmonary disease requiring oxygen, cirrhosis of any cause, renal failure on dialysis, chronic untreatable infectious disease, underlying malignancy undergoing active treatment (chemotherapy, radiation therapy, planned surgical resection of tumor), uncontrolled endocrinologic disorder (thyroid dysfunction, adrenal disease, etc.) requiring ongoing medication titration
- •Previous symptomatic intolerance to right ventricular pacing
- •Enrollment or planned enrollment in another randomized clinical trial
- •Inability to comply with planned study procedures
- •Pregnancy or nursing mothers, or women planning on becoming pregnant
- •Irreversible neurologic function with inability to provide own consent
- •Prisoners
结局指标
主要结局
Feasibility as assessed by percent ventricular capture through Holter monitoring
时间窗: Up to 7 weeks
Patients will be given 48-hour Holter monitors at Week 1, Week 4, and Week 7. The average heart rate in beats per minute (bpm) during sleep hours (midnight-6 AM) will be recorded. Percent ventricular capture will be defined as the percentage of heart rate during this time period that is above the pre-specified heart rate set for each patient during the "sleep" period. Percent will be defined from 0-100%, with the latter indicating all ventricular beats are paced from the right ventricle, and the former indicating that no ventricular beats are paced.
Safety as assessed by number of arrhythmia episodes via device interrogation
时间窗: Up to 3 months
Patients will have patient's ICD devices interrogated throughout the study as per the study protocol, and the number of sustained ventricular tachycardia (VT) episodes, non-sustained VT episodes, and ventricular fibrillation (VF) episodes will be counted and recorded. At the conclusion of each interrogation, the device counter will be reset such that the next interrogation is only reflective of the interim time period.
Safety as assessed by the number of hospitalizations or ER visits for arrhythmia or heart failure
时间窗: Up to 3 months
As per the study protocol, patient interviews and chart reviews will be implemented to count the number of ER visits or hospitalizations for issues related to arrhythmia or clinical heart failure decompensation.
Tolerability as assessed by change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score
时间窗: Baseline, Week 4, Week 8 and Week 12
Patients will fill out the Kansas City Cardiomyopathy Questionnaire at Weeks 0, 4, 8, and 12, and a numerical score is provided at each timepoint and compared. Scores are from 0-100, with higher scores corresponding to improved quality of life and associated with New York Heart Association Class I symptoms, and lower scores associated with poorer quality of life and association with New York Heart Association Class IV symptoms.
Tolerability as assessed by change in distance during 6-minute walk test
时间窗: Baseline and Week 8
Distance (feet) during 6 minute-walk test will be obtained and recorded at Weeks 0 and 8. Larger distances are associated with improved functional status/capacity. Typical distances covered in healthy individuals range from 1300-2300 ft.
Safety as assessed by number of tachytherapies delivered by ICDs
时间窗: Up to 3 months
Patients will have patient's ICD devices interrogated throughout the study as per the study protocol, and the number of tachytherapies delivered (ATP or ICD shocks) will be counted and recorded. At the conclusion of each interrogation, the device counter will be reset such that the next interrogation is only reflective of the interim time period.
Tolerability as assessed by change in Global Well-Being score on a Visual Analog Scale
时间窗: Baseline, Week 4, Week 8 and Week 12
Patients will fill out the Global Well-Being score at Weeks 0, 4, 8, and 12, and a numerical score is provided at each timepoint and compared. The scale is from 0-100, with higher numbers corresponding to improved well-being, and lower numbers corresponding to lower well-being.
Tolerability as assessed by change in Subjective Dyspnea score on a Visual Analog Scale
时间窗: Baseline, Week 4, Week 8 and Week 12
Patients will fill out the Subjective Dyspnea score at Weeks 0, 4, 8, and 12, and a numerical score is provided at each timepoint and compared. The score is from 0-100, with higher scores indicating improved subjective dyspnea, and lower scores indicating worsened subjective dyspnea.
Tolerability as assessed by change in Frailty Index
时间窗: Baseline, Week 4, Week 8 and Week 12
The Frailty Index will be assessed by the Johns Hopkins Older Americans Independence Center Online Frailty Assessment Tool. Patients will by assessed by the Frailty Index at Weeks 0, 4, 8, and 12, and a numerical score is provided at each timepoint and compared. The score is from 0-5, indicating frail (score 3-5), pre-frail (score 1 or 2) or robust (score 0).
Tolerability as assessed by change in Sleep Quality
时间窗: Baseline, Week 1, Week 4, Week 5, Week 8 and Week 12
Sleep Quality will be assessed by Pittsburgh Sleep Quality Index (PSQI). Patients will fill out the Pittsburgh Sleep Quality Index at Weeks 0, 1, 4, 5, 8, and 12, and a numerical score is provided at each timepoint and compared. Scores range from 0-21, with lower scores corresponding to healthier sleep habits and improved sleep quality, and higher scores corresponding to worsened sleep quality.
次要结局
- Presence of dyssynchrony on echocardiography(Baseline, Week 8)
- Change in serum blood urea nitrogen (BUN) values(Baseline, Week 4 and Week 12)
- Change in N-terminal pro b-type natriuretic peptide (NT pro-BNP) values(Baseline, Week 4 and Week 12)
- Change in troponin values (ng/mL)(Baseline, Week 4 and Week 12)
- Change in sodium values (mEq/L)(Baseline, Week 4 and Week 12)
- Change in serum creatinine values (mg/dL)(Baseline, Week 4 and Week 12)