Medical Review of Lit (sleep APNEA)

timer Asked: Feb 2nd, 2019
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Question Description

For each of these 4 articles I need you to right 1 paragraph each to one answer these following questions:

1.Include number of people in the study.

2. People excluded in study and why.

3. What was the exclusion and inclusion criteria?

4. What did they do in the study?

5. What was the results of the study.

Remember to include numbers, statistical data, is it statistically relevant or not.

APA Format.

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Journal of Cardiac Failure Vol. 21 No. 11 2015 Clinical Trials: Methods and Design Design of the remed!e System Pivotal Trial: A Prospective, Randomized Study in the Use of Respiratory Rhythm Management to Treat Central Sleep Apnea MARIA ROSA COSTANZO, MD,1 RALPH AUGOSTINI, MD,2 LEE R. GOLDBERG, MD, MPH,3 PIOTR PONIKOWSKI, MD,4 CHRISTOPH STELLBRINK, MD,5 AND SHAHROKH JAVAHERI, MD6 Naperville, Illinois; Columbus and Cincinnati, Ohio; Philadelphia, Pennsylvania; Wroclaw, Poland; and Bielefeld, Germany ABSTRACT Background: Central sleep apnea is common in patients with cardiovascular disease and worsens outcomes. There is a lack of established therapies for central sleep apnea, and those available are limited by poor patient adherence and potentially adverse cardiovascular effects, at least in a subset of patients. The remed!e System (Respicardia, Minnetonka, Minnesota) is a new physiologic treatment that uses transvenous phrenic nerve stimulation to contract the diaphragm, thereby stabilizing gas exchange and restoring normal breathing throughout the sleep period. Methods: This is a prospective multicenter randomized trial with blinded end points evaluating the safety and efficacy of the remed!e System. Up to 173 patients with central sleep apnea will be randomized 1:1 to remed!e System therapy initiated at 1 month after implantation (treatment) or to an implanted remed!e System that will remain inactive for 6 months (control). Primary efficacy end point is the percentage of patients who experience a reduction in apnea-hypopnea index by a $50% at 6 months (responder analysis). Primary safety end point is freedom from serious adverse events through 12 months. Secondary end points include sleep-disordered breathing parameters, sleep architecture, Epworth Sleepiness Scale score, and Patient Global Assessment. Conclusions: This is the 1st randomized controlled trial of the safety and efficacy of the remed!e System for the treatment of central sleep apnea. (J Cardiac Fail 2015;21:892e902) Key Words: Central sleep apnea, phrenic nerve stimulation, sleep, randomized controlled trial. Central sleep apnea (CSA) occurs commonly in patients with cardiovascular disorders such as heart failure (HF) and atrial fibrillation.1 The major mechanism underlying development of CSA is the increased sensitivity to changes in arterial blood carbon dioxide (PCO2) levels resulting in periods of hyperventilation (hyperpnea) followed by periods of decreased (hypopnea) or lack of breathing (apnea).2 Regardless of the associated comorbidities, acutely, episodes of apnea or hypopnea are associated with hypoxemia and changes in PCO2 followed by arousals and autonomic dysfunction.2 Over the long term, these acute changes result in increased sympathetic activity, which has adverse cardiovascular consequences. Multiple studies have demonstrated that HF patients with CSA have a significantly increased risk of ventricular arrhythmias, HF decompensations, and death.2 Importantly, when CSA is effectively treated, the associated morbidities and From the 1Advocate Heart Institute, Naperville, Illinois; 2Division of Cardiology, Department of Medicine, Ohio State University, Columbus, Ohio; 3 Division of Cardiology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; 4 Department of Heart Diseases, Medical University, Military Hospital, Wroclaw, Poland; 5Bielefeld Medical Center, Bielefeld, Germany and 6 Sleep physician, Bethesda North Hospital, Cincinnati, Ohio and Professor Emeritus, University of Cincinnati, Cincinnati, Ohio. Manuscript received March 4, 2015; revised manuscript received August 11, 2015; revised manuscript accepted August 19, 2015. Reprint requests: Maria Rosa Costanzo, MD, Advocate Medical GroupeMidwest Heart Specialists, Edward Heart Hospital, 4th Floor, 801 South Washington St, PO Box 3226, Naperville, IL 60566. Tel: þ1 630-527-2730; Fax: þ1 630-281-2726. E-mail: mariarosa.costanzo@ Funding: Respicardia, Minnetonka, Minnesota. Identifier: NCT01816776. See page 900 for disclosure information. 1071-9164/$ - see front matter ! 2015 Published by Elsevier Inc. 892 Downloaded for Anonymous User (n/a) at United States Army Medical Centers from by Elsevier on August 23, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. ! System Pivotal Trial Design of the remede mortality decrease.3e5 Use of nocturnal oxygen, carbon dioxide, atrial pacing, theophylline, and acetazolamide have been evaluated in small numbers of CSA patients, but data on long-term efficacy and safety of these therapies are lacking.6 To date, CSA has been primarily treated with positive airway pressure (PAP) therapies. Designed to open closed airways, PAP therapies blow air into the lungs to increase airflow. Patients with CSA receiving PAP therapies have experienced improvement in sleep and cardiovascular variables.3,7e10 However, 1 randomized trial of PAP therapy failed to reduce mortality in its overall CSA population with HF and reduced ejection fraction,11 although survival improved in those patients in whom the apnea-hypopnea index (AHI) was effectively reduced by PAP.3 Recently, however, a large randomized trial of another type of PAP therapy, adaptive pressure-support servoventilation (ASV), showed that, compared with control subjects, patients treated with ASV had a statistically significant 2.5% absolute increased annual risk of cardiovascular mortality.12 Recently, a new physiologic approach to treating CSA has been investigated. The remed!e System (Respicardia, Minnetonka, Minnesota) is a totally implantable leadbased device that delivers unilateral transvenous phrenic nerve stimulation to cause diaphragmatic contraction in a fashion mimicking a normal breathing pattern. The contraction of the diaphragm creates a negative intrathoracic pressure similar to that generated by normal breathing so that airflow is augmented and central apneas occurring during sleep are significantly decreased. Suppression of impending central apneas averts the increases in PCO2 and decreases in PO2 that trigger hyperventilation and reduction in PCO2 below the apneic threshold. A prospective multicenter nonrandomized pilot study of chronic transvenous phrenic nerve stimulation with the remed!e System in CSA patients13 showed that implantation of the remed!e System was uneventful in 86% of patients. From baseline to 3 months, chronic remed!e System therapy improved the AHI by 55% (P ! .001), central apnea index (CAI) by 83% (P ! .001), 4% oxygen desaturation index (ODI4) by 52% (P ! .001), arousal index by 35% (P ! .001), rapid eye movement (REM) sleep by 41% (P ! .001), Patient Global Assessment (PGA) by 45%, and Minnesota Living With Heart Failure score by an average of 10 points (P ! .001). Efficacy was maintained at 6 and 12 months’ follow-up, and therapy was well tolerated. Serious adverse events related to the device, implantation procedure, or therapy are listed in Supplemental Table 1. These adverse events are consistent with those occurring with other cardiac devices, such as cardiac resynchronization therapy devices, at a similar stage of development.14 Given the adverse effects CSA has on morbidity and mortality, the disappointing outcomes of PAP therapies, and the encouraging results of the pilot study of phrenic nerve stimulation, a prospective randomized trial has been designed to evaluate the safety and effectiveness of the " Costanzo et al 893 remed!e System in patients with various etiologies of CSA. The remed!e System has received an investigational device exemption from the United States Food and Drug Administration (FDA), and the FDA endorses the study’s design and planned analysis. The remed!e System Pivotal Trial successfully completed enrollment in May 2015. To date the Data Safety and Monitoring Board (DSMB) has not detected or reported to the Steering Committee or the Sponsor any signals of lack of safety. Data will be analyzed when the enrolled patients have completed 6 months of follow-up. The primary results are expected in 2016. Materials and Methods System Description The remed!e System consists of a neurostimulator, a stimulation lead, and a sensing lead. The neurostimulator is similar in appearance to a standard pacemaker and is implanted in either the left or the right pectoral region (Fig. 1). The stimulation lead is designed to transvenously stimulate the phrenic nerve. Although only a single phrenic nerve is stimulated, both diaphragms move in response to this stimulation during sleep, which restores a full breath (Respicardia data on file). Two types of stimulation leads are available: a 4-French lead that is designed to be implanted in the left pericardiophrenic vein, and a 7-French lead designed for implantation in the right brachiocephalic vein. Clinical experience has shown that both the left pericardiophrenic vein and the right brachiocephalic vein are suitable sites for effective chronic phrenic nerve stimulation.13 In addition, the implanting physician chooses a commercially available small cardiac pacing lead, which is placed in the azygos vein and connected to the device to sense respiration. Fig. 1. Implanted remed!e System. In this patient, the neurostimulator was implanted in the right pectoral area. The right subclavian approach was used to place the stimulation lead (A) in the left pericardiophrenic vein and to place the sensing lead (B) in the azygos vein. Downloaded for Anonymous User (n/a) at United States Army Medical Centers from by Elsevier on August 23, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 894 Journal of Cardiac Failure Vol. 21 No. 11 November 2015 The left pericardiophrenic vein is small (w2 mm diameter), but can be identified angiographically and cannulated with the use of techniques similar to those used for left ventricular pacing lead placement. During angiography, the vein can be seen along the left lateral outline of the heart and can be identified as the target vessel by tracking its movement with the heart. The left pericardiophrenic vein can be accessed from either the left or right side. A sheath is inserted into the subclavian vein and a catheter is advanced to the pericardiophrenic vein. From the right side, the catheter is used to cross from the right brachiocephalic vein to the left brachiocephalic vein, and then the catheter is inserted into the left pericardiophrenic vein for implantation of the stimulation lead. The right brachiocephalic vein may also be used for implantation of the stimulation lead because the right phrenic nerve lies immediately adjacent to the vein’s anterolateral wall as it approaches the superior vena cava. The brachiocephalic neurostimulation lead is designed so that the stimulation electrodes rest directly against the vessel wall to maximize the stimulation current applied to the adjacent phrenic nerve. The remed!e System automatically delivers phrenic nerve stimulation during the scheduled time at night only when the patient is at rest and in a sleeping position, which is detected by a position and motion sensor present within the device (Fig. 2). Respiration is sensed by thoracic impedance15,16 and is used both for patient monitoring and for automatic titration of therapy at night based on changes in the respiratory pattern. Therapy is initiated w1 month after implantation to allow for lead healing. Stimulation levels are set at the time of therapy initiation and can be modified with the use of a proprietary algorithm. The therapy is designed to provide smooth diaphragmatic contraction similar to normal respiratory movement. Study Design The remed!e System Pivotal Study is a prospective multicenter randomized efficacy and safety trial of transvenous unilateral phrenic nerve stimulation therapy delivered by the remed!e System in patients with moderate to severe CSA (as defined below) who are receiving guideline-determined medical management. The assessment of the primary end point is blinded. After giving informed consent, at the time of randomization all patients undergo implantation of the remed!e System. The trial is registered Fig. 2. The therapy algorithm used by the remed!e System to provide phrenic nerve stimulation during sleep. The system uses time of day, activity level, and body position (upright or recumbent) to determine a potential sleeping state and, therefore, if stimulation should occur. All of these parameters are adjustable and can be tailored to each patient’s specific sleeping routine. at (identifier: NCT01816776). The study’s design is shown in Figure 3. Patients The population for this study consists of patients whose sleepdisordered breathing (SDB) is predominantly CSA, defined as an AHI of $20 events per hour of sleep with the CAI accounting for $50% of all apneas and with $30 CSA events according to polysomnography (PSG); furthermore, the obstructive apnea index must be #20% of the total AHI. These criteria ensure enrollment of patients with moderate to severe CSA. Up to 173 patients will be enrolled at up to 25 United States and 7 European centers to yield w147 randomized and successfully implanted patients. Centers were chosen based on documented collaboration between cardiology and sleep medicine specialists as well as the availability of a physician experienced in the implantation of biventricular pacemakers. All patients will be followed through study closure, which is expected to be at the time of United States regulatory approval. Patients will be identified by chart reviews and direct referrals from physicians. It is anticipated that a large proportion of these patients will have HF with reduced ejection fraction, given the high prevalence of CSA in that population. Initial screening may be done via in-home sleep testing (polygraphy [PG]). To enable initial screening of patients, study sites have been provided with a commercially available in-home testing device (NOX T-3 System; Nox Medical, Reykjavik, Iceland) capable of distinguishing different types of SDB (obstructive sleep apnea [OSA] vs CSA) by simultaneously analyzing movements of the chest and abdomen and by detecting airflow and oxygen saturation with the use of a nasal cannula and spirometer (Fig. 4). Within this trial, centers may have the initial screening reviewed by either their own sleep experts or an independent sleep core laboratory (Registered Sleepers, Leicester, North Carolina). After a patient with CSA is identified and provides informed consent, baseline testing and verification of inclusion/exclusion criteria are performed (Table 1). Patients must be medically stable on guideline-determined medical management. Patients must have a diagnosis of HF for $6 months before enrollment. Patients cannot participate in the study if it is anticipated they will not be able to remain off oxygen or other therapies for SDB during the 1st 6 months of follow-up. Patients with a cerebrovascular accident in the past 12 months are excluded. Similarly, all invasive cardiac procedures must be completed $3 months before baseline testing. Patients with evidence of phrenic nerve palsy will be excluded. Baseline testing will include full PSG that will be interpreted by an independent core laboratory according to the American Academy of Sleep Medicine 2007 guidelines17 to ensure consistent diagnosis of the presence and required severity of CSA. Pulmonary function tests, creatinine, liver function tests, and hemoglobin will be reviewed to confirm the presence of inclusion criteria and absence of exclusion criteria. All screening/baseline evaluations are required to be completed within 40 days before implantation. Randomization and Follow-Up Eligible patients will undergo remed!e System implantation after baseline assessments are complete and it is determined that patients meet all of the inclusion criteria and have none of the exclusion criteria. At the time of implantation, patients are randomized 1:1 to remed!e System therapy initiated 1 month after Downloaded for Anonymous User (n/a) at United States Army Medical Centers from by Elsevier on August 23, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. ! System Pivotal Trial Design of the remede " Costanzo et al 895 Fig. 3. The remed!e System Pivotal Trial Plan. Patients will be randomized 1:1 to either active remed!e System therapy (treatment group) or to an inactive remed!e System (control group). All patients will be evaluated with the use of polysomnography at the 1-month postimplantation visit. At that visit, patients in the treatment group will have their remed!e System therapy started and titrated to the output needed to contract the diaphragm to restore regular breathing throughout the night without disturbing the patient’s sleep. For patients in the control group, therapy will remain off at the 1-month post-implantation follow-up visit. However, 6 months later, therapy will be turned on and will remain on for the remainder of the trial. CSA, central sleep apnea. implantation (treatment) or to an implanted remed!e System that will remain inactive for 7 months (control). All patients will undergo PSG at 1 month after implantation (Supplemental Table 2). At the 1-month visit, patients in the treatment group will have their remed!e System therapy started and titrated according to a proprietary algorithm to the output needed to contract the diaphragm and restore regular breathing throughout the night without disturbing the patient’s sleep. Some patients may need therapy output titrated over several visits to allow patient adaptation to therapy, and this titration will be done with the use of the titration schedule shown in Figure 5. For patients in the control group, therapy will be turned on at 7 months (following the effectiveness end point visit) and will remain on for the remainder of the trial. All patients will undergo additional PSG at 6, 12, 18, and 24 months to assess response to therapy. Additionally, PG will be performed at 36 months. All study patients will receive a physical exam and will be assessed for adverse events every 3 months (Supplemental Table 2). Adverse event data gathered during the remed!e System Pivotal Trial is expected to be consistent with that of other implantable device trials. It will include adverse events related to the implantation procedure, the lead and system, and/or therapy. It will also report serious adverse events, including death, lifethreatening illness or injury, hospitalization, or unanticipated medical or surgical intervention (Supplemental Table 3). Finally, quality of life assessment will be performed at the 6- and 12-month follow-up visits (Supplemental Table 2). ! System Therapy Initiation and Titration of remede In patients with the remed!e System, therapy will be started and titrated with the use of a proprietary algorithm. The remed!e System has the ability to automatically modify therapy based on sensed transthoracic impedance.16 If sensing is not optimal, the system can be programmed to compensate and continue to deliver effective therapy. Additional long-term sensing information from the device (respiratory events, position, and activity) may be used to optimize therapy over time and to help identify when additional titration or information, such as PG, are needed. Stimulation is gradually increased over several weeks until consistent diaphragm capture is achieved without disturbing the patient’s sleep (Fig. 5). Once titrated to effectively deliver therapy with minimal patient awareness during sleep, the remed!e System functions automatically and requires no further inter ...
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Medical Review of Lit (Sleep Apnea)
Student’s Name
Institutional Affiliation




Transvenous Phrenic Nerve Stimulation for the Treatment of Central Sleep Apnoea in
Heart Failure
A total number of people that were included in the study to estimate the feasibility of
using unilateral Transvenous phrenic nerve stimulation for the treatment of CSA in heart failure
patients were sixteen. Fifteen people were excluded from the study due to varied reasons. For
example, some of these individuals were eliminated due to technically inadequate capture of the
phrenic nerve during neurostimulation. The inclusion criteria were the ability to hold an apnoeahypopnoea index that is greater than or equals to 15 and a central apnoea index that is greater
than or equal to 15. Exclusion criteria were when a patient had a baseline oxygen saturation that
is less than 90%. Some of the activities that were done in the study were phrenic nerve
stimulation and recording of the electroencephalogram. The investigation resulted in some
issues. For example, there was the elimination of CSA in one of the patients since the effects
were adverse. Moreover, stimulation contributed to significant improvement of all evaluated
indices thus showing the severity of CSA. Therefore, the study portrayed the viability of
unilateral transvenous phrenic nerve stimulation for the treatment of CSA in heart failure.
Treatment of Sleep Apnea in Chronic Heart Failure Patients w...

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