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Supplemental Table 1. MultiSENSE Study Summary
Title of Study
Multisensor Chronic Evaluations in Ambulatory Heart Failure Patients
(MultiSENSE)
Study Timeline
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First patient enrolled in July 2010
Last patient follow up in Dec 2014
Event adjudication completed in May 2015
Clinicaltrials.gov updated to indicate trial completion in October, 2015
Multisensor algorithm finalized using the Development Set data in September
2015
Endpoint discussions completed in August 2016
Prospective Performance Goal (PG) criteria finalized on the morning of
August 12 2016
Algorithm prospectively validated on the sequestered Test Set data on the
afternoon of August 12 2016
Study Device
COGNIS models N119, N120, P107 and P108
Indication
CRT-D indication according to standard clinical practice
Investigational
Software
Investigational software was downloaded into an implanted COGNIS device to
convert it to a Sensor Research Device (SRD). Following conversion, the SRD PG
provided sensor data while maintaining all essential therapy and diagnostic features of
the COGNIS device. At the completion of the subject’s participation in the study, the
device was restored to a COGNIS device.
Study Design
Multi-center, international, prospective, nonrandomized, significant risk IDE study.
Blinding:
Treating clinicians, investigators and clinical event committee members were blinded
to the investigational sensor data.
Number of Subjects Approved to enroll up to 990 subjects in up to 120 centers worldwide
and Sites
Study Population
Subjects, of legal age to give informed consent, who are implanted with a
Boston Scientific COGNIS® cardiac resynchronization therapy defibrillator
(CRT-D).
Inclusion Criteria
• Age 18 or above, or of legal age to give informed consent specific to state and
national law
• Willing and capable of returning for all follow-up visits and emergency care at
the investigational center as medically appropriate
• Willing to participate in all testing associated with this clinical investigation at
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an approved clinical investigational center
• Currently implanted with a CRT-D system including a COGNIS device
(model N119, N120, P107 or P108) with RA, RV and LV leads
• Classified as NYHA Class II, III or IV within the last six months
Exclusion Criteria
• Inability or refusal to sign the Subject Informed Consent
• Inability or refusal to comply with the follow-up schedule
• Documented as pacemaker dependent
• Unable to rest comfortably in a semi-recumbent position for up to 20 minutes
• Implanted with active Medtronic Fidelis lead models: 6930, 6931, 6948 or
6949
• Currently implanted with unipolar RA, RV, or LV leads
• LV sensitivity programmed to less than 0.7 mV AGC
• Subjects that have a history of appropriate tachycardia therapy (external or
implanted) for rates <165 bpm within 1 week of enrollment
• Device battery status indicates approximate time to explant < 2 years
• Likely to undergo lead or PG revision during the course of the study as
determined by the investigator
• Receiving regularly scheduled IV (IV) inotropic therapy as part of
their drug regimen
• Subjects that have received a heart or lung transplant
• Receiving mechanical circulatory support
• Subjects who have been referred or admitted for Hospice care
• A life expectancy of less than 12 months per physician discretion
• Enrolled in any concurrent study, without Boston Scientific written approval
• Subjects whose devices have previously been converted to the SRD and
withdrawn from this study
• Subjects who have received a sub-pectoral COGNIS implant prior to
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February 1st 2011 that has a dash number listed in APPENDIX K
• Women who are known to be pregnant or plan to become pregnant within the
course of the study
• LV offset is programmed to a value greater than zero
Allocation
Chronological allocation to the development and test sets by geography
Development Set
Used to develop the composite index and alert algorithm
Test Set
Sequestered and used for independent validation of algorithm performance.
Follow-up Period
Subjects included in the study were followed for up to 15 months. Subjects
had their devices converted to an SRD no earlier than 30 days post implant
and no later than 44 days post-enrollment. After conversion, subjects
were followed for a maximum of 12 months. Following device re-conversion
the subject were followed for an additional 30 to 44 days.
Once the subject’s COGNIS device was converted to a SRD, sensor data was
continuously stored in device memory. Data stored in the SRD was
recovered from the implanted device using either subject follow-up visits to the
investigational center, or using remote LATITUDE downloads
Endpoint 1
Sensitivity for detecting usable heart failure events >40%. An exact two-sided 95%
confidence interval (CI) for the sensitivity calculated based on the binomial
distribution and the lower bound tested against a performance goal of 40%.
Endpoint 2
Unexplained alert rate (UAR) per patient year <2.0. A two-sided 95% CI for the
unexplained alert rate calculated based on the negative binomial distribution and the
upper bound tested against the performance goal of 2.0.
Heart Failure Event
(HFE) Definition
Primary cause of event was worsening heart failure and
Usable HFE
Definition
•
is admitted for HF and receives an augmented HF regimen with oral or IV
medications, or
• receives unscheduled IV decongestive therapy that does not involve formal inpatient hospital admission, regardless of the setting
HFEs that occurred at least 45 days after initiation of sensor data collection and prior
to device re-conversion. The 45day period was required to establish an index baseline.
Missed study visits resulted in SRDdevice memory overflow and loss of sensor data
(this is not a limitation with commercial implementation); hence at least 60% of
relevant sensor data within a 60 day pre-event window and at least 70% within a 15-
3
day pre-event window were also required.
True Positive (TP)
Alert Definition
•
•
HF Related Alerts
Same onset and recovery window as TP alerts but broader HF definition:
•
•
•
Unexplained
•
Onset before a usable HFEs
Recovery no earlier than 30 days before usable HFE
hospitalizations with a secondary cause of HF,
outpatient visits with a primary cause of HF and augmented oral medication
changes,
HFEs that did not meet sensor data availability criteria or occurred within 45
days of device conversion
All other alerts
Alerts
Assessment of
Events
In agreement with ISO 14155-2011
Ethics
This study was conducted according to the stipulations of the Declaration of
Helsinki, ISO 14155-2011 and all other applicable regulations as determined by
the countries of submission.
Name of Sponsor
Boston Scientific, CRV
Principal
Investigators
John P. Boehmer, M.D.
Clinical Event
Committee
Alfred E. Buxton, Teresa DeMarco , Andrew E. Epstein, J. Thomas Heywood,
Tamara B. Horwich, Brian Jaski, Charles Kennergren, Marrick Kukin, JoAnn
Lindenfeld, Suneet Mittal
Participating
Centers
CZE: Faculty Hospital U sv Anny, Jolana Lipoldova; DEU: Uni Jena, Ralf Surber;
GBR: Golden Jubilee National Hospital, Roy Stuart Gardner; The Heart Hospital,
Pier Lambiase; HKG: Prince of Wales Hospital, Joseph Yat Sun Chan; HUN: Allami
Egeszsegugyi Kozpont Hospital, Gabor Zoltan Duray; Hungarian Institute of
Cardiology, Csaba Foeldesi; Semmelweis University, Cardiovascular Center, Bela
Merkely; ISR: Kaplan Medical Centre, Ofir Paz; ITA: Ospedale Sacro Cuore Don
Calabria, Giulio Molon; Azienda Ospedaliera Lancisi, Alessandro Capucci; MYS:
Institut Jantung Negara, Omar Razali; NLD: Leiden University Medical Center,
Lieselotte van Erven; Universitair Medisch Centrum, Mathias Meine; SVK: Eastern
Slovakia Institute for Cardiac and Vascular Diseases, Branislav Stancak; The National
Institute of Cardiovascular Diseases, Tibor Malacky; THA: Her Majesty Cardiac
Center, Siriraj Hospital, Charn Sriratanasathavorn; Ramathibodi Hospital, Tachapong
Ngarmukos; AK: Providence Alaska Medical Center, Steve Compton; AR: Baptist
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Health Medical Center, Stephen Greer; Cardiology Associates of Northeast Arkansas,
Devi Nair; AZ: Arizona Advanced Arrhythmias, Rajdeep Gaitonde; Cardiovascular
Consultants, LTD, Andy Tran; Southern Arizona VA Health Care System, Sergio
Thal; Tri-City Cardiology, Rodrigo Chan; CA: John Muir Medical Center, Paul
Ludmer; Sharp Memorial Hospital, Charles Athill; USC Medical Center, Philip
Chang; CT: Hartford Hospital, Jeffrey Kluger; DC: Washington Hospital Center,
Zayd Eldadah; FL: Daytona Heart Group, Hanscy Seide; First Coast Cardiovascular,
David Weisman; First Coast Heart & Vascular, Dinesh Pubbi; Lakeland Regional
Medical Center, Kevin Browne; Orlando Regional Medical Center, Pavel Guguchev;
Winter Haven Hospital, Gary Johnson; GA: Emory University Hospital, Andrew
Smith; Northeast Georgia Heart Center, Salem Sayar; St. Joseph’s Hospital of
Atlanta, Niraj Sharma; IA: Genesis Medical Center, Robert Brewer; St. Luke’s
Hospital, Mohit Chawla; IL: Advocate Lutheran General Hospital, Parag Patel; IN:
La Porte Hospital, Mark Dixon; Northern Indiana Research Alliance, Fausto
Devecchi; Parkview Hospital, Inc., David Schleinkofer; St. Marys Medical Center –
Evansville, Umang Patel; St. Vincent’s Hospital, Girish Nair; KY: Baptist Health
Lexington, Gery Tomassoni; St. Joseph Hospital, William Schoen; MA: University of
Massachusetts Memorial Medical Center, Lawrence Rosenthal; MI: Michigan
CardioVascular Institute, Asim Yunus; St. Joseph Mercy Hospital, Radmira
Greenstein; MN: HealthEast St. Joseph’s Hospital, Stuart Adler; University of
Minnesota Medical Center, David Benditt; NC: Sanger Heart and Vascular Institute,
Theodore Frank; NE: Bergan Cardiology, Eric Van De Graaff; NJ: Cardiovascular
Associates of the Delaware Valley, George Mark; Hackensack University Medical
Center, Gunjan Shukla; Morristown Memorial Hospital, Robert Coyne; New Jersey
Cardiology Associates, Marc Roelke; NY: Buffalo Cardiology and Pulmonary,
Grzegorz Rozmus; Long Island Jewish Medical Center, David Slotwiner; Montefiore
Medical Center, Kevin Ferrick; Strong Memorial Hospital of the University of
Rochester, Mehmet Aktas; OH: Cardiovascular Research Institute LLC, Ira
Friedlander; Good Samaritan Hospital, John Wilson; Lindner Center for Research and
Education at Christ Hospital, Edward Schloss; Northwest Ohio Cardiology
Consultants, Mark Richards; Ohio State University Medical Center, Ayesha Hasan;
OhioHealth Research and Innovation Institute - Riverside Methodist Hospital, Seth
Rials; St. Elizabeth Health Center, Allan Katz; OK: Oklahoma Heart Institute, David
Sandler; OR: Rogue Valley Medical Center, Eric Pena; PA: Abington Memorial
Hospital, Charles Gottlieb; Albert Einstein Medical Center, Sumeet Mainigi;
Cardiology Consultants of Philadelphia, Christopher Schulze; Lancaster General
Hospital, Roy Small; Penn State Milton S Hershey Medical Center, Eric Popjes; The
Arrhythmia Institute, Scott Burke; University of Pittsburgh Medical Center, Marc
Simon; RI: Cardiovascular Associates of Rhode Island, Michael Hyder; Rhode Island
Hospital, Michael Kim; SC: Medical University of South Carolina, Michael Gold;
TN: Stern Cardiovascular Foundation, Inc., David Lan; TX: EP Heart, University of
Texas, Ramesh Hariharan; Heart Hospital of Austin, Jeffrey Whitehill; SouthEast
Texas Clinical Research Center, Paris Bransford; Texas Cardiac Arrhythmia
Research, Robert Canby; UT: University of Utah Hospital and Clinics, Roger
Freedman; VA: Chippenham Medical Center, David Gilligan; Sentara Norfolk
General Hospital, John Herre; University of Virginia Medical Center, Andrew Darby;
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Virginia Commonwealth University Health System, Kenneth Ellenbogen; WV:
Monongalia General Hospital, John Lobban.
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Supplemental Table 2. SRD Converted Patient Characteristics
Characteristic
Measurement
Develop.
(N=500)
Test
(N=400)
P-value
66.4 ± 10.7
66.8 ± 10.3
0.52
Age at Implant (years)
Mean ± SD
Gender [N (%)]
Male
366 (73)
288 (72)
0.69
Race [N (%)]
White, Not Of Hispanic Origin
344 (74)
258 (78)
0.47
United States [N (%)]
Yes
462 (92)
329 (82)
<0.0001
History of Cardiac Ischemia [N (%)]
Yes
263 (53)
194 (49)
0.22
History of Dilated Cardiomyopathy [N (%)]
Yes
288 (58)
245 (61)
0.27
History of Valvular Disease [N (%)]
Yes
152 (30)
117 (29)
0.71
History of Valve Surgery [N (%)]
Yes
43 (9)
35 (9)
0.94
Previous MI [N (%)]
Yes
201 (40)
153 (38)
0.54
Previous CABG [N (%)]
Yes
145 (29)
113 (28)
0.80
Primary Atrial Arrhythmia [N (%)]
Atrial Fibrillation (AF)
128 (26)
107 (27)
0.81
Renal Disease [N (%)]
Yes
136 (27)
90 (23)
0.11
NYHA Class [%]
I / II / III / IV
5 / 66 / 28 / 0
5 / 69 / 25 / 1
0.64
LVEF (%)
Mean ± SD
29.3 ± 11.4
30.0 ± 11.4
0.35
Body Mass Index (kg/m2)
Mean ± SD
30.4 ± 6.6
30.6 ± 7.0
0.61
Systolic Blood Pressure (mmHg)
Mean ± SD
122 ± 19
125 ± 19
0.02
Diastolic Blood Pressure (mmHg)
Mean ± SD
71 ± 11
73 ± 11
0.03
Resting Heart Rate (bpm)
Mean ± SD
71 ± 10
71 ± 10
0.60
Resting Respiratory Rate (br/min)
Mean ± SD
18 ± 6
18 ± 7
0.53
Sodium (mEq/L
Mean ± SD
139 ± 3
140 ± 3
0.03
Potassium (mEq/L)
Mean ± SD
4.4 ± 0.6
4.4 ± 0.5
0.98
Hematocrit (%)
Mean ± SD
39.3 ± 4.8
40.3 ± 5.0
0.005
Total Hemoglobin (g/dL)
Mean ± SD
13.1 ± 1.7
13.3 ± 1.8
0.06
Total Plasma Protein (g/dL)
Mean ± SD
7.1 ± 0.7
7.1 ± 0.6
0.62
BUN (mg/dL)
Mean ± SD
25.0 ± 13.6
23.2 ± 11.3
0.05
Urea (mmol/L)
Mean ± SD
5.5 ± 2.7
6.5 ± 1.9
0.07
Serum Creatinine (mg/dL)
Mean ± SD
1.4 ± 0.9
1.3 ± 0.7
0.11
NT-proBNP (pg/mL)
Mean ± SD
2099 ± 5216
1592 ± 3035
0.10
Concomitant Medications [N (%)]
Anticoagulants
446 (89)
326 (82)
0.001
Beta Blockers
467 (93)
372 (93)
0.81
Diuretics
383 (77)
311 (78)
0.68
Ace-Inhibitors + ARBs
418 (84)
330 (83)
0.66
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Aldosterone Antagonist
185 (37)
175 (44)
0.04
Vasoactive Drugs
121 (24)
89 (22)
0.49
Cardiac Glycosides
133 (27)
98 (25)
0.47
Antiarrhythmic Medications
108 (22)
85 (21)
0.90
42 (8)
29 (7)
0.52
Calcium Channel Blockers
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Supplemental Figure 1. Event Classification in the Development Set. HFE, Heart Failure Event.
Dev Set Events Adjudicated
(n=581)
Events Adjudicated as HF
(n=258)
Events Adjudicated with HF as
Primary Cause
(n=228)
Hospitalization Events
(n=96)
Events Adjudicated with HF as
Secondary Cause
(n=30)
Outpatient Visits
(n=132)
IV Treatment
(n=31)
Oral Medication Change
(n=101)
HFE Definition Met
(n=127)
Within 45 days of
conversion?
15 excluded
Met Data Availability Criteria?
16 excluded
Usable HFE
(n=96)
HFE Related Event
(n=162)
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