Bairey Merz MD Eileen M Handberg Chrisandra L Shufelt Puja K Mehta Margo B Minissian Janet Wei Louise E J Thomson Daniel S Berman Leslee ID: 485834
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C. Noel Bairey Merz, MDEileen M. Handberg, Chrisandra L. Shufelt, Puja K. Mehta, Margo B. Minissian, Janet Wei, Louise E. J. Thomson, Daniel S. Berman, Leslee J. Shaw, John W. Petersen, Garrett H. Brown, R. David Anderson, Jonathan J. Shuster, Galen Cook-Wiens, André Rogatko, Carl J. PepineFor the WISE and RWISE Investigators
RWISEA Randomized, Placebo Controlled Trial of Late Na Current Inhibition (ranolazine) in Coronary Microvascular Dysfunction: Impact on Angina and Myocardial Perfusion ReserveSlide2
Online November 11, 2015 http.//dx10.1093/eurheartj/ehv647European Heart JournalRWISEA Randomized, Placebo Controlled Trial of Late Na Current Inhibition (ranolazine) in Coronary Microvascular Dysfunction: Impact on Angina and Myocardial Perfusion ReserveC. Noel Bairey Merz, MD, Eileen M. Handberg, Chrisandra L. Shufelt, Puja K. Mehta, Margo B. Minissian
, Janet Wei, Louise E. J. Thomson, Daniel S. Berman, Leslee J. Shaw, John W. Petersen, Garrett H. Brown, R. David Anderson, Jonathan J. Shuster, Galen Cook-Wiens, André Rogatko, Carl J. PepineFor the WISE and RWISE InvestigatorsSlide3
RWISE Trial OrganizationPrincipal InvestigatorC. Noel Bairey Merz, MDCedars-Sinai Heart InstituteCedars-Sinai Medical CenterExecutive CommitteeCarl J. Pepine MD, Eileen Handberg PhD, Leslee Shaw PhD, Puja Mehta MD, Chrisandra Shufelt MD, MS, Janet Wei MDData Management and Biostatistics
Galen Cook-Wiens MS, Jonathan Shuster PhD, Andre Rogatko PhD Data Safety Monitoring BoardBernard J. Gersh, MD (Chair), Robert Bonow MD, Erika Brittain PhDCMRI Core LabLouise Thomson MBBS,
Daniel S. Berman MD Coronary Angiographic /Physiology Core
LabDavid Anderson MD, John Petersen MD
The study was investigator-initiated as an ancillary trial to the NHLBI-sponsored WISE, funded in part by Gilead Sciences. Statistical analysis was performed by the investigators independent of NHLBI and Gilead. The decision to submit for publication was made by the Principle Investigators who had access to all data after the last subject completed the study.Slide4
WISE Background -1Coronary microvascular dysfunction (CMD) is highly prevalent in 20-54% of subjects with symptoms and signs of ischemia with and without obstructive CAD1-3CMD is associated with elevated IHD morbidity, mortality, and healthcare costs4-8Mechanistic pathways for CMD and no obstructive CAD are not well-defined, large outcome trials are lacking and treatment guidelines absent9WISE = Women’s Ischemia Syndrome Evaluation1. Reis AHJ 2001 doi:10.1067/mhj.2001.114198 ; 2. Buchthal NEJM 200 DOI: 10.1056/NEJM2000032334212010; 3. Murthy Circ 2014 doi: 10.1161/CIRCULATIONAHA.113.008507; 4. Johnson Circ 2004 doi: 10.1161/01.CIR.0000130642.79868.B2 ; 5. von Mering Circ 2004 doi: 10.1161/01.CIR.0000115525.92645.16 ;
6. Pepine JACC 2010 doi:10.1016/j.jacc.2010.01.054; 8. Shaw Circ 2006 doi:10.1016/j.jacc.2004.11.075 ; 9. Fihn JACC 2012 doi:10.1016/j.jacc.2012.07.013Slide5
WISE Background - 2Prior ancillary WISE CMD mechanism trialsTrial (n)Pharmacologic ProbeResults QWISE1 (n=78)quinipril CFR; anginaFemHRT-WISE2(n=35)ethinyl estradiol and norethindrone acetate MRS; anginaEWISE3 (n=41)eplenerone added to ACECFR; anginaSWISE4 (n=23)sildenafil (acute)CFRRWISE pilot5 (n=20)
ranolazineMPRI; anginaCFR = coronary flow reserve, MRS = magnetic resonance spectrosopy; MPRI=myocardial perfusion reserve index; 1. Pauley AHJ 2011 doi:10.1016/j.ahj.2011.07.011; 2. Bairey Merz AHJ 2010doi:10.1016/j.ahj.2010.03.024 ; 3. Bavry AHJ 2014doi:10.1016/j.ahj.2014.01.017 ; 4. Denardo Clin Card 2011 DOI: 10.1002/clc.20935; 5. Mehta JACC Imagingdoi:10.1016/j.jcmg.2011.03.007 Slide6
RWISE Study DesignRandomized, double-blind, placebo-controlled, cross-over, short-term, mechanism trial ClinicalTrials.gov NCT01342029 2 weeks 2 weeks 2 weeksBaseline SAQ Angina/NTGDASI, QoL, BloodCMRI
SAQ Angina/NTGDASI, QoL, BloodCMRISAQ Angina/NTGDASI, QoL, BloodRADOM IZEDCMRI conducted followingwithdrawal of vasoactive and anti-anginal
medicationPrimary
: To mechanistically test short-term late Na current inhibition (ranolazine) in subjects with symptoms, no obstructive CAD but evidence of CMD, on SAQ angina, myocardial perfusion reserve and diastolic filling
Secondary: To investigate if symptoms are related to ischemia in such subjectsSlide7
RWISE Efficacy Endpoints and Statistical AnalysesCo-primary Outcomes:Angina measured by the Seattle Angina Questionnaire (SAQ):- Angina stability, Angina frequency, SAQ-7Secondary Outcome:- Angina measured by diaryOther Outcomes:- Cardiac magnetic resonance imaging (CMRI) gadolinium (Gd) perfusion and diastolic functionQuality of Life (SF-36, MOS-116, HIS-GWB, DASI) Statistical Analyses:- Within-subjects comparison (paired) of the difference between baseline-treatments (SAQ, QoL) or treatment period (CMRI)- Linear regression models for treatment difference outcomeAll subjects receiving both ranolazine and placebo in the appropriate treatment periods were included in the primary analysisSlide8
RWISE Enrollment and Randomization22 Excluded 9 not treated 3 scientific misconduct
5 Excluded (no PCI)
10 Excluded (no PCI)
251
RandomizedSlide9
RWISE Baseline Characteristics Variable (n=128)Mean ± SD, or absolute frequency (%)Age (yrs)55.2 ± 9.8Female123 (96%) Typical Angina40 (31.3%) Shortness of Breath88 (68.8%) Palpitations53 (41.4%) Nausea40 (31.3%)
Angina frequency (baseline SAQ angina frequency domain)59.6 ± 26.9Angina episodes (diary) 4.9±7.8 (wk)NTG usage (diary) 2.6±11.2 (wk)Qualifying CMRI MPRI<2 (n=67)*1.6 ± 0.3Qualifying CFR<2.5 (n=35)*
2.2 ± 0.2Qualifying Ach response<0% (n=36)*
-1.6± 15.6*subjects could have CMRI and CFR and ACH qualifiersSlide10
RWISE Compliance and Safety(n=128)
Ranolazine
Placebo
Washout
Overall compliance (by pill count) 97%
Reduced dosage due to side effects
21%
14%
NA
Adverse events
7
6
2
Serious adverse events*
5
0
2
*hospitalization for NSTEMI [1]; bronchospasm [1]; chest pain, dizziness, and pre-syncope [2]; and syncope [1]), during the washout periods were hospitalization for chest pain (
ranolazine
washout, 1 patient) and bradycardia (placebo washout, 1 patient), and 0 during the placebo. Slide11
RWISE Primary, Secondary and QoL Outcomes
Ranolazine (N=128)
Placebo
(N=128)
Treatment Change*
P
-value
SAQ angina stability
58.40±26.11
51.17±27.68
5.12
0
.24
SAQ angina frequency
63.91±26.09
62.73±25.96
0.08
0
.
97
SAQ-7
63.43±21.09
61.60±22.32
1.31
0
.87
Angina episodes – diary
(per week)
4.78±8.20
4.88±7.75
-0.10
0.81
DASI
6.35±4.85
6.20±5.05
0.31
0.49
HIS-GWB Depressed
4.39±0.74
4.27±0.87
0.20
0.009
*The SAQ,
QoL
, and DASI were measured pre- and post-treatment for both periods; treatment change is the difference
ranolazine
-placebo in post-pre periods. SAQ=Seattle Angina Questionnaire, DASI=Duke Activity Status Inventory, HIS-GWB=Health Insurance Study-General Well-BeingSlide12
RWISE Pharm Stress and CMRI Outcomes
Ranolazine (N=128)
Placebo
(N=128)
Treatment Change
P
-value
Stress HR
95.17±13.50
98.73±14.15
-3.55
<0
.0001
Stress RPP
12082±2707
12611±2796
-523
0
.01
Stress MPRI
1.98±0.46
1.96±0.42
0.01
0
.88
Stress MPRI-mid
subendocardial
1.83±0.48
1.77±0.38
0.06
0.23
PFR
333.3±105.9
328.8±97.1
4.3
0.52
tPFR
163.9±45.3
157.4±37.7
6.6
0.09
Pharm stress and CMRI were measured only post-treatment; treatment change
ranolazine
vs
placeob
. HR=heart rate, RPP=rate pressure product, MPRI=myocardial perfusion reserve index, PFR=peak filling rate,
tPFR
=time PFRSlide13
RWISE Angina and Myocardial Perfusion As the model MPRI-midventricular change increased, SAQ QoL change increased, adjusted for BMI, prior MI and site(top). Similar results were observed with MPRI-mid subendocardial (bottom). All of the angina variables were tried in the model. Two SAQ variables could enter into the models singly, but not at the same time: SAQ QoL and SAQ-7. Each of these had similar associations with the MPRI variables, but QoL has slightly better model fit statistics. A higher MPRI number indicates better myocardial perfusion indexSlide14
RWISE Subgroup Analyses Among subjects with qualifying CRT available CFR and both period MPRI (n=78), lower CFR had significantly greater mid-ventricular MPRI change on ranolazine vs placebo A higher MPRI number indicates better myocardial perfusion indexMPRI change according to qualifying CFR in subjects with invasive CRT Slide15
RWISE Limitations Short-term ranolazine exposureGd MPRI is not a direct measure of CFRSAQ may not measure “angina-equivalents”Invasive CFR determined only in a subsetSlide16
RWISE Summary and Conclusions Short-term late Na current blockade (ranolazine) effective for effort angina in patients with obstructive CAD, did not significantly improve SAQ angina or myocardial perfusion index in subjects with no obstructive CAD but evidence of CMD Changes in the SAQ and myocardial perfusion index were directly related, indicating that symptoms are related to myocardial perfusion index in this populationAngina and perfusion index improved in ranolazine-treated subjects with lower baseline CFR, suggesting these subjects should be included in future trials testing traditional and novel strategies