RWISE
A Randomized, Placebo Controlled Trial of Late Na Current
Inhibition (ranolazine) in Coronary Microvascular
Dysfunction: Impact on Angina
and Myocardial Perfusion Reserve
C. 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. Pepine
For the WISE and RWISE Investigators
European Heart Journal
RWISE
A Randomized, Placebo Controlled Trial of Late Na Current
Inhibition (ranolazine) in Coronary Microvascular
Dysfunction: Impact on Angina
and Myocardial Perfusion Reserve
C. 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 CookWiens, André Rogatko, Carl J. Pepine
For the WISE and RWISE Investigators
Principal Investigator
C. Noel Bairey Merz, MD
Cedars-Sinai Heart Institute
Cedars-Sinai Medical Center
Data Safety Monitoring Board
Bernard J. Gersh, MD (Chair),
Robert Bonow MD, Erika Brittain PhD
CMRI Core Lab
Executive Committee
Louise Thomson MBBS,
Carl J. Pepine MD, Eileen Handberg
Daniel S. Berman MD
PhD, Leslee Shaw PhD, Puja Mehta
Coronary Angiographic /Physiology Core Lab
MD, Chrisandra Shufelt MD, MS,
David Anderson MD, John Petersen MD
Janet Wei MD
Data Management and Biostatistics
Galen Cook-Wiens MS, Jonathan
Shuster PhD, Andre Rogatko PhD
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.
Coronary microvascular dysfunction (CMD) is highly
prevalent in 20-54% of subjects with symptoms and signs
of ischemia with and without obstructive CAD1-3
CMD is associated with elevated IHD morbidity, mortality,
and healthcare costs4-8
Mechanistic pathways for CMD and no obstructive CAD
are not well-defined, large outcome trials are lacking and
treatment guidelines absent9
WISE = Women’s Ischemia Syndrome Evaluation
1. 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.2012.07.013
Trial (n)
Pharmacologic Probe
Results
QWISE1 (n=78)
quinipril
 CFR;  angina
FemHRT-WISE2(n=35)
ethinyl estradiol and
norethindrone acetate
 MRS;  angina
EWISE3 (n=41)
eplenerone added to ACE
CFR; angina
SWISE4 (n=23)
sildenafil (acute)
CFR
RWISE pilot5 (n=20)
ranolazine
MPRI; angina
CFR = 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
Primary: 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 subjects
Randomized, double-blind, placebocontrolled, cross-over, short-term,
mechanism trial
R
A
D
R
O
A
M
NI
D
Z
E
D
ClinicalTrials.gov NCT01342029
WASH -OU T
A
2 weeks
B
2 weeks
B
Baseline SAQ
Angina/NTG
DASI, QoL,
Blood
CMRI
SAQ
Angina/NTG
DASI, QoL,
Blood
2 weeks
A
CMRI conducted following
withdrawal of vasoactive
and anti-anginal medication
CMRI
SAQ
Angina/NTG
DASI, QoL,
Blood
Co-primary Outcomes:
Angina measured by the Seattle Angina Questionnaire (SAQ):
- Angina stability, Angina frequency, SAQ-7
Secondary Outcome:
- Angina measured by diary
Other Outcomes:
- Cardiac magnetic resonance imaging (CMRI) gadolinium (Gd)
perfusion and diastolic function
- Quality 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 outcome
All subjects receiving both ranolazine and placebo in the
appropriate treatment periods were included in the primary analysis
251 Randomized
22 Excluded
9 not treated
3 scientific misconduct
5 Excluded (no PCI)
10 Excluded (no PCI)
Variable (n=128)
Age (yrs)
Female
Typical Angina
Shortness of Breath
Palpitations
Nausea
Angina frequency
(baseline SAQ angina frequency domain)
Mean ± SD, or absolute frequency (%)
55.2 ± 9.8
123 (96%)
40 (31.3%)
88 (68.8%)
53 (41.4%)
40 (31.3%)
59.6 ± 26.9
Angina episodes (diary)
NTG usage (diary)
4.9±7.8 (wk)
2.6±11.2 (wk)
Qualifying CMRI MPRI<2 (n=67)*
Qualifying CFR<2.5 (n=35)*
1.6 ± 0.3
Qualifying Ach response<0% (n=36)*
2.2 ± 0.2
-1.6± 15.6
*subjects could have CMRI and CFR and ACH qualifiers
(n=128)
Ranolazine
Placebo
Washout
21%
14%
NA
Adverse events
7
6
2
Serious adverse events*
5
0
2
Overall compliance (by pill count)
Reduced dosage due to
side effects
97%
*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.
SAQ angina
stability
SAQ angina
frequency
SAQ-7
Ranolazine
(N=128)
Placebo
(N=128)
Treatment
Change*
Pvalue
58.40±26.11
51.17±27.68
5.12
0.24
63.91±26.09
62.73±25.96
0.08
0.97
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-Being
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 PFR
As the model MPRImidventricular 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 index
Among subjects
with qualifying CRT
available CFR and
both period MPRI
(n=78), lower CFR
had significantly
greater midventricular MPRI
change on
ranolazine vs
placebo
A higher MPRI number indicates
better myocardial perfusion
index
MPRI change according to qualifying
CFR in subjects with invasive CRT
Short-term ranolazine exposure
Gd MPRI is not a direct measure of CFR
SAQ may not measure “angina-equivalents”
Invasive CFR determined only in a subset
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 population
Angina 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