JACC: CARDIOVASCULAR IMAGING VOL. 15, NO.

8, 2022

ª 2022 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

ORIGINAL RESEARCH

Efficacy of Diltiazem to Improve

Coronary Vasomotor Dysfunction
in ANOCA
The EDIT-CMD Randomized Clinical Trial

Tijn P.J. Jansen, MD,a Regina E. Konst, MD,a Annemiek de Vos, MD,b Valeria Paradies, MD,c Steven Teerenstra, PHD,d
Stijn C.H. van den Oord, MD, PHD,a Aukelien Dimitriu-Leen, MD, PHD,a Angela H.E.M. Maas, MD, PHD,a
Pieter C. Smits, MD, PHD,c Peter Damman, MD, PHD,a Niels van Royen, MD, PHD,a Suzette E. Elias-Smale, MD, PHDa

ABSTRACT

BACKGROUND Diltiazem is recommended and frequently prescribed in patients with angina and nonobstructive cor-
onary artery disease (ANOCA), suspected of coronary vasomotor dysfunction (CVDys). However, studies sub-
stantiating its effect is this patient group are lacking.

OBJECTIVES The randomized, placebo-controlled EDIT-CMD (Efficacy of Diltiazem to Improve Coronary Microvascular
Dysfunction: A Randomized Clinical Trial) evaluated the effect of diltiazem on CVDys, as assessed by repeated
coronary function testing (CFT), angina, and quality of life.

METHODS A total of 126 patients with ANOCA were included and underwent CFT. CVDys, defined as the presence of
vasospasm (after intracoronary acetylcholine provocation) and/or microvascular dysfunction (coronary flow
reserve: <2.0, index of microvascular resistance: $25), was confirmed in 99 patients, of whom 85 were ran-
domized to receive either oral diltiazem or placebo up to 360 mg/d. After 6 weeks, a second CFT was per-
formed. The primary end point was the proportion of patients having a successful treatment, defined as
normalization of 1 abnormal parameter of CVDys and no normal parameter becoming abnormal. Secondary end
points were changes from baseline to 6-week follow-up in vasospasm, index of microvascular resistance,
coronary flow reserve, symptoms (Seattle Angina Questionnaire), or quality of life (Research and Development
Questionnaire 36).

RESULTS In total, 73 patients (38 diltiazem vs 35 placebo) underwent the second CFT. Improvement of the CFT did not
differ between the groups (diltiazem vs placebo: 21% vs 29%; P ¼ 0.46). However, more patients on diltiazem
treatment progressed from epicardial spasm to microvascular or no spasm (47% vs 6%; P ¼ 0.006). No sig-
nificant differences were observed between the diltiazem and placebo group in microvascular dysfunction,
Seattle Angina Questionnaire, or Research and Development Questionnaire 36.

CONCLUSIONS This first performed randomized, placebo-controlled trial in patients with ANOCA showed that 6 weeks
of therapy with diltiazem, when compared with placebo, did not substantially improve CVDys, symptoms, or
quality of life, but diltiazem therapy did reduce prevalence of epicardial spasm. (Efficacy of Diltiazem to
Improve Coronary Microvascular Dysfunction: A Randomized Clinical Trial [EDIT-CMD]; NCT04777045)
(J Am Coll Cardiol Img 2022;15:1473–1484) © 2022 by the American College of Cardiology Foundation.

From the aDepartment of Cardiology, Radboud University Medical Center, Nijmegen, the Netherlands; bDepartment of Cardiology,
Catharina Hospital, Eindhoven, the Netherlands; cDepartment of Cardiology, Maasstad Hospital, Rotterdam, the Netherlands; and
the dDepartment for Health Evidence, Section Biostatistics, Radboud Institute for Health Sciences, Radboud University Medical
Center, Nijmegen, the Netherlands.

ISSN 1936-878X/$36.00 https://doi.org/10.1016/j.jcmg.2022.03.012

1474 Jansen et al JACC: CARDIOVASCULAR IMAGING, VOL. 15, NO. 8, 2022

Diltiazem to Improve Coronary Vasomotor Dysfunction AUGUST 2022:1473–1484

U
ABBREVIATIONS p to 40% of patients undergoing coronary function retesting to evaluate the effect of
AND ACRONYMS coronary angiography for stable diltiazem on vasomotor dysfunction.
angina do not have obstructive cor-
ACH = acetylcholine
onary artery disease (CAD).1 In w60% to 90% METHODS
ADE = adenosine
of these patients with angina and no obstruc-
ANOCA = angina and no
tive coronary artery disease (ANOCA), the STUDY DESIGN. EDIT-CMD (Efficacy of Diltiazem to
obstructive coronary artery
underlying pathophysiology is coronary Improve Coronary Microvascular Dysfunction: A
disease
vasomotor dysfunction (CVDys). 2,3 In CVDys, Randomized Clinical Trial) is a double-blinded ran-
CCB = calcium-channel blocker
ischemia is caused by coronary (micro) domized placebo-controlled multicenter clinical trial
CCS = Canadian Cardiovascular
vascular vasospasm, and/or coronary micro- to study the effect of diltiazem versus placebo on
Society

vascular dysfunction (CMD), comprising coronary vasomotor function tested by repeated CFT
CFR = coronary flow reserve
impairment of vasodilatation and increased (Figure 1). The protocol was approved by all the local
CFT = coronary function test
microvascular resistance. Institutional Review Boards. All patients gave written
CMD = coronary microvascular
Patients with CVDys often have informed consent. All data were entered into an
dysfunction

continuing episodes of chest pain leading to electronic database (Castor EDC). EDIT-CMD is regis-
CVDys = coronary vasomotor
dysfunction frequent emergency department visits and tered at ClinicalTrials.gov (NCT04777045).
ECG = electrocardiography hospital admissions with associated high STUDY POPULATION. Between October 2019 and
ESC = European Society of health care costs.4 Moreover, CVDys is asso- May 2021, patients referred for a clinically indicated
Cardiology ciated with a worsened cardiovascular prog- CFT were screened for enrollment in 3 hospitals that
IMR = index of microvascular nosis.5 Therefore, proper diagnosis and specialized in ANOCA care in the Netherlands. Pa-
resistance
adequate treatment are of paramount tients (18 years and older) were eligible for randomi-
QoL = quality of life
importance. zation if all the following were present: 1) chronic
RAND-36 = Research and The gold standard to diagnose CVDys is an angina, defined as symptoms at least twice weekly
Development Questionnaire-36
invasive coronary function test (CFT) using despite medical therapy for the last 3 months; 2) no
SAQ = Seattle Angina
acetylcholine (ACH) to diagnose epicardial or signs of obstructive CAD at coronary angiography:
Questionnaire
microvascular vasospasm and adenosine either nonobstructive (<50% stenosis) coronary ar-
SAQSS = Seattle Angina 6
Questionnaire summary score
(ADE) to evaluate CMD. The landmark Cor- teries or intermediate stenosis (between 50% and
7
MicA (Coronary Microvascular Angina) trial 70%) with normal intracoronary physiology (frac-
Tmn = mean transit time
showed that diagnosing the specific endo- tional flow reserve: >0.80; or instant flow reserve:
type of CVDys as determined by CFT allows for >0.89); and 3) an abnormal CFT as described herein.
tailored medication that decreases angina and im- Exclusion criteria were another cause of angina
proves quality of life (QoL). A recent European Soci- deemed highly likely by the treating physician
ety of Cardiology (ESC) position paper on ANOCA (noncardiac origin of chest pain, such as gastrointes-
recommends the use of various pharmacological tinal or musculoskeletal), use of CCBs in the 2 weeks
treatments including calcium-channel blockers prior to start of inclusion in the trial or known intol-
(CCBs), beta-blockers, angiotensin-converting erance for non-dihydropyridine CCBs, left ventricular
enzyme inhibitors, statins, and nitric oxide modula- ejection fraction <50%, percutaneous coronary
tors, of which CCBs have the most prominent role in intervention within the past 3 months, a history of
both endotypes of coronary vasospasms and CMD.6 coronary artery bypass graft, surgically uncorrected
However, evidence substantiating these recommen- significant congenital or valvular heart disease,
dations is lacking, because it is based on studies in a known cardiomyopathy or myocarditis, significant
different population, with small sample sizes or that renal impairment (estimated glomerular filtration
is not placebo-controlled. 8,9 rate: <30 mL/min/1.73 m 2), significant hepatic
Hence, we conducted a randomized, placebo- impairment (history of cirrhosis or abnormal serum
controlled trial in patients with ANOCA to test the alanine or aspartate aminotransferase 3-fold greater
effects of the CCB diltiazem on CVDys as assessed by than the upper limit of normal), pregnant women or
CFT as well as on symptoms and QoL. This is the first women of child-bearing potential who were planning
trial in patients with ANOCA in which we use to become pregnant within the next 3 months,

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received February 22, 2022; revised manuscript received March 23, 2022, accepted March 24, 2022.
JACC: CARDIOVASCULAR IMAGING, VOL. 15, NO. 8, 2022
AUGUST 2022:1473–1484
F I G U R E 1 The EDIT-CMD Trial Design
Acetylcholine spasm
provocation test
Epicardial spasm
Recognizable complaints
Ischemic ECG
>90% vasoconstriction
Microvascular spasm
Recognizable complaints
Ischemic ECG
>90% vasoconstriction
Trial overview illustrating the usefulness of coronary function test to assess treatment effect, as determined by the effect on coronary artery
spasm and coronary microvascular dysfunction. CFR ¼ coronary flow reserve; ECG ¼ electrocardiography; EDIT-CMD ¼ Efficacy of Diltiazem
to Improve Coronary Microvascular Dysfunction: A Randomized Clinical Trial; IMR ¼ index of microvascular resistance.
prior noncardiac illness with an estimated life
expectancy <1 year, contraindication to CFT (ie,
contraindication or known hypersensitivity to ADE or
ACH or ongoing dipyridamole treatment), or inability
to give informed consent. If patients were already
using diltiazem or any other CCB, it was discontinued
after consent. The CFT was only performed when
patients were off CCBs for at least 2 weeks.
Patients were enrolled at the screening visit before
the first CFT and were only randomized when CVDys
was present. If no CVDys was present at the baseline
CFT, or if the patient withdrew from undergoing a
second CFT, they were included in a registry.
STUDY TREATMENT. Patients were
assigned in a 1:1 fashion to either diltiazem or placebo
treatment with the use of a built-in randomization
(Castor EDC). Permuted block randomization was
performed, 2,4,6 with stratification according to sex
and study site. Both patients and physicians were
blinded for allocation. Diltiazem as well as placebo
were provided as blinded capsules. Patients ran-
domized to the diltiazem arm started with diltiazem
HCl capsules of 120 mg daily. Individual dose titration
was performed twice weekly by steps of 120 mg daily
up to 360 mg daily, if well tolerated (based on adverse
Jansen et al 1475
Diltiazem to Improve Coronary Vasomotor Dysfunction
Baseline Coronary Function Test Adenosine bolus
thermodilution
Co
Coronary Microvascular
Dysfunction
Coronary Flow Reserve
Study treatment (CFR) <2.0
and/or
Index of Microvascular
Resistance (IMR) ≥25
Follow-up Coronary Function Test
events and blood pressure). A decrease in the dose
was performed in case of asymptomatic hypotension
with systolic blood pressure <90 mm Hg or symp-
tomatic hypotension. If the starting dose of 120 mg
daily was not tolerated, the study drug was dis-
continued. Treatment continued until the second
CFT, which was performed 6 weeks after the baseline
CFT.
CORONARY FUNCTION TESTING. CFT was per-
formed in accordance with the standardized protocol
as described by Konst et al2 and Ong et al.10 In brief,
patients were instructed to withhold all vasoactive
medication (except for the study treatment before the
randomly second CFT) and methylxanthine-containing sub-
stances for 24-48 hours before the procedure,
depending on half-life time. CFT consisted of a
diagnostic coronary angiography, ACH spasm provo-
cation test, and microvascular function assessment
using ADE. CFT procedures were done in the morning
in fasting state of the patients.
CORONARY VASOSPASM PROVOCATION WITH ACH.
Incremental doses of 2, 20, 100, and 200 m g of ACH
were manually infused over a period of 1-3 minutes
into the left coronary artery through a guiding cath-
eter. After each infusion, cine images were obtained
1476 Jansen et al
Diltiazem to Improve Coronary Vasomotor Dysfunction
to assess the change in coronary diameter. Heart rate,
blood pressure and a 12-lead electrocardiography
(ECG) were continuously monitored. After each dose,
the presence of recognizable symptoms was evalu-
ated. After the 200-m g dose or in case of epicardial
spasm >90%, whichever came first, 0.2 mg nitro-
glycerin was injected into the left coronary artery.
CMD WITH ADE. Subsequently, using a guidewire
with distal pressure and temperature sensors, the
microvascular function was assessed using a bolus
thermodilution method. 11 The left anterior descend-
ing coronary artery was preferred as the prespecified
target vessel reflecting its subtended myocardial
mass and coronary dominance. Additional studies in
other coronary arteries were appropriate if the initial
tests were negative and clinical suspicion was high. 6
First the resting mean transit time (Tmn) was deter-
mined by injections of 3-5 mL room temperature sa-
line into the left anterior descending artery,
averaging $3 consecutive measurements. Next, ADE
(typically 140 m g/kg/min) was administered intrave-
nously to induce steady-state maximal hyperemia—
and thereby minimal microvascular resistance—
and $3 more injections of room temperature saline
were recorded and averaged to determine the hy-
peremic Tmn. The coronary flow reserve (CFR) was
determined by dividing the average resting Tmn by
the average hyperemic Tmn.12 Microvascular resis-
tance, measured as the index of microvascular resis-
tance (IMR), was calculated as the distal pressure at
maximal hyperemia multiplied by hyperemic Tmn.13
All measurements were automatically analyzed by
dedicated software (Coroventis CoroFlow).
DEFINITIONS. We defined CVDys according to the
underlying pathophysiological endotype into pa-
tients with or without coronary spasm as assessed
with ACH, and patients with or without CMD as
measured with ADE. 14 CMD was present when mea-
surements showed an abnormal CFR <2.0 and/or an
abnormal IMR $25, as defined by current consensus
documents. 6 The definitions of epicardial or micro-
vascular spasm were also based on the latest inter-
6,10,15
national criteria as follows: epicardial
vasospasm was defined as a focal or diffuse epicardial
coronary diameter reduction $90% in response to
ACH, compared to the relaxed state after intra-
coronary nitroglycerin infusion, with a reproduction
of recognizable symptoms and ischemic ECG changes.
Microvascular spasm was diagnosed when the patient
experienced the reproduction of recognizable symp-
toms with ischemic ECG changes, in the absence
of $90% epicardial diameter reduction during ACH
infusion. 6 Ischemic ECG changes were defined as
JACC: CARDIOVASCULAR IMAGING, VOL. 15, NO. 8, 2022
AUGUST 2022:1473–1484
transient ST-segment elevation or depression
of $0.1 mV, or ischemic T-wave changes, in at least 2
contiguous leads. Any inconclusive result in response
to ACH (eg, only reproduction of symptoms) was
considered negative. A normal CFT was defined as
both normal ACH and ADE tests.
END POINTS. The primary end point was the pro-
portion of patients having a successful treatment,
defined as normalization of $1 abnormal parameter of
CVDys and none of the normal parameters becoming
abnormal. We defined “normalization” as epicardial
or microvascular spasm becoming no spasm and/or
microvascular dysfunction, defined as abnormal CFR
and/or abnormal IMR, becoming normal at the second
CFT.
Secondary end points were change in the individ-
ual parameters of the CFT: normalization of spasm,
changes from epicardial to microvascular spasm and
changes in CFR and IMR as continuous variables, ef-
fect on symptoms expressed as changes in scores of
the Seattle Angina Questionnaire (SAQ), 16 and change
in angina pectoris Canadian Cardiovascular Society
(CCS) classification. Furthermore, we evaluated the
effect on QoL, by means of changes in Research and
Development Questionnaire-36 (RAND-36). 17 The SAQ
and RAND-36 scales are transformed to a score of 0 to
100, where higher scores indicate better function (eg,
less physical limitation, less angina, and better QoL).
The Seattle Angina Questionnaire summary score
(SAQSS) averages the domains of angina limitation,
frequency, and QoL to provide an overall metric of
angina severity. 18-20 A SAQSS and RAND-36 change of
>5 points was considered clinically relevant.
STATISTICAL ANALYSIS. We considered a 25% suc-
cess rate of treatment with diltiazem clinically rele-
vant. We anticipated a 30% success rate in the
patients treated with diltiazem compared to a 5%
success rate in those treated with placebo. To detect
this difference with type I error rate of 5% and type II
error rate of 80% we included a total of 72 subjects (36
in each group) in the study.
We estimated that, based on prior research,21,22 at
least 60% of the screened patients would have an
abnormal CFT and that 15% would discontinue the
study treatment during the treatment phase. We
therefore calculated a total of 142 patients were
needed to provide the 85 patients to be randomized
to reach the intended sample size of 72 patients.
Continuous variables with normal distributions are
expressed as mean  SD and the differences were
compared between the groups with the use of an in-
dependent samples t-test. Categorical variables were
compared with the use of Fisher exact test or the
JACC: CARDIOVASCULAR IMAGING, VOL. 15, NO. 8, 2022 Jansen et al 1477
AUGUST 2022:1473–1484 Diltiazem to Improve Coronary Vasomotor Dysfunction

F I G U R E 2 Flowchart of the EDIT-CMD Study

Patient with chronic angina and no

obstructive CAD (ANOCA) referred for
Coronary Function Test (CFT)
Exclusions:
n = 126 1. No vasomotor dysfunction: n = 25
2. Obstructive CAD: n = 4
3. Withdrew IC: n = 7
4. Bradycardia: n = 2
5. Spasm of LM: n = 1
6. Difficulty of radial access: n = 1
Randomized patients with coronary 7. Screen failure: n = 1
vasomotor dysfunction
n = 85
One of the following:
- CFR ≤2.0
- IMR >25
- Abnormal reaction to ACH

Placebo Diltiazem
n = 44 n = 41

Drop-out placebo, n = 9: 6 weeks treatment Drop-out diltiazem, n = 2:

1. Persisting complaints, n = 5 (120 - 360 mg/day) 1. Persisting complaints, n = 1
2. Anxiety for second CFT, n = 3
Clinical visit at 2 and 4 weeks 2. Unplanned pregnancy, n = 1
3. Not willing to participate, n = 1

Second coronary
function test

Corelab analysis,
Drop-out after second blinded
Placebo, n = 35
evaluation due to catheter spasm, n = 1
Diltiazem, n = 38

ACH ¼ acetylcholine; ANOCA ¼ angina and no coronary artery obstruction; CAD ¼ coronary artery disease; CFT ¼ coronary function test; IC ¼ informed
consent; LM ¼ left main coronary artery; other abbreviations as in Figure 1.

Pearson chi-square test, where appropriate. The
Sankey plot is based on D3 ’s Sankey code.23 All data
were core lab analyzed by 2 independent researchers,
experienced with the clinical performance of CFTs
(T.P.J.J., P.D.), who were blinded for patient alloca-
tion and timing of the CFT. In case of discrepancy,
consensus was obtained after discussion between the
2 researchers, still in a blinded fashion.
Our primary outcome was to evaluate the effect of
diltiazem on CMD. This was assessed using a per
protocol interpretation, including only patients who
completed the study medication and the follow-up
CFT. Therefore, in patients dropping out during the
6-week treatment period, we did not perform any
further study procedures. To give insight in the effect
of diltiazem in the entire patient population,
including the patients who dropped out, we per-
formed 3 sensitivity analyses, which can be inter-
preted as intention to treat: the most likely, the most
negative, and the most positive scenarios. We hy-
pothesize that patients “most likely” dropped out
because of increase in symptoms, so we assigned all
patients who dropped out to the “deterioration
group.” For the most negative scenario for diltiazem,
all patients from the placebo group were assigned to
“improvement,” whereas all patients from the dilti-
azem group were assigned to “deterioration” and vice
versa for the most positive scenario (see the
1478 Jansen et al JACC: CARDIOVASCULAR IMAGING, VOL. 15, NO. 8, 2022

Diltiazem to Improve Coronary Vasomotor Dysfunction AUGUST 2022:1473–1484

obstruction and were excluded; 7 patients withdrew

T A B L E 1 Patient Characteristics of All Randomized Patients
informed consent because of not wanting to undergo
Total Placebo Diltiazem a second CFT; and 5 patients dropped out for other
(N ¼ 85) (n ¼ 44) (n ¼ 41)
reasons.
Age, y 58  9 58  9 58  9
Therefore, 85 patients were randomized, 44 were
Male 29 (34) 16 (36) 13 (31)
Relevant medical history
assigned to the placebo group, and 41 to the diltiazem
History of MI 14 (17) 8 (18) 6 (15) group. During the treatment period, 11 patients (13%)
History of PCI 19 (22) 10 (23) 9 (22) discontinued treatment (9 placebo, 2 diltiazem). In
History of CVA/TIA/PAD 8 (9) 3 (7) 5 (12) total, 74 underwent second CFT, and of those, 1 pa-
Noninvasive ischemia detection test performed 72 (85) 38 (86) 34 (83) tient was excluded during core lab analysis because of
Cardiovascular risk factors
catheter spasm.
Hypertension 45 (53) 23 (52) 22 (54)
Baseline characteristics of the 85 randomized pa-
Dyslipidemia 37 (44) 18 (41) 19 (46)
Diabetes 8 (9) 4 (9) 4 (10)
tients are shown in Table 1. The mean age was 58
Current/former smoker 41 (48) 23 (54) 17 (41) years; 29% of the patients were male; 22% had a his-
Premature CAD in first-degree relative 44 (52) 23 (52) 21 (51) tory of prior percutaneous coronary intervention; and
Other risk factors 53% had a history of hypertension. Angina charac-
Migraine 12 (14) 7 (16) 5 (12) teristics showed that 48% of patients had severe
Medication angina, defined as CCS class III/IV, and 87% had
Aspirin 42 (49) 20 (46) 22 (54)
angina at rest, with 49% of patients reacting
Beta-blocker 26 (31) 13 (30) 13 (32)
adequately to sublingual nitroglycerine use. Mean
Statin 37 (44) 15 (34) 22 (54)
ACE inhibitor/ARB 35 (41) 17 (39) 18 (44)
final study treatment dose was equal between the
Nitrates 21 (25) 10 (23) 11 (27) groups (301 vs 308 mg/d).
Nicorandil 14 (17) 5 (11) 9 (22) In total, 2 important procedure-related adverse
Laboratory blood tests events occurred (1%). One patient had important
Hemoglobin, mmol/L 8.6  0.8 8.4  0.7 8.7  0.8 bleeding, Bleeding and Academic Research Con-
Creatinine, mmol/L 67  15 68  15 67  15
sortium type >1, and 1 patient had a non–flow limiting
NT-proBNP, pg/mL 56 (10-103) 73 (15-131) 47 (11-83)
minimal coronary artery dissection, which was
LDL cholesterol, mmol/L 2.3  1.0 2.3  1.0 2.3  1.0
treated conservatively and had no clinical
HbA1c, mmol/mol 38  6.1 38  5.6 38  6.8
Angina characteristics consequence.
Angina CCS III/IV 41 (48) 23 (52) 18 (44) CORONARY FUNCTION TESTING. At baseline, ACH
SAQSS <50 44 (52) 21 (48) 23 (56) provocation test revealed epicardial spasm in 36 pa-
Main angina component
tients, microvascular spasm in 18 patients, and
Chest pain 71 (84) 35 (80) 36 (88)
microvascular dysfunction in 48 patients (Table 1).
Dyspnea 14 (16) 9 (20) 5 (12)
Angina at rest 74 (87) 39 (89) 35 (85) PRIMARY END POINT. A total of 8 patients in the
Angina occurs during exercise 65 (77) 34 (77) 31 (76) diltiazem group reached the primary end point of
Angina alleviated by NTG use 42 (49) 23 (52) 19 (46) successful treatment versus a total of 10 patients in
Systolic blood pressure 143  21 142  21 145  20
the placebo group. This difference was not significant
Diastolic blood pressure 83  13 81  12 84  13
(diltiazem 21% vs placebo 29%; P ¼ 0.46) (Central
Final treatment dosage, mg/d 305  86 308  87 301  85
Illustration, Table 2).
First ACH test
Epicardial spasm 43 (51) 24 (55) 19 (48) The remaining 55 patients had an “unsuccessful”
Microvascular spasm 21 (25) 11 (25) 10 (25) treatment: in the placebo group, 4 patients deterio-
No spasm 20 (24) 9 (20) 11 (27) rated and 21 patients had similar results; in the dilti-
Continued on the next page azem group, 9 patients deteriorated and 21 patients
had similar results.
Supplemental Appendix). All reported P values are 2- The sensitivity analysis of the “most likely” sce-
sided and have not been adjusted for multiple testing. nario on the primary end point showed similar results
(Table 2). Furthermore, the most positive and nega-
RESULTS tive scenarios for diltiazem did not show a meaning-
ful higher treatment success for diltiazem as
STUDY FLOW AND BASELINE CHARACTERISTICS. compared to placebo (Supplemental Table 1).
As can be seen in Figure 2, 126 patients were included Supplemental Figure 1 shows the prevalence of
that all underwent the first CFT. Of those, 25 had no spasm and CMD in both groups during the baseline
vasomotor dysfunction; 4 had significant coronary and follow-up tests.
JACC: CARDIOVASCULAR IMAGING, VOL. 15, NO. 8, 2022
AUGUST 2022:1473–1484
SECONDARY END POINTS. ACH measurements. Four
patients in the diltiazem group and 3 patients in the
placebo group improved from spasm to no spasm
(10% vs 8%, respectively; P ¼ NS). A small proportion
of patients deteriorated from no spasm to spasm (8%
vs 3%, respectively; P ¼ NS).
A substantial higher proportion of patients treated
with diltiazem, compared with the placebo group,
changed from epicardial spasm to microvascular
spasm or no spasm (47% vs 6%; P ¼ 0.006) (Figure 3).
ADE measurements. Changes in the prevalence of
microvascular dysfunction were not different be-
tween the diltiazem group and the placebo group
(Table 2). The change in CFR was larger in the
placebo group (D 1.0  2.7 vs D0.3  1.7, respec-
tively; P ¼ 0.012), which was attributable to a
decrease of the resting Tmn by 0.17 seconds in the
placebo group and an increase of 0.06 seconds in the
diltiazem group (P ¼ 0.05). No differences were
found in the hyperemic Tmns and IMR. Patients
treated with diltiazem, compared with those treated
with placebo, showed a significant drop in both
aortic and distal pressures at rest (D 0.8  13.3 vs
D9.7  11.4; P ¼ 0.003 and D1.5  19.6 vs D8.7 
11.7; P ¼ 0.009) (Table 3).
ANGINA AND QoL. The SAQSS and CCS did not show
a different change between diltiazem and placebo
after 6 weeks of treatment (SAQSS: D 1.1  12.8 vs D 3.0
 12.2; P ¼ 0.54; CCS: D 0.46  1.06 vs D0.47  0.94;
P ¼ 0.95), as displayed in Table 4. The SAQSS devel-
oped similarly between the groups (P ¼ 0.67) (Central
Illustration, Table 2). Furthermore, QoL, as expressed
as physical and mental health by RAND-36, also did
not show differences in change between diltiazem
and placebo (physical: D0.10  6.38 vs D 1.01  7.00;
P ¼ 0.58; mental D0.02  10.0 vs D 0.35  6.63;
P ¼ 0.87) (Table 4).
Angina and QoL analysis in different subgroups
seemed to show a decrease in symptoms for patients
with epicardial spasm and an increase for patients
with CMD on diltiazem (Supplemental Table 2),
although this was not significantly different than for
patients on placebo.
The patients that changed from epicardial to
microvascular spasm showed similar SAQSS as pa-
tients who showed epicardial spasm during both
CFTs, whereas patients improving from epicardial to
no spasm tended to improve in SAQSS (epicardial to
microvascular spasm: D 2.5  13.1 vs epicardial
to epicardial spasm: D 0.18  12.5 vs epicardial spasm
to none: D 6.3  3.9; P ¼ 0.30) (data not shown).
There were no sex-specific differences in change in
angina and QoL (Supplemental Table 2).
Jansen et al 1479
Diltiazem to Improve Coronary Vasomotor Dysfunction
T A B L E 1 Continued
Total Placebo Diltiazem
(N ¼ 85) (n ¼ 44) (n ¼ 41)
First ADE test
Both CFR and IMR normal 31 (37) 12 (27) 19 (46)
Only abnormal CFR 6 (7) 5 (11) 1 (2)
Only abnormal IMR 33 (38) 20 (46) 13 (32)
Both CFR and IMR abnormal 15 (18) 7 (16) 8 (20)
Conclusion
Microvascular dysfunction 54 (63) 32 (73) 22 (54)
Normal function 31 (37) 12 (27) 19 (46)
Values are mean  SD, n (%), or median (IQR).
ACE ¼ angiotensin-converting enzyme; ACH ¼ acetylcholine; ADE ¼ adenosine; ARB ¼ angiotensin-receptor
blocker; CAD ¼ coronary artery disease; CCS ¼ Canadian Cardiovascular Society; CFR ¼ coronary flow reserve;
CVA ¼ cerebrovascular accident; HbA1c ¼ glycosylated hemoglobin; IMR ¼ index of microvascular resistance;
LDL ¼ low-density lipoprotein; MI ¼ myocardial infarction; NTG ¼ nitroglycerine; NT-proBNP ¼ N-terminal pro–
B-type natriuretic peptide; PAD ¼ peripheral artery disease; PCI ¼ percutaneous coronary intervention;
SAQSS ¼ Seattle Angina Questionnaire Summary Score; TIA ¼ transient ischemic attack.
DISCUSSION
This is the first randomized placebo controlled trial
evaluating the effect of diltiazem on the various
endotypes of CVDys as assessed by test and retest
CFT in patients with ANOCA. We conclude that
6 weeks of oral therapy with diltiazem did not reduce
coronary vasospasm nor improve CMD. Also, treat-
ment with diltiazem, compared with placebo, did not
improve angina or QoL. However, we did find that
significantly more patients progressed from epicar-
dial spasm to microvascular spasm or no spasm while
on diltiazem treatment compared with placebo.
THE EFFECT OF DILTIAZEM ON CVDys. CCBs are
advised as anti-anginal therapy in both coronary
vasospasm and CMD in patients with ANOCA by a
recent ESC consensus document and for epicardial
vasospasm in the ESC guideline on chronic coronary
syndromes.6,15
CORONARY VASOSPASM. Regarding the use of CCBs
in coronary vasospasm, the ESC guideline refers to
the 2013 Japanese Cardiology Society Joint Working
Group guidelines for diagnosis and treatment of pa-
tients with vasospastic angina. 9 The document gives
a class 1 indication for the use of CCBs for vasospastic
angina, based on a limited number of studies, which
are summarized in Supplemental Table 1. The overall
response of CCBs in these studies was favorable with
regard to symptoms regardless of the specific CCB
used. However, only 2 crossover trials were per-
formed with diltiazem. First, a double-blind crossover
trial of 12 patients with Prinzmetal variant angina24
randomized patients to either diltiazem, in 2 dosage
schedules (120 mg and 240 mg/d), or placebo. After
4 weeks, patients received the alternative treatment
1480 Jansen et al JACC: CARDIOVASCULAR IMAGING, VOL. 15, NO. 8, 2022

Diltiazem to Improve Coronary Vasomotor Dysfunction AUGUST 2022:1473–1484

C E N T R A L IL LU ST R A T I O N Efficacy of 6 Weeks of Diltiazem Treatment to Improve Coronary Vasomotor

Dysfunction, Symptoms, and Quality of Life

Primary Endpoint No Improvement in Coronary Function Test Results

No Additional Effect of Diltiazem in Treatment Success
Coronary Artery Coronary Microvascular
P = 0.46 Spasm Dysfunction

30

29%
Percentage (%)

20
21%

10

0
Placebo Diltiazem
Successful Treatment

No Effect in Improvement in Angina and Quality of Life

P = 0.60 P = 0.77
P = 0.68
50 30 30
Percentage (%)

Percentage (%)

47% 29%
40 P = 0.87 44%
P = 0.58 20 20 24%
30
20 27%
24% 10 10
16% 18% 10%
10 8%
0 0 0
Placebo Diltiazem Placebo Diltiazem
o

m
eb

eb

eb
ze

ze

ze
ac

ac

ac
a

Improvement Improvement
lti

lti

lti
Pl

Pl

Pl
Di

Di

Di

Mental Health Physical Health SAQSS

Jansen TPJ, et al. J Am Coll Cardiol Img. 2022;15(8):1473–1484.

In this first randomized clinical trial in patients with angina and no obstructive coronary artery disease, 6 weeks of treatment showed no effect on coronary
vasomotor dysfunction, symptoms, and quality of life. SAQSS ¼ Seattle Angina Questionnaire summary score.

strategy for 4 weeks. This was followed by an open proven effective in symptom and ischemia reduction
label follow-up period (mean 16 months) to determine in obstructive CAD. 15 Second, the diagnosis of variant
long-time effects. Diltiazem treatment was associated angina used in those studies was mainly based on
with a significant decrease in angina frequency when angina at rest and transient ST-segment deviations on
compared with placebo. Short-term response was the ECG.26 Thus, differentiation of vasomotor
predictive for long-term response. In the second trial dysfunction endotypes could not be made, making a
by Pesola et al,25 diltiazem 60 mg or placebo were direct comparison difficult. Third, we used a different
administered alternatively during 4 randomized 72- method to assess angina (the SAQ as opposed to
hour periods in 10 patients with “variant angina.” angina frequency), which could have led to differ-
During diltiazem treatment periods, a significant ences in results.
reduction in the number of ischemic episodes was In our trial, diltiazem, compared with placebo, did
observed on continuous Holter monitoring. not improve anginal symptoms. Interestingly, our
These small trials demonstrate a favorable effect of results are in line with the study by Kook et al, 27
diltiazem, in contrast to EDIT-CMD. However, there who recently performed a randomized controlled
are several issues to be considered: First, both studies trial comparing the efficacy of nebivolol versus dil-
also included patients with obstructive CAD, which tiazem with regard to the degree of vasoconstriction
could also be a major contributor to the positive in patients with proven coronary vasospasm. Both
treatment effect, because CCBs have been extensively treatments led to a significant improvement in
JACC: CARDIOVASCULAR IMAGING, VOL. 15, NO. 8, 2022 Jansen et al 1481
AUGUST 2022:1473–1484 Diltiazem to Improve Coronary Vasomotor Dysfunction

severity of vasoconstriction after ACH provocation.

T A B L E 2 Primary and Secondary End Point Results
However, this did not lead to a reduction in anginal
symptoms. Primary and Secondary Total Placebo Diltiazem
Analysis (N ¼ 73) (n ¼ 35) (n ¼ 38) P Value
Although we did not observe an improvement in
Primary end pointa 0.46
vasospasm when comparing diltiazem with placebo,
Successful treatment 18 (25) 10 (29) 8 (21)
an important observation is that significantly more Unsuccessful treatment 55 (75) 25 (71) 30 (79)
patients progressed from epicardial spasm to micro- Primary end pointb 0.36
vascular spasm or no spasm while on diltiazem Improvement 18 (25) 10 (29) 8 (21)
treatment compared with placebo. Based on the Similar 42 (57) 21 (60) 21 (55)
28
recent finding by Seitz et al that microvascular Deterioration 13 (18) 4 (11) 9 (24)
Difference in ACH test 0.60
spasm coexisted in almost 50% of patients with
Improvement 7 (10) 3 (8) 4 (10)
epicardial spasm, we hypothesize that these patients
Similar 62 (85) 31 (89) 31 (82)
had combined epicardial and microvascular spasm at Deterioration 4 (6) 1 (3) 3 (8)
baseline, and that diltiazem was only effective on Difference in ADE test 0.77
epicardial spasm, leading to a decrease in epicardial Improvement 19 (26) 10 (29) 9 (24)
spasm but leaving behind a relatively higher number Similar 46 (63) 22 (63) 24 (63)
of microvascular spasm (that was previously classi- Deterioration 8 (11) 3 (9) 5 (13)

fied as epicardial spasm). Difference in SAQSS 0.68

Improvement 32 (44) 16 (42) 16 (42)
This would be of clinical importance if the
Similar 16 (22) 6 (18) 10 (26)
remaining microvascular spasm has a more favorable
Deterioration 24 (33) 12 (35) 12 (32)
prognosis or QoL, which is currently unknown.
Total Placebo Diltiazem
Given that the primary analysis was negative, these
Sensitivity Analysis (N ¼ 85) (n ¼ 44) (n ¼ 41) P Value
are purely hypothesis-generating data.
Primary end pointc 0.93
CORONARY MICROVASCULAR DYSFUNCTION. Improvement 18 (21) 10 (23) 8 (20)
Also for the endotype of CMD, CCBs are recom- Similar 42 (49) 21 (48) 21 (51)

mended, despite the absence of solid evidence. Deterioration 25 (29) 13 (30) 12 (29)

Marinescu et al 8 carried out a systematic review of the

efficacy of current treatment strategies in patients
with CMD defined as CFR <2.5. Only 1 study provided
evidence for the use of CCBs: a case-control study of
16 patients that failed to show an effect of diltiazem
on CFR.29 No studies have been performed on the
effect of oral CCB on IMR.
This is in line with findings from current EDIT-CMD
trial, where diltiazem, compared with placebo, did
not improve microvascular dysfunction. Interest-
ingly, when comparing the changes in physiological
parameters over 6 weeks, we found that patients on
placebo showed an increase in CFR, whereas patients
on diltiazem showed a decrease, suggesting an
improvement of CFR in the placebo group. This dif-
ference was primarily caused by changes in coronary
resting flow, which might be explained by patients
being more comfortable during the second CFT (and
thus having a lower coronary resting flow). This does
not explain the decrease in CFR observed in the dil-
tiazem group. Yong et al30 systematically reviewed
the effects of several different oral drugs on non-
invasively obtained CFR and observed that CCBs led
to an increase in resting coronary flow but not hy-
peremic coronary flow, resulting in a decreased CFR.
This was confirmed in an in vivo animal study,
demonstrating that inhibition of Ca channels
Values are n (%). This table shows the primary end point (treatment success) and the results of the ACH spasm
provocation test and ADE test of microvascular dysfunction, on which the primary end point is based. aPrimary
end point showing treatment success in improving coronary vasomotor dysfunction (CVDys). bPrimary end point
showing the post-treatment condition as assessed by coronary function testing (CFT). cThe sensitivity analysis
shows the results of the primary end point when all patients who dropped out would be classified as
“deterioration.”
Abbreviations as in Table 1.
progressively increased coronary blood flow and
substantially diminished coronary autoregulatory
gain.
STUDY LIMITATIONS. A number of limitations merit
consideration. First, 11 patients dropped out during
the treatment period; more patients had been in the
placebo group and about half of them because of
worsening symptoms. Because the analysis of our
primary outcome, the effect of diltiazem on vaso-
motor dysfunction, was a per-protocol strategy, we
let these patients not undergo follow-up CFT. To give
insight in the effect of diltiazem in the entire patient
population, we performed sensitivity analyses, which
did not change our results. Even in the most positive
scenario for diltiazem, in which all patients who
dropped out from the diltiazem group were assigned
to “improved” and all patients who dropped-out from
the placebo group were assigned to “deterioration,”
showed no meaningfully higher success rate for
1482 Jansen et al JACC: CARDIOVASCULAR IMAGING, VOL. 15, NO. 8, 2022

Diltiazem to Improve Coronary Vasomotor Dysfunction AUGUST 2022:1473–1484

F I G U R E 3 Effect of Diltiazem on ACH-Induced Epicardial and Microvascular Coronary Spasm as Compared to Placebo

6 weeks
First ACH provocation Second ACH provocation
Placebo

Epicardial spasm N = 17 94%

N = 19 Epicardial spasm

6%

20%

Microvascular spasm N = 10 50% N = 6 Microvascular spasm

30%

12%

88% N = 10 No spasm
No spasm N = 8

6 weeks
First ACH provocation Second ACH provocation
Diltiazem

53% N = 12 Epicardial spasm

Epicardial spasm N = 19
31%

16%

N = 14 Microvascular spasm

Microvascular spasm N = 8 88%

12%

18%
9%
No spasm N = 11 N = 12 No spasm
73%

Efficacy of 6 weeks of diltiazem treatment, compared with placebo, in preventing acetylcholine (ACH)-induced epicardial and microvascular coronary
spasm is shown. The Sankey plot illustrates the results of the initial ACH spasm provocation test and the second ACH test, which was performed 6 weeks
later. Diltiazem was more effective than placebo in preventing epicardial (47% vs 6%; P ¼ 0.006).

T A B L E 3 Difference in Change From Baseline Between Diltiazem and Placebo in Physiological Measurements

Change From Baseline

Placebo (n ¼ 35) Diltiazem (n ¼ 38) Estimate 95% CI P Value

Pd, rest 1.5  19.6 8.7  11.7 10.1 2.65 to 17.6 0.009
Pa, rest 0.8  13.3 9.7  11.4 8.9 3.1 to 14.6 0.003
CFR 1.0  2.7 0.34  1.7 1.35 0.3 to 2.4 0.012
IMR 0.26  20.0 3.3  17.5 3.5 5.2 to 12.3 0.43
Tmn, rest 0.17  0.57 0.06  0.56 0.23 0.00 to 0.46 0.05
Tmn, hyperemia 0.001  0.28 0.005  0.22 0.006 0.11 to 0.12 0.92

Values are mean  SD unless otherwise indicated.

Pa ¼ aortic pressure; Pd ¼ distal pressure in left anterior descending artery; Tmn ¼ mean transit time; other abbreviations as in Table 1.
JACC: CARDIOVASCULAR IMAGING, VOL. 15, NO. 8, 2022 Jansen et al 1483
AUGUST 2022:1473–1484 Diltiazem to Improve Coronary Vasomotor Dysfunction

T A B L E 4 Difference in Change From Baseline Between Diltiazem and Placebo in Patient-Reported Health Status Outcomes

Change From Baseline

Placebo (n ¼ 35) Diltiazem (n ¼ 38) Estimate 95% CI P Value

Angina summary score 1.1  12.8 3.0  12.2 1.8 4.1 to 7.7 0.54
CCS 0.46  1.06 0.47  0.94 0.02 0.47 to 0.50 0.95
RAND-36 physical health summary score 0.10  6.38 1.01  7.00 0.91 2.32 to 4.13 0.58
RAND-36 mental health summary score 0.02  10.0 0.35  6.63 0.33 4.3 to 3.7 0.87

Values are mean  SD unless otherwise indicated.

CCS ¼ Canadian Cardiovascular Society; RAND-36 ¼ Research and Development Questionnaire 36.

diltiazem, making our conclusion even stronger.
Although these sensitivity analyses used single
imputation, investigating these scenarios with mul-
tiple imputation would only decrease the precision,
hence increasing the P values, and so would also
strengthen the conclusion of no effect.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
The trial was funded with a research grant from Abbott (to Drs van
Royen and Elias-Smale). The sponsor had no involvement in the
design of the study, data collection or analysis, or the writing of the
manuscript. Dr Smits has received consultancy fees and institutional
research grants from Abbott. Dr Damman has received consultancy

Second, based on previous publications, one might fees from Philips and Abbott; and research grants from Philips. Dr van
Royen has received consultancy fees from Abbott; and research
argue that the treatment and follow-up duration was
grants from Philips and Abbott. Drs Damman and van Royen are part
too short, because, according to clinical experience, of the larger Dutch Cardiovascular Alliance consortium IMPRESS
patients tend to experience an increase in symptoms (2020B004). Dr Elias-Smale has received a research grant from
Abbott. All other authors have reported that they have no relation-
for a short time after CFT. However, the smaller
31 ships relevant to the contents of this paper to disclose.
randomized trials by Pepine et al used comparable
short-term follow-up, whose results were predictive
ADDRESS FOR CORRESPONDENCE: Dr Suzette Elias-
for long-term effect. On the other hand, remodeling
Smale, Department of Cardiology, Radboud Univer-
of the microvasculature might need more time than
sity Medical Center, Postbus 9101, 6500 HB,
6 weeks.
Nijmegen, the Netherlands. E-mail: suzette.
Furthermore, our study was not powered on the
elias-smale@radboudumc.nl.
effect of diltiazem on individual endotypes of CVDys.
Larger trials are needed to further investigate this
PERSPECTIVES
issue, as well as the clinical meaning of the
improvement of epicardial to microvascular
vasospasm. COMPETENCY IN MEDICAL KNOWLEDGE: Six weeks of
treatment with diltiazem, compared to placebo, in patients with

CONCLUSIONS ANOCA did not substantially improve coronary vasomotor func-

tion or symptoms and QoL, but it did reduce prevalence of
In this first double-blind, placebo-controlled ran- epicardial spasm.
domized trial making use of test retesting with CFT,
TRANSLATIONAL OUTLOOK 1: Additional studies are war-
6-week treatment with diltiazem, compared with
ranted to further explore the effect of CCBs on the specific
placebo, did not reduce coronary vasospasm, improve
endotypes of CVDys, symptoms, QoL, and prognosis.
CMD, or improve symptoms or QoL in patients with
ANOCA. However, a higher proportion of patients
TRANSLATIONAL OUTLOOK 2: This study underlines the
treated with diltiazem changed to microvascular
paucity and thus necessity of large randomized clinical placebo
spasm or no spasm, as compared to patients on pla-
controlled trials in this rather underexplored patient population
cebo. Larger clinical trials are warranted to further
to acquire evidence based on patient-tailored treatment.
explore the effect of CCBs on the specific endotypes
of CVDys, symptoms, QoL, and prognosis.
1484 Jansen et al
Diltiazem to Improve Coronary Vasomotor Dysfunction
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KEY WORDS acetylcholine, adenosine,
ANOCA, coronary artery spasm, coronary
function test, coronary vasomotor
dysfunction, diltiazem, microvascular
dysfunction
A PPE NDI X For a supplemental figure and
tables, please see the online version of this
paper.
Go to http://www.acc.org/
jacc-journals-cme to take
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