Clinical Implication According to Spasm Type of Single Coronary Artery provoked by

Intracoronary Ergonovine Tests in patients without significant organic stenosis

Dae-Won Kim, Sung-Ho Her, Youngkeun Ahn, Dong IL Shin, Seung Hwan

Han, Dong-Soo Kim, Dong-Ju Choi, Hyuck Moon Kwon, Hyeon-Cheol Gwon, Sang-Ho Jo, Seung-Woon Rha, Sang Hong Baek

The Catholic University of Korea, Daejeon St. Mary's Hospital

DECLARATION OF INTEREST

Nothing

• It is well revealed that coronary spasm frequently occurs at site of

significant atherosclerotic stenosis

• The cardiac event in single coronary spasm without organic

stenosis was not still evaluated well

• This study focused on the 24-month clinical outcomes according

to the spasm types of VSA patients without significant organic

coronary stenosis

Background and purpose

• A total of 2,960 patients who underwent ergonovine provocation test were consecutively enrolled into the VA-KOREA (Vasospastic Angina in KOREA) registry from 11 cardiovascular centers from May 2010 to June 2015 and were selected as the study subjects.

METHODS

Figure 1. Study population

PROVOCATION TEST FOR VSA. • Incremental doses of 20 (E1), 40 (E2) and 60 μg (E3) of intracoronary ergonovine were

injected into the left coronary artery (LCA). If coronary spasm was not provoked on the LCA, incremental doses of 10 (E1), 20 (E2) and 40 μg (E3) were injected into the right coronary artery (RCA).

• Once coronary spasm was induced, intracoronary nitrate was injected. Accordingly, this

study has an inherent limitation as follows. If RCA was induced, it must be pure single

coronary artery because RCA was induced, just in case LCA was not induced. However, in

case of LCA, the study group could partially include mixed type or multi-vessel spasm in

the enrollment because if LCA was induced first, we had to inject intracoronary nitrate due

to ethical issue in a real world.

• Positive spasm : >90% luminal diameter narrowing, intermediate spasm : 50% to 90%

luminal narrowing, negative spasm : < 50% luminal narrowing

METHODS

DEFINITIONS AND STUDY END-POINTS. • The types of spasm were classified into focal, diffuse and mixed types. The focal type was

defined as a discrete spasm localized in 1 coronary segment, whereas the spasm observed continuously from the proximal to the distal segments was regarded as the diffuse type. The mixed type was defined as the spasm in which at least 1 coronary artery had focal spasm, and the other had diffuse spasm

• single vessel spasm was defined as coronary artery spasm merely in one major epicardial

coronary artery.

• The primary outcome was a composite of cardiac death, new-onset arrhythmia and acute

coronary syndrome (ACS).

• Unstable angina pectoris represented recurrence or worsening of chest discomfort or pain

associated with ischemic electrocardiogram changes.

• Patients who presented with arrhythmia such as atrial or ventricular tachycardia/fibrillation,

symptomatic premature beats, sick-sinus rhythm and atrioventricular block for the first

time during the follow-up were thought to have the new-onset arrhythmia

METHODS

STATISTICAL ANALYSES

• Student t-test and Chi-square test (or the Fisher exact test) were used to compare the means and proportion of baseline characteristics between 2 groups. Continuous variables were expressed as the mean ± standard deviation and categorical variables were presented as frequencies and percentage .

• The incidences of the primary endpoints in the focal and diffuse groups of VSA patients were estimated at 24 months and were presented in tables and Kaplan-Meier curves. The log-rank test was performed to compare the incidences of the endpoints between the 2 groups.

• Cox proportional hazard model was used to estimate the hazard ratio (HR) with 95% confidence interval (CI) for the comparison of primary outcomes.

• Multivariate logistic regression analyses were carried out to identify the independent predictors associated with the primary outcomes in VSA patients.

METHODS

RESULTS

Data are presented as mean ± SD, and number (percentage) where appropriate.

Baseline clinical characteristics Table 1.

diffuse

(n = 705)

focal

(n = 543)

P value

Age, yrs 55.7± 11.7 54.6± 10.4 0.079

Male 453 (64.3) 341 (62.8) 0.596

Body mass index, kg/m2 24.7± 3.0 24.7± 3,2 0.876

Blood pressure, mmHg

Systolic

Diastolic

125.9 ± 18.0

76.5 ± 12.1

126.7 ± 18.7

77.9± 12.7

0.417

0.053

Alcohol (number of drinks/week) 1.1± 1.7 1.3± 1.9 0.064

Risk factors of coronary artery disease

Hypertension 282 (40.0) 209 (38.5) 0.588

Diabetes 70 (9.9) 47 (8.7) 0.444

Current smoking 286 (40.6) 243 (44.8) 0.138

Dyslipidemia 114 (16.2) 100 (18.4) 0.297

History of coronary artery disease 91 (12.9) 78 (14.4) 0.456

Medication

Calcium-channel blocker 642 (91.1) 508 (93.6) 0.105

Long-acting nitrate 588 (83.4) 455 (83.8) 0.854

Antiplatelet 328 (46.5) 298 (54.9) 0.003

Beta-blocker 52 (7.4) 28 (5.2) 0.113

Statin 345 (48.9) 306 (56.4) 0.009

ARB/ACE inhibitor 130 (18.4) 99 (14.4) 0.456

Baseline Laboratory, Echocardiographic and Angiographic Characteristics Table 2.

Values are mean ± SD or n (%).

CK-MB = creatinine kinase-MB; HDL = high-density lipoprotein; hsCRP = high-sensitivity C-reactive

protein ; LDL = low-density lipoprotein; LVEF = left ventricular ejection fraction; NT-proBNP = N-

terminal pro-B-type natriuretic peptide

diffuse

(n = 705)

focal

(n = 543) P value

Creatinine, mg/dl

0.8 ± 0.2

0.8 ± 0.7

0.352

Troponin I, ng/ml 0.2 ± 1.3 0.9 ± 6.5 0.048

CK-MB, ng/ml 3.9 ± 8.2 7.3 ± 18.9 <0.001

hsCRP, ml/l 1.3 ± 9.6 0.7 ± 6.0 0.302

NT-proBNP, pg/ml 104.1 ± 301.2 144.2 ± 407.1 0.209

Lipid profile, mg/dl

Total cholesterol 176.7 ± 36.7 172.9 ± 35.8 0.080

Triglyceride 146.5 ± 114.3 140.2 ± 101.2 0.333

HDL cholesterol 47.4 ± 12.9 46.3 ± 11.9 0.120

LDL cholesterol 105.6 ± 32.4 102.4 ± 31.3 0.107

Cardiac function

LVEF, % 64.4 ± 6.3 64.8 ± 6.8 0.319

Mitral E/E’ 8.9 ± 3.0 9.4 ± 9.9 0.238

Coronary artery

LAD 255 (36.2) 203 (37.4) 0.659

LCX 50 (7.1) 28 (5.2) 0.161

RCA 400 (56.7) 312 (57.5) 0.799

24-Month Cumulative Outcomes in VSA patients Table 3.

Univariate analysis

Multivariate analysis

Diffuse

(n=705)

Focal

(n=543) p-value

log rank

p-value HR 95% CI p-value HR 95% CI p-value

Primary endpoint 19(2.7) 28(5.2) 0.024 0.038 1.834 1.024 3.283 0.041 1.658 1.272 2.162 <0.001

Arrhythmia 8(1.1) 7(1.3) 0.804 0.892 1.073 0.389 2.959 0.892

Acute coronary syndrome 12(1.7) 22(4.1) 0.012 0.018 2.284 1.130 4.614 0.021

Unstable angina 10(1.4) 19(3.5) 0.016 0.023 2.365 1.100 5.087 0.028

STEMI 0(0.0) 0(0.0) - - - - - -

NSTEMI 1(0.1) 2(0.4) 0.583 0.436 2.511 0.228 27.695 0.451

Cardiac death 0(0.0) 1(0.2) 0.435 - - - - -

Rehospitalization/ED visit 117(16.6) 94(17.3) 0.738

Medication change 442(62.7) 336(61.9) 0.768

LAD n=255 n=203

(Arrhythmia+ACS+CD) 9(3.5) 5(2.5) 0.510 0.450 0.658 0.220 1.963 0.453

Arrhythmia 4(1.6) 2(1.0) 0.698 0.531 0.585 0.107 3.194 0.536

Acute coronary syndrome 5(2.0) 3(1.5) >0.999 0.643 0.714 0.171 2.988 0.645

Unstable angina 3(1.2) 3(1.5) >0.999 0.828 1.194 0.241 5.917 0.828

STEMI 0(0.0) 0(0.0) - - - - - -

NSTEMI 1(0.1) 0(0.4) >0.999 0.355 - - - -

Cardiac death 0(0.0) 0(0.0) - - - - - -

LCX n=50 n=28

(Arrhythmia+ACS+CD) 0(0.0) 2(7.1) 0.126 0.069 - - - -

Arrhythmia 0(0.0) 0(0.0) - - - - - -

Acute coronary syndrome 0(0.0) 2(7.1) 0.126 0.069 - - - -

Unstable angina 0(0.0) 2(7.1) 0.126 0.069 - - - -

STEMI 0(0.0) 0(0.0) - - - - - -

NSTEMI 1(0.1) 2(0.4) - - - - - -

Cardiac death 0(0.0) 1(0.2) - - - - - -

RCA n=400 n=312

(Arrhythmia+ACS+CD) 10(2.5) 21(6.7) 0.006 0.009 2.612 1.230 5.547 0.013 2.494 1.776 3.501 <0.001

Arrhythmia 4(1.0) 5(1.6) 0.515 0.520 1.535 0.412 5.717 0.523

Acute coronary syndrome 7(1.8) 17(5.5) 0.011 0.010 3.020 1.253 7.283 0.014

Unstable angina 7(1.8) 14(4.5) 0.032 0.042 2.487 1.004 6.162 0.049

STEMI 0(0.0) 0(0.0) - - - - - -

NSTEMI 0(0.0) 2(0.6) 0.192 0.114 - - - -

Cardiac death 0(0.0) 1(0.3) 0.438 0.264 - - - -

Table 4. Correlated Factors for Primary Outcome of Single Coronary Focal Spasm Type in VSA Patients

CI, confidence interval; HR, hazard ratio ; other abbreviations as in Table 1.

Univariate analysis

Multivariate analysis

HR 95% CI p-value HR 95% CI p-value

Current smoking 2.483 1.354 4.551 0.003 2.449 1.857 3.230 <0.001

Alcohol 1.056 0.910 1.225 0.475

Troponin-I 1.033 0.997 1.071 0.076

CK-MB 1.020 1.009 1.032 <0.001 1.012 1.006 1.018 <0.001

hsCRP 1.003 0.968 1.039 0.874

NT-proBNP 1.001 1.000 1.002 0.001 1.001 1.000 1.001 <0.001

LVEF 0.959 0.920 0.999 0.045 0.974 0.957 0.992 0.006

Calcium-channel blocker 1.260 0.384 4.132 0.703

Long-acting nitrate 1.357 0.568 3.238 0.492

Antiplatelet 1.486 0.821 2.690 0.191

Statin 1.248 0.693 2.250 0.461

ARB/ACE inhibitor 0.910 0.419 1.974 0.811

Beta-blocker 0.309 0.042 2.268 0.248

LAD 0.723 0.383 1.366 0.318

LCX 0.658 0.157 2.764 0.568

RCA 1.479 0.800 2.733 0.212

Multi-vessel 3.708 0.447 30.766 0.225

Supplemental Table 1. 24-Month Cumulative Outcomes in the RCA of the VSA Patients

Values are n (%). Adjusted by the center variance component (age, CK-MB).

Univariate analysis

Multivariate analysis

Diffuse

(n=400)

Focal

(n=312) p-value

log rank

p-value HR 95% CI p-value HR 95% CI p-value

RCA

(Arrhythmia+ACS+CD) 10(2.5) 21(6.7) 0.006 0.009 2.612 1.230 5.547 0.013 2.388 1.106 5.154 0.026

Arrhythmia 4(1.0) 5(1.6) 0.515 0.520 1.535 0.412 5.717 0.523

Acute coronary

syndrome 7(1.8) 17(5.5) 0.011 0.010 3.020 1.253 7.283 0.014

Unstable angina 7(1.8) 14(4.5) 0.032 0.042 2.487 1.004 6.162 0.049

STEMI 0(0.0) 0(0.0) - - - - - -

NSTEMI 0(0.0) 2(0.6) 0.192 0.114 - - - -

Cardiac death 0(0.0) 1(0.3) 0.438 0.264 - - - -

RESULTS

Figure 1. Study Population

Figure 2-A. Event-Free Kaplan-Meier Curve for the Primary Endpoint in Single Coronary Artery

Figure 2-B. Event-Free Kaplan-Meier Curve for the Primary Endpoint in RCA

Figure 3. Incidence of Clinical Outcomes According to Spasm Type in Single Coronary Artery

Inci

dence

(n)

CLINICAL OUTCOMES OF THE STUDY POPULATION

• The median follow-up duration was 30 months

• The cumulative rates of primary end-point including cardiac death, new-onset arrhythmia and ACS were significantly higher in the focal type than in the diffuse type of single vessel coronary artery spasm at 24 months (19 [2.7%] vs. 28 [5.2%], P=0.024, Table 3)

• These primary cardiac events would be driven by unstable angina in ACS components (unstable angina, HR 2.365 [1.100-5.087], P=0.028 at 24 months, Table 3)

• The Kaplan-Meier curve for the primary endpoint is shown in Figure 2-A

• Compared the culprit lesions of LAD and LCX with those of RCA, the prevalence of primary outcome was significantly higher in the RCA (Table 3 & figure 3).

• Culprit lesion of RCA primarily affected the primary outcome in this study (Table 3 & figure 2-B)

• It was consistent even in the pure single RCA (Supplemental table 1)

RESULTS

PREDICTORS FOR PRIMARY OUTCOME IN VSA PATIENTS

• In the multivariable logistic regression model, current smoking, CK-MB and NT-proBNP of VSA patients were independent predictors for the primary outcome (Table 4)

• Multivariable logistic regression also revealed that left ventricular ejection fraction (LVEF) is the predictor for the lower prevalence of primary outcome (adjusted HR = 0.974, P=0.006)

• The culprit lesion of RCA, LCX, LAD didn’t affect the primary outcome of single coronary focal spasm as correlated factors in VSA patients (Table 4)

RESULTS

MAIN AND NOVEL FINDINGS

• Focal-type of single-vessel spasm had a significant correlation with the composite of arrhythmia, ACS and cardiac death

IMPORTANT IMPLICATIONS

1. Focal-type of single-vessel spasm had a significant correlation with the composite

of arrhythmia, ACS and cardiac death

• This result was driven by the effect of ACS outcome, mainly due to adverse effects of unstable angina, even after adjustments for several confounding factors (Table 3)

• This study showed that the incidence of clinical outcomes according to the types of single vessel coronary artery spasm was more prominent in RCA territory than in other territories of coronary arteries (Table 3 and figure 3)

2. One of the most important findings in this study is the identification of the

certain independent predictors for poor outcome in focal spasm type of VSA

patients after ergonovine provocation test.

• Current smoking, CK-MB, NT-proBNP and LVEF were the independent predictors for primary outcome in focal type of single vessel coronary artery spasm

Discussion

Pathophysiology

1. Focal spasm could be associated with rapid progression of organic coronary

stenosis

• Coronary spasms could induce the release of potent vasoconstrictors, and thus, provoke vascular injury that leads to the formation of neo-intimal hyperplasia

• The reduction in the coronary blood flow and the increase in the platelet activation that causes local thrombus formation in the spasm positive coronary segments could also contribute to the progression of atherosclerosis

• More plaque burden was observed in the proximal part of the coronary arteries in patients with focal vasospasm

=> These prevalent atherosclerotic changes in focal spasm might have contributed to

the adverse outcomes, even after adjustments for higher proportional uses of

statins and antiplatelet agents in focal spasm type

2. Dynamic obstruction could be associated with the etiology of unstable angina

• Intensive focal spasm of a segment of an epicardial coronary artery unassociated with coronary atherosclerosis could precipitate the coronary vasoconstriction.

• The spasm occurs adjacent to a nonobstructive atheromatous plaque

=> Both of them appear to be due to hypercontractility of vascular smooth muscle

and endothelial dysfunction occurring in the region of spasm

Discussion

Pathophysiology

3. Focal spasms have smaller areas of dysfunction compared to diffuse spasms

• Focal spasms may have more potent spasmogenicity because they are more susceptible for medical therapy rather than diffuse spasms

• We should employ active approaches to stabilize coronary tone, especially in patients with spasm related MI, syncope or severe life-threatening arrhythmias due to focal spasms because patients with diffuse spasms had relatively poor responses to medical therapy

=> The same dose of medical therapy may have clinical limitations in suppressing chest

pain attacks

Discussion

• Patients with significant atherosclerosis (>50% luminal diameter narrowing), mixed type of spasm or multivessel spasm were initially excluded from the analysis, although mixed type of spasm or multivessel spasm in LCA were unavoidably included in part due to ethical matter in a real world.

• We have to take low prevalence in non-asian ethnicity and lack of ergonovine availability outside Korea into consideration

• We didn’t evaluate clinical outcomes of each spasm types of coronary arteries according to medical treatments in our study

• Combined MACE endpoint is underpowered and of uncertain relevance

• An analysis of underlying atherosclerosis (intravascular ultrasound or optical coherence tomography) would be useful to understand mechanisms of focal VSA

Limitations

• The present multicenter study conducted using data collected from VA-KOREA registry

• Focal type of single vessel coronary artery spasm in VSA patients is associated with adverse outcomes.

• The evaluation of spasm type may provide useful information for the risk stratification of VSA patients

CONCLUSION