Author + information
- Received December 9, 2011
- Revision received March 2, 2012
- Accepted March 30, 2012
- Published online September 4, 2012.
- Yuya Matsue, MD⁎,⁎ (, )
- Makoto Suzuki, MD, PhD⁎,
- Mitsuhiro Nishizaki, MD, PhD†,
- Rintaro Hojo, MD‡,
- Yuji Hashimoto, MD, PhD⁎ and
- Harumizu Sakurada, MD, PhD‡
- ↵⁎Reprint requests and correspondence:
Dr. Yuya Matsue, Department of Cardiology, Kameda Medical Center, 929 Higashi-chou, Kamogawa-City, Chiba 296-8602, Japan
Objectives The present study was performed to investigate the clinical implications of an implantable cardioverter-defibrillator (ICD) in patients with vasospastic angina (VSA) resuscitated from lethal ventricular arrhythmia.
Background The prognosis of VSA is known to be good with medication; however, ventricular arrhythmia and cardiopulmonary arrest are rare but life-threatening complications of this disease. The ICD is a proven modality for patients with ventricular arrhythmia, but the clinical implications in this population remain to be elucidated.
Methods We conducted a retrospective, observational, multicenter study involving patients with an ICD due to documented ventricular arrhythmia and VSA diagnosed by acetylcholine provocation test. All patients were followed up for appropriate ICD therapy, sudden cardiac arrest, or death from all causes.
Results Twenty-three patients were included in the present study and completely followed up. All patients are still alive. During a follow-up of 2.9 years (median 2.1 years), 4 ventricular fibrillations and 1 episode of pulseless electrical activity occurred in 5 patients (21.7%). There were no statistically significant differences in patient characteristics between the recurrence and nonrecurrence groups, including medication, smoking status, and whether the patient was or was not free of symptoms after ICD implantation.
Conclusions Patients with VSA and lethal ventricular arrhythmia are a population at high risk for recurrence of cardiopulmonary arrest, and there is no reliable indicator for predicting recurrence of ventricular arrhythmia. Insertion of an ICD with medication for VSA is appropriate for this high-risk population.
Vasospastic angina (VSA) is 1 of the causes of chest pain without coronary artery stenotic lesions. The prognosis of VSA is generally good when treated with calcium-channel blockers, with or without nitrates. However, VSA may rarely trigger lethal ventricular arrhythmia and lead to cardiopulmonary arrest (1–3). Moreover, increased ventricular vulnerability and repolarization abnormalities have been reported even during the symptom-free periods (4,5). The implantable cardioverter-defibrillator (ICD) has become a proven device for secondary prevention of sudden cardiac death due to lethal ventricular arrhythmia (6,7). However, the clinical implications of ICD as a secondary prevention of malignant arrhythmia due to VSA are not well understood, and the indication of ICD for this population is controversial because VSA can be controlled by medication. Here, we performed a retrospective review of patients with lethal ventricular arrhythmia due to VSA to assess the clinical significance of ICD in this high-risk population.
Patients with an ICD inserted for lethal arrhythmia and VSA at Kameda Medical Center, Yokohama Minami Kyosai Hospital, and Tokyo Metropolitan Hiroo Hospital from December 1999 to September 2011 were included retrospectively in this study. All patients fulfilled the following criteria, defined by Myerburg et al. (2): 1) documented VF or sustained rapid ventricular tachycardia; 2) absence of a previous history of angina pectoris or acute myocardial infarction; 3) normal left ventricular ejection fraction and no wall motion abnormality; 4) absence of significant coronary artery stenosis (>50%); and 5) absence of identifiable or reversible cause of lethal ventricular arrhythmia. A definite diagnosis was made in all patients according to the Guidelines for Diagnosis and Treatment of Patients with Vasospastic Angina of the Japanese Circulation Society (8). All patients had angiographically normal coronary arteries, and all underwent acetylcholine provocation test more than 1 week after the initial episode of cardiac arrest. The acetylcholine provocation test was performed according to the method included in the Guidelines for Diagnosis and Treatment of Patients with Vasospastic Angina of the Japanese Circulation Society (Fig. 1) (8). A medical history was taken from all patients, followed by physical examination. Patients were considered smokers if they did not quit smoking after ICD insertion. Approval was obtained from the ethics committees of all participating hospitals (institutional review boards of Kameda Medical Center, Yokohama Minami Kyosai Hospital, and Tokyo Metropolitan Hiroo Hospital). Informed consent from individual patients was not required under Japanese law as the present study was purely observational.
All patients underwent insertion of an ICD during their first admission after resuscitation, and were followed up at each clinic after discharge. The medical history was taken, adherence to prescribed medication was evaluated by medical interview, and 12-lead electrocardiogram was performed at each visit. Patients were also asked carefully at each visit regarding the presence or absence of chest pain. The length of follow-up was measured from the initial lethal arrhythmic event.
Clinical follow-up data were obtained by reviewing outpatient records. Study endpoints included appropriate ICD therapy for ventricular arrhythmia, sudden cardiopulmonary arrest due to pulseless electrical activity (PEA), or asystole.
In the review of device use, appropriate therapy was defined as antitachycardia or defibrillation treatment administered for ventricular tachyarrhythmia that had not terminated spontaneously before the device administered the therapy. Appropriate treatment and diagnosis of arrhythmia were identified from episode electrograms analyzed by expert staff.
All continuous variables are presented as mean ± SD, and dichotomous data are shown as percentages. Baseline characteristics were analyzed for significance of differences between groups by 1-way analysis of variance for continuous variables, and by the chi-square test or Fisher's exact test for categorical variables. Event-free survival curves were constructed using the Kaplan-Meier survival method. In all analyses, p < 0.05 was taken to indicate statistical significance.
Two of 25 patients with VSA and lethal ventricular arrhythmia were excluded from the study because they refused ICD insertion. Therefore, 23 patients were included in the study. Demographic and clinical data of the subjects are shown in Table 1. Echocardiography showed no structural heart disease that contributed to sudden cardiac death in any patient. All patients had normal results on physical examination and no previous history of cardiac disease. Four patients had atrial fibrillation on electrocardiograms. No patients had abnormal findings on echocardiography, or structural heart disease, or were taking antiarrhythmic drugs. On acetylcholine provocation test, the average number of coronary arteries with stenosis that were provoked was 2.1 ± 0.6. None of the patients had a family history of coronary artery disease or sudden cardiac death.
The follow-up period after the first lethal arrhythmic event was 2.9 years (median 2.1 years). All patients were still alive and symptom free with prescribed medication after ICD implantation.
Kaplan-Meier survival concerning the arrhythmic event-free survival curve is shown in Figure 2. During the follow-up period, 5 patients reached endpoints, including 4 patients with appropriate therapy by ICD (Fig. 3) and 1 patient with PEA. Arrhythmias treated by ICD were all ventricular fibrillation, which were identified by a review of stored electrocardiograms, and there were no episodes of ventricular tachycardia. All 4 patients with ventricular fibrillation were treated appropriately by ICD and resuscitated. One patient presented to hospital with sudden cardiac arrest after chest pain, and electrocardiography at the emergency department showed PEA. Intracardiac electrogram showed no ventricular arrhythmia. This patient was successfully resuscitated, and is still alive. All patients who reached the study endpoint were reevaluated with regard to medication adherence by medical interview from patients and family members. One patient with appropriate ICD therapy discontinued prescribed medication on his own initiative, but adherence to medication was good in all other patients. The average time for appropriate ICD therapy from ICD insertion was about 1 year (range 50 to 600 days; median 292 days). Only 2 of 5 patients with recurrent lethal arrhythmia had symptoms of chest pain before ICD therapy. However, the chest pain before ICD therapy was the first episode for all of these patients.
After the first episode of appropriate ICD therapy, no recurrent ICD therapy was administered in those 4 patients.
To determine the factors that influence the recurrence of lethal arrhythmia in this population, the cohort was divided according to whether appropriate ICD therapy was or was not administered after discharge. However, there were no factors that were significantly different between the 2 groups (Table 2).
Our retrospective observational study demonstrated a high recurrence rate of ventricular arrhythmia in VSA patients, and revealed the clinical implications of ICD in this high-risk population. Moreover, predicting the risk of recurrent arrhythmia was difficult, which also indicated that ICD therapy would be appropriate for all patients resuscitated from ventricular arrhythmia and VSA, even if the symptoms are well controlled by medication.
VSA and lethal arrhythmia
The prevalence of VSA in patients who were resuscitated from cardiopulmonary arrest and without significant coronary artery stenosis was reported as 6% in Japan (1). Thus, VSA is not a rare cause of out-of-hospital cardiac arrest (OHCA), and provocation test was necessary to accurately diagnose the cause of OHCA in patients without significant coronary artery stenosis. The occurrence of ventricular arrhythmia in patients with VSA was first described by Prinzmetal et al. (9), in 1 patient with documented ventricular tachycardia during chest pain. Since then, many case reports have described the relationship between VSA and ventricular lethal arrhythmia, namely, sudden cardiac death. Although defining the risk factors for stratifying the risk of sudden cardiac death in VSA patients is important, this is still controversial. One study indicated that obstructive coronary artery disease was more common in patients with arrhythmia as compared to patients without arrhythmia (10). However, there were no correlations between lethal arrhythmia and the presence of obstructive coronary artery disease in 3 other studies (1,11,12). Indeed, none of the patients included in the present study had obstructive coronary artery disease. Thus, patients with OHCA require provocation test of VSA even if they do not have obstructive coronary artery disease, because undiagnosed VSA without appropriate medication may pose a high risk of sudden cardiac death. Indeed, in 1 of the studies cited (1), a patient who died after resuscitation stopped taking his medication on his own initiative. Moreover, this large prospective cohort study showed that the incidences of cardiac death and nonfatal myocardial infarction were significantly increased in patients in whom medications were reduced or discontinued. In the present study, 1 patient treated with appropriate ICD shock also discontinued the calcium-channel blocker. These observations suggest that discontinuing or reducing medication may increase the risk of recurrence of lethal arrhythmic events. Therefore, patients with VSA should not discontinue medical therapy, particularly those with lethal arrhythmia.
We performed acetylcholine provocation test in all patients to diagnose VSA. According to the Japanese guidelines of VSA, both acetylcholine and ergonovine are recommended for provocation test. However, the biological half-life of acetylcholine is extremely short compared with that of ergonovine, and this short-acting effect of acetylcholine is important to perform vasospasm provocation test safely in patients who are predicted to have severe symptoms and multivessel coronary spasm (13). As the accuracy of acetylcholine provocation test was reported to be good in patients with multivessel vasospastic angina and some fatal cases have been reported as complications of ergonovine provocation test, acetylcholine is recommended for use in this high-risk population (14,15).
ICD insertion for VSA
The present study included 23 patients with cardiopulmonary arrest caused by VSA in 3 hospitals in Japan. This study was large, second in size only to another Japanese study that included 35 patients with OHCA (1). However, all patients with VSA with lethal arrhythmia underwent ICD insertion, and ours is the largest number of such cases reported to date.
Takagi et al. (1) reported that the prognosis of patients with VSA and OHCA was poorer than that of patients with VSA but not OHCA. Importantly, an ICD was inserted in 14 patients and 2 appropriate shocks were applied; sudden cardiac death occurred in 1 of the 21 patients without ICD implantation, and this patient discontinued medication himself before the event. Although maintenance of medication with calcium-channel blocker is very important to prevent lethal arrhythmic events, particularly in patients with OHCA and VSA as described, this sudden cardiac death may have been prevented if this patient had had an ICD.
Implantation of ICD in patients with VSA remains controversial. According to the guidelines (16), patients who survive cardiac arrest due to ventricular fibrillation or hemodynamically unstable sustained ventricular tachycardia are recommended for an ICD after exclusion of any “completely reversible causes.” In VSA patients without lethal arrhythmia (i.e., with only chest pain), the symptom is well controlled with only medication, and the prognosis is good. With regard to ICD, Meisel et al. (17) reported that, of 8 patients with VSA and lethal arrhythmia, ventricular arrhythmia reoccurred in all 7 patients who had residual symptoms despite using calcium-channel blocker, and they concluded that patients who remain symptomatic despite medical therapy should be considered for ICD insertion.
However, some studies have shown that vasospasm was provoked even in patients whose symptoms were relieved by calcium-channel blocker and/or vasodilator treatment (18,19). Moreover, many cases of VSA and lethal arrhythmia have been reported with ST-segment elevation and without chest pain (2,4,20), indicating that symptoms are unreliable during treatment with medication. In the present study, all 4 patients treated with appropriate ICD shocks reported feeling no chest pain and no discomfort before the occurrence of lethal ventricular arrhythmia. As patients who have VSA and ventricular arrhythmia represent a population with a very high risk of sudden cardiac death, these results suggest that the indication for ICD should not be decided on the basis of symptoms, and all patients should be considered for ICD insertion at the time of the first ventricular arrhythmic event.
Limitation of ICD for ventricular arrhythmia in patients with VSA
Although ICD therapy could be beneficial to VSA patients with arrhythmia, there seems to be some limitations. In the report of Letsas et al. (21), 1 patient also with multivessel VSA had polymorphic ventricular fibrillation and PEA despite repeated defibrillation delivered by the ICD. In the present study, 1 patient had sudden PEA under optimal medication, and he also had multivessel spasm provoked by acetylcholine. These observations suggest that, in addition to ICD insertion, a novel therapeutic modality that can ameliorate vascular function itself may be needed, particularly in patients with multivessel VSA.
First, this study was not a randomized controlled trial and was based on a small number of Japanese patients in only 3 cardiovascular centers in Japan. Therefore, the clinical significance of this study in patients of other ethnic groups may need further evaluation. The cohort in the present study included only patients with VSA who had a history of lethal ventricular arrhythmia, and thus the data shown here cannot be extrapolated to the whole VSA population.
Medication compliance was evaluated only by medical interview with patients, and that may have caused over-estimation of patient compliance for prescribed medication. We included only 23 of the 25 patients as 2 patients were excluded for refusing ICD implantation, and that may have resulted in selection bias. However, the incidence of recurrence of lethal ventricular arrhythmia remains high even if these 2 patients were considered to be free of recurrence of lethal ventricular arrhythmia.
Although medical therapy is absolutely imperative for patients with VSA and a history of lethal arrhythmia, our multicenter observational study of VSA patients who underwent ICD insertion suggested that ICD therapy should be strongly recommended for patients with VSA and lethal arrhythmia. However, further large-scale studies are required to determine whether ICD therapy can improve the prognosis of this high-risk group of patients.
The authors have reported they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- implantable cardioverter-defibrillator
- out-of-hospital cardiac arrest
- pulseless electrical activity
- vasospastic angina
- Received December 9, 2011.
- Revision received March 2, 2012.
- Accepted March 30, 2012.
- American College of Cardiology Foundation
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