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Psychosomatic Medicine 67:688-691 (2005)
© 2005 American Psychosomatic Society

ORIGINAL ARTICLES

Does Panic Disorder Increase the Risk of Coronary Heart Disease? A Cohort Study of a National Managed Care Database

Andres Gomez-Caminero, PhD, William A. Blumentals, PhD, Leo J. Russo, PhD, Regina R. Brown, MS and Ruby Castilla-Puentes, MD

From the Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (A.G.-C., L.J.R., R.C.-P.); Department of Epidemiology and Public Health, University of Miami Miller School of Medicine, Miami, Florida (W.A.B.); Worldwide Epidemiology, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania (R.R.B.); Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina (R.C.-P.)

Address correspondence and reprint requests to Ruby Castilla-Puentes, BX4-406E, 200 Crossing Boulevard, PO Box 6890, Bridgewater, NJ 08807-0890. E-mail: castilla{at}email.unc.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: The association between panic disorder (PD) and coronary heart disease (CHD) was examined in a large national managed care database.

Methods: The Integrated Health Care Information Services managed care database is a fully de-identified, Health Insurance Portability and Accountability Act-compliant database and includes complete medical history for more than 17 million managed care lives; data from more than 30 United States health plans covering 7 census regions and from patient demographics, including morbidity, age, and gender. A cohort study was designed with a total of 39,920 PD patients and an equal number of patients without PD. The Cox proportional hazards regression models were used to assess the risk of CHD adjusted for age at entry into the cohort, tobacco use, obesity, depression, and use of medications including angiotensin converting enzyme inhibitors, beta blockers, and statins.

Results: Patients with PD were observed to have nearly a 2-fold increased risk for CHD (HR = 1.87, 95% CI = 1.80–1.91) after adjusting for these factors. There was some evidence of a possible trend toward increased risk in a subgroup of patients diagnosed with depression. After controlling for the aforementioned covariates and comparing these patients with those who did not have a diagnosis of depression, it was noted that patients with a comorbid diagnosis of depression were almost 3 times more likely to develop CHD (HR = 2.60, 95% CI = 2.30–3.01).

Conclusions: The risk of CHD associated with a diagnosis of PD suggests the need for cardiologists and internists to monitor panic disorder to ensure a reduction in the risk of CHD.

Key Words: panic disorder • risk • coronary heart disease • Integrated Health Care Information Services • acute myocardial infarction

Abbreviations: CHD = coronary heart disease; HR = hazard ratio; CI confidence interval; IHCIS = Integrated Health Care Information Services; PD = panic disorder; ACE = angiotensin converting enzyme; NPD = nonpanic disorder.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
There has been increased interest in the role of psychological conditions and the risk for developing cardiovascular disease over the last 15 years. Depression has been the most extensively studied psychological condition influencing the development and prognosis of coronary heart disease (CHD) (1–16). Very little is known, however, about the risk of CHD conferred by a history of panic disorder (PD).

PD is characterized by unpredictable and devastating feelings of fear accompanied by a variety of symptoms of sympathetic nervous system arousal, such as sweating, tremor, palpitations, and diarrhea (17). Symptoms associated with PD are very similar to those of acute cardiovascular events, such as sweating, shortness of breath, palpitations, sensation of choking, and hot flashes (18–21). Recent evidence suggests that PD is prevalent among 7 to 53% of CHD patients and 3 to 8% of patients in the primary care setting (22–24). The large overlap between PD and CHD suggests a potentially common mediated etiology between these 2 conditions.

To our knowledge, no truly prospective study has examined whether PD is a risk factor for the development of CHD. Several studies have reported increased overall and cardiovascular mortality among patients with PD (19, 23–26). However, any conclusions from these studies are hampered by several methodological issues that include small sample size, lack of standard PD diagnoses or cardiovascular outcomes, and unaccounted confounders in the statistical models.

The primary objective of this study was to elucidate the temporal relationship between PD and CHD and to assess the health care burden associated with a history of PD, after controlling for traditional cardiovascular disease risk factors. Second, this study addresses the relationship of a history of PD, a concurrent diagnosis of depression (a comorbid condition with PD), and the risk of CHD.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Study Population
All patients in our study were part of the Integrated Health Care Information Services (IHCIS) managed care database. The IHCIS is a fully de-identified, Health Insurance Portability and Accountability Act compliant database and includes complete medical history for more than 17 million managed care lives. It includes data from more than 30 health plans covering 7 census regions and patient demographics including morbidity, age, and sex. In addition, this database has complete mental health data on plan participants from January 1, 1997 through March 31, 2002.

The study population consisted of patients diagnosed with PD (ICD-9 codes: 300.01, V67.3), and a comparison group of patients with no PD (non-PD) diagnosis. These comparison patients were identified during the same year as PD patients. Cohort entry criteria included at least 1 diagnosis of PD based on ICD-9 codes. To be included, patients had to be between 18 to 55 years of age and considered "active" in the IHCIS database for at least 6 months before their first PD diagnosis. In addition, the patients with a history of cardiovascular or cerebrovascular disease, type 2 diabetes mellitus, spinal cord injuries, and/or a history of cancer were excluded from the entry into the study.

A cohort study design was used to follow patients from the date of their first PD diagnosis to the first occurrence of CHD, defined as presence of an acute myocardial infarction, unstable angina, or angina pectoris (ICD-9 codes: 410.9, 411.1, 413.9), or in the absence of CHD, patients were followed up to the last date recorded in the database. This design allows for the most direct assessment of the temporal relationship between the presence of a diagnosis of PD and the risk of coronary heart disease, without incurring any of the recall biases associated with retrospective designs such as those present in case-control studies.

Demographic and Clinical Measures
Baseline characteristics for the PD cohort and the comparison group were described in the form of means and frequencies and included age at entry into the cohort; gender; smoking; obesity diagnoses; and the use of antidepressants, angiotensin converting enzyme (ACE) inhibitors, beta-adrenergic blockers, diuretics, calcium channel blockers, and hydroxymethylglutaryl coenzyme A reductase inhibitors (statins).

Statistical Analyses
To assess the effect of a PD diagnosis, unadjusted incident rates of CHD, defined as the presence of acute myocardial infarction, or angina pectoris, were calculated for PD and non-PD patients. Multivariate analyses were conducted using Cox proportional hazards regression models to calculate adjusted hazard ratios of CHD for both groups. Before computing Cox regression analysis, the proportional hazards assumption was tested by inspecting log (–log) transformed survival curves. Detailed inspection showed no violation of the proportional hazard assumption.

Secondary analyses focused on the CHD risk conferred by having a diagnosis of depression concurrent with a diagnosis of PD. To determine the risk conferred by having concurrent diagnoses of depression and PD, 2 sets of Cox proportional models similar to those described previously were conducted in patients with PD alone and among those with concurrent diagnoses of PD and depression. All analyses were performed with the use of SAS software (version 8.0; SAS, Cary, NC). A 2-sided P value of <.05 was considered to indicate statistical significance.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Study results showed the average duration between a diagnosis of PD and an incident diagnosis of a CHD event to be about 1.5 years. As seen in Table 1, the mean age of PD patients and nonpanic disorder (NPD) patients at entry into the study was very similar, 36.3 and 35.8 years, respectively. PD patients were more likely to be female, overweight, smokers, and as expected have a history of depression.


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  		TABLE 1. Baseline Characteristics of the Panic Disorder (PD) Cohort and Comparison Group of Patients Without PD

 

Overall, patients with a history of PD were also more likely to use cardiovascular drugs, either antihypertensives or lipid lowering drugs. The percentage of patients without PD on ACE inhibitors was 0.02% compared with 0.35% of those with PD. Among NPD patients, 0.03% were prescribed beta blockers, whereas 1.8% of PD patients were prescribed beta blockers. The percentage of patients without PD on statins was 0.02% versus 0.70% of patients diagnosed with PD (Table 1).

The purpose of the analyses was to determine whether PD was a predictor of CHD. Table 2 illustrates a nearly 2-fold increase in the risk of CHD among patients with a history of PD (HR = 1.87, 95% CI = 1.80, 1.91), after adjusting for the following variables including: age at entry into cohort, diagnosis, smoking, obesity, and use of ACE inhibitors, beta blockers, diuretics, and statins.


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  		TABLE 2. Association Between PD and Acute Myocardial Infarction

 

Table 3 illustrates the risk of CHD associated with the presence of PD and depression. The results showed an increased risk of CHD in the presence of depression, after controlling for tobacco use, obesity, and use of antihypertensives or lipid lowering drugs. In patients with a history of depressive disorders, patients with PD were nearly 3 times more likely to develop CHD (HR = 2.61, 95% CI = 2.32, 2.95), when compared with the non-PD patients.


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  		TABLE 3. Association Between PD and Coronary Heart Disease Stratified by Depression Diagnosis

 


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
The goal of this study was to assess if the presence of PD could contribute to the development of CHD and if patients with comorbid psychological conditions in addition to PD could be at an increased risk of developing CHD. The results of our study suggest that this may be true and that the association is stronger than previously believed.

To our knowledge, this is the first truly prospective study examining the question of whether having a diagnosis of PD is a risk factor for the development of CHD. Results from this study suggest a nearly 2-fold increased risk for coronary artery disease among patients diagnosed with PD, when compared with the NPD controls. In addition, the study data demonstrates a general increased risk for CHD among patients with a comorbid diagnosis of depression. A direct relationship between mental stress and sudden death has been observed in special circumstances, such as inherited long-QT-interval syndrome, in which there is electrical instability of the heart muscle (27). An example includes the observed increase in the rates of nontraumatic sudden death among people with underlying coronary disease during the 1994 Los Angeles earthquake (28). In PD, the episodes of recurring and often inexplicable anxiety can be regarded as repeated mental stress reactions. Thus, a link between PD and subsequent cardiac event is possible.

The mechanism by which cardiac risk is increased by PD is not known, but it has been thought to involve activation of the sympathetic nerves of the heart, predisposing it to ventricular arrhythmias. Hyperventilation, often a concomitant occurrence with a panic attack, can precipitate coronary spasm in the presence of atheroma (29), even in coronary arteries free of atherosclerosis (30). In the research laboratory, patients with spontaneous panic attacks have shown a substantial increase in adrenaline secretion and sympathetic nervous system activity (31). However, adrenaline typically increases, rather than decreases, coronary blood flow by means of beta-adrenergic coronary vasodilation. Similarly, sympathetic nervous system stimulation usually causes coronary vasodilation and increases blood flow, not only through the attendant metabolic myocardial stimulation but also through direct effects on the vasculature (32). In some circumstances, disorders of coronary vasomotion have been linked to dysfunction of the vascular endothelium. In some circumstances, patients with primary cardiac arrhythmias may be misdiagnosed as having PD (33). Similarly, it might also be argued that for some patients who had angina, the myocardial ischemia was a cause of the panic disorder. However, the nature of our study design (exclusion of prevalent cases of heart disease at study entry), guarantees that in this case the majority of panic disorders preceded the myocardial ischemia.

Theoretically, the anxiety disorder can develop after misdiagnosing of the cause of the chest pain. However, our data and previously published studies (34,35) suggest this is not the case. Instead PD seems to be a risk for the coronary event.

A secondary finding in our study was the increased risk for a coronary event among those patients with a comorbid diagnosis of depression. The direct pathophysiological alterations caused by depression have been described. These alterations include decreased heart rate variability, as a consequence of an imbalance in the autonomic tone (36), alterations of coagulation factors (37), and impairment of platelet functions (38–41). Also, immune activation and hypercortisolemia as stress responses to depression (42–45) may result in decreased insulin resistance and increased steroid production and blood pressure, thereby increasing the risk of cardiac disease (46). Unhealthy lifestyles, have also been found to be more common among depressed than nondepressed people (47, 48), and antidepressants, specifically tricyclic antidepressants, may have a cardiotoxic effect (49). However, in a community-based sample, antidepressants were used only sparingly and dosages were generally low (50). Adjustment for antidepressants in the analyses did not change the relative risks for minor and major depression, and therefore cannot explain our results. Finally, it is possible that depression may be an indirect indication of disease severity, or it may represent a reaction to subclinical cardiovascular symptoms (e.g., dyspnea) that places subjects at greater risk for cardiac disease (51). However, data from our study suggest that the effects of depression and PD could affect the cardiovascular system differently. Thus, contributing to the cumulative risk effects observed in this study.

Our study contributes to the previous literature by confirming earlier results using a claims database with a very large population of patients diagnosed with PD. The use of a large administrative database does, however, have some limitations. One limitation would be that the IHCIS database represents patients who have sought treatment for PD and CHD, and this often includes more severe cases. And while patients with a history of cardiovascular disease and diabetes were excluded from the cohort, there may have been patients with undetected comorbidities or underlying disease. However, we are not aware of any evidence that can confirm this occurrence. Because of the fact that claims were used to define the diagnosis of panic disorder, the potential for misclassification bias exists. Patients with a true diagnosis of PD may have been misclassified as not having the disease. This type of misclassification may attenuate the association observed in this study between panic disorder and CHD. Therefore, the true relationship could be even stronger than what is suggested by the study results.

Cardiovascular disease affects more than 61 million people in the United States and is predicted to remain the highest ranked cause of death worldwide through 2020 (19,20). In 2002, the annual number of American men between the ages 29 to 44 diagnosed with new or recurrent heart attack was 34,000 (20). However, there were 257,000 new or recurrent heart attacks among American men 45 to 64 years of age and 430,000 new or recurrent heart attacks among American men ages 65 and older (20). Our study suggests that PD may provide a useful clinical model for studying the possible link between stress and heart disease. These results reaffirm the need for early intervention by identifying patients who may be suffering from panic or anxiety disorder and who may be at risk for developing CHD. Early detection of PD may prevent the occurrence of CHD. Inarguably, the development of therapeutic agents and surgical procedures has helped to prevent, treat and to reduce the risk of mortality from CHD. Nevertheless, health care utilization costs continue to increase (21). The application of cost-effective analyses likely will identify which form of prevention or treatment may provide optimal benefits clinically and economically for patients with PD.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 

Received for publication November 16, 2004; revision received April 20, 2005.

DOI:10.1097/01.psy.0000174169.14227.1f


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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