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Posttraumatic Stress, Nonadherence, and Adverse Outcome in Survivors of a Myocardial Infarction

From the Departments of Psychiatry (E.S., R.Y.), and Pediatrics (E.S.), Mount Sinai Medical Center, New York, NY, and the Clinical Pharmacological Research Unit, The Cardiology Institute, Assaf-Harofeh Medical Center, Zerifin, (O.M., I.D., Z.V., G.C.), and Sackler School of Medicine (A.R.), Tel Aviv University, Tel Aviv, Israel.

Address correspondence and reprint requests to Eyal Shemesh, M.D., Mount Sinai Medical Center, Box 1230, 1 Gustave L. Levy Place, New York, NY 10029. E-mail: eyal.shemesh{at}mssm.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS AND IMPLICATIONS NOTES REFERENCES

 
OBJECTIVE: Posttraumatic stress disorder (PTSD) symptoms have been reported in patients with coronary vascular disease, after the trauma of a myocardial infarction (MI). The effect of these symptoms on post-MI disease control has not been elucidated. We conducted a study that sought to determine whether PTSD symptoms post-MI are associated with increased likelihood of cardiovascular readmission and with nonadherence to treatment recommendations.

METHODS: Patients were recruited during a visit in a cardiology clinic 6 months post-MI and were followed for 1 year. Adherence to aspirin was measured by platelet thromboxane production (an indication of aspirin’s effect). Medical outcome was measured as rate of admission due to cardiovascular causes during the follow-up period. Self-report measures of PTSD (Impact of Event Scale), Depression, and Global Distress (SCL-90-R) were administered at enrollment.

RESULTS: Seventy-three patients were studied. Above-threshold PTSD symptom scores at enrollment, but not depression or global distress scores, were significant predictors of nonadherence to aspirin and of an increased likelihood of cardiovascular readmission over the course of the following year.

CONCLUSIONS: PTSD symptoms predicted poor disease control in this cohort of MI survivors. The data suggest that screening MI survivors for symptoms of PTSD may be beneficial if this high-risk population is to be targeted for interventions.

Key Words: posttraumatic stress, • myocardial infarction, • adherence.

Abbreviations: PTSD = posttraumatic stress disorder;; MI = myocardial infarction;; IES = Impact of Event Scale;; SCL-90-R = Symptom Checklist-90-Revised.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS AND IMPLICATIONS NOTES REFERENCES

 
Amyocardial infarction (MI) is an acute, life-threatening event that may elicit feelings of fear and loss of control at the time it happens. Therefore, it may qualify as a traumatic life event as defined in the fourth edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV-TR, 1). Approximately 10% to 20% of MI survivors report substantial posttraumatic stress disorder (PTSD) symptoms after the MI (2–4).

It has been known for some time that MI survivors are at risk for the development of depressive symptoms, and that depressed MI survivors are at risk for adverse medical or quality-of-life outcomes (5–12). In contrast, little is known about whether the presence of PTSD in MI survivors is similarly associated with adverse medical outcomes. Although PTSD and major depressive disorder (MDD) share common symptoms and alterations in common biological pathways, these disorders can also be distinguished on the basis of both phenomenology and pathophysiology. PTSD is an anxiety disorder in which the primary symptoms relate to intrusive recollections of the traumatic event accompanied by avoidance of traumatic material and increased physiological arousal. In contrast, MDD is a mood disorder characterized by dysphoria, anhedonia, and impairment in sleep, appetite, and movement, as well as excessive guilt and low self-esteem (1). PTSD and MDD appear to also be distinct from a neuroendocrine perspective in that the former has been associated with a greater responsiveness to neuroendocrine challenge, and the latter, with reduced responsiveness to neuroendocrine challenge (13–17). Accordingly, it is quite possible that these disorders may have different effects on outcomes after a MI.

One potential effect of PTSD is that it may worsen medical outcome by increasing nonadherence to medication regimens (2,18,19). We previously hypothesized that the MI survivor with PTSD symptoms may view medications as traumatic reminders and would therefore wish to avoid the medications (eg, consistent with the avoidance symptom cluster of PTSD, to avoid reminders of the event) (1). Nonadherence to medical recommendations was shown to be associated with adverse outcome in patients who suffer from coronary heart disease (20–22). Thus, PTSD may be associated with adverse outcome indirectly by affecting adherence behavior.

There may also be a biological link between PTSD and adverse medical outcomes in MI patients. Both the catecholaminergic system and the hypothalamic-pituitary-adrenal (HPA) axis are altered in PTSD in a manner that might exacerbate medical outcomes in MI patients. PTSD is associated with increased heart rate (23), elevated basal catecholamines, and increased responsiveness to noradrenergic challenge, as well as alterations of the HPA axis (14) suggestive of an enhanced functional responsiveness to corticosteroids. The HPA axis alterations in PTSD patients include an increased cortisol and glucocorticoid receptor response to dexamethasone administration (reflecting an enhanced negative feedback inhibition). Under these conditions of enhanced negative feedback inhibition, ambient cortisol levels might be lower than normal, resulting in a relative inability to contain catecholaminergic and other hormone-mediated stress responses. Unmitigated stress responses (which may include persistently elevated heart rates (23), hypertension, etc.) may lead to increased morbidity in patients with coronary heart disease.

PTSD symptoms are very common immediately after a traumatic event, as an initial "adjustment phase" that, in most people, subsides after a few weeks. These early symptoms are not necessarily associated with disability, and most of the people who have them recover on their own (24). For this reason, if one attempts to identify patients whose PTSD symptoms post-MI are disabling and may necessitate treatment, assessment and treatment are best done a few months after the MI and not immediately afterward (25).

To evaluate whether PTSD symptoms are associated with both specific measures of adherence to medications and with increased rates of inpatient admission due to cardiovascular morbidity, we conducted a prospective study of MI survivors in a cardiology clinic. To determine whether any associations with medical outcomes and PTSD symptoms are explained by comorbid conditions, we also examined the association between symptoms of depression or global distress and the same outcome measures in the cohort.

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS AND IMPLICATIONS NOTES REFERENCES

 
Experimental Design
The study was conducted in a cardiology center in Israel. The routine management of post-MI patients in our community includes monthly visits to the primary care physician, quarterly visits to the HMO cardiologist, and 1 visit (6 months after the acute MI) to the outpatient clinics of the Medical Center. Consecutive patients were enrolled 6 months after MI and followed up for 1 year after enrollment. We approached all patients who were invited for a 6-month post-MI usual clinic visit, during June to November 2001 (that is, all patients who were admitted with acute MI between January and June 2001). Figure 1 summarizes the study design and enrollment figures.

View larger version (37K): [in this window] [in a new window]   Figure 1. Study design and enrollment.

Inclusion/Exclusion Criteria
To be included in the study, patients must have been followed at our institution, must have had a MI 6 months before enrollment, must have consented to the study procedures, and must have been prescribed aspirin by a community cardiologist. We excluded patients who were not prescribed aspirin. We intended to exclude patients who were not able to understand the questionnaires because of language or cognitive barriers, but this did not turn out to be a problem in the present cohort, which was comprised of Hebrew speakers.

Adherence Detection Method
We examined adherence to aspirin in the entire cohort. A detailed description of the adherence detection procedure that we used in this cohort has been described elsewhere (26). In brief, we examined the rates of thromboxane production by patients’ platelets as an indication of aspirin effect. We also conducted face-to-face interviews to ascertain that patients were indeed prescribed aspirin and discussed with the patients the results of the thromboxane production tests when these indicated no aspirin effect. Patients who were potentially aspirin-resistant (that is, showed no aspirin effect on platelets, but claimed that they took aspirin when shown the results) were excluded from the final analyses.

Follow-up and Outcome Variables
Patients were followed for 1 year after enrollment (1.5 years post-MI). The adherence outcome measure was whether or not the results of the thromboxane production test coupled with the interview indicated nonadherence to aspirin. The morbidity measure was the likelihood of an inpatient admission due to cardiovascular causes during the study follow-up period. We used a measure that is tied to cardiovascular morbidity rather than a general service utilization variable (such as rate of admissions due to any cause). This is because we examined the association with symptoms of PTSD that are specifically related to the MI. We were therefore interested in an outcome measure that is related to disease-specific morbidity and disability rather than a measure that is, potentially, tied to general and nonspecific distress. A cardiovascular readmission was defined as readmission due to the following.

1. Re-infarction: MI adjudication was done by 2 independent cardiologists, using the ACC/AHA/ESC guidelines for diagnosis of MI (27).
   
2. Unstable angina: clinical symptoms of angina accompanied by ECG changes including major ST depressions (1 mm) or deep T-wave inversion (3 mm) in at least 2 leads directed at the same myocardial wall (28).
   
3. Hypertension or its complications: High (above 140/90) blood pressure leading to admission that was directly related to these readings and to the existence of hypertensive complications (eg, renal, vision).
   
4. Indications of heart failure: exacerbation of pulmonary edema or progressive weakness due to heart failure leading to significant dysfunction that necessitated an admission.
   

Urgent revascularization procedures that followed an acute cardiovascular compromise as defined above were, by definition, captured as "cardiovascular admissions" because of the event that preceded them.

Cerebrovascular events are sometimes included in definitions of cardiovascular complications in research pertaining to MI survivors. Nevertheless, we did not include cerebrovascular events as an outcome measure in the present cohort. This is because we were concerned that episodes of dissociation in PTSD patients might be mislabeled as cerebrovascular events and, if so, will skew our data and make it appear as though patients with PTSD suffer from more vascular complications then they really do. We did perform a post hoc analysis to see if this exclusion resulted in any meaningful difference in the interpretation of the results

Posttraumatic Stress Questionnaire
The impact of event scale (IES) (29) was used to determine emotional distress associated with posttraumatic symptoms. The IES is a 15-item questionnaire that is asking about current (within the last week) symptoms of intrusion and avoidance of posttraumatic stress disorder. The IES has been the most widely used measure of posttraumatic stress symptoms, and it was previously examined in numerous clinical settings (29,30). Cutoff points have been established; we previously used cutoff points in MI survivors (2) to determine above-threshold scores in the aggregate measure. The cutoff score was 17 points for each of the subscales, and only patients who met the threshold on both scales were considered to be "positive" for PTSD symptoms in this study. The presence of above-threshold scores on this measure has previously been reported to predict nonadherence to medications after MI (2). We specifically worded the questionnaire so that it related to the MI as the traumatic event that was examined in the present study (eg, "did you think about the MI when you did not want to?"). Hence, this study examined only PTSD symptoms that were related to the MI as the identified trauma, and not symptoms that may relate to any other traumas that subjects may have had in their lives.

Symptom Checklist-90-Revised (SCL-90-R)
This is a widely used general psychiatric/distress measure that was validated in numerous clinical settings (31,32). We used the subscale measures of depression and global distress as they are defined in the SCL-90-R manual (32). Cutoff points (above which medical morbidity or nonadherence is increased) are not available for SCL-90-R subscales in MI patients. However, it is possible that only an above-threshold value is significant in this population. Therefore, we analyzed the scores both as a continuous variable (the "traditional" way, the summary score for each subscale) and as a dichotomy. To create a dichotomy, we divided the cohort using the median score in the sample (above median and below median scores) and reanalyzed the data using this cutoff point.

Statistical Analysis
Fisher exact tests were performed to examine the relationships between PTSD (dichotomous—above or below threshold), SCL-90-R (below and above the median score in the present cohort), and adherence (dichotomous) variables. When SCL-90-R scores were expressed as a summary value without a specific cutoff point and compared with a dichotomous PTSD determination, we used a 2-tailed t test. Logistic regression was applied to the data to examine the impact of several risk factors on readmission and to calculate relevant odds ratios. Kaplan-Meier survival analysis was used to compare time to cardiovascular admission between PTSD and non-PTSD patients. P values of 0.05 were regarded as significant.

	RESULTS

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Subject Characteristics
One hundred patients were called, 82 came to the scheduled visit, and 76 consented to the study procedures. Prescribed aspirin dosage and follow-up with a community cardiologist were ascertained. Three patients who were not prescribed 100 mg of aspirin daily were excluded. The final cohort, therefore, consisted of 73 patients: 73% of the initial contact number, and 96% of those who consented (we excluded only 3, or 4%, of patients who consented to the study). Consenting patients were asked, at enrollment, to give a blood sample for TxB2 studies, and were told that a follow-up assessment visit would be scheduled to discuss the results if they were abnormal. The psychological questionnaires were administered at this step. All 73 patients who met the inclusion criteria and consented were followed to completion. Baseline characteristics of the 73 patients who enrolled in the study are presented in Table 1.

Outcome
During 1 year of follow-up, 18 patients (24.7%) were readmitted because of cardiovascular causes. Of these, 9 (12.3%) sustained a severe cardiac ischemic event including 1 patient (1.4%) who died, 4 patients sustained a recurrent MI (5.5%), 4 patients (5.5%) were admitted because of severe unstable angina, and 1 because of intractable hypertension. There was no admission related to a cerebrovascular event in the "not admitted" group of patients; hence, cerebrovascular events did not change the interpretation of the outcome data in the present study. Variables from Table 1 were evaluated as potential predictors for cardiovascular readmission. Significant predictors for readmission are presented in Table 2.

View larger version (26K): [in this window] [in a new window]   Figure 2. Kaplan-Meier analysis of the likelihood of a cardiovascular readmission during the study as a function of the PTSD symptom status. PTSD = above-threshold scores on the Impact of Event Scale. No PTSD = below-threshold scores on the Impact of Event Scale.

The relative significance of PTSD as a predictor of readmission when compared with other predictors that were found to be significant in the present study is presented in Table 2.

PTSD and SCL-90-R Depression and Global Distress Subscales
The correlations between the IES scores and the SCL-90-R depression and global distress scores were highly significant (Table 3). When above and below median scores were used to define the SCL-90-R results (dichotomizing this data), the association between above-threshold PTSD and above-median SCL-90-R depression and general distress scores remained significant (p < .001 in each comparison).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS AND IMPLICATIONS NOTES REFERENCES

The present study used a PTSD self-report measure that is specifically targeting the symptom clusters of avoidance and intrusion, and not the less specific cluster of hyperarousal. This measure was chosen because we previously observed that these symptoms were associated with nonadherence to medications after MI (2). In particular, the avoidance cluster of PTSD could explain why patients who suffer from these symptoms would not take their medications (as a means to avoid being reminded that they are sick) (2). The clinical diagnosis of PTSD, although undoubtedly related to the existence of these symptom clusters, was not examined in the present study.

Associations between PTSD symptoms and nonadherence after MI (2), PTSD and poor medical outcome after a heart transplant (33), and PTSD symptoms and nonadherence after liver transplantation in children (18) were previously reported. The present study, therefore, adds to an increasing body of literature that is describing the relationship between PTSD symptoms and poor disease control in individuals who are traumatized by their medical illness.

Our relatively small sample size may be the reason why we did not detect the previously well-documented adverse effects of depression on medical outcome and adherence (we may not have had sufficient power to detect such an effect). However, the fact that we did detect an adverse effect of PTSD symptoms in this small cohort suggests that the effect of PTSD symptoms on the chosen outcomes may be larger than the effect of depression or global distress.

We only excluded 3 patients from the study. Our exclusion criteria, therefore, did not result in substantial attrition. However, 24 patients did not show up or declined participation before we even assessed them. Therefore, our results likely underestimate the prevalence of nonadherence because we only studied persons who adhered to the 6-month follow-up visit. Also, 8 patients who did participate declined to answer the psychiatric questionnaires; it is possible that some patients with PTSD symptoms avoided answering the questionnaires because of the avoidance symptom cluster, and, hence, our data may underrepresent the true rate of post-MI PTSD symptoms. Hence, our data may underrepresent the prevalence of both PTSD symptoms and of nonadherence that may be encountered by practitioners in a cardiology clinic.

A strength of the study is that we were able to follow up all of the patients who enrolled. This is because the study was conducted in the only government-operated tertiary facility in the area. Patients who are seen at our clinic are followed up only in government facilities (usually, in a clinic that is physically located in the same area as ours). Sharing of information between these facilities is easily streamlined if a patient’s consent is obtained.

The increased rates of cardiovascular readmissions in post-MI patients who report significant levels of PTSD symptoms may be related to nonadherence to medications or they may also be related to the biological correlates of PTSD, which may put an additional strain on an already ailing heart. Further studies could investigate the biological correlates of PTSD post-MI in an attempt to verify whether biological (eg, increased heart rate or HPA-axis alterations) or behavioral (eg, nonadherence to medications) mechanisms, or both, best explain the association between PTSD symptoms and poor cardiovascular outcome after MI.

	CONCLUSIONS AND IMPLICATIONS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS AND IMPLICATIONS NOTES REFERENCES

 
Symptoms of posttraumatic stress related to acute MI are associated with nonadherence to medications and increased likelihood of cardiovascular readmission after MI. Our study adds to an expanding body of literature that report that PTSD symptoms are associated with poor disease control in patients who suffer from an acute medical event. Our data suggest that PTSD symptoms after MI should not be overlooked. Although these associations need to be further investigated before firm recommendations can be made, it might be clinically beneficial to screen for PTSD symptoms after MI and attempt treatment in selected cases.

	NOTES

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS AND IMPLICATIONS NOTES REFERENCES

 
Supported, in part, by a National Institutes of Health grant MH63755 to Eyal Shemesh, MD. Also partially supported by a generous award from the Y. H. Mirzoeff and Sons Foundation.

Received for publication July 21, 2003.

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TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION CONCLUSIONS AND IMPLICATIONS NOTES REFERENCES

 

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