Suspicion of Obstructive Sleep Apnea by Berlin Questionnaire predicts events in patients with Acute Coronary Syndrome

Abstracts

FUNDAMENTO: De um ponto de vista mecanístico, a apneia obstrutiva do sono (SAOS) pode causar distúrbios extras à homeostase cardiovascular na presença de síndrome coronariana aguda (SCA). OBJETIVO: Investigar se um diagnóstico clínico padronizado de SAOS, em pacientes com SCA, prediz o risco de eventos cardiovasculares durante hospitalização. MÉTODOS: Em um estudo de coorte prospectivo, um grupo de 200 pacientes com diagnóstico de SCA estabelecido entre Setembro de 2005 e Novembro de 2007, foram estratificados pelo Questionário de Berlim (QB) para o risco de SAOS (alto ou baixo risco). Foi testado se o subgrupo de alto risco para SAOS apresenta maior tendência à eventos cardiovasculares. O endpoint primário avaliado foi um desfecho composto de morte cardiovascular, eventos cardíacos isquêmicos recorrentes, edema pulmonar agudo e acidente vascular cerebral durante a hospitalização. RESULTADOS: Noventa e quatro (47%) dos pacientes identificados pelo QB apresentavam suspeita de SAOS. Alto risco para SAOS estava associado com uma mortalidade mais elevada, embora sem diferença estatística (4,25% vs 0,94%; p=0,189), mas com uma estatisticamente significante maior incidência de desfecho composto de eventos cardiovasculares (18,08% vs 6,6%; p=0,016). No modelo de regressão logística, os preditores multivariados de desfecho composto de eventos cardiovasculares foram idade (OR = 1,048; IC95%: 1,008 a 1,090; p=0,019), fração de ejeção do VE (OR = 0,954; IC95%: 0,920 a 0,989; p=0,010), e risco mais elevado de SAOS (OR = 3,657; IC95%: 1,216 a 10,996; p=0,021). CONCLUSÃO: O uso de um questionário simples e validado (QB) para identificar pacientes com risco mais elevado de SAOS pode ajudar a prever o desfecho cardiovascular durante a hospitalização. Além disso, nossos dados sugerem que SAOS é muito comum em pacientes com SCA.

Apneia obstrutiva do sono; questionários; síndrome coronariana aguda

FUNDAMENTO: Desde un punto de vista mecanístico, la apnea obstructiva del sueño (SAOS) puede ocasionar disturbios extras a la homeostasis cardiovascular en la presencia del síndrome coronario aguda (SCA) OBJETIVO: Investigar si un diagnóstico clínico estandarizado de SAOS, en pacientes con SCA, predice el riesgo de eventos cardiovasculares durante la hospitalización. MÉTODOS: En un estudio de cohorte prospectivo, un grupo de 200 pacientes con diagnóstico de SCA elecido entre Septiembre de 2005 y Noviembre de 2007, fueron estratificados por el Cuestionario de Berlín (CB) para el riesgo de SAOS (alto o bajo riesgo). Se probó si el subgrupo de alto riesgo para SAOS presenta mayor tendencia a eventos cardiovasculares. El endpoint primario evaluado fue un desenlace conformado por muerte cardiovascular, eventos cardíacos isquémicos recurrentes, edema pulmonar agudo y accidente vascular cerebral durante la hospitalización. RESULTADOS: Noventa y cuatro (47%) de los pacientes identificados por el CB presentaban sospecha de SAOS. Alto riesgo para SAOS estaba asociado con una mortalidad más elevada, aunque sin diferencia estadística (4,25% vs 0,94%; p=0,189), pero con una estadísticamente significativa mayor incidencia de desenlace conformada por eventos cardiovasculares (18,08% vs 6,6%; p=0,016). En el modelo de regresión logística, los predictores multivariados de desenlace conformado por eventos cardiovasculares fueron edad (OR= 1,048; IC95%: 1,008 a 1,090; p=0,019), fracción de eyección del VI (OR= 0,954; IC95%: 0,920 a 0,989; p=0,010), y riesgo más elevado de SAOS (OR= 3,657; IC95%: 1,216 a 10,996; p=0,021). CONCLUSIÓN: El uso de un cuestionario sencillo y validado (CB) para identificar a pacientes con riesgo más elevado de SAOS puede ayudar a prever el desenlace cardiovascular durante la hospitalización. Además de ello, nuestros datos sugieren que SAOS es mucho común en pacientes con SCA.

Apnea obstructiva del sueño; cuestionarios; síndrome coronario agudo

ORIGINAL ARTICLES

Suspicion of Obstructive Sleep Apnea by Berlin Questionnaire predicts events in patients with Acute Coronary Syndrome

Eryca Vanessa S. de Jesus^I; Euvaldo B. Dias-Filho^I; Bethania de M. Mota^I; Luiz de Souza^III; Celi Marques-Santos^II; João Bosco G. Rocha^II; Joselina L. M. Oliveira^I,II; Antônio C. S. Sousa^I,II; José Augusto Barreto-Filho^I,II

^IDepartamento de Cardiologia da Universidade Federal de Sergipe, Aracaju, SE

^IIServiço de Cardiologia da Clínica e Hospital São Lucas, Ribeirão Preto, SP - Brazil

^IIIDepartamento de Estatística da USP - Ribeirão Preto, Ribeirão Preto, SP - Brazil

Mailing address

ABSTRACT

BACKGROUND: From a mechanistic standpoint, obstructive sleep apnea (OSA) may further disturb cardiovascular homeostasis in the setting of acute coronary syndrome (ACS).

OBJECTIVE: We sought to investigate if a standardized clinical diagnosis of OSA, in acute coronary syndrome patients, predicts the risk of cardiovascular events during hospitalization.

METHODS: In a prospective cohort study, a group of 200 patients diagnosed with ACS between September 2005 and November 2007 were stratified by the Berlin Questionnaire (BQ) regarding the risk for OSA (high or low risk). We tested if the subgroup of high risk for OSA was prone to a higher frequency of cardiovascular events. The primary endpoint evaluated was a composite outcome of cardiovascular death, recurrent cardiac ischemic events, acute pulmonary edema and stroke during hospitalization.

RESULTS: Ninety four (47%) patients assessed by the BQ were likely to have OSA. High risk for OSA was associated with a non-significant higher mortality (4.25% vs 0.94%; p=0.189), but a significant higher incidence of composite cardiovascular events (18.08% vs 6.6%; p=0.016). In the logistic regression model, multivariate predictors of composite cardiovascular events were age (OR = 1.048; 95% CI 1.008 to 1.090; p=0.019), left ventricular ejection fraction (OR = 0.954; 95% CI 0.920 to 0.989; p=0.010), and higher risk for OSA (OR= 3.657; 95% CI 1.216 to 10.996; p=0.021).

CONCLUSION: The use of a simple and validated questionnaire (BQ) to identify patients with higher risk for OSA may help in the prediction of cardiovascular outcome during hospitalization. Moreover, our data suggests that OSA is very common in patients with ACS.

Key words: Sleep apnea, obstructive/complications; questionnaires; acute coronary syndrome.

Introduction

Obstructive sleep apnea (OSA) is an emerging cardiovascular risk factor. From an epidemiological standpoint, ample evidence supports that OSA may cause hypertension^1,2, stroke³, heart failure^4,5 and may increase the risk of atrial fibrillation^6,7. Moreover, OSA is associated with signs of surrogate markers of premature atherosclerosis⁸. In addition, the hallmarks of OSA pathophysiology in regard to the imbalance of oxygen delivery and demand suggest that apnea-related hypoxemia may impose an additional risk to patients in the setting of acute coronary syndromes (ACS)^9-12. Nevertheless, it is surprising that very little is known about the impact of OSA adding risk to patients with ACS.

Polysomnography is the gold standard method to diagnose sleep apnea syndrome; nevertheless it has potential limitations to its widespread use in clinical practice^6,13. The Berlin Questionnaire (BQ) is a simple and validated method to diagnose OSA in the general population¹³ and, recently, it has also been validated in cardiovascular patients⁶. Therefore, we tested the impact of the clinical diagnosis of OSA suspected by BQ in predicting cardiovascular events during hospitalization of ACS patients.

Methods

Study design

In this prospective, observational study, all patients referred to the Chest Pain Unit in São Lucas Hospital, state of Sergipe, Brazil, from September 2005 to November 2007, and diagnosed with ACS were invited to respond the BQ and were followed until hospital discharge. The protocol was approved by the local ethics review board, and all subjects provided written informed consent before study enrollment.

Subjects

Inclusion criteria included a diagnosis of ACS defined by medical history and at least one of the following findings: electrocardiographic changes consistent with ACS, serial increases in serum markers of cardiac necrosis and documentation of coronary artery disease (coronary angiography or detection of myocardial ischemia by noninvasive method). Patients were diagnosed with ST-segment elevation myocardial infarction (STEMI), non-STEMI or unstable angina according to current guidelines^14,15. Patients who refused to be enrolled in the present investigation, who was transfered to other hospital or who were not capable of answering the questionnaire were excluded.

Baseline assessment

Data on demographic characteristics, prior medical history and life habits were obtained with the use of a standardized questionnaire administered by a trained medical resident (EVSJ) and corroborated by the data in the medical files. Risk-factor data included history of hypertension, diabetes mellitus, dyslipidemia, smoking or prior cardiovascular disease, either reported by the patient on the baseline medical record or based on the current therapy used by the patient. Renal failure was defined by creatinine at hospital admission above the upper limit of normality.

The patients' height and weight were recorded and used to calculate the body-mass index (BMI). Obesity was defined as a BMI > 30 kg/m². Biochemical and electrocardiographic findings, treatment practices and hospital outcome data were collected. Echocardiography was performed at the discretion of the patient's physician and left ventricular ejection fraction (LVEF) was analyzed according to the current guidelines.

Patients were considered to have clinical signs of acute congestive heart failure (CHF) at admission in the presence of rales or crackles in the lungs, an S3 gallop, and elevated jugular venous pressure, frank acute pulmonary edema (APE) or cardiogenic shock (defined as hypotension, measured as systolic blood pressure lower than 90 mmHg, and evidence of peripheral vasoconstriction).

Risk of OSA (Berlin questionnaire)

Risk of OSA was assessed by the Berlin questionnaire. Patients were divided in high risk and low risk of OSA based on responses to symptom questions grouped in three categories. A patient was considered to be at high risk for sleep apnea if 2 of the 3 following criteria were met: 1) snoring with two of the following features: louder than talking, at least 3 to 4 times a week, complaints by others about snoring, witnessed breathing pauses at least 3 to 4 times a week; 2) early morning and daytime fatigue exceeding 3 to 4 times a week or having fallen asleep while driving; and 3) presence of hypertension or obesity¹³.

Outcome

Patients were followed for clinical endpoints and adverse events during their index hospitalization. The cardiovascular events of interest were cardiovascular death, recurrent ischemic events (angina, infarction or reinfarction), APE and stroke. A diagnosis of recurrent myocardial ischemia was based on recurrent ischemic symptoms, new electrocardiographic changes compared to the index ECG that were not considered an evolution of the index recording and/or a subsequent increase in CKMB levels after a decrease from a previous peak value^14,15. APE was classified as a relevant cardiovascular outcome due to the epidemiological and pathophysiological association of OSA and heart failure⁴. APE was defined as the presence of clinical signs of left ventricular failure, manifestation of dyspnea, signs of hypoxia and fluid in the lungs (i.e. chest auscultation revealing rales and a chest radiography showing bilateral pulmonary infiltrates consistent with congestion). Stroke was defined as rapidly developing clinical signs of focal (or global) disturbance of cerebral function lasting for more than 24h with no apparent cause other than a vascular origin.

Statistical analysis

Baseline characteristics of patients in the 2 groups were expressed as means (with standard deviations) and counts (with percentages). Patients with BQ suggestive of OSA were compared to patients with low probability of OSA by the 2-tailed T test and X² test or Fisher exact test.

To ascertain the independent effect of high risk of OSA on primary endpoints, we identified potential confounding variables and covariates by performing univariate analysis, comparing patients with high and low risk of OSA and patients with and without cardiovascular composite events. Significant confounders (p < 0.10) identified at the univariate analysis were included in the model for the multivariate logistic regression. A stepwise logistic regression was used to develop a multivariate model that identified the best set of variables associated with composite cardiovascular events. The multivariate model was constructed based on the Hosmer-Lemeshow approach. A forward stepwise procedure was used to identify the final model. Statistical significance was established by p < 0.05. All analyses were performed using SPSS 16.0 for Windows (SPSS Inc., Chicago, Illinois).

Results

Characteristics of the study population

Two hundred and seventy-three patients were selected for the study. Of these, 50 declined participation, 19 were not capable of answering the questionnaire and 4 were transferred to another hospital, resulting in a final study population of 200 patients. The baseline characteristics of the excluded patients were similar to those of the participants in the study (data not shown).

Population baseline characteristics are described in Table 1. High risk of OSA was identified in 94 (47%) patients. Patients with high risk of OSA presented a higher prevalence of hypertension (92.55 versus 59.43 %; p<0.001), obesity (40.42% versus 15.09%; p<0.001) and a trend to have lower ejection fraction (54.67% ± 13.67 versus 58.29% ± 13.06, p=0.083). Signs of CHF upon admission at the emergency room, form of ACS presentation and positive markers of cardiac necrosis were not different. Ninety-one percent of the patients (181 patients) underwent coronary angiography. There were no significant differences between the groups with respect to prevalence of multivessel and left main coronary artery disease (CAD). In addition, no differences were observed in regard to evidence-based treatments between the two groups (Table 1).

Characteristic of patients with cardiovascular events

Of the total number of patients, 24 (12%) presented cardiovascular events during hospitalization (Table 2). The total mortality of the population was 2.5% (05 patients). The group with higher risk of OSA presented 4.25% (04 patients) of mortality compared with 0.94% (01 patient) in the group with low clinical probability of OSA (p=0.189). The OSA group presented 18.08% (n=17) of composite cardiovascular events compared to 6.6% (n=07) in the group without suspicion of OSA (p=0.016) (Table 1). Patients with cardiovascular events presented higher prevalence of hypertension (p=0.011), higher prevalence of medical history of prior CHF (p=0.021) and signs of CHF upon hospital admission (p=0.025), lower ejection fraction (p<0.001), higher prevalence of ST elevation ACS (p=0.028) and older age (p=0.016). There were no significant differences between patients with and without cardiovascular events with respect to the prevalence of multivessel and left main coronary artery disease. No differences were observed in treatment strategies when comparing the two groups (Table 2).

Association of suspicion of OSA with cardiovascular events

A higher risk of OSA by the BQ persisted significantly associated with composite cardiovascular events during hospitalization after adjustment (Table 3). The variables age and ejection fraction were also independently associated with CV events in the multivariate model.

Discussion

The novel finding of this study is that the subgroup of patients with ACS and high clinical suspicion of OSA by the BQ are at higher risk of composite cardiovascular events during hospitalization. Moreover, the study also confirmed that the incidence of OSA in the setting of ACS is much higher than that in the general population^6,16,17.

It is reasonable to hypothesize that OSA is an emerging cardiovascular factor^{1,3,4,6-10, 18,19}. Nevertheless, this hypothesis is not universally accepted¹⁶. In addition, very limited information is known about the role of OSA as an aggravating factor to established cardiovascular disease.

ACS is generally caused by reduced myocardial perfusion as a consequence of a thrombus that develops on a disrupted plaque. The hallmark of OSA pathophysiology is intermittent episodes of hypoxia elicited by the mechanical interruption of upper airway flow^10,17. The cardiovascular response during hypoxia in order to compensate systemic oxygen desaturation is complex and may be altered in pathological conditions^20,21. In patients with ACS and OSA, the association of a) severe reduction in coronary blood flow, b) acute oxygen desaturation during apneic episodes, c) impairment of coronary defense response during hypoxia caused by endothelial dysfunction and atherosclerosis and d) blood pressure elevation during hypoxemia increasing myocardial oxygen demand may, altogether, aggravate myocardial ischemia and further impair cardiac function. Although it is tempting to suppose that OSA may be a risk factor for atherothrombosis and aggravate the ACS prognosis, the concept is yet to be proven.

OSA is associated with surrogate pathways and markers of premature atherosclerosis^8,22. CAD is more prevalent in OSA patients^18,19 and the respiratory disturbance index is a predictor of cardiovascular mortality in small cohorts⁹. Sleep apnea has been implicated in patients with nocturnal angina pectoris. Nocturnal angina and ST depression are diminished during treatment of sleep apnea by CPAP^{10, 23}. Similarly, Hanly et al²⁴ observed that the ST depression occurred in about a third of patients with severe OSA. ST depression was markedly attenuated during nasal CPAP. However, these patients did not have proven coronary artery disease, and artifactual ST changes related to breathing patterns may have contributed. Araújo et al²⁵, studying a group of 53 patients with stable coronary disease, did not observe significant difference in the number or duration of ischemic episodes during sleep among patients with OSA and controls. Moreover, in this study there were no alterations in the circadian pattern of myocardial ischemia in OSA or related to sleep apnea and heart rate variability or arrhythmias.

In longer-term studies, OSA in patients with CAD was associated with a significant increase in the composite endpoint of death, myocardial infarction (MI), and cerebrovascular events at a 5-year median follow-up interval²⁶. However, neither oxygen desaturation index nor AHI was independently predictive of single endpoints of MI or death. In a case-control study, there was a graded increase in the odds of acute MI with increased sleep apnea severity, even after adjustment for possible confounding factors²⁷.

In a large cohort study, OSA was associated with risk of death and stroke, even when adjusted by hypertension or other confounders³. It was observed that OSA patients presented a higher risk of having sudden cardiac death during sleep time²⁸. The same group also showed that patients with nocturnal onset of acute myocardial infarction had a higher likelihood of having OSA²⁹. Collectively, the data point out to OSA as a condition that may be a trigger for cardiovascular death, stroke and ACS. Although much is known about the association between OSA and CAD, myocardial ischemia and infarction, the data provide mostly observational, albeit valuable, insights.

We studied patients with ACS who were admitted to a single cardiovascular center. The BQ identified that 47% of the overall population presented high probability of having OSA. This is in agreement with recent studies showing the extremely high prevalence of OSA in this scenario (57% and 66.6%)^16,18,19 . Taken together, these numbers underscore the high frequency of OSA in patients with ACS and the necessity of further research to understand the OSA-ACS interaction.

In addition, modeling the association of OSA and cardiovascular events to covariates that generally are accepted as confounder factors demonstrated that clinical suspicion of OSA was independently associated to cardiovascular events during hospitalization. In our population, differences in treatment strategies did not explain the higher prevalence of cardiovascular events in OSA patients (Table 1).

When compared to patients with low risk of OSA, it was demonstrated that high risk of OSA was associated with an increased risk of composite adverse cardiovascular events (i.e. cardiovascular mortality, recurrent myocardial ischemic events, APE and stroke). It should be stressed that the sample size was relatively small to detect differences in cardiovascular mortality between OSA and non-OSA patients. Nevertheless, recurrent cardiac ischemic events and APE (Table 1) were more prevalent in OSA patients. In addition to the potential role of hypoxic episodes precipitating ischemic cardiac events, the association of OSA, heart failure and impairment in cardiac function has also been documented^4,30. Moreover, hypoxia may increase pulmonary vascular permeability through an endothelin-related mechanism increasing the risk of pulmonary edema³¹. This evidence was the base of our choice to include APE as a cardiovascular endpoint in this prospective study and may explain our finding of a higher prevalence of APE in OSA patients.

In a prospective cohort study, patients with and without OSA were compared regarding the frequency of MI during different intervals of the day based on the time of onset of chest pain²⁹. The odds of having OSA in patients whose MI occurred between 12 AM and 6 AM was 6-fold higher than in cases whose MI occurred during the remaining 18 h of the day (95% confidence interval: 1.3 to 27.3, p > 0.01). Of all patients having an MI between 12 AM and 6 AM, 91% had OSA. These findings suggest that OSA may be a trigger for MI.

Cassar et al¹⁹ have reported, in a retrospective and observational study, that OSA patients submitted to PCI who remained adherent to OSA treatment with CPAP presented lower cardiovascular mortality compared with the untreated control group during a 5-year follow-up. It should be stressed that 70% of the patients were submitted to PCI during the course of an ACS event, demonstrating that OSA may have a negative impact in patients who suffered an ACS. In another study, Yumino et al¹⁸ performed sleep studies in all patients who were submitted to PCI during the course of ACS. They demonstrated that the incidence of MACE (cardiac death, reinfarction and target vessel revascularization) was higher in OSA patients (23.5 vs 5.3%; p=0.02). In addition, they documented that OSA was an independent predictor of MACE, greater angiographic late loss and a higher binary restenosis rate.

A second prospective observational study assessed the incidence of fatal and nonfatal cardiovascular events in healthy men, snorers, and patients with treated and untreated OSA. In men with severe untreated OSA (AHI > 30), both fatal and nonfatal cardiovascular events were markedly increased. In contrast, fatal and nonfatal cardiovascular events in treated OSA patients approached levels seen in simple snorers³².

A recent study reported different conclusions from ours. Mehra et al¹⁶ analyzed 104 patients with ACS and complete sleep studies performed within 72 h of hospital admission. Similar to our data, they observed a very high prevalence (66.4%) of OSA in the setting of ACS. However, that did not demonstrate OSA as a predictive factor for cardiovascular events during a 6-month follow-up. In spite of the merits of their study for having performed polysomnography to diagnose OSA, the absence of an objective definition of relevant cardiovascular events as potential limitations may have masked the real impact of OSA in the setting of ACS.

One major limitation of our study was the fact that it was not possible to use polysomnography to confirm our data as the gold standard method. In the study of Mehra et al¹⁶, neither the pre-test probability for sleep apnea through the Cleveland questionnaire, an expanded Berlin Questionnaire, nor the degree of subjective sleepiness predicted OSA. Araújo et al²⁵ observed that 23 patients (43.4%) of the 53 classified as having high risk for OSA by the BQ had an AHI <" 15. Nevertheless, the BQ has been validated in several clinical scenarios and has been used in the identification of patients with suspicion of OSA with reasonable sensitivity and specificity^6,13,33. Gami et al⁶ reported that the risk of AF was increased in OSA patients identified by the BQ. Recently, these data were confirmed, by the same group, in a larger study using polysomnography, supporting the role of the BQ in the clinical scenario⁷. In addition, because of the epidemiological importance of ACS and the major economic and logistical obstacles to the widespread use of sleep studies in patients with ACS, new simple and inexpensive methods to identify patients with OSA are urgently desirable.

One strength of the current study includes the high prevalence of ACS, the growing epidemiological importance of OSA and the major economic and logistical obstacles to the widespread use of sleep studies in all patients with ACS.

Conclusions and clinical implications

The first major finding of this study is that almost half of patients with ACS may also have OSA. The second major finding is that our data suggest that OSA is an aggravating cardiovascular risk factor for patients in the setting of ACS. Therefore, further research is necessary to confirm our data and, more importantly, to test the effects of treating OSA on cardiovascular endpoints during the course of ACS. A randomized trial addressing this issue will be essential to answer this fundamental question, especially if considering the potential harmful effect of continuous positive airway pressure (CPAP) at aggravating myocardial ischemia³⁴. Finally, our data disclosures the possibility of improving our prediction model of cardiovascular events during ACS hospitalization by using a simple and inexpensive method.

Acknowledgments

The authors gratefully acknowledge the help of the cardiologists from the Chest Pain Unit and the Coronary Care Unit of São Lucas Hospital whose cooperation made this study possible.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

This study was partially funded by Projeto PIBIC do CNPq/UFS.

Study Association

This study is not associated with any post-graduation program.

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Publication Dates

• Publication in this collection
  06 Aug 2010
• Date of issue
  Sept 2010

History

• Accepted
  24 Nov 2009
• Reviewed
  01 Nov 2009
• Received
  11 Aug 2009