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Incidence and predictors of 30-day cardiovascular complications in patients
undergoing head and neck cancer surgery
Haapio E MD 1, Kiviniemi T MD, PhD 2, Irjala H MD, PhD 1, Koivunen P MD, PhD 3, Airaksinen J.K.E. MD, PhD 2,
Kinnunen I MD, PhD 1
1 Department of Otorhinolaryngology, Turku University Hospital and University of Turku, Turku, Finland.
2 Heart Center, Turku University Hospital and University of Turku, Turku, Finland.
3 Department of Otorhinolaryngology, Oulu University Hospital and University of Oulu, Oulu, Finland.
Corresponding author
Eeva Haapio, MD
Turku University Hospital, Kiinamyllynkatu 4-8
FIN-20521, Turku, Finland, Tel: +3582 3130408, fax: +358 2 3132030
E-mail: [email protected]
Compliance with Ethical Standards:
Funding: This study was funded by the Finnish Foundation for Cardiovascular Research, Helsinki, Finland; by State
Research Founding (EVO); Kirsti and Tor Johansson Cancer and Heart Foundation, Raasepori, Finland.
Conflicts of interest: None declared.
Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical
standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or
comparable ethical standards.
Key words: cardiovascular complication; head and neck cancer; acute coronary syndrome; heart failure; preoperative
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Abstract
Background: Incidence and predictors of perioperative or postoperative cardiovascular complications in head and neck
cancer surgery remains poorly elucidated. In this retrospective study we investigated the rate and preoperative risk
factors for cardiovascular and cerebrovascular complications.
Methods: This study included all patients (n=456) operated for head and neck cancer between 1999 and 2008. Patients’
medical records were reviewed and the adjudication of endpoints was performed by adjudication committee.
Results: The 30-day incidence of cardiovascular and cerebrovascular complications was 7.2%. Cardiac mortality at 30d
was 1.0%. Univariate predictors of MACCE (major adverse cardiac and cerebrovascular events) at the 30-days follow
up were history of myocardial infarction (OR 4.56, 95% CI 1.73-11.97, p=0.002); history of heart failure (OR 4.14,
95% CI 1.32-13.02, p=0.015); pre-existing coronary artery disease (OR 3.98, 95% CI 1.75-9.06, p=0.001); prior aspirin
medication ( OR 3.73, 95% CI 1.81-7.71, p<0.001); prior betablocker medication (OR 3.67, 95% CI 1.79-7.51,
p<0.001); hypertension (OR 2.55, 95% CI 1.25-5.19, p=0.010); increasing age (OR 1.08, 95% CI 1.05-1.12, p<0.001).
In a multivariate model independent predictors of MACCE were pre-existing coronary artery disease (OR 2.45, 95% CI
1.03-5.80, p=0.042) and increasing age ( OR 1.08, 95% CI 1.04-1.11, p<0.001).
Conclusions: Patients having surgery for head and neck cancer are at high (>5%) risk of developing vascular
complications. Prior coronary artery disease and increasing age are independent risk factors for MACCE.
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Introduction
Based on European Society of Cardiology Guidelines patients undergoing head and neck surgery have an intermediate
(1-1.5%) risk for myocardial infarction and cardiac death within 30 days after surgery [1] but a high (>5%) risk for
cardiac complications is reported with major head and neck cancer surgery (12%-25%) [2-3]. Major postoperative
complications are independently associated with decreased overall survival [4]. Earlier studies on cardiovascular
complications in head and neck surgery have generally focused on specific patient subgroups. Patients with head and
neck squamous cell carcinoma undergoing extensive oncologic and reconstructive surgery, for instance, presented high
incidence (12-25%) of cardiovascular complications [2-3, 5], which is partly explained by the extend of the surgery.
Other relevant issue is the known association between cancer and thrombosis. Nevertheless, little is known about the
incidence of adverse cardiovascular events in a contemporary unselected cohort of patients undergoing head and neck
surgery and oncologic treatment; including also patients treated with palliative intent.
In this retrospective registry trial, we sought to assess the incidence and predictors of major
cardiovascular and cerebrovascular complications (MACCE) as well as their derivatives (myocardial infarction,
decompensated heart failure, an episode of atrial fibrillation requiring cardiologist consultation, stroke, transient
ischemic attack (TIA), pulmonary embolism, venous thromboembolism and cardiac death) in a cohort of patients
undergoing head and neck cancer surgery.
Methods
The present population based retrospective study was performed at the Department of Otorhinolaryngology-head and
neck surgery at the tertiary care academic hospital in Turku, Finland. Turku University Hospital takes care of all head
and neck cancer patients, despite the age and general health, from the region of about 1 million residents. This study
was conducted in accordance with the Helsinki declaration as revised in 2002. The study protocol was reviewed and
approved by the Ethics Committee of the Hospital District of Southwest Finland. This registry is part of wider protocol
assessing thrombotic and bleeding events in patients undergoing surgery [6-8].
Patients and source of data
Inclusion criteria consisted allconsecutive patients (n=456) diagnosed with head and neck cancer at Turku University
Hospital between 1999 and 2008. Patients with cancer in following sites were included; oral cavity, pharynx, larynx,
major salivary gland, nasal cavity and paranasal sinuses. Patients receiving palliative procedures were also included.
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Patients whose treatment had started in another institute or whose treatment was not finished in our institute and
patients with primary diagnosis of skin cancer were excluded from this study. All head and neck cancer operations
(n=591) were assessed (Table 1). Information was collected by the first author of this article from referral letters, patient
files, anesthesiology reports, intensive care unit reports, laboratory database, radiology database, electrocardiograms
and pathology reports. Certification of death was provided by the Statistics Finland – a national authority for collecting
and compiling statistics on various fields of society and economy.
Endpoints
The primary endpoints was a composite of major adverse cardiac and cerebrovascular events (MACCE) during the first
30 day after surgery including myocardial infarction, decompensated heart failure, new-onset atrial fibrillation, transient
ischemic attack (TIA), stroke, pulmonary embolism, venous embolism and cardiac death. Perioperative myocardial
infarction was not routinely screened, but if suspected, a troponin level > 3x normal 99th percentile level was required
for the diagnosis. ST elevations, ST depressions and T wave inversions were classified according to the guidelines of
the European society of Cardiology. TIA was defined as a focal transient (<24h) neurological deficit adjudicated by a
neurologist; and stroke as a permanent focal neurological deficit adjudicated by a neurologist and confirmed by
computed tomography or magnetic resonance imaging. Systemic embolism was defined as a sign/symptom of
peripheral ischemia associated with a positive imaging test. Diagnosis of decompensated heart failure was based
ondyspnea and positive findings in chest X-ray and/or a diagnosis confirmed by a cardiologist. Atrial fibrillation was
documented using ECG if clinically indicated and only new onsets of atrial fibrillation were evaluated.
To assess whether MACCE occur also after minor head and neck ongolocig surgery, patients with pre-treatment
evaluation of distribution of cancer using panendoscopy examination as the only form of surgery were analyzed
separately. The adjudication of the endpoints was performed case by case by an adjudication committee consisting of a
cardiologist and an otorhinolaryngologist.
Statistical analysis
Data are presented as means ± standard deviations, median [interquartile range] and frequencies (%) where appropriate.
Continuous variables were analyzed using independent samples t-test. Categorical variables were analyzed using a chisquare test and Fisher’s exact as appropriate. Univariate and multivariate analysis were used to evaluate possible
predictors of acute myocardial infarction and decompensated heart failure. Adjusted hazard rations (HR), 95%
confidence intervals (CI) and P-values were calculated for each predictor. Analysis of predictors for atrial fibrillation,
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stroke, pulmonary embolism or venous thrombosis was not performed due to the low incidence of events. Significance
was set at p value <0.05. Analysis was performed with SPSS-statistics 22.0 software for MAC (SPSS Inc., Chicago,
IL).
Results
During the period of 1999-2008 altogether 456 patients with head and neck cancer were operated on in 591 operations
at Turku University Hospital. The operations are described in Table 1. Al together 97 (16.4%) patients had more than
one operation. The mean age was 63 years (range 23-93) and 152/456 (33.4%) of patients were females. Of the patients,
141 had preoperative oncologic treatment, 81 had only radiation therapy and 60 had chemoradiation therapy.
Rates of cardiac and cerebrovascular complications
A total number of adverse cardiac and cerebrovascular events as well as their derivatives at a 30-day follow-up are
presented in Table 2. During the 30-day follow up 15/456 patients died (3.3%), in 6 of them the main cause of death
was cardiovascular. Primary cardiac arrest and complete heart block did not occur. The incidence of MACCE in the
whole study group was 33/456 patients (7.2%) and in patients with microvascular surgery 12/103 (11.7%). The
characteristics of patients with and without MACCE are shown in Table 3. Decompensated heart failure and acute
myocardial infarction were the most common individual components of MACCE.
Predictors of adverse events
In a binary logistic regression analysis, the univariate predictors of MACCE at the 30-days follow up were prophylactic
low-molecular weight heparin (LMWH) (OR 5.01, 95% CI 2.37-10.62); history of myocardial infarction (OR 4.56, 95%
CI 1.73-11.97, p=0.002); history of heart failure (OR 4.14, 95% CI 1.32-13.02, p=0.015); pre-existing coronary artery
disease (OR 3.98, 95% CI 1.75-9.06, p=0.001); prior aspirin medication ( OR 3.73, 95% CI 1.81-7.71, p<0.001); prior
betablocker medication (OR 3.67, 95% CI 1.79-7.51, p<0.001); hypertension (OR 2.55, 95% CI 1.25-5.19, p=0.010);
increasing age (OR 1.08, 95% CI 1.05-1.12, p<0.001). Independent predictors of MACCE were pre-existing coronary
artery disease (OR 2.45, 95% CI 1.03-5.80, p =0.042) and increasing age (OR 1.08, 95% CI 1.04-1.11, p<0.001), in a
multivariate logistic regression analysis including all the significant univariate predictors in the model. Moreover,
patients over 70-years had a higher risk for MACCE compared to those under age of 70-years (OR 5.24, 95% CI 2.4511.31, p<0.001).
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In total, 106 patients had previous aspirin medication, 43 of those were operated on without
discontinuation of medication, 23 had a minimum of 5 day discontinuation and for 40 patients the information about
discontinuation was not found. Discontinuation of aspirin medication had no effect on incidence of MACCE. Similarly,
thrombosis prophylaxis with low-molecular weight heparin had no effect on cardiovascular complications.
The univariate predictors of decompensated heart failure were male gender (OR 4.7, CI 95% 1.6013.62, p= 0.005); hypertension (OR 2.98, 95% CI 1.10-8.08, p=0.032); increasing age (OR 1.10, 95% CI 1.04-1.15,
p<0.001).
The univariate predictors of acute myocardial infarction were pre-existing coronary artery disease (OR
5.0, 95% CI 1.45-17.03, p=0.011) and increasing age (OR 1.08, 95% CI 1.02-1.14, p=0.005).
MACCE were observed also after minor operations and not only in major surgery. From all, 5(3.8%)
adverse events ( including 2 strokes, 1 myocardial infarction, 1 decompensated heart failure, 1 atrial fibrillation)
occurred after pre-treatment evaluation of the distribution of the cancer using a panendoscopy examination as the only
form of surgery. All these patients were female (median age 65) having a history of tobacco and alcohol use but only
one of them had a history of coronary artery disease. MACCE was also detected after local resection in four cases
(Table 1), including one myocardial infarction and three decompensated heart failures.
Discussion
Decompensated heart failure and acute myocardial infarction were the most common cardiovascular complications in
this real world registry of patients undergoing head and neck cancer surgery. Increasing age and co-morbidities were
independent predictors of adverse events. Importantly, adverse cardiac and cerebrovascular events were detected in all
kinds of head and neck cancer operations and not only in major surgery.
In general, head and neck surgery patients have an intermediate (1-5%) risk of suffering cardiovascular
complications [1]. However, the risk appears higher (<5%) in patients undergoing head and neck surgery due to cancer
[2-3]. A relevant factor increasing the risk is the known association between thrombosis and cancer. Cancer patients
have increased risk for both venous and arterial thrombosis, because of the activation of coagulation and endothelial cell
damage [9-11]. Cancer related venous embolism is also associated with increased mortality and poor prognosis [12-13].
In our study, incidence of cardiac and cerebrovascular events was 7.2 %, which is in line with previous reports (7-13%)
[5]. We discovered only one venous thrombosis and one pulmonary embolism. The low number of these events can
originate from the heterogeneity of the cohort and to prompt mobilization of most patients after surgery. Our study
included all patients with head and neck cancer and the risk for cardiovascular complications in surgery varied from low
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to intermediate. When patients with extensive surgery with microvascular reconstruction were assessed separately the
complication rate was slightly higher (11.7%), but even the minor surgery, such as panendoscopy examination and local
resection, was not without risk of thrombotic complications. Events during and after minor head and neck oncologic
surgery can be explained by the cancer associated thrombosis [11] with possible influence of comorbidities.
Presence of comorbidities has proven to be an independent predictor of postoperative events and the
presence of two or more comorbidities has been associated with a higher overall postoperative complication rate [1415]. Hypertension is a strong risk factor for cardiac and cerebrovascular complications in the general population [16]. In
line with this information, coronary artery disease and hypertension were also significant risk factors for cardiac
complications in the present setting. Heavy smoking and alcohol abuse are common in patients with head and neck
cancer but were not independent risk factors for cardiovascular complications in this study.
Increasing age is a well-known risk factor for adverse cardiac events [5]. Previously, an age of over 70
years has been associated with a higher complication rate in head and neck surgery [5]. Similarly, we found that a oneyear increase in age increased the risk of cardiac complications by 8-10% and patients over 70 years of age had over 5fold risk of MACCE compared with younger patients. Nevertheless, old age by itself does not seem to be the only risk
factor for complications, but the various co-morbidities increasing with aging [17-18]. Pre-existing coronary artery
disease, chronic kidney disease and cancer are independent predictors of perioperative myocardial infarction [19-22].
Moreover, coronary artery disease and congestive heart failure were found to be the strongest independent risk factors
for myocardial infarction in a United States nationwide retrospective analysis of risk factors for in-hospital myocardial
infarction after total joint arthroplasty [19]. Patients with myocardial infarctation had significantly greater comorbidity
burden [19]. Simeoni et al (2015) recently reported that one-third of patients with head and neck squamous cell
carcinoma had clinically significant cardiac comorbidity [23].
The strong relationship between cancer and coagulation abnormalities and thrombosis is well
established [9-11, 24-26]. Venous thromboembolism occurs roughly in every fifth cancer patient [24], but there are also
other manifestations of a prothrombotic state [9-11]. In head and neck cancer patients Jagielska et al. [26] showed that
abnormal fibrinolysis was observed before treatment in all cases of locally advanced cancer (T3-T4). There was an
increased incidence of thrombotic events in our cohort of head and neck cancer patients. On the other hand routine use
of thromboprophylaxis seems to have no benefit in oncologic head and neck patients [27]. In line, the use of thrombosis
prophylaxis had no effect on incidence of MACCE in our study. On the contrary, LMWH seemed to be a risk factor for
MACCE, but this is explained by patient selection. Only patients undergoing major head and neck surgery had
prophylactic LMWH and the incidence of MACCE is higher in major surgery.
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Limitations
These findings need to be interpreted cautiously. This study has all the inherent limitations of an observational study
including individual risk based decision-making in the treatment choices. Nevertheless, the strength of this study is the
inclusion of unselected head and neck patients; we have included all the cancer patients and in the population that we
have to evaluate in real life too and try to identify the risk patients from that population. Because of the inclusion
criteria the heterogeneity of operations is high.
Conclusion
Prior coronary artery disease, increasing age and cancer itself are important risk factors for perioperative, and
postoperative cardiac and cerebrovascular complications after head and neck cancer operations. Importantly,
cardiovascular complications are not rare even in minor surgery. This study increases the knowledge of cardiac risk and
independent risk factors for patients undergoing head and neck cancer surgery. Further research is needed to discover
how to prevent MACCE.
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