The Nordic Consortium for Acute type A Aortic Dissection (NORCAAD): objectives and design^*

Abstract

Objectives. The Nordic Consortium for Acute Type A Aortic Dissection (NORCAAD) is a collaborative effort of Nordic cardiac surgery centers to study acute type A aortic dissection (ATAAD). Here, we outline the overall objectives and the design of NORCAAD. Design. NORCAAD currently consists of eight centers in Denmark, Finland, Iceland and Sweden. Data was collected for patients undergoing surgery for ATAAD from 2005 to 2014. A total of 194 variables were retrospectively collected including demographics, past medical history, preoperative medications, symptoms at presentation, operative variables, complications, bleeding and blood transfusions, need for late reoperations, 30-day mortality and long-term survival. Results. Information was gathered in the database for 1159 patients, of which 67.6% were male. The mean age was 61.5 ± 12.1 years. The mean follow-up was 3.1 ± 2.9 years with a total of 3535 patient years. Conclusions. NORCAAD provides a foundation for close collaboration between cardiac surgery centers in the Nordic countries. Substudies in progress include: short-term outcomes, long-term survival, time interval from diagnosis until operation, effects of surgical techniques, malperfusion syndrome, renal failure, bleeding and neurological complications on outcomes and the rate of late reoperations.

Keywords:

• Type A aortic dissection
• NORCAAD
• surgery
• outcome
• complications
• survival

Introduction

Acute type A aortic dissection involves the ascending aorta and to a varying degree the aortic arch and the descending aorta.[1] It is a life threatening condition, associated with high morbidity and mortality. Death and complications occur due to free rupture of the aorta, pericardial tamponade, acute aortic insufficiency together with critical end-organ malperfusion.[2]

According to the Centers for Disease Control and Prevention, diseases of the aorta and its branches account for 43,000 to 47,000 deaths annually in the United States.[3] Though the precise number of these deaths attributable to thoracic aortic diseases is unclear, the number of patients presenting with ATAAD are estimated to increase, given the longer life expectancy and increased prevalence of risk factors such as high blood pressure.[4] A nationwide population-based study from Sweden showed that the prevalence and the incidence for thoracic aneurysm or dissection increased by 52% in men and 28% in females from 1987 to 2002. During the same period of time, the number of operations for these diseases also increased, as did survival rates of patients undergoing associated surgery.[5] However, it is not clear whether the true incidence of aortic dissection is rising, or if the increase is related to improved diagnostics, increased awareness and/or higher rates of operations for the condition. In Iceland the incidence of thoracic aortic dissections did not change significantly from 1992 to 2013, but an increase in the proportion of patients that underwent an operation for ATAAD was observed.[1]

ATAAD requires immediate surgical intervention since the in-hospital mortality rate is unacceptably high without surgery.[6] Operations for ATAAD are among the most complex surgeries performed and associated complications (e.g. excessive postoperative bleeding, stroke and neurological changes, renal failure, respiratory failure and multiorgan failure) occur at a higher frequency than for elective open-heart operations. ATAAD patients are critically ill and the treatment causes strain on intensive care units (ICU) and hospital resources. Contemporary data from the International Registry of Acute Aortic Dissection (IRAD) shows, however, that the overall hospital mortality has decreased from 31% to 22% from 1995 to 2013, and many other centers have described similar reduction.[6–10]

The objective of this multicenter research project is to collect and combine the surgical outcome of ATAAD of several major cardiac surgery centers in the Nordic countries for the purpose of investigating specific areas of interest related to ATAAD.

Materials and methods

Centers

NORCAAD consists of eight cardiac surgery centers in Denmark, Finland, Iceland and Sweden. These include Aarhus University Hospital, Skejby, Denmark; Tampere University Hospital, Tampere, Finland; Turku University Hospital, Turku, Finland; Landspitali University Hospital, Reykjavik, Iceland; Karolinska University Hospital, Stockholm, Sweden; Örebro University Hospital, Örebro, Sweden; Sahlgrenska University Hospital, Gothenburg, Sweden; Skåne University Hospital, Lund, Sweden. The estimated population covered by participating centers is at least 9,500,000.

Data source

Data were collected independently by each participating center for all patients that underwent an operation for ATAAD from January 1, 2005 to December 31, 2014. ATAAD was defined as disruption of the media layer of the aorta with bleeding or hematoma formation within and along the wall of the ascending aorta resulting in separation of the aortic layers.[3] The operation had to occur within 2 weeks of diagnosis or occurrence of symptoms. Patients that underwent repair of a chronic dissection were excluded. All potential patient identifiers were blinded and each center obtained approval from their corresponding bioethics and data protection committees or commissions. As individual patients were not identified, obtaining individual consent for the study was waived.

Variables

A total of 194 variables were collected (Table 1) and an additional 53 variables were derived from the collected variables.

Table 1. Variables collected by participating NORCAAD centers.

	Essential	Non-essential
Demographics	Sex Age Day and time of admission Day and time of diagnosis	Day and time of first symptoms
Past medical history	Hypertension Known history of thoracic aortic aneurysm Connective tissue disease Bicuspid aortic valve Family history of dissection Family history of thoracic aneurysm History of type B dissection Diabetes mellitus Hyperlipidemia History of stroke History of transient ischemic attack Chronic kidney disease COPD Coronary artery disease Atrial fibrillation History of smoking Height Weight	Evidence of untreated hypertension Size of known aneurysm Location of aneurysm Prior aortic surgery Prior cardiac surgery History of vascular disease
Preoperative medications	Aspirin Clopidogrel Ticagrelor Warfarin Any antihypertensive medications	Fondaparinux Low molecular weight heparin Thrombolysis within 24 h of surgery Betablockers ACE inhibitors Angiotensin receptor II inhibitors
Clinical symptoms at presentation	Systolic blood pressure (SBP) Diastolic blood pressure (DBP) Acute chest and/or back pain Cardiogenic shock Initial SBP <90 mmHg Cardiopulmonary arrest 24 h prior to operation Hemopericardium at time of surgery Signs of pericardial tamponade Any malperfusion syndrome^a Cardiac malperfusion Gastrointestinal malperfusion Renal malperfusion Extremity malperfusion Cerebral malperfusion Spinal malperfusion DeBakey classification^b Intramural hematoma Iatrogenic dissection Penn Classification^c	Syncope
Methods of diagnosis	Primary imaging method Computed tomography (CT), Transthoracic echocardiogram (TTE) Transesophageal echo (TEE) Magnetic resonance imaging (MRI) Aortography Coronary catheterization	Additional imaging methods Largest diameter of aorta
Operative variables	Day and time of primary surgery Proximal repair AV resuspension + ascending graft Ascending graft replacement only Mechanical composite root Biological composite root Valve sparing root replacement Remodeling – ad modum Yacoub Reimplantation – ad modum David AVR + ascending (root not replaced) Ascending graft only (prior AVR) Distal repair Ascending aorta Hemiarch Total arch Additional aortic repair Aortic wrapping with mesh Intraluminal graft Suture of aortic layers only Elephant trunk Frozen elephant trunk Aortic valve annuloplasty Open distal anastomosis Hypothermic circulatory arrest (HCA) HCA techniques HCA only Antegrade cerebral perfusion Retrograde cerebral perfusion Combination of techniques Location of primary tear Excision of primary tear Additional procedures performed Operative time (skin to skin) Cardiopulmonary bypass time Cross-clamp time HCA time Lowest temperature of HCA Redo sternotomy Arterial cannulation sites  Femoral  Axillary/innominate  Ascending aorta’  Ventricle  Other Venous cannulation sites  Femoral  Right atrium  Bicaval  Other	Time interval First symptoms until surgery Admission to surgery Diagnosis until surgery Indication for root replacement Use of glue Use of felt Time of  Retrograde cerebral perfusion  Antegrade cerebral perfusion Use of neurocerebral monitoring
Postoperative complications^d	Reoperation for bleeding Revision of prior cardiac operation Deep sternal wound infection Renal replacement therapy (RRT) Respiratory failure Stroke Reoperation for bleeding Myocardial infarction/necrosis  CK-MB >70 μg/L, new Q wave,  interventricular conduction delays Stroke Transient neurological ischemia (TIA) Superficial sternal wound infection Deep sternal infection Postoperative mediastinitis Sternal dehiscence Septicemia Acute kidney injury (RIFLE)^e Ventilator support >48 h Tracheostomy Pneumonia Acute limb ischemia Cardiac arrest Cardiac tamponade Postoperative atrial fibrillation (POAF)	Interval time for reoperation Number of reoperations for bleeding Sternum left open for bleeding control Revision of primary operation Non-cardiac operation Coma for >24 h no sedation Focal neurological deficits Changes in mental status Delirium, agitation, confusion Lower extremity infection Urinary tract infection (UTI) Time on ventilator Number of reintubations Pulmonary embolism Pneumothorax Pleural effusion requiring drainage Heart block requiring pacemaker Anticoagulation complication Gastrointestinal complications Multisystem organ failure (MSOF) Gastrostomy or jejunostomy tube Deep venous thrombosis
Bleeding and blood transfusion	Bleeding for the first 24 h Transfusion requirement Packed red blood cells Platelets Fresh frozen plasma Fibrinogen Recombinant factor VIIa Tranexamic acid Aprotinin	Bleeding for the first 12 h Total bleeding volume
Laboratory test results	Highest value preoperative and postoperative  CK-MB  Serum creatinine  Lactate.
Outcome data	Survival status at time of discharge Survival 30 days after surgery Intraoperative death Day of discharge from hospital Mortality status on 31 December 2014 Alive Dead Unknown Day of death	Cause of death Cardiac Bleeding Neurological Other Unknown Length of stay in hospital Length of stay in intensive care unit
Echocardiography data		Preoperative aortic insufficiency (0–4) Preoperative ejection fraction (%) Postrepair aortic insufficiency Aortic insufficiency (0–4) on last echo
Reoperation data		Proximal reoperation Type of proximal operation AVR Root replacement Ascending graft Indication for proximal reoperation Severe aortic insufficiency Proximal pseudoaneurysm Endocarditis Graft infection Root aneurysm Other Date of proximal reoperation Distal reoperation Type of distal reoperation TAAA repair Hemiarch Total arch TEVAR Combination of TEVAR and other Indication for distal reoperation TAAA extent 1 TAAA extent 2 Distal pseudoaneurysm Graft infection Aneurysm undefined Date of distal reoperation Patient died following reoperation

Non-essentials variables were collected ad lib. COPD: chronic obstructive pulmonary disease; ACE: angiotensin-converting enzyme; AV: aortic valve; TAAA: thoracoabdominal aortic aneurysm, TEVAR: thoracic endovascular aneurysm repair.

^a Clinical malperfusion syndromes with documented dissection flap at or proximal to relevant organ system: Cardiac malperfusion (ST-changes, myocardial ischemia on echocardiogram or CK-MB >70 μg/L); Gastrointestinal malperfusion (mesenteric ischemia or ischemia of the liver); Renal malperfusion (anuria with documented occlusion of renal arteries); Extremity malperfusion (lack of pulses and loss of sensory or motor function of relevant extremity); Cerebral malperfusion (preoperative stroke with lateralizing symptoms or other neurological deficits); Spinal malperfusion (paraplegia).

^b DeBakey class I (Dissection involving ascending, arch, descending and abdominal aorta), DeBakey class II (Dissection involving ascending and arch only).[13]

^c Penn Class (A: No ischemia, B: Localizes ischemia, C: Generalized ischemia, B&C: Both localized and general ischemia).[14]

^d All complications apply to the time period between surgical repair of the dissection and discharge from the hospital and were defined as in the Society of Thoracic Surgeon dataset.[15]

^e RIFLE criteria (Risk >1.5× increase in s-creatinine, Injury >2.0× increase in s-creatinine, Failure >3.0× increase in s-creatinine, Loss – renal replacement therapy.[16]

Statistical methods

Data was collected in Microsoft Excel^® (Seattle, WA) from each center and then combined into a single database. Additional statistical analysis was performed in R (R Foundation for Statistical Computing, Vienna, Austria, http://www.R-project.org/) and then made available to participating centers in R, SPSS and STATA format. Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables as percentages. Odds ratio (OR) with 95% confidence interval (CI) were estimated with logistic regression. In NORCAAD substudies, specific statistical methods are applied to address risk factor analysis, short- and long-term survival and related issues.

Results

A total of 1159 operations were performed over the 10-year period at the participating institutions with a mean of 116 operations per year (SD 24.2, range 77–150). The total number of operations performed at each center during the study period ranged from 30 to 262 and were as follows: Tampere 62; Turku 62; Reykjavik 30; Karolinska 262; Skåne 227; Örebro 101; Sahlgrenska 243; Skejby 172. Combined number of operations performed at all centers per year increased from 85 in 2005 to 150 in 2014 (OR 1.130, 95%CI 1.103–1.157, p < .001) (Figure 1). The mean age at time of surgery was 61.5 ± 12.1 years and 67.6% of patients were male. Basic demographics and past medical history including sex, age, hypertension, bicuspid aortic valve, history of stroke and chronic obstructive pulmonary disease (COPD) were similar between different centers. The mean follow-up time was 3.1 ± 2.9 years with a total of 3535 patient years.

Figure 1. Annual number of operations performed for acute type A aortic dissection at each participating center from 2005 to 2014. Data was not available for Sahlgrenska University Hospital for the years 2005–2006.

For the entire combined database of collected variables 20.9% ± 24.7% had missing values. For essential variables the rate of missing values was 8.8% ± 13.8% of which the following had >5% missing values: Time of admission, family history of dissection and aneurysm, smoking, height, weight, hypotension on admission, systolic blood pressure (SBP), diastolic blood pressure (DBP), malperfusion (cardiac, gastrointestinal, renal, extremities, cerebral, spinal), techniques used during hypothermic circulatory arrest (HCA), operative time, cardiopulmonary bypass time, cross-clamp time, HCA time, lowest temperature of HCA, redo sternotomy, acute kidney injury (AKI), bleeding, blood transfusion variable and laboratory tests. For the remaining variables only 1.4% ± 1.3% had missing values.

Discussion

With the launching of NORCAAD, we have now created the third largest database on ATAAD. There are currently two large clinical databases on aortic dissection. The largest is the IRAD, an international registry of 30 centers in 11 countries containing over 3800 cases of acute aortic dissection.[6] The other is the German Registry for Acute Aortic Dissection Type A (GERAADA) that comprises 56 centers in Germany, Austria and Switzerland which started in 2006 and currently has over 3300 ATAAD cases.[11] We are of the opinion that there is a need for a Nordic database on ATAAD and that by combining the results of several Nordic centers we would not only create a large database, but also foster collaboration between Nordic cardiothoracic surgeons. Additional rationales and potential strengths of NORCAAD include similar health care systems in the Nordic countries, homogeneous populations of which long-term follow-up is nearly complete through centralized national identity registry, rather equivalent training systems for cardiothoracic surgeons. In the Nordic countries there are several centers of excellence in cardiac surgery and academic institutions that would provide resources for the different research projects. The weakness of NORCAAD is that of large registry study, and is mostly related to incomplete datasets and the fact that its catchment area includes less than half of the population of all the Nordic countries. Future versions of NORCAAD will involve more centers and thereby increase the number of cases captured significantly.

Despite the large volume of data published on ATAAD, detailed evidence related to operative treatment is still lacking. Registry such as NORCAAD will continue to advance the literature and hopefully contribute to improvement in the management of ATAAD. Clinical decision-making in regards to surgical techniques, related to the proximal and distal extent of the aortic replacement are needed but also conceptual frameworks involving the complex management of patients presenting with severe symptoms of malperfusion; should root-sparing or valve-sparing techniques be used instead of composite root replacement; and should distal anastomosis be performed as open anastomosis using hypothermic arrest or is less extensive repair with aortic cross-clamp sufficient?[12] What type of perfusion techniques should be used during HCA? More extensive operative techniques tend to be more complex and require more training and experience to be successfully performed. For various reasons (operator and team experience, urgency, local treatment traditions) conservative methods are sometimes favored over more extensive and complex approaches. The primary goal of operative treatment for ATAAD is survival of the patient, regardless of the operative technique used. Various aspects of intraoperative and postoperative care affect the high rates of postoperative complications that are observed following surgery for ATAAD. Operative techniques and ICU care has changed markedly over the last decade and contemporary information on temporal changes and actual rates of mortality and complications would aid physicians in the treatment of patients with ATAAD. To address these issues we have initiated several substudies of NORCAAD, led by different participating centers shown in Table 2. In some instances, these substudies will address the same issues that other large databases on ATAAD have addressed before, while other substudies will focus on previously less investigated fields. Each substudy is headed by a predefined participating center but will also involve active participation of surgeons, trainees and medial students from other centers to a varying degree. This will ensure active collaboration between participants of NORCAAD.

Table 2. Current NORCAAD research projects.

Projects
Short-term outcome and predictors of surgical mortality
Long-term survival and predictors of long-term survival
Role of surgical techniques, perfusion techniques on outcomes
Effects of malperfusion of specific organ systems on outcome
Effects of postoperative acute kidney injury on outcomes
Bleeding complications after ATAAD repair, role of prior antiplatelet therapy
Duration of symptoms, time until surgery and it effects on outcome
Distal and proximal late reoperations
Neurological complications following ATAAD repair
Difference in outcome between male and females

ATAAD: acute type A aortic dissection.

In the current edition, the cost of data collection is covered by each participating center and surgeons. The future objectives for NORCAAD are to develop a prospective online data collection with expanded collection of operative variables and to include other large Nordic cardiothoracic centers that have not been able to participate at this time. That will require more substantial funding and comes with its unique regulatory challenges to ensure patient confidentiality and data protection. Additional validity checking will also be required to ensure more uniform and complete data collection than the current NORCAAD provided.

In summary, ATAAD remains a highly complex disease, often difficult to diagnose and challenging to treat. Untreated it is highly lethal and even if expeditiously diagnosed and appropriately managed, both short- and long-term morbidity and mortality remain high mandating investigating ways to further improve its outcomes. There still remain numerous unanswered questions related to the management of ATAAD. The recently developed NORCAAD aims to provide contemporary information on the outcomes of the operative treatment of ATAAD with specific interest in the Nordic countries. It will hopefully enhance our knowledge of this complex disease in addition to foster collaboration and collegiality among Nordic cardiothoracic surgeons.

Acknowledgement

The following individuals also contributed to the study: Erik Björklund MD, Josefine Carrell RN, Erik Herou MD, Sigrun H. Lund PhD, Inga H. Melvinsdottir MD, Emily Pan BM and Johan Sjögren MD PhD.

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.