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Population-Based Assessment of the Incidence of Aortic Dissection, Intramural Hematoma, and Penetrating Ulcer, and Its Associated Mortality From 1995 to 2015

Originally publishedhttps://doi.org/10.1161/CIRCOUTCOMES.118.004689Circulation: Cardiovascular Quality and Outcomes. 2018;11:e004689

    Abstract

    Background

    Aortic syndromes (ASs), including aortic dissection, intramural hematoma, and penetrating aortic ulcer, carry significant acute and long-term morbidity and mortality. However, the contemporary incidence and outcomes of AS are unknown.

    Methods and Results

    We used the Rochester Epidemiology Project record linkage system to identify all Olmsted County, MN, residents with AS (1995–2015). Diagnostic imaging, medical records, and death certificates were reviewed to confirm the diagnosis and AS subtype. Age- and sex-adjusted incidence rates were estimated using annual county-level census data. Survival for patients with AS was compared with age- and sex-matched controls using Cox regression to adjust for comorbid conditions. We identified 133 patients with AS (77, aortic dissection; 21, intramural hematoma; and 35, penetrating aortic ulcer). Average age was 71.8 years (SD=14.1), and 57% were men. The age- and sex-adjusted incidence was 7.7 per 100 000 person-years, was higher for men than women (10.2 versus 5.7 per 100 000 person-years), and increased with age. Among subtypes, the incidence of aortic dissection was highest (4.4 per 100 000 person-years), whereas the incidence of penetrating aortic ulcer and intramural hematoma was lower (2.1 and 1.2 per 100 000 person-years). Overall, the incidence of AS was stable over time (P trend=0.33), although the incidence of penetrating aortic ulcer seemed to increase from 0.6 to 2.6 per 100 000 person-years (P=0.008) with variability over the study interval. Patients with AS had more than twice the mortality rate at 5, 10, and 20 years when compared with population-based controls (5-, 10-, and 20-year mortality 39%, 57%, and 91% versus 18%, 41%, and 66%; overall adjusted mortality hazards ratio=2.1; P<0.001). Survival was lower than expected up to 90 days after AS diagnosis and did not differ significantly by subtype or by 5-year strata of diagnosis.

    Conclusions

    Overall, the incidence of aortic dissection and intramural hematoma has remained stable since 1995, despite the decline noted for other cardiovascular disease. AS confers increased early and long-term mortality that has not changed. These data highlight the need to improve long-term care to impact the prognosis of this patient group.

    Introduction

    WHAT IS KNOWN

    • Aortic dissection (AD), intramural hematoma, and penetrating ulcer are associated with significant aortic-related mortality and morbidity.

    • Historical estimates suggest an incidence of AD of 3.5 per 100 000 person-years, but this is from data collected before 1995.

    WHAT THE STUDY ADDS

    • This study defines the contemporary incidence of AD, intramural hematoma, and penetrating aortic ulcer using a population-based approach.

    • The incidence of AD and intramural hematoma has remained stable from 1996 to 2015, and the incidence of penetrating aortic ulcer may be increasing.

    • AD, intramural hematoma, and penetrating ulcer confer significant acute (within 14 days of diagnosis) and subacute (up to 90 days) mortality compared with population controls.

    Aortic syndromes (ASs) include aortic dissection (AD), intramural hematoma (IMH), and penetrating aortic ulcer (PAU) and represent an injury to the inner aortic layers resulting in emergent aortic pathology. These are highly morbid diagnoses that carry significant acute and long-term mortality risks. Acute dissections of the ascending aorta (Stanford A) carry a mortality that historically approaches 1% per hour.1 Although less morbid, acute dissections of the descending thoracic aorta (Stanford B) are associated with a 10% to 25% mortality at 30 days.2 IMH mortality ranges from 10% to 50%, and 40% of the patients progress to overt dissection.2

    Despite the known morbidity of these pathologies, the current epidemiology of them is unknown. Our knowledge of the epidemiology of these diseases in the United States is derived from data collected from 1980 to 1994, with a population-based reported incidence of AD of 3.5 per 100 000 person-years.3 However, our current understanding of the presentation, treatment patterns, and outcomes is predominantly from registries at large referral centers,4 claims data,5,6 or single-center series that are more center based. Advances in the prevention and treatment of cardiovascular disease have resulted in a decline of acute myocardial infarction (MI)7 and abdominal aortic aneurysm.8,9 However, it is unknown if there has been a concurrent decline in the incidence of these pathologies. Limited data from Sweden suggest that the incidence of AD has increased,10 yet no current data exist on the incidence of AS in the United States.

    The purpose of this study was to measure the contemporary incidence of AS using a geographically defined population within Southeast Minnesota and to assess their survival compared with the expected survival of community controls.

    Methods

    Olmsted County is relatively isolated from other urban/suburban centers with only a few medical providers. These include Mayo Clinic and Olmsted Medical Center and their affiliated clinics. Because of the unique isolated nature of the region and few providers, billing data on all medical services are collated through the Rochester Epidemiology Project (REP).11,12 This enables identification of incident diagnosis of medical conditions and permits review of treatments, evaluations, autopsy reports, and death certificates for decedents. We assembled a cohort of people with AS among adults (≥18 years of age) residing in Olmsted County, MN. The Mayo Clinic and Olmsted Medical Center Institutional Review Boards approved this study. In addition, per Minnesota statutes, each patient identified with AS had provided authorization for the use of their medical record for research. No patients with AS were excluded because of lack or research authorization. The data cannot be made public because all residents were located in a specific Minnesota County. Any geographic subdivision smaller than a state cannot be deidentified according to the Health Insurance Portability and Accountability Act of 1996 definition of protected health information.

    Identification of Incident Cohort and Controls

    All unique patients with diagnosis code for AD, IMH, or PAU using the International Classification of Diseases (ICD), Ninth Revision diagnosis code (441.0–441.9), equivalent ICD-10 codes (I71.00–I71.03, I71.1–I71.6, I71.8, and I71.9, for October–December 2015) or Hospital Adaptation of the International Classification of Diseases, Second Edition (a modification of the ICD-8)13 from REP providers were obtained from inpatient and outpatient encounters (1995–2015). All patient charts were reviewed, including clinical data, imaging, autopsy reports, and death certificates to verify the diagnosis of AS. All patients were confirmed residents of Olmsted County at time of diagnosis to allow a true population-based assessment of incidence. For diagnosis, patients were required to have imaging confirmation of AS (computed tomography with arterial contrast, magnetic resonance imaging, ultrasound, or conventional angiography), primary diagnosis of AS on their death certificate, or autopsy confirmation of AS. Categorization of AS was based on standard criteria; acute AD was defined as an intimal tear with the presence of a false lumen. IMH was defined as crescent or circular thickening of the aortic wall without an intimal tear or dissection. PAU was defined as a focal lesion of the aorta with erosion of the intima and the absence of IMH or dissection.14 AD was classified using the DeBakey and Stanford Classification systems, and IMH classified with the Stanford system based on the involved portion of the aorta.14 In instances of uncertainty about the classification of AS based on imaging review, a vascular radiologist (Dr Macedo) reviewed the imaging to render a final determination. If >1 aortic pathology was identified, primary categorization was based on the most severe pathology (AD>IMH>PAU). Additional pathologies were captured for further characterization. To ensure capture of all AS events, we also screened patients diagnosed with atherosclerosis of the aorta (ICD-9 440.0). A random 5% sample was reviewed, and only 1 PAU was identified (0.4%) of all screened patients; no further screening was performed. Patients were categorized according to the interval between onset of symptoms and diagnosis. Presentations were defined as acute (symptom onset within 14 days of diagnosis), subacute (symptom onset 15–90 days before diagnosis), chronic (symptom onset >90 days before diagnosis), or unknown (if the exact date of symptom onset was never identified). For patients for whom onset of symptoms was not clearly documented, or whose pathology was asymptomatic (eg, PAU), the date the pathology was identified was considered the incident date.

    We obtained 2 sets of population controls to assess the impact of AS on mortality. First, we used the expected survival of age- and sex-adjusted white residents of Minnesota (population controls), as the population in Olmsted County is predominantly white. Second, we randomly selected 3:1 Olmsted County residents as a control cohort (resident controls). On the basis of survival data for Olmsted County residents and those with AD, we calculated that a 3:1 matching ratio of controls to cases with an α of 0.05 and power of 0.8% would detect a minimum hazard ratio for death of 1.95. Resident controls were matched for birth year and sex to cases, and their charts were reviewed to confirm that no diagnosis of AS was present. As with AS cases, mortality and cause of death were ascertained in a similar manner.

    The Charlson comorbidities were obtained for AS cases and resident controls. Assignment of comorbidities used a refined algorithm that required 2 episodes of a diagnosis within the 5 years before the date of AS diagnosis as done previously within the REP.15 For resident controls, their matched AS case diagnosis date was used as the anchor date from which to base preexisting comorbid conditions and define long-term events.

    Assessment of Mortality

    Mortality was assessed through 2 mechanisms. First, the REP data sources were queried for mortality status, and the death certificates were reviewed for cause. This included aortic related (because of acute complications from AS or treatment of AS), cardiovascular related (MI, congestive heart failure, or stroke related), or because of other reasons. Second, vital status and death date information was queried using an institutionally approved fee-based Internet research location service (Accurint, accurint.com) to ensure that vital status was complete for all cases and resident controls. This service queries multiple databases for assessment of mortality and retrieval of death certificates. If death occurred outside Minnesota, death certificates were retrieved as permissible by the vital records statutes within the state in which the decedent passed away. Of all cases, 3 deaths occurred out of state, and the death certificates could not be obtained.

    Statistical Analysis

    The incidence rates were estimated based on the number of new cases of AS in age-specific, sex-specific, and calendar year–specific stratum (numerator). The corresponding denominators were derived from annual census figures of Olmsted County, MN, population (aged ≥18 years) from 1990, 2000, and 2010 US census, with linear interpolation for the intercensal years, assuming that the entire adult population was at risk. Incidence is reported as age- and sex-adjusted rates per 100 000 person-years, based on direct standardization against the 2010 US white population, with 95% CIs estimated using the Poisson distribution.11 Multivariable Poisson regression modeling assessed the association of calendar year on incidence rate over the study period, adjusted for age and sex. Survival was evaluated as time to event and displayed as Kaplan-Meier curves. The association of AS diagnosis on mortality was assessed by a stratified Cox proportional hazards modeling adjusting for age, sex, and Charlson comorbidity score to account for the case/control design. Patients with an autopsy diagnosis of AS were assigned a survival of 0 days. Survival was also evaluated by AS subtype and 5-year epoch. Univariate associations of baseline characteristics with type of AS were made using ANOVA for continuous variables across the 3 groups, and χ2 was used for categorical variables (with Fisher exact correction as needed for low event rates). Standardized mortality ratios were calculated using the observed versus expected risk of death based on age and sex of the study population with the risk of death among similar patients in Minnesota resident life tables.15 For statistical comparisons, a P value <0.05 was considered significant. Statistical analyses were performed with STATA (College Station, TX) and SAS (Cary, NC).

    Results

    Over the study interval, we identified 133 cases of AS (77 AD, 21 IMH, and 35 PAU). Overall, patients were predominantly white (86.5%) and men (57.1%). Mean age was 71.8 years (SD=14.1, range 28–93) and was lowest for AD and highest for PAU. Overall, 59.4% presented acutely, 3.0% presented subacute, 2.3% presented chronic, and 35.3% had an unknown event date before diagnosis and otherwise would constitute a chronic presentation (Table 1). Stanford A classification was most common for AD (58.4%), but Stanford B was more common for IMH (76.2%). Diagnosis was predominantly by computed tomography scan for all subtypes; however, echocardiography was more frequent in patients with AD. Other details of presentation are presented in Table 1. Diagnosis was on autopsy for 6 patients (4.5%), all of which were after acute AD.

    Table 1. Baseline Characteristics of Incident Aortic Syndrome Cohort

    TotalADIMHPAUP Value
    (N=133)(N=77)(N=21)(N=35)
    Age, y, mean (SD)71.8 (14.1)68.9 (15.6)73.5 (11.5)77.1 (10.0)0.01
    Sex (men)76 (57.1%)46 (59.7%)11 (52.4%)19 (54.3%)0.77
    Ethnicity0.01
     Hispanic/Latino2 (1.5%)2 (2.6%)0 (0.0%)0 (0.0%)
     Not Hispanic/Latino119 (89.5%)63 (81.8%)21 (100.0%)35 (100.0%)
     Unknown12 (9.0%)12 (15.6%)0 (0.0%)0 (0.0%)
    Race0.15
     White115 (86.5%)64 (83.1%)18 (85.7%)33 (94.3%)
     Unknown11 (8.3%)10 (13.0%)1 (4.8%)0 (0.0%)
     Black3 (2.3%)1 (1.3%)1 (4.8%)1 (2.9%)
     Asian3 (2.3%)1 (1.3%)1 (4.8%)1 (2.9%)
     Hawaii/Pacific Island1 (0.8%)1 (1.3%)0 (0.0%)0 (0.0%)
    Acuity of diagnosis<0.01
     Acute79 (59.4%)52 (67.5%)17 (81.0%)10 (28.6%)
     Subacute4 (3.0%)2 (2.6%)1 (4.8%)1 (2.9%)
     Chronic3 (2.3%)2 (2.6%)0 (0.0%)1 (2.9%)
     Unknown47 (35.3%)21 (27.3%)3 (14.3%)23 (65.7%)
    Other clinical features at presentation
     Malperfusion6 (4.5%)5 (6.5%)1 (4.8%)0 (0.0%)0.36
     Rupture12 (9.0%)9 (11.7%)2 (9.5%)1 (2.9%)0.36
     Coronary ischemia7 (5.3%)5 (6.5%)2 (9.5%)0 (0.0%)0.24
     Cardiac tamponade10 (7.5%)10 (13.0%)0 (0.0%)0 (0.0%)0.02
     Aortic valve insufficiency14 (10.5%)14 (18.2%)0 (0.0%)0 (0.0%)<0.01
    Blood pressure at presentation
     Systolic139.2 (33.3)136.8 (34.8)139.7 (35.3)143.6 (29.0)0.62
     Diastolic73.6 (16.8)74.6 (19.0)71.1 (17.2)73.1 (11.6)0.70
    Shock at presentation8 (6.3%)7 (9.9%)1 (4.8%)0 (0.0%)0.14
    BMI27.5 (6.8)27.4 (6.7)28.8 (7.1)26.9 (6.7)0.60
    Medications at presentation
     Aspirin58 (43.6%)28 (36.4%)12 (57.1%)18 (51.4%)0.13
     β blocker53 (39.8%)28 (36.4%)11 (52.4%)14 (40.0%)0.41
     ACEI/ARB43 (32.3%)21 (27.3%)9 (42.9%)13 (37.1%)0.31
     Statin42 (31.6%)21 (27.3%)6 (28.6%)15 (42.9%)0.25
    Laboratory values at presentation
     Hemoglobin12.7 (2.0)13.3 (1.9)12.1 (1.9)12.0 (1.9)<0.01
     Creatinine1.3 (1.2)1.4 (1.6)1.1 (0.3)1.2 (0.4)0.44
     INR1.3 (0.6)1.3 (0.6)1.3 (0.6)1.3 (0.6)0.96
     Platelets214.6 (85.6)207.7 (69.3)220.3 (112.3)225.0 (98.2)0.61
     PTT37.0 (34.7)31.9 (16.3)50.9 (66.4)34.1 (14.5)0.25
    Risk factors
     Bicuspid aortic valve3 (2.3%)1 (1.3%)1 (4.8%)1 (2.9%)0.38
     Aortic atherosclerosis111 (83.5%)57 (74.0%)20 (95.2%)34 (97.1%)<0.01
     Prior aortic dilatation64 (51.6%)36 (50.7%)13 (68.4%)15 (44.1%)0.23
     Connective tissue disorder8 (6.0%)8 (10.4%)0 (0.0%)0 (0.0%)0.18
     Iatrogenic7 (5.3%)6 (7.8%)1 (4.8%)0 (0.0%)0.11
     Prior aortic surgery14 (10.5%)8 (10.4%)2 (9.5%)4 (11.4%)0.97
    Diagnostic modality
     ECHO15 (11.3%)13 (16.9%)2 (9.5%)0 (0.0%)0.01
     CT105 (78.9%)53 (68.8%)19 (90.5%)33 (94.3%)<0.02
     MRI4 (3.0%)2 (2.6%)0 (0.0%)2 (5.7%)0.62
     Angiography3 (2.3%)3 (3.9%)0 (0.0%)0 (0.0%)0.32
    Stanford class
     A45 (58.4%)5 (23.8%)<0.01
     B32 (41.6%)16 (76.2%)
    DeBakey class
     I24 (31.2%)
     II21 (27.3%)
     IIIa8 (10.4%)
     IIIb24 (31.2%)

    ACE inhibitors indicates angiotensin-converting enzyme inhibitors; AD, aortic dissection; ARB, angiotensin receptor blockers; BMI, body mass index; CT, computed tomography; ECHO, echocardiography; IMH, intramural hematoma; INR, international normalized ratio; MRI, magnetic resonance imaging; PAU, penetrating aortic ulcer; and PTT, partial thromboplastin time.

    The overall age- and sex-adjusted incidence of AS was 7.7 per 100 000 person-years (95% CI, 6.4–9.0). There was no significant change in incidence over the study interval. We observed the lowest age- and sex-adjusted rate of 6.4 per 100 000 person-years from 2005 to 2009 and a high of 9.8 in both the 2000 to 2005 and 2010 to 2015 (P=0.33) time periods. The overall age- and sex-adjusted incidence of AD, IMH, and PAU was 4.4 (95% CI, 3.4–5.3), 1.2 (95% CI, 0.7–1.8), and 2.1 (95% CI, 1.4–2.7) per 100 000 person-years, respectively. The incidence of AD and IMH was stable. Although the incidence of PAU increased significantly from 0.6 to 2.6 per 100 000 person-years (P=0.008), this occurred in the setting of significant variability over the study interval (Table 2). AS was most common in men and those >70 years of age (Table 3). Compared with county controls, those with AS had a higher prevalence of prior MI, peripheral vascular disease, chronic obstructive pulmonary disease, and chronic liver disease. Patients with AS had a higher Charlson comorbidity index compared with resident controls (2.6 versus 1.7; P<0.001) at the time of diagnosis (Table 4).

    Table 2. Incidence of Aortic Syndrome and Subtypes in Olmsted County Minnesota From 1995 to 2015

    Overall (1995–2015)1995–19992000–20042005–20092010–2015P Value*
    Incidence95% CIIncidence95% CIIncidence95% CIIncidence95% CIIncidence95% CI
    AS
    Overall (age/sex adjusted)7.676.36–8.978.55.39–11.689.796.61–12.986.444.05–8.8359.786.71–12.870.33
    Women (age adjusted)5.694.20–7.196.783.18–10.386.653.24–10.064.942.13–7.757.263.69–10.84
    Men (age adjusted)10.247.89–12.589.894.81–14.9713.897.95–19.828.674.36–12.9713.497.90–19.08
    Aortic dissection
    Overall (age/sex adjusted)4.373.38–5.354.363.93–9.506.7152.22–6.354.291.83–5.395.253.008–7.500.21
    Women (age adjusted)3.071.98–4.163.072.12–8.515.312.38–9.552.470.48–4.503.721.13–6.31
    Men (age adjusted)5.864.14–7.605.863.29–12.247.770.48–4.455.971.92–8.467.533.38–11.69
    Intramural hematoma
    Overall (age/sex adjusted)1.240.70–1.771.230.02–2.441.170.02–2.311.170.14–2.201.980.61–3.360.66
    Women (age adjusted)0.990.61–2.400.950.00–2.271.060.00–2.521.20.00–2.791.240.00–2.65
    Men (age adjusted)1.500.38–1.621.430.00–3.421.260.00–3.011.160.00–2.562.850.33–5.37
    Penetrating aortic ulcer
    Overall (age/sex adjusted)2.061.38–2.750.590.00–1.424.342.20–6.481.650.43–2.882.560.97–4.14<0.01
    Women (age adjusted)1.620.82–2.430.5140.00–1.523.130.78–5.481.250.00–2.672.290.27–4.31
    Men (age adjusted)2.881.57–4.180.690.00–2.056.662.26–11.052.30.03–4.603.100.35–5.86

    P values for overall trend from 1995–2015. AS indicates aortic syndrome.

    *Poisson model including age, sex, and calendar year of diagnosis; the P value is the significance of a calendar year change in incidence over the time interval.

    Table 3. Unadjusted Rates of Aortic Syndrome Across Age and Sex Strata in Olmsted County Minnesota From 1995 to 2015

    Age GroupIncidence Rate (Per 100 000 Person-Years)
    MenWomenTotal
    18–490.940.620.78
    50–596.491.684.02
    60–6912.728.0010.25
    70–7940.4826.3832.71
    80+62.9632.8243.14
    Total7.585.296.39

    Table 4. Charlson Comorbidities for Aortic Syndrome Cases and Controls in Olmsted County

    Charlson ScoresCaseControlTotal
    (N=133)(N=399)(N=532)P Value
    Prior myocardial infarction19 (14.3%)13 (3.3%)32 (6.0%)<0.01
    Congestive heart failure24 (18.0%)45 (11.3%)69 (13.0%)0.04
    Peripheral vascular disease54 (40.6%)56 (14.0%)110 (20.7%)<0.01
    Cerebrovascular artery disease26 (19.5%)53 (13.3%)79 (14.8%)0.08
    Dementia9 (6.8%)23 (5.8%)32 (6.0%)0.67
    COPD31 (23.3%)58 (14.5%)89 (16.7%)0.02
    Gastric ulcer7 (5.3%)10 (2.5%)17 (3.2%)0.12
    Chronic liver disease11 (8.3%)15 (3.8%)26 (4.9%)0.04
    Diabetes mellitus without complications23 (17.3%)75 (18.8%)98 (18.4%)0.69
    Rheumatic or connective tissue disease7 (5.3%)20 (5.0%)27 (5.1%)0.91
    Diabetes mellitus with end organ complications6 (4.5%)23 (5.8%)29 (5.5%)0.58
    Hemiplegia5 (3.8%)2 (0.5%)7 (1.3%)<0.01
    Renal insufficiency18 (13.5%)32 (8.0%)50 (9.4%)0.06
    Prior malignancy26 (19.5%)80 (20.1%)106 (19.9%)0.90
    Moderate/severe liver disease1 (0.8%)2 (0.5%)3 (0.6%)1
    Metastatic solid tumor5 (3.8%)8 (2.0%)13 (2.4%)0.33
    AIDS0001
    Charlson comorbidity index2.6 (2.6)1.7 (2.1)1.9 (2.3)<0.01

    COPD indicates chronic obstructive pulmonary disease.

    Over a median follow-up of 10.1 years, 73 deaths occurred in our AS cohort and 144 in Olmsted County controls. Mortality in cases was predominantly aortic related (32%); cardiovascular-related death occurred in 29%, whereas 40% were because of other causes (8 cancer related, 2 respiratory related, 16 from other causes, and 3 unknown). Overall, survival was significantly lower for patients with AS compared with Olmsted County age- and sex-matched controls (resident controls), P<0.001, with median survivals of 7.3 and 14.7 years, respectively. Survival after diagnosis of AS was significantly lower than controls, both from the Olmsted County resident controls and from the expected survival of Minnesota residents (population controls; Figure 1). The 1-, 5-, 10-, and 20-year survival for those with AS was 81%, 61%, 43%, and 9% compared with Olmsted County resident controls, 97%, 82%, 59%, and 34% (P<0.001) or expected survival of Minnesota white population controls (95%, 78%, 54%, and 27%; P<0.001). In a model including the case status along with age, sex, and Charlson comorbidity score, the adjusted hazard ratio for death for patients with AS compared with Olmsted County resident controls was 2.1 (95% CI, 1.6–2.9; P<0.001). Given the high acute mortality after diagnosis, we also analyzed long-term survival excluding deaths within 14 days of diagnosis (follow-up started day 15, which removed 15 patients from the analysis), including the same additional variables in the model. AS was still associated with an increased age- and sex-adjusted risk for death when eliminating acute mortality compared with Olmsted County controls (hazard ratio, 1.8; 95% CI, 1.3–2.5; Figure 2). Survival was not different between AD, IMH, or PAU (P=0.82; Figure 3) or between years of diagnosis (5-year increments; P=0.92; Figure 4).

    Figure 1.

    Figure 1. Survival for patients with aortic dissection, intramural hematoma, or penetrating ulcer compared with population controls. Cases, aortic syndrome patients; controls, matched Olmsted County controls; expected, Minnesota white population. Log-rank for cases vs controls P<0.001, cases vs expected P<0.001. SE<10%.

    Figure 2.

    Figure 2. Survival for patients with aortic dissection, intramural hematoma, or penetrating ulcer compared population controls removing deaths <14 d after diagnosis. Cases, aortic syndrome patients; controls, match Olmsted County Controls; expected, Minnesota white population. Log-rank for cases vs controls P<0.001, cases vs expected P<0.001. SE<10%.

    Figure 3.

    Figure 3. Survival after diagnosis of aortic dissection, intramural hematoma (IMH), and penetrating aortic ulcer (PAU). Log-rank P=0.87. Dotted lines represent SE>10%.

    Figure 4.

    Figure 4. Survival after diagnosis for patients with aortic dissection, intramural hematoma, or penetrating ulcer over time from 1995 to 2015. Log-rank P=0.73. Dotted lines represent SE>10%.

    To assess mortality risk of AS after diagnosis at various time intervals, standardized mortality ratios were calculated in patients with AS compared with similar age and sex residents of Minnesota. Patients with AS had increased risk of death at 0 to 14 days from diagnosis (standardized mortality ratio, 66.8; 95% CI, 37.4–110.18) and 15 to 90 days (4.4; 95% CI, 1.42–10.24) and 1 to 2 years (2.36; 95% CI, 1.18–4.22; Figure 5).

    Figure 5.

    Figure 5. Standardized mortality rates after diagnosis of aortic dissection, intramural hematoma, or penetrating ulcer. Left-sided y-axis rates for 0 to 14d after diagnosis. Right-sided y-axis values for 15 d and beyond.

    Discussion

    In this population-based assessment of AS, the incidence of AS has remained stable since 1995 at 7.7 per 100 000 person-years in Olmsted County, despite the known reduction in several cardiovascular diseases. Additionally, the incidence of AD and IMH has remained stable, and the incidence of PAU seems to have increased during that interval. The incidence of AS is higher for men (nearly 2-fold) and those >70 years of age. Compared with local controls, patients with AS have higher rates of cardiac and vascular disease and chronic obstructive lung disease and carry a higher comorbidity burden than controls. Median survival after AS was 7.3 years and was lower than both population and resident control patients. Even with adjustment for acute mortality, long-term survival remained lower for patients with AS, and a dramatic increased risk of death extends to 90 days from diagnosis. Finally, there seems to be no obvious survival improvement after AS over time in our cohort. With these data, future work can focus on defining targets to improve the prognosis of these aortic pathologies.

    The publication of the incidence of acute AD by Clouse et al3 from 1980 to 1994 reported an age- and sex-adjusted incidence of 3.4 per 100 000 person-years (95% CI, 2.4–4.6) based on the 1990 US white populations. In our study, which reported incidence from 1995 to 2015, we saw a similar incidence of acute dissection (4.4 per 100 000 person-years), suggesting little change in the incidence of this disease since 1980. Although Clouse et al3 noticed an increasing trend in the incidence of AD (that did not reach significance), we did not see any notable increase in our population over the past 20 years. Only PAU had an increase in incidence, predominantly because of a sharp rise from 1995 to 1999 to the later years. However, there was a peak from 2000 to 2004 and then subsequent decrease after this. Because of few events and this variability, it is difficult to definitely conclude that PAU incidence is increasing. It is also unclear the cause for this apparent increase. One hypothesis may be increased axial imaging and the incidental identification of asymptomatic PAU. However, mortality for this pathology remained similar over time, symptomatic presentation was similar over time (40%), and the distribution of acute presentations was also similar over time (29%). Thus, our data do not support the hypothesis that we identified more asymptomatic disease. Symptomatic PAU has historically been included in the description of acute aortic pathologies because of its potential for symptoms and development of IMH. However, it is a distinct pathology from AD and IMH. As a chronic atherosclerotic process, the contributors to PAU are likely to be more centered on atherosclerotic risk factors. In contrast, AD and IMH are more related to structural and genetic factors. Further research on these patients is necessary to identify the cause for this rise in incidence compared with AD and IMH.

    The finding that overall AS incidence is stable contrasts sharply with what has been observed for other cardiovascular diseases. In particular, the incidence of coronary artery disease and abdominal aortic aneurysms is declining.9,16 One of the key drivers for the decline in coronary disease and abdominal aortic aneurysm likely is the concomitant decline in smoking among adults.8 Interestingly, the association between tobacco use and AS is less established, and our finding may suggest that it has a small impact on the development of AS. Within the same geographic region (Olmsted County, MN), major changes in the epidemiology of MI have been reported. From 1987 to 2006, there has been a decline in the incidence of ST-segment–elevation MI, a decrease in the severity of infarction, and improvements in mortality after MI.7 Similar trends have been reported in other settings,1719 and the discrepancy with the trends for AS was unanticipated. Lead time bias could be hypothesized, whereby more asymptomatic or incidental disease is identified. As discussed above, increased computed tomography imaging that identifies more disease would explain our stable incidence, if this were true. Yet, we see similar mortality trends over the study interval. This would suggest that we continue to identify patients with similar acuity and prognosis and are likely not identifying a greater proportion of patients with less severe or morbid disease. With unchanged acuity or long-term hazards of AS over time, it is likely that the incidence has remained stable. AD has several known nonmodifiable risk factors, such as bicuspid aortic valve, connective tissue disease, and chromosomal abnormalities, and these would not be expected to alter with atherosclerotic disease trends. However, few patients had these risk factors identified in the medical record. Further understanding of modifiable and nonmodifiable risk factors is needed to identify targets to reduce the incidence of AS. Further work on family trees and potential genetic triggers for aortic disease in this cohort is planned to try to determine the role that genetics may play across all 3 pathologies.

    Epidemiology data on thoracic aortic pathology are scarce in the literature. One of the only other recent epidemiological studies on AD and aneurysms came from the Swedish national healthcare registry.10 Our data differ from those in Sweden that suggest that the incidence of thoracic aortic pathology (dissection and aneurysm) has increased from 1987 to 2002. Although their study interval differs slightly from ours, they demonstrated a rise in the incidence in men by 52% (10.7–16.3 per 100 000 person-years) and women by 28% (7.1–9.1 per 100 000 person-years). Comparison to our data is difficult because they did not report the specific incidence of AD; however, they report a similarly high rate of aortic-related deaths (39%). In addition, 31% of long-term deaths were because of cardiovascular disease. This is similar to our findings. Thus, aortic-related events are the most prevalent cause for acute mortality and long-term death. The proclivity for AS to result in long-term aortic pathology is well known. Approximately 50% of patients will have aortic growth after acute Stanford B dissection, and over 25% will need intervention.20 Although lifetime blood pressure control has been the historic treatment paradigm after presentation, alternative treatment may be needed to improve these results. Thoracic endovascular aortic repair may improve long-term outcomes and could represent such an option.21 However, further work is needed to define what the optimal care for these patients should be beyond initial diagnosis and acute treatment.

    On the basis of historical data, the increased mortality associated with AD was noted to be within 14 days and has defined the acute period.1 We confirmed that there is an excessive mortality risk in the acute (<14 day) time period for those with AS. However, we also noted an increased risk of death to 90 days, and this confirms that the subacute phase of these pathologies carries additional mortality risk. After this, mortality risk seems to be similar to the general population, with the exception of 1 and 2 years postdiagnosis. This may be because of interventions performed or other cardiovascular events occurring at later times. Future work will look to define why this was observed, as we study fatal and nonfatal cardiovascular and aortic-related events for this cohort.

    Our study has several limitations that should be acknowledged to aid in the interpretation of the results. The generalizability of our data is limited by the demographical characteristics of Olmsted County, notable a predominantly white population. However, prior data have shown that age, sex, and ethnic characteristics of Olmsted County are similar to those of Minnesota and the upper Midwest. Additionally, mortality among Olmsted County is similar to the United States overall.22 We did note that the mortality rate of resident controls was better than the Minnesota white population, and this suggests that residents in Olmsted County may be slightly healthier than state residents overall. Although we have tried to identify all possible cases, there may be patients with sudden death who did not undergo autopsy that would have been missed. Last, we have been inclusive in all dissection cases (including iatrogenic) to define the total incidence of the clinical pathology in our population beyond only spontaneous cases.

    Our study is strengthened by the fact that this represents the most contemporary epidemiological assessment of AS in the United States. There are limited resources to conduct such robust epidemiology research in the United States. Because our patient cohort is not subject to referral bias seen in registry or tertiary center reports, we can assess cause of death for nearly all patients, and all healthcare payers are included in the REP. With this, we have shown a stable incidence of AS since 1995, and these patients carry significantly higher rates of cardiac and peripheral vascular disease. Improvements in other cardiovascular trends have not translated to this patient group, and our findings strengthen the need to understand the modifiable and nonmodifiable risk factors for AS to decrease its occurrence. Additionally, the overall survival after AS diagnosis is significantly reduced compared with population controls, and the mortality prognosis of AS seems unchanged. Improvements in postdiagnosis and long-term care are needed to improve the overall survival of this complex patient population. Further work will focus on these factors to improve outcomes and enhance guidelines for management of patients with AS.

    Footnotes

    The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCOUTCOMES.118.004689.

    https://www.ahajournals.org/journal/circoutcomes

    Randall R. DeMartino, MD, MS, Division of Vascular and Endovascular Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905. Email

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