Thoracic aortic dissection (TAD) is a severe and oftentimes lethal complication in hypertensive patients. While there are other aortic syndromes such as aortic aneurysms or intramural hematomas, TADs are considered one of the most deadly aortic diseases with variable etiology and poor prognosis. In 1760, King George II of England was the first documented case of aortic dissection, diagnosed by autopsy (Nicholls 1761). Since then, many have studied aortic dissections and advances in the diagnosis and treatments have significantly benefited patients with this deadly condition.
Description of the condition
TADs can be described as hemorrhage into the medial layer of the aorta through a tear in the intima. The thoracic aorta can be divided into multiple segments – ascending aorta, transverse aortic arch, and descending aorta. The ascending aorta begins distal to the aortic valves, with the sinus of Valsalva and continues to the first branch of the aortic arch. The transverse aortic arch begins at the brachiocephalic artery and ends just distal to the left subclavian artery. Finally, the descending aorta starts beyond the left subclavian artery and continues to the point of penetration into the diaphragm.
Two classification systems have been commonly used in literature to describe the location of the TAD. The DeBakey system describes type I dissections as involvement of the entire thoracic aorta. Type II dissections describe involvement of only the ascending aorta. Type III describe dissections only affecting the descending aorta and may involve the abdominal aorta. The Stanford classification system simplifies the description to type A involving the ascending aorta and may involve the rest of the aorta; type B dissections involve the descending aorta and possibly the abdominal aorta, but strictly without involvement of the ascending aorta. In this systematic review, aortic dissections will be described using the Stanford classification system.
Epidemiology of TAD
Although many have studied aortic dissections, it is believed that the number of TADs reported is an underestimate as many of these patients die before ever reaching a medical facility. It is estimated that three to four cases of TAD occur every 100,000 persons per year and is increasing, probably due to increased reported cases with improved recognition of symptoms and diagnostic imaging (LeMaire 2011). Studies have shown that the prevalence of type A dissections (67%) are more common than type B dissections (33%) (LeMaire 2011). The mean age of onset is typically in the mid-60s and TAD is twice as likely to occur in men than women, with women having an older mean age of onset of 67 compared to 60 in men (Isselbacher 2007; LeMaire 2011).
TAD typically has a poor prognosis, dependent on the anatomical location and extent of the dissection, time between onset and diagnosis, and the treatment administered (LeMaire 2011). Type A dissections have the worst prognosis with an overall in-hospital mortality of 30% (LeMaire 2011; Trimarchi 2010). It has been estimated that mortality rate increases by 1% for every hour after onset of symptoms if left untreated (Meszaros 2000). If only treated medically without surgical intervention, type A dissections have an in-hospital mortality rate of 59%, compared to 23% with surgical treatment (LeMaire 2011; Trimarchi 2010).
Type B dissections tend to have a better prognosis than type A dissections, having an overall in-hospital mortality rate of 13% (Tsai 2006). With surgical intervention, mortality rate of type B dissections is approximately 20%, given that complicated cases are treated surgically. Medical treatment has a mortality rate of approximately 10% (Tsai 2006).
Etiology and Risk Factors of TAD
Thoracic aortic dissections may have many different underlying etiologies but there is one common theme to its pathogenesis. Weakening of the aortic walls is believed to be the key pathology leading to the actual dissection (Chen 1997; Hiratzka 2010; Isselbacher 2007; LeMaire 2011; Nienaber 2003). Aortic dilatation is believed to be one of the risk factors of TAD, with the risk of dissection significantly increasing when the ascending aorta dilates > 6cm and the descending aorta > 7cm (LeMaire 2011). However, it is not the dilatation that causes a TAD, but rather, it increases the risk of a TAD; a tear in the intimal wall is needed to induce a TAD.
Hypertension has been analyzed extensively in TAD cases and has been well recognized to be one of the key causative factors of TAD (Chen 1997; Hiratzka 2010; Isselbacher 2007; LeMaire 2011; Nienaber 2003). Chronic hypertension increases the force of systolic ejection jet against the aortic wall, which over time, may weaken from continuous strain and eventually suffer from an intima tear. A sustained high blood pressure will propagate the false lumen within the walls of the aorta, hence forming the TAD.
Connective tissue disorders have been identified as a risk factor for TAD. These include genetic conditions such as Marfan Syndrome, Loeys-Dietz Syndrome, Ehler-Danlos Syndrome, and Turner Syndrome. Congenital vascular diseases such as bicuspid aortic valve and coarctation of the aorta have also been identified as risk factors for TAD. Any forms of aortitis can increase the risk of TAD, such as giant cell arteritis, Takayasu arteritis, Behcet’s disease, systemic lupus erythematous or syphilis. Other risk factors identified include trauma, iatrogenic causes from catheter interventions or valvular/aortic surgery, cocaine use, and pregnancy (Chen 1997; Hiratzka 2010; Isselbacher 2007; LeMaire 2011; Nienaber 2003).
Description of the intervention
Surgical intervention is almost always the recommended therapy for type A dissections due to the poor prognosis if left untreated (LeMaire 2011). Type B dissections have a significantly better prognosis and are entitled to different treatment options. Uncomplicated type B aortic dissections can be managed with medical therapy. Initial management of aortic dissection with anti-hypertensive medications is to decrease the aortic wall shear stress. Aortic wall stress is affected by the velocity of ventricular contraction, the rate of ventricular contraction, and blood pressure. Intravenous beta-blockers have been recommended by guidelines as the mainstay first-line therapy in its ability to decrease aortic wall stress (Hiratzka 2010). Guidelines recommend controlling heart rate to a target of less than 60 beats per minute and a systolic blood pressure between 100 – 120 mmHg or as tolerated while maintaining adequate end-organ perfusion (Hiratzka 2010). Intravenous non-dihydropyridine calcium channel blockers (Non-DHP CCB), diltiazem and verapamil, are suggested as an alternative for chronotropic control for patients with contraindications or intolerance to beta-blockers, and can also be used to reduce blood pressure (Hiratzka 2010). If systolic blood pressure remains above target, intravenous vasodilators and angiotensin-converting enzyme (ACE) inhibitors can also be used to reduce blood pressure (Hiratzka 2010). Once stabilized, patients should be transitioned to oral medications and continued on medical therapy long-term (Hiratzka 2010). Other anti-hypertensive medication classes include the angiotensin II receptor blockers (ARB), diuretics, alpha-blockers, and centrally acting alpha-agonists. Resistant hypertension occurs frequently and a median of four anti-hypertensive medications are used in chronic aortic dissections (Eggbrecht 2005). Guideline recommendations emphasize the use of beta-blockers, ACE inhibitors, and ARBs for anti-hypertensive therapy in patients with thoracic aortic disease (Hiratzka 2010). But the evidence in the approach to medical management and the selection of anti-hypertensive medications in chronic type B aortic dissections remains scarce. Beta-blockers have shown some evidence to reduce aortic root dilatation in children with Marfan syndrome (Shores 1994). Also, long-term use of beta-blockers appears to reduce the need for dissection-related surgery and the progression of aortic dilatation compared to treatment with other anti-hypertensive medications (Genoni 2001). However, a recently updated Cochrane review emphasized that beta-blockers are less effective in controlling hypertension as a first-line therapy when compared to other anti-hypertensive medications (Wiysonge 2012). Furthermore, another Cochrane review demonstrated evidence and recommended the use of other classes of anti-hypertensive medications over beta-blockers (Chen 2010). ACE inhibitors, in particular perindopril, have also been shown to reduce aortic root diameter in patients with Marfan syndrome (Ahimastos 2007). Takeshita et al. showed that the use of ACE inhibitors reduced the risk of long-term aortic events in patients with type B aortic dissections (Takeshita 2008). Valsartan, an ARB, demonstrated a reduction in composite cardiovascular outcomes and in aortic dissection incidences (Mochizuki 2007). Also, a small study by Brooke et al. showed ARBs slowing the rate of aortic root enlargement in children with Marfan syndrome (Brooke 2008). Recently, analysis of data from the International Registry of Acute Aortic Dissection (IRAD) showed CCBs being associated with improved survival in type B aortic dissections (Suzuki 2012). Benefit with other anti-hypertensive medications and comparisons between medication classes in aortic dissections remain unclear.
Why it is important to do this review
Due to the deadly nature of this cardiovascular disease, the treatments of TADs need to be well studied to maximize its efficacy and to improve patient prognosis. This systematic review will focus on medical therapeutics for the treatment of type B thoracic aortic dissections. Type B dissections tend to have a better prognosis with medical treatment compared to type A dissections. Although therapeutic guidelines have been developed, there has been limited literature on the direct comparison between the different medications used to treat TADs (Suzuki 2012).
This review will guide physicians in their clinical decision-making on the optimal treatment regimen for their patients. Although beta-blockers are currently considered first-line therapy, there is still research yet to be done to compare the different possible alternatives as feasible first-line pharmacological agents. Through this systematic review, data from past studies comparing the different medications will be synthesized and analyzed for the ease of physicians to interpret and utilize as their future therapeutic guidelines.
To assess the effects of first-line beta-blockers compared to other anti-hypertensive medications for treating chronic type B thoracic aortic dissections.
Criteria for considering studies for this review
Types of studies
The review will be based only on data from randomized controlled trials comparing different anti-hypertensive medications in the treatment of chronic type B aortic dissections.
Types of participants
Patients with chronic type B thoracic aortic dissections of all etiologies (including Marfan syndrome, Ehler-Danlos syndrome, Turner syndrome, iatrogenic or traumatic cause) that were not prescribed surgical therapy as a first-line treatment will be considered for this systematic review.
Types of interventions
First-line beta-blockers will be assessed in comparison to other anti-hypertensive medications, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), diuretics, vasodilators, renin inhibitors, alpha-blockers, and central alpha-agonists.
Types of outcome measures
Because TAD is often a lethal complication of hypertension, the major outcomes of concern would be the total mortality rate (TMR). Studies must provide TMR data to be included in this review.
The total non-fatal serious adverse events relating to this cardiovascular disease will be assessed as a secondary outcome. If medical treatment fails or if the dissection progresses, surgical intervention is usually the next therapeutic approach. The number of patients not requiring surgery using these compared medical interventions will also be assessed. Measurement of the progression of aortic dimensions will be considered as it may be an effective monitoring tool in the medical intervention of TAD.
Search methods for identification of studies
The Database of Abstracts of Reviews of Effectiveness (DARE) and the Cochrane Database of Systematic Reviews (CDSR) will be searched for related reviews.
Searches in The Hypertension Group specialised register, The Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (1946-present), and Ovid Embase (1974-present), ClinicalTrials.gov will be conducted. Reference lists of all included studies and any relevant systematic reviews identified will be checked. Authors will be contacted for information about ongoing or unpublished studies.
The MEDLINE search strategy (Appendix 1) will be translated into the other databases using the appropriate controlled vocabulary as applicable. There will be no language restriction.
Data collection and analysis
The initial search in the listed databases will be performed to identify publications with potential relevance. These titles and abstracts will be screened and those that are clearly irrelevant will be excluded. The full text versions of the remaining articles deemed relevant will then be retrieved and analyzed for inclusion of this review based on the specified criteria. Reference lists of identified articles will also be manually searched and assessed. Two independent reviewers will be assessing the eligibility of selected articles to be included in this review. A third reviewer will resolve any discrepancies.
Selection of studies
Review Manager software will be used to maintain references and abstracts after the appropriate search inclusion, based on the criteria listed above.
Data extraction and management
Data will be extracted independently by two independent reviewers using a standard form, and then cross-checked. All numeric calculations and graphic interpolations will be confirmed by a second person.
Because mortality and survival rates from literature sources will be reported in different time frames (i.e. one year, three years, five years survival rate, etc.), extracted data will need to be separately categorized.
Assessment of risk of bias in included studies
The risk of bias of the selected trials will be assessed by two independent reviewers according to the Cochrane Handbook Chapter 8 using the following criteria:
1. Random Sequence generation
2. Allocation concealment
3. Blinding of outcome assessment
4. Incomplete outcome data
5. Selective reporting
6. Other sources of bias
Measures of treatment effect
The TMR between different types of anti-hypertensive medications compared to first-line beta-blockers to treat TAD will be assessed as dichotomous data to compare the risk ratio (RR) with a 95% confidence interval (95%) between the different types of medications.
The total TAD-related non-fatal serious adverse events and the number of patients not requiring surgery will also be treated as dichotomous data to compare the RR with 95% CI of the respective outcomes.
If adequate data is provided, the effect of anti-hypertensive medications on the progression of aortic dimensions of the TAD will be assessed as dichotomous data to determine the RR of whether or not the compared interventions had any difference in its ability to decrease TAD aortic dimensions. If insufficient events occur to calculate RR, the odds ratio (OR) will be considered.
Dealing with missing data
In case of missing information in the included studies, investigators will be contacted (using email, letter and/or fax) to obtain the missing information. Longitudinal studies risk the possibility of patient drop-out or withdrawal. With instances with patient drop-out or withdrawal, exclusion of data will be determined on a case-by-case basis.
Assessment of heterogeneity
The heterogeneity between trials will be assessed using the chi-squared test. Tests with P value < 0.05 will be considered to have significant heterogeneity. The fixed-effect model will be used when homogeneity is assessed and random-effect model will be used to test for statistical significance if there is heterogeneity. Heterogeneity assessment will then be further analyzed using I
The Cochrane Review Manager software will be used in data synthesis and analysis. Results will be presented in tables and forest plots based on Cochrane guidelines. Full details of all trials included and excluded will be presented.
Subgroup analysis and investigation of heterogeneity
Patients with underlying collagen diseases have a different etiology than the general population of TAD patients and will be considered as a subgroup. Studies with combined populations of various etiologies may limit the availability of subgroup data and will be commented on in the Appendix.
Heterogeneity in the usage of different medications could be due to different medications within a medication class or the dosage used.
The authors would like to acknowledge the help provided by the Cochrane Hypertension Group.
Appendix 1. MEDLINE search strategy
Database: Ovid MEDLINE(R) 1946 to Present with Daily Update
1 exp adrenergic beta-antagonists/
2 (acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol or bisoprolol or bopindolol or bornaprolol or brefonalol or bucindolol or bucumolol or bufetolol or bufuralol or bunitrolol or bunolol or bupranolol or butofilolol or butoxamine or carazolol or carteolol or carvedilol or celiprolol or cetamolol or chlortalidone cloranolol or cyanoiodopindolol or cyanopindolol or deacetylmetipranolol or diacetolol or dihydroalprenolol or dilevalol or epanolol or esmolol or exaprolol or falintolol or flestolol or flusoxolol or hydroxybenzylpinodolol or hydroxycarteolol or hydroxymetoprolol or indenolol or iodocyanopindolol or iodopindolol or iprocrolol or isoxaprolol or labetalol or landiolol or levobunolol or levomoprolol or medroxalol or mepindolol or methylthiopropranolol or metipranolol or metoprolol or moprolol or nadolol or oxprenolol or penbutolol or pindolol or nadolol or nebivolol or nifenalol or nipradilol or oxprenolol or pafenolol or pamatolol or penbutolol or pindolol or practolol or primidolol or prizidilol or procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol or spirendolol or talinolol or tertatolol or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or tribendilol or xibenolol).tw.
3 (beta adj2 (adrenergic? or antagonist? or block$ or receptor?)).tw.
5 exp Aortic Aneurysm/
6 Aneurysm, Dissecting/
7 exp Aneurysm, Ruptured/
8 (aort$ adj5 (aneurys$ or dissect$ or ruptur$ or tear$ or trauma$ or split$)).tw.
9 chronic dissect$.tw.
11 randomized controlled trial.pt.
12 controlled clinical trial.pt.
15 drug therapy.fs.
20 animals/ not (humans/ and animals/)
21 19 not 20
22 4 and 10 and 21
Last assessed as up-to-date: 13 January 2013.
Contributions of authors
Kenneth Chan and James M. Wright formulated the idea for the review and registered the review title.
Kenneth Chan and Peggy Lai developed the basis and wrote the protocol.
Kenneth Chan and Peggy Lai will be identifying and assessing studies, extracting and analyzing data, and writing the review.
Declarations of interest
Sources of support
- Faculty of Medicine, University of British Columbia, Canada.
- Lower Mainland Pharmacy Services, Canada.
- No sources of support supplied