Abstract
The use of systemic heparin in patients with ruptured abdominal aortic aneurysms (rAAAs) remains a contentious issue with no clear guidelines. This review reports the current understanding, at a molecular and clinical level, of the possible benefits and risks of heparin in emergency aneurysm repair (both open and endovascular). MEDLINE, EMBASE, AMED, SCOPUS, CINAHL and Cochrane Library were searched for all articles containing the keywords ‘rupture’, ‘abdominal’, ‘aneurysm’ and ‘heparin’. Current experience, indications and outcomes were analyzed. Articles were searched for both endovascular and open repair of AAAs. A total of eight studies were included for analysis in the systematic review. Of these, only one paper focused specifically on heparin use in open repair of ruptures and suggested a benefit. Of the remaining seven, two were self-reporting retrospective studies assessing individual surgeons’ practice, one was a case report and the remaining four included mention of heparin use but with no outcome data. The evidence available suggests that a pro-coagulable state exists in rAAAs. This may be responsible for the morbidity and mortality postprocedure, which arises predominantly from multiple organ failure and cardiac compromise rather than outright hemorrhage. This diathesis may respond well to heparin administration, suggesting that heparin administration in ruptured aneurysms is appropriate.
Introduction
The mortality from ruptured abdominal aortic aneurysms (rAAAs) remains high with in excess of 3500 deaths per year in the UK. 1 There have been a number of advances in technique in the last few years with the development of endovascular repair of ruptured aneurysms 2,3 and the introduction of a national screening program to detect asymptomatic aneurysms prior to rupture. 4 These aspects have all seen the mortality from elective aneurysm repair (either open or endovascular) fall. The mortality from emergency repair has remained, on the whole, static despite the above-mentioned advances.
One of the specific changes in elective aneurysm management has been the widespread use of heparin where a clear reduction in morbidity and mortality predominantly from cardiac causes has been demonstrated. 5 This contrasts with the repair of emergency aneurysms where the role for heparin in ruptured aneurysms is more contentious with the need for balancing the risk of exacerbating bleeding against the cardioprotective and other benefits of heparin. This disparity is reflected in the fact that more than 80% of surgeons use heparin in elective repairs while fewer than 50% do so in emergencies. 6,7
This review looks to assess the available literature regarding the use of heparin in ruptured aneurysms in an effort to establish whether the evidence exists for advocating a more widespread use of heparin in the context of ruptured aneurysms.
Methods
A systematic review of the literature was performed using the MEDLINE, EMBASE, AMED, SCOPUS and CINAHL databases. The keyword searches were ‘rupture’, ‘abdominal’, ‘aneurysm’, ‘heparin’ and ‘coagulation’. Abstracts from all articles that reported heparin use in rAAA repair were reviewed, as were additional papers found through review of reference lists and related citations. Papers were excluded if they were either not published in English or had no mention of heparin use. Relevant papers were examined for discussion of the role of heparin in patient outcome. Papers covering both open and endovascular repair were included in the search criteria.
Results
The search identified 285 potentially relevant papers. Following application of the exclusion criteria (Figure 1 – QUORUM flow chart), a total of only eight papers were identified to include in the final analysis. Of the original 285, 40 were excluded on language criteria and the remaining 237, though discussing aneurysm surgery, had no inclusion of heparin use.
QUORUM flow chart demonstrating literature search outcomes
The eight papers remaining for analysis included only one paper specific to the use of heparin in rAAAs. 8 This prospective, non-randomized cohort study of 131 patients performed in 2008 compared 63 patients who had received heparin (at a standard dose of 5000 units) and 68 who had not. This study only contained patients undergoing open repair of their aneurysms. The patients were given heparin based on the individual choice of different surgeons in the same hospital. The results showed that the addition of heparin improved morbidity and mortality without any adverse increase in hemorrhagic side-effects. The heparinized group had lower (but not significant) recorded blood loss and a similar blood transfusion requirement. There was, however, a significantly lower operative mortality for the heparinized group than for the non-heparinized group as well as 30-day mortality (16 versus 43%, P = 0.001). This reduction in mortality was thought to be due to a reduction in thrombotic events not only in the coronary and peripheral circulation but also in visceral circulation.
There was not a correspondingly significant reduction in morbidity; however, it was lower in the heparinized group than in the non-heparinized group, although, surprisingly, the rate of non-fatal myocardial ischemia was higher in the heparinized group. When patients who died intraoperatively were excluded, 8% required embolectomy in the heparin group compared with 14% in the non-heparinized group (P = 0.06). The paper concluded that heparin use was an independent predictor of a positive outcome (P = 0.036 by multivariate analysis).
Two of the remaining eight papers were self-reporting retrospective studies assessing whether surgeons used heparin in their emergency procedures. The first suggested that only 53% of American surgeons and 34% of European surgeons used systemic heparin in emergency AAA repair. 6 The second found a lower overall incidence of only 16%. 7
The remaining five papers documented the use of heparin in their rAAA repairs but gave no specific results or analysis related to its use. 9–13 These papers therefore provided no useful results.
Discussion
This paper has identified a clear lack of evidence or guidance for the use of heparin in ruptured aneurysm repair, with only one paper providing level B/II c evidence 8 and seven level D/III evidence. 6,7,9–13 This is in contrast to elective aneurysm repair where heparin use is widely accepted. 6,7 This discrepancy may be due to the concerns associated with exacerbating hemorrhage in patients with ruptured aneurysms by the administration of heparin anticoagulation.
The use in elective repair is based primarily on evidence provided by a retrospective study 14 and a prospective randomized control trial. 5 The former study assessed heparin use and outcome in patients with tube and bifurcated grafts. For tube graft patients, the non-heparinized patients had a shorter mean anesthetic time (145 versus 172 minutes, P < 0.004), less mean blood loss (846 versus 1493 mL, P < 0.004) and fewer cell-saver (416 versus 652 mL, P < 0.004) and postoperative transfusions (5 versus 7, P < 0.004). The heparinized bifurcated graft group also showed increased mean blood loss (1288 versus 870, P – NS) and postoperative transfusion requirement (5 versus 1, P – NS). There appeared to be no difference between the heparinized and non-heparinized groups regarding major morbidity and mortality.
In 1996, a prospective, randomized case-control trial was performed on 284 patients. 5 This paper showed no difference in the amount of blood lost and transfusion needed and no difference in the pre- and postoperative hemoglobin, hematocrit and platelet count. Significant bleeding (defined by the operator) was seen in eight heparinized and 13 non-heparinized patients. Morbidity and mortality, especially in the incidence of myocardial infarction, were increased in the non-heparinized group with an overall mortality of 4.2% for the heparinized group and 7.8% for the non-heparinized group (P = 0.05). This latter finding is a possible cause for the uptake in heparinization of elective aneurysm patients and appears in contrast to the paper in ruptured aneurysms, which suggests a higher rate of myocardial ischemia in heparinized patients. 14
There is no evidence from the eight identified papers that heparin use in ruptures increases the risk of bleeding. Indeed, the benefits of heparin in countering the pro-coagulant state that results in the majority of postoperative complications (myocardial infarction, thromboembolism, multiple organ failure) secondary to micro- and macrovascular complications may be great. 15,16
While there is little clinical evidence for heparin use in ruptured aneurysms, there is a reasonable body of evidence for the argument to suggest that using heparin may confer benefit on a physiological level. A prospective study performed in 1997 compared the coagulation and fibrin pathways in ruptured and non-ruptured aneurysms. 17 This paper found that there was a statistically significant increase in thrombin generation (thrombin-antithrombin III complex [TAT] and prothrombin fragment [PF] 1 + 2) in rAAAs. This difference lasted through the perioperative period and up to 24 hours after surgery. There was, in addition, a marked inhibition of systemic fibrinolysis due to the elevated tissue plasminogen activator (t-PA) antigen, reduced t-PA activity and elevated plasminogen activator inhibitor (PAI) activity. These results suggest that the use of heparin in ruptures may be useful in reversing this pro-coagulant state and reducing cardiac-related morbidity and mortality. This is supported by a later publication showing significantly decreased D-dimer and PF 1 + 2 postadministration of low-molecular-weight heparin in elective aneurysm repair. 18
The physiological argument for heparin use in ruptured aneurysms is further supported by a prospective study of 20 patients which showed a significant negative correlation between preoperative t-PA activity and cardiac troponin 1 (cTnI) and a significantly positive correlation between preoperative PAI activity and cTnI before operation. The conclusion drawn from this study was that the pro-coagulant, hyperfibrinolytic state during rAAA repair was associated with perioperative myocardial cell necrosis and treating this state with heparin may be beneficial. In addition, this state may exacerbate the coagulopathy associated with rupture. 19
The procoagulant state that accompanies ruptured AAAs may have a more significant effect on postoperative recovery. 20 Significantly higher levels of D-dimer, tissue plasminogen activator antigen and PAI-1 were demonstrated in a prospective study of 95 patients comparing ruptured aneurysms with non-ruptured aneurysms, indicating a higher fibrinolytic activity. In addition, significantly increased levels of TAT, PF (1 + 2) and von Willebrand factor antigen in patients with rAAAs compared with AAAs, and especially in those with rAAAs and shock, have been demonstrated. 21–23 These may all respond to intra- and perioperative heparin administration.
Disseminated intravascular coagulation (DIC) has been shown to be linked to all forms (intact, dissecting and ruptured) of AAAs. 24 It is clear that DIC can take acute 25 and chronic 26,27 forms and is a complication of both treated and untreated AAAs. 28 The majority of research into DIC and AAAs is case report-based and treatments involved in these cases range from pharmacological to surgical. In some cases, it has been described that heparin can be used to treat this diathesis. 18,20,29
The assumption from the above evidence is that the pro-coagulant and hyperfibrinolytic state is the biggest factor in morbidity and mortality in rAAAs, suggesting that the use of heparin in rAAAs is the physiologically correct treatment for ruptured aneurysm patients.
Conclusion
The evidence for the use of heparin in ruptured aneurysm is poor. There appears to be a reasonable physiological argument for both peri- and postoperative heparin administration, which would suggest that there would be a benefit in ruptured aneurysms. We would support the more routine use of heparin in ruptured aneurysms in line with the policy in elective aneurysm repair on the basis of the available evidence.