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Prevalence, indications and appropriateness of antiplatelet therapy in patients operated for acute aortic dissection: associations with bleeding complications and mortality
  1. Emma C Hansson1,
  2. Mikael Dellborg2,3,
  3. Vincenzo Lepore1,
  4. Anders Jeppsson1,3
  1. 1Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
  2. 2Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden
  3. 3Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  1. Correspondence to Dr Anders Jeppsson, Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg SE-413 45, Sweden; anders.jeppsson{at}vgregion.se

Abstract

Objective To assess the prevalence, indications and appropriateness of antiplatelet therapy in patients operated for acute aortic dissection and its associations with bleeding complications and mortality.

Design A retrospective single-centre study comparing patients with and without ongoing antiplatelet therapy.

Setting University Hospital in Western Sweden.

Patients 133 consecutive patients operated during 2007–2011.

Interventions All patients were operated for acute aortic dissection type A.

Main outcome measures Indication and appropriateness of antiplatelet therapy; perioperative bleeding complications, transfusions and mortality.

Results 43 of 133 patients (32%) had ongoing platelet inhibition at the time of surgery, 19 (14%) with acetylsalicylic acid (ASA) alone and 24 (18%) with ASA and clopidogrel. Unspecific chest pain and ST depression were the most common indications (42% and 23%, respectively). 2.3% had ST elevation and 12% had elevated biomarkers for myocardial injury. Only 29% of the patients with dual antiplatelet therapy had appropriate treatment according to current guidelines. Patients with ongoing platelet inhibition had significantly larger intraoperative (1800 (IQR 950–4250) vs 800 ml (500–2500), p=0.010) and postoperative bleeding volumes (800 (420–1605) vs 500 ml (390–1070), p=0.037). 30-day mortality in patients on dual antiplatelet therapy was 30.4% compared with 13.0% in patients with no or single antiplatelet therapy (p=0.038).

Conclusions The indication for immediate antiplatelet therapy in patients later operated for acute aortic dissection was weak or absent in the majority of cases. Patients with ongoing platelet inhibition had more bleeding complications. Dual antiplatelet therapy was associated with increased early mortality.

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Introduction

Outcome in patients with acute coronary syndrome (ACS) is improved if they are treated with the platelet inhibitor acetylsalicylic acid (ASA), and is further improved if a second platelet inhibitor is added. Dual antiplatelet therapy (DAT) is a cornerstone in ACS treatment1 and is indicated for all patients who lack contraindications.2 ,3 It is currently recommended for early initiation and in patients for whom emergent coronary angiography and catheter-based reperfusion are planned, even prehospital treatment is recommended. Upstream treatment of patients with DAT may reduce mortality in those with ST-segment elevation ACS.4 However, antiplatelet therapy also increases the risk of major bleeding, especially if the patient requires acute surgery.1 ,5 Accurate diagnosis of ACSs is based on the presence of typical chest pain, elevation of cardiac biomarkers and electrocardiographic changes. There are several important differential diagnoses, among them acute aortic dissection.

Aortic dissection is a severe disease with high mortality. In acute aortic dissection involving the ascending aorta (type A), immediate surgery is recommended.6 Early mortality is still considerable, and ranges from 5% to 25% in contemporary series,7–9 but without surgery the prognosis is even worse.6 ,10 Thus, early diagnosis is essential but sometimes proves difficult, although recent data suggest that a scoring system or the use of biomarkers may be useful.11–13 The most common symptom of aortic dissection is sudden chest pain,6 which it shares with the more frequent ACS. Consequently, some patients with acute dissection are incorrectly diagnosed as ACS and receive immediate antiplatelet treatment in accordance with contemporary guidelines.2 When the correct diagnosis is set, surgery will have to be performed under ongoing platelet inhibition.

We wanted to determine the prevalence, indications and appropriateness of antiplatelet therapy in patients who were later operated for acute aortic dissection, and its associations with bleeding complications, transfusion requirements and short-term mortality. For this purpose, a retrospective observational single-centre study was performed.

Methods

Patients

Overall, 133 consecutive patients who underwent surgery for acute dissection of the ascending aorta (Stanford type A) at the Sahlgrenska University Hospital from January 2007 to June 2011 were identified through the hospital's surgical database and included in the study. In all, 34% were women (n=46) and the mean age was 60±11 years. Patient characteristics are given in table 1.

Table 1

Preoperative and perioperative characteristics in patients with and without antiplatelet therapy

The Sahlgrenska University Hospital is the only provider of cardiac and aortic surgery in western Sweden. The catchment area has 1.4 million inhabitants. The study was approved by the Regional Research Ethics Committee.

Study design and data collection

The study was conducted as a retrospective single-centre observational study. Data were collected by a review of patient records, including copies of records from referring hospitals. Mortality data were obtained from the Swedish Population Registry. Two patients were lost to follow-up regarding 30-day mortality. Both patients were foreign visitors who were referred to their home hospital after 5 and 13 days. The perioperative observations for these patients are included in the analysis.

The following factors were tested for associations with mortality and bleeding >1000 ml: age, gender, heart rate, blood pressure, serum creatine, cardiac tamponade (yes/no), intramural haematoma (yes/no), ejection fraction, antiplatelet therapy (yes/no), DAT (yes/no), total operation time, cardiopulmonary bypass (CPB) time, aortic clamp time, circulatory arrest (yes/no), circulatory arrest time, systemic temperature, brain perfusion (yes/no) and use of aprotinin (yes/no). Associations with mortality were also analysed for intraoperative and postoperative bleeding, massive bleeding (yes/no) and transfusions.

Clinical management

All operations were performed through a median sternotomy with the patient on CPB. The arterial cannulation was performed on the femoral or the subclavian artery while the venous return was obtained from the femoral vein or the right atrium. A total of 116 patients (87%) were operated with circulatory arrest, 102 in deep hypothermia (15–24°C) and 14 patients in moderate hypothermia (25–28°C). Antegrade (92%) or retrograde (8%) brain perfusion was used in patients operated in moderate hypothermia. In the deep hypothermia group, antegrade brain perfusion was used in 20%, retrograde brain perfusion in 48% and in 32% no brain perfusion was used. The remaining 17 patients were operated without circulatory arrest, four in moderate hypothermia and 12 in mild hypothermia (29–36°C). One patient died before cooling started.

In 112 patients (84%), a supracoronary graft was inserted while in 18 patients (14%) a composite graft was used. In two patients (1.5%), a combination of supracoronary graft and valve prosthesis was used. One patient died before the aorta was resected. In 12 patients (9%), concomitant coronary artey bypass grafting (CABG) was performed. Cell saver was used intraoperatively in all patients. In all, 24 patients (18%) received aprotinin intraoperatively and 123 patients (92%) received tranexamic acid.

The institutional transfusion algorithm recommends red blood cell transfusion when blood haemoglobin level decreases to <80 g/l in stable patients and <100 g/l in patients with ongoing bleeding, or if the patient has symptomatic anaemia. Platelets should be transfused in patients with ongoing bleeding, documented or suspected platelet dysfunction or low platelet count (<75×109/l). Plasma should be transfused in patients with ongoing bleeding and signs of impaired coagulation on thromboelastometry.

Definitions

In the patients for whom treatment with dual antiplatelet agents was started before surgery, it was exclusively restricted to treatment with clopidogrel in addition to ASA. Routinely, a loading dose of ASA of 300 mg was given to previously untreated patients, followed by 75 mg daily. In accordance with local and national guidelines, a loading dose of 300 mg clopidogrel was given, followed by a dose of 75 mg daily.2 Appropriate dual antiplatelet treatment was defined retrospectively by two independent observers; differences of opinion were resolved by consensus. Based on the inclusion criteria for major, published randomised trials,1 ,14 ‘appropriate DAT’ was defined as any use in patients scheduled to undergo primary percutaneous coronary intervention (PCI) due to typical chest pain and either new onset left bundle branch block or ST-segment elevation in at least two leads, that is, conventional definition of ST elevation myocardial infarction (STEMI). Appropriate DAT use in other ACS patients had to be based on the occurrence of typical chest pain and objective signs of myocardial ischaemia or infarctions, that is, either ST-segment changes or elevated biomarkers (troponin T or I exclusively). Any other use was labelled ‘less appropriate’. ASA was considered appropriate for all patients without contraindications.

Dissections were defined as acute if diagnosed and treated within 14 days after onset of symptoms.6 Diagnosis was usually confirmed by CT. Tamponade was defined as pericardial haemorrhage with some degree of effect on systemic circulation. Intramural haematoma was defined as the presence of blood within the aortic wall. Intraoperative bleeding volume was estimated by surgical staff from swabs and suction containers. Postoperative bleeding volume was defined as the total amount of chest tube drainage during the first 12 h after surgery. Massive postoperative bleeding was defined from the The Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study15 as postoperative bleeding through chest tubes exceeding 1500 ml over any 8-h period, reoperation surgery for haemorrhage or cardiac tamponade within 24 h of surgery, transfusion of more than 10 units of red blood cells after surgery, and/or death from haemorrhage within 30 days.

Statistics

Data are presented as mean and SD where normal distribution is expected, otherwise as median with IQR or frequencies and percentages. Continuous variables were compared by the use of Student t test for normally distributed values and Mann–Whitney U test for values that were not normally distributed. Categorical variables were compared with χ2 test. Survival was estimated by Kaplan–Meier survival analysis and compared by log-rank test. Factors univariately associated with 30-day mortality and bleeding of more than 1000 ml were identified with logistic regression. Statistical significance was assumed with p values of <0.05.

Results

General

Median time from symptom to surgery was 7 h (IQR 5–21). Overall, 31 patients (23%) presented with cardiac tamponade and 22 (17%) had intramural haematoma. Mean total operation time was 412±148 min, mean CPB time 199±59 min, mean aortic clamp time 87±35 min and mean circulatory arrest time 26±12 min.

Prevalence, indications and appropriateness of platelet inhibition

A total of 43 of 133 patients (32%) were treated with one or two antiplatelet agents at the time of surgery, 19 (14%) with ASA alone and 24 (18%) with DAT. In the 43 patients, the indication for antiplatelet therapy was ST elevation in one case (2.3%) and release of cardiac enzymes such as cardiac troponins in five cases (12%) (figure 1). Nine patients (21%) presented with unspecific ECG changes or ST depression and in 18 cases (42%) the indication for treatment was chest pain alone. In two cases (4.7%), no reason for treatment was specified. Eight patients had antiplatelet therapy initiated before the present event of aortic dissection.

Figure 1

Indications for antiplatelet therapy in 43 patients operated for acute aortic dissection.

In the 24 patients treated with DAT the indication for clopidogrel was in one case (4%) STEMI, in five patients (21%) release of cardiac enzymes and in eight patients (33%) unspecific ECG changes or ST depression. In seven cases (29%), the treatment was started due to chest pain alone. Two patients (8%) were given the treatment in the prehospital setting without a clearly stated indication and one patient had DAT initiated before the present event. As defined above, DAT treatment was appropriate in seven of the 24 patients (29%) treated with clopidogrel and was considered less appropriate in 17 cases (71%).

Bleeding

Patients who received any kind of platelet inhibition had a median intraoperative bleeding of 1800 ml (IQR 950–4250) as opposed to 800 ml (IQR 500–2500) in the group without platelet inhibition (p=0.010). Median bleeding volumes during the first 12 h after surgery were 800 ml in patients on ASA or DAT (IQR 390–1070) and 500 ml (IQR 420–1605) in the group without inhibition (p=0.037) (table 1). Overall, 18 patients (46%) on ASA or DAT bled >1000 ml/12 h postoperatively compared with 24 (28%) in the group without antiplatelet therapy (p=0.045). There was no significant difference in intraoperative and postoperative bleeding between patients treated with ASA or DAT (data not shown).

In univariate testing, time on CPB (OR 1.01 per min, 95% CI 1.00 to 1.02, p=0.006), preoperative haemoglobin concentration (OR 0.97 per g/l, 95% CI 0.95 to 0.99, p=0.031) and lowest perioperative systemic temperature (OR 0.91 per degree Celsius, 95% CI 0.83 to 0.99, p=0.044) were significant predictors of bleeding in excess of 1000 ml. Intraoperative administration of aprotinin had a reducing effect on bleeding >1000 ml (OR 0.26, 95% CI 0.07 to 0.92, p=0.036).

Transfusions

There was a trend of more transfusions in patients on ASA or DAT: median 14 units of red blood cell (IQR 7.5–24) as opposed to nine units (IQR 3–17) in patients without antiplatelet therapy (p=0.066), 12 units of plasma (IQR 6–25) versus nine units (IQR 3–19) (p=0.17) and five units of platelets (IQR 3–8) versus three units (IQR 2–7) (p=0.08). Transfusion of any kind was 32 units (IQR 19–55) in the ASA or DAT group versus 20 units in patients without therapy (IQR 8–42) (p=0.10). There was no significant difference in the number of transfusions between patients who were treated with ASA or DAT (data not shown).

Neurological events

In all, 17 patients (13%) suffered from perioperative cerebral ischaemic events verified by computerised tomography, 12/90 (13%) in the no antiplatelet group and 5/43 (11%) in the antiplatelet group (p=0.78).

Mortality

A comparison of patients who did not survive at 30 days after surgery and those who did survive is presented in table 2.

Table 2

Survivors >30 days versus non-survivors

At presentation, non-survivors had a higher prevalence of cardiac tamponade, lower ejection fraction, lower systolic blood pressure and a higher prevalence of DAT. Perioperative differences were intraoperative and postoperative bleeding, transfusion of red blood cells, plasma and total transfusions, and prevalence of massive bleeding. Number of cerebral ischaemic events did not differ significantly between groups. Mortality during the first 30 days after surgery was not significantly different in patients who did or did not undergo antiplatelet therapy: 15% versus 19% (p=0.56). In contrast, in the subgroup treated with DAT, mortality during the first 30 days after surgery was significantly higher than in patients treated with ASA alone or in those without platelet inhibition: 30% versus 5% and 15%, respectively (p=0.038; figure 2).

Figure 2

Thirty-day mortality in patients operated for acute aortic dissection with ongoing treatment with acetylsalicylic acid (ASA) and clopidogrel, with ongoing treatment with ASA alone, or with no antiplatelet therapy. There was a significant difference in mortality between patients who were treated with clopidogrel and those who were not (p=0.038).

The following factors predicted 30-day mortality in univariate testing: red blood cell transfusion (OR 1.04 per unit, 95% CI 1.02 to 1.07, p=0.001), postoperative bleeding (OR 1.05 per 100 ml, 95% CI 1.01 to 1.09, p=0.012), cardiac tamponade (OR 3.00, 95% CI 1.12 to 8.01, p=0.028), left ventricular ejection fraction (OR 0.95, 95% CI 0.89 to 0.99, p=0.035), systolic blood pressure (OR 0.98, 95% CI 0.97 to 0.99, p=0.042) and DAT (OR 2.94, 95% CI 1.03 to 8.40, p=0.044).

Discussion

The main findings of the present study were that a third of patients who were operated for acute aortic dissection had ongoing antiplatelet treatment at the time of surgery. The indication for acute platelet inhibition in patients later diagnosed with acute aortic dissection was frequently less clear, and may often be considered less appropriate. Patients with ongoing platelet inhibition bled more perioperatively, and elevated perioperative bleeding and DAT were both associated with increased early mortality.

In this study, almost a third of the patients later operated for acute aortic dissection were initially erroneously diagnosed as having an ACS, and they were treated acutely with platelet inhibitors. This may appear inevitable, since the symptoms of the two diseases are similar and the incidence of ACS is 200 times that of acute aortic dissection.6 ,16 However, when the indications for ASA or DAT were examined in the present study, it appears that the indication for DAT was less appropriate in the majority of cases. Objective signs of myocardial necrosis (ST elevation and biomarkers) were present in only 29% of the patients who underwent DAT. In the remainder of cases, patients presented with chest pain of uncertain significance, normal ECG, no release of biomarkers and, in one case, received DAT—although the patient presented with a concurrent head trauma. One patient had ongoing DAT prior to the dissection due to PCI 2 years previously, which is in conflict with current national guidelines. There was no indication in the hospital records for the reasons for prolonged DAT, which serves to illustrate that adherence to guidelines regarding discontinuation is not always achieved. It is clear that in case of retrograde advancement of the aortic dissection in the ascending aorta and involvement of the coronary arteries with subsequent myocardial ischaemia and ST elevation, ACS and acute aortic dissection may become indistinguishable. Avoidance of treatment with DAT in such patients is probably not possible, but this was rarely the case. Instead, chest pain only and uncharacteristic ST changes were the most common indications for DAT.

The results suggest that the impact of an erroneous diagnosis and subsequent antiplatelet therapy is not trivial. Patients treated with platelet inhibitors bled considerably more and received more transfusions than patients without platelet inhibition. Perioperative bleeding and transfusions are well-known risk factors for severe outcome after different cardiac and non-cardiac surgical procedures.17 ,18 In the present study, increased bleeding and the number of transfusions were associated with increased mortality (table 2). Our results confirm a previous report from Hansen et al from 2007 in which patients undergoing acute dissection surgery with ongoing ASA treatment bled more and tended to have a higher mortality.19 The present study extends the results to patients on DAT with ASA and clopidogrel. Furthermore, the present results suggest that patients on DAT have an increased early mortality compared with those with no antiplatelet treatment or ASA alone (figure 2).

In contrast to the study of Hansen et al, no tendency towards an association between treatment with ASA alone and increased mortality could be demonstrated in the present study. This may be explained by the introduction of DAT to patients with suspected ACS. Patients with a perceived higher risk may today be treated with DAT instead of ASA, while patients with lower risk are treated with ASA only. This discussion remains speculative since conclusive data are lacking in the present study.

Recent analysis from a large contemporary registry of patients in the same country (Sweden) points to the merit of upstream clopidogrel treatment in patients with STEMI.4 However, as in several other registry studies, this analysis is restricted to patients who actually did have an ongoing STEMI when DAT was initiated. The patients in our study with DAT originated from a more unselected group, that is, patients with suspected STEMI where this diagnosis was not confirmed. Thus, any analysis of the merits of upstream loading of potent DAT must also include patients who turned out not to have ACS to fully assess the effect of very early treatment with potent antiplatelet therapy. Given the increased risk of bleeding with more potent antiplatelet agents, for example, ticagrelor or prasugrel, which are now incorporated in the guidelines,2 meticulous attention must be paid to treating exclusively patients who do have an ongoing ACS in order to avoid increasing problems with inappropriate dual antiplatelet treatment in patients with chest pain. Prehospital treatment algorithms that delegate potent dual antiplatelet treatment to paramedics or inexperienced acute-care physicians should be continuously monitored and carefully assessed to avoid increasing mortality in patients who have other conditions, for example, acute aortic dissection.

In the present study, 24 patients (18%) were treated intraoperatively with aprotinin. Aprotinin is an unspecific serine protease inhibitor with anti-fibrinolytic properties.20 Administration of aprotinin to patients undergoing high-risk cardiac and aortic surgery was common until the BART study was presented in 2008.15 In numerous studies, the use of aprotinin has been associated with reduced bleeding and transfusion requirements but there are also reports indicating an increased risk of myocardial infarction, renal failure and death.15 ,21 In the present study, aprotinin use was significantly associated with reduced intraoperative bleeding but not with mortality. However, the number of patients on aprotinin was low and no firm conclusions can be made.

The present study has important limitations. It was a retrospective single-centre study and selection bias for referring patients to acute surgery may have occurred. However, the study comprised 100% of the patients operated for acute aortic dissection of type A in the catchment area from 2007 until June 2011. Data regarding indication for treatment were collected from emergency charts from referring hospitals, and in many cases also documented upon admission to the surgical unit. Even so, there may have been a small risk of miscommunication. There is also a possibility of bias, since surgeons and anaesthetists were aware of which patients were treated with antiplatelet agents prior to surgery, which probably affects awareness of bleeding during surgery and propensity to administer procoagulants. Originally, a multivariate analysis was intended to identify independent risk factors of short-term mortality. However, all factors associated with 30-day mortality but one, that is, ejection fraction, were related to bleeding and consequently multivariate analysis is inappropriate due to interactions.

In conclusion, this study has shown that a substantial proportion of patients undergoing surgery for acute aortic dissection are subject to less appropriate treatment with dual platelet inhibition at the time of surgery. The indication for antiplatelet therapy is often weak and DAT increases bleeding, transfusion requirements and probably also mortality.

Key messages

  • A substantial proportion of patients undergoing surgery for acute aortic dissection are subject to less appropriate treatment with dual platelet inhibition at the time of surgery. The indication for antiplatelet therapy is often weak and dual antiplatelet therapy increases bleeding, transfusion requirements and is associated with increased mortality.

Acknowledgments

We thank biostatistician Sofia Zetterstrand, PhD, for expert statistical advice and calculations. This work was supported by the Swedish Heart and Lung Foundation (grant number 20090488 to AJ) and Sahlgrenska University Hospital (ALF/LUA grant number 146281 to AJ). The study sponsors had no influence on the analysis and interpretation of data, in the writing of the report or in the decision to submit the paper for publication.

References

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Footnotes

  • Contributors ECH collected the data and participated in the data analysis and writing of the manuscript. MD and VL participated in the data analysis and the writing of the manuscript. AJ designed the study and participated in the analysis of the data and the writing of the manuscript.

  • Competing interests None.

  • Ethics approval Research Ethics Committee in Gothenburg.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional unpublished data are available.

  • Patient consent statement The Research ethics committee waived individual patient consent.

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