1. The Influence of Risk Factors on Mortality Rates after Elective Open Repair of Abdominal Aortic Aneurysms (AAA) Class 5 1 st Year Mestrado Integrado em Medicina

2. IntroductionResearch Question and AimsParticipants and MethodsResultsDiscussion

3. Abnormal widening of abdominal aorta below the renal arteries (at least 1.5-folds the normal diameter); 13 th cause of death in the United States (US): 200,000 new diagnosis each year; 40,000 surgical repairs each year; 15,000 die from rupture each year. 3rd cause of sudden death in men >60 in US; 75% are asymptomatic until their rupture. Introduction Abdominal Aortic Aneurysm (AAA)

4. Risk Factors for AAA Age>50 y.o. and male gender Hypertension Atherosclerosis Chronic obstructive pulmonary disease Smoking Family history of AAA Previous vascular surgery Introduction

5. Elective Open Repair (EOR) of AAA Established procedure for patients >40 years Invasive surgery procedure with insertion of a prosthetic tube-like graft Excludes aneurysm and prevents growth Proven, long-term results Considered the “gold standard” Operative mortality rounds 1% to 5% Introduction

6. Petr Utikala (2004), Biomed Papers 148(2), 183–187 Elective Open Repair (EOR) of AAA

7. Postoperative Complications of EOR Venous Bleeding/Haemorrhage Gastrointestinal ischemia and/or dysfunction Cardiac events (including Myocardial Infarction) Pulmonary insufficiency Organ Failure Renal failure Graft infection Introduction

8. Research Question and AimsParticipants and MethodsResultsDiscussion

9. Research Question and Aims Research Questions: Which risk factors mostly contribute to mortality after EOR? Is it possible to improve the prediction of patients’ outcome after EOR? Aims: Develop a meta-analysis review; Summarize the risk factors, postoperative complications and mortality rates of patients with AAA undergoing EOR; Analyze the influence of risk factors on patients’ outcome after EOR; Contribute to the improvement of the prediction of patients’ outcome. Research Question and Aims

10. IntroductionResearch Question and AimsParticipants and MethodsResultsDiscussion

11. Participants and Methods Type of StudyStudy ParticipantsStudy DesignVariables SelectionStatistical Analysis Participants and Methods

12. Meta-Analysis Review Type of Study

13. Participants and Methods All articles (n=203) published on PubMed Database considering: "abdominal aortic aneurysm"[Text Word] OR "aortic aneurysm, abdominal"[MeSH Terms] OR aaa[Text Word] AND elective[All Fields] AND open[All Fields] AND ((("wound healing"[TIAB] NOT Medline[SB]) OR "wound healing“[MeSH Terms] OR repair[Text Word]) OR ("surgery"[Subheading] OR "operative surgical procedures"[Text Word] OR "surgical procedures, operative"[MeSH Terms] OR "surgery"[MeSH Terms] OR surgery[Text Word])) AND mortality[Text Word] Study Participants

14. Study Design: 1 st Triage Step Participants and Methods Inclusion Criteria Abdominal aortic aneurysms (AAA) Elective open repair/surgery (EOR) Mortality rates after elective open repair Postoperative complications Patient’s outcome Exclusion Criteria Other types or “mixed” aortic aneurysms (n=10) Emergency repair of ruptured AAA (n=13) Patients submitted to endovascular repair (EVAR) (n=51) Other papers as reviews, systematic reviews, meta-analysis, letters or editorials (n=20) Papers in other languages rather than English, French, Spanish or Portuguese (n=16) Not related studies (n=26)

15. Participants and Methods Study Design: 1 st Triage Step

16. Participants and Methods Inclusion Criteria Full paper available Provide data about preoperative clinical variables and risk factors Provide data about postoperative complications Provide data about patients’ mortality/outcome Exclusion Criteria Impossibility to obtain full article by on line request, library acquisition or e-mail request to authors (n=13) Other types of articles such as, review (n=1) or meeting abstract (n=1) Not related to the study (n=5) Absence of data about risk factors (n=10) Absence of data about mortality (n=4) Absence of data combining mortality associated to risk factors (n=29) Study Design: 2 nd Triage Step

17. Participants and Methods Study Design: 2 nd Triage Step

18. Participants and Methods Study characteristics Name of first Author, Year of Publication Type of Study Country of Origin Sample Size (n) Preoperative clinical variables Age (mean) Aneurysm Diameter (mean) Gender (male and female %) Risk Factors exposition Diabetes Mellitus, DM (%) History of Cardiac Disease, CDH (%) – History of myocardial infarction and/or angina Hypertension, HT (%) History of Pulmonary Disease, PDH (%) – History of COPD or pulmonary embolism Chronic Renal Failure, CRF (%) – Creatinine levels (>2.0mg/dL) Smoking Habits (%) Selected Variables

19. Participants and Methods Postoperative Complications Morbidity Events, (%) Venous Bleeding, (%) Gastrointestinal Ischemia, GIsch (%) MultiOrgan Failure, MOF (%) Renal Failure, RF (%) Cardiac Complications, CardiacC (%) Myocardial Infarction, MI (%) Respiratory Complications, RespC (%) Patients Outcome Mortality (%) Statistical Data Risk factor associated Odds Ratio Risk factor associated Confidence Interval Selected Variables

20. Participants and Methods Data input on Database using Statistical Package for Social Sciences (SPSS) Version 16.0 used to summarize the mean frequencies, confidence intervals and standard deviations of all clinical variables, risk factors exposition, postoperative complications, and mortality rates; Epi Info™, Version 6 to perform a χ 2 analysis to determine the Odds Ratio (OR) and 95% confidence interval for the association of risk factors influence on patients’ outcome; R Version 2.6.2 to elaborate the Forest Plot graphics in order to combine the information about the influence of risk factors on patients’ outcome. Statistical Analysis

21. IntroductionResearch Question and AimsParticipants and MethodsResultsDiscussion

22. Results 1)Summarize risk factors and postoperative complications, as well as the mortality rate within all studies. 2)Determine the Odds Ratio (OR) and 95% confidence interval for the influence of risk factors on patients’ outcome and elaborate the Forest Plots in order to combine the information from all studies. Systematic ReviewMeta-Analysis Results

23. Combine data from 46 articles (29 + 17) which result in 50 individual studies regarding the frequencies of: Risk Factors Postoperative complications Morbidity rates Mortality rates Results Systematic Review

24. Results Number of Studies Median (%)Std. DeviationMinimum (%)Maximum (%)Mean (%) Mean Age (y.o.) 4571,0 3,4 65,883,071,4 Mean Aneurysm Diameter (cm) 295,9 0,5 4,706,55,9 Frequency of Males in Patients Group 4686,9 7,7 67,099,285,1 Frequency of Patients with DM 379,5 6,4 2,936,010,4 Frequency of Patients with CDH 3844,3 18,8 2,476,041,1 Frequency of Patients with HT 3660,0 14,8 30,088,659,2 Frequency of Patients with PDH 3323,0 13,6 6,758,824,9 Frequency of Patients with CRF 309,5 6,6 1,526,011,5 Frequency of Patients with Smoking 3054,2 26,8 4,097,153,1 Frequency of Total Morbidity events 1731,0 19,8 0,368,131,9 Frequency of Bleeding events 163,8 5,6 0,420,06,1 Frequency of GIsch events 141,7 7,3 0,228,63,9 Frequency of MOFailure events 83,7 2,8 0,88,03,9 Frequency of RFailure events 181,5 4,6 0,217,13,8 Frequency of CardiacC events 255,7 6,4 1,025,77,3 Frequency of MI events 172,2 3,4 0,610,94,0 Frequency of RespC events 237,5 11,2 0,540,011,4 Frequency of Deaths504,0 3,2 0,017,14,4 Systematic Review

25. Summary Median % of Male Gender is 86.9% Median % of patients with HT is 60.0% Median % of patients with Smoking habits is 54.2% Median % of patients with CDH is 44.3% Median % of Cardiac Complications is 5.7% Median % of Respiratory Complications is 7.5% Median occurrence of Morbidity events of 31.0% Median frequency of Mortality was 4.0% Results Systematic Review

26. Combine data regarding the influence of risk factors on patients’ outcome: Mean Age (y.o.) Mean Aneurysm Diameter (cm) Gender Diabetes Mellitus, DM History of Cardiac Disease, CDH Hypertension, HT History of Pulmonary Disease, PDH Chronic Renal Failure, CRF Smoking Habits Results Meta-Analysis

27. Mean Age Results Meta-Analysis Rigberg DA (2006) Hertzer NR (2005) Hua HT (2005) Leon LR (2005) Zeebregts CJ (2004) Kruger A (2002) Lederle FA (2002) Brady AR (2000) Adjusted OR OR=1.07 95% CI (1.05 – 1.09) p<0.001 Test of heterogeneity: Q: 21,35 d.f.: 7 p.value: 0,003 1.0 2.0 5.010.0 0.5

28. Meta-Analysis Mean Aneurysm Diameter Test of heterogeneity: Q: 0,19 d.f.: 2 p.value: 0,910 Results Hertzer NR (2005) Lederle FA (2002) Brady AR (2000) Adjusted OR OR=1.58 95% CI (1.11 – 2.25) p=0.011 0.5 1.0 2.0

29. Meta-Analysis Female Gender Results Test of heterogeneity Q: 4,87 d.f.: 7 p.value: 0,676 0.2 1.0 10.00.52.05.020.0 OR=1.58 95% CI (1.39 – 1.80) p<0.001 Rigberg DA (2006) Hertzer NR (2005) Leon LR (2005) Nesi F (2004) Bianchari F (2003) #1 Bianchari F (2003) #2 Rayan SS (2002) Brady AR (2000) Adjusted OR

30. Diabetes Mellitus Results Meta-Analysis 1.0 2.0 5.010.0 20.0 0.5 Hua HT (2005)Ari Bianchari F (2003) #1 Bianchari F (2003) #2 Rayan SS (2002) Adjusted OR OR=1.28 95% CI (0.80 – 2.06) p=0.309 Test of heterogeneity Q: 1,24 d.f.: 3 p.value: 0,744

31. Cardiac Disease History (CDH) Results Meta-Analysis 0.2 1.0 0.52.05.020.0 50.0 0.1 0.05 OR=1.93 95% CI (1.42 – 2.62) p<0.001 Test of heterogeneity Q: 20 d.f.: 6 p.value: 0,003 Conrad MF (2007) Hirzalla O (2006) Hua HT (2005) Nesi F (2004) Bianchari F (2003) #1 Bianchari F (2003) #2 Hertzer NR (2002) Adjusted OR

32. Hypertension (HT) Results 0.2 1.0 10.00.52.05.020.0 50.0 0.1 0.05 Test of heterogeneity Q: 51,04 d.f.: 5 p.value: <0,001 OR=2.95 95% CI (2.14 – 4.05) p<0.001 Bonardelli S (2007) Hua HT (2005) Nesi F (2004) Bianchari F (2003) #1 Bianchari F (2003) #2 Liapis CD (2003) Adjusted OR Meta-Analysis

33. Pulmonary Disease History (PDH) Results Meta-Analysis 0.2 1.0 10.00.52.05.0 0.1 Bonardelli S (2007) Hertzer NR (2005) Hua HT (2005) Nesi F (2004) Bianchari F (2003) #1 Bianchari F (2003) #2 Hertzer NR (2002) Adjusted OR Test of heterogeneity Q: 6,26 d.f.: 6 p.value: 0,394 OR=1.32 95% CI (0.94 – 1.87) p=0.112

34. Chronic Renal Failure (CRF) Results Meta-Analysis Bonardelli S (2007) Conrad MF (2007) Hirzalla O (2006) Hertzer NR (2005) Hua HT (2005) Bianchari F (2003) #1 Bianchari F (2003) #2 Hertzer NR (2002) Adjusted OR Test of heterogeneity Q: 9,29 d.f.: 7 p.value: 0,232 OR=2.78 95% CI (2.21 – 3.47) p<0.001 1.0 5.0 100.0 2.0 10.050.0 0.5 20.0

35. Smoking Habits Results Meta-Analysis 0.1 0.5 5.00.21.0 2.00.05 Hirzalla O (2006) Hua HT (2005) Nesi F (2004) Bianchari F (2003) #1 Bianchari F (2003) #2 Adjusted OR OR=1.00 95% CI (0.99 – 1.01) p=0.987 Test of heterogeneity Q: 4,29 d.f.: 4 p.value: 0,368

36. Resuming the influence of risk factor in patient’s outcome after EOR Hypertension (OR=2.95; p<0.001) Chronic Renal Failure (OR=2.78; p<0.001) Cardiac Disease History (OR=1.93; p<0.001) Female Gender (OR=1.58; p<0.001) Aneurysm Diameter (OR=1.58; p=0.011) Pulmonary Disease History (OR=1.32; p=0.112) Diabetes Mellitus (OR=1.28; p=0.309) Mean Age (OR=1.07; p<0.001) Smoking (OR=1.00; p=0.987) Results Meta-Analysis

37. IntroductionResearch Question and AimsParticipants and MethodsResultsDiscussion

38. Related to study design: Search only in ONE online Database (PubMed). Related to the query: Absence of a unique MeSh term to define “elective open repair”; The “huge” number of risk factors and postoperative complications; Difficulty to define the outcome as <30 days after surgery. Related to studies: Heterogeneity of the studies; Absence of data relative to the most common risk factors; Absence of data relative to risk factors associated outcome. Limits of the Study

39. Epidemiological Data Systematic review revealed: Increased frequency of Male Gender (median 86.9%); Patients are diagnosed with advanced age (mean 71.4 y.o); Increased Aneurism Diameter (mean 5.9 cm); Our results show similar distribution to those shown in literature referring that AAA are more common in men with age ranging 65-75 y.o. and diagnosed with a diameter of the aorta below the renal arteries of >3.0 cm. Gillum RF. J Clin Epidemiol. 1995 Nov;48(11):1289-98. Flemming C, et al. Ann. Intern. Med. 142 (3): 203-11. Lederle FA, et al. Arch Intern Med. 2000;160:1425-30. Discussion of Results Discussion

40. Risk Factors The most common risk factors found were: Male Gender (median 86.9%); Advanced age (mean 71.4 y.o); History of Hypertension, HT (median 60.0%) Smoking Habits (median 54.2%) History of Cardiac Diseases, CDH (median 44.3%) The great majority of studies, including the “ACC/AHA 2005 guidelines” refer age, smoking, and gender as the most significant AAA risk factors, although, hypertension and history of cardiac disease are also considered Lederle FA, et al. Arch Intern Med. 2000;160:1425-30. Hirsch AT, et al. J Am Coll Cardiol 2006 Mar 21;47(6):1239-312 Discussion of Results Discussion

41. Morbidity/Postoperative Complications The median occurrence of Morbidity events was of 31.0%, and the most frequent postoperative complications found were: Respiratory Complications (median 7.5%) Cardiac Complications (median 5.7%) There is a wide variety of postoperative complications, and most of them are correlated with the healthy condition of the patient prior to the surgery, or also to the experience of the surgical team. Nevertheless, it is accepted that between 5-25% of all patients will at least suffer one complication. Hirsch AT, et al. J Am Coll Cardiol 2006 Mar 21;47(6):1239-312 Wilt TJ, et al. Evid Rep Technol Assess (Full Rep). 2006 Aug;(144):1-113. Discussion of Results Discussion

42. Mortality Rate The median frequency of Mortality found was 4.0%. Mortality rates <30days after surgery for patients undergoing EOR ranges between 1-5%, although in some surgical teams this can be 0%. Despite the differential conditions of patients, in-hospital care conditions are extremely important to prevent higher mortality rates. Hirsch AT, et al. J Am Coll Cardiol 2006 Mar 21;47(6):1239-312 Moreover, mortality rates seem to be influenced by patients’ risk factor exposition and therefore can vary within studies. Lederle FA, et al. Arch Intern Med. 2000;160:1425-30. Discussion of Results Discussion

43. Influence of risk factor in patient’s outcome after EOR 1.Smoking is considered to represent a significant risk marker for AAA development, although, statistical analysis revealed that patient’s outcome was not influenced by Smoking Habits. 2.Despite statistical analysis did not provide significant data, Pulmonary Disease History and Diabetes Mellitus may influence the outcome since they represent an increase of 32% and 28%, respectively, in the risk for death after EOR if present. Nevertheless, these two risk factors require more studies to clarify its effect on patients’ outcome. Discussion of Results Discussion

44. Influence of risk factor in patient’s outcome after EOR 3.Statistical analysis revealed that Hypertension or Chronic Renal Failure represent an almost 3-folds increased risk for death after EOR. These risk factors are strictly correlated with patients’ health condition and are extremely important in the recovery after any surgical procedure. 4.As expected Cardiac Disease History represent an increased risk factor for death after EOR (almost 2-folds), since it is common that people who suffered cardiac events may have repetitions shortly in time. Discussion of Results Discussion

45. Influence of risk factor in patient’s outcome after EOR 5.Remarkably interesting is the fact that Female Gender revealed a 58% increase risk of death after EOR. Male gender represent a risk factor, however, when females develop AAA, usually it has more severe consequences and death can occur shortly after surgery. 6.Statistical analysis also revealed that an increment of 1cm of the Aneurysm Diameter represents a 58% increase risk of death after EOR. 7.Age has also proved to influence the risk of death after EOR, with an increment of 7% per year. Discussion of Results

46. Discussion Despite the fact that EOR has been substituted by Endovascular Repair, EOR has proven to have good results in AAA management, but may require experienced surgeons and good in-hospital intensive care unites in order to contribute for the improvement of AAA management. Our study revealed important findings that contribute to the prediction of patient’s outcome after EOR, by simple analysis of risk factor exposition. Moreover, it may allow the development of a decision tree for the selection of patients that can be submitted to EOR and expect a good outcome. Final Conclusions

47. The Influence of Risk Factors on Mortality Rates after Elective Open Repair of Abdominal Aortic Aneurysms (AAA) Class 5 1 st Year Mestrado Integrado em Medicina