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REVIEWS A Meta-Analysis of Minimally Invasive Versus Conventional Sternotomy for Aortic Valve Replacement Kevin Phan, BS(Adv), Ashleigh Xie, Marco Di Eusanio, MD, PhD, and Tristan D. Yan, MBBS, PhD The Collaborative Research (CORE) Group, Macquarie University, Sydney, New South Wales, Australia; Cardiovascular Surgery Department, Sant’Orsola-Malpighi Hospital, Bologna University, Bologna, Italy; and Department of Cardiothoracic Surgery, Royal Prince Alfred Hospital, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia Minimally invasive aortic valve replacement (AVR) is increasingly used as an alternative to conventional AVR, despite limited randomized evidence available. To assess the evidence base, a systematic search identified 50 comparative studies with a total of 12,786 patients. A metaanalysis demonstrated that minimally invasive AVR is associated with reduced transfusion incidence, intensive care stay, hospitalization, and renal failure, and has a mortality rate that is comparable to conventional AVR. The evidence quality was mostly very low. Given the inadequate statistical power and heterogeneity of available studies, prospective randomized trials are needed to assess the benefits and risks of minimally invasive AVR approaches. (Ann Thorac Surg 2014;98:1499–511) Ó 2014 by The Society of Thoracic Surgeons M Material and Methods Address correspondence to Dr Yan, The Collaborative Research (CORE) Group, 2 Technology Pl, Macquarie University, Sydney, NSW 2109, Australia; e-mail: tristanyan@annalscts.com. Ó 2014 by The Society of Thoracic Surgeons Published by Elsevier Literature Search Strategy Electronic searches were performed using Ovid Medline, PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, American College of Physicians Journal Club, and Database of Abstracts of Review of Effectiveness from their date of inception to November 2013. To achieve the maximum sensitivity of the search strategy, the terms “minimally invasive” or “ministernotomy” or “minithoracotomy” or “robotic” and “aortic valve” and “surgery” were combined as key words or medical subject heading terms. The reference lists of all retrieved articles were reviewed for further identification of potentially relevant studies. Selection Criteria Eligible studies for the present systematic review and meta-analysis included comparative studies in which patient cohorts underwent MIAVR by ministernotomy and minithoracotomy vs conventional sternotomy. When duplicate studies with accumulating numbers of patients or increased lengths of follow-up were published, only the most complete reports were included for quantitative assessment at each time interval. All publications were limited to those that involved human subjects. Abstracts, The Supplementary Table 1 and Supplementary Figures 1 and 2 can be viewed in the online version of this article [http://dx.doi.org/10.1016/j.athoracsur.2014. 05.060] on http://www.annalsthoracicsurgery.org. 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.05.060 REVIEW inimally invasive aortic valve replacement (MIAVR) was first described by Cosgrove and Sabik in 1996 [1]. Since this pioneering study, minimally invasive surgical techniques for AVR have increasingly gained acceptance in the surgical realm, with the aim of achieving equivalent or superior outcomes compared with conventional AVR (CAVR). Encouraging institutional reports of surgical efficacy, reduced trauma, shorter hospitalization, and improved cosmesis have propelled the expansion of MIAVR in recent years [2–4]. Several randomized controlled trials (RCTs) have assessed the efficacy and risks of MIAVR compared with CAVR [5–11]. However, the small sample sizes and insufficient reporting of postoperative outcomes have left these studies underpowered. Previous studies have demonstrated similar rates of mortality and morbidity for MIAVR and CAVR, but the available evidence for some outcomes was inadequate, thus limiting its applicability to clinical decision making [12]. To assess the evidence base with adequate power, we initiated a meta-analysis in which RCTs and non-RCTs were included. To determine whether minimally invasive surgical interventions are an adequate modality for AVR, the present meta-analysis compared clinical outcomes of MIAVR by ministernotomy or minithoracotomy vs CAVR. 1500 REVIEW PHAN ET AL META-ANALYSIS OF MIAVR VS CAVR case reports, conference presentations, editorials, and expert opinions were excluded. Review articles were omitted because of potential publication bias and duplication of results. Data Extraction and Critical Appraisal of Evidence All data were extracted from article texts, tables, and figures. Two investigators independently assessed and reviewed each retrieved article (K.P, A.X.). Expert advice from international authorities was consulted (M.D.E, T.D.Y.). Discrepancies between the reviewers were resolved by discussion and consensus. The senior investigator (T.D.Y.) reviewed the final results. Statistical Analysis Clinical outcomes were analyzed using standard and cumulative meta-analysis, with the risk ratio (RR) or weighted mean difference (WMD) used as a summary statistic. In the present study, fixed-effects and randomeffect models were both tested. The fixed-effects model assumed that treatment effect in each study was the same, whereas the random-effects model assumed that there were variations between studies. The c2 test was used to study heterogeneity between trials. The I2 statistic was used to estimate the percentage of total variation across studies, owing to heterogeneity rather than chance, with values greater than 50% considered as substantial heterogeneity [13]. If there was substantial heterogeneity, the possible clinical and methodologic reasons were explored Fig 1. Search strategy of meta-analysis of minimally invasive vs conventional aortic valve replacement (AVR). (TAVI ¼ transcatheter aortic valve implantation.) Ann Thorac Surg 2014;98:1499–511 qualitatively. All p values were two-sided. The statistical analysis was conducted with Review Manager 5.2.1 software (Cochrane Collaboration, Software Update, Oxford, United Kingdom) and Comprehensive Meta-Analysis 2.2 software (Biostat, Englewood, NJ). Assessment and Evaluation of the Quality of Evidence The risk of bias assessment in RCTs was performed according to Cochrane methodology, considering random sequence generation, allocation concealment, blinding of participants, personnel and outcome assessment, incomplete outcome data, and selective reporting [13]. The quality of evidence for each main outcome was assessed using the Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) scoring system [14], using GRADE profiler 3.2.2. software. Results Literature Search A total of 959 references were identified through 6 electronic database searches. After detailed evaluation of these articles and assessment according to inclusion criteria, 50 comparative studies were selected for analysis, as shown in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) chart (Fig 1) [15], comparing 5,162 MIAVR patients and 7,624 CAVR patients. REVIEW Ann Thorac Surg 2014;98:1499–511 REVIEW PHAN ET AL META-ANALYSIS OF MIAVR VS CAVR 1501 Table 1. Studies of Minimally Invasive Aortic Valve Replacement vs Conventional Aortic Valve Replacement Included in the Current Meta-Analysis Study Type UK USA NR 1996–1997 Matched OS OS 14 17 14 14 1999 Spain NR RCT 20 20 Byrne [26] Chang [27] Christiansen [28] Liu [29] Machler [7] Szwerc [30] Walther [31] Ehrlich [32] Lee [33] 1999 1999 1999 1999 1999 1999 1999 2000 2000 1996–1999 NR 1996–1997 1996–1998 1996–1997 1997–1998 1996–1997 1998–1999 1997–1999 OS OS OS OS RCT OS OS OS OS 19 18 29 86 60 50 36 6 46 20 16 84 78 60 50 84 21 40 Bonacchi [8] 2002 USA Taiwan Germany Germany Austria USA Germany Germany Republic of Korea Italy 1999–2001 RCT 40 40 Detter [34] Doll [35] 2002 2002 Germany Germany 1999–2001 1999–2000 OS OS 70 176 70 258 Masiello [36] De Vaumas [37] Corbi [38] Dogan [5] Farhat [39] 2002 2003 2003 2003 2003 Italy France France Germany France 1997–1999 NR 1997–2000 NR 2000 OS Matched OS OS RCT OS 100 41 30 20 50 100 41 70 20 50 Stamou [40] 2003 USA 1997–2001 OS 56 455 De Smet [41] Mihaljevic [42] 2004 2004 Belgium USA NR 1996–2003 OS OS 100 526 91 516 Sharony [16] Suenaga [43] Tyszka [44] 2004 2004 2004 USA Japan Brazil 1995–2002 1998–2000 2002–2003 PSM OS OS 233 24 12 233 18 12 Vanoverbeke [45] Wheatley [46] 2004 2004 Belgium USA 1997–2001 1998–2002 OS OS 174 58 97 58 Bakir [47] Leshnower [48] Moustafa [9] Tabata [17] Calderon [11] Foghsgaard [49] Brinkman [4] 2006 2006 2007 2007 2009 2009 2010 Turkey USA Egypt USA France Denmark USA 1997–2004 2000–2004 NR 1996–2005 2003–2007 2003–2007 1996–2009 OS OS RCT PSM RCT OS OS 232 22 30 73 38 98 90 274 36 30 67 39 50 360 Korach [3] Ruttmann [18] Hiraoka [50] 2010 2010 2011 Israel Austria Japan 1995–2005 2006–2009 2006–2011 OS PSM OS 164 87 37 302 87 107 Bang [19] 2012 1997–2010 PSM 73 765 Fortunato J unior [51] Johnston [20] 2012 Republic of Korea Brazil 2006–2011 OS 40 20 2012 USA 1995–2004 PSM 1,193 1,496 Year Bridgewater [24] Frazier [25] 1998 1998 Aris [6] Country MIAVR (No.) CAVR (No.) MIAVR Approach Transverse sternotomy Right parasternal thoracotomy Reverse L or C ministernotomy Upper ministernotomy I-shaped ministernotomy J-shaped ministernotomy Upper ministernotomy L-shaped ministernotomy J-shaped ministernotomy Upper ministernotomy J-shaped ministernotomy Transverse and upper sternotomy Reverse L or C ministernotomy L-shaped ministernotomy J or reverse T-shaped ministernotomy Upper ministernotomy Minithoracotomy V-shaped ministernotomy Reverse L ministernotomy Reverse T-shaped ministernotomy L or reverse T ministernotomy J-shaped ministernotomy Upper or parasternal ministernotomy Minithoracotomy Upper ministernotomy Superior median ministernotomy Upper ministernotomy Port access with minithoracotomy J-shaped minithoracotomy Inverted T ministernotomy Reverse L ministernotomy Upper ministernotomy Reverse L ministernotomy Upper ministernotomy Port access with minithoracotomy Upper ministernotomy Anterolateral minithoracotomy Port access with minithoracotomy Upper or transverse ministernotomy Right anterolateral minithoracotomy Upper J ministernotomy (Continued) REVIEW Study Period First Author 1502 REVIEW PHAN ET AL META-ANALYSIS OF MIAVR VS CAVR Ann Thorac Surg 2014;98:1499–511 Table 1. Continued Country Study Period Study Type MIAVR (No.) CAVR (No.) First Author Year Klokocovnik [52] 2012 Slovenia 1996–2010 OS 217 236 Murzi [21] 2012 Italy 2006–2011 PSM 100 100 Sansone [53] Ahangar [10] Gilmanov [22] 2012 2013 2013 Italy India Italy 2005–2010 2010–2012 2004–2011 OS RCT PSM 50 30 182 50 30 182 Glauber [23] Mikus [54] Paredes [55] Pineda [56] 2013 2013 2013 2013 Italy Italy Spain USA 2005–2010 2007–2012 2007–2012 2005–2011 PSM OS OS OS 138 38 83 36 138 52 532 41 MIAVR Approach Upper ministernotomy or minithoracotomy Right anterior minithoracotomy Right minithoracotomy Minithoracotomy Ministernotomy and minithoracotomy Right minithoracotomy Upper J ministernotomy Upper J ministernotomy Right minithoracotomy CAVR ¼ conventional aortic valve replacement; UK ¼ United Kingdom; MIAVR ¼ minimally invasive aortic valve replacement; NR ¼ not reported; OS ¼ observational study; PSM ¼ propensity-score matched; RCT ¼ randomized controlled trial; USA ¼ United States of America. Table 2. Quality of Evidence Assessment for Clinical Outcomes by the Grades of Recommendation, Assessment, Development and Evaluation Working Group Approach Patient: Setting: REVIEW Requires aortic valve replacement UK, USA, Spain, Taiwan, Germany, Austria, Republic of Korea, Italy, France, Japan, Brazil, Belgium, Turkey, Egypt, Denmark, Israel, Slovenia, Kashmir, Spain Minimally invasive aortic valve replacement Conventional aortic valve replacement Quality of Evidence Main Reasons for Rating 1, 2 for RCTs, 1, 2, 7 for non-RCTs 1, 2, 7 for RCTs, 1, 2, 7, 8 for non-RCTs 1, 2, 5, 7 for RCTs, 1, 2, 7, 8 for non-RCTs 1, 7, 8 for non-RCTs 1, 2, 8 for RCTs, 1, 2, 3, 8 for non-RCTs 1, 2 for RCTs and non-RCTs 1, 5, 7 for RCTs, 1, 7, 8 for non-RCTs 1, 2, 4, 7 for RCTs, 1, 2, 7, 8 for non-RCTs 1, 2, 5, 7 for non-RCTs 1, 2, 7 for RCTs 1, 2, 7, 8 for non-RCTs 1, 2, 5, 7, 8 for non-RCTs 1, 2, 7 for non-RCTs 1, 2 for RCTs,1, 2, 8 for non-RCTs 1, 2, 5, 7 for RCTs, 1, 2, 7 for non-RCTs 2, 7 for RCTs, 1, 2, 5, 7, 8 for non-RCTs 1, 7, 8 for non-RCTs 1, 3, 4, 5, 7, 8 for non-RCTs Intervention: Comparison: Outcomes Mortality Neurologic Renal failure Respiratory failure Transfusions Reoperation for bleeding Atrial fibrillation Pacemakers Myocardial infarction Pericardial effusions Pneumonia Pleural effusions Sternal/wound infection Pneumothorax Prolonged ventilation Pain Cost Limitation in design: 1. Not blinded (blind method for patients, surgeons and staff not mentioned). 2. There may be bias in some studies (not contemporary studies, not consecutive enrolment, pilot study, different operative skills). 3. Significant heterogeneity, might not be sufficiently explained. 4. Only one study. 5. Small sample size, small number of studies, small number of events. 6. The 95% confidence interval for total effect was too wide. 7. Potential publication bias. 8. Because different complications were reported in different studies, there may be publication bias. Quality of evidence: ¼ very low; RCT ¼ randomized controlled trial; ¼ low; UK ¼ United Kingdom; ¼ moderate; ¼ high. USA ¼ United States of America. Ann Thorac Surg 2014;98:1499–511 REVIEW PHAN ET AL META-ANALYSIS OF MIAVR VS CAVR 1503 Table 3. Summary of Perioperative Characteristics and Complications Outcome Major outcomes Perioperative death Neurologic events Renal failure Respiratory failure Operative variables Cross-clamping CBP Total operative time Intubation, h ICU stay, d Length of stay, d Hematologic outcomes Transfusion Reoperation for bleeding Cardiac events Atrial fibrillation Pacemaker implant Myocardial infarction Study Type Studies, No. % of Mini % of Full Overall RCT Non-RCT Overall RCT Non-RCT Overall RCT Non-RCT Overall RCT Non-RCT 46 5 41 29 2 27 19 0 19 10 0 10 1.9 2.5 1.9 2.2 1.3 2.2 2.5 . 2.5 3.6 . 3.6 3.3 3.1 3.3 2.2 0 2.3 4.2 . 4.2 5.3 . 5.3 Overall RCT Non-RCT Overall RCT Non-RCT Overall RCT Non-RCT Overall RCT Non-RCT Overall RCT Non-RCT Overall RCT Non-RCT 45 7 38 43 6 37 19 5 14 23 6 17 31 5 26 38 7 31 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Overall RCT Non-RCT Overall RCT Non-RCT 19 3 16 33 4 29 36.0 40.8 35.8 4.7 3.8 4.6 52.4 53.5 53.4 4.9 5.7 4.5 0.77 0.77 0.77 0.97 0.79 1.04 Overall RCT Non-RCT Overall RCT Non-RCT Overall RCT Non-RCT 23 2 21 12 1 11 14 0 14 23.5 13.3 23.8 3.3 0 3.4 0.4 . 0.4 24.7 8.3 25.0 4.0 0 4.1 0.7 . 0.7 0.91 1.60 0.90 0.82 RR/WMD (95% CI) 0.74 0.83 0.73 0.99 3 0.98 0.72 (0.56–0.96) (0.24–2.83) (0.56–0.96) (0.73–1.34) (0.12–72.20) (0.72–1.32) (0.53–0.99) . 0.72 (0.53–0.99) 0.67 (0.01–2.53) . 0.67 (0.01–2.53) 8.09 2.64 9.05 8.16 4.63 8.74 8.97 –19.71 16.03 –4.05 –1.04 –5.39 –0.60 –0.69 –0.60 –1.34 –1.16 –1.50 p Value (95% CI) 1.00 0.77 0.99 0.81 . 0.79 0.88 . 0.88 0.18 . 0.18 I 2 0 0 0 0 . 0 0 . 0 28 . 28 p Value for Overall Effect 0.02 0.77 0.02 0.93 0.50 0.88 0.04 0.04 0.08 . 0.08 (5.40–10.79) (–1.45 to 6.73) (5.87–12.24) (4.14–12.19) (-3.29–12.54) (4.18–13.29) (–1.69 to 19.62) (–70.20 to 30.77) (5.21–26.85) (–5.87 to –2.23) (–3.43 to 1.35) (–8.83 to –1.94) (–0.95 to –0.25) (–1.08 to –0.29) (–1.00 to –0.21) (–1.73 to –0.95) (–2.17 to –0.15) (–1.95 to –1.05) <0.00001 0.0009 <0.00001 <0.00001 <0.0001 <0.00001 <0.00001 <0.00001 <0.00001 <0.00001 <0.00001 <0.00001 <0.00001 0.03 <0.00001 <0.00001 <0.00001 <0.00001 94 79 94 95 87 95 93 97 91 98 98 98 98 72 98 90 88 91 <0.00001 0.21 <0.00001 <0.0001 0.25 0.0002 0.10 0.44 0.004 <0.0001 0.39 0.002 0.0007 0.0007 0.003 <0.00001 0.02 <0.00001 (0.66–0.90) (0.58–1.03) (0.65–0.91) (0.80– 1.18) (0.24–3.54) (0.82–1.33) <0.00001 0.40 <0.00001 0.83 0.34 0.75 72 0 76 0 10 0 0.001 0.08 0.003 0.78 0.69 0.73 34 0 38 0 . 0 0 . 0 0.13 0.38 0.11 0.26 . 0.26 0.54 . 0.54 (0.80–1.03) (0.55–4.62) (0.79–1.02) (0.57–1.16) . 0.82 (0.57–1.16) 0.78 (0.35–1.74) . 0.78 (0.35–1.74) 0.05 0.71 0.04 0.76 . 0.76 0.77 . 0.77 (Continued) REVIEW Heterogeneity 1504 REVIEW PHAN ET AL META-ANALYSIS OF MIAVR VS CAVR Ann Thorac Surg 2014;98:1499–511 Table 3. Continued Heterogeneity Outcome Pericardial effusions Pulmonary events Pneumonia Pleural effusion Sternal infection Pneumothorax Pain scores Study Type Studies, No. % of Mini % of Full RR/WMD (95% CI) Overall RCT Non-RCT 11 3 8 7.0 1.8 8.2 2.6 10.9 1.3 2.39 (0.83–6.90) 0.41 (0.01–13.49) 4.15 (1.98–8.71) Overall RCT Non-RCT Overall RCT Non-RCT Overall RCT Non-RCT Overall RCT Non-RCT Overall RCT Non-RCT 5 0 5 7 1 6 31 4 27 6 0 6 9 5 4 3.6 . 3.6 8.4 0 8.7 0.9 1.4 0.9 4.7 . 4.7 . . . 2.9 . 2.9 4.6 0 4.7 1.5 2.1 1.4 2.2 . 2.2 . . . 1.23 (0.68–2.23) . 1.23 (0.68–2.23) 1.41 (0.97–2.04) . 1.41 (0.97–2.04) 0.71 (0.47–1.08) 0.76 (0.08–7.21) 0.71 (0.46–1.09) 1.57 (0.70–3.53) . 1.57 (0.70–3.53) –0.87 (–1.43 to –0.31) –0.66 (–1.16 to –0.16) –1.15 (–1.99 to –0.32) p Value (95% CI) 0.02 0.06 0.66 0.46 . 0.46 0.55 . 0.55 0.97 0.23 0.97 0.29 . 0.29 <0.00001 <0.0001 <0.00001 I 2 p Value for Overall Effect 55 72 0 0.11 0.061 0.0002 18 . 18 0 . 0 0 29 0 19 . 19 95 85 94 0.49 . 0.49 0.07 . 0.07 0.11 0.81 0.11 0.28 . 0.28 0.002 0.010 0.007 CBP ¼ cardiopulmonary bypass; CI ¼ confidence interval; Full ¼ conventional aortic valve repair; ICU ¼ intensive care unit; Mini ¼ minimally invasive aortic valve repair; RCT ¼ randomized controlled trial; RR ¼ relative risk; WMD ¼ weighted mean difference. REVIEW Quality Assessment Patient Characteristics Included were seven RCTs (n ¼ 477) [5–11], eight propensity score–matched studies (n ¼ 5,147) [16–23], and 35 observational studies (n ¼ 7162; Table 1) [3, 4, 24–56]. Twenty-two studies [5, 6, 8–11, 24–28, 32, 33, 37, 43, 44, 48, 50, 51, 54–56] included fewer than 100 patients, including six of seven RCTs, thus downgrading the quality of the evidence (Table 2). Aside from the small sample sizes, the RCTs also failed to specify the methods used for blinding, and whether blinding was applied to all patients, surgeons, or surgical staff. Blinding of patients, surgeons, or surgical staff was also not specified for follow-up examinations. Five studies [16, 20, 40, 42, 47] investigated more than 500 patients. The ministernotomy approach was used in 34 studies [3, 5–9, 11, 17, 19, 20, 24, 26–36, 38–45, 48, 49, 54, 56], the minithoracotomy approach was used in 14 studies [4, 10, 16, 18, 21, 23, 25, 37, 46, 47, 50, 51, 53, 56], and two studies [22, 52] used mixed incisions. Perioperative deaths, cross-clamping, cardiopulmonary bypass (CBP), intensive care unit (ICU) stay, and hospitalization were well reported by at least six RCTs and 38 non-RCT studies. However, other outcomes were poorly reported by randomized studies, including neurologic events, renal failure, respiratory failure, atrial fibrillation, pacemaker implantations, myocardial infractions, and pulmonary events. The outcomes were assessed using the GRADE approach (Table 3). The seven RCTs were also assessed qualitatively using tools recommended by the Cochrane Collaboration for risk of bias (Supplementary Figs 1 and 2). Baseline patient characteristics such as age (64.3 vs 65.7 years), gender (59.2% vs 57.4% male), left ventricular ejection fraction (0.47 vs 0.468), neurologic events (12.8% vs 15.6%), diabetes (8.6% vs 8.5%), hypertension (60.5% vs 58.7%), and renal failure (4.5% vs 5.6%) were not significantly different between MIAVR and CAVR cohorts (Supplementary Table 1). The indications for aortic operations were also similar, with the predominant pathology being aortic stenosis (65.6% vs 65.3%), followed by mixed aortic pathology (21.2% vs 24.2%) and aortic regurgitation (19.8% vs 19.6%). Cross-Clamp, CBP, and Operative Times Cross-clamp duration was significantly longer for the MIAVR group overall (WMD, 8.09 minutes) and in non-RCTs (WMD, 9.05 minutes) but was comparable for RCTs. CBP duration was also longer for MIAVR compared with CAVR overall (WMD, 8.16 minutes) and in non-RCTs (WMD, 9.05 minutes), but no difference was observed for RCTs. Greater overall operative duration for the MIAVR group was also observed for non-RCTs (WMD, 16.03 minutes) but not for RCTs. All crossclamp, CBP and operative outcomes were significantly heterogeneous with I2 exceeding 50% (Table 3). Perioperative Deaths Overall, early deaths were significantly lower in the MIAVR arm compared with CAVR arm (1.9% vs 3.3%). This difference was not significant for RCTs but was Ann Thorac Surg 2014;98:1499–511 REVIEW PHAN ET AL META-ANALYSIS OF MIAVR VS CAVR 1505 REVIEW Fig 2. Perioperative mortality in patients undergoing minimally invasive aortic valve replacement (MIAVR) vs conventional aortic valve replacement (CAVR). (M-H ¼ Mantel-Haenszel test.) The solid squares denote the risk ratio and are proportional to the weights used in the meta-analysis. The solid vertical line indicates no effect. The diamond denotes the weighted risk ratio, and the lateral tips of the diamond indicate the associated confidence intervals (CIs). The horizontal lines represent the 95% CIs. significant for non-RCTs (1.9% vs 3.3%). Subgroup analysis demonstrated that this significant difference was evident for the ministernotomy approach (2.0% vs 3.5%) but not for the minithoracotomy approach (1.2% vs 2.3%; Fig 2). Cumulative meta-analysis of early mortality outcomes showed that the risk ratio and point values have stabilized in recent years, with decreasing 95% confidence intervals and p values (Fig 3). Neurologic Events and Renal Failure No significant difference was found between MIAVR and CAVR for neurologic events overall (Fig 4), for RCTs and in non-RCTs. Renal failure occurred less frequently in the minimally invasive group in non-RCTs (2.5% vs 4.2%) but was not reported in RCTs (Table 3). Pulmonary Events and Sternal/Wound Infection Respiratory failure was also comparable between MIACR and CAVR in non-RCTs, but was not well reported in RCTs. No significant differences were found between the MIAVR and CAVR groups in rates of pneumonia, pleural effusion, pneumothorax, and sternal/wound infections across all studies. Subgroup analysis also showed significantly fewer wound infections in the minithoracotomy 1506 REVIEW PHAN ET AL META-ANALYSIS OF MIAVR VS CAVR Ann Thorac Surg 2014;98:1499–511 Fig 3. Cumulative perioperative mortality in patients undergoing minimally invasive aortic valve replacement (MIAVR) vs conventional aortic valve replacement (CAVR). The solid squares denote the cumulative risk ratio and are proportional to the weights used in meta-analysis. The solid vertical line indicates no effect. The diamond denotes the weighted mean risk ratio, and the lateral tips of the diamond indicate the associated confidence intervals (CIs). The horizontal lines represent the 95% CIs. REVIEW group (0.3% vs 2.0%) compared with the conventional group, but no difference was observed for ministernotomy (1.0% vs 1.3%; Fig 5). Cardiac Events No significant difference was observed between MIAVR and CAVR for atrial fibrillation, pacemaker implants, myocardial infarctions, and pericardial effusions across all studies. However, pericardial effusions were significantly greater in the MIAVR group in non-RCTs (8.2% vs 1.3%; Table 3). Hematologic Outcomes The frequency of perioperative transfusions was lower with MIAVR than with CAVR overall (36.0% vs 52.4%) and in non-RCTs (35.8% vs 53.4%) but was comparable in RCTs. Reoperations for bleeding were comparable between the two arms across all studies (Table 3). Pain Nine studies reported pain scores. The pooled WMD was –0.87 points, suggesting less pain with the minimally invasive approach (Fig 6). The differences were also maintained when considering only RCTs (WMD, –0.66 points) or non-RCTs (WMD, –1.15 points; Table 3). ICU and Hospital Days The MIAVR group required significantly fewer days in the ICU compared with the conventional sternotomy group overall (WMD, –0.60 days), in RCTs (WMD, –0.69 days), and in non-RCTs (WMD, –0.60 days). Length of stay was also shorter in the MIAVR group overall (WMD, –1.34 days), RCTs (WMD, –1.16 days), and in non-RCTs (WMD, –1.50 days). There was significant heterogeneity across the studies for ICU and length of stay outcomes (Table 3). Ann Thorac Surg 2014;98:1499–511 REVIEW PHAN ET AL META-ANALYSIS OF MIAVR VS CAVR 1507 Comment The present meta-analysis demonstrated that MIAVR can be safely performed, with no significant difference in mortality rates when considering only RCTs. However, given the small sizes of the RCTs, averaging 40 patients per arm, and the low mortality rate associated with AVR procedures, it is necessary to include non-RCTs to expand the available evidence and yield adequate power to determine any differences. Furthermore, cumulative meta-analyses demonstrated that the magnitude and precision of early-mortality point values have both stabilized in recent years, which may reflect the technical maturation or learning curve associated with MIAVR. Evidence from the current literature supports that MIAVR has at least comparable mortality rates to the full sternotomy approach. The available evidence remains inconsistent and limited when considering alternative minimally invasive approaches such as minithoracotomy [16, 18, 23]. Subgroup analysis in the present study demonstrated that ministernotomy techniques were associated with lower mortality compared with full sternotomy, whereas minithoracotomy was comparable. However, these results may have been profoundly influenced by factors such as patient selection and enthusiasm, skill, and prominence of the surgeon, introducing bias into reports of new minimally invasive surgical techniques. In contrast, a study by Miceli and colleagues [57] that directly compared ministernotomy vs minithoracotomy approaches demonstrated comparable in-hospital mortality (1.3% vs 1.2%). In light of the lack of robust evidence, future prospective randomized trials should directly compare and assess the benefits and risks of ministernotomy and minithoracotomy approaches. We found no statistically significant difference between MIAVR and CAVR in perioperative respiratory failure, reoperations for bleeding, atrial fibrillation, pacemaker implants, myocardial infarctions, pneumonia, pleural effusions, sternal infections, or pneumothorax. Although Gammie and colleagues [58] previously suggested that minimally invasive operations are associated with higher incidence of cerebrovascular accidents, this was not reflected in the current meta-analysis, where no difference was found in neurologic events. REVIEW Fig 4. Neurologic events in patients undergoing minimally invasive aortic valve replacement (MIAVR) vs conventional aortic valve replacement (CAVR). (M-H ¼ Mantel-Haenszel test.) The solid squares denote the risk ratio and are proportional to the weights used in the meta-analysis. The solid vertical line indicates no effect. The diamond denotes the weighted risk ratio, and the lateral tips of the diamond indicate the associated confidence intervals (CIs). The horizontal lines represent the 95% CIs. 1508 REVIEW PHAN ET AL META-ANALYSIS OF MIAVR VS CAVR Ann Thorac Surg 2014;98:1499–511 Fig 5. Sternal/wound complications in patients undergoing minimally invasive aortic valve replacement (MIAVR) vs conventional aortic valve replacement (CAVR). (M-H ¼ Mantel-Haenszel test.) The solid squares denote the risk ratio and are proportional to the weights used in the meta-analysis. The solid vertical line indicates no effect. The diamond denotes the weighted risk ratio, and the lateral tips of the diamond indicate the associated confidence intervals (CIs). The horizontal lines represent the 95% CIs. REVIEW The minimally invasive approach to AVR has advantages of decreased ICU days and hospital stay, which may be attributed to the reduced surgical trauma associated with MIAVR. Furthermore, subgroup analysis demonstrated decreased wound infections with minithoracotomy than with ministernotomy and CAVR. These benefits may be translated from the smaller incision, sternum preservation, and integrity of the costal cartilages associated with the minithoracotomy approach. Our meta-analysis demonstrated a significantly reduced incidence of renal failure and transfusions associated with MIAVR but also documented a fivefold increase in pericardial effusions. The reduction in renal failure may be attributed to the significantly lower use of blood products in the MIAVR cohort, which is associated with the development of renal failure in patients undergoing cardiac operations [59]. The smaller incisions of MIAVR would result in less hemorrhage and surgical trauma. Although proponents of CAVR have argued that these advantages of MIAVR are offset by drawbacks of longer operation durations, the current meta-analysis indicates that differences in CPB and cross-clamp durations are, in fact, relatively short (range, 8 to 9 minutes). Given the reduced surgical trauma of MIAVR, MIAVR was expected to induce less postoperative pain than CAVR. Greater stretching of the sternum and increased sternal fractures during a full sternotomy may be responsible for an increased pain profile after CAVR compared with a minimally invasive approach [60]. Pain scores were significantly reduced in the MIAVR group. The significant heterogeneity is likely due to the lack of standardized strategy to pain scoring strategy or pain management protocol among the few studies that reported postoperative pain outcomes. Thus, use of pool estimates of pain scores has limited usefulness in this context. One study [30] performed quantitative cost-analysis of its MIAVR program, whereas seven studies discussed costs qualitatively [16, 28, 35, 39, 42, 45, 56]. Szwerc and colleagues [30] retrospectively studied 50 patients who underwent MIAVR by partial upper sternotomy vs 50 CAVR patients. The direct and indirect costs of the two groups were comparable ($17,410 $7,485 vs $16,382 $9,674), attributed to the similar duration of CBP, ICU stay, and hospitalization length of both groups. This contrasts with earlier reports [1, 61] that claimed a 19% Ann Thorac Surg 2014;98:1499–511 REVIEW PHAN ET AL META-ANALYSIS OF MIAVR VS CAVR 1509 Fig 6. Pain scores in patients undergoing minimally invasive aortic valve replacement (MIAVR) vs conventional aortic valve replacement (CAVR). (IV ¼ inverse variance; SD ¼ standard deviation.) The solid squares denote the mean difference and are proportional to the weights used in the meta-analysis. The solid vertical line indicates no effect. The diamond denotes the weighted mean difference, and the lateral tips of the diamond indicate the associated confidence intervals (CIs). The horizontal lines represent the 95% CIs. Future Directions The limitations of this meta-analysis emphasize the current deficiencies in the evidence base, where conclusions regarding the benefits and risks of MIAVR vs CAVR cannot be made definitively. This reinforces the need for adequately powered, multiinstitutional, prospective RCTs that directly compare MIAVR vs CAVR and ministernotomy vs minithoracotomy approaches. Costeffectiveness analyses are also required to inform future policies and evidence-based surgical guidelines. To address the lack of standardized definitions and reporting criteria for several critical variables, such as pain and economics analysis, clinical consensus by the international AVR community needs to be attained. Uniform and consistent reporting formats and grading systems will help ensure the validity of comparisons of future institutional studies. In conclusion, current evidence suggests that MIAVR is associated with reduced death, ICU stay, hospitalization, renal failures, transfusions, and pain, but only slightly longer durations of cross-clamping and CPB. Given the paucity of high-quality evidence, a multicenter prospective RCT should be conducted prospectively with adequate power and follow-up duration to measure clinical, resource, and time-related outcomes to definitively assess MIAVR procedures. References 1. Cosgrove DM 3rd, Sabik JF. 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