ISMICS Consensus Conference and Statements of Randomized Controlled Trials of Off-Pump Versus Conventional Coronary Artery Bypass Surgery.

OBJECTIVE: At this consensus conference, we developed evidence-informed consensus statements and recommendations on the practice of off-pump coronary artery bypass graft (OPCAB) by systematically reviewing and performing meta-analysis of the randomized controlled trials (RCTs) comparing OPCAB and conventional coronary artery bypass (CCAB). METHODS: All RCTs of OPCAB versus CCAB through April 2013 were screened, and 102 relevant RCTs (19,101 patients) were included in a systematic review and meta-analysis (15 RCTs of 9551 high-risk patients; and 87 RCTs of 9550 low-risk patients) in accordance with the Cochrane Collaboration and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology. Consensus statements for the risks and benefits of OPCAB surgery in mortality, morbidity, and resource use were developed based on best available evidence. RESULTS: Compared to CCAB, it is reasonable to perform OPCAB to reduce risks of stroke [class IIa, level of evidence (LOE) A], renal dysfunction/failure (class IIa, LOE A), blood transfusion (class I, LOE A), respiratory failure (class I, LOE A), atrial fibrillation (class I, LOE A), wound infection (class I, LOE A), ventilation time, and ICU and hospital length of stay (class I, LOE A). However, OPCAB may be associated with a reduced number of grafts performed (class I, LOE A) and with diminished graft patency (class IIa, LOE A, with increased coronary reintervention at 1 year and beyond (class IIa, LOE A), as well as increased mortality at a median follow-up of 5 years (class IIb, LOE A). CONCLUSIONS: OPCAB compared with CCAB may improve outcomes in the short-term (stroke, renal dysfunction, blood transfusion, respiratory failure, atrial fibrillation, wound infection, ventilation time, and length of stay). However, over the longer-term, OPCAB may be associated with reduced graft patency, and increased risk of cardiac re-intervention and death.

Drug, devices, technologies, and techniques for blood management in minimally invasive and conventional cardiothoracic surgery: a consensus statement from the International Society for Minimally Invasive Cardiothoracic Surgery (ISMICS) 2011.

OBJECTIVE: The objectives of this consensus conference were to evaluate the evidence for the efficacy and safety of perioperative drugs, technologies, and techniques in reducing allogeneic blood transfusion for adults undergoing cardiac surgery and to develop evidence-based recommendations for comprehensive perioperative blood management in cardiac surgery, with emphasis on minimally invasive cardiac surgery. METHODS: The consensus panel short-listed the potential topics for review from a comprehensive list of potential drugs, devices, technologies, and techniques. The process of short-listing was based on the need to prioritize and focus on the areas of highest importance to surgeons, anesthesiologists, perfusionists, hematologists, and allied health care involved in the management of patients who undergo cardiac surgery whether through the conventional or minimally invasive approach. MEDLINE, Cochrane Library, and Embase databases were searched from their date of inception to May 2011, and supplemental hand searches were also performed. Detailed methodology and search strategies are outlined in each of the subsequently published systematic reviews. In general, all relevant synonyms for drugs (antifibrinolytic, aprotinin, [Latin Small Letter Open E]-aminocaproic acid, tranexamic acid [TA], desmopressin, anticoagulants, heparin, antiplatelets, anti-Xa agents, adenosine diphosphate inhibitors, acetylsalicylic acid [ASA], factor VIIa [FVIIa]), technologies (cell salvage, miniaturized cardiopulmonary bypass (CPB) circuits, biocompatible circuits, ultrafiltration), and techniques (transfusion thresholds, minimally invasive cardiac or aortic surgery) were searched and combined with terms for blood, red blood cells, fresh-frozen plasma, platelets, transfusion, and allogeneic exposure. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of each recommendation. RESULTS AND RECOMMENDATIONS: Database search identified more than 6900 articles, with 4423 full-text randomized controlled trials assessed for eligibility, and the final 125 systematic reviews and meta-analyses were used in the consensus conference. The results of the consensus conference, including the evidence-based statements and the recommendations, are outlined in the text, with references given for the relevant evidence that formed the basis for the statements and recommendations. RECOMMENDATIONS FOR ANTIFIBRINOLYTICS: The lysine analogs ?-aminocaproic acid (Amicar) and tranexamic acid (TA) reduce exposure to allogeneic blood inpatients undergoing on-pump cardiac surgery. These agents are recommended to be used routinely as part of a blood conservation strategy especially in patients at risk of undergoing onpump cardiac surgery (Class I, Level A). It is important not to exceed maximum TA total dosages (50Y100mg/kg) because of potential neurotoxicity in the elderly and open-heart procedures (Class IIb, Level C). Aprotinin is not recommended in adult cardiac surgery until further studies on its safety profile have been performed (Class III, Level A). RECOMMENDATIONS FOR TA IN OFF-PUMP CORONARY ARTERY BYPASS: Tranexamic acid may be recommended as part of a blood conservation strategy in high risk patients undergoing off-pump coronary artery bypass (OPCAB) surgery (Class I, Level A).Tranexamic acid dosing in OPCAB surgery needs further study particularly with regard to possible neurotoxicity such as seizures.In addition, the benefit-risk ratio in OPCAB needs further eludication because of the lower inherent risk for bleeding in this group (Class IIb, Level C). RECOMMENDATIONS FOR DDAVP: DDAVP can be considered for prophylaxis in coronary artery bypass grafting (CABG) surgery, in particular, for patients onASA within 7 days or prolonged CPB more than 140 minutes (Class IIa, Level A). Caution should be used with the DDAVP infusion rate to avoid significant systemic hypotension (Class I, Level A). RECOMMENDATIONS FOR TOPICAL HEMOSTATICS: The routine use of topical antifibrinolytics in cardiac surgery isnot recommended (Class IIa, Level A). Topical fibrin sealants may be considered in clinical situations where conventional approaches of surgical and medical improvement of hemostasis are not effective, that is, with bleeding problems more local than generalized, bearing in mind the blackbox warning of bovine thrombin by the US Food and Drug Administration (Class IIb, Level C).Recommendations for FVIIa:Prophylactic use of FVIIa cannot be recommended because of a significant increase in the risk of thromboembolic events and stroke (Class IIa, Level A).Factor VIIa may be considered in clinical situations where conventional approaches of surgical and pharmacologic hemostasis have failed and uncontrollable hemorrhage poses a high risk of severe and life-threatening outcomes (Class IIb, Level B). RECOMMENDATIONS FOR ERYTHROPOIETIN PLUS IRON: It is reasonable to administer erythropoietin preoperatively to increase red blood cell mass in patients who are anemic or refuse blood products (such as for Jehovah's Witness faith) or who are likely to have postoperative anemia (Class IIa, Level A). RECOMMENDATIONS FOR ANTIPLATELETS BEFORE CARDIAC SURGERY: Acetylsalicylic acid may be continued until surgery (Class IIa,Level B) For stable elective CABG procedures with no drug-elutingstent, stop clopidogrel 5 days before surgery (Class I, Level A).h For stable elective CABG procedures with drug-eluting stents less than 1 year old, consider continuing clopidogrel or heparin as abridge to surgery (Class IIb, Level C).h Direct-acting P2Y12 receptor antagonists may be a better alternative than clopidogrel in acute coronary syndrome patients undergoing CABG surgery (Class IIa, Level B). RECOMMENDATIONS FOR ANTIPLATELETS AFTER CARDIAC SURGERY: In stable CABG surgery (nonYacute coronary syndrome patients), the routine use of postoperative clopidogrel with ASAis not warranted (Class IIb, Level B). RECOMMENDATIONS FOR ACUTE NORMOVOLEMIC HEMODILUTION: Acute normovolemic hemodilution can be considered in selected patients with adequate preoperative hemoglobin to reduce post-CPB bleeding (Class IIa, Level A).The routine use of acute normovolemic hemodilution is not recommended (Class IIb, Level B). RECOMMENDATIONS FOR RETROGRADE AUTOLOGOUS PRIMING: Retrograde autologous priming is recommended as a blood conservation modality to reduce allogeneic blood transfusion for onpump cardiac surgery (Class I, Level A). RECOMMENDATIONS FOR CELL SALVAGE: Routine use of cell salvage is recommended in operations where an increased blood loss is expected (Class 1, Level A). Cell salvage should be used throughout the entire operation and not merely as a replacement for CPB cardiotomy suction (Class IIa, Level A). RECOMMENDATIONS: BIOCOMPATIBLE CPB CIRCUITS: The routine use of biocompatible coated CPB circuitry may be considered as part of a multimodal blood conservation program. However, the heterogeneity of surface-modified products, anticoagulation management, and CPB technique does not significantly impact surgical blood loss and transfusion needs (Class IIb,Level A). RECOMMENDATIONS FOR MINIATURIZED EXTRACORPOREAL CARDIOPULMONARY CIRCUIT VERSUS CONVENTIONAL EXTRACORPOREAL CARDIOPULMONARY CIRCUIT: Miniaturized extracorporeal cardiopulmonary circuit can be considered as a blood conservation technique to reduce allogeneic blood exposure (Class IIa, Level A); however, issues related to heparinization management and biocompatible coatings remain to be clarified. RECOMMENDATIONS FOR ULTRAFILTRATION (CONTINUOUS OR MODIFIED):h Ultrafiltration may be considered for blood conservation (Class IIb, Level A); however, the impact on clinically relevant outcomes remains unknown. RECOMMENDATIONS FOR PLATELET PLASMAPHERESIS:It is reasonable to recommend platelet plasmapheresis for blood management in cardiac surgery (Class IIa, Level A), although the impact on clinically relevant outcomes remains unknown. RECOMMENDATIONS FOR POINT-OF-CARE MONITORING:The evidence is too premature to recommend point-of-caretechnology for routine use because its use has not been shown to impact clinical outcome (Class IIb, Level A). RECOMMENDATIONS FOR SURGICAL TECHNIQUES FOR OPCAB, MINIMALLY INVASIVE STERNOTOMY FOR AORTIC VALVE SURGERY, MINIMALLY INVASIVE STERNOTOMY FOR MITRAL VALVE SURGERY, AND TRANSCATHETHER AORTIC VALVE IMPLANTATION: Although these minimally invasive procedures are not primarily selected for the purpose of blood management, the reduced allogeneic blood exposure should be considered in the balance of benefits and risks when selecting the appropriate surgery for patients.

Minimally invasive versus open mitral valve surgery: a consensus statement of the international society of minimally invasive coronary surgery (ISMICS) 2010.

OBJECTIVE: : The purpose of this consensus conference was to deliberate the evidence regarding whether minimally invasive mitral valve surgery via thoracotomy improves clinical and resource outcomes compared with conventional open mitral valve surgery via median sternotomy in adults who require surgical intervention for mitral valve disease. METHODS: : Before the consensus conference, the consensus panel reviewed the best available evidence up to March 2010, whereby systematic reviews, randomized trials, and nonrandomized trials were considered in descending order of validity and importance. The accompanying meta-analysis article in this issue of the Journal provides the systematic review of the evidence. Based on this systematic review, evidence-based statements were created for prespecified clinical questions, and consensus processes were used to derive recommendations. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of each recommendation. RESULTS AND CONCLUSIONS: : Considering the underlying level of evidence, and notwithstanding the limitations of the evidence base (retrospective studies with important differences in baseline patient characteristics, which may produce bias in results of the evidence syntheses), the consensus panel provided the following evidence-based statements and overall recommendation:In patients with mitral valve disease, minimally invasive surgery may be an alternative to conventional mitral valve surgery (Class IIb), given that there was comparable short-term and long-term mortality (level B), comparable in-hospital morbidity (renal, pulmonary, cardiac complications, pain perception, and readmissions) (level B), reduced sternal complications, transfusions, postoperative atrial fibrillation, duration of ventilation, and intensive care unit and hospital length of stay (level B). However, this should be considered against the increased risk of stroke (2.1% vs 1.2%) (level B), aortic dissection (0.2% vs 0%) (level B), phrenic nerve palsy (3% vs 0%) (level B), groin infections/complications (2% vs 0%) (level B), and, prolonged cross-clamp time, cardiopulmonary bypass time, and procedure time (level B). The available evidence consists almost entirely of observational studies and must not be considered definitive until future adequately controlled randomized trials further address the risk of stroke, aortic complications, phrenic nerve complications, pain, long-term survival, need for reintervention, quality of life, and cost-effectiveness.

Minimally invasive versus conventional open mitral valve surgery: a meta-analysis and systematic review.

OBJECTIVE: : This meta-analysis sought to determine whether minimally invasive mitral valve surgery (mini-MVS) improves clinical outcomes and resource utilization compared with conventional open mitral valve surgery (conv-MVS) in patients undergoing mitral valve repair or replacement. METHODS: : A comprehensive search of MEDLINE, Cochrane Library, EMBASE, CTSnet, and databases of abstracts was undertaken to identify all randomized and nonrandomized studies up to March 2010 of mini-MVS through thoracotomy versus conv-MVS through median sternotomy for mitral valve repair or replacement. Outcomes of interest included death, stroke, myocardial infarction, aortic dissection, need for reintervention, and any other reported clinically relevant outcomes or indicator of resource utilization. Relative risk and weighted mean differences and their 95% confidence intervals were analyzed as appropriate using the random effects model. Heterogeneity was measured using the I statistic. RESULTS: : Thirty-five studies met the inclusion criteria (two randomized controlled trials and 33 nonrandomized studies). The mortality rate after mini-MVS versus conv-MVS was similar at 30 days (1.2% vs 1.5%), 1 year (0.9% vs 1.3%), 3 years (0.5% vs 0.5%), and 9 years (0% vs 3.7%). A number of clinical outcomes were significantly improved with mini-MVS versus conv-MVS including atrial fibrillation (18% vs 22%), chest tube drainage (578 vs 871 mL), transfusions, sternal infection (0.04% vs 0.27%), time to return to normal activity, and patient scar satisfaction. However, the 30-day risk of stroke (2.1% vs 1.2%), aortic dissection/injury (0.2% vs 0%), groin infection (2% vs 0%), and phrenic nerve palsy (3% vs 0%) were significantly increased for mini-MVS versus conv-MVS. Other clinical outcomes were similar between groups. Cross-clamp time, cardiopulmonary bypass time, and procedure time were significantly increased with mini-MVS; however, ventilation time and length of stay in intensive care unit and hospital were reduced. CONCLUSIONS: : Current evidence suggests that mini-MVS maybe associated with decreased bleeding, blood product transfusion, atrial fibrillation, sternal wound infection, scar dissatisfaction, ventilation time, intensive care unit stay, hospital length of stay, and reduced time to return to normal activity, without detected adverse impact on long-term need for valvular reintervention and survival beyond 1 year. However, these potential benefits for mini-MVS may come with an increased risk of stroke, aortic dissection or aortic injury, phrenic nerve palsy, groin infections/complications, and increased cross-clamp, cardiopulmonary bypass, and procedure time. Available evidence is largely limited to retrospective comparisons of small cohorts comparing mini-MVS versus conv-MVS that provide only short-term outcomes. Given these limitations, randomized controlled trials with adequate power and duration of follow-up to measure clinically relevant outcomes are recommended to determine the balance of benefits and risks.

Surgical Ablation for Atrial Fibrillation in Cardiac Surgery: A Consensus Statement of the International Society of Minimally Invasive Cardiothoracic Surgery (ISMICS) 2009.

OBJECTIVE: : This purpose of this consensus conference was to determine whether surgical atrial fibrillation (AF) ablation during cardiac surgery improves clinical and resource outcomes compared with cardiac surgery alone in adults undergoing cardiac surgery for valve or coronary artery bypass grafting. METHODS: : Before the consensus conference, the consensus panel reviewed the best available evidence, whereby systematic reviews, randomized trials, and nonrandomized trials were considered in descending order of validity and importance. Evidence-based statements were created, and consensus processes were used to determine the ensuing recommendations. The American Heart Association/American College of Cardiology system was used to label the level of evidence and class of recommendation. RESULTS: : The consensus panel agreed on the following statements in patients with AF undergoing cardiac surgery concomitant surgical ablation: CONCLUSIONS: : Given these evidence-based statements, the consensus panel stated that, in patients with persistent and permanent AF undergoing cardiac surgery, concomitant surgical ablation is recommended to increase incidence of sinus rhythm at short- and long-term follow-up (class 1, level A); to reduce the risk of stroke and thromboembolic events (class 2a, level B); to improve EF (class 2a, level A); and to exercise tolerance (class 2a, level A) and long-term survival (class 2a, level B).

Surgical ablation for atrial fibrillation in cardiac surgery: a meta-analysis and systematic review.

OBJECTIVES: : This meta-analysis sought to determine whether surgical ablation improves clinical outcomes and resource utilization compared with no ablation in adult patients with persistent and permanent atrial fibrillation (AF) undergoing cardiac surgery. METHODS: : A comprehensive search was undertaken to identify all randomized (RCT) and nonrandomized (non-RCT) controlled trials of surgical ablation versus no ablation in patients with AF undergoing cardiac surgery up to April 2009. The primary outcome was sinus rhythm. Secondary outcomes included survival and any other reported clinically relevant outcome or indicator of resource utilization. Odds ratios (OR) and weighted mean differences (WMD) and their 95% confidence intervals (95% CI) were analyzed as appropriate using the random effects model. Heterogeneity was measured using the I statistic. Meta-regression was performed to explore the relationship between the benefit from surgical AF and duration of follow-up. RESULTS: : Thirty-three studies met the inclusion criteria (10 RCTs and 23 non-RCTs) for a total of 4647 patients. The number of patients in sinus rhythm was significantly improved at discharge in the surgical AF ablation group versus (68.6%) the surgery alone group (23.0%) in RCTs (OR 10.1, 95% CI 4.5-22.5) and non-RCTs (OR 7.15, 95% CI 3.42-14.95). This effect on sinus rhythm (74.6% vs. 18.4%) remained at follow-up of 1 to 5 years (OR 6.7, 95% CI 2.8-15.7 for RCT, and OR 15.5, 95% CI 6.6-36.7 for non-RCT). The risk of all-cause mortality at 30 days was not different between the groups in RCT (OR 1.20, 95% CI 0.52-3.16) or non-RCT studies (OR 0.99, 95% CI 0.52-1.87). In studies reporting all-cause mortality at 1 year or more (up to 5 years), mortality did not differ in RCT studies (OR 1.21, 95% CI 0.59-2.51) but was significantly reduced in non-RCT studies (OR 0.54, 95% CI 0.31-0.96). Stroke incidence was not reduced significantly; however, in meta-regression, the risk of stroke decreased significantly with longer follow-up. Other clinical outcomes were similar between groups. Operation time was significantly increased with surgical AF ablation; however, overall impact on length of stay was variable. CONCLUSIONS: : In patients with persistent or permanent AF who present for cardiac surgery, the addition of surgical AF ablation led to a significantly higher rate of sinus rhythm in RCT and non-RCT studies compared with cardiac surgery alone, and this effect remains robust over the longer term (1-5 years). Although non-RCT studies suggest the possibility of reduced risk of stroke and death, this remains to be proven in prospective RCTs with adequate power and follow-up.

Minimally invasive direct coronary artery bypass and off-pump coronary artery bypass surgery: anesthetic considerations.

Many new surgical technologies are being developed, with the overall aim of improving outcomes. One common feature of many new technologies is that they offer a safer approach than previous techniques; one of the greatest forces for change over the last 30 years is risk reduction. Cardiac surgery risk has been effectively undercut by percutaneous-based procedures, which have offered dramatic reductions in risk--at least in the short term. Beating heart techniques, whether minimally invasive direct coronary artery bypass (MIDCAB), off-pump coronary artery bypass surgery (OPCAB), or in other forms, such as percutaneous valve replacement, are likely to dramatically increase over the next decade. What role OPCAB and MIDCAB techniques will play in this new era is anyone's guess.

Impact of the opening of a specialized cardiac surgery recovery unit on postoperative outcomes in an academic health sciences centre.

PURPOSE: It is controversial as to whether cardiac surgery patients are optimally managed in a mixed medical-surgical intensive care unit (ICU) or in a specialized postoperative unit. We conducted a prospective cohort study in an academic health sciences centre to compare outcomes before and following the opening of a specialized cardiac surgery recovery unit (CSRU) in April 2005. METHODS: The study cohort included 2,599 consecutive patients undergoing coronary artery bypass grafting (CABG), valve and combined CABG-valve procedures from April 2004 to March 2006. From April 2004 to March 2005 (year 1) all patients received postoperative care in mixed medical-surgical ICUs at two different sites staffed by critical care consultants, fellows and residents. From April 2005 until March 2006 (year 2) patients were cared for in a newly-established CSRU on one site staffed by cardiac anesthesiology fellows, a nurse practitioner and consultants in critical care, cardiac anesthesiology and cardiac surgery. The effect of this change on in-hospital mortality, the incidence of ten major postoperative complications, postoperative ventilation hours, readmission rates and case cancellations due to a lack of capacity was assessed using Chi-square or Wilcoxon tests, where appropriate. RESULTS: Coronary artery bypass grafting, valve and combined CABG-valve mortality rates were similar in years 1 and 2. There was a significant reduction in the composite major complication rate (16.3% to 13.0%, P=0.02) and in median postoperative ventilation hours (8.8 vs 8.0 hr, P=0.005) from year 1 to 2. On multivariable logistic regression analysis, the pre-merger interval (year 1) was a significant independent predictor of the occurrence of death or major complications. CONCLUSION: A specialized CSRU with a multi-disciplinary consultant model was associated with stable or improved outcomes postoperatively, when compared to a mixed medical- surgical ICU model of cardiac surgical care.

Randomized assessment of resource use in fast-track cardiac surgery 1-year after hospital discharge.

BACKGROUND: The authors assessed the safety and resource use associated with fast-track cardiac anesthesia (FTCA) after coronary artery bypass graft surgery (CABG) over a 1-yr period. METHODS: One hundred twenty patients were initially randomized to FTCA (n = 60) or conventional anesthetic (n = 60) for primary elective CABG surgery. Patients were followed for 1-yr after index surgery through linkage to universal administrative databases. Acute care hospital readmission rates and length of stay (LOS) and the downstream use of health resources were compared. Resource use was analyzed as use of hospital and rehabilitation center bed-days, expenditures on physician services, and use of cardiac drugs. RESULTS: There were no deaths during the 1-yr follow-up after initial discharge; 15 (25%) patients from both groups were readmitted to acute care hospitals in the follow-up period. The mean LOS for acute care readmission was 0.3 (1.0) in the FTCA and 1.6 (6.3) days in the conventional group at 3 months; P= 0.01, 95% CI (0.1, 5.7) and 0.8 (1.8) and 2.9 (9.6) days at 12 months; P= 0.01, 95% CI (0.2, 7.5). Two (3.3%) patients in the FTCA group and 9 (15%) patients in the conventional group were transferred to rehabilitation facilities. The LOS was 0.3 (1.5) and 2.3 (5.7) days respectively; P= 0.001, 95% CI (0.6, 4.0). Specialist visits were more frequent in the FTCA group 6.2 (13.2) versus 1.9 (2.2) visits respectively; P= 0.002, 95% CI (-9.0, -1.3). Percentage reduction of FTCA cost was 68% at 3 months, P= 0.0002 and 49.5% at 1-yr, P= 0.004 after index hospital discharge. CONCLUSIONS: Fast-track cardiac anesthesia is a safe practice that decreases resource use for a 1-yr period after index hospitalization.

Oxygen therapeutics (blood substitutes) in cardiac surgery.

PURPOSE OF REVIEW: Discuss and summarize recent published literature related to the use of 'blood substitutes' in cardiac surgery patients. RECENT FINDINGS: Concerns about safety, inventory and the cost of allogenic blood transfusion have led to the continued interest to find an ideal oxygen carrier 'blood substitute' for cardiac surgery patients. Two classes of oxygen therapeutics 'blood substitutes' are being investigated: (1) perfluorocarbons are synthetic fluorinated hydrocarbons which increase dissolved oxygen in the fluid phase and (2) hemoglobin-based oxygen carriers, modified to improve oxygen dissociation properties and side effects profiles of free hemoglobin. Hemoglobin-based oxygen carriers from bovine and human sources are being tested in phase III trials in cardiac surgery patients as well as a variety of other surgical and nonsurgical settings. Recombinant human hemoglobin and encapsulated hemoglobins of any source are emerging. Safety and cost effectiveness are being evaluated for their use as an alternative to blood transfusion or along with other strategies of blood conservation in cardiac surgery. SUMMARY: One hemoglobin-based oxygen carrier (Hemopure) has been approved for use in humans in South Africa as well as another hemoglobin-based oxygen carrier (Gelenpol) and a perfluorocarbon (Perfluoron) in Russia. Phase III trials in Europe and North America will be concluded very soon. We anticipate seeing one or two products approved in North America and Europe by the year 2003/2004.