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Program Of Master of Public Health in Biostatistics 516 705: Statistical Methods in Clinical Trials Effect of percutaneous transvenous mitral commissurotomy on resolution of left atrial thrombus in mitral stenosis patients Protocol January 2001 Advisor: Bandit Thinkhamrop, Ph.D. Student: Truong Nguyen, MD Principal investigator: Songkwan Silaruks, MD Department of Biostatistics and Demography Faculty of Public Health Khon Kaen University 1 Table of contents 1.SUMMARY ................................................................................................................................... 2 2.DESCRIPTION OF THE PROJECT ......................................................................................... 3 2.1.INTRODUCTION AND IDENTIFICATION THE PROBLEM .............................................................. 3 2.2.JUSTIFICATION ......................................................................................................................... 3 2.3.GOALS AND OBJECTIVES .......................................................................................................... 3 2.4.HYPOTHESIS ............................................................................................................................. 4 3.STUDY DESIGN ........................................................................................................................... 5 3.1.INTERVENTIONS ....................................................................................................................... 5 3.1.1.Experimental arm: OA and PTMC ................................................................................... 5 3.1.2.Control arm: OA only ....................................................................................................... 5 3.2.METHODOLOGY ....................................................................................................................... 5 3.2.1.Study population:.............................................................................................................. 5 3.2.2.Sample size: ...................................................................................................................... 5 3.2.3.Random allocation technique: .......................................................................................... 6 3.2.4.Blinding: ........................................................................................................................... 6 3.2.5.Outcome and outcome measurement:............................................................................... 7 3.2.6.Follow-up procedures: ..................................................................................................... 7 3.3.DATA ANALYSIS ....................................................................................................................... 9 Interim analysis: ........................................................................................................................ 9 Stopping rules:........................................................................................................................... 9 3.4.ETHICAL CONSIDERATION ...................................................................................................... 10 4.DURATION OF THE TRIAL ................................................................................................... 10 5.EXPECTED OUTCOME OF THE STUDY ............................................................................ 10 6.BUDGET ...................................................................................................................................... 10 7.REFERENCES ............................................................................................................................ 10 8.APPENDICES ............................................................................................................................. 11 APPENDIX 8.1 ............................................................................................................................... 12 Study information .................................................................................................................... 12 Consent form ........................................................................................................................... 14 APPENDIX 8.2 DATA COLLECTION FORM ...................................................................................... 15 APPENDIX 8.3 DUMMY TABLES .................................................................................................... 17 Table 1. Characteristics of patients at trial entry ................................................................... 17 Table 2. The different rate of complete LAT resolution after 4 and 6 months of treatment .... 17 of NYHA functional class and complication between two group ............................................ 17 Table 3. Multivariate logistic regression results: treatment effects on complete LAT ............ 18 resolution adjusted for potential confounding factors............................................................. 18 APPENDIX 8.4 TIMELINE FOR THE TRIAL ...................................................................................... 19 APPENDIX 8.5.ALGORITHM FOR RECORDING ALL PATIENTS DURING THE TRIAL PERIOD ............ 20 APPENDIX 8.6 ............................................................................................................................... 21 Allocation instructions............................................................................................................. 21 Sequence of treatment allocating ............................................................................................ 22 2 1.Summary Background: Mitral stenosis (MS) is one of a common life-threatening health problem in the developing countries. Approximately 25% of MS patients have thrombus in left atrium. This will frequently lead to systemic embolism. The optimal treatment to remove the thrombus is to perform surgery. However percutaneous transvenous mitral commissurotomy (PTMC) has become an effective and safe alternative to surgical treatment of severe MS but the presence of left atrial thrombus (LAT) is generally considered a contraindication to this procedure. Additionally, in developing countries, surgical treatment is not only far too expensive but also can not meet the increasing demand. Patients have to wait for the surgery for approximately 9 - 15 months. While they were waiting, they must take an oral anticoagulant (OA) regularly. By this, LAT of some patients were dissolved and thus can perform PTMC safely. Successful resolution of LAT has been reported in our previous study. However the duration of LAT to disappear is considerably long, i.e., the mean duration of LAT resolution was 16 months. This means the MS patients are taking the risk of embolism during this period. Another study conducted by some of our members showed that PTMC could be performed safely if thrombus is confined in LA appendage. We belief that the improvement of hemodynamic status may enhances the resolution of the thrombus. Thus the combination of PTMC and OA is expected to shorten the duration of LAT resolution. Therefor, a randomized controlled trial is needed to demonstrate that. Findings from this trial will contribute enormously to the developing world. Aside from saving life and improving the quality of life of the patients, replacing surgery with PTMC and OA combined could save a large amount of money per year. Objective: The main objective is to compare the rate of complete LAT resolution between treated by OA only and the combination PTMC and OA at 4 and 6 months after treatment. Methods: This will be a hospital-based, parallel, single blind, randomized controlled trial. Study subjects refer to MS patients with thrombus confined in LA appendage who do not have absolute contraindications of performing PTMC, and their hemodynamic status are stable. We exclude those who have contraindications of performing TEE, or not satisfy the conditions of performing PTMC right after randomization, or pregnant. The primary outcome is complete LAT resolution at 4 and 6 months after the treatment. Subjects will be randomly allocated to be treated by OA only or combination OA and PTMC using block randomization with varied block size of 2, 4, and 6. The sample size of 115 for each arm was planned to have the power of 80% to detect 10-20% difference rates of complete LAT resolution after 4 months of treatment between the two arms, with significance level of 0 . 0 5 , t w o - s i d e d t e s t . 3 2.Description of the project 2.1.Introduction and identification the problem Rheumatic heart disease, sequelae of rheumatic fever, is more common in developing than developed countries. As a result, mitral stenosis (MS) is higher in the developing ones. Approximately 25% of MS patients have thrombus in left atrium. This will frequently lead to systemic embolism. The optimal treatment to remove the thrombus is to perform surgery. However percutaneous transvenous mitral commissurotomy (PTMC) has become an effective and safe alternative to surgical treatment of severe MS, particularly when regurgitation and valvular calcifications are limited. 1-5 But the presence of left atrial thrombus (LAT) is generally considered a contraindication to this procedure because of embolic risk, which may arise when catheters and wires are manipulated in the left atrium.1-6 Figure 1 presents conceptual framework pathophysiology of LAT and its current t r e a t m e n t . In developing countries, surgical treatment is not only far too expensive but also can not meet the increasing demand. Patients have to wait for the surgery for approximately 9 - 15 months. While they were waiting, they must take an oral anticoagulant (OA) regularly. By this, LAT of some patients were dissolved and thus can perform PTMC safely. Successful resolution of LAT has been reported in our previous study. 7 However the duration of LAT to disappear is considerably long, i.e., the mean duration of LAT resolution was 16 months. This means they are taking the risk of embolism during this period. Another study conducted by some of our members showed that PTMC can be performed safely if thrombus is confined in LA appendage.8 We belief that the improvement of hemodynamic status may enhance the resolution of the thrombus. Thus the combination of PTMC and OA is expected to shorten the duration of LAT resolution. A randomized controlled trial is needed to demonstrate that. Findings from this trial will contribute enormously to the developing world. Aside from saving life and improving the quality of life of the patients, replacing surgery with PTMC and OA combined could save a large amount of money per year. Unit cost of an opened heart surgery is more than triple as much as that of PTMC, i.e., around 2500USD c o m p a r e d w i t h 7 0 0 U S D r e s p e c t i v e l y . 2.2.Justification Due to the evidence of a high prevalence of MS with LAT and the long waiting list for mitral valve surgery leading to the risk of systemic embolism of the patients, an alternative approach is urgently needed. Although there was an evidence that LAT can be dissolved by OA only and then the PTMC can be performed safely and successfully, the patients are still at risk of embolism unnecessarily due to the long course of OA. The positive findings of a randomized controlled trial could strongly effect the current management of MS patients with LAT locally and other developing countries. 2.3.Goals and objectives The ultimate goal of this clinical trial is to reduce mortality and morbidity of MS patients due to systemic embolism and improve their quality of life. At the end of this trial, it will 4 be established whether the combination PTMC and OA can be an alternative treatment for MS patient having thrombus confined in LA appendage. The main objective is to compare the rate of complete LAT resolution between treated by OA only and the combination PTMC and OA at 4 and 6 months after treatment. 2.4.Hypothesis The hypothesis to be tested in this trial is that, among MS patients, the rate of complete LAT resolution at 4 and 6 months after treated by combination PTMC and OA is higher than by OA alone. Figure 1. Conceptual framework pathophysiology of LAT and current treatment Dislodge 25% Mitral stenosis Systemic embolism Thrombus in LA 20% among patients having atrial fibrillation Dilated atrium Atrial fibrillation Sluggish flow TREATMENT Surgery is unavailable Perform surgery if available Recover normal hemodynamic status Remove thrombus Candidate of PTMC (-) Oral anticoagulation Wait for surgery Candidate of PTMC (+) Oral anticoagulation (INR = 2.5 to 3.5) Perform PTMC after thrombus disappears Change to surgery if hemodynamic is unstable Conditions of performing PTMC: Do not have clot in LA, or the clot is small, fixed in LA appendage Absolute contraindications: thrombus attached to the atrial septum, thrombus close to the mitral orifice or mobile thrombus Regurgitation and valvular calcification are limited 5 3.Study design This will be a hospital-based, parallel, single blind, randomized controlled trial. Overview of the trial is shown in Figure 2. 3.1.Interventions 3.1.1.Experimental arm: OA and PTMC Patients will be treated by OA. PTMC will be performed as soon as possible by an experienced operator while the LAT still exists. After the procedure, OA will still be continued The dose will be adjusted based on the International Normalized Ratio (INR), preferably, ranges from 2.5 to 3.5 or as high as the patients can tolerate. This range of INR has been suggested by Songkwan et al (2001). 3.1.2.Control arm: OA only All patients will be treated by oral anticoagulation with the adjusted dose based on INR similar to what was described in the experimental arm. PTMC will be performed only after the thrombus had been disappeared. 3.2.Methodology 3.2.1.Study population: MS patients have thrombi in left atrial appendage and are candidates for PTMC. Inclusion criteria: MS patients with thrombus confined in LA appendage. Do not have absolute contraindications of performing PTMC Hemodynamic status is stable Exclusion criteria: Have contraindications of performing TEE. Not satisfy the conditions of performing PTMC right after randomization. Pregnant women. 3.2.2.Sample size: From previous study (Silaruks, 1999), among 108 mitral stenosis patients there were 48 patients whose LAT area are smaller 2 cm2. By treating with OA only, the rate of complete LAT resolution in this group is 68.75% (33 patients) after 6 months of follow-up. In this trial, all patients will be performed TEE to measure the thrombus at 4 and 6 months after the beginning of treatment. The combination of OA and PTMC has been expected to gain a better result. The sample size will be calculated to detect the difference between two thrombus disappearance rates after 4 months, at significant level of 95% and power of 80% (two-sided test), using the approach of Lachin that was reviewed in the paper of Donner, 1984.9 n { Z 2 P ( 1 P ) Z PE ( 1 PE ) PC ( 1 PC ) } 2 / 2 Where: PC = anticipated thrombus disappearance rate among control group patients PE = anticipated thrombus disappearance rate among experimental group patients P = (PC + PE)/2 6 = (PE – PC) = the difference in even rates regarded as clinically important to detect n = the number of patients in per group Table: Required sample size at different rate of thrombus disappearance P-control P-experimental Alpha level Power Patients in one group 0.50 0.58 5% 80% 691.79 0.50 0.60 5% 80% 386.90 0.50 0.63 5% 80% 245.78 0.50 0.70 5% 80% 92.90 0.60 0.69 5% 80% 442.07 0.60 0.72 5% 80% 243.17 0.60 0.75 5% 80% 151.70 0.60 0.80 5% 80% 81.13 The sample size of 93 patients in each group will be chosen because of its feasibility. Such sample size can detect 20% difference of thrombus disappearance rate between two groups, at 95% significant level, with the power of 80%. The anticipated drop out rate is about 10%. Thus, the sample size will be inflated as following: n = 93 / (1-0.1)2 = 114.8 Finally, the required number of patients for each group is 115 3.2.3.Random allocation technique: After signing on the consent form, all eligible patients will be enrolled in the trial and then randomized to receive the treatment of OA only or OA and PTMC. The method of block randomization, with block size varies from 2 to 6, will be used to allocate treatments. The allocation ratio is 1:1. The allocation sequence will be generated by computer, using STATA software. Based on the obtained schedule, the number of sealed envelopes, which are equal to the required blocks, will be prepared and labeled. Each envelope contains the corresponding sealed allocation cards that will allocate treatments to patients. The instruction of allocation process is given in appendix 8.6. The people, who prepare the randomized scheme, will not involve in the trial. The allocation schedule will be concealed until the end of trial. 3.2.4.Blinding: Because of the difference between two treatments, only the observers, who measure the outcome (LAT size), will be blinded from the treatments. 7 The echocardiographers will assess the thrombus through videotape record, which does not include patient’s name. They will be provided only the picture of left atrial appendage. The status of mitral valve will be kept secret in order to ensure that the treatment can not be guessed 3.2.5.Outcome and outcome measurement: The main outcome is complete LAT resolution. It is measured by TEE. The TEE will be performed at 4 and 6 months after the treatment. 3.2.6.Follow-up procedures: Patients will be asked to return for clinical examination, monitoring INR every 3 months or whenever they experience any discomfort. They will also return at 4 and 6 months to perform TEE Drop out could happen in the following manners: Control arm Died of complication of MS Change to surgery because unstable hemodynamic status Change to PTMC because of preference of patients Experiment arm Died of complication of MS Change to surgery because unstable hemodynamic status 8 Figure 2. Design overview of the study Mitral stenosis TEE routinely: 25%MS have LAT Ideally treated by surgery LAT (-) LAT (+) The present study Candidate of PTMC (-) Candidate of PTMC (+) OA Wait for surgery Recruitment eligible patients Random allocation OA as usual PTMC when LAT disappears New treatment: PTMC + OA Expected duration is shorter Measure clot size by TEE, after 4 months of treatment Repeat TEE 2 months later, if clot still remained at 4 month-TEE Primary outcome: complete resolution of LAT measured by TEE 9 3.3.Data analysis There were two main parts of analysis – describing selected characteristics of the study patients and analysis for answering the research questions. The first part, selected baseline characteristics of the patients in each treatment were compared i.e. age, sex, underlying diseases, etc. Comparability of the distribution of those selected characteristics based on judgment rather than statistical significant tests. In this part, proportion was use for summarizing categorical data. For continuos data, the statistics include mean, standard deviation, minimum, maximum, and median. For the second part, the analysis was based on the group in which the study patients were randomized (intention-to-treat basis). The different rate of complete resolution between the two arms of the trial and its 95% confidence interval will be calculated. This will be done at 4 and 6 months after the treatment. Z-test will be used for testing if such differences are different from zero. Multiple logistic regression will be used to control effects of some baseline imbalance, if any. The statistical analysis of this clinical trial will be performed based on intention to treat principle. All hypothesis tests are two-tailed at significant level of 0.05. Statistical package for all analysis is STATA. Interim analysis: The necessary duration for recruitment is estimated about 48 months. Interim analyses are planned to be performed every 10 months, thus, the number of interim analyses will be 4. The stopping boundaries are constructed based on the approach of O’Brien and Fleming as the following: Interim analysis number 1 2 3 4 Zc 4.084 2.888 2.358 2.042 p-value 0.00005 0.0039 0.0184 0.0412 Stopping rules: Let the thrombus disappearance rates of control and experimental groups, at the first interim analysis, are pc and pe, respectively. The test statistic of treatment effect is given by Z = pe - pc / se (pe - pc) The null hypothesis (pe = pc) will be rejected if Zis larger than the corresponding Zc, that was specified above. The above steps will be repeated for each subsequent interim analysis until the trial is stopped or until it is finished. Crossed stopping boundary is just the statistical guideline, not the rule, for terminating the trial early. Making decision of early trial termination should consider other factors rather than only the statistical guideline. 10 3.4.Ethical consideration This trial protocol, which includes the study information and consent form (appendix 1), must be accepted by the Ethical Committee before to start recruiting patients into the study. The investigator must ensure that all patients will be received adequate verbal and written information about the purpose, procedures, potential risk and benefit of the study. The investigator must be responsible to obtain the appropriate consent form from the patients before to recruit patients into the study. 4.Duration of the trial A timeline is given in appendix 8.4 to indicate the estimated time that various stages of the trial will take to complete. It is anticipated that the whole trial need more than 4 years to complete if this time schedule is adhered to. The recruitment will begin right after obtaining the approval of Ethical Committee. Such long duration of recruitment is the limitation of this trial. 5.Expected outcome of the study It will be established whether the LAT resolution rate is higher among group treated by combination PTMC and OA, compared to those treated by OA only. If so, the combination PTMC and OA will become the new approach for mitral stenosis patients having LAT. The result of this study then will be published and applied not only to the developing countries, but also to all over the world. In this study, PTMC will be performed by only one high experience operator. To guarantee the safety of the procedure if the new treatment has been established, the next necessary steps is to train the cardiology operators in order to make them have ability to do PTMC successfully in mitral stenosis patients having LAT. 6.Budget 7.References 1. 2. 3. 4. 5. Participants NBR. Multicenter experience with balloon mitral commissurotomy. NHLBI Balloon Valvuloplasty Registry Report on immediate and 30-day follow-up results. The National Heart, Lung, and Blood Institute Balloon Valvuloplasty Registry Participants. In: Circulation; 1992:448-61. Inoue K, Owaki T, Nakamura T, Kitamura F, Miyamoto N. Clinical application of transvenous mitral commissurotomy by a new balloon catheter. J Thorac Cardiovasc Surg. 1984; 87:394-402. Vahanian A, Michel PL, Cormier B, Vitoux B, Michel X, Slama M, Sarano LE, Trabelsi S, Ben Ismail M, Acar J. Results of percutaneous mitral commissurotomy in 200 patients. Am J Cardiol. 1989; 63:847-52. Nobuyoshi M, Hamasaki N, Kimura T, Nosaka H, Yokoi H, Yasumoto H, Horiuchi H, Nakashima H, Shindo T, Mori T, et al. Indications, complications, and short-term clinical outcome of percutaneous transvenous mitral commissurotomy. Circulation. 1989; 80:782-92. Hung JS, Chern MS, Wu JJ, Fu M, Yeh KH, Wu YC, Cherng WJ, Chua S, Lee CB. Short- and long-term results of catheter balloon percutaneous transvenous mitral commissurotomy. Am J Cardiol. 1991; 67:854-62. 11 6. 7. 8. 9. Kronzon I, Tunick PA, Glassman E, Slater J, Schwinger M, Freedberg RS. Transesophageal echocardiography to detect atrial clots in candidates for percutaneous transseptal mitral balloon valvuloplasty. J Am Coll Cardiol. 1990;16:1320-2. Silaruks S. Resolution of left atrial thrombi with anticoagulant therapy in candidates for percutaneous transvenous mitral commissurotomy. Unpublished. 1999. Tansuphasawadikul S., Silaruk S. Transesophageal echocardiography during percutaneous mitral commissurotomy in patients with left atrial thrombus. In press. Donner A. Approaches to sample size estimation in the design of clinical trials - A review. Statistics in medicine. 1984; 3:199-214. 8.Appendices 8.1.Consent form and statement 8.2.Data collection form 8.3.Dummy tables 8.4.Timeline for the trial 8.5.Algorithm for recording all patients during the trial period 8.6.Allocation instructions 12 Appendix 8.1 STUDY INFORMATION We would like to know if you would be interested in taking part in an experimental study being carried out to evaluate the new treatment of mitral stenosis patients in Thailand. We provide the follow information in order to help you know more about this study. General description: The symptomatic mitral stenosis patients will be treat currently by PTMC. PTMC is an operation that widens the stenosed mitral valve orifice and make the heart function recovered. Currently, if patients have clot in left atrium, they must take drug to make clot disappear before being performed PTMC. The average duration to wait for clot disappearance is 16 months. We do not know whether performing PTMC while the clot still does exist will shorten the duration of clot disappearance. The purpose of this study is to find this out. The patients entering this study will be followed up 6 months with two times of ultrasound checking, and then they will be changed to the usual follow-up schedule. Treatment procedures: The conventional treatment is taking drug and then performing PTMC after clot disappears. The test treatment is performing PTMC first and then taking drug. The patients will randomly receive either conventional or test treatment. If you do not want to participate in this study, you will receive the conventional treatment. Risks and discomforts: PTMC is an operation, so the patient may suffer a complication at a certain level, however, we confirm that it is very rare. We will let only the operator having high experience performs PTMC for you. Please note that, even in case you do not participate in this study, you will receive the conventional treatment for mitral stenosis that will also include PTMC at finally. After 4 and 6 months of treatment, you will be checked by ultrasound. We will put a small probe in your esophagus to examine whether or not the clot has disappeared. It may cause you a little discomfortable. This feeling will vanish right after the procedure. Benefit: The possible benefit, if you randomly receive the test treatment, is your heart function may improve earlier compared to the conventional treatment. All medications and tests are of charge. Only examinations and ultrasound checking at 6 months will be provided to you free. The information obtained from this study will enable us to help other patients with this disease. Confidentiality: Data, including personal information such as name and address, will be stored in a computer. All personal information is confidential and available only to study personnel. No report will be presented or published which reveal your identity. 13 Responsibilities of patient: Participate in this study entirely voluntary. You have the right to withdraw from the study at any time that will in no way affect to care or treatment you are receiving. However, anyone who drops out after enrollment reduces the scientific value of the study. Hence, you should not participate in if you are uncertain about the value of this study or if you know that you can not fulfill the study requirement. Otherwise, you should be compliant to your doctor after your participation. If you are satisfied with the explanation of this study and do decide to participate in it, p l e a s e s i g n t h e a t t a c h e d c o n s e n t f o r m . If you have any question, please feel free to ask your doctor or nurse. 14 Consent form Study title Effect of percutaneous transvenous mitral commissurotomy on resolution of left atrial thrombus in mitral stenosis patients Principal investigator: Purpose of study: To evaluate whether the combination percutaneous transvenous mitral commissurotomy and oral anticoagulation can be an alternative treatment of surgery for mitral stenosis patient having left atrial thrombus. Consent statement I have read the foregoing information, or it has been read to me. I have had the opportunity to ask any question and I have satisfied with all answers. I consent to participate in this study to evaluate the effect of percutaneous transvenous mitral commissurotomy on resolution of left atrial thrombus in mitral stenosis patients, as outlined above. I understand that I am free to withdraw my consent at any time without, in any way, affecting my current and future care and without losing any benefits. Signature:……………………………………….. Date: ___/___/___ I, Dr. ____________________, the principle investigator, have explained the purpose, procedure, potential risk and benefit of this study to __________________ Signature:…………………………………….. Date: ___/___/___ 15 Appendix 8.2 DATA COLLECTION FORM ID: Effect of percutaneous transvenous mitral commissurotomy on resolution of left atrial thrombus in mitral stenosis patients 2.7.Diabetus mellitus 1.Yes 2.No Day/ month/ year Patient number 2.8.Hypertension 1.Yes 2.No Name:…………………………………………… Address:…………………………………..…… 2.9.Smoking 1.Yes 2.No 1.Status 1.1 Age (years) 2.10.Hemoptysis 1.Yes 2.No 1.2.Sex 1.Male 2.Female 2.11.Dyspnea on exertion 1.Yes 2.No 1.3.Occupation 1.Farmer 3.Commercial 2.Officer 4.Employment 2.12.Admission for CHF 1.Yes 2.No 3.NYHA class (class I-IV) 2.History 2.1.Duration (months) (from first symptom to visiting doctor) 2.2.Congestive heart failure 2.2.1.Paroxysmal nocturnal dyspnea 1.Yes 2.No 4.Prothrombin time 4.1.Baseline, INR 4.2.At 3m, INR 2.2.2.Orthopnea 1.Yes 2.No 4.3.At 6m, INR 2.3.Syncope 1.Yes 2.No 2.4.Stroke 1.Yes 2.No 5.EKG 5.1.Atrial fibrillation 1.Yes 2.No 5.2.LA enlarge 1.Yes 2.No 2.5.Peripheral embolism 1.Yes 2.No 5.3.RAE 1.Yes 2.No 2.6.Palpitation 1.Yes 2.No 5.4.RVH 1.Yes 2.No 16 6.ECHO 6.1.MVA (2D) (cm2) 6.2.Pressure-half time 6.10.LA clot after 6 months 6.10.1.LA clot size at 6m Width (mm) Length (mm) Area (mm2) 6.3.Mitral valve score (4-16) 6.10.3.Number of LA clot at 6m (1-5) 6.4.LA diameter (mm) 6.5.Mitral regurgitation (grade 1-4) 6.6.Triscupid regurgitation (m/sec) 6.7.LASEC (grade 1-4) 6.8.LA clot 6.8.1.LA clot size Width (mm) Length (mm) Area (mm2) 6.8.2.Mobility of clot 1.Mobile 2.Linear 3.Fixed 6.8.3.Number of LA clot (1-5) 6.9.LA clot after 4 months 6.9.1.LA clot size at 4m Width (mm) Length (mm) Area (mm2) 6.9.2.Number of LA clot at 4m (1-5) 7.Follow up 7.1.Complication Stroke 1.Yes 2.No Peripheral embolism 1.Yes 2.No Infective endocarditis 1.Yes 2.No 7.2.NYHA class after 6m (class I-IV) 8.Drop out 1.Yes 2.No If yes, specify:…………….. 17 Appendix 8.3 Dummy tables Table 1. Characteristics of patients at trial entry Values refer to number (%) unless indicated otherwise PTMC and OA (n= ) Characteristics OA only (n= ) Mean age (SD), years Male : Female Smoking Atrial fibrillation NYHA Class II Class III-IV Mean INR (SD) LA thrombus Mean width (SD), cm Mean length (SD), cm Mean area (SD), cm2 Mean LA diameter (SD), cm Mean mitral valve score (SD) Mitral regurgitation Grade II Grade III-IV Mean MVA (SD), cm2 LASEC on TEE Grade 2 Grade 3 Grade 4 Table 2. The different rate of complete LAT resolution after 4 and 6 months of treatment of NYHA functional class and complication between two group PTMC and OA (n= ) % Complete LAT resolution After 4 months After 6 months NYHA after 6 months Class I Class II Class III-IV Complication NNTs (95%CI): OA only (n= ) % Different rate (95%CI) p-value 18 Table 3. Multivariate logistic regression results: treatment effects on complete LAT resolution adjusted for potential confounding factors Treatment PTMC and OA OA only LA area (1cm2 increase) LASEC on TEE Grade 1 Grade 2 Grade 3 Grade 4 INR after 3 months Crude OR (95%CI) Adjusted OR (95%CI) 1 1 1 1 p-value 19 Timeline for the trial Appendix 8.4 2000 Jan Feb 2001 Mar Apr Protocol development Ethics application Recruitment Interim analysis Analysis Reporting The necessary duration for recruitment is estimated about 48 months. Feb Dec 2001 2003 Sep Jun 2004 Mar Apr May Jun 20 Appendix 8.5. Algorithm for recording all patients during the trial period Total number of eligible MS patients (n = …) Randomization (n = …) Not randomized (n = …) Reasons Refused consent Other, specify ……………………… …………… Received control treatment as allocated Did not received control treatment as allocated Received test treatment as allocated Did not received test treatment as allocated Followed up after 4 months Followed up after 6 months Followed up after 4 months Followed up after 6 months Withdraw Died of MS complication Change to surgery Change to PTMC Completed trial (n = …) Withdraw Died of MS complication Change to surgery Other Completed trial (n = …) n 21 Appendix 8.6 Allocation instructions Effect of percutaneous transvenous mitral commissurotomy on resolution of left atrial thrombus Description of allocation scheme: The scheme was prepared for allocating a total of 230 patients. These were randomly divided into 61 blocks with varied block size. One sealed envelope refers to one block. The block size also randomly varies from 2 to 6, i.e., there are 2, 4 or 6 allocation cards within each sealed envelope. Each allocation card was sealed by 3 stickers. In the last sentence of each allocation card, there is one number corresponding with the sequence of patients within block. Name of patient and hospital number must be recorded before breaking the seals. There is the code of treatment inside each allocation card. How to allocate patients? When the first eligible patient entry the trial, Block 1 will be opened. Then the Allocation card within each block will be broken. This has to be done in sequence as specified in the Allocation number. By this process, the code of treatment will be identified as either “PTMC and OA” or “OA only”. The next block then will be opened in sequence as specified in the Block number. Role of people involving in allocation process: There should be one nurse in charge in management the allocation process. Once a patient was enrolled and the doctor asked for the allocation code, she will be the one who opens the envelope. First, she has to choose the allocation card in the sequence, then records the patient’s name and the hospital number before breaking the allocation card, and finally reads the type of treatment to the doctor. She is also the one who keeps all allocation cards for further reference. The doctor will know what type of treatment to be provided to a certain patient only after asking the nurse who is in charge in the allocation process. The echocardiographers must not aware of what type of treatment was given to a patient whose image was being measured for the outcome. 22 Sequence of treatment allocating The first column: code of patients The second column: code of blocks The third column: size of blocks The fourth column: sequence of patient within block The fifth column: treatments NOTE: the following sequence is just an example to demonstrate how the sequence of treatment allocating is. It is different with the true sequence of the clinical trial. 1 1 2 1 PTMC+OA 139 37 6 1 PTMC+OA 2 1 2 2 OA 140 37 6 2 OA 3 2 4 1 OA 141 37 6 3 PTMC+OA 4 2 4 2 PTMC+OA 142 37 6 4 OA 5 2 4 3 PTMC+OA 143 37 6 5 PTMC+OA 6 2 4 4 OA 144 37 6 6 OA 7 3 4 1 OA 145 38 2 1 PTMC+OA 8 3 4 2 OA 146 38 2 2 OA 9 3 4 3 PTMC+OA 147 39 4 1 OA 10 3 4 4 PTMC+OA 148 39 4 2 OA 11 4 4 1 PTMC+OA 149 39 4 3 PTMC+OA 12 4 4 2 PTMC+OA 150 39 4 4 PTMC+OA 13 4 4 3 OA 151 40 2 1 OA 14 4 4 4 OA 152 40 2 2 PTMC+OA 15 5 4 1 PTMC+OA 153 41 6 1 OA 16 5 4 2 PTMC+OA 154 41 6 2 PTMC+OA 17 5 4 3 OA 155 41 6 3 PTMC+OA 18 5 4 4 OA 156 41 6 4 OA 19 6 2 1 OA 157 41 6 5 OA 20 6 2 2 PTMC+OA 158 41 6 6 PTMC+OA 21 7 4 1 OA 159 42 2 1 OA 22 7 4 2 OA 160 42 2 2 PTMC+OA 23 7 4 3 PTMC+OA 161 43 4 1 OA 24 7 4 4 PTMC+OA 162 43 4 2 OA 25 8 2 1 OA 163 43 4 3 PTMC+OA 26 8 2 2 PTMC+OA 164 43 4 4 PTMC+OA 27 9 4 1 PTMC+OA 165 44 2 1 PTMC+OA 28 9 4 2 PTMC+OA 166 44 2 2 OA 29 9 4 3 OA 30 9 4 4 OA