Thromboprophylaxis in Cancer Patients with Central Venous Catheters by Annie Young A thesis submitted to The University of Birmingham for the degree of DOCTOR OF PHILOSOPHY College of Medical and Dental Sciences Birmingham, November 2010 Acknowledgments I would like to acknowledge my supervisors, Professors Collette Clifford and Keith Wheatley who have inspired me to participate in and lead research for the past 15 years and who have encouraged and supported me to complete this thesis. I would like to thank many of the Clinical Trials Team in Birmingham, in particular Gulnaz Begum, Laura Buckley and Cindy Billingham who steered me through some of the statistical analysis. I must also acknowledge the excellent clinical teams in the 68 UK centres who participated in the WARP trial, many of whom I have now met. Lastly and most importantly, I would like to express appreciation to all the patients, willing to be randomised into the trial. After all these years, even though I have never met them, I feel I know or knew them well. Thank you. Dedicated to my family: David, my remarkable husband who put up with me hiding in the study night after night and my three wonderful and patient children, Stewart, Sarah and Fiona; my dad, two sisters, who care for me always and in memory of my mum who died in November 2008 and when well, constantly encouraged me to „go for it‟. 2 CONTENTS 1. Glossary 18 2. Abstract 20 3. Introduction and Background 21 3.1 Introduction 21 3.2 Aims and Objectives of Thesis 23 3.3 Background 24 3.3.1 Venous Thromboembolism 24 3.3.2 The Clotting Process 24 3.3.2.1 Introduction 24 3.3.2.2 Primary Haemostasis 25 3.3.2.2.1 Platelet Activation 25 3.3.2.3 Thrombotic Cascade 27 3.3.2.3.1 Tissue Factor 29 3.3.2.3.2 Thrombin 32 3.3.2.3.3 Phospholipid Membrane 32 3.3.2.4 Regulation of blood coagulation by anticoagulant factors 33 3.3.2.5 Removal of clot by fibrinolysis 35 3.3.3 Anticoagulant Drugs 37 3.3.3.1 Warfarin 37 3.3.3.1.1 Mechanism of action of warfarin 37 3.3.3.1.2 Pharmacokinetics of warfarin 39 3.3.3.1.3 Laboratory investigation for warfarin: International Normalised Ratio (INR) 40 3 3.3.3.1.4 Complications of warfarin therapy 41 3.3.3.1.5 INR variations in cancer patients 42 3.3.3.1.6 Interaction between warfarin and other drugs 42 3.3.3.2 Low Molecular Weight Heparin 44 3.3.3.2.1 Mechanism of Action 44 3.3.3.2.2 Pharmacokinetic Profile 45 3.3.3.2.3 Side effects 45 3.3.3.3 New Anticoagulants 45 3.3.4 Thrombotic Events Associated with Carcinogenesis 46 3.3.4.1 Introduction 46 3.3.4.2 Tumour Biology: Link between Cancer and Thrombosis 47 3.3.4.3 Intrinsic Factors 48 3.3.4.3.1 Tissue Factor in Malignancy 49 3.3.4.4 Extrinsic Factors 51 3.3.5 Clinical Picture: Thrombosis and Carcinogenesis 51 3.3.5.1 Introduction 51 3.3.5.2 The scale of the problem 53 3.3.5.2.1 Incidence of Venous Thromboembolism in Cancer Patients 54 3.3.5.3 Adverse Consequences of Venous Thromboembolism in Patients with Cancer 55 3.3.5.4 Clinical Presentation of Venous Thromboembolism 57 3.3.5.5 Risk Factors for Thrombosis in Cancer Patients 57 3.3.5.5.1 Cancer-related Risk Factors 58 3.3.5.5.2 Treatment-related Risk Factors 59 3.3.5.5.3 Patient-related Risk Factors 62 4 3.3.5.5.4 Prediction of Venous Thromboembolism Risk 62 3.3.5.6 The Impact of Anticoagulants on the Survival of Cancer Patients 63 3.3.5.6.1 Impact of Haemostatic System on Cancer Growth and Progression 64 3.3.6 Central Venous Catheters and Thrombosis 69 3.3.6.1 Central Venous Catheters 69 3.3.6.1.1 Types of Central Venous Catheters 71 3.3.6.2 CVC Use in Cancer Therapy 74 3.3.6.2.1 Basis of infusional chemotherapy 74 3.3.6.3 Catheter-related Thrombosis 75 3.3.6.3.1 Pathophysiology of Catheter-related Thrombosis 76 3.3.6.3.2 Types of Catheter-related Thromboses 76 3.3.6.3.3 Incidence of Catheter-related Venous Thromboembolism 78 3.3.6.3.4 Risk Factors for Central Venous Catheter-related Thrombosis 82 3.3.6.4 Clinical Presentation of Catheter-related Thrombosis 83 3.3.6.5 Other Complications of Central Venous Catheters 84 3.3.6.6 Diagnosis of Venous Thromboembolism in Patients with Central Venous Catheters 85 3.3.6.7 Managing Established Catheter-related Thrombosis 86 3.3.7 Prophylaxis of Venous Thromboembolism in Cancer Patients with Central Venous Catheters 87 4. Methods 88 4.1 Survey of UK Practice of Thromboprophylaxis for Cancer Patients with CVCs (Pre-trial Survey) 88 4.2 WARP Trial 89 4.2.1 Aims 89 5 4.2.1.1 Primary: 89 4.2.1.2 Secondary: 89 4.2.2 Outcomes 89 4.2.2.1 Primary: 89 4.2.2.2 Secondary: 90 4.2.3 Trial Design 90 4.2.3.1 Blinding 92 4.2.3.2 Trial Design Amendment 93 4.2.4 Patient Eligibility 97 4.2.4.1 Inclusion Criteria 97 4.2.4.2 Exclusion Criteria 97 4.2.5 Treatment Plan 98 4.2.5.1.1 Overview 98 4.2.5.1.2 WARP Catheter Care Guidelines 99 4.2.6 Analytical Plan 100 4.2.6.1 Outcome Measures 100 4.2.6.2 Categorisation, Grading and Assessment of Thrombosis 101 4.2.6.3 Intention to treat 102 4.2.6.4 A Priori Patient Numbers 103 4.2.6.5 Number of Patients - Protocol Amendment 104 4.2.6.6 Randomisation and Randomisation Procedure 105 4.2.6.6.1 Timing of Randomisation 106 4.2.6.6.2 Stratification 106 4.2.6.7 Interim analysis 107 4.2.6.8 Health Economics 107 6 4.2.6.9 Examination of INRs in one centre 107 4.2.6.10 Statistical Tests Utilised 108 4.2.6.10.1 Comparison of rates of thrombotic events 108 4.2.6.10.2 Survival Analyses 109 4.2.6.10.3 Comparison of Time to thrombosis in patients with an event 110 4.2.6.10.4 Comparison of major and minor bleeding episodes 110 4.2.6.10.5 Exploratory Prognostic Modelling 111 4.2.7 Trial Management 113 4.2.7.1 Ethical Considerations 113 4.2.7.1.1 Informed Consent 114 4.2.7.1.2 Nurses Taking Informed Consent 115 4.2.7.1.3 Ethics Committees Approval 116 4.2.7.1.4 Protocol Amendments 116 4.2.7.2 Regulatory Considerations 118 4.2.7.2.1 Trial Monitoring 118 4.2.7.3 Data Handling 121 4.2.7.3.1 Adverse Event Reporting 123 4.2.7.4 Database and Construction 124 4.2.7.5 Trial Funding 124 4.2.7.6 Building and sustaining the trials network 125 4.2.7.6.1 Centre Visits 125 4.2.7.6.2 Newsletters 125 4.3 Meta-analysis 126 4.3.1 Overview 126 4.3.2 Protocol for Meta-analysis 128 7 4.3.2.1 PRISMA Reporting System 128 4.3.2.2 Data Sources and Searches 128 4.3.2.3 Study Selection – Inclusion and Exclusion Criteria 129 4.3.2.4 Quality Assessment 129 4.3.2.5 Data Extraction 130 4.3.2.6 Data Synthesis and Analysis 130 5. Results 131 5.1 Pre-WARP Survey 131 5.2 WARP Trial 136 5.2.1 Overall Recruitment 136 5.2.1.1 Recruitment by Randomised Treatment Arm 141 5.2.1.2 Stratification Variables 142 5.2.1.3 Randomisation Procedures 143 5.2.1.4 Timing of Randomisation 143 5.2.1.5 Eligibility 145 5.2.2 Baseline Characteristics 147 5.2.3 Protocol Compliance 150 5.2.3.1 Return of Case Record Forms 150 5.2.3.2 Assigned Treatment Compliance 150 5.2.3.3 Warfarin Dose Compliance 152 5.2.4 Primary Endpoint 154 5.2.4.1 Catheter – related thrombotic events 154 5.2.4.2 Location of Catheter-related Events 156 5.2.4.3 Assessment Technique for Diagnosis of Catheter-related Events 156 5.2.4.4 Side of Thrombosis 156 8 5.2.4.5 Removal of catheters in relation to Catheter-related thrombosis 157 5.2.4.6 Time-to-event analysis: Catheter-related Thrombosis 157 5.2.4.7 Time to Catheter-related Thrombosis 157 5.2.4.8 Grading of Catheter-related Venous Thromboses 161 5.2.5 Secondary Outcomes 161 5.2.5.1 All thrombotic events 161 5.2.5.2 Location of non-Catheter Related Thromboses 162 5.2.5.3 Assessment Technique for Diagnosis of All Thromboses 162 5.2.5.4 Removal of Catheters in relation to non-Catheter-related Thromboses 162 5.2.5.5 Time to All Thromboses 162 5.2.5.6 Grading of All Thromboses 165 5.2.5.7 Exploratory Multivariate Analysis – Patient Factors; All Thromboses 166 5.2.5.8 Trial-related toxicities 167 5.2.5.8.1 Major Bleeding 167 5.2.5.8.2 Minor Bleeds 173 5.2.5.8.3 Composite Endpoint – Bleeding plus CRT 174 5.2.5.9 Overall Survival 176 5.2.6 INR Values and Maintenance from One Centre 178 5.2.6.1 Fixed Dose Warfarin Analysis 179 5.2.6.2 Dose Adjusted Warfarin Analysis 181 5.2.7 Central Venous Catheters 182 5.2.7.1 Central Venous Catheter Baseline Characteristics 182 5.2.7.2 Catheter-specific risk factors for thrombosis: 185 5.2.7.3 CVC Patency 185 9 5.2.7.4 Catheter Complications 186 5.2.7.4.1 Infection 187 5.2.7.5 Flushing, Fibrinolytic Locks and Positive Pressure Devices 188 5.2.8 Health Resource Usage 190 5.3 Meta-analyses 191 5.3.1 Thromboprophylaxis for Cancer Patients having Chemotherapy 191 5.3.1.1 Flow of Information through the Meta-Analysis 191 5.3.1.2 Patients with Central Venous Catheter - Warfarin vs No Warfarin 192 5.3.1.3 All patients; warfarin versus no warfarin 193 5.3.1.4 Patients with Central Venous Catheters - Low molecular weight heparin vs control 193 5.3.1.5 All patients – Low Molecular weight heparin vs control 194 5.3.2 Anticoagulant Effect on Mortality in Patients having chemotherapy 196 5.3.2.1 Flow of Information through the Meta-analysis 196 5.3.2.2 Warfarin vs No Warfarin 197 5.3.2.3 Low Molecular Weight Heparin vs Control 197 5.3.2.4 Summary of the Results of the Meta-analyses 198 6.