Exploring the effectiveness of statins for primary prevention of cardiovascular disease in people with severe mental illness Name: Ruth Marion Blackburn Institution name: UCL Degree: Epidemiology Declaration: I, Ruth Marion Blackburn confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 1 Abstract Cardiovascular disease (CVD) is the leading cause of death amongst people with severe mental illness (SMI) and drives substantial portion of the 15-20 year deficit in life expectancy experienced by this group relative to the general population. Statins form a core part of CVD prevention in the general population, but the evidence-base for people with SMI is unclear. Evidence on the effectiveness of statins for primary prevention of CVD was systematically searched but did not identify any studies investigating CVD events or associated mortality in people with SMI; therefore highlighting the need for studies on the long term impacts of statin prescribing. Two analytical studies were undertaken using longitudinal data from The Health Improvement Network (THIN) primary care database to investigate: 1) CVD screening and statin prescribing in people with and without SMI and 2) to explore the effectiveness of statins for CVD prevention in individuals with SMI. Collectively the work has established that CVD screening and statin prescribing is increasingly accessed by individuals with SMI at levels that are comparable to people without similar mental health conditions. The results from this study provide the first evidence that statin prescribing to people with SMI is associated with statistically significant reductions in total cholesterol (of 1.2mmol/L for up to 2 years, p<0.001). There were small non-significant reductions in the rate of combined MI and stroke (0.89; 95% CI; 0.68-1.15) and all-cause mortality 0.89 (95% CI; 0.78, 1.02). This study provides evidence that statin prescribing to people with SMI may have a magnitude of effectiveness that is broadly similar to the general population. 2 Acknowledgements Thank you to the many people who have made my time as a PhD student a richer and far more enjoyable experience. Special thanks go to my supervisors David Osborn, Irene Petersen and Kate Walters who have offered invaluable support, ideas and advice. Thank you also to Irwin Nazareth for his input and perspective, to my upgrade examiners Jonathan Bartlett and Kate Walters for providing such constructive and encouraging feedback and to John Wood, Milena Falcaro and Angela Wood for their statistical support and expertise. I would like to thank all members (past and present) of the PRIMROSE and THIN teams, who have been so generous in sharing their insight and expertise. Being part of these teams has been inspiring and has provided me with a broader and deeper understanding of the complexities and importance of spanning the gap between mental and physical healthcare. Thank you to the small but mighty army of proof-readers who have read and re-read this thesis. Particular thanks go to Jane Blackburn, Alexandra Burton, Hilary Davies, Katherine Henderson, Susan Huntington, Mike Lifford, Manuj Sharma and Alicia Thornton. Thank you also to Hilary - my PhD “twin” – with whom I have shared many milestones over the past three years. Last (but never least) huge thanks to Mike, Mum and Dad for their incredible support, good humour and patience. 3 Contents 1 Chapter 1: Background (Chapter Content) ................................................................. 14 2 Introduction ................................................................................................................ 14 3 Epidemiology of SMI ................................................................................................... 15 3.1 Schizophrenia, schizo-affective disorder and associated psychoses ....................... 15 3.2 Bipolar disorder and associated conditions ........................................................... 18 4 Epidemiology of CVD .................................................................................................. 21 4.1 Definition and background ................................................................................... 21 4.2 Epidemiology ...................................................................................................... 22 4.3 Burden of disease and life-course:........................................................................ 23 4.4 Prevention and management ............................................................................... 24 5 CVD risk in people with SMI ........................................................................................ 25 5.1 Lipid profile ......................................................................................................... 27 5.2 Other components of the Framingham score for CVD risk ...................................... 27 5.3 Psychiatric medication ......................................................................................... 29 5.4 Lifestyle factors ................................................................................................... 30 5.5 Economic and social factors ................................................................................. 30 5.6 Comorbidity ........................................................................................................ 31 5.7 Genetic factors .................................................................................................... 31 5.8 Healthcare Factors .............................................................................................. 32 6 Management of CVD in people with SMI ...................................................................... 32 7 Context ...................................................................................................................... 33 8 Summary and scope of this thesis................................................................................ 33 9 Research aims and objectives ..................................................................................... 34 1 Chapter 2: Systematic review (Chapter Content)........................................................ 35 2 Rationale for investigating the effectiveness of statins for primary prevention of CVD in people with SMI ................................................................................................................. 35 4 2.1 Evidence-base for statin prescribing for primary prevention of CVD in the general population...................................................................................................................... 36 2.2 To what extent does the evidence-base for statin use in randomised trials reflect the effectiveness in people with SMI? .............................................................................. 36 3 Aims .......................................................................................................................... 37 4 Methods ..................................................................................................................... 38 4.1 Population, Intervention, Comparison and Outcome (PICO) criteria ........................ 38 4.2 Overarching search strategy and methodology ...................................................... 38 4.3 Searching for literature ........................................................................................ 41 4.4 Searching for registered clinical trials.................................................................... 42 4.5 Updating the review............................................................................................. 43 5 Screening literature and registered trials identified from the systematic review search ..... 43 5.1 Literature search ................................................................................................. 43 5.2 Registered trials .................................................................................................. 46 6 Results....................................................................................................................... 47 6.1 Literature ............................................................................................................ 47 6.2 Registered trials .................................................................................................. 59 7 Discussion.................................................................................................................. 65 7.1 Key findings ........................................................................................................ 65 7.2 Evaluation of search methodology ........................................................................ 66 7.3 Implications for this thesis regarding the effectiveness of statins for prevention of CVD in people with SMI .................................................................................................. 67 1 Chapter 3: THIN data and quality (Chapter content) ................................................... 68 2 Requisite features of a data source to investigate the effectiveness of statins on CVD events in people with SMI ................................................................................................... 68 2.1 Advantages and disadvantages of observational data relative to data from experimental study designs for investigating effectiveness ...............................................