Monitoring of patients for the development of adverse reactions to antihypertensive drugs in ...

367 Pages·2011·2.48 MB·English

MONITORING OF PATIENTS FOR
THE DEVELOPMENT OF ADVERSE
REACTIONS TO ANTIHYPERTENSIVE
DRUGS IN GENERAL PRACTICE

by

SARAH ELIZABETH MCDOWELL

A thesis submitted to the
University of Birmingham
for the degree of
DOCTOR OF PHILOSOPHY

School of Clinical and Experimental Medicine
College of Medicine and Dental Sciences
University of Birmingham
May 2011
University of Birmingham Research Archive

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Abstract

Guidelines generally recommend the monitoring of serum electrolyte and creatinine
concentrations in patients treated with antihypertensive therapy in order to detect
potential adverse reactions to treatment. However, it is not well known to what extent
these guidelines are followed in primary care.

I undertook a retrospective analysis of 74096 adult patients from the General Practice
Research Database with newly diagnosed hypertension and prescribed a single
antihypertensive agent. Baseline biochemical testing was undertaken in 31 094
patients (42%) and 37 365 (50%) patients had at least one biochemical monitoring test
in the year after starting antihypertensive treatment. Monitoring was significantly
more likely in patients treated with angiotensin-converting enzyme inhibitors than
thiazide diuretics, older patients, and patients with diabetes mellitus. These patient
factors were significantly associated with monitoring when multiple imputation was
used to control for the potential bias introduced by missing data. In general, follow-up
monitoring was infrequent, irregular, and did not change in response to events such as
abnormal test results.

Patients who were monitored after the initiation of antihypertensive treatment were
significantly more likely to be admitted to hospital and discontinue therapy, which is
likely a result of reactive instead of planned monitoring. Using propensity score
methods to control for confounding, I demonstrated a decreased risk of these same
adverse outcomes in patients with baseline testing, which may be because these
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patients were less likely to have any follow-up monitoring and not the protective
effect of the baseline testing.

I described several barriers to biochemical monitoring including the lack of consensus
in published guidelines, uncertain responsibility for monitoring, patient non-
adherence, and absence of alerts or reminders to monitor. More work is needed to
improve the primary evidence base for monitoring and to improve the guidelines on
the nature and frequency of monitoring for adverse drug reactions, particularly in
patients at greater risk of drug-induced harm.

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For my family.
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Acknowledgements

I am extremely grateful to my supervisor, Professor R E Ferner. I have learnt so much
from Professor Ferner and his feedback, support, and guidance have been invaluable.
I wish to thank and acknowledge Professor Jon Deeks for his readiness to share his
expert knowledge of systematic reviews and statistics and for being so generous with
his time.

I would also like to thank Dr Jamie Coleman, with whom a lot of the initial work for
this thesis was carried out. His clinical knowledge, guidance, and energy have been of
great help. Professor Stephen Evans from the London School of Hygiene and Tropical
Medicine has provided me with significant guidance and help with statistical concerns
and queries, for which I am most grateful. He introduced me to the concept of
immortal time bias and underscored the need to adjust for this type of bias, which is
often ignored in various types of research. I would also like to acknowledge Dr
Paramjit Gill for his help with the identification and further refinement of appropriate
clinical codes.

I am very grateful to my former colleagues at the West Midland Centre for Adverse
Drug Reactions for their assistance and support. Mr Christopher Anton assisted me
with database manipulation and design and Dr Anthony Cox provided valuable
comments and discussions.

The study protocol was approved by the Independent Scientific Advisory Committee
for Medicines and Healthcare products Regulatory Agency database (MHRA)
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research. This study is based in part on data from the Full Feature General Practice
Research Database obtained under licence from the MHRA. However, the
interpretation and conclusions contained in this thesis are mine alone.
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Table of contents
Chapter 1 ........................................................................................... 1
1.1 Adverse drug reactions ............................................................................... 1
1.2 Adverse drug reactions associated with antihypertensive drugs ................ 4
1.2.1 Hyperkalaemia and antihypertensive drugs ......................... 5
1.2.2 Hypokalaemia and antihypertensive drugs ........................... 6
1.2.3 Hyponatraemia and antihypertensive drugs ......................... 7
1.3 Monitoring patients for adverse drug reactions .......................................... 7
1.4 Monitoring guidelines for adverse reactions to drugs used in the treatment
of hypertension ........................................................................................... 9
1.5 Aims and objectives of the thesis ............................................................. 13
1.6 Outline of the thesis .................................................................................. 14
Chapter 2 ......................................................................................... 16
2.1 Background and research questions ......................................................... 16
2.2 Selection criteria ....................................................................................... 17
2.3 Search strategy for the identification of studies ....................................... 18
2.3.1 Electronic search ................................................................ 18
2.3.2 Methods of the review ......................................................... 20
2.4 Results ...................................................................................................... 20
2.4.1 Narrative review of included studies .................................. 22
2.4.2 Summary of studies ............................................................. 27
2.4.3 Summary of the primary outcome measure ......................... 28
2.4.4 Summary of secondary outcomes measures ........................ 30
2.5 Critical appraisal of prior studies of monitoring of patients treated with
antihypertensive drugs .............................................................................. 32
2.6 Conclusions .............................................................................................. 39
Chapter 3 ......................................................................................... 40
3.1 The use of large databases in pharmacoepidemiology ............................. 40
3.2 The General Practice Research Database ................................................. 41
3.2.1 Validation of the General Practice Research Database ..... 43
3.2.2 Limitations of the General Practice Research Database .... 44
3.3 Development of the study cohort ............................................................. 44
3.3.1 Ethics approval ................................................................... 44
3.3.2 Database development ........................................................ 45
3.3.3 Baseline patient covariates ................................................. 50
3.3.4 Assessment of biochemical serum concentrations .............. 52
3.3.5 Changes or alterations to antihypertensive treatment ........ 53
3.3.6 Patient outcomes ................................................................. 56
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Chapter 4 ......................................................................................... 61
4.1 Descriptive analyses ................................................................................. 61
4.2 Statistical analyses .................................................................................... 65
4.2.1 Logistic regression modelling ............................................. 65
4.2.2 Time-to-event analyses ........................................................ 65
4.3 Immortal time bias.................................................................................... 66
4.3.1 The effect of immortal time bias .......................................... 67
4.3.2 The extent of immortal time bias in the literature ............... 70
4.3.3 Controlling for immortal time bias in the analysis of follow-
up biochemical monitoring ................................................. 70
Chapter 5 ......................................................................................... 74
5.1 Identification of the study cohort ............................................................. 74
5.2 Describing the nature of baseline biochemical testing ............................. 78
5.3 Follow-up monitoring............................................................................... 81
5.3.1 What is the nature of follow-up monitoring? ...................... 81
5.3.2 What is the regularity of follow-up monitoring? ................ 89
5.3.3 How responsive is follow-up monitoring? .......................... 91
5.4 What proportion of patients had both baseline testing and follow-up
monitoring? .............................................................................................. 94
5.5 What are the patient factors associated with biochemical monitoring? ... 96
5.6 What is the association between follow-up monitoring and adverse patient
outcomes? ................................................................................................. 99
5.7 Assessing the impact of the definition of baseline testing and follow-up
monitoring .............................................................................................. 107
5.8 Investigating the impact of immortal time bias on the results ............... 108
5.8.1 Quantifying the impact of immortal time bias .................. 108
5.8.2 Dealing with immortal time bias ....................................... 112
5.9 Discussion .............................................................................................. 113
5.10 Strengths and weaknesses of this analysis ............................................. 118
5.10.1 Strengths ............................................................................ 118
5.10.2 Weaknesses ........................................................................ 119
5.11 Conclusions ............................................................................................ 121
Chapter 6 ....................................................................................... 123
6.1 Introduction ............................................................................................ 123
6.2 Methods .................................................................................................. 125
6.2.1 Assessment of electrolyte monitoring and biochemical ADRs
........................................................................................... 126
6.2.2 Statistical methods ............................................................ 127
6.3 Results .................................................................................................... 127
6.3.1 What are the patient factors associated with hyponatraemia?
........................................................................................... 135
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6.3.2 Patients with baseline testing and follow-up monitoring .. 136
6.4 Discussion .............................................................................................. 138
6.5 Conclusions ............................................................................................ 143
Chapter 7 ....................................................................................... 144
7.1 Missing data ........................................................................................... 144
7.1.1 Approaches used to determine the mechanism of missing
data .................................................................................... 145
7.1.2 Commonly used techniques for handling missing data ..... 146
7.1.3 Simple imputation methods for handling missing data ..... 147
7.1.4 Multiple imputation for handling missing data ................. 147
7.1.5 Handling missing data in the General Practice Research
Database ........................................................................... 155
7.2 Using multiple imputation in the analysis of the GPRD ........................ 156
7.2.1 Introduction ....................................................................... 156
7.2.2 Methods ............................................................................. 157
7.2.3 Results ............................................................................... 160
7.3 Discussion .............................................................................................. 178
7.4 Conclusions ............................................................................................ 180
Chapter 8 ....................................................................................... 181
8.1 Controlling for confounding in observational research .......................... 181
8.1.1 Comparing randomized controlled trials with observational
studies ................................................................................ 181
8.1.2 Controlling for confounding in observational studies ...... 183
8.2 A summary of propensity score methods ............................................... 186
8.2.1 Estimating the propensity score ........................................ 186
8.2.2 Common support of the propensity score model ............... 188
8.2.3 Propensity score methods ................................................. 189
8.2.4 A comparison of propensity score methods ...................... 195
8.2.5 Diagnostics of propensity score matching methods .......... 198
8.2.6 The use of propensity score methods ................................ 202
8.2.7 Benefits and limitations of propensity score methods ....... 209
8.3 Application of propensity score methods to the GPRD ......................... 213
8.3.1 Introduction ....................................................................... 213
8.3.2 Methods ............................................................................. 214
8.3.3 Results ............................................................................... 219
8.4 Discussion .............................................................................................. 238
8.4.1 Limitations ........................................................................ 240
8.4.2 Potential further statistical analysis using propensity score
methods ............................................................................. 241
8.4.3 Conclusion ........................................................................ 242
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