Smoking is a major cause of premature mortality and preventable morbidity in the United Kingdom and worldwide.1
Treatments such as varenicline, bupropion, and nicotine replacement therapy, along with advice and referral to smoking cessation services, are recommended by the National Institute for Health and Care Excellence as options for smokers who want to quit smoking.3
Since its UK launch in 2006, varenicline (Champix in the UK, Chantix in the United States) has been widely used; there were about one million community prescriptions of varenicline in England in 2011.4
Bupropion, marketed as Zyban, is the other main product used in the UK for smoking cessation that does not contain nicotine. It is also used to treat depressive illnesses in some countries, but is not licensed for this indication in the UK.3
Since their launch, there have been concerns from spontaneous reporting systems that varenicline and bupropion could increase the risk of fatal and non-fatal self harm; these have resulted in safety warnings by regulatory agencies, including the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK and the Food and Drug Administration in the United States.7
Possible biological mechanisms for the increased suicide risk with varenicline might be through its action as a partial nicotinic agonist, because nicotine receptors could influence impulsivity and aggression.9
Furthermore, smoking may be used as self treatment for depression; consequently, smoking cessation could lead to depression, which increases the risk of suicide.10
Concerns about the safety of varenicline are still ongoing; Pfizer has settled the majority of lawsuits brought against varenicline in the US.11
Because suicide is a rare event, randomised controlled trials and meta-analyses of trials usually lack statistical power to investigate safety signals of this outcome.12
Large databases that record general practitioner prescribing and clinical outcomes—such as the UK’s Clinical Practice Research Datalink (CPRD), formerly known as the General Practice Research Database (GPRD)—provide an alternative source of information in the investigation of safety issues for rare outcomes.
However, results from observational studies could be compromised by factors such as incomplete recording of outcomes and confounding by indication. Confounding by indication occurs when the characteristics of patients prescribed a treatment systematically differ from those prescribed the control agent. For example, smokers have a higher risk of mental illness and suicide than non-smokers.13
This increased risk could account for the higher numbers of suicides that have been observed with those prescribed agents for smoking cessation.15
A basic approach to overcome confounding by indication is to compare adverse event rates between drugs used to treat the same condition—that is, to compare the risk of fatal and non-fatal self harm in people prescribed varenicline with those prescribed other smoking cessation products, such as bupropion and nicotine replacement therapy. However, if there are subtle differences in the baseline characteristics of patients prescribed each of these drugs, for instance, if certain pharmacological treatments are less likely to be prescribed to those considered to be at a higher risk of suicide or self harm, then the results from observational studies can still be biased.
In an earlier study, we reported on the risk of fatal and non-fatal suicidal behaviour among people prescribed varenicline versus those prescribed other smoking cessation medicines; the hazard ratio for self harm among people prescribed varenicline was 1.12 (95% confidence interval 0.67 to 1.88) compared with those prescribed nicotine replacement therapy.16
However, this study had several limitations: there was limited study power, because only 10
973 people had been prescribed varenicline in a 20 month period and there was evidence of an underestimation of suicide deaths (the ratio of non-fatal self harm was 80:1, whereas it is 20-30:1 in the general population).17
Furthermore, adjusting for a range of confounders led to a reversal in the direction of the hazard ratio, suggesting that unmeasured confounders further suppressed an increased risk in relation to varenicline. Other approaches for tackling confounding by indication include the use of propensity score methods and instrumental variable analysis.18
The aim of this study was to estimate the risk of suicide related outcomes derived from linked mortality data from the Office for National Statistics (ONS) and Hospital Episode Statistics (HES) in patients prescribed varenicline or bupropion compared with those prescribed nicotine replacement therapy in the CPRD. We used conventional and novel methods to assess the possible effect of confounding by indication.