This case control study has shown for the first time that a protective association exists between calcium channel blocking drugs and PCDD. This association appears to be solely attributable to the modified release preparations of these drugs. No protective effect against perforation was found for antimuscarinic drugs.
The main potential source of bias in this study is likely to arise from inaccuracies in the recording of drug use in hospital records. Bias could arise if the completeness of medication histories differed between cases and controls. The increased use of calcium channel blockers in the control groups might reflect a more thorough drug history or a better recall of medication in a group of healthier patients. However, this explanation is unlikely as patients admitted with perforation were recorded as taking more medications than either of the two control groups and the prevalence of cardiovascular medication use was similar for all groups (41–46%). These rates are also similar to the reported prevalence of cardiovascular medication use in a large UK population survey of older people (38–47%).20
This suggests that the hospital records were accurate for the recording of cardiovascular medication for both cases and controls. Furthermore, the similarity of cardiovascular drug use between the control groups in this study and the UK population survey20
suggests that these were valid groups to use.
Selection bias is unlikely to have influenced the findings of this study as all patients with a diverticular perforation who were eligible for inclusion in this study should have been identified. Patients with an abscess or peritonitis secondary to diverticular perforation nearly always require hospital admission. Furthermore, the ICD-10 codes used in this investigation were shown to have a high sensitivity for identifying cases of diverticular perforation in a previous study.3
Finally, the selection criteria included only the severe manifestations of diverticular perforation which are diagnoses easily confirmed by reviewing hospital records. Consequently, the selection criteria were not open to diagnostic interpretation, minimising the chance of misclassification.
The use of hospital control groups can be problematic but in this study we used two different groups of patients with conditions that have no known link with the use of calcium channel blockers. All patients with a previous history of complicated diverticular disease were excluded from the control groups but the exact prevalence of asymptomatic or mildly symptomatic diverticular disease in these groups was unknown. Previous studies however have suggested that in a population with a median age of 74 years (as in the control groups), the prevalence of diverticular disease will be as high as 65%.21
This supports the conclusion that the protective effect of calcium channel blockers is associated with the perforation of a diverticulum rather than its initial formation.
The consistency of the findings between cases and both control groups greatly strengthens the observation that calcium channel blocker use is lower in patients with colonic diverticular perforation. Furthermore, the strength of the protective effect of calcium channel blockers and plausible biological mechanisms for this effect suggests that the association is real. Calcium channels are involved in the generation of myoelectrical activity and smooth muscle contraction throughout the colon. L-type calcium channel blockers, which include most of the drugs in clinical use, selectively reduce the amplitude and duration of slow wave action potentials generated by colonic pacemaker cells without affecting their frequency.22
This may produce a beneficial reduction in the strength and duration of colonic contractions, minimising episodes of high intracolonic pressure while maintaining basal activity and colonic transit. Clinically, calcium channel blockers have been shown to suppress the colonic pressure waves normally associated with eating12
and parasympathetic stimulation,23
particularly in patients with excessive colonic contractility.24,25
Antimuscarinic drugs have similar effects in blocking extrinsic stimuli but do not affect slow wave activity.19
The lack of a protective effect for antimuscarinics may indicate that suppression of slow wave amplitude and duration is important in protecting against perforation. Alternatively, calcium channel blockers may be acting through other mechanisms such as increasing gastrointestinal mucosal blood flow, helping to promote cytoprotective activity and repair in the diverticular mucosa.14
A further possibility is that the duration of action of a drug is important as the protective association of calcium channel blockers was attributable to modified release drugs. Modified release preparations are likely to produce more gradual and sustained effects on motility, which may explain why no association was seen for shorter acting calcium channel blockers and antimuscarinics.
In view of the findings of this investigation, further aetiological studies are required to confirm the protective association between calcium channel blockers and perforated colonic diverticular disease. These studies should ideally involve community control groups and use interviews with patients to obtain more detailed data, particularly on the duration of use of medications. Confirmation of a causal relationship would support therapeutic trials of calcium channel blockers in patients at high risk of developing complications secondary to diverticular perforation. Such a group might include those who have had two or more episodes of inflammation and who would currently be advised to undergo surgical resection. This study has also shed light on possible mechanisms through which diverticular perforation may be prevented. Future investigations should examine other pharmacological factors that reduce colonic motility or augment mucosal blood flow. Identification of an effective drug treatment for preventing perforation would be a major advance in the management of patients with known colonic diverticular disease. As well as preventing perforation, drugs such as calcium channel blockers might also help to reduce the abdominal symptoms attributed to colonic spasm. Such a measure could potentially improve the quality of life of patients as well as reducing the healthcare resources required to treat them.