Methods: All cases of acute PCDD were identified over a five year period in two hospitals in Norfolk, UK. Each case was matched for age, sex, and date of admission to two controls groups: (1) patients undergoing cataract surgery and (2) patients with basal cell carcinoma. Data on drug use prior to hospital admission were obtained from medical and nursing records and compared between cases and controls.

Results: A total of 120 cases of PCDD were identified and matched to 240 controls in each group. A statistically significant protective association was seen between calcium channel blocker use and PCDD using both control groups. The odds ratios were 0.41 (95% confidence interval (CI) 0.18–0.93) using the ophthalmology control group and 0.36 (95% CI 0.16–0.82) using the dermatology control group.

Two factors are likely to be important in the mechanism of diverticular perforation. Firstly, excessive colonic segmentation may increase intracolonic pressures leading to mechanical weakening of the thin diverticular wall.^4–6 Secondly, impairment of the mucosal barrier of the diverticulum, through alterations in mucus secretion, microbial colonisation, or epithelial cell function,⁷ may lead to further weakening. Therefore, drugs that reduce intracolonic pressures or protect the colonic mucosa may help to prevent perforation. To date, the only medications found to be associated with diverticular perforation are non-steroidal anti-inflammatory drugs (NSAIDs)^8–10 which may cause this complication by impairing the integrity of the mucosa.¹¹

Calcium channel blockers are a group of drugs that could potentially protect against perforation. They relax gastrointestinal smooth muscle and reduce the frequency of high pressure waves in the colon.¹² Furthermore, nifedipine has been shown to increase gastrointestinal mucosal blood flow and protect against immunosuppressant induced intestinal injury.^13,14 Although calcium channel blockers are most commonly prescribed for ischaemic heart disease and hypertension, their smooth muscle relaxant properties have been used to treat patients with irritable bowel syndrome,¹⁵ oesophageal spasm,¹⁶ and anal fissures.¹⁷ However, no study has examined their role in the treatment of colonic diverticular disease or in preventing perforation. A second group of drugs that might protect against perforation are those with antimuscarinic properties which reduce gastrointestinal tone¹⁸ and eliminate the prolonged postprandial colonic activity seen in diverticular disease.¹⁹ Antimuscarinic medications are commonly prescribed for depression, psychoses, Parkinson’s disease, bladder instability, and respiratory conditions. Their gastrointestinal relaxant properties have also been used to treat patients with irritable bowel syndrome but no study has investigated whether they may protect against diverticular perforation. The aim of this case control study was to test, for the first time in an epidemiological study, the hypotheses that both calcium channel blockers and antimuscarinic drugs protect against perforated colonic diverticular disease (PCDD).

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.