Results
Sample Selection
The distribution of the exclusion criteria is shown in Figure 1. At entry, the 68,970 patients who were included into the cohort had mean age of 76.2 years (SD 12.5 years) and 71% of them were women. During follow-up these patients accumulated 220,135 person-years of observation and generated 804 hospital admissions for UGIC, with an incidence rate of 36.5 cases per 10,000 person-years. The 804 patients who experienced hospitalization for UGIC (case patients) were matched to 12,787 controls.
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Figure 1.
Study flow diagram. AIFA-BEST Project, Italy, 2003–2007. Flow chart of inclusion and exclusion criteria. BPs: Bisphosphonates.
Patients
At the cohort entry, mean age of cases and controls was 79.9 years (SD: 9.9 years), and nearly 72% of them were women (matching variables). As shown in Table 1, there was not statistical evidence that case patients and controls differed for use to BPs during the entire observational period, as well as during current and past periods. Similarly, there was not evidence that cases and controls differ for BPs type and regimen refilled during the current period. Conversely, with the exception of statins and calcium channel blockers, co-treatments with the other considered drugs, as well as the presence of at least one sign of chronic comorbidity, were more frequent among cases than controls.
Use of Bisphosphonates and the Risk of Upper Gastrointestinal Complications
Compared with non users, patients who used BPs anytime during the entire observational period, as well as those who were exposed during current or past period, did not show significant risk excess of UGIC (Figure 2). In addition, there was no evidence that UGIC risk was heterogeneous across the categories of both types and regimens of BPs refilled anytime during the observational period, nor during current and past periods.
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Figure 2.
Adjusted odds ratios (and 95% confidence intervals) of upper gastrointestinal complications associated with anytime, current and past exposure to bisphosphonates as a whole (all) as well as to type (alendronate and risedronate) and regimen (daily and weekly) of the latest dispensed bisphosphonates. AIFA-BEST Project, Italy, 2003–2007. Odds ratios estimated with conditional logistic regression model. Estimates concerning main analysis (all) were adjusted for use of other medicaments in the 60-day period and for the Charlson index measured before the index date. Estimates concerning subgroup analysis were obtained by including the interaction terms combining the effect of anytime, current or past exposure to BPs together with type and regimen of the dispensed BPs. P-values concern comparison of BPs effect across patient subgroups. BPs: Bisphosphonates.
As shown in Figure 3, there was not statistical evidence that the UGIC risk associated with current use of BPs was heterogeneous across the categories of patients stratified according with co-treatments and comorbidity. It should be observed, however, that large confidence intervals were obtained for some strata. This was due to the few patients who concomitantly used BPs and other medicaments such as corticosteroids, statins or calcium channel blockers (being the corresponding prevalence 8.6%, 9.3% and 13.3% respectively).
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Figure 3.
Combined action of current exposure to bisphosphonates, concurrent exposure to other medicaments and categories of Charlson comorbidity index on the risk of upper gastrointestinal complications. AIFA-BEST Project, Italy, 2003–2007. Odds ratios estimated with conditional logistic regression model. Estimates were obtained by including the interaction terms combining the effect of current exposure to BPs together with concurrent use of other medicaments and the categories of the Charlson index. P-values concern comparison of BPs effect across patient subgroups. BPs: Bisphosphonates.
Sensitivity Analyses
Figure 4 shows that the adjusted OR did not substantially change by varying criteria for defining diagnosis of UGIC (box A) nor the length of exposure time-window for defining current use of BPs (box B).
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Figure 4.
Influences of diagnostic criteria for defining upper gastrointestinal complications (panel A), and of the time-window length for defining current use of BPs (panel B) on the observed odds ratio of upper gastrointestinal complications associated with current exposure to bisphosphonates. AIFA-BEST Project, Italy, 2003–2007. Odds ratios estimated with conditional logistic regression model. Estimates were adjusted for use of medicaments in the 60-day period and for the Charlson index measured before the index date. Details for diagnostic criteria are reported in Additional file 1. BPs: Bisphosphonate.