Re-prescribing After Serious Drug-induced Upper GI Bleeding
Re-prescribing After Serious Drug-induced Upper GI Bleeding
We found that users of SSRI, VKA, clopidogrel and dipyridamol had a relatively high cumulative rate of re-prescribing (55–82%) within the first year and that the prescriptions were redeemed shortly after discharge from hospital. This is an elderly population and use of DAHAs may put them in a very high risk of re-bleeding. For users of NSAID and low-dose ASA, we found a more slow reintroduction. The rate of re-prescribing without PPIs was markedly lower for all drug classes. Particularly low rates were seen for NSAID, low-dose ASA and VKA.
There are two likely explanations for the marked difference between Kaplan–Meier curves with and without PPIs taken into consideration: the PPIs are prescribed simply because of a recent serious bleeding episode, or the PPIs are prescribed specifically to prevent UGIB from the re-prescribed DAHA. The use of PPIs among subjects who had not taken DAHA prior to their UGIB Figure 2 suggests the latter. The proportion of PPI use was as low as 30%, which would only explain a small difference between the Kaplan–Meier curves with and without PPI taken into consideration.
The curves are determined by several other factors: the physicians' or patients' fear of new UGIBs, their awareness of the UGIB risk with different DAHAs and the strength of the indication for the DAHA. For example, the slow reintroduction of NSAID and its high coverage suggest a high degree of awareness of NSAID associated bleeding and a non-imperative indication, i.e. that the NSAID is not deemed vital for the patient. The relatively high re-prescribing rate and low PPI coverage for SSRIs might reflect a low awareness of the SSRI-UGIB association. The fast re-introduction for VKA and strikingly high PPI coverage suggest an imperative indication and a high awareness of the UGIB risk. These patterns may not necessarily reflect the current evidence. NSAID are by far the drug class with the strongest association with UGIB. VKA and ASA are not particularly prone to induce UGIB, having ORs in the order of two. PPI use has been documented as a prophylactic measure against UGIB related to NSAID, low-dose ASA, clopidogrel and SSRI use, but to a lesser degree for VKA and dipyridamol. We find it reassuring that low-dose ASA is quickly reintroduced in the vast majority of patients. A newly published controversial study by Sung et al. suggests that prophylactic low-dose ASA should be continued even during the current bleeding event. The increased risk for recurrent UGIB is outweighed by a reduced overall mortality.
We have only found few other studies investigating the re-prescription pattern of DAHA after an episode of UGIB. Massó González et al. have reported data on the risk of recurrent UGIB associated with continued use of potential causative drugs. Other groups have reported that PPI utilisation is suboptimal in certain risk groups using low-dose ASA and NSAID. Even though our results are only indirectly comparable to these studies, our results imply that physicians generally are very cautious and to a high extent prescribe PPI to patients using DAHA.
Massó González et al. found that 21% of long-term users were still using NSAID 1 year after an episode of UGIB and in the group of long-term low-dose ASA users, 28% were using low-dose ASA 1 year after the bleeding event.
The current study has several strengths; first we used only manually validated cases from a previous study by this group. Second; the study is a true population-based approach with full coverage of all admissions and prescription data. A potential limitation to this study is, as in any observational study, we cannot be certain of the patients' compliance. Also, some NSAID and low-dose ASA was available over-the-counter during the study period. However, the coverage of our data source for these drugs, i.e., the proportion sold on prescription is 88% and 98.5% respectively. Another potential limitation could be the low odds ratios associating VKA, ASA, SSRIs, clopidogrel and dipyridamol with UGIB. Most are in the order of 2, which imply an attributable proportion of 0.5. In other words only half of the UGIB patients who were exposed to these drugs were associated with them. The other half was in reality bleedings that would have occurred irrespective of DAHA use. As we can never know which half is drug induced, it is difficult to use this in clinical management.
In conclusion, we find a markedly rational approach to re-prescribing of DAHA in patients who have experienced a serious adverse reaction. Particularly, the very extensive use of PPIs in these patients is reassuring and emphasises the clinicians' awareness of the issue.
Discussion
We found that users of SSRI, VKA, clopidogrel and dipyridamol had a relatively high cumulative rate of re-prescribing (55–82%) within the first year and that the prescriptions were redeemed shortly after discharge from hospital. This is an elderly population and use of DAHAs may put them in a very high risk of re-bleeding. For users of NSAID and low-dose ASA, we found a more slow reintroduction. The rate of re-prescribing without PPIs was markedly lower for all drug classes. Particularly low rates were seen for NSAID, low-dose ASA and VKA.
There are two likely explanations for the marked difference between Kaplan–Meier curves with and without PPIs taken into consideration: the PPIs are prescribed simply because of a recent serious bleeding episode, or the PPIs are prescribed specifically to prevent UGIB from the re-prescribed DAHA. The use of PPIs among subjects who had not taken DAHA prior to their UGIB Figure 2 suggests the latter. The proportion of PPI use was as low as 30%, which would only explain a small difference between the Kaplan–Meier curves with and without PPI taken into consideration.
The curves are determined by several other factors: the physicians' or patients' fear of new UGIBs, their awareness of the UGIB risk with different DAHAs and the strength of the indication for the DAHA. For example, the slow reintroduction of NSAID and its high coverage suggest a high degree of awareness of NSAID associated bleeding and a non-imperative indication, i.e. that the NSAID is not deemed vital for the patient. The relatively high re-prescribing rate and low PPI coverage for SSRIs might reflect a low awareness of the SSRI-UGIB association. The fast re-introduction for VKA and strikingly high PPI coverage suggest an imperative indication and a high awareness of the UGIB risk. These patterns may not necessarily reflect the current evidence. NSAID are by far the drug class with the strongest association with UGIB. VKA and ASA are not particularly prone to induce UGIB, having ORs in the order of two. PPI use has been documented as a prophylactic measure against UGIB related to NSAID, low-dose ASA, clopidogrel and SSRI use, but to a lesser degree for VKA and dipyridamol. We find it reassuring that low-dose ASA is quickly reintroduced in the vast majority of patients. A newly published controversial study by Sung et al. suggests that prophylactic low-dose ASA should be continued even during the current bleeding event. The increased risk for recurrent UGIB is outweighed by a reduced overall mortality.
We have only found few other studies investigating the re-prescription pattern of DAHA after an episode of UGIB. Massó González et al. have reported data on the risk of recurrent UGIB associated with continued use of potential causative drugs. Other groups have reported that PPI utilisation is suboptimal in certain risk groups using low-dose ASA and NSAID. Even though our results are only indirectly comparable to these studies, our results imply that physicians generally are very cautious and to a high extent prescribe PPI to patients using DAHA.
Massó González et al. found that 21% of long-term users were still using NSAID 1 year after an episode of UGIB and in the group of long-term low-dose ASA users, 28% were using low-dose ASA 1 year after the bleeding event.
The current study has several strengths; first we used only manually validated cases from a previous study by this group. Second; the study is a true population-based approach with full coverage of all admissions and prescription data. A potential limitation to this study is, as in any observational study, we cannot be certain of the patients' compliance. Also, some NSAID and low-dose ASA was available over-the-counter during the study period. However, the coverage of our data source for these drugs, i.e., the proportion sold on prescription is 88% and 98.5% respectively. Another potential limitation could be the low odds ratios associating VKA, ASA, SSRIs, clopidogrel and dipyridamol with UGIB. Most are in the order of 2, which imply an attributable proportion of 0.5. In other words only half of the UGIB patients who were exposed to these drugs were associated with them. The other half was in reality bleedings that would have occurred irrespective of DAHA use. As we can never know which half is drug induced, it is difficult to use this in clinical management.
In conclusion, we find a markedly rational approach to re-prescribing of DAHA in patients who have experienced a serious adverse reaction. Particularly, the very extensive use of PPIs in these patients is reassuring and emphasises the clinicians' awareness of the issue.