Normal potassium concentrations in the blood (3.5 to 5.1 mmol/L) are important for heart function and rhythm. Abnormal levels outside these limits have been shown to increase mortality from cardiac causes (cardiovascular mortality). Based on the assumption that the potassium concentration might be affected by potassium-influencing drugs, we focused on two specific drug classes with the potential to decrease potassium concentrations in the blood. Firstly, non-potassium-sparing diuretics (such as hydrochlorothiazide, clopamide, chlortalidone, indapamide, furosemide, bumetanide, and torasemide), which are prescription drugs to treat hypertension and heart failure, and secondly, laxatives (such as senna, bisacodyl, picosulfate and others), which are over-the-counter-drugs against constipation.
Our research question was as follows: Do participants with non-potassium-sparing diuretics who additionally use laxatives have a higher risk to die from cardiac causes than those participants without the concurrent use of these two drug classes?
By using the data of 105,359 UK Biobank participants with antihypertensive drug treatment (which includes individuals with hypertension and heart failure) we investigated the associations of separate and combined use of non-potassium-sparing diuretics and laxatives with cardiovascular mortality. Compared to non-users, participants using only non-potassium-sparing diuretics had a 1.4-fold increased risk to die from cardiac causes (Hazard ratio [95%-confidence interval]: 1.37 (1.23; 1.52)), while users of only laxatives showed no statistically significant increased risk [1.19 (0.96; 1.48)]. If users of non-potassium-sparing diuretics additionally took laxatives (concurrent users) they had an even 2-fold increased risk to die from cardiac causes (1.98 (1.43; 2.75).
In conclusion, a drug-drug interaction of non-potassium-sparing-diuretics and laxatives appears plausible. Therefore, physicians are advised to clarify additional laxatives use in patients who use non-potassium-sparing diuretics, and pharmacists should ask patients who regularly purchase laxatives in a pharmacy about non-potassium-sparing diuretics use. Patients should be aware of the risk of concurrent use of these two drug classes, and report both prescription and self-medication drugs to their responsible physicians and pharmacists.
Impact of non-potassium-sparing diuretics and regular laxative use on cardiovascular mortality of subjects receiving anti-hypertensive treatment
We will address the research question: ?How safe is regular laxative use, in particular in combination with non-potassium-sparing diuretics?? For this purpose, we will compare cardiovascular mortality of subjects regularly using only non-potassium-sparing diuretics, only laxatives, both laxatives and non-potassium-sparing diuretics, or other anti-hypertensives than non-potassium-sparing diuretics. We have performed these analyses also in a German, population-based cohort with 9949 study participants (ESTHER study) but these revealed no significant results because simultaneous, regular diuretic and laxative use is rare. However, we expect significant findings for the meta-analysis of the results from the ESTHER study and the UK Biobank. The importance of adequate potassium levels to prevent life-threatening health outcomes is already well-known. However, data investigating the relationship between potassium level affecting drugs and cardiovascular mortality in the general population is lacking. Furthermore, reliable estimates for the occurrence of adverse events caused by interactions between prescribed non-potassium-sparing diuretics and additionally used laxatives have not yet been assessed in large studies. Up to date, authentic assessments of adverse health outcomes in large population samples can only be generated by prospective cohort studies involving direct contact with both the patients and the physicians, as done in the UK Biobank study. To assess the risk of laxatives in general, cardiovascular mortality of regular laxative users will be compared to a group of non-users with comparable characteristics. In addition, for assessing the risk of interaction between non-potassium-sparing diuretics and laxatives, we will compare the risk of cardiovascular mortality in hypertension-treated subjects within the following four distinct groups: Regular use of non-potassium-sparing diuretics only, regular use of laxatives only, regular use of both non-potassium-sparing diuretics and laxatives, and no use of these drugs. The underlying baseline cardiovascular risk of all four groups will be quite comparable because all groups receive anti-hypertensive drugs. To assess the risk of laxatives in general, cardiovascular mortality of regular laxative users will be compared to a group of non-users with comparable characteristics. To identify subjects with comparable characteristics, the total cohort will be needed. In particular, we need access to the self-reported medication data of about 60,000 participants receiving anti-hypertensive medication and of about 15,000 subjects with self-reported use of laxatives. In addition, we will require the medication data obtained from the verbal interviews during the UK Biobank Assessment Centre of the full study cohort in order to complete and validate the aforementioned data.
|Lead investigator:||Dr Ben Schöttker|
|Lead institution:||German Cancer Research Center (DKFZ)|
|2907||The Associations of Diuretics and Laxatives Use with Cardiovascular Mortality. An Individual Patient-Data Meta-analysis of Two Large Cohort Studies||Hoppe et al||2019||Cardiovascular Drugs and Therapy (2019)|