“High sodium levels in drugs 'putting patients at risk',” The Guardian reports. A study in the BMJ highlights the often overlooked fact that 'everyday' soluble drugs such as painkillers, contain high levels of salt (sodium) which may cause health problems if taken on a long-term basis.
For example, the study points out, if you take the maximum recommended dosage of soluble paracetamol per day for an adult this would exceed the daily recommended salt / sodium intake of 6g, roughly equivalent to a teaspoon.
The study in question looked at whether people who regularly took these types of soluble medications had an increased risk of cardiovascular diseases compared to their peers, who took similar medications, but without sodium.
Researchers found a link between the use of soluble medications and high blood pressure and non-fatal stroke, but no significant link was found with heart attacks as some of the reporting implied.
Also crucially, the study design, a case control study, cannot prove cause and effect. The study also focused on sodium intake from medicines only, and did not account for potentially large differences in sodium obtained in the diet via salt, as well as other factors that influence disease risk.
So ultimately, there is currently no evidence that soluble drugs directly cause cardiovascular diseases.
Never the less the research opens a debate about whether drug manufactures could or should include information on sodium content on drug packaging.
The study was carried out by researchers from Ninewells Hospital and Medical School, Dundee and UCL School of Pharmacy, London. It was funded by TENOVUS Scotland and the publication reported the funder had no role in the design, conduct or data interpretation of the study.
Most of the media reports presented the findings as factual, suggesting the association between medicines high in salt and increased risk of cardiovascular diseases such as heart attacks was conclusive. This is not the case.
By not reporting on the limitations of the study, readers were poorly served as they were left less informed to make a rounded judgement on the potential risks.
This was a case control study.
A case control study compares information on the exposures of people who have had a particular disease outcome, to exposures among very similar people (for example, matched by age or occupation) who have not had the disease outcome.
The aim is to identify underlying differences that may explain why some got the disease and others didn’t.
This type of study cannot prove cause and effect and suffers from various limitations.
A randomised control trial would be the ideal study design to investigate whether medicines containing sodium are causing higher levels of disease than equivalent medicines without sodium.
However, a trial randomising people to a regular intake of a medicine such as paracetamol for an extended period of time, purely to monitor cardiovascular effects, would not be feasible or ethical.
The authors report that many observational studies have shown that excess salt (sodium chloride) is detrimental to cardiovascular health, but the effect of sodium contained in commonly prescribed medicines is unknown.
Readers may be surprised to know that certain medicines, such as soluble aspirin or other soluble/dispersible pain killers contain more than trace amounts of sodium.
The study compared 61,072 adults who had had a cardiovascular event (cases) with 61,072 adults who hadn’t (controls) to see whether taking formulations of medicines containing sodium was linked to a higher level of disease.
The cardiovascular events they looked at included:
This information was obtained from a large medical research database (the UK Clinical Practice Research Datalink database). For each case, the researchers selected one matched control person with the same year of birth, sex, and general practice. All cases and controls in the database had received at least two prescriptions of sodium-containing formulations or matched standard formulations of the same drug without sodium, between January 1987 and December 2010.
Patients had information spanning an average of 7.23 years.
The main analysis looked at whether the cases with cardiovascular disease were more likely than controls without cardiovascular disease to have taken sodium-containing medicines. A secondary analysis looked at what the increased risk associated with sodium containing medicines was in each of the cardiovascular events listed above.
The group of cases had significantly more smokers. There was also an increased history of diseases, such as angina, heart failure, chronic obstructive pulmonary disease, peripheral vascular disease, diabetes mellitus, and chronic kidney disease.
Likewise there were also more prescriptions for cardiovascular disease drugs, NSAIDs (painkillers such as ibuprofen), and potassium supplements than in the control group. All these parameters, however, were included in and adjusted for in the final analysis.
The odds of a case who had experienced one of the following cardiovascular events having been exposed to sodium-containing medicines, relative to disease free controls, were as follows:
The researchers’ concluded that “exposure to sodium-containing formulations of effervescent [usually tablets that break up in water], dispersible, and soluble medicines was associated with significantly increased odds of adverse cardiovascular events compared with standard formulations of those same drugs. Sodium-containing formulations should be prescribed with caution only if the perceived benefits outweigh these risks.”
This large case control study suggested that people who had experienced disease of the heart and blood vessels were more likely to have taken sodium-containing medicines than people without cardiovascular disease. Put in other words this can be interpreted that people who took sodium-containing medicines were at a higher risk of experiencing cardiovascular disease than people who took the same medications in formulations free of sodium. The increased risk appeared to be driven mostly by an increased risk of hypertension and to a lesser extent, non-fatal stroke.
The study has some strengths including its large sample size, reasonable follow up time (over seven years on average), and direct measure of cardiovascular illness (recorded in a medical database).
However, it does contain significant limitations that weaken the strength of its conclusions.
Firstly the research design means that it cannot prove cause and effect. Furthermore, there may be many factors, some measured (confounders, adjusted for in the analyses), and some not (bias), that could influence the results found that have nothing to do with sodium containing medicines.
Secondly, the researchers did not measure dietary intake of sodium in the form of regular salt. It may be that the cases suffering cardiovascular disease had higher dietary salt intake than the disease-free controls. And this could explain why they had hypertension and more disease, irrespective of the influence of sodium containing medicines.
Further examples of factors that could have influenced the result (confounders) are family history of disease, other healthy lifestyle behaviours, and medicines bought over the counter, none of which were measured or were factored into the study analysis.
Many millions of people buy over the counter pain killers without a prescription so any proven risk increases could potentially impact a very large number of people. The study only investigated prescribed medicines not over the counter medications but any effect in one is quite likely to be found in the other.
All of these limitations were fully acknowledged by the study authors, but the media failed to report this important information.
The bottom line is that this study alone does not provide solid evidence that sodium in medicines is causing excess disease, because other sources of sodium levels, such as from the diet, were not recorded.
However, this research serves to open a debate about whether more vigilance or consideration is needed before prescribing sodium containing medicines for certain groups at already high risk of diseases such as hypertension or stoke. And whether pharmaceutical companies have a duty of care to provide clear labelling about salt intake for consumers, who might otherwise be unaware that some medicines may be contributing significantly to their daily intake.