Both those with or without hypertension should avoid inadvertent excessive sodium intake via sodium-containing paracetamol (acetaminophen) in fizzy or soluble drug preparations, recommends a “compelling” Harvard observational study in European Heart Journal. An accompanying editorial call for urgent action on the potential dangers of fast-acting prescription and over-the-counter drugs alike.
An accompanying European Heart Journal editorial said that the message from this “compelling” study is clear — there are likely to be millions of people worldwide taking paracetamol on a daily basis in a fast-acting effervescent or soluble formulation who are increasing their risks of cardiovascular disease and premature death. In the UK alone, in 2014 there were some 42m paracetamol-containing medicines prescribed, with a further 200m packs sold over the counter, write correspondents Aletta E Schutte of the University of New South Wales and Bruce Neal of the George Institute for Global Health in Australia.
“Fortunately, only a small proportion of paracetamol formulations contain sodium but, with ‘fast-acting’ and ‘fizzy’ medications increasing in popularity, the adverse effects of medication-related sodium intake look set to rise rather than fall. There are also many more effervescent, dispersible, and soluble medications and vitamin pills that contain large quantities of hidden sodium. A study done in 2018 in France found that 27% of a general population sample who underwent medical check-ups had consumed ‘fizzy’ tablets in the past 30 days,” the editorial noted.
“The weight of the evidence makes ongoing inaction on sodium-containing medications untenable. The widespread use of effervescent medication in the general population, and the enormous doses of sodium that can be consumed inadvertently by unsuspecting consumers requires urgent action.”
Scope of the study
A large UK database of electronic health records revealed significant excess in one-year incidence of myocardial infarction, stroke, and heart failure associated with sodium-containing acetaminophen therapy use compared with standard formulations: a 59% relative increase in risk for those with hypertension, and a 45% relative increase in risk for those without hypertension.
All-cause mortality risk over a year was twice as elevated in the hypertension patients taking sodium-containing acetaminophen and 87% elevated in users without hypertension. Risk increased in step with more prescriptions and longer durations of use of these medications, according to the study authors.
Similar risks were observed for the subgroups of patients also using sodium-containing ibuprofen or ranitidine, reported epidemiologist Yuqing Zhang of Massachusetts General Hospital and Harvard Medical School and colleagues in the European Heart Journal.
“Sodium-containing drugs are an important source of sodium intake that could be easily overlooked,” they wrote. “Given that the pain-relief of non-sodium-containing acetaminophen is similar to that of sodium-containing acetaminophen, our results suggest re-visiting the safety profile of effervescent and soluble acetaminophen use.”
Whereas traditional formulations in tablet, oral suspension, or capsule form do not contain sodium, fizzy or soluble drug preparations rely on it for fast-acting disintegration.
And the sodium can really add up, cautioned Aletta Schutte and Bruce Neal, both of The George Institute for Global Health in Sydney, Australia.
If a given fizzy acetaminophen tablet has 400mg of sodium, a day’s worth at full dose would add 3,000mg of sodium per day, far above the daily recommended sodium intake for an adult, they wrote in an accompanying editorial.
“Large increments would also be anticipated for other types of effervescent medications, with a single 5g sachet of effervescent antacids containing 850mg of sodium, fizzy vitamins 280mg of sodium per tablet, and urinary alkalinisers some 644mg of sodium per dose,” they estimated.
As such, Schutte and Neal urged “urgent action” on sodium-containing medications.
“Particularly concerning is the observation in some surveys that up to 94% of uses of fizzy medications are self-medication using over-the-counter preparations. There is an immediate need for protection of consumers against these risks. The most plausible and effective strategy is likely to be the mandatory labelling of all medications containing significant quantities of sodium, with a front-of-pack warning label,” they said.
“Information programmes that raise public and practitioner awareness of the hidden sodium in medications, and educate about the need to avoid effervescent, dispersible, and soluble medicines in all but essential circumstances should also be considered.”
The study was based on the Health Improvement Network with patient records spanning 2000 to 2017. Included were nearly 300,000 people (average age in the early 70s) with physician-ordered acetaminophen prescriptions started during the study period.
Sodium-containing formulations were prescribed to 3.0% of individuals with hypertension and 3,6% of those without it. Significantly more women were in the group taking sodium-containing acetaminophen.
Zhang’s team acknowledged that the study was limited by the potential for residual confounding and the lack of urinary sodium excretion or dietary sodium intake data. Investigators also couldn’t adjust for over-the-counter acetaminophen use.
“The results are compelling. The effects were consistent across several different methodological approaches and in a series of sensitivity analyses,” Schutte and Neal maintained.
“Large-scale supplementation of dietary sodium in a randomised trial studying cardiovascular outcomes has never been done and would almost certainly be viewed as unethical. This type of analysis is as close as researchers are ever likely to come to doing that trial, and, while the current report is observational in nature, it provides strong evidence of harmful effects of adding large quantities of sodium to the diet,” they said.
Study details
Sodium-containing acetaminophen and cardiovascular outcomes in individuals with and without hypertension
Chao Zeng, Lynn Rosenberg, Xiaoxiao Li, Luc Djousse, Jie Wei, Guanghua Lei, Yuqing Zhang.
Published in American Heart Journal on 24 February 2022
Abstract
Aims
Previous studies have found high sodium intake to be associated with increased risks of cardiovascular disease (CVD) and all-cause mortality among individuals with hypertension; findings on the effect of intake among individuals without hypertension have been equivocal. We aimed to compare the risks of incident CVD and all-cause mortality among initiators of sodium-containing acetaminophen with the risk of initiators of non-sodium-containing formulations of the same drug according to the history of hypertension.
Methods and results
Using The Health Improvement Network, we conducted two cohort studies among individuals with and without hypertension. We examined the relation of sodium-containing acetaminophen to the risk of each outcome during 1-year follow-up using marginal structural models with an inverse probability weighting to adjust for time-varying confounders. The outcomes were incident CVD (myocardial infarction, stroke, and heart failure) and all-cause mortality. Among individuals with hypertension (mean age: 73.4 years), 122 CVDs occurred among 4,532 initiators of sodium-containing acetaminophen (1-year risk: 5.6%) and 3051 among 146,866 non-sodium-containing acetaminophen initiators (1-year risk: 4.6%). The average weighted hazard ratio (HR) was 1.59 [95% confidence interval (CI) 1.32–1.92]. Among individuals without hypertension (mean age: 71.0 years), 105 CVDs occurred among 5351 initiators of sodium-containing acetaminophen (1-year risk: 4.4%) and 2079 among 141 948 non-sodium-containing acetaminophen initiators (1-year risk: 3.7%), with an average weighted HR of 1.45 (95% CI 1.18–1.79). Results of specific CVD outcomes and all-cause mortality were similar.
Conclusion
The initiation of sodium-containing acetaminophen was associated with increased risks of CVD and all-cause mortality among individuals with or without hypertension. Our findings suggest that individuals should avoid unnecessary excessive sodium intake through sodium-containing acetaminophen use.
Key question
Previous studies have found high sodium intake to be associated with increased risks of cardiovascular disease and all-cause mortality among individuals with hypertension; findings on the effect of intake among individuals without hypertension have been equivocal.
Key finding
Sodium-containing acetaminophen was associated with a statistically significant higher risk of incident cardiovascular disease and all-cause mortality than the non-sodium-containing acetaminophen initiation among individuals with and without hypertension.
Take-home message
Both individuals with and without hypertension should avoid unnecessary excessive sodium intake through sodium-containing acetaminophen use.
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