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Association between cardiovascular events and sodium-containing effervescent, dispersible, and soluble drugs: nested case-control study

BMJ 2013; 347 doi: (Published 26 November 2013) Cite this as: BMJ 2013;347:f6954
  1. Jacob George, senior lecturer/honorary consultant in clinical pharmacology1,
  2. Waseem Majeed, core medical trainee in medicine2,
  3. Isla S Mackenzie, senior lecturer/honorary consultant in clinical pharmacology3,
  4. Thomas M MacDonald, professor of clinical pharmacology3,
  5. Li Wei, senior lecturer in medical statistics34
  1. 1Division of Medical Science, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
  2. 2NHS Tayside, Ninewells Hospital, Dundee DD1 9SY, UK
  3. 3Medicines Monitoring Unit and Hypertension Research Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
  4. 4Department of Practice and Policy, UCL School of Pharmacy, London WC1H 9JP, UK
  1. Correspondence to: T MacDonald tom{at}
  • Accepted 13 November 2013


Objective To determine whether patients taking formulations of drugs that contain sodium have a higher incidence of cardiovascular events compared with patients on non-sodium formulations of the same drugs.

Design Nested case-control study.

Setting UK Primary Care Patients registered on the Clinical Practice Research Datalink (CPRD).

Participants All patients aged 18 or over who were prescribed at least two prescriptions of sodium-containing formulations or matched standard formulations of the same drug between January 1987 and December 2010.

Main outcome measures Composite primary outcome of incident non-fatal myocardial infarction, incident non-fatal stroke, or vascular death. We performed 1:1 incidence density sampling matched controls using the UK Clinical Practice Research Datalink (CPRD). For the secondary analyses, cases were patients with the individual components of the primary study composite endpoint of hypertension, incident heart failure, and all cause mortality.

Results 1 292 337 patients were included in the study cohort. Mean follow-up time was 7.23 years. A total of 61 072 patients with an incident cardiovascular event were matched with controls. For the primary endpoint of incident non-fatal myocardial infarction, incident non-fatal stroke, or vascular death the adjusted odds ratio for exposure to sodium-containing drugs was 1.16 (95% confidence interval 1.12 to 1.21). The adjusted odds ratios for the secondary endpoints were 1.22 (1.16 to 1.29) for incident non-fatal stroke, 1.28 (1.23 to 1.33) for all cause mortality, 7.18 (6.74 to 7.65) for hypertension, 0.98 (0.93 to 1.04) for heart failure, 0.94 (0.88 to 1.00) for incident non-fatal myocardial infarction, and 0.70 (0.31 to 1.59) for vascular death. The median time from date of first prescription (that is, date of entry into cohort) to first event was 3.92 years.

Conclusions Exposure to sodium-containing formulations of effervescent, 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.


  • Contributors: JG conceived the idea for the study. JG, TMM, and LW obtained funding for the study. JG, TMM, ISM, and LW were involved in design, analysis, and interpretation of data. JG, WM, and IS were involved in data collection. All authors were responsible for drafting the article or revising it critically for important intellectual content and approved the final version. LW is guarantor.

  • Funding: This study was funded by TENOVUS Scotland (ref T10/12). The funder had no role in the design, conduct or data interpretation of the study.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Ethical approval: This study was approved by the independent scientific advisory committee (ISAC) for the UK Medicines and Healthcare Products Regulatory Agency (MHRA) database research (protocol No 11_100).

  • Transparency: The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Data sharing: No additional data available.

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