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Risk vs Benefits of Thiazides in Clinical Use: Need for a Holistic Approach

      To the Editor:
      Ravioli et al,
      • Ravioli S
      • Bahmad S
      • Funk GC
      • Schwarz C
      • Exadaktylos A
      • Lindner G
      Risk of electrolyte disorders, syncope, and falls in patients taking thiazide diuretics: results of a cross-sectional study.
      through their cross-sectional observational analysis, conclude that thiazide use is a risk factor for hyponatremia, hypokalemia, syncope, and fall. However, a cause-and-effect relationship cannot be established merely based on observational data. Moreover, data from patients admitted to the emergency department are not representative of the general hypertensive population.
      Two groups (no thiazide vs thiazide) were imbalanced at baseline for the following factors that affect electrolyte disturbance, syncope, and fall:
      • Age: there were significantly more elderly patients in the thiazide group. Several conditions common in the elderly (Parkinson disease, diabetes, autonomic neuropathy, cerebrovascular diseases, cardiovascular disease) could cause syncope.
        • Goyal P
        • Maurer MS
        Syncope in older adults.
      • Chronic kidney disease and acute kidney injury: results in electrolyte derangements,
        • Dhondup T.
        • Qian Q
        Electrolyte and acid-base disorders in chronic kidney disease and end-stage kidney failure.
        including increased medications like loop diuretics.

        Huxel C, Raja A, Ollivierre-Lawrence MD. Loop diuretics. Available at: https://www.ncbi.nlm.nih.gov/books/NBK546656/. Accessed on 13 Dec 2021.

        Significantly greater use of loop diuretics indicates presence of renal insufficiency in the thiazide group and hence, this causation is erroneous.
      • Nonsteroidal anti-inflammatory drugs: Inhibition of renal prostaglandin synthesis can cause electrolyte and acid-base disturbances (sodium retention, hyponatremia, hyperkalemia, and decreased renal function).
        • Kim S
        • Joo KW
        Electrolyte and acid-base disturbances associated with non-steroidal anti-inflammatory drugs.
      • Renin-angiotensin-aldosterone system (RAAS) inhibitors: may lead to higher incidence of hypotension, acute renal failure, or hyperkalemia. RAAS inhibitors may cause hyponatremia due to their anti-aldosterone action.
        • Bhuvaneshwari S
        • Saroj PVS
        • Vijaya D
        • Sowmya MS
        • Kumar RS
        Hyponatremia induced by angiotensin converting enzyme inhibitors and angiotensin receptor blockers-a pilot study.
      Hyponatremia in patients on thiazides (alone or with RAAS inhibitors) usually occurs in the presence of precipitating events like central nervous system disorders, infections, etc., which may cause syndrome of inappropriate antidiuretic hormone secretion. Thus, it is important to identify induced syndrome of inappropriate antidiuretic hormone secretion prior to classifying it as thiazide-induced hyponatremia.
      • Pareek A
      • Mehta RT
      • Purkait I
      • et al.
      Hyponatremia in patients on thiazides - SIADH vs. true TIH. Comment on: Ware JS, Wain LV, Channavajjhala SK, et al. Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia.
      Considering cardiovascular outcome benefits of thiazide-like diuretics and stringent blood pressure target of <130/80 mm Hg advocated by the European Society of Cardiology/European Society of Hypertension and American College of Cardiology/American Heart Association hypertension guidelines, use of thiazides becomes imperative in many patients. For hydrochlorothiazide, commonly used dosages are 12.5/25 mg, and the corresponding dose of chlorthalidone is 6.25/12.5 mg. As the adverse effects of thiazides are dose related,
      • Pareek A
      • Ram CVS
      • Mehta RT
      • Dharmadhikari S
      Optimising TRIUMPH with 6·25 mg chlorthalidone.
      using low-dose thiazides in combination is the way forward to minimize adverse events and achieve the blood pressure goal.
      In conclusion, the study does not represent thiazide use in the general population. The authors have ascribed electrolyte disturbances, syncope, and fall to thiazides without assessing the impact of comorbidities and co-medications.

      References

        • Ravioli S
        • Bahmad S
        • Funk GC
        • Schwarz C
        • Exadaktylos A
        • Lindner G
        Risk of electrolyte disorders, syncope, and falls in patients taking thiazide diuretics: results of a cross-sectional study.
        Am J Med. 2021; 134: 1148-1154
        • Goyal P
        • Maurer MS
        Syncope in older adults.
        J Geriatr Cardiol. 2016; 13: 380-386
        • Dhondup T.
        • Qian Q
        Electrolyte and acid-base disorders in chronic kidney disease and end-stage kidney failure.
        Blood Purif. 2017; 43: 179-188
      1. Huxel C, Raja A, Ollivierre-Lawrence MD. Loop diuretics. Available at: https://www.ncbi.nlm.nih.gov/books/NBK546656/. Accessed on 13 Dec 2021.

        • Kim S
        • Joo KW
        Electrolyte and acid-base disturbances associated with non-steroidal anti-inflammatory drugs.
        Electrolyte Blood Press. 2007; 5: 116-125
        • Bhuvaneshwari S
        • Saroj PVS
        • Vijaya D
        • Sowmya MS
        • Kumar RS
        Hyponatremia induced by angiotensin converting enzyme inhibitors and angiotensin receptor blockers-a pilot study.
        J Clin Diagn Res. 2018; 12: FC01-FC03
        • Pareek A
        • Mehta RT
        • Purkait I
        • et al.
        Hyponatremia in patients on thiazides - SIADH vs. true TIH. Comment on: Ware JS, Wain LV, Channavajjhala SK, et al. Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia.
        J Clin Invest. 2017; 127 (https://www.jci.org/eletters/view/89812#sec1. Accessed on 13 Dec 2021): 3367-3374
        • Pareek A
        • Ram CVS
        • Mehta RT
        • Dharmadhikari S
        Optimising TRIUMPH with 6·25 mg chlorthalidone.
        Lancet Glob Health. 2020; 8: e175