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Bleeding associated with indapamide SR therapy

Senior Fellow Department of Internal Diseases and Functional Diagnostics A Aliyev Azerbaijan State Institute of Advanced Training for Doctors 8 Gulu Guliyev St, Apt 112 AZ 1007 Baku, Azerbaijan hassanovae{at}hotmail.com

Nahida E Agasiyeva, MD PhD

Associate Professor Department of Internal Diseases and Functional Diagnostics A Aliyev Azerbaijan State Institute of Advanced Training for Doctors

Published Online, December 8, 2004. www.theannals.com, DOI 10.1345/aph.1E323

Case Report.

A 58-year-old woman with a 10-year history of moderate hypertension was taking indapamide SR 1.5 mg/day. Other medications or herbal products were not administered. About 18 months after starting indapamide SR treatment, she experienced bleeding from the mucous membrane of the tongue.

Blood chemistries revealed mild thrombocytopenia (hemoglobin 13 g/dL, erythrocytes 4.21 x 10⁶/mm³, leukocytes 5.5 x 10³/mm³, platelets 132 x 10³/mm³, normal differential cell count). Erythrocyte sedimentation rate was 20 mm/h. Until that time, the patient's hematologic parameters had been unremarkable. She had no family or personal history of congenital bleeding diathesis, and no history of liver disease or blood transfusion. Physical examination revealed only petechiae affecting the upper extremities and anterior chest. There was no lymphadenopathy or hepatosplenomegaly.

The monotherapy suggested indapamide SR as the cause of bleeding in this patient. Treatment was discontinued immediately, and propranolol 80 mg/day was initiated. Bleeding stopped promptly after cessation of indapamide SR therapy. The platelet count rose to a normal level (250 x 10³/mm³) 10 days after withdrawal of indapamide SR, without further treatment of bleeding. The skin lesions on the woman's anterior chest faded quickly and resolved completely within 2 weeks. Given the serious nature of the bleeding, we decided not to reinitiate indapamide SR. The Naranjo probability scale indicated a probable relationship between indapamide SR and mucosal bleeding.²

Discussion.

To our knowledge, as of November 28, 2004, this is the first report of indapamide SR causing mucosal bleeding. No additional cases of bleeding with indapamide SR were available from the manufacturer (Laboratoires Servier).

Theoretically, the possible mechanism of the effect of indapamide on vascular–platelet hemostasis may be its antiaggregating property, which could contribute to normalizing the hyperresponsiveness of platelets from hypertensive patients. Indapamide inhibited the second wave of adenosine diphosphate–induced aggregation and inhibited collagen-induced aggregation of platelet-rich plasma by 50% in vitro.³ Indapamide also can suppress the production of thromboxane A₂.⁴ Indapamide added to standard anihypertensive treatment has led to a decrease of platelet aggregation in hypertensive patients.⁵

This case report posits indapamide SR as a likely cause of mucosal bleeding and alerts clinicians to the possibility of this additional complication with indapamide SR. Since the frequency of this adverse effect is not known, it may be difficult at present to recommend routine platelet count monitoring for this complication. However, prescribers should be aware that bleeding may occur in patients who receive a high cumulative dose during long-term treatment.

References

1. Ambrosioni E, Safar M, Degaute JP, Malin PL, MacMahon M, Pujol DR, et al. Low-dose antihypertensive therapy with 1.5 mg sustained-release indapamide: results of randomized double-blind controlled studies. European study group. J Hypertens 1998;16: 1677-84. DOI 10.1097/00004872-199816110-00015[Medline]
2. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions.Clin Pharmacol Ther 1981;30:239-45.[Medline]
3. Rendu F, Bachelot C, Molle D, Caen J, Guez D. Indapamide inhibits human platelet aggregation in vitro: comparison with hydrochlorothiazide.Cardiovasc Pharmacol 1993;22(suppl 6):S57 -63.
4. Grose JH, Gbeassor FM, Lebel M. Differential effects of diuretics on eicosanoid biosynthesis. Prostaglandin Leukot Med 1986;24: 103-9. DOI 10.1016/0262-1746(86)90118-6[CrossRef]
5. Iakovlev VM, Sokolov GS. [The possibilities of arifon in the combined therapy of unstable stenocardia in persons with arterial hypertension] Russian. Ter Arkh 1997;69(6):53 -5.

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