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Original research article
Digoxin and clinical outcomes in the Global Rheumatic Heart Disease Registry
  1. Ganesan Karthikeyan1,
  2. Niveditha Devasenapathy2,
  3. Liesl Zühlke3,4,
  4. Mark Emmanuel Engel4,
  5. Sumathy Rangarajan5,
  6. Koon K Teo5,
  7. Bongani M Mayosi4,
  8. Salim Yusuf5
  9. on behalf of the Global Rheumatic Heart Disease Registry (REMEDY) Investigators
    1. 1 Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
    2. 2 Indian Institute of Public Health, Gurgaon, India
    3. 3 Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital and University of Cape Town, Cape Town, South Africa
    4. 4 Department of Medicine, Groote Schuur Hospital and University of Cape Town, Cape Town, South Africa
    5. 5 Population Health Research Institute, Hamilton Health Sciences and McMaster University, Hamilton, Ontario, Canada
    1. Correspondence to Dr Ganesan Karthikeyan, Department of Cardiology, All India Institute of Medical Sciences, New Delhi 110029, India; karthik2010{at}
    • BMM is deceased.


    Objective Digoxin is widely used in patients with rheumatic heart disease (RHD) despite a lack of data on its impact on clinical outcomes. We aimed to determine the association of digoxin use on clinical outcomes in patients with RHD.

    Methods We performed a retrospective analysis of the association of digoxin use with mortality at 2 years in a large RHD registry. Secondary outcomes were recurrent heart failure (HF) and hospitalisation for any cause. We assessed associations using multivariable logistic regression in the entire cohort and in subgroups of patients with atrial fibrillation (AF) and HF. We also estimated average treatment effects from propensity-adjusted analyses using inverse probability treatment weighting.

    Results Information on digoxin use at baseline was available for 98.7% (3298/3343) of patients. In the overall population, digoxin was significantly associated with mortality (OR 1.63, 95% CI 1.30 to 2.04, p<0.0001) and recurrent HF (OR 1.48, 95% CI 1.07 to 2.04, p=0.019). On propensity-weighted analyses, this effect was markedly attenuated (OR 1.05, 95% CI 1.01 to 1.09, p=0.005). Patients in sinus rhythm without HF had a higher propensity-adjusted odds of death with digoxin use (OR 1.06, 95% CI 1.01 to 1.12, p=0.015), but those with both AF and HF had lower mortality (OR 0.88, 95% CI 0.80 to 0.98, p=0.019).

    Conclusion Digoxin use is associated with higher mortality in patients with RHD, but this is greatly attenuated on propensity adjustment, indicating the presence of substantial treatment bias. The adjusted estimates may therefore not be reliable, and large randomised trials are needed to determine the true effect of digoxin in patients with RHD.

    • valvular heart disease
    • heart failure
    • atrial fibrillation

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    • Contributors Conception and design: GK, ND. Data acquisition: LZ, MEE, SR, GK. Data analysis: ND. Data interpretation: all authors. Drafting of manuscript: GK. Critical revision for important intellectual content: all authors. Approval of final version: all authors. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

    • Funding REMEDY was funded principally by the Canadian Network and Centre for Trials Internationally (CANNeCTIN) to GK as part of the Clinical Research Initiative of Canadian Institutes of Health Research. The other sources of funding were the South African Medical Research Council, Lily and Ernst Hausmann Trust, the Else Kroner Fresenius Foundation, the University of Cape Town, the National Research Foundation of South Africa, Harold and Ethel Pupkewitz Heart Foundation (Namibia) and the World Heart Federation. The Jos site was funded by the Jos University Teaching Hospital, the Heart Aid Trust and Faith Alive Foundation. The Sudan sites had partial funding from Sheikan Insurance. LZ was funded in part by the Discovery Foundation, a US National Institutes of Health Fogarty International Clinical Research Fellowship, Thrasher Research Fund Early Career Award, Wellcome Trust Clinical Infectious Disease Research Initiative (CIDRI) Research Officer Award, the Hamilton Naki Clinical Scholarship and by Medtronic Foundation through support to Rheumatic Heart Disease Action. SY is funded by the Marion Burke Chair of the Heart and Stroke Foundation of Canada.

    • Competing interests None declared.

    • Patient consent Not required.

    • Ethics approval Ethics committees of all participating sites approved the study protocol.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators The REMEDY Investigators: clinical investigators and sites: Egypt: Benha University: Azza Abul Fadl (Principal Investigator); Cairo University: Sahar S Sheta (Principal Investigator). Ethiopia: University of Jimma: Abraham Haileamlak (Principal Investigator); University of Addis Ababa: Senbeta G Abdissa, Dufera M Begna, Wandimu Daniel, Araya G Desta, Dejuma Yadeta Goshu (Principal Investigator), Bekele A Shasho. Kenya: University of Nairobi: Bernard Gitura, Stephen Ogendo (Principal Investigator). Malawi: University of Malawi: Neil Kennedy (Principal Investigator). Mozambique: Eduardo Mondlane University: Albertino Damasceno (Principal Investigator); Instituto Nacional de Saúde: Ana Olga Mocumbi (Principal Investigator). Namibia: Windhoek Hospital: Christopher Hugo-Hamman (Principal Investigator). Nigeria: University of Abuja: Dike Ojji (Principal Investigator); University of Jos: Ganiyu A Amusa, Fidelia Bode-Thomas (Principal Investigator), Christopher C Yilgwan, Olukemi Ige, Basil Okeahialam; Kano University: Mahmoud U Sani (Principal Investigator); University of Ibadan: Okechukwu S Ogah (Principal Investigator); Federal Medical Centre, Abeokuta: Taiwo Olunuga; University College Hospital, Ibadan: Abiodun M Adeoye, Okechukwu Ogah (Principal Investigator). Rwanda: King Faisal Hospital: Joseph Mucumbitsi (Principal Investigator). South Africa: University of Cape Town: Blanche Cupido; University of Limpopo: Phindile Mntla (Principal Investigator), Christopher Sutton (Principal Investigator), Rajeev Misra. Sudan: Alzaiem Alazhari University: Ahmed ElSayed (Principal Investigator), Ahmed S Ibrahim; Ahmed Gasim Teaching Hospital: Huda HM Elhassan (Principal Investigator). Uganda: Makerere University: Peter Lwabi, Charles Mondo (Principal Investigator), Emmy Okello. Yemen: University of Sana’a: Mohammed M Al-Kebsi (Principal Investigator). Zambia: University of Lusaka: John Musuku (Principal Investigator).

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