Spironolactone Versus Clonidine as a Fourth-Drug Therapy for Resistant Hypertension: The ReHOT Randomized Study (Resistant Hypertension Optimal Treatment)

doi:10.1161/HYPERTENSIONAHA.117.10662

Randomized Controlled Trial

. 2018 Apr;71(4):681-690.

doi: 10.1161/HYPERTENSIONAHA.117.10662. Epub 2018 Feb 20.

Spironolactone Versus Clonidine as a Fourth-Drug Therapy for Resistant Hypertension: The ReHOT Randomized Study (Resistant Hypertension Optimal Treatment)

Eduardo M Krieger¹, Luciano F Drager², Dante M A Giorgi², Alexandre C Pereira², José Augusto Soares Barreto-Filho², Armando R Nogueira², José Geraldo Mill², Paulo A Lotufo², Celso Amodeo², Marcelo C Batista², Luiz C Bodanese², Antônio C C Carvalho², Iran Castro², Hilton Chaves², Eduardo A S Costa², Gilson S Feitosa², Roberto J S Franco², Flávio D Fuchs², Armênio C Guimarães², Paulo C Jardim², Carlos A Machado², Maria E Magalhães², Décio Mion Jr², Raimundo M Nascimento², Fernando Nobre², Antônio C Nóbrega², Antônio L P Ribeiro², Carlos R Rodrigues-Sobrinho², Antônio F Sanjuliani², Maria do Carmo B Teixeira², Jose E Krieger²; ReHOT Investigators

Collaborators, Affiliations

Collaborators

ReHOT Investigators:
Alessandro Betito, Diogo Duarte Fagundes Moia, Silvia Beatriz Paulino Cavasin de Souza, Hilton de Castro Chaves Júnior

Affiliations

¹ From the Hypertension Unit, Heart Institute-InCor (E.M.K., L.F.D., D.M.A.G.), Hypertension Unit, Renal Division (L.F.D., D.M.), and Laboratory of Genetics and Molecular Medicine, Heart Institute-InCor (A.C.P., J.E.K.), University of Sao Paulo Medical School, Brazil; Division of Cardiology, Federal University of Sergipe, Brazil (J.A.S.B.-F.); Department of Clinical Research, Hospital Universitario Clementino Fraga Filho, Brazil (A.R.N.); Department of Physiological Sciences, Federal University of Espírito Santo, Brazil (J.G.M.); Division of Internal Medicine, Center for Clinical and Epidemiological Research, University Hospital (P.A.L.) and Ribeirao Preto Medical School (F.N.), University of Sao Paulo, Brazil; Department of Hypertension and Nephrology, Dante Pazzanese Institute of Cardiology, Sao Paulo, Brazil (C.A.); Division of Nephrology, Department of Medicine (M.C.B.) and Department of Cardiology (A.C.C.C.), Universidade Federal de São Paulo, Brazil; Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Brazil (L.C.B.); Institute of Cardiology, University Cardiology Foundation, Porto Alegre, Brazil (I.C.); Department of Clinical Medicine, Federal University of Pernambuco, Recife, Brazil (H.C.); Department of Cardiology, Universidade Federal do Para, Belem, Brazil (E.A.S.C.); Escola Bahiana de Medicina e Saude Pública, Salvador, Brazil (G.S.F.); Division of Nephrology, Department of Internal Medicine, Botucatu Medical School, Sao Paulo State University, Brazil (R.J.S.F.); Division of Cardiology, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Brazil (F.D.F.); Federal University of Bahia, Salvador, Brazil (A.C.G.); Faculty of Medicine, Federal University of Goias, Goiânia, Brazil (P.C.J.); Department of Cardiology, School of Medicine, Federal University of Sao Paulo, Brazil (C.A.M.); Serviço de Cardiologia do Hospital Universitario Pedro Ernesto da Universidade do Estado do Rio de Janeiro, Brazil (M.E.M.); Department of Medicine, Ouro Preto Federal University, Brazil (R.M.N.); Hospital Universitario Antonio Pedro, Universidade Federal Fluminense, Rio de Janeiro, Brazil (A.C.N.); Department of Internal Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil (A.L.P.R.); Department of Cardiology, Federal University of Ceara, Fortaleza, Brazil (C.R.-S.); Discipline of Clinical and Experimental Pathophysiology, Rio de Janeiro State University, Brazil (A.F.S.); and Universidade Estadual de Ciencias da Saude de Alagoas, Maceio, Brazil (M.d.C.B.T.). eduardo.krieger@incor.usp.br.
² From the Hypertension Unit, Heart Institute-InCor (E.M.K., L.F.D., D.M.A.G.), Hypertension Unit, Renal Division (L.F.D., D.M.), and Laboratory of Genetics and Molecular Medicine, Heart Institute-InCor (A.C.P., J.E.K.), University of Sao Paulo Medical School, Brazil; Division of Cardiology, Federal University of Sergipe, Brazil (J.A.S.B.-F.); Department of Clinical Research, Hospital Universitario Clementino Fraga Filho, Brazil (A.R.N.); Department of Physiological Sciences, Federal University of Espírito Santo, Brazil (J.G.M.); Division of Internal Medicine, Center for Clinical and Epidemiological Research, University Hospital (P.A.L.) and Ribeirao Preto Medical School (F.N.), University of Sao Paulo, Brazil; Department of Hypertension and Nephrology, Dante Pazzanese Institute of Cardiology, Sao Paulo, Brazil (C.A.); Division of Nephrology, Department of Medicine (M.C.B.) and Department of Cardiology (A.C.C.C.), Universidade Federal de São Paulo, Brazil; Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Brazil (L.C.B.); Institute of Cardiology, University Cardiology Foundation, Porto Alegre, Brazil (I.C.); Department of Clinical Medicine, Federal University of Pernambuco, Recife, Brazil (H.C.); Department of Cardiology, Universidade Federal do Para, Belem, Brazil (E.A.S.C.); Escola Bahiana de Medicina e Saude Pública, Salvador, Brazil (G.S.F.); Division of Nephrology, Department of Internal Medicine, Botucatu Medical School, Sao Paulo State University, Brazil (R.J.S.F.); Division of Cardiology, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Brazil (F.D.F.); Federal University of Bahia, Salvador, Brazil (A.C.G.); Faculty of Medicine, Federal University of Goias, Goiânia, Brazil (P.C.J.); Department of Cardiology, School of Medicine, Federal University of Sao Paulo, Brazil (C.A.M.); Serviço de Cardiologia do Hospital Universitario Pedro Ernesto da Universidade do Estado do Rio de Janeiro, Brazil (M.E.M.); Department of Medicine, Ouro Preto Federal University, Brazil (R.M.N.); Hospital Universitario Antonio Pedro, Universidade Federal Fluminense, Rio de Janeiro, Brazil (A.C.N.); Department of Internal Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil (A.L.P.R.); Department of Cardiology, Federal University of Ceara, Fortaleza, Brazil (C.R.-S.); Discipline of Clinical and Experimental Pathophysiology, Rio de Janeiro State University, Brazil (A.F.S.); and Universidade Estadual de Ciencias da Saude de Alagoas, Maceio, Brazil (M.d.C.B.T.).

PMID: 29463627
DOI: 10.1161/HYPERTENSIONAHA.117.10662

Randomized Controlled Trial

Spironolactone Versus Clonidine as a Fourth-Drug Therapy for Resistant Hypertension: The ReHOT Randomized Study (Resistant Hypertension Optimal Treatment)

Eduardo M Krieger et al. Hypertension. 2018 Apr.

. 2018 Apr;71(4):681-690.

doi: 10.1161/HYPERTENSIONAHA.117.10662. Epub 2018 Feb 20.

Authors

Collaborators

ReHOT Investigators:
Alessandro Betito, Diogo Duarte Fagundes Moia, Silvia Beatriz Paulino Cavasin de Souza, Hilton de Castro Chaves Júnior

Affiliations

¹ From the Hypertension Unit, Heart Institute-InCor (E.M.K., L.F.D., D.M.A.G.), Hypertension Unit, Renal Division (L.F.D., D.M.), and Laboratory of Genetics and Molecular Medicine, Heart Institute-InCor (A.C.P., J.E.K.), University of Sao Paulo Medical School, Brazil; Division of Cardiology, Federal University of Sergipe, Brazil (J.A.S.B.-F.); Department of Clinical Research, Hospital Universitario Clementino Fraga Filho, Brazil (A.R.N.); Department of Physiological Sciences, Federal University of Espírito Santo, Brazil (J.G.M.); Division of Internal Medicine, Center for Clinical and Epidemiological Research, University Hospital (P.A.L.) and Ribeirao Preto Medical School (F.N.), University of Sao Paulo, Brazil; Department of Hypertension and Nephrology, Dante Pazzanese Institute of Cardiology, Sao Paulo, Brazil (C.A.); Division of Nephrology, Department of Medicine (M.C.B.) and Department of Cardiology (A.C.C.C.), Universidade Federal de São Paulo, Brazil; Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Brazil (L.C.B.); Institute of Cardiology, University Cardiology Foundation, Porto Alegre, Brazil (I.C.); Department of Clinical Medicine, Federal University of Pernambuco, Recife, Brazil (H.C.); Department of Cardiology, Universidade Federal do Para, Belem, Brazil (E.A.S.C.); Escola Bahiana de Medicina e Saude Pública, Salvador, Brazil (G.S.F.); Division of Nephrology, Department of Internal Medicine, Botucatu Medical School, Sao Paulo State University, Brazil (R.J.S.F.); Division of Cardiology, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Brazil (F.D.F.); Federal University of Bahia, Salvador, Brazil (A.C.G.); Faculty of Medicine, Federal University of Goias, Goiânia, Brazil (P.C.J.); Department of Cardiology, School of Medicine, Federal University of Sao Paulo, Brazil (C.A.M.); Serviço de Cardiologia do Hospital Universitario Pedro Ernesto da Universidade do Estado do Rio de Janeiro, Brazil (M.E.M.); Department of Medicine, Ouro Preto Federal University, Brazil (R.M.N.); Hospital Universitario Antonio Pedro, Universidade Federal Fluminense, Rio de Janeiro, Brazil (A.C.N.); Department of Internal Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil (A.L.P.R.); Department of Cardiology, Federal University of Ceara, Fortaleza, Brazil (C.R.-S.); Discipline of Clinical and Experimental Pathophysiology, Rio de Janeiro State University, Brazil (A.F.S.); and Universidade Estadual de Ciencias da Saude de Alagoas, Maceio, Brazil (M.d.C.B.T.). eduardo.krieger@incor.usp.br.
² From the Hypertension Unit, Heart Institute-InCor (E.M.K., L.F.D., D.M.A.G.), Hypertension Unit, Renal Division (L.F.D., D.M.), and Laboratory of Genetics and Molecular Medicine, Heart Institute-InCor (A.C.P., J.E.K.), University of Sao Paulo Medical School, Brazil; Division of Cardiology, Federal University of Sergipe, Brazil (J.A.S.B.-F.); Department of Clinical Research, Hospital Universitario Clementino Fraga Filho, Brazil (A.R.N.); Department of Physiological Sciences, Federal University of Espírito Santo, Brazil (J.G.M.); Division of Internal Medicine, Center for Clinical and Epidemiological Research, University Hospital (P.A.L.) and Ribeirao Preto Medical School (F.N.), University of Sao Paulo, Brazil; Department of Hypertension and Nephrology, Dante Pazzanese Institute of Cardiology, Sao Paulo, Brazil (C.A.); Division of Nephrology, Department of Medicine (M.C.B.) and Department of Cardiology (A.C.C.C.), Universidade Federal de São Paulo, Brazil; Pontificia Universidade Catolica do Rio Grande do Sul, Porto Alegre, Brazil (L.C.B.); Institute of Cardiology, University Cardiology Foundation, Porto Alegre, Brazil (I.C.); Department of Clinical Medicine, Federal University of Pernambuco, Recife, Brazil (H.C.); Department of Cardiology, Universidade Federal do Para, Belem, Brazil (E.A.S.C.); Escola Bahiana de Medicina e Saude Pública, Salvador, Brazil (G.S.F.); Division of Nephrology, Department of Internal Medicine, Botucatu Medical School, Sao Paulo State University, Brazil (R.J.S.F.); Division of Cardiology, Hospital de Clinicas de Porto Alegre, Federal University of Rio Grande do Sul, Brazil (F.D.F.); Federal University of Bahia, Salvador, Brazil (A.C.G.); Faculty of Medicine, Federal University of Goias, Goiânia, Brazil (P.C.J.); Department of Cardiology, School of Medicine, Federal University of Sao Paulo, Brazil (C.A.M.); Serviço de Cardiologia do Hospital Universitario Pedro Ernesto da Universidade do Estado do Rio de Janeiro, Brazil (M.E.M.); Department of Medicine, Ouro Preto Federal University, Brazil (R.M.N.); Hospital Universitario Antonio Pedro, Universidade Federal Fluminense, Rio de Janeiro, Brazil (A.C.N.); Department of Internal Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil (A.L.P.R.); Department of Cardiology, Federal University of Ceara, Fortaleza, Brazil (C.R.-S.); Discipline of Clinical and Experimental Pathophysiology, Rio de Janeiro State University, Brazil (A.F.S.); and Universidade Estadual de Ciencias da Saude de Alagoas, Maceio, Brazil (M.d.C.B.T.).

PMID: 29463627
DOI: 10.1161/HYPERTENSIONAHA.117.10662

Abstract

The aim of this study is to compare spironolactone versus clonidine as the fourth drug in patients with resistant hypertension in a multicenter, randomized trial. Medical therapy adherence was checked by pill counting. Patients with resistant hypertension (no office and ambulatory blood pressure [BP] monitoring control, despite treatment with 3 drugs, including a diuretic, for 12 weeks) were randomized to an additional 12-week treatment with spironolactone (12.5-50 mg QD) or clonidine (0.1-0.3 mg BID). The primary end point was BP control during office (<140/90 mm Hg) and 24-h ambulatory (<130/80 mm Hg) BP monitoring. Secondary end points included BP control from each method and absolute BP reduction. From 1597 patients recruited, 11.7% (187 patients) fulfilled the resistant hypertension criteria. Compared with the spironolactone group (n=95), the clonidine group (n=92) presented similar rates of achieving the primary end point (20.5% versus 20.8%, respectively; relative risk, 1.01 [0.55-1.88]; P=1.00). Secondary end point analysis showed similar office BP (33.3% versus 29.3%) and ambulatory BP monitoring (44% versus 46.2%) control for spironolactone and clonidine, respectively. However, spironolactone promoted greater decrease in 24-h systolic and diastolic BP and diastolic daytime ambulatory BP than clonidine. Per-protocol analysis (limited to patients with ≥80% adherence to spironolactone/clonidine treatment) showed similar results regarding the primary end point. In conclusion, clonidine was not superior to spironolactone in true resistant hypertensive patients, but the overall BP control was low (≈21%). Considering easier posology and greater decrease in secondary end points, spironolactone is preferable for the fourth-drug therapy.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01643434.

Keywords: blood pressure; clinical trial; humans; hypertension; risk; therapeutics.

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Comment in

Was hilft noch bei resistenter Hypertonie?
Zidek W. Zidek W. MMW Fortschr Med. 2018 Aug;160(14):35. doi: 10.1007/s15006-018-0819-z. MMW Fortschr Med. 2018. PMID: 30105697 German. No abstract available.

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Spironolactone Versus Clonidine as a Fourth-Drug Therapy for Resistant Hypertension: The ReHOT Randomized Study (Resistant Hypertension Optimal Treatment)

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Spironolactone Versus Clonidine as a Fourth-Drug Therapy for Resistant Hypertension: The ReHOT Randomized Study (Resistant Hypertension Optimal Treatment)

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