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Randomized Controlled Trial
. 2021 Mar;116(3):443-451.
doi: 10.36660/abc.202190703.

Effects of Anti-TNF alpha Therapy on Blood Pressure in Resistant Hypertensive Subjects: A Randomized, Double-Blind, Placebo-Controlled Pilot Study

[Article in English, Portuguese]
Ana Paula de Faria  1 , Alessandra M V Ritter  1 , Arthur Santa-Catharina  1 , Débora P Souza  1 , Estephania P Naseri  1 , Manoel B Bertolo  1 , Mariana Rodrigues Pioli  1 , Caio C Carvalho  2 , Rodrigo Modolo  1 , Heitor Moreno  1
Affiliations
Randomized Controlled Trial

Effects of Anti-TNF alpha Therapy on Blood Pressure in Resistant Hypertensive Subjects: A Randomized, Double-Blind, Placebo-Controlled Pilot Study

[Article in English, Portuguese]
Ana Paula de Faria et al. Arq Bras Cardiol. 2021 Mar.

Abstract
in English, Portuguese

Background: The cytokine tumor necrosis factor-alpha (TNF-α) is elevated in resistant hypertension (RH), but the effects of a TNF-α inhibitor in this population is unknown.

Objective: The aim of this trial was to evaluate whether a single dose of infliximab controlled by placebo acutely reduces blood pressure (BP) in RH subjects.

Methods: A double-blind, placebo-controlled, crossover trial was conducted, and randomized RH subjects received either infliximab or placebo. The primary endpoint was the change in mean BP levels relative to the baseline immediately after the infusion obtained by continuously beat-to-beat non-invasive hemodynamic assessment. Secondary endpoints included changes in office, ambulatory and central BP measurements; endothelial function; and inflammatory biomarkers after 7 days. The level of significance accepted was alpha=0.05.

Results: Ten RH subjects were enrolled. The primary endpoint analysis showed an acute decrease in mean BP values (mean of differences ± standard deviation = -6.3 ± 7.2 mmHg, p=0.02) from baseline, after the application of infliximab compared with placebo. Diastolic BP levels (-4.9 ± 5.5 mmHg, p=0.02), but not systolic BP levels (-9.4 ± 19.7 mmHg, p=0.16), lowered after infliximab infusion. No further significant differences were identified in either the other hemodynamic parameters or in secondary endpoints, except for TNF-α levels, which increased continuously after infliximab infusion. No adverse events were reported during the protocol.

Conclusions: A single-dose of infliximab decreased the mean and diastolic BP levels immediately after its infusion, when compared to the placebo in RH. The anti-TNF-α therapy was found to be safe and well-tolerated. The results of this proof-of-concept are hypothesis-generating and need to be further investigated. (Arq Bras Cardiol. 2021; 116(3):443-451).

Fundamento: A citocina fator de necrose tumoral alfa (TNF-α) é elevada na hipertensão resistente (HAR), mas os efeitos dos inibidores de TNF-α nessa população ainda são desconhecidos.

Objetivos: O objetivo deste estudo foi avaliar se uma única dose de infliximabe controlada por placebo reduz a pressão arterial (PA) de forma aguda em pacientes com HAR.

Métodos: Realizamos um estudo cruzado, randomizado, duplo-cego e controlado por placebo em que pacientes com HAR receberam infliximabe ou placebo. O desfecho primário foi a alteração dos níveis de PA média em relação ao basal imediatamente após a infusão, obtida por avaliação hemodinâmica não invasiva contínua, batimento a batimento. Os desfechos secundários incluíram alterações em medidas de PA central, ambulatorial e em consultório, na função endotelial, e nos biomarcadores inflamatórios após 7 dias. O nível de significância aceito foi alfa=0,05.

Resultados: Foram incluídos dez portadores de HAR. O resultado do desfecho primário demonstrou uma redução aguda dos níveis de PA média (média das diferenças ± desvio padrão = -6,3 ± 7,2 mmHg, p=0,02) em relação ao basal, após o uso de infliximabe, em comparação com o placebo. Os níveis de PA diastólica (-4,9 ± 5,5 mmHg, p=0,02), mas não os níveis de PA sistólica (-9,4 ± 19,7 mmHg, p=0,16), reduziram após a infusão de infliximabe. Não foram identificadas diferenças significativas nos demais parâmetros hemodinâmicos, nem nos resultados dos desfechos secundários, com exceção dos níveis de TNF-α, que aumentaram continuamente após o uso de infliximabe. Não foram relatados eventos adversos durante o protocolo.

Conclusões: Uma dose única de infliximabe reduziu os níveis de PA média e diastólica imediatamente após sua infusão, em comparação com placebo em HAR. A terapia com anti-TNF-α foi considerada segura e bem tolerada. Os resultados desse estudo prova de conceito são geradores de hipótese e precisam ser investigados em maior detalhe. (Arq Bras Cardiol. 2021; 116(3):443-451).

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Conflict of interest statement

Potencial conflito de interesses

Declaro não haver conflito de interesses pertinentes.

Figures

Figura 1
Figura 1. Fluxograma do estudo.
Figura 2
Figura 2. Delta absoluto da pressão arterial média (Δ PAM, 2,3 ± 12,6 versus -4,0 ± 12,5 mmHg, p=0,02) relativo ao basal imediatamente após (T1-T0) as infusões de placebo e infliximabe, respectivamente, nos pacientes estudados. Os dados foram expressos como média e desvio padrão. O teste t de Student pareado foi aplicado para comparar os valores de delta entre o infliximabe e o placebo,
*p<0,05 versus placebo.
Figura 3
Figura 3. Deltas absolutos dos parâmetros hemodinâmicos batimento a batimento relativos ao basal imediatamente após (T1-T0) as infusões de placebo e infliximabe, respectivamente, nos pacientes estudados. A. Delta pressão arterial sistólica (ΔPAS, 6,1 ± 21,1 versus -3,3 ± 15,2 mmHg, p=0,16); B. Delta pressão arterial diastólica (ΔPAD, 1,6 ± 9,9 versus -3,3 ± 9,8 mmHg, p=0,02); C. Delta débito cardíaco (ΔDC, -0,14 ± 0,98 versus 0,30 ± 1,21 mmHg, p=0,44); D. Delta resistência vascular periférica total (ΔRVPT, -6,9 ± 615 versus -248 ± 543 mmHg, p=0,12). Os dados foram expressos como média e desvio padrão. O teste t de Student pareado foi aplicado para comparar os valores de delta entre o infliximabe e o placebo,
*p<0,05 versus placebo.
Figure 1
Figure 1. Study flow diagram.
Figure 2
Figure 2. Absolute delta mean blood pressure (Δ MBP, 2.3 ± 12.6 vs. -4.0 ± 12.5 mmHg, p=0.02) relative to baseline immediately after (T1-T0) the placebo and infliximab infusions, respectively, in the studied subjects. Data were expressed as mean and standard deviation. Paired Student’s t-test was applied to compare delta values between infliximab and placebo.
*p<0.05 versus placebo.
Figure 3
Figure 3. Absolute deltas of beat-to-beat hemodynamic parameters relative to baseline immediately after (T1-T0) placebo and infliximab infusions, respectively, in the studied subjects. A. Delta systolic blood pressure (Δ SBP, 6.1 ± 21.1 vs. -3.3 ± 15.2 mmHg, p=0.16); B. Delta diastolic blood pressure (Δ DBP, 1.6 ± 9.9 vs. -3.3 ± 9.8 mmHg, p=0.02); C. Delta cardiac output (Δ CO, -0.14 ± 0.98 vs. 0.30 ± 1.21 mmHg, p=0.44); D. Delta total peripheral resistance (Δ TPR, -6.9 ± 615 vs. -248 ± 543 mmHg, p=0.12). Data were expressed as mean and standard deviation. Paired Student’s t-test was applied to compare delta values between infliximab and placebo.
*p<0.05 versus placebo.
See this image and copyright information in PMC

Comment in

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