This document discusses refractory hypertension, which is defined as hypertension that cannot be controlled despite using more than 5 different types of antihypertensive medications. It notes that refractory hypertension is a new and uncommon phenotype affecting less than 5% of hypertensive patients. Risk factors include being female, young, having comorbidities, and being of African descent. The causes of refractory hypertension are suggested to be hypervolemia, hyperaldosteronism, and increased sympathetic tone. The document recommends properly selecting and escalating drug therapies for refractory hypertension and notes some promising experimental therapies.

1. MANEJO DEL
HIPERTENSO
REFRACTARIO
Dr. Cristian Pedreros Rosales
Médico Internista - Nefrólogo
Hospital Las Higueras de Thno.
Profesor Asistente
Departamento de Medicina Interna
Universidad de Concepción

2. HTA resistente ≠ HTA refractaria

3. ¿Qué es hipertensión refractaria?

4. Hipertensión que no puede
controlarse con ningún
régimen antihipertensivo”
–Acelajado MC, et al. J Clin Hypertens (Greenwich). 2012;14:7–12.
“

5. –Dudenbostel T, et al. Hypertension. 2015;66:126–133
Hipertensión que no puede controlarse a
pesar de usar >5 tipos diferentes de
antihipertensivos (incluida tiazida y
antagonista MC”.
“
–Dudenbostel T, et al. Hypertension. 2015;66:126–133

6. –Dudenbostel T, et al. Hypertension. 2016 Jun;67(6):1085-92. Epub 2016 Apr 18.

7. Pasos para
manejar HTA
resistente en
atención
ambulatoria
Con
fi
rmar “resistencia” al tratamiento
Excluir pseudoresistencia
Modi
fi
car estilo de vida
Descontinuar “sustancias”
Descartar HTA 2ria.
Optimizar tratamiento
Derivar
2

8. –Siddiqui M, et al. Hypertension. 2016 Jun;67(6):1085-92. Epub 2016 Apr 18.
Prevalence of resistant and refractory hypertension
Hipertensión
Resistente
21%
HTA-R
No controlada
32%
HTA-R
Controlada
65%
HTA
Refractaria
3%

9. Factores de riesgo de HTA refractaria
–Dudenbostel T, et al. Hypertension. 2016 Jun;67(6):1085-92. Epub 2016 Apr 18.
Mujeres
Afroamericanos
Jóvenes
Diabetes Mellitus 2
ERC
ICC / Stroke
Factores de riesgo para HTA refractaria

10. ¿Cuál es la causa de la HTA refractaria?

11. Volume Indicators of Resistant Hypertension
–Taler SJ, et al. Hypertension. 2002;39:982–988.

12. –Taler SJ, et al. Hypertension. 2002;39:982–988.
Volume Indicators of Resistant Hypertension

13. Results of Pulsatile and Impedance Hemodynamics in Patients With
Refractory and Controlled Resistant Hypertension
–Dudenbostel T, et al. Hypertension. 2015;66:126– 133.

14. Biochemical Characteristics of Patients With Refractory and
Controlled Resistant Hypertension
–Dudenbostel T, et al. Hypertension. 2015;66:126– 133.

15. ≠
HTA resistente HTA refractaria

16. ¿Qué hacer con un refractario real?

17. “
”
Derivado!
a especialista en hipertensión

18. “
”
Derivado!
a especialista en hipertensión

19. Evaluar y Disminuir
consumo de sal
Optimizar régimen
farmacológico
Considerar terapia
experimental

20. UNa 24h [+ UCr]
Na oral 24h
=

21. <6g de Sal (NaCl)
<2,3g de Na (100 mEq/día)

22. Combinación >3 drogas
Acción prolongada
Esquema simple
Diurético SIEMPRE

23. Characterization of Resistant Hypertension
Association Between Resistant Hypertension, Aldosterone, and Persistent
Intravascular Volume Expansion
–Gaddam KK, et al. Arch Intern Med. 2008;168(11):1159.
BNP ANP

24. Characterization of Resistant Hypertension
Association Between Resistant Hypertension, Aldosterone, and Persistent
Intravascular Volume Expansion
–Gaddam KK, et al. Arch Intern Med. 2008;168(11):1159.
Característica
HTA resistente
(n=279)
Control
(n=53)
Signi
fi
cancia
Aldosterona (ng/dL) 13 8,4 p<0,001
Potasio (mEq/L) 3,9 4,3 p<0,001
PAC/PRA 22 6 p<0,001

25. Characterization of Resistant Hypertension
Association Between Resistant Hypertension, Aldosterone, and Persistent
Intravascular Volume Expansion
–Gaddam KK, et al. Arch Intern Med. 2008;168(11):1159.

27. Revisiting the NaCl cotransporter regulation by
with-no-lysine kinases (WNK)
–Silvana Bazúa-Valenti & Gerardo Gamba. Am J Physiol Cell Physiol 308: C779–C791, 2015.
Disease NCC Activity Gene
Gitelman ↓↓ SLC12A3
PHAIIA ? ?
PHAIIB ↑ WNK4
PHAIIC ↑ WNK1
PHAIID ↑↑↑ KLHL3
PHAIIE ↑↑↑↑ CUL3

28. A model of WNK-SPAK/OSR1 regulation of NCC and its role in
the pathogenesis of Familial Hyperkalemic Hypertension (FHHt)
–Subramanya A, Ellison D. Clin J Am Soc Nephrol. 2014 Dec 5; 9(12): 2147–2163.

29. Revisiting the NaCl cotransporter regulation by
Role of the epithelial sodium channel in salt- sensitive hypertension
–Sun Y, et al. Acta Pharmacologica Sinica (2011) 32: 789–797.
Disease ENaC Activity Genetic variation
HTA ↑ G589S
HTA NS T594M
HTA NS R597H
HTA NS R624C
HTA NS E632G
HTA NS G442V
HTA NS V434M
HTA NS V546I
HTA NS 594insP
HTA NS R631H
HTA ↑ G2139A

30. Tiazida
Antagonista RMC
✗
✗

32. Are Chlorthalidone and Hydrochlorothiazide Equivalent Blood-
Pressure–Lowering Medications?
–Khosla N, et al. J Clin Hypertens. 2005 Jun;7(6):354-6.

33. Steady state after initiation of a thiazide diuretic
–Maronde R, et al. JAMA. 1983;249(2):237-241

35. Ef
fi
cacy of low-dose spironolactone in subjects with resistant
hypertension
–Nishizaka MK, et al. Am J Hypertens. 2003;16(11 Pt 1):925
◼︎ PA (n=349
☐ W/PA (n=42)

36. ASCOT ASPIRANT PATHWAY-2
n=1411
Espironolac. 25mg
⬇︎
22/10 mmHg
n=117
Espironolac. 25mg
⬇︎
5,4/1,0 mmHg
n=285
Espironolac. 25-50mg
⬇︎
PAS 10 mmHg
Chapman N, et al.
Hypertension. 2007;49(4):839.
Václavík J, et al.
Hypertension. 2011;57(6):1069.
Williams B, et al.
Lancet. 2015;386(10008):2059.

37. Spironolactone versus placebo, bisoprolol, and doxazosin to
determine the optimal treatment for drug-resistant hypertension
(PATHWAY-2): a randomised, double-blind, crossover trial
–Williams B, et al. Lancet. 2015;386(10008):2059.
IECA/ARAII
BCC
Tiazida

38. IECA/ARAII + Tiazida + BCC + ß-B / α-B
Espironolactona
Minoxidil
Clonidina
?

39. Espironolactona / Esplerenona
Minoxidil
Clonidina
?
…Cambio de tiazida
…Da lo mismo cual
…Falta de evidencia
…Mucho efecto 2rio
IECA/ARAII + Tiazida + BCC + ß-B / α-B

42. SYMPLICITY-HTN-3
SYMPLICITY-HTN-1 SYMPLICITY-HTN-2
n=45
Seguimiento 1 año
⬇︎
27/17 mmHg
n=100
Seguimiento 6 meses
⬇︎
32/12 mmHg
n=535
Seguimiento 6 meses
⬇︎
14/23 mmHg
Bhatt D, et al.
NEJM. 2014 Apr;370(15):1393-401
Krum H, et al.
Lancet. 2009;373:1275-81.
Esler MD, et al.
Lancet. 2010;376:1903-9.

43. SYMPLICITY-HTN-1
n=45
Seguimiento 1 año
⬇︎
27/17 mmHg
Krum H, et al.
Lancet. 2009;373:1275-81.

44. SYMPLICITY-HTN-2
n=100
Seguimiento 6 meses
⬇︎
32/12 mmHg
Esler MD, et al.
Lancet. 2010;376:1903-9.

45. SYMPLICITY-HTN-3
n=535
Seguimiento 6 meses
⬇︎
14/23 mmHg
Bhatt D, et al.
NEJM. 2014 Apr;370(15):1393-401

46. Kidney involvement of the function on renal afferent and efferent nerves
–Blankestijn PJ, et al. Nephrol Dial Transplant. 2014 Jun;29(6):1120-3

47. Potential patient groups likely to bene
fi
t of renal denervation
–Blankestijn PJ, et al. Nephrol Dial Transplant. 2014 Jun;29(6):1120-3
ERC sin diálisis
ERC con diálisis
Riñón nativo en TX
Sd. Dolor renal
ICC
Obesidad /Sd metabólico
DM tipo 2

48. Randomized controlled trials of renal denervation
–Lobo M, et al. Eur Heart J. 2016 Jul 11. pii: ehw303. [Epub ahead of print]

49. Renal artery sympathetic denervation:
Observations from the UK experience
–Sharp AS, et al. Clin Res Cardiol. 2016 Jun;105(6):544-52.
n=253

52. An historical perspective on our understanding of baroreceptor physiology
–Victor R, et al. Nature Reviews Cardiology 12, 451–463 (2015)

53. The mechanical component of carotid barore
fl
ex deactivation is blocked
by local application of catecholamines to the carotid sinus in dogs
–Heymans C, van den Heuvel-Heymans, G. Circulation 4(4), 581–586 (1951).

54. Management of uncontrollable hypertension with a carotid sinus
stimulation device
–Mohaupt MG, et al. Hypertension 50(5), 825–828 (2007)

55. Carotid baroreceptor stimulation, sympathetic activity, barore
fl
ex
function, and blood pressure in hypertensive patients
–Heusser, K. et al. Hypertension 55(3), 619–626 (2010)

56. Rheos pivotal trial
Barore
fl
ex activation therapy lowers blood pressure in patients with resistant
hypertension: results from the double-blind, randomized, placebo-controlled.
–Bisognano JD. J Am Coll Cardiol. 2011;58(7):765.
n=265

57. Carotid barore
fl
ex activation therapy for resistant hypertension
–Victor R, et al. Nature Reviews Cardiology 12, 451–463 (2015)

60. Creation of an iliac arteriovenous shunt lowers blood pressure in
chronic obstructive pulmonary disease patients with hypertension
–Faul J, et al. J Vasc Surg 2014;59:1078-83
P<0,01 P<0,05 P<0,01

61. –Lobo M, et al. Eur Heart J. 2016 Jul 11. pii: ehw303. [Epub ahead of print]

62. Central arteriovenous anastomosis for the treatment of patients with
uncontrolled hypertension (the ROX CONTROL HTN study): RCT.
–Lobo MD, et al. Lancet. 2015;385(9978):1634.
(n=83)

63. Terapia de
activación
barore
fl
eja
Fístula AV
Iliaca
Denervación
renal

64. Mensajes para la casa…

65. Resistente ≠ Refractario
Fenotipo “nuevo” y poco frecuente (<5%)
FR: Mujer, joven, comorbilidades, afroamericana
Hipervolemia, hiperaldo, tono simpático
Seleccionar adecuadamente y escalonar drogas
Terapias experimentales promisorias