Emerging concepts for patients with treatment-resistant hypertension

Abstract

Treatment resistant hypertension (TRH) is defined as elevated blood pressure despite treatment with three properly dosed antihypertensive drugs, and is associated with adverse cardiovascular and renal outcomes and increased mortality. Treatment of patients with TRH focuses on maximizing the doses of antihypertensive drugs and adding drugs with complementary mechanisms of action, including a combination of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, calcium channel blockers, and thiazide-like diuretics. Randomized clinical trials have demonstrated the efficacy of the mineralocorticoid receptor antagonist spironolactone as a fourth-line therapy for patients with TRH. Other pharmacologic considerations include adding α-blockers, combined α-β-blockers, centrally acting α-agonists, or direct vasodilators. However, a small, but important subset of patients remain hypertensive despite combination regimens with multiple antihypertensive drugs, underscoring the need for novel blood pressure-lowering therapies. Over recent years, alternative approaches for treating TRH have emerged, including agonists of natriuretic peptides, endothelin receptor antagonists, and additional vasoactive drugs. Lastly, device-based interventions, such as renal denervation or carotid baroreflex activation, may supplement drug therapy for these patients. This review summarizes current knowledge on the management of TRH, with focus on novel therapeutic strategies designed to achieve optimal blood pressure control.

Clinical efficacy and safety of spironolactone in patients with resistant hypertension

“…[ 6 ] Although some randomized controlled trials (RCTs) have demonstrated the efficacy of spironolactone as a fourth-line therapy for patients with RH, there are no available high-quality, large-scale clinical trials to evaluate the efficacy and safety of spironolactone for RH. [ 8 ]…”

Endogenous Purification of NR4A2 (Nurr1) Identified Poly(ADP-Ribose) Polymerase 1 as a Prime Coregulator in Human Adrenocortical H295R Cells

“…For treatment of PA, surgical adrenalectomy is applied for patients with unilaterally increased aldosterone production [ 11 ], and patients with bilateral increased aldosterone production are treated with drugs such as MR antagonists (spironolactone or eplerenone) [ 12 ]. However, a small, but considerable subset of patients remain hypertensive despite administration of these drugs known as treatment-resistant hypertension (TRH), underscoring the need for development of a novel drug [ 13 , 14 ].…”

Resistant Hypertension On Treatment (ResHypOT): sequential nephron blockade compared to dual blockade of the renin-angiotensin-aldosterone system plus bisoprolol in the treatment of resistant arterial hypertension – study protocol for a randomized controlled trial

“…Interventions with three different classes of antihypertensive agents, including a diuretic at the ideal dose, are necessary to achieve target values of BP in resistant hypertensive patients [ 10 , 15 , 20 , 27 , 28 ]. However, some resistant hypertensive patients, despite treatment with a three-drug regimen need at least four antihypertensive agents to gain adequate BP control [ 11 , 13 , 29 , 30 ].…”

“…Regarding the recommendations on research priorities published by Professor Iain Chalmers, [ 31 ] we can state that studies of the pathophysiology of RH emphasize persistent fluid retention, increased sodium sensitivity, excessive salt intake, hyperaldosteronism and a certain degree of renal dysfunction as common underlying causes that contribute to the hypervolemic state found in these patients [ 15 , 28 , 32 – 37 ]. On the other hand, RH patients may present different pathophysiological mechanisms in terms of etiology and so consistently demonstrated sympathetic nervous hyperactivity as evidenced by the measurement of 24-h urinary metanephrines, increased resting heart rate (HR) mainly during sleep, increased HR variability during 24-h spectral analysis with Holter monitoring, increased arterial stiffness inferred by pulse wave velocity and increased peripheral arterial resistance [ 38 , 39 ].…”

“…Regulation in hypertension differs from the regulation in healthy individuals as the baroreceptors and renal control systems of blood volume seem to set the BP at a higher level. Thus, identifying the contribution of blood volume and serum renin in maintaining BP levels could help tailor more effective hypertension treatment, whether by acting on the control of blood volume, the sodium balance, or by acting on the effects of the RAAS on the kidney [ 12 , 28 , 35 , 50 ].…”