Sequential nephron blockade versus sequential renin–angiotensin system blockade in resistant hypertension: a prospective, randomized, open blinded endpoint study

Objective: To compare two drug regimens to treat resistant hypertension. Methods: In a prospective, randomized, open blinded endpoint study, 167 patients with mean baseline daytime ambulatory blood pressure 135 mmHg or more and/or 85 mmHg or more, despite 4 weeks’ treatment with irbesartan 300 mg/day, hydrochlorothiazide 12.5 mg/day and amlodipine 5 mg/day, were randomized to sequential nephron blockade (group 1, n = 85) or sequential renin–angiotensin system blockade (group 2, n = 82). First, spironolactone 25 mg/day in group 1 or ramipril 5 mg/day in group 2 were added for 4 weeks. Treatment was increased at weeks 4, 8 or 10 if home blood pressure was 135 mmHg or more and/or 85 mmHg or more by sequentially administering furosemide 20 mg/day, furosemide 40 mg/day and amiloride 5 mg/day in group 1, or ramipril 10 mg/day, bisoprolol 5 mg/day and bisoprolol 10 mg/day in group 2. The primary endpoint was change in systolic daytime ambulatory blood pressure at week 12. Results: At week 12, the mean between-group difference in daytime ambulatory blood pressure was 10/4 mmHg (95% confidence interval: 7–14/2–7; P < 0.001/P = 0.0014) in favour of the group 1. The blood pressure goal (daytime ambulatory blood pressure <135/85 mmHg) was achieved in 58% in the group 1 and 20% in the group 2 (P < 0.0001). Discontinuation for drug-related adverse events was low (group 1, n = 7; group 2, n = 6). Conclusion: In patients with resistant hypertension, sequential nephron blockade induces a large and well tolerated reduction in blood pressure via a progressive increase in sodium depletion, and is more effective than sequential renin–angiotensin system blockade.

[1]  Bryan Williams,et al.  Management of hypertension: summary of NICE guidance , 2011, BMJ : British Medical Journal.

[2]  J. Václavík,et al.  Addition of Spironolactone in Patients With Resistant Arterial Hypertension (ASPIRANT): A Randomized, Double-Blind, Placebo-Controlled Trial , 2011, Hypertension.

[3]  B. Álvarez-Álvarez,et al.  Management of resistant arterial hypertension: role of spironolactone versus double blockade of the renin–angiotensin–aldosterone system , 2010, Journal of hypertension.

[4]  B. Psaty,et al.  Minimizing bias due to confounding by indication in comparative effectiveness research: the importance of restriction. , 2010, JAMA.

[5]  E. Muxfeldt,et al.  Efficacy of Spironolactone Therapy in Patients With True Resistant Hypertension , 2010, Hypertension.

[6]  M. Moser,et al.  Use of diuretics in patients with hypertension. , 2009, The New England journal of medicine.

[7]  B. Imholz,et al.  Aldosterone-receptor antagonism in hypertension , 2009, Journal of hypertension.

[8]  G. Bakris,et al.  Resistant hypertension: an overview of evaluation and treatment. , 2008, Journal of the American College of Cardiology.

[9]  Daniel W. Jones,et al.  Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. , 2008, Circulation.

[10]  J. Ménard,et al.  Teletransmission of home blood pressure monitoring: making it easier. , 2008, Journal of hypertension.

[11]  S. Yusuf,et al.  Telmisartan, ramipril, or both in patients at high risk for vascular events. , 2008, The New England journal of medicine.

[12]  A. Dominiczak,et al.  2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension. , 2007, Journal of hypertension.

[13]  F. Zannad.  Aldosterone antagonist therapy in resistant hypertension , 2007, Journal of hypertension.

[14]  M. Moser,et al.  Resistant or Difficult-to-Control Hypertension , 2006 .

[15]  M. Moser,et al.  Clinical practice. Resistant or difficult-to-control hypertension. , 2006, The New England journal of medicine.

[16]  W. Ambrosius,et al.  Improvement in Blood Pressure With Inhibition of the Epithelial Sodium Channel in Blacks With Hypertension , 2005, Hypertension.

[17]  G. MacGregor,et al.  Systematic Review of Combined Angiotensin-Converting Enzyme Inhibition and Angiotensin Receptor Blockade in Hypertension , 2005, Hypertension.

[18]  J. Ménard,et al.  REFRACTORY HYPERTENSION: EFFICACY AND SAFETY OF A TRIPLE DIURETIC ASSOCIATION , 2004 .

[19]  J. Ménard,et al.  Combined Blockade of the Renin-Angiotensin System With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Antagonists , 2004, Circulation.

[20]  Daniel W. Jones,et al.  Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. , 2003, Hypertension.

[21]  J. Ménard,et al.  Dual renin–angiotensin system blockade restores blood pressure–renin dependency in individuals with low renin concentrations , 2003, Journal of hypertension.

[22]  Thomas Lumley,et al.  Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. , 2003, JAMA.

[23]  Gnana Bharathy,et al.  Upregulation of Na+ transporter abundances in response to chronic thiazide or loop diuretic treatment in rats. , 2003, American journal of physiology. Renal physiology.

[24]  S. Nielsen,et al.  Sodium transporter abundance profiling in kidney: effect of spironolactone. , 2002, American journal of physiology. Renal physiology.

[25]  François Gueyffier,et al.  J-Shaped Relationship between Blood Pressure and Mortality in Hypertensive Patients: New Insights from a Meta-Analysis of Individual-Patient Data , 2002, Annals of Internal Medicine.

[26]  F. Magrini,et al.  High prevalence of cardiac and extracardiac target organ damage in refractory hypertension , 2001, Journal of hypertension.

[27]  P. Meneton,et al.  Differential subcellular localization of ENaC subunits in mouse kidney in response to high- and low-Na diets. , 2000, American journal of physiology. Renal physiology.

[28]  G. Parati,et al.  Task force IV: Clinical use of ambulatory blood pressure monitoring. Participants of the 1999 Consensus Conference on Ambulatory Blood Pressure Monitoring. , 1999, Blood pressure monitoring.

[29]  J. Laragh,et al.  β-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects , 1999 .

[30]  J. Laragh,et al.  Beta-adrenergic receptor blockade as a therapeutic approach for suppressing the renin-angiotensin-aldosterone system in normotensive and hypertensive subjects. , 1999, American journal of hypertension.

[31]  E. Mutschler,et al.  Sequential nephron blockade breaks resistance to diuretics in edematous states. , 1997, Journal of cardiovascular pharmacology.

[32]  J. Hall,et al.  Role of the renin-angiotensin system in control of sodium excretion and arterial pressure. , 1990, Acta physiologica Scandinavica. Supplementum.

[33]  G. Mancia,et al.  Clinical use of ambulatory blood pressure monitoring. , 1989, American journal of hypertension.

[34]  J. Ménard,et al.  Efficacy and tolerance of spironolactone in essential hypertension. , 1987, The American journal of cardiology.

[35]  J. Staessen,et al.  Double-blind comparison between propranolol and bendroflumethiazide in captopril-treated resistant hypertensive patients. , 1983, American heart journal.

[36]  F. Finnerty.  Diuretics as initial treatment for essential hypertension. , 1979, British journal of clinical pharmacology.

[37]  J. Laragh,et al.  The renin axis and vasoconstriction volume analysis for understanding and treating renovascular and renal hypertension. , 1975, The American journal of medicine.