We assessed the effectiveness of fourth-line mineralocorticoid receptor antagonists in comparison with other fourth-line anti-hypertensive agents in resistant hypertension.
Methods and results
We systematically searched Medline, EMBASE and the Cochrane library from database inception until January 2016. We included randomised and non-randomised studies that compared mineralocorticoid receptor antagonists with other fourth-line anti-hypertensive agents in patients with resistant hypertension. The outcome was change in systolic blood pressure, measured in the office, at home or by ambulatory blood pressure monitoring. Secondary outcomes were changes in serum potassium and occurrence of hyperkalaemia. We used random effects models and assessed statistical heterogeneity using the I2 test and corresponding 95% confidence intervals. From 2,506 records, 5 studies met our inclusion criteria with 755 included patients. Two studies were randomised and three were non-randomised. Comparative fourth-line agents included bisoprolol, doxazosin, furosemide and additional blockade of the renin angiotensin-aldosterone system. Using data from randomised studies, mineralocorticoid receptor antagonists reduced blood pressure by 7.4 mmHg (95%CI 3.2 – 11.6) more than the active comparator. When limited to non-randomised studies, mineralocorticoid receptor antagonists reduced blood pressure by 11.9 mmHg (95% CI 9.3 – 14.4) more than the active comparator.
Conclusion
On the basis of this meta-analysis, mineralocorticoid receptor antagonists reduce blood pressure more effectively than other fourth-line agents in resistant hypertension. Effectiveness stratified by ethnicity and comorbidities, in addition to information on clinical outcomes such as myocardial infarction and stroke, now needs to be determined.
KearneyPMWheltonMReynoldsK. Global burden of hypertension: Analysis of worldwide data. Lancet2005; 365(9455): 217–223.
2.
LimSSVosTFlaxmanAD. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: A systematic analysis for the Global Burden of Disease Study 2010. Lancet2013; 380(9859): 2224–2260.
3.
AchelrodDWenzelUFreyS. Systematic review and meta-analysis of the prevalence of resistant hypertension in treated hypertensive populations. Am J Hypertens2015; 28(3): 355–361.
4.
National Institute for Health and Care Excellence. Hypertension in adults: Diagnosis and management. NICE guidelines (CG127). NICE: London, 2011.
DaughertySLPowersJDMagidDJ. Incidence and prognosis of resistant hypertension in hypertensive patients. Circulation2012; 125(13): 1635–1642.
7.
YiannakopoulouECPapadopulosJSCokkinosDV. Adherence to antihypertensive treatment: A critical factor for blood pressure control. Eur J Cardiovasc Prev Rehabil2005; 12(3): 243–249.
8.
Alvarez-AlvarezBAbad-CardielMFernandez-CruzA. Management of resistant arterial hypertension: Role of spironolactone versus double blockade of the renin-angiotensin-aldosterone system. J Hypertens2010; 28(11): 2329–2335.
9.
TsioufisCKordalisAFlessasD. Pathophysiology of resistant hypertension: The role of sympathetic nervous system. Int J Hypertens2011; 2011.
10.
RimoldiSFMesserliFHBangaloreS. Resistant hypertension: What the cardiologist needs to know. Eur Heart J2015; 36(40): 2686–2695.
11.
WilliamsB. Resistant hypertension: An unmet treatment need. Lancet2009; 374(9699): 1396–1398.
12.
ManciaGFagardRNarkiewiczK. 2013 ESH/ESC guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J2013; 34(28): 2159–2219.
13.
GoASBaumanMAKingSMC. An effective approach to high blood pressure control: A science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. J Am Coll Cardiol2014; 63(12): 1230–1238.
14.
JamesPAOparilSCarterBL. 2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA2014; 311(5): 507–520.
15.
LiuGZhengXXuY. Effect of aldosterone antagonists on blood pressure in patients with resistant hypertension: A meta-analysis. J Hum Hypertens2015; 29(3): 159–166.
16.
DahalKKunwarSRijalJ. The effects of aldosterone antagonists in patients with resistant hypertension: A meta-analysis of randomized and nonrandomized studies. Am J Hypertens2015; 28(11): 1376–1385.
17.
WilliamsBLindholmLHSeverP. Systolic pressure is all that matters. Lancet2008; 371(9631): 2219–2221.
18.
DownsSHBlackN. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health1998; 52(6): 377–384.
19.
HigginsJThompsonSG. Quantifying heterogeneity in a meta-analysis. Stat Med2002; 21(11): 1539–1558.
20.
LauJIoannidisJPTerrinN. The case of the misleading funnel plot. BMJ2006; 333(7568): 597–600.
21.
Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
22.
MoherDLiberatiATetzlaffJ. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann Int Med2009; 151(4): 264–269.
23.
BobrieGFrankMAziziM. Sequential nephron blockade versus sequential renin-angiotensin system blockade in resistant hypertension: A prospective, randomized, open blinded endpoint study. J Hypertens2012; 30(8): 1656–1664.
24.
RodillaECostaJAPerez-LahigueraF. Spironolactone and doxazosin treatment in patients with resistant hypertension. Rev Esp Cardiol2009; 62(2): 158–166.
25.
Verdalles GuzmanUGarcia De VinuesaS. Management of resistant hypertension (RHT): Aldosterone antagonists or intensification of diuretic therapy?J Hypertens2015; 33: e360–e360.
26.
WilliamsBMacDonaldTMMorantS. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): A randomised, double-blind, crossover trial. Lancet2015; 386(10008): 2059–2068.
27.
AchrafiH. Action of nitroprusside in multidrug-resistant hypertension. Lancet1989; 2(8667): 867–867.
28.
AmbrosioGB. Minoxidil in resistant hypertension. Lancet1977; 2(8047): 1087–1087.
29.
FrankMBobrieGAziziM. Superiority of low dose diuretics combination over renin-angiotensin blockers combination in resistant hypertension. J Hypertens2010; 28: A276–A276.
30.
Garcia-DonaireJACerezoCGuerreroL. Long-term evolution of blood pressure control in resistant hypertension. J Clin Hypertens. (Greenwich) 2012; 14(S1): 1–1.
31.
KriegerEMDragerLFGiorgiDM. Resistant hypertension optimal treatment trial: A randomized controlled trial. Clin Cardiol2014. Epub ahead of print 11 December 2013. DOI: 10.1002/clc.22228.
32.
BassanFBRodriguesMLValencaD. Behavior of endothelial function and blood pressure after use of spironolactone or clonidine in patients with resistant hypertension. Hypertension2012; 60: A656–A656.
33.
Colina-ChourioJAGodoyNOliveros-PalaciosM. Long-term (3 years) sustained antihypertensive and metabolic actions of nitrendipine in severe, complicated, and resistant hypertension. J Cardiovasc Pharmacol1991; 18: S84–S90.
34.
DargieHJDolleryCTDanielJ. Minoxidil in resistant hypertension. Lancet1977; 2(8037): 515–518.
35.
RussellGISwartSBingRF. Combined prazosin and hydralazine in resistant hypertension. Lancet1980; 1(8167): 543–543.
36.
WeinbergerMH. Treatment-resistant hypertension: Efficacy of angiotensin-converting enzyme inhibition with captopril. Prev Med1980; 9(3): 459–459.
37.
WhiteNJRajagopalanBYahayaH. Captopril and frusemide in severe drug-resistant hypertension. Lancet1980; 2(8186): 108–110.
38.
SeguraJCerezoCGarcia-DonaireJASchmiederRE. Validation of a therapeutic scheme for the treatment of resistant hypertension. J Am Soc Hypertens2011; 5(6): 498–504.
39.
CuestaVCannataJHerreraJ. [Prazosin in the treatment of resistant arterial hypertension associated with nephropathy]. Rev Clin Esp (Barc)1981; 161(1): 37–39.
40.
KuriyamaSYokoyamaKHaraY. Effect of aliskiren in chronic kidney disease patients with refractory hypertension undergoing hemodialysis: A randomized controlled multicenter study. Clin Exp Nephrol2013; 18(5): 821–830.
41.
RamsayLESilasJHFreestoneS. Diuretic treatment of resistant hypertension. Br Med J1980; 281(6248): 1101–1103.
42.
MannSJParikhNS. A simplified mechanistic algorithm for treating resistant hypertension: Efficacy in a retrospective study. J Clin Hypertens (Greenwich)2012; 14(4): 191–197.
43.
KarnsADBralJMHartmanD. Study of aldosterone synthase inhibition as an add-on therapy in resistant hypertension. J Clin Hypertens (Greenwich)2013; 15(3): 186–192.
44.
GuoHXiaoQ. Clinical efficacy of spironolactone for resistant hypertension: A meta analysis from randomized controlled clinical trials. Int J Clin Exp Med2015; 8(5): 7270–7270.
45.
EttehadDEmdinCAKiranA. Blood pressure lowering for prevention of cardiovascular disease and death: A systematic review and meta-analysis. Lancet2016; 387(10022): 957–967.
46.
MyersMGGodwinMDawesM. Conventional versus automated measurement of blood pressure in primary care patients with systolic hypertension: Randomised parallel design controlled trial. BMJ2011; 342: d286–d286.
47.
CalhounDAJonesDTextorS. American Heart Association Professional Education Committee. 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. Circulation2008; 117(25): e510–e526.
48.
DolanEStantonAThijsL. Superiority of ambulatory over clinic blood pressure measurement in predicting mortality: The Dublin outcome study. Hypertension2005; 46(1): 156–161.
49.
CohenATGotoSSchreiberK. Why do we need observational studies of everyday patients in the real-life setting?Eur Heart J Suppl2015; 17: D2–D8.
DelyaniJA. Mineralocorticoid receptor antagonists: The evolution of utility and pharmacology. Kidney Int2000; 57(4): 1408–1411.
53.
RoushGCKaurRErnstME. Diuretics: A review and update. J Cardiovasc Pharmacol Ther2014; 19(1): 5–13.
54.
FujimuraNNomaKHataT. Mineralocorticoid receptor blocker eplerenone improves endothelial function and inhibits rho associated kinase activity in patients with hypertension. Clin Pharmacol Ther2012; 91(2): 289–297.
55.
EggerMJuniPBartlettC. How important are comprehensive literature searches and the assessment of trial quality in systematic reviews? Empirical study. Health Technol Assess2003; 7(1): 1–76.
56.
BianchiSBigazziRCampeseV. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. Kidney Int2006; 70(12): 2116–2123.
57.
ValentineJCPigottTDRothsteinHR. How many studies do you need? A primer on statistical power for meta-analysis. J Educ Behav Stat2010; 35(2): 215–247.
58.
EvangelouEIoannidisJPPatsopoulosNA. Uncertainty in heterogeneity estimates in meta-analyses. Br Med J2007; 335(7626): 914–916.
59.
RossignolPMassyZAAziziM. The double challenge of resistant hypertension and chronic kidney disease. Lancet2015; 386(10003): 1588–1598.
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
