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Meta-Analysis
. 2009 Oct 7;2009(4):CD007187.
doi: 10.1002/14651858.CD007187.pub2.

Blood pressure lowering efficacy of diuretics as second-line therapy for primary hypertension

Affiliations
Meta-Analysis

Blood pressure lowering efficacy of diuretics as second-line therapy for primary hypertension

Jenny Mh Chen et al. Cochrane Database Syst Rev. .

Abstract

Background: Diuretics are widely prescribed for hypertension not only as a first-line drug but also as a second-line drug. Therefore, it is essential to determine the effects of diuretics on blood pressure (BP), heart rate and withdrawals due to adverse effects (WDAEs) when given as a second-line drug.

Objectives: To quantify the additional reduction in systolic blood pressure (SBP) and diastolic blood pressure (DBP) of diuretic therapy as a second-line drug in patients with primary hypertension

Search strategy: CENTRAL (The Cochrane Library 2008, Issue 2), MEDLINE (1966-July 2008), EMBASE (1988-July 2008) and bibliographic citations of articles and reviews were searched.

Selection criteria: Double-blind, randomized, controlled trials evaluating the BP lowering efficacy of a diuretic in combination therapy with another class of anti-hypertensive drugs compared with the respective monotherapy (without a diuretic) for a duration of 3 to 12 weeks in patients with primary hypertension.

Data collection and analysis: Two review authors independently extracted the data and assessed trial quality.

Main results: Fifty-three double-blind RCTs evaluating a thiazide in 15129 hypertensive patients (baseline BP of 156/101 mmHg) were included. Hydrochlorothiazide was the thiazide used in 49/53 (92%) of the included studies. The additional BP reduction caused by the thiazide as a second drug was estimated by comparing the difference in BP reduction between the combination and monotherapy groups. Thiazides as a second-line drug reduced BP by 6/3 and 8/4 mmHg at doses of 1 and 2 times the manufacturer's recommended starting dose respectively. The BP lowering effect was dose related. The effect was similar to that obtained when thiazides are used as a single agent. Only 3 double-blind RCTs evaluating loop diuretics were identified. These RCTs showed a BP lowering effect of a starting dose of about 6/3 mmHg.

Authors' conclusions: Thiazides when given as a second-line drug have a dose related effect to lower blood pressure that is similar to when they are added as a first-line drug. This means that the BP lowering effect of thiazides is additive. Loop diuretics appear to have a similar blood pressure lowering effect as thiazides at 1 times the recommended starting dose. Because of the short duration of the trials and lack of reporting of adverse events, this review does not provide a good estimate of the incidence of adverse effects of diuretics given as a second-line drug.

PubMed Disclaimer

Conflict of interest statement

None

Figures

1
1
QUOROM flow diagram. *The protocols of the three other reviews have been published recently (Chen 2008a; Chen 2008b; Chen 2008c)
2
2
Methodological quality graph: review authors' judgments about each methodological quality item presented as percentages across all included studies.
3
3
Blood pressure lowering efficacy of thiazides (as multiples of the starting dose) in combination with other antihypertensive drug classes.
4
4
Blood pressure lowering efficacy of HCTZ 12.5mg/day in combination with other antihypertensive drug classes.
5
5
Blood pressure lowering efficacy of HCTZ 25mg/day in combination with other antihypertensive drug classes.
1.1
1.1. Analysis
Comparison 1 Combination therapy (with thiazide ≤0.5x start dose) vs monotherapy (without thiazide), Outcome 1 Change in SBP.
1.2
1.2. Analysis
Comparison 1 Combination therapy (with thiazide ≤0.5x start dose) vs monotherapy (without thiazide), Outcome 2 Change in DBP.
2.1
2.1. Analysis
Comparison 2 Combination therapy (with thiazide 1x start dose) vs monotherapy (without thiazide), Outcome 1 Change in SBP.
2.2
2.2. Analysis
Comparison 2 Combination therapy (with thiazide 1x start dose) vs monotherapy (without thiazide), Outcome 2 Change in DBP.
3.1
3.1. Analysis
Comparison 3 Combination therapy (with thiazide 2x start dose) vs monotherapy (without thiazide), Outcome 1 Change in SBP.
3.2
3.2. Analysis
Comparison 3 Combination therapy (with thiazide 2x start dose) vs monotherapy (without thiazide), Outcome 2 Change in DBP.
4.1
4.1. Analysis
Comparison 4 Combination therapy (with thiazide ≥3x start dose) vs monotherapy (without thiazide), Outcome 1 Change in SBP.
4.2
4.2. Analysis
Comparison 4 Combination therapy (with thiazide ≥3x start dose) vs monotherapy (without thiazide), Outcome 2 Change in DBP.
5.1
5.1. Analysis
Comparison 5 Combination therapy (with thiazide ‐ all doses) vs monotherapy (without thiazide), Outcome 1 Change in SBP.
5.2
5.2. Analysis
Comparison 5 Combination therapy (with thiazide ‐ all doses) vs monotherapy (without thiazide), Outcome 2 Change in DBP.
5.3
5.3. Analysis
Comparison 5 Combination therapy (with thiazide ‐ all doses) vs monotherapy (without thiazide), Outcome 3 Change in Heart rate.
5.4
5.4. Analysis
Comparison 5 Combination therapy (with thiazide ‐ all doses) vs monotherapy (without thiazide), Outcome 4 Withdrawals due to adverse events.
6.1
6.1. Analysis
Comparison 6 Combination therapy (with loop diuretic ‐ all dose) vs monotherapy (without loop diuretic), Outcome 1 Change in SBP.
6.2
6.2. Analysis
Comparison 6 Combination therapy (with loop diuretic ‐ all dose) vs monotherapy (without loop diuretic), Outcome 2 Change in DBP.
6.3
6.3. Analysis
Comparison 6 Combination therapy (with loop diuretic ‐ all dose) vs monotherapy (without loop diuretic), Outcome 3 Withdrawals due to adverse events.
7.1
7.1. Analysis
Comparison 7 Direct Comparison, Outcome 1 Change in SBP.
7.2
7.2. Analysis
Comparison 7 Direct Comparison, Outcome 2 Change in DBP.

Update of

  • doi: 10.1002/14651858.CD007187

References

References to studies included in this review

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Canter 1994 {published data only}
    1. Canter D, Frank GJ, Knapp LE, Phelps M, Quade M, Texter M. Quinapril and hydrochlorothiazide combination for control of hypertension:assessment by factorial design. Quinapril InvestigatorGroup [see comments]. Journal of Human Hypertension 1994;8(3):155–62. - PubMed
Cappuccio 1993 {published data only}
    1. Cappuccio FP, Markandu ND, Singer DRJ, MacGregor GA. Amlodipine and Lisinopril in Combination for the Treatment of Essential Hypertension: Efficacy and Predictors of Response. Journal of Hypertension 1993;11:839‐47. - PubMed
Chalmers 1982 {published data only}
    1. Chalmers JP, Wing LMH, Grygiel JJ, West MJ, Graham JR, Bune AJ. Effects of Once Daily Indapamide and Pindolol on Blood Pressure, Plasma Aldosterone Concentration and Plasma Renin Activity in a General Practice Setting. Eur J Clin Pharmacol 1982;22:191‐6. - PubMed
Chalmers 1986 {published data only}
    1. Chalmers JP, Wing LMH, West MJ, Bune AJC, Elliott JM. Effects of Enalpril and Hydrochlorothiazide on Blood Pressure, Renin‐angiotensin System, and Atrial Natriuretic Factor in Essential Hypertension: A Double‐blind Factorial Cross‐over Study. Aust NZ J Med 1986;16:475‐480. - PubMed
Chrysant 1992 {published data only}
    1. Chrysant SG, Chappel C, Farnham DJ, Levin B, Lueg M, McCluskey D, Steiner C. Antihypertensive and metabolic effects of single and combined atenolol regimens. Journal of Clinical Pharmacology 1992;32(1):61‐5. [MEDLINE: ; CN‐00081715; EMBASE1992169096] - PubMed
Crowe 1987 {published data only}
    1. Crowe PF, Finnegan OC, Rusell CJMcL, Varma MPS. A Double‐blind Study of INderex in the Treatment of Essential Hypertension. The British Journal of Clinical Practice 1987;41(10):967‐970. - PubMed
Dahlof 1993 {published data only}
    1. Dahlof B, Jonsson L, Borgholst O, Ekblad G, Engstrand C, Grundestam I, Lindh A. Improved antihypertensive efficacy of the felodipine‐metoprolol extended‐release tablet compared with each drug alone.. Blood Pressure Supplement 1993;1:37‐45. - PubMed
Dargie 1986 {published data only}
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De Divitiis 1981 {published data only}
    1. Divitiis O, Petitto M, Somma S, et al. Atenolol, chlorthalidone, and reserpine in mild‐moderate hypertension: Double‐blind comparison. Drugs Under Experimental & Clinical Research 1981;7(6):773‐779.
De Divitiis 1983 {published data only}
    1. Divitiis O, Somma S, Petitto M, Fazio S, Ligouri V. Indapamide and Atenolol in the Treatment of Hypertension: Double‐blind Comparative and Combination Study. Current Medical Research Opinion 1983;8(7):493‐500. - PubMed
Durel 1992 {published data only}
    1. Durel LA, Hayashi PJ, Weidler DJ, Schneiderman N. Effectiveness of Antihypertensive Medications in Office and Ambulatory Settings: A Placebo‐Controlled Comparison of Atenolol, Metroprolol, Chlorthalidone, Verapamil, and an Atenolol‐Chlorthalidone Combination. J Clin Pharmacol 1992;32:564‐570. - PubMed
Erwteman 1984 {published data only}
    1. Erwteman TM, Nagelkerke N, Lubsen J, Koster M, Dunning AJ. Beta blockade, diuretics, and salt restriction for the management of mild hypertension: a randomised double blind trial. British medical journal (Clinical research ed.) 1984 Aug;289(6442):406‐9. - PMC - PubMed
Fernandez 1980 {published data only}
    1. Fernandez PG, Zachariah PK, Bryant DG, Missan SS. Anithypertensive efficacy of alpah‐methyldopa, chlorothiazide and Supres‐150 (alpha‐methyldopa‐chlorothiazide). CMA Journal 1980;123:284‐287. - PMC - PubMed
Forette 1979 {published data only}
    1. Forette F, Henry JF, Hervy MP, Forette B, Berthaux P. The treatment of hypertension in the elderly using a beta‐blocker: acebutolol [Traitement de l'hypertension artérielle du sujet âgé par un bêta‐bloquant: l'acébutolol.]. La Nouvelle presse médicale 1979;8(36):2881‐4. - PubMed
Frishman 1987 {published data only}
    1. Frishman WH, Goldberger J, Sherman D. Enalapril, hydrochlorothiazide, and combination therapy in patients with moderate hypertension.. Journal of Clinical Hypertension 1987;3(4):520‐7. - PubMed
Hart 1985 {published data only}
    1. Hart HC, Van dLDL, Lustermans FAT, et al. Double‐blind comparison of dytenzide, atenolol and the combination of dytenzide and atenolol in patients with essential hypertension.. CURR‐THER‐RES,‐CLIN‐EXP 1985;38(5):702‐709. [CN‐00175975; EMBASE 1986040698]
Hunter 1999 {published data only}
    1. Hunter SJ, Wiggam MI, Ennis CN, Whitehead HM, Sheridan B, Atkinson AB, Bell PM. Comparison of effects of captopril used either alone or in combination with a thiazide diuretic on insulin action in hypertensive Type 2 diabetic patients: a double‐blind crossover study.[see comment].. Diabetic Medicine 1999;16(6):482‐7. - PubMed
Jaattela 1979 {published data only}
    1. Jaattela A. The Fixed Combination of Propanolol and Bendrofluazide in the Treatment of Hypertension. Annals of Clinical Research 1979;11:80‐82. - PubMed
Jackson 1986 {published data only}
    1. Jackson G, Rowland M, Adam G, MacFarlane E, Jackson PG. Placebo Controlled Double‐blind Randomised Cross‐over Trial of Atenolol, Hydrochlorothiazide and Amiloride, and the Combination (Kalten) in Patients Over 60 Years of Age. The British Journal of Clinical Practice 1986;40(6):230‐234. - PubMed
Khalil 1982 {published data only}
    1. Khalil SI, Zein O, Mahadi Bella M. A double‐blind, crossover study of acebutolol and hydrochlorothiazide/amiloride diuretic in Sudanese patients with essential hypertension.. Current medical research and opinion 1982;1:39‐43. - PubMed
Kieso 1983 {published data only}
    1. Kieso HA, Gould BA, Mann S, Hornung RS, Altman DG, Raftery EB. Effect on Intra‐aterial Blood Pressure of Slow Release Metoprolol Combined with Placebo or Chlorthalidone. British Medical Journal 1983;287:717‐720. - PMC - PubMed
Koh 2007 {published data only}
    1. Koh KK, Quon MJ, Lee Y, et al. Additive Beneficial Cardiovascular and Metabolic Effects of Combination Therapy with Ramipril and Candesartan in Hypertensive Patients. European Heart Journal 2007;28:1440‐7. - PubMed
Kubik 1979 {published data only}
    1. Kubik M, Kendall M, Ebbutt A, John V. Metoprolol with and without chlorthalidone in hypertension. Clinical pharmacology and therapeutics 1979;25(1):25‐32. - PubMed
Lang 1991 {published data only}
    1. Lang H. The results of a large multicentre study comparing low‐dose lisinopril‐hydrochlorothiazide with the monocomponents.. Journal of Human Hypertension 1991;5 Suppl 2:73‐6. - PubMed
Lechi 1982 {published data only}
    1. Lechi A, Pomari S, Berto R, et al. Clinical Evaluation of Labetolol Alone and Combined with Chlorthalidone in Essential Hypertension: A Double‐blind Multicentre Controlled Study. European Journal of Clinical Pharmacology 1982;22:289‐93. - PubMed
Leonetti 1986 {published data only}
    1. Leonetti G, Pasotti C, Capra A. Low‐dose atenolol‐chlorthalidone combination for treatment of mild hypertension.. International journal of clinical pharmacology, therapy, and toxicology 1986 Jan;24(1):43‐7. - PubMed
Magee 1986 {published data only}
    1. Magee PFA, Freis ED. Is Low‐Dose Hydrochlorothiazide Effective?. Hypertension 1986;8 (suppl II):135‐139. - PubMed
Mehta 1988 {published data only}
    1. Mehta J, Lopez LM, Thorman AD. Lisinopril Versus Lisinopril plus Phydrochlorothiazide in Essential Hypertension. Am J Cardiol 1988;61:803‐6. - PubMed
Middlemost 1994 {published data only}
    1. Middlemost SJ, Tager R, Davis J, Sareli P. Effectiveness of enalapril in combination with low‐dose hydrochlorothiazide versus enalapril alone for mild to moderate systemic hypertension in black patients.. American Journal of Cardiology 1994;73(15):1092‐7. - PubMed
Moncloa 1980 {published data only}
    1. Moncloa F, Hwang IK, Muccilli AC. Multiclinic evaluation of the antihypertensive effect of a methyldopa, hydrochlorothiazide, and amiloride combination.. Clinical Therapeutics 1980;3(3):168‐75. [MEDLINE: ; CN‐00024331; EMBASE1981086995] - PubMed
Morgan 1992 {published data only}
    1. Morgan TO, Anderson A. Hemodynamic Comparisons of Enalapril and Felodipine and Their Combination. Kidney International 1992;41 (Suppl 36):S78‐81. - PubMed
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Morgan 2002 {published data only}
    1. Morgan T, Anderson A. A comparison of candesartan, felodipine, and their combination in the treatment of elderly patients with systolic hypertension.. American Journal of Hypertension 2002;15(6):544‐9. - PubMed
Muiesan 1976 {published data only}
    1. Muiesan G, Magnani B, Agabiti‐Rosei E, Alicandri C, Ambrosioni E, Miele N. Evaluation of the effect of timolol alone and in combination with hydrochlorothiazide and amiloride in the treatment of mild to moderate arterial hypertension: a double‐blind, controlled study. Clinical Science & Molecular Medicine ‐ Supplement 1976;3:529s‐531s. [MEDLINE: ; CN‐00015916] - PubMed
Neutel 2006 {published data only}
    1. Neutel JM, Smith DHG, Weber MA, et al. Efficacy of Combination Therapy With Amlodipine Besylate/Benazepril Hydrochloride for Lowering Systolic Blood Pressure in Stage 2 Hypertension. The American Journal of Geriatric Cardiology 2006;15(3):142‐50. - PubMed
Petrie 1975 {published data only}
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Ricciardelli 1985 {published data only}
    1. Hemodynamic effects of the antihypertensive treatment with atenolol plus chlortalidone in fixed combination: A double‐blind crossover comparison with atenolol. Ricciardelli B, Cuocolo A, De LN, et al. Current Therapeutic Resesarch 1985;37(5):901‐11.
Rosenthal 1989 {published data only}
    1. Rosenthal J, Letzel H, Blumner E, Volger K‐D. Antihypertensive Therapy ‐ Dose‐Effect Relationship Between a Combination of Triamterene/Hydrochlorothiazide and Verapamil. Munch. med. Wschr 1989;131(16):319‐22.
Salako 1990 {published data only}
    1. Salako LA, Falase AO, Aderounmu AF, Walker O. Assessment of a Fixed‐dosage Combination of Atenolol and Chlorthalidone (Tenoretic) in Hypertensive Nigerians. Afr. J. Med. Sci 1990;19:57‐61. - PubMed
Salvetti 1987 {published data only}
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Salvetti 1989 {published data only}
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Scholze 1993 {published data only}
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Singer 1987 {published data only}
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Tonkin 1990 {published data only}
    1. Tonkin AL, Wing LMH, Russell AE, et al. Diltiazem and atenolol in essential hypertension: additivity of effect on blood pressure and cardiac conduction with combination therapy. Journal of Hypertension 1990;8:1015‐1019. - PubMed
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VACSGAA 1977 {published data only}
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Viskoper 1997 {published data only}
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Weinberger 1983 {published data only}
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Wing 1988 {published data only}
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Wing 1994 {published data only}
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