Efficacy and safety of dual combination
therapy of blood pressure lowering drugs as initial treatment for hypertension – a
systematic review & meta-analysis of randomised controlled trials
Supplementary file
Supplementary Table S1: Literature search strategy (MEDLINE 1946 to Aug Week 2 2017)
1 exp Calcium Channel Blockers/
2 (calcium adj2 (antagonist? or block$ or inhibit$)).tw.
3 (amlodipine or aranidipine or barnidipine or bencyclane or benidipine or bepridil or
cilnidipine or cinnarizine or clentiazem or darodipine or diltiazem or efonidipine or elgodipine or etafenone or fantofarone or felodipine or fendiline or flunarizine or gallopamil or isradipine or lacidipine or lercanidipine or lidoflazine or lomerizine or manidipine or mibefradil or nicardipine or nifedipine or niguldipine or nilvadipine or nimodipine or nisoldipine or
nitrendipine or perhexiline or prenylamine or semotiadil or terodiline or tiapamil or verapamil or cardizem or dilacor or tiazac or cardizem or calan or isoptin or calan or isoptin or
verelan).mp.
4 Ccb?.tw.
5 1 or 2 or 3 or 4 6 exp Thiazides/
7 exp Sodium Chloride Symporter Inhibitors/
8 (sodium chloride adj (symporter? or cotransporter? or co-transporter?)).tw.
9 (potassium depleting adj2 diuretic?).tw.
10 (Hydrochlorothiazide or chlorthalidone or benzothiadiazine or bendrofluazide or buthiazide or bendroflumethiazide or benzhydroflumethiazide or bezthiazide or chlorothiazide or cyclopenthiazide or cyclothiazide or diucardin or diuril or enduron or esidrix or ezna or hydroflumethiazide or methyclothiazide or microzide or polythiazide or mykrox or naqua or naturetin or renese or trichlormethiazide or metolazone or thiazide?).mp.
11 (chlorthalidone or chlortalidone or phthalamudine or chlorphthalidolone or clopamide or clopamine or clorexolone or diapamide or fenquizone or hydromox or oxodoline or thalitone or hygroton or indapamide or isodapamide or lozol or mefruside or metindamide or
oxodoline or quinethazone or zaroxolyn or s-1520 or s1520 or se-1520 or se1520 or xipamide).mp.
12 6 or 7 or 8 or 9 or 10 or 11
13 ((loop or ceiling) adj diuretic?).tw.
14 exp sodium potassium chloride symporter inhibitors/
15 (sodium potassium chloride adj2 (cotransporter? or co-transporter? or symporter?)).tw.
16 (azosemide or furosemide or frusemide or fursemide indacrinone or ozolinone or
phenoxybenzoic acid or muzolimine or bumetanide or burinex or cicletanine or etozolonie or torsemide or ethacrynic acid or veratide or piretanide or ticrynafen or tienilic acid or
tizolemid).mp.
17 13 or 14 or 15 or 16
18 exp aldosterone antagonists/
19 ((K or potassium) adj sparing adj diuretic$).tw.
20 (amiloride or triamterene or canrenoate potassium or canrenone$ or spironolactone$ or aldosterone antagonist$ or aldactone$ or practon$ or sc-9420$ or spiractin$ or sc-14266$ or soldactone$ or soludactone$ or aldadiene$ or phanurane$ or sc-9376 or eplerenone$).mp.
21 18 or 19 or 20
22 exp Angiotensin-Converting Enzyme Inhibitors/
23 ((angiotensin$ or dipeptidyl$ or kininase) adj3 (convert$ or enzyme or inhibit$ or recept$ or block$)).tw.
24 (ace adj2 inhibit$).tw.
25 Acei.tw.
26 (alacepril or altiopril or ancovenin or benazepril or captopril or ceranapril or ceronapril or cilazapril or deacetylalacepril or delapril or derapril or enalapril or epicaptopril or fasidotril or fosinopril or foroxymithine or gemopatrilat or idapril or imidapril or indolapril or libenzapril or lisinopril or moexipril or moveltipril or omapatrilat or pentopril$ or perindopril$ or pivopril or quinapril$ or ramipril$ or rentiapril or saralasin or s nitrosocaptopril or spirapril$ or
temocapril$ or teprotide or trandolapril$ or utibapril$ or zabicipril$ or zofenopril$).mp.
27 22 or 23 or 24 or 25 or 26
28 exp Angiotensin Receptor Antagonists/
29 (angiotensin adj3 (receptor antagon$ or receptor block$)).tw.
30 arb?.tw.
31 (abitesartan or azilsartan or candesartan or elisartan or embusartan or eprosartan or
forasartan or irbesartan or losartan or milfasartan or olmesartan or saprisartan or tasosartan or telmisartan or valsartan or zolasartan or fimasartan).mp.
32 28 or 29 or 30 or 31
33 exp Adrenergic beta-Antagonists/
34 (beta adj2 (adrenergic? or antagonist? or block$ or receptor?)).tw.
35 (acebutolol or adimolol or afurolol or alprenolol or amosulalol or arotinolol or atenolol or befunolol or betaxolol or bevantolol or bisoprolol or bopindolol or bornaprolol or brefonalol or bucindolol or bucumolol or bufetolol or bufuralol or bunitrolol or bunolol or bupranolol or butofilolol or butoxamine or carazolol or carteolol or carvedilol or celiprolol or cetamolol or chlortalidone cloranolol or cyanoiodopindolol or cyanopindolol or deacetylmetipranolol or diacetolol or dihydroalprenolol or dilevalol or epanolol or esmolol or exaprolol or falintolol or flestolol or flusoxolol or hydroxybenzylpinodolol or hydroxycarteolol or hydroxymetoprolol or indenolol or iodocyanopindolol or iodopindolol or iprocrolol or isoxaprolol or labetalol or landiolol or levobunolol or levomoprolol or medroxalol or mepindolol or
methylthiopropranolol or metipranolol or metoprolol or moprolol or nadolol or oxprenolol or penbutolol or pindolol or nadolol or nebivolol or nifenalol or nipradilol or oxprenolol or pafenolol or pamatolol or penbutolol or pindolol or practolol or primidolol or prizidilol or
procinolol or pronetalol or propranolol or proxodolol or ridazolol or salcardolol or soquinolol or sotalol or spirendolol or talinolol or tertatolol or tienoxolol or tilisolol or timolol or
tolamolol or toliprolol or tribendilol or xibenolol).mp.
36 33 or 34 or 35
37 exp adrenergic alpha antagonists/
38 (adrenergic adj2 (alpha or antagonist?)).tw.
39 ((adrenergic or alpha or receptor?) adj2 block$).tw.
40 ((adrenergic or alpha or receptor?) adj2 block$).tw.
41 (alfuzosin or bunazosin or doxazosin or metazosin or neldazosin or prazosin or silodosin or tamsulosin or terazosin or tiodazosin or trimazosin).mp.
42 37 or 38 or 39 or 40 or 41
43 (renin inhibi$ or renin blocker).tw.
44 (aliskiren or ciprokiren or ditekiren or enalkiren or remikiren or rasilez or tekturna or terlakiren or zankiren).mp.
45 43 or 44
46 (Centra$ adj2 antihypertensive$).tw.
47 (reserpine or serpasil or rauwolfia or clonidine or catapres or methyldopa or guanfacine or guanabenz or guanadrel or guanethidine).mp.
48 46 or 47
49 (hydralazine or diazoxide or minoxidil or nitroprusside sodium).mp.
50 5 and (12 or 17 or 21 or 27 or 32 or 36 or 42 or 45 or 48 or 49) 51 12 and (17 or 21 or 27 or 32 or 36 or 42 or 45 or 48 or 49) 52 17 and (21 or 27 or 32 or 36 or 42 or 45 or 48 or 49) 53 21 and (27 or 32 or 36 or 42 or 45 or 48 or 49) 54 27 and (32 or 36 or 42 or 45 or 48 or 49) 55 32 and (36 or 42 or 45 or 48 or 49) 56 36 and (42 or 45 or 48 or 49) 57 42 and (45 or 48 or 49) 58 45 and (48 or 49) 59 48 and 49
60 50 or 51 or 52 or 53 or 54 or 55 or 56 or 57 or 58 or 59 61 Drug Therapy, Combination/
62 (Fixed adj2 combination$).tw.
63 (combin$ fixed dose or triple or dual or double or single pill or multi$).tw.
64 61 or 62 or 63
65 Antihypertensive Agents/
66 64 and 65
67 60 or 66
68 randomized controlled trial.pt.
69 controlled clinical trial.pt.
70 randomized.ab.
71 placebo.ab.
72 clinical trials as topic.sh.
73 randomly.ab.
74 trial.ti.
75 68 or 69 or 70 or 71 or 72 or 73 or 74
76 ((first line or firstline or earl$ or initia$ or start$ or upfront) adj2 combin$).tw.
77 ((first line or firstline or earl$ or initia$ or start$ or upfront) adj2 fixed dose).tw.
78 ((drug or treatment or therapy or medic$ or antihyperten$) adj2 na?v$).tw.
79 (Untreated or never treated).tw.
80 (Never adj2 treat$).tw.
81 76 or 77 or 78 or 79 or 80 82 67 and 75 and 81
83 animals/ not (humans/ and animals/)
84 Pregnancy/ or Hypertension, Pregnancy-Induced/ or Pregnancy Complications, Cardiovascular/ or exp Ocular Hypertension/
85 (pregnancy-induced or ocular hypertens$ or preeclampsia or pre-eclampsia).ti.
86 82 not (83 or 84 or 85)
Supplementary Table S2: Standard doses of BP lowering drugs
Antihypertensive drug WHO – ATC/DDD
BNF Martindale MIMS online STANDARD DOSE
atenolol 75 mg 25-50 daily 50-100 daily 50-100 daily 50 mg
bisoprolol 10 mg 10 mg 10 mg 10 mg 10 mg
carvedilol 37.5 mg 25 mg 25 mg 25-50 mg 25 mg
celiprolol 200 mg 200 mg 200-400 mg - 200 mg
amlodipine 5 mg 5 - 10 mg 5 - 10 mg 2.5 - 10 mg 5 mg
verapamil 240 mg 240- 480 mg 240 mg 240 mg 240 mg
felodipine 5 mg 5-10 mg 2.5-10 mg 5-10 mg 5 mg
diltiazem 240 mg - 180 -360 mg - 180 mg
benazepril 7.5 mg - 20-40 mg - 20 mg
fosinopril 15 mg 10-40 mg 10-40 mg 10-40 mg 10 mg
lisinopril 10 mg 20 mg 20 mg 10-20 mg 20 mg
quinapril 15 mg 20-40 mg 20-40 mg 10-40 mg 20 mg
trandolapril 2 mg 1-2 mg 1 - 2 mg 1- 2 mg 2 mg
enalapril 10 mg 20 mg 10-20 mg 10-40 mg 20 mg
perindopril 5 mg 5 mg 5-10 mg - 5 mg
cilazapril 2.5 mg 2.5-5 mg 2.5-5 mg - 2.5 mg
ramipril 2.5 mg 2.5 - 10 mg 2.5 - 10 mg 2.5 - 10 mg 2.5 mg
losartan 50mg 50 mg 50 mg 50 mg 50 mg
valsartan 80mg 80 mg 80-160 mg 80 mg 80 mg
irbesartan 0.15g 150 -300 mg 150 mg 150 mg 150 mg
candesartan 8mg 8 mg 8 mg 8-16 mg 8 mg
hydrochlorothiazide 25 mg - 25-50 mg - 25 mg
nebivolol 5 mg 5 mg 5- 40 mg 5 mg 5 mg
indapamide 2.5 mg 2.5 mg 1.25-2.5 mg 2.5 mg 2.5 mg
triamterene 100 mg 150-250 mg 150-250 mg - 150 mg
Supplementary Table S3: Summary of characteristics of included trials
Study BP Eligibility mmHg
Sample size
Female (%)
Previously untreated
(%)
Mean Age, years
BP measure Baseline SBP mmHg
Baseline DBP mmHg
BP lowering drug class
Treatment duration
weeks
Applegate 1996 seDBP 95–115 336 35 NR 55 seated, trough 155 101 ACEI + CCB 6
Benz 1998 seDBP 95–115 871 40 NR (26) 52 seated, trough 153 101 ARB + TD 8
Burris 1990 suDBP 95-100 300 38 NR 52 supine, trough 152 99 CCB + TD 6
Chan 1997 seDBP 95-114 156 40 NR 72 seated, trough 168 105 ACEI + CCB 12
Chrysant 1994 seDBP 100-114 505 38 NR 53 seated, trough 154 104 ACEI + TD 8
Cushman 1998 seDBP 95-115 867 32 NR 54 seated, trough NR 102 ACEI + CCB 12
DeQuattro 1997 suDBP 95-114 726 37 NR 55 supine, trough 150 100 ACEI + CCB 6
Farsang 2001 seDBP 95-114 341 32 99 (29) 53 seated, trough 164 103 ARB + CCB 8
Fernandez 1994 seDBP 95-110 67 66 1 (1) 53 seated, trough 149 101 ACEI + TD 8
Frishman 1995 (A) seDBP 100-115 332 37 NR 54 seated, trough 157 105 ACEI + CCB 10
Frishman 1995 (B) se stage I/II HTN 547 28 NR NR seated, trough 151 101 BB + TD 4
Giles 2014 seDBP 95-110 4161 24 NR 51 seated, trough 155 100 ARB + BB 8
Gradman 1997 seDBP 95 -115 707 35 NR 54 seated, trough 156 102 ACEI + CCB 8
Group 1997 seDBP 100-110 272 37 NR 49 seated, trough 155 102 ACEI + CCB 8
Kochar 1999 seDBP 95-110 683 35 NR 55 seated, trough 151 100 ARB + TD 8
Heesen 1998 ISH, suSBP>=160, suDBP<95
51 76 51 (100) 68 supine, NR 179 90 TD + KSD 26
Kuschnir 1996 seDBP 100-120 308 55 NR 57 seated, trough 167 107 ACEI + CCB 8
levine 1995 seDBP 95-114 186 56 NR 53 seated, trough 150 101 ACEI + CCB 4
Messerli 1998 seDBP 95-114 631 36 NR 55 seated, trough 152 101 ACEI + CCB 6
MacKay 1996 seSBP 95-115 703 40 NR 53 seated, trough 152 101 ARB + TD 12
Mallion 2000 seDBP 95–114 446 52 134 (30) 56 supine, trough 163 101 ACEI + TD 12
Myers 2000 suDBP 95-114 438 43 101 (23) 55 supine, trough 162 104 ACEI + TD 8
Neutel 2005 seSBP 160-200, seDBP<=100, daytime ambulatory SBP 150–200, DBP 60–100
443 53 NR 68 seated, NR 169 88 ACEI + CCB 8
Philipp 2007 seDBP 95-109 1911 47 NR 54 seated, trough 153 99 ARB + CCB 8
Pool 2001 seSBP 100-115 454 37 NR 54 seated, trough 155 104 ACEI + CCB 8
Pool 1997 seDBP 95-109 551 39 NR 52 seated, trough 150 100 ACEI + TD 8
Pordy 1994 seDBP 95-115 1138 40 NR 54 seated, trough NR 100 ACEI + TD 4
Poisson 1996 seDBP 95-115 642 44 208 (32) 58 supine, trough 165 102 ACEI + CCB 12
Scholze 1998 seDBP 100-115 424 NR 222 (52) NR seated, trough NR NR ACEI + CCB 6
Weinberger 2010 seDBP 95-109 1346 45 511 (38) 53 seated, trough 152 99 ARB + TD 8
Weir 1992 suDBP 95-110 303 32 NR 54 supine, trough 152 100 CCB + TD 12
Saruta 2007 seDBP 95-115 942 40 395 (41) 55 seated, trough 155 101 ARB + TD 8
Veratran 1997 seDBP 100-110 234 40 NR 49 seated, trough 155 101 ACEI + CCB 8
ACEI=angiotensin converting enzyme inhibitor, ARB=angiotensin receptor blocker, CCB=calcium channel blocker, DBP=diastolic blood pressure, NR=not reported, SBP=systolic blood pressure, se=seated, su=supine, TD=thiazide diuretic
Supplementary Figure S1: Risk of bias in included trials
(X-axis): Right to left, <1+<1, 1+<1, 1+1, top compared to one standard-dose, bottom compared to placebo (these were the comparisons with most data)
Supplementary Figure S2: Funnel plots for change in SBP
P = 0.113 and 0.264 for heterogeneity between subgroups for SBP and DBP respectively.
Low-std=low-to-standard-dose, N=number of participants
Supplementary Figure S3: SBP and DBP reduction with dual combination vs. 1 standard-dose monotherapy
Supplementary Figure S4: SBP reduction with dual combination vs. <1 and all >1 standard-dose monotherapies
P = 0.569 and 0.292 for heterogeneity between subgroups for SBP and DBP respectively.
Supplementary Figure S5: SBP and DBP reduction with dual combination vs. Placebo
P = 0.10 for heterogeneity between classes
Supplementary Figure S6a: SBP reduction with dual combination of <1+<1 standard-dose vs. Placebo by antihypertensive drug class
P = 0.33 for heterogeneity between classes
P = 0.00 for heterogeneity between classes
Supplementary Figure S6c: SBP reduction with dual combination of 1 + 1 standard-dose vs. placebo by antihypertensive drug class
P and I2 values for heterogeneity between subgroups= 0.220, 55% and 0.831, 16% for BP control with lower & higher Dual vs. 1 standard-dose monotherapy & placebo respectively. N=patients
Supplementary Figure S7: BP control with dual combination vs. 1 standard-dose monotherapy and placebo
P and I2 values for heterogeneity between subgroups= 0.675; 0.0% and 0.612; 0.0% for WDAEs with lower & higher Dual vs. 1 standard-dose monotherapy & placebo respectively.
* One study (Levine 1995) reported zero events in dual combination and standard-dose monotherapy group was not included E=events, N=patients
Supplementary Figure S8: Withdrawals due to adverse events with dual combination vs. 1 standard-dose monotherapy and placebo
P and I2 values for heterogeneity between subgroups= 0.561; 0.0% and 0.226; 0.0% for Dizziness with Dual vs. 1 standard-dose monotherapy & placebo respectively.
Supplementary Figure S9: Dizziness with dual combination vs. 1 standard-dose monotherapy and placebo
