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Antihypertensive Treatment and Development
of Heart Failure in Hypertension
A Bayesian Network Meta-analysis of Studies in Patients
With Hypertension and High Cardiovascular Risk
Sebastiano Sciarretta, MD; Francesca Palano, MD; Giuliano Tocci, MD;
Rossella Baldini, PhD; Massimo Volpe, MD

Background: It is still debated whether there are dif-
ferences among the various antihypertensive strategies
in heart failure prevention. We performed a network meta-
analysis of recent trials in hypertension aimed at inves-
tigating this issue.
Methods: Randomized, controlled trials published
from 1997 through 2009 in peer-reviewed journals
indexed in the PubMed and EMBASE databases were
selected. Selected trials included patients with hyperten-
sion or a high-risk population with a predominance of
patients with hypertension.
Results: A total of 223 313 patients were enrolled in
the selected studies. Network meta-analysis showed
that diuretics (odds ratio [OR], 0.59; 95% credibility in-
terval [CrI], 0.47-0.73), angiotensin-converting en-
zyme (ACE) inhibitors (OR, 0.71; 95% CrI, 0.59-0.85)
and angiotensin II receptor blockers (ARBs) (OR, 0.76;
95% CrI, 0.62-0.90) represented the most efficient
classes of drugs to reduce the heart failure onset com-
pared with placebo. On the one hand, a diuretic-based
therapy represented the best treatment because it was
significantly more efficient than that based on ACE in-
hibitors (OR, 0.83; 95% CrI, 0.69-0.99) and ARBs
(OR, 0.78; 95% CrI, 0.63-0.97). On the other hand, di-
uretics (OR, 0.71; 95% CrI, 0.60-0.86), ARBs (OR, 0.91;
95% CrI, 0.78-1.07), and ACE inhibitors (OR, 0.86;
95% CrI, 0.75-1.00) were superior to calcium channel
blockers, which were among the least effective first-line
agents in heart failure prevention, together with
-blockers and -blockers.
Conclusions: Diuretics represented the most effective
class of drugs in preventing heart failure, followed by re-
nin-angiotensin system inhibitors. Thus, our findings sup-
port the use of these agents as first-line antihyperten-
sive strategy to prevent heart failure in patients with
hypertension at risk to develop heart failure. Calcium
channel blockers and -blockers were found to be less
effective in heart failure prevention.
Arch Intern Med. 2011;171(5):384-394.
Published online November 8, 2010.
doi:10.1001/archinternmed.2010.427

Author Affiliations:
Department of Cardiology,
Second School of Medicine
(Drs Sciarretta, Palano, Tocci,
Baldini, and Volpe), University
of Rome Sapienza, S. Andrea
Hospital, Rome, Italy; and
Istituto di Ricovero e Cura a
Carattere Scientifico, Istituto
Neuromed Polo Molisano,
University of Rome Sapienza,
Pozzilli (IS), Italy (Dr Volpe).
H
EART FAILURE (HF) REP-
resents the final com-
mon pathway of the clini-
cal history of different
cardiac diseases, and it is
viewed today as one of the major health
care problems worldwide.1 Arterial hyper-
tension represents the most common cause
of predisposition to the development of
HF, which is also independent of the oc-
currence of coronary artery disease,2,3 as
highlighted by the Framingham Heart
study4 and the Rotterdam study.5
See Invited Commentary
at end of article
and also page 471
Despite this evidence, over the past
years HF has been often considered a
soft end point in the main hyperten-
sion clinical trials, and greater attention
has been given to myocardial infarction
and stroke.6 A recent analysis from our
group7 examining the main clinical trials
in hypertension published in the past de-
cade has substantially challenged this
CME available online at
www.jamaarchivescme.com
and questions on page 377
view by showing that the incidence of
HF in hypertension is as frequent as that
of stroke, being even more common in
older patients, patients with diabetes
mellitus, blacks, and patients at very
high cardiovascular risk. The impor-
tance of HF is documented by the fact
that it still represents one of the leading

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824 Identified and screened reports
790 Excluded:
Trials conducted on patients without
hypertension or specifically
conducted on patients with HF
No intervention trials or subanalysis
of intervention trials or trial design
publications
Observational studies or trials
not reporting data on primary
cardiovascular events
Other drug interventions
Patients with hypertension comprise
< 65% of populations in high-risk
patients trials
34 Trials available for further evaluation
8 Excluded:
Absence of specific data on HF
Patients with high-normal BP
26 Trials included in the network meta-analysis
Figure 1. Algorithm for studies selection. BP indicates blood pressure; HF, heart failure.
causes of hospitalization, disabil- sons between active treatments. We
ity, and mortality, and it imposes report herein the results of a
heavy medical and financial bur- network meta-analysis of recent
dens on communities, which are trials conducted in patients with
expected to further rise in the next hypertension, or in patients at
2 decades.8,9 Thus, it seems neces- high cardiovascular risk with a
sary to optimize strategies for pre- predominant proportion with
venting HF, especially in the pres- hypertension. 10-35 We compared
ence of predisposing conditions, antihypertensive strategies in HF
such as hypertension. prevention. Network meta-analysis
On the one hand, over the past is a meta-analytic technique that
years, numerous trials have pro- synthesizes the available evidence
vided evidence regarding the from clinical trials evaluating a
efficacy of different antihyper- wide range of drug comparisons in
tensive drugs in preventing a single meta-analysis, in which
HF development in patients direct evidence of different therapy
with hypertension. 10-35 Placebo- comparisons are combined with
controlled studies have consistently indirect evidence that are con-
shown that all principal antihyper- structed from studies that have
tensive strategies reduce the inci- treatments in common.36
dence of HF, thus confirming that
blood pressure reduction is a fun- METHODS
damental strategy to prevent HF in
patients with hypertension. On the SEARCH METHODS
other hand, clinical studies based
on active treatment comparisons We systematically reviewed the medi-
suggest that calcium channel cal literature to identify the clinical
blockers (CCBs) are less effective trials to be used for the analysis. These
than renin-angiotensin system studies had to fulfill predefined, spe-
(RAS) inhibitors, diuretics, and cific qualitative criteria and provide
-blockers in reducing HF develop- information on demography and the
ment. No conclusive evidence definition of HF diagnosis. Thus,
about the optimal antihypertensive the selected studies had to adhere to
the following criteria: they had to be
therapy, however, has been pro-
randomized, controlled design for
vided. This issue has not been clinical studies published in peer-
resolved by recent hypertension reviewed journals indexed in medical
meta-analyses, which are often databases, available by 1997; they had
based on a series of small meta- to include patients with hypertension
analyses and on limited compari- or a population characterized as having
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a high cardiovascular risk profile and
a predominance of patients with hyper-
tension (65%); the sample size had
to have at least 200 patients; and infor-
mation on the absolute incidence of
HF and other major cardiovascular
events had to be included. The com-
puterized search was performed using
the PubMed and EMBASE databases
through December 2009. The specific
keywords were antihypertensive
drugs and cardiovascular risk, and
the limits of the search were a date of
publication between 1997 and 2009
and the selection of randomized con-
trolled trials. We also checked in the
references of a recently published
meta-analysis for the presence of other
trials matching our inclusion criteria.37
Two investigators (S.S. and F.P.) inde-
pendently searched the trials and veri-
fied the specific recruitment criteria.
We decided to consider only trials
published in the past decade because
the clinical feature of included patients
and the different antihypertensive
strategies in these studies reflect more
properly the present hypertension
clinical practice. We arbitrarily chose
1997 as the first date for study selec-
tion because in the previous year a
landmark analysis evaluating the
prevention of HF in hypertension
trials was published. 38 From a total
of 824 screened clinical studies,
34 were considered to be eligible
for the present analysis 1 0 - 3 5 , 3 9 - 4 6
( F i g u r e 1 ). Seven studies were
excluded because they did not report
specific data on HF, 39-45 and 1 was
excluded because it referred to patients
with high-normal blood pressure lev-
els. 4 6 Although the prevalence of
patients with hypertension in the study
population of the Heart Outcomes Pre-
vention Evaluation Study (HOPE)
study21 was lower than 65%, we con-
sidered this trial in the analysis anyway
since the cutoff used for hypertension
diagnosis was a systolic blood pressure
higher than 160 mm Hg.47 All of the
included trials met at least 2 criteria
defining the quality of clinical trials.48
A list of the selected studies is pro-
vided in Table 1 and Table 2.
PRESPECIFIED ANALYSES
AND HYPOTHESIS
All data from each completed primary
publication were tabulated into a com-
puterized spreadsheet (Microsoft
Excel; Microsoft Corp, Redmond, Wash-
ington). First, we performed a series
of traditional meta-analyses of studies
that directly compared different antihy-
pertensive drugs as first-line agents.
WWW.ARCHINTERNMED.COM
 Table 1. Clinical Characteristics of Patients Included in the Analyzed Trials and Their Different Definitions of Heart Failure (HF)
as Clinical End Point

Definition of HF as End Point

Clinical Study Follow-up, Diagnostic

and Year y Treatment Prevalence Study Population Criteria Type Description
Syst-Eur,10 1997 2 CCB/placebo 0 Elderly with isolated systolic HT VE Secondary Fatal and nonfatal
Syst-China,11 1998 2 CCB/placebo 0 Elderly with isolated systolic HT VE Secondary Fatal and nonfatal
UKPDS,12 1998 8.4 ACEI/BB 0 HT with type 2 DM NR Secondary NR
ABCD,13 1998 5.7 ACEI/CCB NR HT with type 2 DM VE Secondary Fatal and nonfatal
VHAS,14 1997 2 CCB/BB 0 HT VE Secondary Nonfatal
CAPPP,15 1999 6.1 ACEI/BB-DD 0.34/0.18 HT VE Secondary NR
NICS-EH,16 1999 5 CCB/DD 0 Elderly with HT VE Primary Fatal and nonfatal
STOP-2,17 1999 6 CCB/BB-DD/ACEI 2/1.5 Elderly with HT NR Primary NR
INSIGHT,18 2000 4 CCB/DD 0 HT with 1 additional RF VE Primary Fatal and nonfatal
NORDIL,19 2000 5 CCB/BB-DD 0 HT VE Primary NR
ALLHAT,20 2000 3.3 AB/DD 0 HT with 1 additional RF VE Secondary Fatal, nonfatal
hospitalized, treated
nonhospitalized
HOPE,21 2000 5 ACEI/placebo 0 VD or DM with 1 additional RF VE Secondary Hospitalized or
nonhospitalized
RENAAL,22 2001 4.5 ARB/placebo 0 Type 2 DM and nephropathy VE Secondary Hospitalization
LIFE,23 2002 4 ARB/BB 0 HT with ECG-documented LVH VE Secondary Hospitalization
CONVINCE,24 2003 3 CCB/BB-DD 0 HT with 1 additional RF VE Secondary Hospitalization
ALLHAT,25 2002 4.9 CCB/DD/ACEI 0 HT with 1 additional RF VE Secondary Fatal, nonfatal
hospitalized, treated
nonhospitalized
VALUE,26 2004 4.2 ARB/CCB 0 High-risk HT with additional RFs VE Primary Fatal, nonfatal, and
or VD hospitalized
27
ANBP2, 2003 4.1 ACEI/DD 0 Elderly with HT VE Primary Fatal and nonfatal
SHELL,28 2003 5 CCB/DD 0 Elderly with isolated systolic HT VE Secondary Fatal and nonfatal
FEVER,29 2005 3 CCB/placebo 6.2/6.5 HT with 1-2 additional RFs VE Secondary Fatal and nonfatal
ASCOT-BPLA,31 2005 5.5 CCB/BB 0 HT with 3 additional RFs NR Secondary Fatal and nonfatal
E-COST,30 2005 3 ARB/CT (mostly 8.7/17 Elderly with HT and nephropathy NR Primary NR
CCB)
Jikei Heart Study,32 3.1 ARB/CT (mostly 11/11 HT, CHD, and VD VE Primary Hospitalization
2007 CCB)
HYVET,34 2008 2.1 DD/placebo 2.9/2.9 Elderly with persistent HT FC Secondary Fatal and nonfatal
ONTARGET,33 2008 4.6 ACEI/ARB 0 CVD, DM with organ damage VE Secondary Hospitalization
TRANSCEND,35 2008 4.6 ARB/placebo 0 CVD, DM with end-organ damage VE Secondary Hospitalization

Abbreviations: AB, -blocker; ABCD, Appropriate Blood Pressure Control in Diabetes; ACEI, angiotensin-converting enzyme inhibitor; ALLHAT, Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial; ANBP2, Second Australian National Blood Pressure Study; ARB, angiotensin II receptor blocker;
ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm; BB, -blocker; CAPPP, Captopril Prevention Project; CCB, calcium channel
blocker; CHD, coronary heart disease; CONVINCE, Controlled Onset Verapamil Investigation of Cardiovascular End Points; CT, conventional treatment;
CVD, cardiovascular disease; DD, diuretic; DM, diabetes mellitus; E-COST, Efficacy of Candesartan on Outcome in Saitama Trial; FC, Framingham criteria;
FEVER, Felodipine Event Reduction; HOPE, Heart Outcomes Prevention Evaluation; HT, hypertension; HYVET, Hypertension in the Very Elderly Trial;
INSIGHT, Intervention as a Goal in Hypertension Treatment; LIFE, Losartan Intervention For Endpoint; LVH, left ventricular hypertrophy; NICS-EH, National Intervention
Cooperative Study in Elderly Hypertensives Study; NORDIL, Nordic Diltiazem; NR, not reported; ONTARGET, Ongoing Telmisartan Alone and in Combination with
Ramipril Global Endpoint Trial; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; RF, risk factor; SHELL, Systolic Hypertension in
the ELderLy; STOP-2, Swedish Trial in Old Patients with Hypertension-2; Syst-China, Systolic Hypertension in China; Syst-Eur; Systolic Hypertension in Europe;
TRANSCEND, Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease; UKPDS, UK Prospective Diabetes Study;
VALUE, Valsartan Antihypertensive Long-term Use Evaluation; VD, vascular disease; VE, validated end point; VHAS, Verapamil in Hypertension and
Atherosclerosis Study.

Then we performed a Bayesian net-
work meta-analysis to compare differ-
ent antihypertensive drug-based thera-
pies (angiotensin-converting enzyme
[ACE] inhibitors, angiotensin II receptor
blockers [ARBs], diuretics, CCBs,
-blockers, conventional treatment, and
-blockers) to placebo and one to each
other.
We also performed additional net-
work meta-analyses in 5 subgroups
of studies: (1) a subgroup including only
studies that did not enroll patients
with a history of HF (186 559 pa-
tients)15,17,29,31-33; (2 and 3) subgroups in-
cluding trials that enrolled a greater
proportion of males (153 447 patients)*
and a greater proportion of females
(69 866 patients) ; and (4 and 5) sub-
groups including trials with a mean age
of the enrolled population younger than
67 years (151 832 patients) or 67 or older
*References 11-13, 15, 20-22, 25, 26, 29,
30, 32, 34, 35.
References 10, 14, 16-19, 23, 24, 27, 28,
31, 33.
References 11-15, 19, 21-25, 29, 30, 32,
34, 35.
years (71 482 patients)10,16-18,20,26-28,31,33.
This value represents the median of the
mean age of the populations of the trials
included in our investigation.
STATISTICAL ANALYSIS
Statistical analysis was performed by
using SPSS software (version 16.0; SPSS
Inc, Chicago, Illinois), SAS software (ver-
sion 8.2; SAS Institute Inc, Cary, North
Carolina), and WinBUGS packages
(MRC Biostatistics Unit, Cambridge,
England). Estimates of the effects of

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 Table 2. Incidence of Heart Failure in the Clinical Trials Included in the Network Meta-analysis

BP Reduction No. (%)

Difference
Between Groups
Clinical Treatments Initial BP, Final BP, [Group 2-Group 1], Incidence P All-Cause P CV P
Study (No. of Patients) SBP/DBP SBP/DBP SBP/DBP of HF Value Mortality Value Mortality Value
Syst-Eur10 CCB (2398) 173.8/85.5 150.8/78.5 37 (1.5) 123 (5.1) 59 (2.5)
10/5 .12 .22 .07
Placebo (2297) 173.9/85.5 160.9/83.5 49 (2.1) 137 (6) 77 (3.4)
11
Syst-China CCB (1253) 170.5/86 150.5/81 4 (0.3) 61 (4.9) 33 (2.6)
9.1/3.7 .13 .003 .004
Placebo (1141) 170.5/86 159.6/84.7 8 (0.7) 82 (7.2) 44 (3.9)
UKPDS12 ACEI (400) 159/94 144/83 12 (3) 75 (18.8) 48 (12)
1/1 .66 .44 NR
BB (358) 159/93 143/81 9 (2.5) 59 (16.5) 34 (9.5)
ABCD13 ACEI (235) 155/98 132/78 5 (2.1) 17 (7.2) 10 (4.3)
5/8 NR NR NR
CCB (235) 156/98 138/86 6 (2.6) 13 (5.5) 5 (2.1)
VHAS14 CCB (707) 169.1/102 141.5/85 2 (0.3) 5 (0.7) 5 (0.7)
1/0.4 NR NR NR
DD (707) 168.8/102.3 140.2/85.7 0 (0) 4 (0.6) 4 (0.6)
CAPPP15 ACEI (5492) 161.8/99.8 150/90 75 (1.4) NR 76 (1.4)
2.2/1.7 .3 .49 .09
BB/DD (5493) 159.6/98.1 150/90 66 (1.2) NR 95 (1.7)
NICS-EH16 CCB (204) 171.9/94.2 147/81 0 (0) NR NR
0.7/1.2 NR NR NR
DD (210) 172.6/93.4 147/79 3 (1.4) NR NR
17
STOP-2 CCB (2196) 194/98 159/80 186 (8.5) .02 362 (16.5) .71 212 (9.7) .89
1/1
BB/DD (2205) 194/998 159/81 177 (8) .56 369 (16.7) .76 221 (10) .72
1/0
ACEI (2213) 194/98 158/81 149 (6.8) .90 380 (17.2) .90 226 (10.2) .67
INSIGHT18 CCB (3157) 173/99 138/82 26 (0.8) 153 (4.8) 60 (1.9)
0/0 .02 .95 .45
DD (3164) 173/99 138/82 12 (0.4) 152 (4.8) 52 (1.6)
NORDIL19 CCB (5410) 173.5/105.8 152.2/87.6 63 (1.2) 231 (4.3) 131 (2.4)
3/0.1 .42 .99 .41
BB/DD (5471) 173.4/105.7 149.1/87.4 53 (1) 228 (4.2) 115 (2.1)
ALLHAT AB (9067) 145/84 137/76 491 (5.4) 514 (5.7) 130 (1.4)
200020 2/1 .001 .56 NR
DD (15268) 145/83 135/76 420 (2.8) 851 (5.6) 218 (1.4)
HOPE21 ACEI (4645) 139/79 136/76 417 (9) 482 (10.4) 282 (6.1)
3/1 .001 .005 .001
Placebo (4652) 139/79 139/77 535 (11.5) 569 (12.2) 377 (8.1)
RENRAL22 ARB (751) 152/82 140/74 89 (11.9) 158 (21) NR
1/0 .01 .88 NR
Placebo (762) 153/82 142/74 127 (16.7) 155 (20.3) NR
LIFE23 ARB (4605) 174.3/97.9 144.1/86.3 153 (3.3) 383 (8.3) 204 (4.4)
1.1/5.2 .76 .12 .20
BB (4588) 174.5/97.7 145.4/80.9 161 (3.5) 431 (9.4) 234 (5.1)
CONVINCE24 CCB (8179) 150.1/86.8 136.4/79 126 (1.5) 337 (4.1) 152 (1.9)
0.1/0.7 .05 .32 .47
BB/DD (8297) 150.1/86.8 136.5/79.7 100 (1.2) 319 (3.8) 143 (1.7)
ALLHAT CCB (9048) 146.2/83.9 134.7/74.6 706 (7.8) 2203 (24) 992 (11)
200225 0.8/0.7 .20 .98
.001
DD (9054) 146.2/84 133.9/75.4 1.8/0.1 870 (5.7) 1256 (14) .90 592 (6.5) .53
ACEI (15255) 146.4/84.1 135.9/75.4 612 (6.8) 1314 (8.6) 609 (4)
VALUE26 ARB (7649) 154.5/87.4 139.3/79.2 354 (4.6) 841 (11) 304 (4)
2.1/1.7 .12 .45 .90
CCB (7596) 154.8/87.6 137.5/77.7 400 (5.3) 818 (10.8) 304 (4)
ANBP227 ACEI (3044) 167/91 141/79 69 (2.3) 195 (6.4) 84 (2.8)
0/0 .33 .27 .94
DD (3039) 168/91 142/79 78 (2.6) 210 (6.9) 82 (2.7)
SHELL28 CCB (942) 178.1/86.9 143.2/79.5 23 (2.4) 145 (15.4) NR
1.3/0.2 .56 .09 NR
DD (940) 178.2/86.8 142/79.2 19 (2.0) 122 (13) NR
FEVER29 CCB (4841) 154.2/91 138.1/82.3 18 (0.4) 112 (2.3) 73 (1.5)
3.3/1.3 .26 .005 .01
Placebo (4870) 154.4/91.3 141.6/83.9 27 (0.6) 151 (3.1) 101 (2.1)
ASCOT-BPLA31 CCB (9639) 164.1/94.8 136.1/77.4 134 (1.4) 738 (7.7) 263 (2.7)
1.8/0.3 .12 .02 .001
BB (9618) 163.9/94.5 137.7/77.4 159 (1.7) 820 (8.5) 342 (3.6)
E-COST30 ARB (1053) 162/91.1 140.1/78.9 35 (3.3) NR NR
CT (mostly CCB) 165.9/95.9 138.4/81.1 5.6/2.6 41 (4.1) NR NR NR NR NR
(995)
Jikei Heart ARB (1541) 139.2/81.4 132/76.7 19 (1.2) 28 (1.8) 9 (0.6)
Study32
0.4/0.1 .02 .75 .95
CT (mostly CCB) 138.8/81.4 132/76.6 36 (2.3) 27 (1.8) 9 (0.6)
(1540)
HYVET34 DD (1933) 173/90.8 143.5/77.9 22 (1.1) 196 (10.1) 99 (5.1)
15/6.1 .001 .02 .06
Placebo (1912) 173/90.8 158.5/84 57 (3) 235 (12.3) 121 (6.3)
33
ONTARGET ACEI (8576) 141.8/82.1 135.4/77.8 514 (6) 1014 (12) 603 (7)
1/0.7 NR NR NR
ARB (8542) 141.7/82.1 134.3/77.1 537 (6.3) 989 (11.6) 598 (7)
TRANSCEND35 ARB (2954) 140.7/81.8 NR 134 (4.5) 364 (12.3) 227 (7.7)
4/2.2 .69 .49 .77
Placebo (2972) 141.3/82 NR 129 (4.3) 349 (11.7) 223 (7.5)

Abbreviations: AB, -blocker; ABCD, Appropriate Blood Pressure Control in Diabetes; ACEI, angiotensin-converting enzyme inhibitor; ALLHAT, Antihypertensive
and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ANBP2, Second Australian National Blood Pressure Study; ARB, angiotensin II receptor blocker;
ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm; BB, -blocker; BP, blood pressure; CAPPP, Captopril Prevention Project;
CCB, calcium channel blocker; CONVINCE, Controlled Onset Verapamil Investigation of Cardiovascular End Points; CT, conventional treatment; CV, cardiovascular;
DBP, diastolic blood pressure; DD, diuretic; E-COST, Efficacy of Candesartan on Outcome in Saitama Trial; FEVER, Felodipine Event Reduction; HF, heart failure;
HOPE, Heart Outcomes Prevention Evaluation; HYVET, Hypertension in the Very Elderly Trial; INSIGHT, Intervention as a Goal in Hypertension Treatment;
LIFE, Losartan Intervention For Endpoint; NICS-EH, National Intervention Cooperative Study in Elderly Hypertensives; NORDIL, Nordic Diltiazem; NR, not reported;
ONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; RENRAL, Reduction of Endpoints in NIDDM with the Angiotensin II
Antagonist Losartan; SBP, systolic blood pressure; SHELL, Systolic Hypertension in the ELderLy; STOP-2, Swedish Trial in Patients with Hypertension-2; Syst-China,
Systolic Hypertension in China; Syst-Eur, Systolic Hypertension in Europe; TRANSCEND, Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with
cardiovascular Disease; UKPDS, UK Prospective Diabetes Study; VALUE, Valsartan Antihypertensive Long-term Use Evaluation; VHAS, Verapamil in Hypertension and
Atherosclerosis Study.

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single direct comparisons between 2
strategies in HF prevention were calcu-
lated by using the 2 test. Meta-
analytical overall estimates of the effect
of direct comparisons were calculated ac-
cording to the meta-analytical tech-
nique.49,50 The assumption of homoge-
neity of treatment effect between
different individual studies and sub-
groups of studies was tested using the
2 test for homogeneity. When appro-
priate, publication bias was tested as pre-
viously described.51,52
Network meta-analysis was per-
formed using the Bayesian hierarchical
model proposed by Lu and Ades.36 The
advantages of a Bayesian meta-analytic
approach are represented by the fact
that direct probability statements can
be made, all evidence regarding a spe-
cific problem can be taken into ac-
count, and predictive statements can
be easily made. The disadvantages are
related to the use of prior beliefs that
may undermine objectivity; to elicita-
tion of priors, which is nontrivial with
few guidelines; and to its computa-
tional complexity and the long period
of time needed to perform it.
This model is the k-comparison ver-
sion of the SST model of Smith et al53 pro-
posed by them to analyze the compari-
sons between treatments through
adequate parameterizations. The esti-
mates were obtained by using the
Markow Chains Monte Carlo Method
(MCMC). Specifically, 2 chains were gen-
erated with 5000 initial iterations (burn
in), and 100 000 iterations were used for
the estimations. The number of initial
iterations (burn in) was determined on
the basis of Gelman-Rubin approach. The
accuracy of the posterior estimates was
found by calculating the Monte Carlo er-
ror for each parameter. As a rule of
thumb, the Monte Carlo error for each
parameter of interest is less than 5% of
the sample standard deviation. For the
present analysis, following Lu and Ades,54
among 5 models presented by those 2
authors (all incorporating the random
multivariate treatment effects), we chose
the SST-2-HOM model: random effects
baselines with homogeneous treatment
variance. We also used noninformative
priors that represented complete lack of
credible prior information. The Win-
Bugs code for SST-2-HOM model is in-
cluded in the current article.
All results for the mixed-treatment
analysis are reported as posterior
median with corresponding 95% cred-
ibility intervals (CrIs). To evaluate
whether variability of results across
different comparisons of the network
may have affected the results, the
inconsistency of the model was calcu-
lated as suggested by Lu and Ades.54
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2011 American Medical Association. All rights reserved.
When the confidence interval of effect
estimates did not cross the unit, these
were considered significant.
RESULTS
The main clinical and methodologi-
cal characteristics of each trial are
shown in Table 1 and Table 2. The
studies selected were performed in
patients enrolled on the basis of a
diagnosis of hypertension (186 378
[83.5%])10-20,23-31,33 or in a popula-
tion at high cardiovascular risk
with a predominant presence of
hypertensive patients (36 935
[16.5%]).21,22,32,34,35 The beginning
year of recruitment ranged from
1987 to 2004. All studies were pub-
lished from 1997 through 2009.
A total of 223 313 patients were
enrolled in the selected studies.
Among these individuals, 24 009
(10.8%) were randomized to receive
a conventional treatment. In the Cap-
topril Prevention Project (CAPPP),15
Controlled Onset Verapamil Inves-
tigation of Cardiovascular End Points
(CONVINCE),24 Swedish Trial in
Old Patients with Hypertension2
(STOP-2),17 and Nordic Diltiazem
(NORDIL)19 studies, patients receiv-
ing conventional treatment were
treated with -blockers or diuretics
or both, whereas in the Jikei Heart
Study32 and Efficacy of Candesartan
on Outcome in Saitama Trial
(E-COST)30 the conventional treat-
ment included any agent different
from the active drug (ARBs). These
agents were mostly CCBs, whereas
only a negligible portion of these pa-
tients were receiving diuretic-based
treatment (4%).
A total of 40 516 patients (18.1%)
were specifically assigned to a
diuretic-based therapy, 9067 (4.1%)
to an -blockerbased strategy,
and 14 564 (6.5%) to a -blocker
based therapy. The remaining pa-
tients were treated with an antihy-
pertensive strategy based on the
newer antihypertensive drug classes,
including CCBs (55 805 [25%]),
ACE inhibitors (33 651 [15.1%]),
and ARBs (27 095 [12.1%]). In ad-
dition, 18 606 patients (8.3%) were
randomized to receive placebo.
In the pooled studies, a total of
8554 cases of HF were recorded dur-
ing the follow-up (3.8% of patients).
WWW.ARCHINTERNMED.COM
388
We performed a series of con-
ventional meta-analyses to summa-
rize the results of trials directly com-
paring the same classes of drugs.
These results are reported in
Figure 2, in which we constructed
a diagram of the network of clinical
trials comparing specific antihyper-
tensive strategies. According to these
direct comparisons, ACE inhibi-
tors, ARBs, CCBs, and diuretics were
superior to placebo (Figure 2). Di-
uretic-based therapies were more ef-
fective than those based on -
blockers and CCBs, and slightly
better than those based on ACE in-
hibitors. However, conventional
treatment, ACE inhibitors, and ARBs
showed higher efficacy than CCBs
in preventing HF (Figure 2). No sig-
nificant heterogeneity was detected
in any of these meta-analyses
(P.05), with the exception of that
comparing ARBs vs placebo (P=.02).
No significant publication bias was
detected (P .10).
As shown in Figure 3 and
Table 3, network meta-analysis con-
firmed the trends observed in the di-
rect comparisons, since all the ac-
tive treatments, with the exception of
-blockers, were more effective than
placebo in HF prevention. In the case
of -blockers, however, the differ-
ence was not statistically significant.
Antihypertensive therapies based on
diuretics, ACE inhibitors, and ARBs
were the most effective therapeutic
strategy in HF prevention. Among
these treatments, diuretics were sig-
nificantly more effective than RAS in-
hibitors. Calcium channel blockers
and -blockers seemed to be less ef-
fective as first-line antihypertensive
classes, since they were significantly
inferior to diuretics, and they tended
to be inferior to RAS inhibitors. The
overall inconsistency of the model
was low (W 2
= 0.06), as also repre-
sented by the posterior probability
that W 2
2 (posterior mean of be-
tween-trials variance) (where w in-
dicates the weighting factor, which
was equal to 0.42).
Similar results were obtained in
all the subgroup analyses
(Table 4) since diuretics, closely
followed by RAS inhibitors,
seemed to be superior to CCBs
and -blockers in HF prevention.
Interestingly, in studies with
greater proportions of women and
 ALLHAT
DDs ABs
0.49 (0.43-0.55)

T
HA
LL
L ,A
EL AN
SH BP
-E H, 0.8 2,
ICS ) 6( AL
,N .79 0.7 LH
HT 4-0 8- AT
SIG (0.
6 0.9
, IN 0.7
1 5)
AS

0.3
VH

HY
7(

VE
0.2

T
3-0
.61
ABCD, STOP-2, ALLHAT

)
CCBs ACEIs
0.84 (0.76-0.93)
Syst-
NORDIL, CONVINCE, STOP-2

Eur, S
yst-C OP-2
hina, P, ST
0.67 FEVE CAPP
0.84 (0.72-0.98)

(0.48 R 0)
6-1.1

0.78 (0.69-0.98)
-0.94
) 0.9 2 (0.7

HOPE
VA
0.8 LU S
E PD
8( .0)
CT 0.7 UK -2 Placebo
6-1
. 01 0.34
) 3(
0.8

.84-1.08)
E-CO
ST, J
ikei

5-1.3 END
0.67
(0.47

ET 0.95 (0

1)
-0.95

C
ASC

0.85 , TRANS
)
0.8
4 (0

OT-

(0.5
BPL
.66

ONTARG

AAL
-1.0

REN
5)

LIFE
BBs ARBs
0.97 (0.78-1.21)

Figure 2. Network of clinical trials of antihypertensive drugs in which the incidence of heart failure (HF) was reported. For each pair-wise comparison, the arrowhead
points to a class of antihypertensive drugs with a lower risk of incident HF in traditional meta-analyses or single trials comparing 2 specific strategies. Summary of odds
ratio (OR) and 95% CI for comparison are shown below the arrow. Meta-analyses are performed according to a fixed-effect model, with the exception of those of
angiotensin II receptor blockers (ARBs) vs placebo, which was calculated according to a random-effect model (significant heterogeneity present). AB indicates
-blocker; ABCD, Appropriate Blood Pressure Control in Diabetes13; ACEI, angiotensin-converting enzyme inhibitor; ALLHAT, Antihypertensive and Lipid-Lowering
Treatment to Prevent Heart Attack Trial20; ANBP2, Second Australian National Blood Pressure Study27; ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes TrialBlood
Pressure Lowering Arm31; BB, -blocker; CAPPP, Captopril Prevention Project15; CCB, calcium-channel blocker; CONVINCE, Controlled Onset Verapamil Investigation of
Cardiovascular End Points24; CT, conventional treatment; DD, diuretic; E-COST, Efficacy of Candesartan on Outcome in Saitama Trial30; FEVER, Felodipine Event
Reduction29; HOPE, Heart Outcomes Prevention Evaluation21; HYVET, Hypertension in the Very Elderly Trial34; INSIGHT, Intervention as a Goal in Hypertension
Treatment18; Jikei, Jikei Heart Study32; LIFE, Losartan Intervention For Endpoint23; NICS-EH, National Intervention Cooperative Study in Elderly Hypertensives16;
NORDIL, Nordic Diltiazem19; ONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial33; RENAAL, Reduction of Endpoints in
NIDDM with the Angiotensin II Antagonist Losartan22; SHELL, Systolic Hypertension in the ELderLy28; STOP-2, Swedish Trial in Patients with Hypertension-217;
Syst-China, Systolic Hypertension in China11; Syst-Eur, Systolic Hypertension in Europe10; TRANSCEND, Telmisartan Randomised AssessmeNt Study in ACE iNtolerant
subjects with cardiovascular Disease35; UKPDS, UK Prospective Diabetes Study12; VALUE, Valsartan Antihypertensive Long-term Use Evaluation26; and VHAS, Verapamil
in Hypertension and Atherosclerosis Study.14

elderly patients, the difference COMMENT tors, ARBs) are the most effective
between diuretics and ACE inhibi- class of drugs, a diuretic-based treat-
tors was smaller. Moreover, in ment being the more effective first-
studies with greater percentages of To our knowledge, our study is the line antihypertensive intervention for
men and younger subjects, the dif- largest network meta-analysis ever preventing HF. Our analysis also
ference between CCBs and RAS performed in essential hyperten- shows that CCBs and -blockers are
inhibitors was less evident with sion, and it was aimed specifically significantly less effective than di-
respect to the results of the other at investigating the efficacy of dif- uretics as first-line agents, and they
analyses. However, these interest- ferent antihypertensive strategies in tend to be inferior to RAS inhibi-
ing results should be interpreted the prevention of HF. The main find- tors. These results do not seem to be
taking into account that the ing of our analysis is that all antihy- significantly influenced by age and
sample size, and therefore the pertensive strategies are better than sex, as highlighted by our subanaly-
power of these subanalyses, was placebo in HF prevention, with the ses (Table 4).
lower than that of the main exception of -blockers. Diuretics Our results extend the evidence
analysis. and RAS inhibitors (ACE inhibi- provided by previous meta-analy-

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 OR (95% CrI)
DDs 0.59 (0.47-0.72)
ACEIs 0.71 (0.58-0.84)
ARBs 0.76 (0.62-0.90)
CT 0.77 (0.60-0.95)
CCBs 0.83 (0.67-0.99)
BBs 0.87 (0.64-1.12)
ABs 1.22 (0.85-1.69)
Placebo
1.0
Figure 3. Results of network meta-analysis with placebo considered as a referent treatment.
ABs indicates -blockers; ACEIs, angiotensin converting enzyme inhibitors; ARBs, angiotensin II receptor
blockers; BBs, -blockers; CCBs, calcium channel blockers; CrI, credibility interval; CT, conventional
treatment; DDs, diuretics; and OR, odds ratio.
ses. In 2003, Psaty et al55 published
the results of a network meta-
analysis that demonstrated that low-
dose diuretics were the most effec-
tive class of drugs in the prevention
of total cardiovascular mortality and
morbidity, particularly HF, com-
pared with other classes of antihy-
pertensive agents, especially CCBs.
Our current analysis is based on a sub-
stantially larger number of studies, it
is more specifically oriented to HF
outcomes, and it is up to date, in-
cluding all the most recent trials
published over the past 6 years. The
recent trials (eg, the Anglo-Scan-
dinavian Cardiac Outcomes Trial
Blood Pressure Lowering Arm
[ASCOT-BPLA]31 and the Ongoing
Telmisartan Alone and in Combina-
tion with Ramipril Global Endpoint
Trial [ONTARGET]33/Telmisartan
Randomised AssessmeNt Study in
ACE iNtolerant subjects with cardio-
vascular Disease [TRANSCEND]35
trials) mostly evaluated newer an-
tihypertensive drugs as CCBs, ACE
inhibitors, and ARBs, which are ex-
tensively used today in hyperten-
sion treatment. Based on these rea-
sons, our results significantly update
and consolidate previous data and
may provide evidence that can be
more appropriately translated within
our current clinical contexts.
With respect to a landmark
meta-analysis of the Blood Pressure
Lowering Treatment Trialists Colla-
boration (BPLTTC) study,56 also pub-
lished in 2003, our data confirm that
diuretics are more effective than CCBs
in HF prevention in patients with hy-
pertension, but also extend substan-
tially the analysis of ACE inhibitors
and ARBs. In keeping with our results,
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Table 3. Network Meta-analytical
Estimates of the Effects
of Different Comparisons
Among Active Treatments
Main Analysis,
OR (95% CrI,
Comparison 2.50%-97.50%)
CCBs vs placebo 0.84 (0.68-0.99)
REFERENT
ACEIs vs placebo 0.72 (0.59-0.84)
0.5 0.0 0.5 DDs vs placebo 0.60 (0.47-0.73)
Ln OR CT vs placebo 0.78 (0.61-0.96)
BBs vs placebo 0.88 (0.64-1.13)
ARBs vs placebo 0.76 (0.62-0.90)
ABs vs placebo 1.22 (0.86-1.70)
ACEIs vs CCBs 0.86 (0.75-1.01)
DDs vs CCBs 0.71 (0.60-0.86)
DDs vs ACEIs 0.83 (0.69-0.99)
it has been recently demonstrated in CT vs CCBs 0.93 (0.79-1.11)
a metaregression analysis conducted CT vs ACEIs 1.08 (0.90-1.30)
CT vs DDs 1.30 (1.04-1.64)
in patients with hypertension or in BBs vs CCBs 1.05 (0.83-1.32)
patients with a high cardiovascular BBs vs ACEIs 1.22 (0.93-1.55)
risk profile that RAS inhibitors are BBs vs DDs 1.47 (1.10-1.92)
more effective than CCBs in HF pre- BBs vs CT 1.13 (0.85-1.48)
vention, although in that study CCBs ARBs vs CCBs 0.91 (0.78-1.08)
were also shown to be significantly ARBs vs ACEIs 1.06 (0.90-1.25)
ARBs vs DDs 1.28 (1.04-1.59)
more effective than placebo.37
ARBs vs CT 0.98 (0.81-1.20)
On the one hand, a major advan- ARBs vs BBs 0.87 (0.70-1.11)
tage of our current meta-analytical ABs vs CCBs 1.46 (1.07-2.05)
approach is obviously the larger size ABs vs ACEIs 1.70 (1.24-2.36)
compared with individual trials, in ABs vs DDs 2.04 (1.57-2.72)
which HF usually represents a sec- ABs vs CT 1.57 (1.11-2.24)
ABs vs BBs 1.39 (0.96-2.10)
ondary end point. The approach used
ABs vs ARBs 1.60 (1.14-2.28)
in our current study differs from tra-
ditional meta-analyses, which are Abbreviations: ABs, -blockers;
characterized by a series of smaller ACEIs, angiotensin-converting enzyme inhibitors;
meta-analyses of different active com- ARBs, angiotensin II receptor blockers;
parisons, which provide less robust BBs, -blockers; CCBs, calcium channel blockers;
CrI, credibility interval; CT, conventional
information. Although specific com- treatment; DDs, diuretics; and OR, odds ratio.
parisons between some classes of an-
tihypertensive drugs have been in- lationship between blood pressure
vestigated in multiple studies, other reduction differences and HF inci-
comparisons have been performed dence cannot be excluded. Accord-
only in a single trial, and to our ing to the blood pressure differ-
knowledge some other compari- ences observed in the different
sons have never been performed. In studies, however, this aspect is likely
the network meta-analysis it is pos- to play a role in the comparisons be-
sible to combine the results of direct tween different active treatments and
comparisons to indirect compari- placebo. On the contrary, the small
sons extrapolated by trials that have differences between blood pressure
treatments in common. Previous em- reductions induced by the various
pirical evidence has validated indi- antihypertensive agents do not seem
rect comparisons in many condi- to account for the different effects on
tions and interventions.57 HF prevention. This is in line with
On the other hand, some impor- the analysis by Psaty et al,55 in which
tant issues cannot be resolved by our the various treatment strategies were
study and require a comment. First associated with slightly different de-
of all, our methodological ap- grees of blood pressure reductions.
proach did not analyze the influ- Moreover, in the analysis by the
ence on HF prevention of the dif- BPLTTC study56 the reduction of HF
ferences in blood pressure reductions incidence associated with different
achieved with the different thera- antihypertensive strategies was in-
pies. Therefore, the existence of a re- dependent of the extent of blood
WWW.ARCHINTERNMED.COM
390
 Table 4. Network Meta-analytical Estimates of the Effects of Different Comparisons Among Active Treatments
in Different Subanalyses

Subanalysis a

1 2 3 4 5

OR (95% CrI, OR (95% CrI, OR (95% CrI, OR (95% CrI, OR (95% CrI,
Comparisons 2.50%-97.50%) 2.50%-97.50%) 2.50%-97.50%) 2.50%-97.50%) 2.50%-97.50%)
CCBs vs placebo 0.86 (0.66-1.03) 0.84 (0.55-1.08) 0.62 (0.43-0.94) 0.84 (0.57-1.13) 0.64 (0.43-0.99)
ACEIs vs placebo 0.75 (0.61-0.90) 0.78 (0.59-1.04) 0.43 (0.28-0.68) 0.77 (0.58-1.02) 0.46 (0.29-0.78)
DDs vs placebo 0.64 (0.48-0.81) 0.63 (0.39-0.94) 0.42 (0.29-0.64) 0.61 (0.36-0.90) 0.43 (0.29-0.68)
CT vs placebo 0.68 (0.47-0.91) 0.87 (0.56-1.42) 0.53 (0.35-0.84) 0.88 (0.54-1.43) 0.60 (0.38-1.08)
BBs vs placebo 0.92 (0.67-1.19) 0.93 (0.49-1.44) 0.49 (0.25-1.08) 0.92 (0.49-1.25) NA
ARBs vs placebo 0.81 (0.67-0.97) 0.78 (0.58-1.10) 0.45 (0.25-0.93) 0.78 (0.58-1.01) 0.55 (0.34-0.97)
ABs vs placebo 1.29 (0.88-1.84) 1.28 (0.67-2.27) NA NA 0.92 (0.54-1.71)
ACEIs vs CCBs 0.88 (0.75-1.08) 0.93 (0.75-1.38) 0.69 (0.53-0.91) 0.92 (0.72-1.21) 0.72 (0.52-1.12)
DDs vs CCBs 0.75 (0.63-0.92) 0.74 (0.54-1.19) 0.66 (0.50-0.89) 0.72 (0.49-0.92) 0.70 (0.49-0.10)
DDs vs ACEIs 0.85 (0.70-1.03) 0.81 (0.53-1.15) 0.94 (0.61-1.35) 0.79 (0.50-1.15) 0.92 (0.61-1.20)
CT vs CCBs 0.79 (0.61-1.03) 1.05 (0.70-1.86) 0.84 (0.69-1.06) 0.10 (0.76-1.71) 0.94 (0.69-1.63)
CT vs ACEIs 0.90 (0.65-1.21) 1.12 (0.75-1.73) 1.23 (0.93-1.65) 1.05 (0.74-1.65) 1.30 (0.90-2.13)
CT vs DDs 1.06 (0.76-1.42) 1.38 (0.84-2.53) 1.20 (0.89-1.65) 1.33 (0.89-1.77) 1.34 (0.88-2.52)
BBs vs CCBs 1.07 (0.85-1.37) 1.11 (0.71-1.65) 0.78 (0.43-1.57) 1.06 (0.59-1.67) NA
BBs vs ACEIs 1.23 (0.93-1.56) 1.20 (0.67-1.77) 1.13 (0.61-2.29) 1.15 (0.64-2.29) NA
BBs vs DDs 1.44 (1.07-1.89) 1.50 (0.78-2.37) 1.15 (0.59-2.42) 1.43 (0.76-2.42) NA
BBs vs CT 1.36 (0.96-1.94) 1.07 (0.52-1.80) 0.92 (0.52-1.78) 1.09 (0.60-1.78) NA
ARBs vs CCBs 0.95 (0.81-1.19) 0.93 (0.73-1.35) 0.73 (0.43-1.32) 0.94 (0.67-1.32) 0.86 (0.63-1.39)
ARBs vs ACEIs 1.09 (0.92-1.31) 1.01 (0.74-1.29) 1.07 (0.61-1.95) 1.02 (0.75-1.95) 1.20 (0.75-1.98)
ARBs vs DDs 1.27 (1.02-1.63) 1.25 (0.81-1.93) 1.05 (0.59-2.06) 1.29 (0.84-2.06) 1.23 (0.80-2.22)
ARBs vs CT 1.20 (0.90-1.70) 0.90 (0.56-1.34) 0.87 (0.53-1.49) 0.97 (0.68-1.49) 0.92 (0.58-1.36)
ARBs vs BBs 0.89 (0.72-1.15) 0.84 (0.55-1.50) 0.94 (0.65-1.30) 0.94 (0.65-1.30) NA
ABs vs CCBs 1.51 (1.11-2.18) 1.51 (0.90-2.93) NA NA 1.44 (0.86-2.61)
ABs vs ACEIs 1.73 (1.23-2.41) 1.65 (0.88-2.82) NA NA 2.00 (1.08-3.55)
ABs vs DDs 2.03 (1.54-2.67) 2.03 (1.32-3.19) NA NA 2.05 (1.38-3.41)
ABs vs CT 1.91 (1.29-3.01) 1.48 (0.70-2.74) NA NA 1.54 (0.74-2.73)
ABs vs BBs 1.41 (1.97-2.12) 1.36 (0.75-3.06) NA NA NA
ABs vs ARBs 1.60 (1.10-2.25) 1.63 (0.89-2.99) NA NA 1.66 (0.83-3.06)

Abbreviations: ABs, -blockers; ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; BBs, -blockers; CCBs, calcium
channel blockers; CrI, credibility interval; CT, conventional treatment; DDs, diuretics; NA, not applicable; OR, odds ratio.
a Subanalysis 1: Network meta-analytical estimates of the effects of different comparisons among active treatments considering only studies with patients
without a history of heart failure. Subanalysis 2: Network meta-analytical estimates of the effects of different comparisons among active treatments considering
only studies with a predominance of male patients. Subanalysis 3: Network meta-analytical estimates of the effects of different comparisons among active
treatments considering only studies with a predominance of female patients. Subanalysis 4: Network meta-analytical estimates of the effects of different
comparisons among active treatments considering only studies with patients younger than 67 years. Subanalysis 5: Network meta-analytical estimates of the
effects of different comparisons among active treatments considering only studies with patients 67 years or older.

pressure reduction. Finally, the re-
cent analysis by Verdecchia et al37
demonstrated that a RAS inhibitor
based therapy is more effective than
CCB-based therapy in HF preven-
tion, independently of blood pres-
sure reductions.
The clinical heterogeneity of the
trials included in our analysis might
also have implications for the varia-
tions in HF incidence observed in the
studies, particularly when consid-
ering the variability in the diagnos-
tic criteria for HF assessment and the
different doses of active treatments
used in the various trials. In a pre-
vious published analysis,7 we dem-
onstrated that in hypertension trials,
a diagnosis of HF based on less rig-
orous criteria was not associated
with an overestimation of HF diag-
nosis. Previous analyses may sug-
gest that HF clinical diagnosis in
clinical trials is in agreement with
other different diagnostic criteria for
HF.58 Moreover, in our study no sig-
nificant heterogeneity in tradition-
ally performed meta-analyses was
detected, and the inconsistency of
the network meta-analysis was low.
This implies that differences among
studies did not have a substantial im-
pact on the results, which there-
fore seem to be consistent and reli-
able. Of course, this aspect does not
represent a bias within each of the
trials used for the analysis because
the same diagnostic criteria of HF
were applied to treatment arms.
Our analysis did not allow us to
specifically test the efficacy of dif-
ferent antihypertensive strategies
in patients with and without diabe-
tes mellitus, nephropathy, and a
history of myocardial infarction.
However, with regard to diabetes
mellitus, a substudy of the Antihy-
pertensive and Lipid-Lowering
Treatment to Prevent Heart Attack
Trial (ALLHAT)59 demonstrated the
superiority of diuretics compared
with ACE inhibitors and CCBs. Be-
cause heterogeneity and inconsis-
tency among trials were low, it is
likely that our results do not signifi-
cantly differ among these catego-
ries of patients. Further specific stud-
ies may be required to address this
issue.
Another possible limitation of
our analysis is the different sample
size among patients prescribed dif-
ferent antihypertensive therapies

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and a relative low overall incidence
of HF. Moreover, the multiple anti-
hypertensive treatment regimens in
the different trials could not be
specifically considered in the
analysis, so only first-line agents
effects were generally evaluated. Fi-
nally, the aim of our study was to
evaluate specifically the impact of dif-
ferent antihypertensive treatments in
the prevention of HF, while cardio-
vascular mortality, myocardial in-
farction, and stroke were not ad-
dressed. Therefore, it is important to
note that our results are limited to the
impact of antihypertensive treat-
ment in the prevention of HF, which
continues to be a major issue in hy-
pertension treatment.7 Indeed, none
of the antihypertensive drugs were
found to be clearly superior to oth-
ers with respect to cardiovascular
mortality beside the blood pressure
lowering effect.60 The different effi-
cacy of antihypertensive classes in HF
prevention reported in our study can-
not be extended to prevention of other
cardiovascular outcomes. In fact, with
regard to prevention of important out-
comes, such as nonfatal myocardial
infarction and stroke, there is evi-
dence that several classes are equally
effective. For instance, CCBs, which
were found to be less effective in HF
prevention in our analysis, are effec-
tive in stroke prevention.61
Altogether, our results seem to
support the use of diuretics and ACE
inhibitors (or ARBs) as first-line
therapy for HF prevention in hyper-
tension. Therefore, especially in pa-
tients at risk of developing HF, di-
uretics alone or in combination with
RAS-inhibiting drugs could be pre-
ferred. Further studies comparing dif-
ferent combination therapies are re-
quired to assess this latter hypothesis.
Unfortunately, the only trial address-
ing the effects of combination thera-
pies on outcomes (ACCOMPLISH44)
did not provide data on HF inci-
dence. Based on our current results,
it would have been interesting to com-
pare associations based on a diuretic
and ACE inhibitor vs combinations
of CCBs with ACE inhibitors in the
prevention of HF in patients with
hypertension.44
On the other hand, based on our
results and the results of other re-
cently published analyses,37,62 CCBs
and -blockers should not be pre-
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2011 American Medical Association. All rights reserved.
ferred as first-line agents in patients
with hypertension at higher risk to
develop HF.
In conclusion, our results seem
to support the use of diuretics and
RAS-inhibiting drugs alone or in
combination as first-line therapies
for HF prevention in hypertension.
These classes of drugs should be pre-
ferred to CCBs and -blockers in pa-
tients with hypertension at high risk
of developing HF. Further studies in
these clinical subgroups of hyper-
tensive patients, as well as studies
comparing different combination
therapies, may be helpful to cor-
roborate our findings.
Accepted for Publication: June 9,
2010.
Published Online: November 8, 2010.
doi:10.1001/archinternmed
.2010.427
Correspondence: Massimo Volpe,
MD, Department of Cardiology, Sec-
ond Faculty of Medicine, Univer-
sity of Rome La Sapienza, Via di
Grottarossa 1039, Rome, Italy
(massimo.volpe@uniroma1.it).
Author Contributions: Dr Volpe had
full access to all of the data in the
study and takes responsibility for the
integrity of the data and the accu-
racy of the data analysis. Study con-
cept and design: Sciarretta, Palano,
and Volpe. Acquisition of data: Sciar-
retta and Palano. Analysis and inter-
pretation of data: Tocci and Baldini.
Drafting of the manuscript: Sciar-
retta, Palano, Tocci, Baldini, and
Volpe. Critical revision of the manu-
script for important intellectual con-
tent: Volpe. Statistical analysis: Sciar-
retta and Baldini. Study supervision:
Sciarretta, Palano, Tocci, and Volpe.
Financial Disclosure: None re-
ported.
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ONLINE FIRST
The Difficult Task of Finding the Best
Antihypertensive Agent
T here are a few silent epi-
demics in medicine, and
heart failure certainly is one
of them. There are good reasons to
care about it: End-stage HF is more
deadly than most cancers, and only
recently has the idea of HF with pre-
served ejection fraction been trans-
formed into being accepted as dia-
stolic heart failure. Now diastolic HF
is interesting for 2 reasons: (1) it is
more common in womena sub-
group notoriously underdiag-
nosed, undertreated, and underrep-
resented in clinical trials; and (2)
from a global perspective, one of the
major risk factors for its develop-
ment is hypertension and the ensu-
ing hypertensive heart disease. Hy-
pertension, however, does not only
lead to diastolic HF but, from a
global perspective, it represents the
major risk factor for the develop-
ment of HF as such.1
In this issue of the Archives,
Sciarretta et al present the results
from a Bayesian network meta-
analysis with respect to possible
differences of individual antihyper-
tensive strategies regarding the
prevention of HF. They report on
223 313 individuals included in 26
antihypertensive trials. Of these,
186 378 individuals (83.5%) had
an established diagnosis of arterial
hypertension on inclusion in the
respective trials, and a total of
8554 individuals (3.8%) were diag-
nosed as having HF during the
course of their respective study.
The main result is that diuretics
and ACE inhibitors/ARBs were the
most effective treatment and
should therefore be considered
(REPRINTED) ARCH INTERN MED/ VOL 171 (NO. 5), MAR 14, 2011
Downloaded from www.archinternmed.com at Capes Consortia, on March 15, 2011
2011 American Medical Association. All rights reserved.
Effects of different regimens to lower blood pres-
sure on major cardiovascular events in older and
younger adults: meta-analysis of randomised trials.
BMJ. 2008;336(7653):1121-1123.
61. Verdecchia P, Reboldi G, Angeli F, et al. Angiotensin-
converting enzyme inhibitors and calcium chan-
nel blockers for coronary heart disease and stroke
INVITED COMMENTARY
first-line therapy with respect to
HF prevention.
There are several interesting as-
pects of this meta-analysis. First, the
most reassuring probably is the fact
thatwith the exception of - and
-blockersall active treatment
strategies were effective in prevent-
ing HF when compared with pla-
cebo. This is good news because pre-
vention of HF is not the only goal
of any antihypertensive treatment
and therefore not the only influ-
ence on our choice of drug. Also, this
corroborates the finding of a previ-
ous meta-analysis2 in which, with the
exception of -blockers, all other
drug classes showed comparable re-
duction of left ventricular mass.
Second, subanalyses did not show
significant alterations of these find-
ings when examining sex- or age-
dependent effects. This finding is in
line with those of other large-scale
analyses3,4 with respect to these con-
founders. Interestingly, in this study
the advantage of diuretics over ACE
inhibitors was smaller the higher the
percentage of women and elderly pa-
tients, as was the difference be-
tween CCBs and RAS inhibitors in
studies with younger and/or pre-
dominantly male patients. Again,
this is good news because in clini-
cal practice it should help to dimin-
ish any potential treatment bias with
respect to age and/or sex.
Third, and most interestingly, fol-
lowing the network diagram, CCBs,
ACE inhibitors, and ARBs could be
tested directly against all of the other
drugclasses,whereasdiureticsspecifi-
callycouldnot.Nowitisoneofthevir-
tues of network meta-analyses to be
WWW.ARCHINTERNMED.COM
394
prevention. Hypertension. 2005;46(2):386-
392.
62. Bangalore S, Wild D, Parkar S, Kukin M, Mes-
serli FH. Beta-blockers for primary prevention of
heart failure in patients with hypertension in-
sights from a meta-analysis. J Am Coll Cardiol.
2008;52(13):1062-1072.
able to get past this limitation, but at
least some of the evidence in favor of
diuretics is only indirect.
So, are we to abandon -block-
ers as an antihypertensive option al-
together and head toward use of di-
uretics? Before jumping to this
conclusion, we should remember that
especially in meta-analyses the choice
of subgroup and, most important, the
choice of end point will influence our
results. In a recent meta-analysis by
Law et al,5 -blockers, for example,
did not significantly reduce the over-
all incidence of coronary heart dis-
ease events. However, in persons with
preexisting coronary heart disease
there was even a special protective
effect. More important, there was sig-
nificant heterogeneity with respect to
HF prevention in that -blockers
without cardioselective properties
lacked any protective effect whereas
-blockers with cardioselective prop-
erties did not. Unfortunately, the
present study did not differentiate the
individual properties.
Furthermore, this picture changes
if one looks at stroke or mortality as
end points. Calcium channel block-
ers seem to be slightly more effec-
tive than the rest in preventing
stroke.5,6 This seems plausible be-
cause they also best reduce interin-
dividual variation in blood pres-
surea measure that indicates risk
of stroke independently of effects on
mean blood pressure.7 Having said
this, it should be noted that the level
of blood pressure reduction is im-
portant with respect to composite
cardiovascular end points, and larger
reductions in blood pressure seem
to lead to larger reductions in risk.6