Arguedas JA, Perez MI, Wright JM - PRIMARY CARE TIPS · Contact address: Jose Agustin Arguedas,...

Treatment blood pressure targets for hypertension (Review)

Arguedas JA, Perez MI, Wright JM

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library

2009, Issue 3

http://www.thecochranelibrary.com

Treatment blood pressure targets for hypertension (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

13DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

16AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

17REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

20CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 1 Total Mortality. . . . . . . . 29

Analysis 1.2. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 2 Cardiovascular mortality. . . . . 30

Analysis 1.3. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 3 Non-CV mortality. . . . . . . 30

Analysis 1.4. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 4 Total serious adverse events. . . . 31

Analysis 1.5. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 5 Myocardial infarction. . . . . . 31

Analysis 1.6. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 6 Strokes. . . . . . . . . . . 32

Analysis 1.7. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 7 Congestive heart failure. . . . . 32

Analysis 1.8. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 8 Major CV events. . . . . . . . 33

Analysis 1.9. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 9 End-stage renal disease. . . . . . 33

Analysis 1.10. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 10 Achieved systolic blood pressure. . 34

Analysis 1.11. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 11 Achieved diastolic blood pressure. 35

Analysis 1.12. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 12 Patients not achieving the target blood

pressure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Analysis 1.13. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 13 Withdrawals due to adverse effects. 36

Analysis 1.14. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 14 Number of antihypertensive drugs

needed. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36

36APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iTreatment blood pressure targets for hypertension (Review)


[Intervention Review]

Treatment blood pressure targets for hypertension

Jose Agustin Arguedas1, Marco I Perez2, James M Wright2

1Depto de Farmacologia Clinica, Facultad de Medicina, Universidad de Costa Rica, San Pedro de Montes de Oca, Costa Rica.2Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada

Contact address: Jose Agustin Arguedas, Depto de Farmacologia Clinica, Facultad de Medicina, Universidad de Costa Rica, San Pedro

de Montes de Oca, Costa Rica. [email protected]. (Editorial group: Cochrane Hypertension Group.)

Cochrane Database of Systematic Reviews, Issue 3, 2009 (Status in this issue: New)


DOI: 10.1002/14651858.CD004349.pub2

This version first published online: 8 July 2009 in Issue 3, 2009.

Last assessed as up-to-date: 30 September 2008. (Help document - Dates and Statuses explained)

This record should be cited as: Arguedas JA, Perez MI, Wright JM. Treatment blood pressure targets for hypertension. Cochrane

Database of Systematic Reviews 2009, Issue 3. Art. No.: CD004349. DOI: 10.1002/14651858.CD004349.pub2.

A B S T R A C T

Background

When treating elevated blood pressure, doctors need to know what blood pressure (BP) target they should try to achieve. The standard

of clinical practice for some time has been ≤ 140 - 160/ 90 - 100 mmHg. New guidelines are recommending BP targets lower than

this standard. It is not known whether attempting to achieve targets lower than the standard reduces mortality and morbidity.

Objectives

To determine if lower BP targets (≤ 135/85 mmHg) are associated with reduction in mortality and morbidity as compared with

standard BP targets (≤ 140-160/ 90-100 mmHg).

Search strategy

Electronic search of MEDLINE (1966-2008), EMBASE (1980-2008), and CENTRAL (up to June 2008); references from review

articles, clinical guidelines, and clinical trials.

Selection criteria

Randomized controlled trials comparing patients randomized to lower or to standard BP targets and providing data on any of the

primary outcomes below.

Data collection and analysis

Two reviewers (JAA, MIP) independently assessed the included trials and data entry. Primary outcomes were total mortality; total

serious adverse events; total cardiovascular events; myocardial infarction, stroke, congestive heart failure and end stage renal disease.

Secondary outcomes were achieved mean systolic and diastolic BP and withdrawals due to adverse effects.

Main results

No trials comparing different systolic BP targets were found. Seven trials (22,089 subjects) comparing different diastolic BP targets were

included. Despite a -4/-3 mmHg greater achieved reduction in systolic/diastolic BP, p< 0.001, attempting to achieve “lower targets”

instead of “standard targets” did not change total mortality (RR 0.92, 95% CI 0.86-1.15), myocardial infarction (RR 0.90, 95% CI

0.74-1.09), stroke (RR 0.99, 95% CI 0.79-1.25) , congestive heart failure (RR 0.88, 95% CI 0.59-1.32), major cardiovascular events

(RR 0.94, 95% CI 0.83-1.07), or end-stage renal disease (RR 1.01, 95% CI 0.81-1.27). The net health effect of lower targets cannot

be fully assessed due to lack of information regarding all total serious adverse events and withdrawals due to adverse effects in 6 of 7

1Treatment blood pressure targets for hypertension (Review)


mailto:[email protected]

http://www3.interscience.wiley.com/cgi-bin/mrwhome/106568753/DatesStatuses.pdf

trials. A sensitivity analysis in diabetic patients and in patients with chronic renal disease also did not show a reduction in any of the

mortality and morbidity outcomes with lower targets as compared to standard targets.

Authors’ conclusions

Treating patients to lower than standard BP targets, ≤140-160/90-100 mmHg, does not reduce mortality or morbidity. Because

guidelines are recommending even lower targets for diabetes mellitus and chronic renal disease, we are currently conducting systematic

reviews in those groups of patients.

P L A I N L A N G U A G E S U M M A R Y

Aiming for blood pressure targets lower than 140/90 mmHg is not beneficial

High blood pressure (BP) is linked to an increased risk of heart attack and stroke. High BP has been defined as any number larger

than 140 to 160 /90 to 100 mmHg and as a result this range of BPs has become the standard blood pressure target for physicians

and patients. Over the last five years a trend toward lower targets has been recommended by hypertension experts who set treatment

guidelines. This trend is based on the assumption that the use of drugs to bring the BP lower than140/90 mmHg will reduce heart

attack and stroke similar to that seen in some population studies. However, this approach is not proven.

This review was performed to find and assess all trials designed to answer whether lower blood pressure targets are better than standard

blood pressure targets. Data from 7 trials in over 22,000 people were analysed. Using more drugs in the lower target groups did achieve

modestly lower blood pressures. However, this strategy did not prolong survival or reduce stroke, heart attack, heart failure or kidney

failure. More trials are needed, but at present there is no evidence to support aiming for a blood pressure target lower than 140/90

mmHg in any hypertensive patient.

B A C K G R O U N D

Description of the condition

Epidemiological studies show a continuous direct relationship

between adverse cardiovascular events and blood pressure. (

MacMahon 1990; Prospective Studies). The relationship has a

greater slope with increasing levels of blood pressure. Furthermore

elevated arterial blood pressure is one of the major risk factors for

adverse cardiovascular events (Stokes 1987; Stamler 1993; Kannel

1996). Several mechanisms involved in the pathogenesis of hyper-

tension and hypertension-related cardiovascular disease have been

described (Oparil 2003). The primary goal of the management of

patients with elevated blood pressure is to maximize the reduction

in mortality and morbidity (Chalmers 1999; Oparil 2003; ESH-

ESC 2007). The lower threshold at which this relationship no

longer applies has not been definitively identified (Kannel 1996;

Prospective Studies). Any numerical cut-off value above which el-

evated blood pressure (hypertension) is defined is arbitrary. The

standard for diagnosis of arterial hypertension is based on consen-

sus recommendations, which attempt to predict the blood pres-

sure above which treatment provides more benefit than harm in a

population. At present this threshold has not been defined.

Description of the intervention

When treating elevated blood pressure there are two critical and

important questions: 1) what is the threshold of blood pressure

above which treatment is required? And 2) what target blood pres-

sure should be the surrogate goal of therapy? The first question

has been answered arbitrarily as between 140 and 160 mmHg

systolic and between 90 and 100 mmHg diastolic. The threshold

is becoming lower with advancing time. The second question is

the primary topic of this review and is affected by the answer to

the first question. It is the critical question that the practitioner

in clinical practice must answer to make treatment decisions. For

example, if the diastolic blood pressure target is less than or equal

to 90 mmHg and the diastolic blood pressure is documented as

92 mmHg then the practitioner would increase the antihyperten-

sive treatment by increasing the dose or adding another drug. If

the diastolic blood pressure is 90 mmHg or lower then the prac-

titioner would not change therapy. The standard target pressure

has generally been the arbitrary threshold blood pressure above

which treatment is recommended. Thus the standard target sys-

tolic blood pressure declined from a target of ≤ 160 mmHg to

a target of ≤ 140 mmHg. Similarly the diastolic blood pressure

target has decreased from ≤ 100 mmHg to ≤ 90 mmHg. In most

of the published randomized controlled trials designed to test the

benefits and harms of treatment titrated to achieve a specific blood

pressure goal, the target was either a SBP below 150 mmHg or 160



mmHg for isolated systolic hypertension trials, or a DBP below

90 mmHg or 100 mmHg for most other trials. (Wright 1999) It

is important to appreciate that 30% to 40% of patients in these

trials do not achieve the defined target, despite the requirement to

titrate doses and add up to 3 or 4 antihypertensive drugs.

How the intervention might work

Blood pressure targets lower than standard targets are becoming

more prevalent in recent clinical guidelines, (ADA 2008; Arauz-

Pacheco 2002) and thus in clinical practice. This trend toward “the

lower the pressure the better”, was expressed in an editorial accom-

panying the publication of the 2004 British Hypertension Soci-

ety guidelines (Laurent 2004), and assumes that treating to lower

blood pressure targets with antihypertensive drugs will achieve

a reduction in cardiovascular morbidity and mortality similar to

that seen in epidemiological observation studies. However, this

assumption remains unproven. Furthermore, it has been recently

demonstrated that achieving lower blood pressures does not pro-

vide an additional reduction in cardiovascular mortality and mor-

bidity in the ONTARGET 2008 trial. In this trial combination

of an ACE inhibitor and an angiotensin receptor blocker caused

greater blood pressure lowering, but did not reduce cardiovascular

endpoints.

Why it is important to do this review?

The importance of this review is emphasized by the blood pressure

targets recommended in guidelines published in recent years for

example:

1- The Joint National Committee-7 Report (JNC 7 2003) rec-

ommends “treating systolic BP and diastolic BP to targets that are

less than 140/90 mm Hg”, but “because most patients with hy-

pertension, especially those aged at least 50 years, will reach the

diastolic BP goal once systolic BP is at goal, the primary focus

should be on achieving the systolic blood BP goal” . “In patients

with hypertension with diabetes or renal disease, the BP goal is

less than 130/80 mm Hg”.

2- The 2003 World Health Organization (WHO) / International

Society of Hypertension (ISH) (WHO/ISH 2003) states that “the

primary goal of therapy is to lower systolic blood pressure, and

the pragmatic target of below 140 mmHg is reaffirmed”, and “the

diastolic blood pressure to about 90 mmHg”. There is also a small

section entitled “Targets for blood pressure lowering in hyperten-

sive patients at high risk” referring to patients with established

cardiovascular disease, diabetes, and renal insufficiency; for them

the conclusion is that “a target of <130/80 mmHg seems appro-

priate”.

3- Similar to the two previous guidelines, the Kidney Out-

comes Quality Initiative (K/DOQI) clinical practice guidelines (

K/DOQI 2004) recommends a blood pressure goal lower than in

uncomplicated hypertension, below 130/80 mmHg rather than

140/90 mmHg, in order to better preserve renal function in pa-

tients with renal disease.

4- The British Hypertension Society guidelines for hypertension

management 2004 (BHS 2004) states that “for most patients a

target of less than or equal to 140 mmHg systolic blood pressure

and less than or equal to 85 mmHg diastolic blood pressure is

recommended. For patients with diabetes, renal impairment or

established cardiovascular disease a lower target of less than or

equal to 130/80 mmHg is recommended”.

5- The 2007 European Society of Hypertension - European Society

of Cardiology guidelines for the management of arterial hyperten-

sion (ESH-ESC 2007) recommends that “blood pressure should

be reduced to at least below 140/90 mmHg (systolic/diastolic)

and to lower values, if tolerated, in all hypertensive patients”, and

“target BP should be at least < 130/80 mm Hg in diabetics and in

high risk patients, such as those with associated clinical conditions

(stroke, myocardial infarction, renal dysfunction, proteinuria)”.

6- The 2007 guidelines for the Treatment of Hypertension in the

Prevention and Management of Ischemic Heart Disease from The

American Heart Association “recommend a target BP of less than

130/80 mm Hg for individuals with demonstrated coronary artery

disease or risk equivalents (carotid artery disease, peripheral arterial

disease, abdominal aortic aneurysm), and for high-risk individuals,

defined as those with diabetes mellitus, chronic renal disease, or

a 10-year Framingham risk score of more than 10%” based on

epidemiological data, despite recognizing that “epidemiological

correlations cannot be used as proof of the value of treatment” (

AHA 2007).

7- Finally, the 2008 American Diabetes Association (ADA 2008)

standards of medical care states that “patients with diabetes should

be treated to a systolic blood pressure <130 mmHg”, and “to a

diastolic blood pressure < 80 mmHg”.

Attempting to achieve lower blood pressure targets has several con-

sequences. The most obvious is the need for large doses and in-

creased number of antihypertensive drugs. This has inconvenience

and economic costs to patients. More drugs and higher doses will

also increase adverse drug effects, which if serious could negate any

potential benefit associated with any achieved lower blood pres-

sure. There is also the potential that lowering blood pressure too

much may cause adverse cardiovascular events. Some observations

have suggested that excessive lowering of the diastolic blood pres-

sure with drugs is associated with an increased number of deaths

due to coronary heart disease (Farnett 1991). This relationship,

called the “J-curve phenomenon”, was initially described in hy-

pertensive patients with ischaemic heart disease, and the curve’s

inflection point was said to be around 85 mmHg (Cruickshank

1988). An increased risk of stroke was described with treated di-

astolic blood pressure lower than 65 mmHg as compared with

higher pressures (Voko 1999). More recently, a post-hoc subgroup

analysis of the HOT trial has raised concern about the possibility



that a J-shaped curve exists in smokers with elevated blood pres-

sure due to a significantly increased risk of total and cardiovas-

cular deaths, major cardiovascular events and stroke in smokers

randomized to diastolic blood pressures in the two lower blood

pressure target groups as compared with a target of less than or

equal to 90 mmHg (Zanchetti 2003; Lund-Johansen 2003).

In summary, the ideal blood pressure target in the treatment of pa-

tients with elevated blood pressure has not been established. Fur-

thermore, the assumption that lowering blood pressure by pharma-

cological means results in the same cardiovascular risk reduction

as that associated with similarly lower blood pressures recorded

in epidemiological studies needs to be tested in randomized con-

trolled trials. The only way to prove that a lower target is benefi-

cial is a trial where patients are randomized to different treatment

targets.

Our goal therefore was to identify all randomized controlled trials

where patients were randomized to blood pressure targets lower

than standard as compared with standard blood pressure targets.

The “lower target” category is defined as any systolic blood pressure

target less than or equal to 135 mmHg, and any diastolic blood

pressure target less than or equal to 85 mmHg. The “standard tar-

get” category is defined as a systolic blood pressure target less than

or equal to 140-160 mmHg, and a diastolic blood pressure target

less than or equal to 90-100 mmHg. We have chosen a range for

both target categories to be inclusive and made sure that the two

treatment groups are mutually exclusiv. Treatment targets higher

than 160 mmHg systolic and higher than 100 mmHg diastolic are

not eligible because they are considered to be inappropriately high.

The specific aim of this systematic review is to determine whether

treatment of patients with elevated blood pressure to “lower tar-

get” blood pressures is associated with reduction in mortality and

morbidity as compared with treatment to “standard target” blood

pressures.

O B J E C T I V E S

Primary objective

To determine if there is a reduction in total mortality and morbid-

ity associated with treatment of blood pressure to “lower targets” as

compared with “standard targets” in the management of patients

with elevated arterial blood pressure. “Lower targets” are defined

as blood pressure targets ≤ 135/85 mmHg. “Standard targets” are

defined as blood pressure targets ≤ 140-160/90-100 mmHg.

Secondary objectives

1.To determine if there is a change in mean achieved systolic and

diastolic blood pressure associated with “lower targets” as com-

pared with “standard targets” in patients with elevated blood pres-

sure.

2.To determine if there is a change in withdrawals due to adverse

events with “lower targets” as compared with “standard targets”,

in patients with elevated blood pressure.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Only randomized controlled clinical trials will be considered. Tri-

als cannot be blinded as to blood pressure targets because the treat-

ing physicians must know the target to which each patient has

been assigned in order to make the proper adjustment in the ther-

apy to achieve the blood pressure goal.

All trials that reported any of the outcomes will be included. Trials

will not be limited by any concomitant disease, other factor or

baseline cardiovascular risk. There will be no language restriction.

Types of participants

Participants must be adults, with elevated blood pressure docu-

mented in a standard way on at least 2 occasions, or adults already

receiving treatment for elevated blood pressure.

Since any numerical definition of elevated blood pressure is arbi-

trary, we accepted any trial where patients were randomised to the

two targets described below and did not require that the patients

at baseline have any specific blood pressure.

Types of interventions

Trials were included if individuals were randomized to a “lower”

target systolic/diastolic blood pressure (≤ 135/85 mmHg) as com-

pared with a “standard” target blood pressure (≤ 140-160 /90-

100 mmHg).

Types of outcome measures

Primary Outcomes:

1. All-cause mortality plus cardiovascular and non-cardio-

vascular mortality separately

2. Total serious adverse events

3. Cardiovascular serious adverse events combined and

separately: myocardial infarction, stroke, congestive

heart failure, end-stage renal failure.

4. All other serious adverse events.

Secondary Outcomes:

1. Systolic blood pressure achieved

2. Diastolic blood pressure achieved

3. Proportion of patients not achieving the target blood

pressure levels

4. Withdrawals due to adverse effects



5. Number of antihypertensive drugs needed per patient.

Search methods for identification of studies

The search strategy used the standard Cochrane strategy for ran-

domized controlled trials plus the following terms: hypertension,

arterial hypertension, high blood pressure, elevated blood pres-

sure, hypertensive patients, target level, target blood pressure, tar-

get systolic blood pressure, target diastolic blood pressure, inten-

sive treatment, intensive blood pressure treatment, intensive con-

trol, intensive blood pressure control, tight control, tight blood

pressure control, strict control, strict blood pressure control. A de-

tailed description of the search is provided in Appendix 1.

The following databases were reviewed:

• MEDLINE from 1966 to April 2008

• EMBASE from 1980 to April 2008

• CENTRAL (Cochrane Central Register of Controlled

Trials) up to April 2008

Reference lists from review articles (Arauz-Pacheco 2002; Aung

2003; Cruickshank 2000; Hansson 2000; Hansson 2001; Izzo

2000; Prisant 2003; Snow 2003; Vijan 2003), clinical guidelines

(ADA 2008; ESH-ESC 2007, AHA 2007, JNC 7 2003; ESH-

ESC 2007; WHO/ISH 2003; JNC 7 2003; McAlister 2002), and

clinical trials were also browsed for any study that may have not

been identified by the search strategy.

Data collection and analysis

The outcomes to be compared and the trial eligibility criteria were

specified before the result of any contributing trial was known. Two

independent reviewers (JAA, MIP) assessed and determined which

trials were included or excluded. Discrepancies were resolved by

discussion or by a third individual if necessary.

Data from the trials was extracted independently by 2 reviewers

(JAA, MIP) from the included trials. For the synthesis and analysis

of the data, Cochrane review manager software, RevMan 5, was

used. Quantitative analyses of outcomes were based on intention-

to-treat principle. Risk ratio (RR) and a fixed effects model were

used to combine outcomes across trials. A standard chi-square

statistic was used to test for heterogeneity of treatment effect be-

tween the trials (Lau 1997). An I2 value >50% was considered in-

dicative of significant heterogeneity. A random effects model was

used to test for statistical significance when significant heterogene-

ity existed (Lau 1997; Whitehead 1991). An alpha value of < 0.05

was accepted as statistically significant for the primary outcomes,

however, in order to avoid an inflated chance of a type I error due

to the multiple comparisons performed, an alpha value of < 0.01

was required for all secondary outcomes and sensitivity analyses.

The assessment of risk of bias of the trials was based on considering

the six potential sources of systematic bias in trials that need to be

assessed for a review according to the Cochrane Reviewers’ Hand-

book: sequence generation, allocation concealment, blinding, loss

to followup, selective reporting and other.

The following sensitivity analyses were performed:

a.To increase the difference in blood pressure between the “lower”

and the “standard” targets, a sensitivity analysis was performed

comparing only those trials where the difference in the targets was

at least 10 mmHg.

b.Based on the guidelines recommending lower blood pressure

targets in patients with concomitant diabetes mellitus or chronic

renal disease a sensitivity analysis was performed in patients with

diabetes mellitus at baseline and in patients with chronic renal

disease at baseline.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies; Characteristics of ongoing studies.

The majority of the references identified in the search were rejected

after reading the abstract or the complete report, because most of

them were review articles or cohort studies. This left 24 references,

which appeared to be appropriate for this systematic review.

The detailed analysis of those 24 papers revealed:

• 7 randomized controlled trials from 18 publications

which met the inclusion criteria and reported data for

this systematic review

• 6 randomized controlled trials which had to be excluded

for various reasons (see Characteristics of excluded

studies).

Characteristics of included studies

1. Modification of Diet in Renal Disease trial (MDRD):

a. Methods:

Randomized, open label, controlled trial. Patients were random-

ized to two different blood pressure targets and also to two differ-

ent protein diets.

Blood pressure was measured monthly. The time of day when

blood pressure was measured was not provided. The same nurse

or technician took the sitting blood pressure three times in a quiet

room, and the average of the last two was used as the blood pressure

for the visit.

The recommended antihypertensive regimen was an ACE in-

hibitor with or without a diuretic agent. A calcium channel blocker

and other medications could be added as needed.

The mean follow-up was 2.2 years.



b. Participants:

840 patients with various chronic renal diseases were included.

Chronic renal disease was established as a creatinine clearance of

less than 70 ml per minute per 1.73 m2 of body surface area.

To be included the participants had to be between 18 and 70

years old, and have a mean arterial pressure of 125 mmHg or

less. Mean arterial pressure was calculated as one third of systolic

blood pressure plus two thirds of diastolic blood pressure. Arterial

hypertension was not an inclusion criterion, but 86% of included

participants were described as hypertensives; how hypertension

was defined was not provided.

The main exclusion criteria were pregnancy, insulin requiring dia-

betes mellitus, weight severely over or under normal, and urinary

protein excretion exceeding 10 grams per day.

c. Interventions:

Patients were randomly assigned to a “usual”- or “low-blood pres-

sure” group. “Usual blood pressure” was defined as a mean arte-

rial pressure ≤ 107 mmHg (approximately 140/90 mmHg) for

patients < 60 years of age and ≤ 113 mmHg (approximately ≤

160/90 mmHg) for patients > 60 years, whereas “low blood pres-

sure” was defined as a mean arterial pressure ≤ 92 mmHg (ap-

proximately ≤ 125/75 mmHg) for patients < 60 years and ≤ 98

mmHg (approximately ≤ 135/80 mmHg) for > 60 years.

d. Outcomes:

The rate of change in glomerular filtration rate was the primary

outcome measure. Other recorded outcomes were death, end-stage

renal disease requiring dialysis or transplantation, and other serious

medical conditions.

e. Additional notes:

Patients were also randomized to usual- or low-protein diet.

2. Toto et al (Toto):

a. Methods:

The study was a 2 X 2 factorial, randomized controlled trial. Pa-

tients were randomized to either placebo or enalapril and to either

“strict” or “conventional” blood pressure ranges. Before random-

ization, diastolic blood pressure was lowered to 80 mmHg or less

over a 3 to 6 months initial assessment period. Patients able to

achieve that target were randomized and included in the study.

Blood pressure was measured in the supine position with a mercury

sphygmomanometer after a minimum of 5 minutes rest. The time

of day when blood pressure was measured was not provided. Three

measurements were taken at 2-minute intervals. The mean of those

measurements was used.

Patients were randomly assigned to receive enalapril or placebo. In

addition, to achieve the target diastolic blood pressure a stepped-

care approach with antihypertensive medications was used: a di-

uretic was the initial drug, followed by a beta-blocker, hydralazine

or minoxidil, and clonidine, alpha-methyldopa or an alpha-1

blocker. With the exception of the diuretic, the maximum dose of

each agent was used before moving to the next step. In patients

assigned to “conventional” group, diastolic blood pressure was al-

lowed to increase to the 85 to 95 mmHg range, whereas it had to

be maintained between 65 and 80 mmHg in those assigned to the

“strict” group.

Mean follow-up was 40.5 ± 1.8 months in the “strict” group, and

42.2 ± 2.1 months in the “conventional” group.

b. Participants:

87 patients with hypertensive nephrosclerosis were initially con-

sidered for the trial. Their age ranged from 25 to 73 years. The

inclusion criteria were a diastolic blood pressure higher than or

equal to 95 mmHg, a serum creatinine greater than 1.6 mg/dL but

lower than 7.0 mg/dL and a glomerular filtration rate less than or

equal to 70 ml/min/1.73m2, history of long-standing hyperten-

sion, an inactive urine sediment, a urinary protein excretion rate

lower than 2 grams per day, and no physical or biochemical evi-

dence for a humoral-mediated cause for hypertension. Exclusion

criteria were diabetes mellitus, a recent history (in the previous 4

months) of malignant hypertension, stroke or myocardial infarc-

tion, acute renal failure of any cause, analgesic abuse, polycystic

kidney disease and other causes of chronic renal disease, evidence

of significant hepatic impairment, mental incapacity, pregnancy

or lactation, primary hyperaldosteronism, renovascular hyperten-

sion, pheochromocytoma.

Based on the initial assessment period, 77 patients were classified

as “responders” and 10 patients were “non-responders”. Since they

were not randomized, “non-responder” patients were not included

in this study.

c. Interventions:

“Responder” patients were randomized to either placebo or

enalapril, in a double-blind design. They were also randomized

to either “strict” or “conventional” blood pressure ranges in an

open label design. “Strict” was defined as a diastolic blood pressure

lower than 80 mm Hg, whereas “conventional” was defined as a

diastolic pressure between 85 and 95 mm Hg.

After randomization, the blinded study drug was titrated to max-

imum allowable dose and the unblinded antihypertensive agents

were back-titrated as needed to achieve and maintain blood pres-

sure control.

d. Outcomes:

The primary outcome was the rate of decline in glomerular fil-

tration rate, measured by the renal clearance of I125 -iothalamate.

Other outcomes were death, end-stage renal disease and 50% de-

cline in glomerular filtration rate or doubled serum creatinine

(from baseline).


Assignment to enalapril versus placebo did not change the results

of the blood pressure control.

The exclusion of patients not able to achieve the lower target

during the pre-randomization period is a limitation of the trial

as the results are only relevant to “responders” as defined in this

study.

3. Hypertension Optimal Treatment trial (HOT):



a. Methods:

Randomized, open label, 3 X 2 factorial design controlled trial,

with blinded endpoint evaluation (PROBE) design. An Indepen-

dent Clinical Event Committee, masked to the group allocation,

evaluated all clinical events.

Blood pressure was measured three times, by an oscillometric semi-

automatic device, with the patient in the sitting position after 5

minutes of rest. The time of day when blood pressure was mea-

sured was not specified.

Patients were randomly assigned to one of three diastolic blood

pressure target groups. Block randomization was performed tak-

ing into consideration the following baseline variables: age, sex,

previous antihypertensive therapy, smoking, previous myocardial

infarction, previous coronary heart disease, previous stroke and

diabetes mellitus.

All patients were treated with the same drugs in the same order. The

following were the required steps allowed to attempt to achieve

the target blood pressure:

Step 1- felodipine 5 mg once a day

Step 2- a starting dose of an angiotensin converting enzyme (ACE)

inhibitor or beta-blocker was added

Step 3- the dose of felodipine was increased to 10 mg once a day

Step 4- the dose of the ACE inhibitor or the beta-blocker was

doubled

Step 5- a diuretic was added

The average follow-up was 3.8 years.

b. Participants:

19193 patients with elevated blood pressure, aged 50-80 years,

were initially included, but the study population was composed of

18790 patients. Four hundred and three patients were excluded

early in the trial because of the suspicion of incorrect inclusion.

Baseline diastolic blood pressure between 100 mmHg and 115

mmHg on two occasions, at least one week apart, was an inclusion

criterion.

The main exclusion criteria were malignant hypertension, sec-

ondary hypertension, diastolic blood pressure > 115 mmHg,

stroke or myocardial infarction within 12 months prior to ran-

domization, decompensated congestive heart failure, other serious

concomitant diseases which could affect survival during the next

2-3 years, patients who required a beta-blocker, ACE inhibitor

or diuretic for reasons other than hypertension, patients who re-

quired antiplatelet or anticoagulant therapy, and insulin treated

diabetics.

c. Interventions:

Patients were randomly assigned to one of three diastolic blood

pressure target groups: ≤ 90 mmHg, ≤ 85 mmHg, or ≤ 80 mmHg

and to low dose acetylsalicylic acid 75 mg or placebo.

d. Outcomes:

The outcomes measured were: total and cardiovascular mortality,

all (fatal and non-fatal) myocardial infarctions including silent in-

farctions, all (fatal and non-fatal) strokes, and major cardiovas-

cular events (all myocardial infarctions plus all strokes plus other

cardiovascular deaths).


24% of all investigators’ reported events were rejected by the Clin-

ical Event Committee.

4. Appropriate Blood Pressure Control in Diabetes trial H (

ABCD (H))

a. Methods:

Randomized, open label clinical trial. Patients were randomized to

“intensive” versus “moderate” blood pressure control. They were

also allocated to either nisoldipine or enalapril as the initial an-

tihypertensive medication. If the target blood pressure was not

achieved with increasing doses, then open-label antihypertensive

medications were added in a step-wise fashion, initially with meto-

prolol, then hydrochlorothiazide or additional drugs, but neither

a calcium channel blocker nor an ACE inhibitor.

Blood pressure recordings were obtained at the time when peak

drug levels were expected and were an average of three seated

readings obtained at each visit.

An independent end point committee, which was blinded to the

study intervention arms, reviewed all cardiovascular events.

The follow-up period was 5 years.

b. Participants:

Four hundred and seventy patients, between the ages of 40 and 74

years, with type 2 diabetes mellitus and a diastolic blood pressure

equal to or higher than 90 mm Hg were included.

Exclusion criteria included myocardial infarction or a cerebrovas-

cular accident within the previous 6 months, coronary artery by-

pass surgery within the previous 3 months, unstable angina pec-

toris within the previous 6 months, congestive heart failure NYHA

class III or IV, a demonstrated absolute need for ACE inhibitors

or CCB, and a serum creatinine level > 3 mg/dL.

c. Interventions:

Patients were randomized into two treatment arms consisting of

“intensive” treatment with a diastolic blood pressure goal of 75

mmHg, and “moderate” treatment with a diastolic blood pressure

goal of 80-89 mmHg.

d. Outcomes:

The primary end point was the change in 24-hour creatinine

clearance. Secondary end points included cardiovascular events,

retinopathy, clinical neuropathy, and urinary albumin excretion.


Patients were also randomized to either nisoldipine or enalapril as

the initial antihypertensive medication. A test for interaction be-

tween study-drug assignment and blood-pressure-control strategy

showed that no interaction was present.

5. Appropriate Blood Pressure Control in Diabetes trial N (

ABCD (N))

a. Methods:

Randomized, open label controlled clinical trial. Patients were ran-

domized to “intensive” (10 mm Hg below the baseline diastolic

blood pressure) versus “moderate” (80-89 mm Hg) diastolic blood

pressure control.



Patients in the “moderate” therapy group were given placebo,

whereas patients randomized to “intensive” therapy received ei-

ther nisoldipine or enalapril in a blinded manner as the initial

antihypertensive medication. If the target blood pressure was not

achieved with increasing doses, then open-label antihypertensive

medications were added in a step-wise fashion, initially with meto-

prolol, then hydrochlorothiazide or additional drugs, but not a

calcium channel blocker nor ACE inhibitor.

Blood pressure recordings were obtained at the time when peak

drug levels were expected and were an average of three seated

readings obtained at each visit.

An independent end point committee, which was blinded to the

study intervention arms, reviewed all cardiovascular events. The

follow-up period was 5 years.

b. Participants:

Four hundred and eighty patients, between the ages of 40 and 74

years, with type 2 diabetes mellitus were included. All of them had

a baseline diastolic blood pressure between 80 and 89 mmHg and

were not receiving antihypertensive medications at the random-

ization visit.

The main exclusion criteria were: myocardial infarction or cere-

brovascular accident within the previous 6 months, coronary artery

bypass surgery within the previous 3 months, unstable angina pec-

toris within the previous 6 months, congestive heart failure NYHA

class III or IV, a demonstrated absolute need for ACE inhibitors

or CCB, and a serum creatinine level > 3 mg/dl.

c. Interventions:

Patients were randomized into two treatment arms consisting of

“intensive” or “moderate” treatment. The goal in the “intensive”

treatment group was to achieve a decrease of 10 mmHg below

baseline in diastolic blood pressure (i.e. 70 to 79 mmHg), whereas

the goal in the “moderate” treatment group was to maintain a

diastolic blood pressure between 80 and 89 mmHg.

d. Outcomes:

The primary end point was the change in 24-hour creatinine

clearance. Secondary end points included cardiovascular events,

retinopathy, clinical neuropathy, and urinary albumin excretion.


Patients randomized to intensive therapy received either nisoldip-

ine or enalapril in a blinded manner as the initial antihypertensive

medication. Patients in the moderate group were given placebo.

However, by the end of the study 117 patients (48%) initially ran-

domized to moderate therapy required treatment (systolic blood

pressure > 159 and/or diastolic blood pressure > 89 mmHg on

two consecutive visits). These individuals were started on either

nisoldipine or enalapril according to randomization at entry into

the study with the goal of maintaining the systolic blood pressure

< 160 mmHg and diastolic blood pressure < 90 mmHg.

A test for interaction between study-drug assignment and blood-

pressure-control strategy showed that no interaction was present

6. African American Study of Kidney Disease and Hyperten-

sion trial (AASK)

a. Methods

Randomized 3 x 2 factorial trial. Participants were randomly as-

signed to 1 of 2 mean arterial pressure goals, and to initial treatment

with a beta-blocker (metoprolol), an ACE inhibitor (ramipril) or

a dihydropyridine calcium channel blocker (amlodipine). Open-

label agents were added sequentially to achieve the blood pressure

goal.

Three consecutive seated blood pressure readings were measured

with a sphygmomanometer after at least 5 minutes rest, with the

mean of the last 2 readings recorded. The time of day when blood

pressure was measured was not reported.

All cardiovascular events, including cardiovascular deaths and

hospitalizations for myocardial infarctions, strokes, heart failure,

revascularization procedures, and other hospitalized cardiovascu-

lar events were reviewed and classified by a blinded end points

committee.

The follow-up was 3 to 6.4 years.

b. Participants

One thousand and ninety four participants (18 to 70 years old),

self-identified as African-Americans, with diastolic blood pressure

higher than 94 mmHg were included in the study. They also had

to have a glomerular filtration rate between 20 and 65 ml/min

per 1.73 m2, and no identified cause of renal disease other than

elevated blood pressure.

Exclusion criteria were known history of diabetes mellitus, urinary

protein to creatinine ratio of more than 2.5, accelerated or ma-

lignant hypertension within 6 months, secondary hypertension,

evidence of non-BP-related causes of chronic kidney disease, se-

rious systemic disease, clinical congestive heart failure, or specific

indication for or contraindication to a study drug procedure.

c. Interventions

Participants were randomized to a “usual” mean arterial pres-

sure goal of 102 mmHg (approximately 135/85 mmHg) to 107

mmHg (approximately 140/90 mmHg) or to a “lower” mean arte-

rial pressure goal of less than or equal to 92 mmHg (approximately

<125/75 mmHg).

d. Outcomes

The primary analysis in the trial was based on the rate of change in

glomerular filtration rate (GFR slope), assessed by renal clearance

of I125 iothalamate.

The protocol also designated a main secondary composite out-

come, which included any of the following: a confirmed reduction

in GFR by 50% or by 25 mL/min per 1.72 m2 from the mean of

the two baseline GFRs; end stage renal disease (dialysis or trans-

plantation); or death.

7. Renoprotection in patients with non-diabetic chronic renal

disease (REIN-2)

a. Methods

Multicentre, randomized, controlled trial. Before randomization,



patients were treated with antihypertensive drugs (apart from ACE

inhibitors, angiotensin-II-receptor antagonists, and dihydropyri-

dine calcium-channel blockers) to maintain diastolic blood pres-

sure at less than 90 mm Hg. Participants were then randomly as-

signed to either conventional blood-pressure control (diastolic <

90 mm Hg, irrespective of systolic blood pressure) or intensified

blood-pressure control . To achieve the intensified blood-pressure

level, patients received add-on therapy with the dihydropyridine

calcium-channel blocker felodipine 5 mg/day, and up-titrated the

dose after a week to 10 mg/day according to blood-pressure re-

sponse. In both arms up- and down-titration of concomitant drugs

was allowed to maintain the target blood pressure and to avoid

symptomatic hypotension.

Blood pressure was measured 1 week, 2 weeks, and 3 weeks after

randomization, and every 3 months thereafter. Additional mea-

surements were done within 1 week after any change in antihy-

pertensive therapy.

The blood pressure was the mean of three values taken 2 minutes

apart, after 5 minutes rest in the sitting position, on the same arm

by a standard sphygmomanometer. The time of day when blood

pressure was measured was not reported.

The median follow-up was 19 months.

b. Participants

Three hundred and thirty eight patients, who had non-diabetic

nephropathy and persistent proteinuria, and who had not received

ACE-inhibition therapy for at least 6 weeks. Persistent proteinuria

was defined as urinary protein excretion exceeding 1 g per 24 h for

at least 3 months without evidence of urinary-tract infection or

overt heart failure (NYHA class III-IV). Patients with proteinuria

of 1-3 g per 24 h were included if their creatinine clearance was

less than 45 mL/min per 1.73 m2; those with a proteinuria of 3

g per 24 h or more were included if their creatinine clearance was

less than 70 mL/min per 1.73 m2.

Exclusion criteria were treatment with corticosteroids, non-

steroidal antiinflammatory drugs, or immunosupressive drugs;

acute myocardial infarction or cerebrovascular accident in the pre-

vious 6 months, severe uncontrolled hypertension, evidence or

suspicion of renovascular disease, obstructive uropathy, type 1 dia-

betes mellitus, collagen disease, cancer, higher serum aminotrans-

ferase concentrations, or chronic cough, history of allergy, or poor

tolerance to ACE inhibitors or dihydropiridine calcium-channel

blockers, pregnancy, breastfeeding.

c. Interventions

Participants were randomly assigned to either “conventional” (di-

astolic < 90 mm Hg) or intensified (systolic/diastolic < 130/80

mm Hg) blood-pressure control.

d. Outcomes

The primary outcome was progression to end-stage renal disease.

Other outcomes were GFR decline, residual proteinuria, fatal and

non-fatal cardiovascular events.

e. Additional notes

After the first interim analysis, done as per protocol, an indepen-

dent adjudicating panel stated that the study had to be stopped

for futility because the outcomes were similar in both arms despite

more effective blood-pressure reduction in the intensified blood-

pressure control arm.

Excluded studies

Treat Blood Pressure Better Study or BBB for Behandla

Blodtryck Bättre in Swedish (BBB)

Randomized, open label, controlled trial. Two thousand one hun-

dred and twenty seven hypertensive patients aged 45-67 years were

included. To be included, they had to be receiving antihyperten-

sive treatment, and their treated diastolic blood pressures on at

least three consecutive visits were in the range between 90 and 100

mmHg.

Patients were randomized to “intensified” or “unchanged” therapy.

In the group allocated to “intensified” treatment, the purpose was

to reduce the diastolic blood pressure to less than or equal to 80

mmHg. In the group allocated to “unchanged” therapy, the aim

was to maintain the diastolic blood pressure in the range of 90-

100 mmHg.

This study, which showed no difference in morbidity or mortal-

ity outcomes between the target groups, was excluded from this

meta-analysis because the number of patients randomized to each

treatment arm was not reported and an attempt to obtain the in-

formation from the authors was unsuccessful.

Hypertension in Diabetes Study IV (HDS)

Seven hundred and fifty eight hypertensive diabetic patients were

included in this randomized controlled trial. The mean blood

pressure at entry was 160/94 mmHg. This trial compared “tight

control” of blood pressure aiming at a blood pressure of < 150/85

mmHg, with “less tight control” aiming at a blood pressure of <

180/105 mmHg.

This study was excluded from the meta-analysis because the target

for systolic blood pressure in the “tight control” group was higher

than that stated in our protocol. In addition and more impor-

tantly the targets for both systolic and diastolic blood pressure in

the “less tight control group” were much higher than specified in

the protocol for this systematic review. These “less tight” pressures

are similar to the escape criteria in most placebo or no treatment

controlled antihypertensive trials, and much higher than conven-

tional treatment goals prevalent since the 1970’s.

Furthermore, it is likely that participants in this trial represent a

subgroup of patients included in UKPDS 38, because the study

design is similar and the authors are the same.

United Kingdom Prospective Diabetes Study (UKPDS)

One thousand one hundred and eighty four hypertensive diabetic

patients were included in this randomized controlled trial com-



paring “tight control” of blood pressure with “less tight control”.

The “tight control”group aimed at a blood pressure of < 150/85

mmHg. In the “less tight control” group the target was originally

set at < 200/105 mmHg, but was reduced to < 180/105 mmHg

5 years after the start of the study.

This study was excluded from the meta-analysis because the target

for systolic blood pressure in the “tight control” group was higher

than that stated in our protocol. In addition and more impor-

tantly the targets for both systolic and diastolic blood pressure in

the “less tight control group” were much higher than specified in

the protocol for this systematic review. These “less tight” pressures

are similar to the escape criteria in most placebo or no treatment

controlled antihypertensive trials, and much higher than conven-

tional treatment goals prevalent since the 1970’s.

Lewis et al (Lewis)

Randomized controlled trial. 129 patients with type 1 diabetes

mellitus and diabetic nephropathy were randomly assigned to a

mean arterial blood pressure (MAP) goal less than or equal to 92

mmHg or a MAP goal between 100 and 107 mmHg.

The primary outcomes in this trial were surrogate markers of re-

nal function in order to determine the impact of assignment to

different levels of blood pressure control on the course of type 1

diabetic nephropathy.

It was excluded because it did not provide data on any of the

outcomes defined for this systematic review. The only reported

clinical event was end-stage renal disease (ESRD). Twelve patients

reached ESRD, but the distribution of those patients according

to the blood pressure target assigned was not provided. It also

reported achieved blood pressure but as mean arterial pressure, not

as systolic and/or diastolic blood pressure achieved. The authors

did not respond to written requests for the additional information

required for this review.

Steno-2 study (Steno-2)

This study was a randomized, open, parallel study. Eighty patients

with type-2 diabetes were randomly assigned to receive conven-

tional treatment in accordance with national guidelines in Den-

mark, and 80 patients to receive intensive treatment. The inten-

sive treatment arm included stepwise implementation of behavior

modification and pharmacologic therapy that targeted more strict

values for systolic blood pressure (< 140 mmHg during the initial

7 years and < 130 mmHg during the last 2 years in the intensive

treatment arm vs < 160 mmHg and < 135 mmHg respectively

in the conventional treatment arm) and diastolic blood pressure

(< 85 mmHg during the initial 7 years and < 80 mmHg during

the last 2 years in the intensive treatment arm vs < 95 mmHg

and 85 mmHg respectively in the conventional treatment arm),

but also more strict targets for glycosylated hemoglobin, fasting

total serum cholesterol and fasting serum triglycerides, treatment

with an ACE inhibitor irrespective of blood pressure, and aspirin

therapy for patients with peripheral artery disease, and also aspirin

therapy for patients without coronary artery disease or without

peripheral artery disease during the last 2 years.

This trial was not included because the multifactorial intervention

prevented any inference as to whether any difference in clinical

outcomes could be attributed to a lower blood pressure target or

to any of the other combined interventions.

SANDS (SANDS)

This was a randomized, open-label, blinded-to-end-point study

performed in 499 American Indians with diabetes and no prior

cardiovascular events. The primary end point was progression of

atherosclerosis determined by ultrasonographic measurement of

the common carotid artery intimal medial thickness. The inci-

dence of clinical events was a secondary outcome. Patients were

randomized to standard or aggressive treatment groups. The stan-

dard treatment was designed as a systolic blood pressure target of

130 mm Hg or lower and LDL-C target of 100 mg/dL or lower,

whereas aggressive treatment was defined as a systolic blood pres-

sure target of 115 mm Hg or lower and LDL-C target of 70 mg/dL

or lower.

This trial was not included because the dual intervention would

not allow discrimination of events specifically associated with a

lower blood pressure target. Besides, both systolic blood pressure

targets in this trial were within the values considered as “lower

targets” in our systematic review.

Risk of bias in included studies

Three of the multi-site studies (HOT, MDRD, and REIN-2)

reported that randomization was done at the study coordinating

center.

Blocked randomization was mentioned in MDRD, HOT, REIN-

2, ABCD (H) and ABCD (N). Randomization was computer-

generated in HOT, but the method of randomization was not

described in the other 6 trials.

In Toto, the exclusion of patients not able to achieve the lower

target during the prerandomization period is a limitation of the

trial as the results are only relevant to “responders” as defined in

that study.

None of the trials was blinded to blood pressure goal because of

the need to titrate treatment to achieve the specific target.

In HOT, 486 patients (2.6%) were lost to follow-up; they were

equally distributed between the three target arms. The AASK re-

ported that 0 patients withdrew from the study. In the MDRD

trial 14 patients (1.6%) were lost to follow-up, but their distribu-

tion according to target is not provided. In REIN-2, 9 patients (5

in the conventional control group and 4 in the intensified control

group) were lost to follow-up (1 and 2 of them never took study

drugs respectively). No specific information about drop-outs was

provided in the remaining trial reports.

HOT, ABCD (H), ABCD (N), and AASK trials specifically stated

that an independent clinical event committee, masked to the group

allocation, evaluated all clinical events. Such information was not

mentioned in the other two trial reports.



Effects of interventions

The results are discussed according to the hierarchy of outcomes

previously mentioned. Several outcomes were not reported in the

published trials. Missing information was requested by e-mail sent

to the main authors of each trial, but it was not obtained. The

authors of the AASK trial replied that they are going to include the

missing information in a paper they are preparing to submit for

publication. There was no reply from the authors of the remaining

trials.

Some additional information, not included in the original pub-

lished reports, was provided by the Blood Pressure Lowering Treat-

ment Trialists’ Collaboration (BPLTTC 2003). That information

is described for each outcome.

1. Primary outcomes

1.1 Mortality

1.1.1 Total mortality

Information from 6 of the 7 trials was available for this outcome.

The mortality data from the Modification of Diet in Renal Disease

Study (MDRD) could not be included for the following reasons.

The original publication of the MDRD trial mentioned 30 deaths,

without specifying to which group they belonged (MDRD). An

additional publication of the same trial (Lazarus 1997) provided

the distribution, according to blood pressure goal, of 16 patients

who died before reaching a study point, but not for 14 patients

who died after a stop point but before their scheduled close-out

visit.

The data on mortality from the ABCD (H) trial deserve an expla-

nation. The first publication of the trial (ABCD (H)) mentioned

30 deaths in total, but it did not provide details on the distribution

according to blood pressure targets, because it focused on the com-

parison between the antihypertensive drugs used. A later publica-

tion stated that “patients randomized to intensive therapy had a

lower incidence of all-cause mortality when compared to moderate

therapy, 5.5% vs 10.7%, p= 0.037” (Estacio 2000), without pro-

viding absolute numbers. Given that 237 patients were assigned to

the intensive treatment group, and 233 patients to the moderate

treatment group, the absolute numbers of deaths calculated from

the reported percentages would be 13 and 25 respectively, for a to-

tal of 38 deaths, which differs from the total mortality mentioned

in the first report. Finally, the Blood Pressure Lowering Treatment

Trialists’ Collaboration (BPLTTC 2003) reported 32 deaths in

the same trial, 10 in the intensive treatment group and 22 in the

moderate treatment group. Due to the lack of concordance, the

information from BPLTTC was used for this analysis, because it

was the only one providing absolute numbers and because they

were closer to the figures mentioned in the original report.

In the meta-analysis there was no difference in total mortality

between the two blood pressure target groups: RR 0.99, 95% CI

(0.86, 1.15), p= 0.93. The decrease in total mortality reported in

the ABCD (H) trial was not seen in the other trials.

1.1.2 Cardiovascular mortality

The comparison for cardiovascular mortality does not include the

trial by Toto et al, since cause of death was not given for the single

patient who died in that trial. The information from the ABCD

(H) trial was provided by the BPLTTC.

The meta-analysis showed no difference in cardiovascular mortal-

ity between the two blood pressure target groups: RR 1.03, 95%

CI (0.83, 1.28), p= 0.8.

1.1.3 Non-cardiovascular mortality

Likewise the meta-analysis showed no difference in non-cardio-

vascular mortality: RR 0.96, 95% CI (0.78, 1.18), p= 0.69. The

comparison does not include the trial by Toto et al for the previ-

ously specified reason.

1.2 Total serious adverse events

Only the REIN-2 trial reported total serious adverse events, and

there was no difference between the groups: RR 1.39, 95% CI

(0.90, 2.15), p= 0.14.

1.3 Other cardiovascular serious adverse events

Each trial reported separately several cardiovascular serious adverse

events. However, none of the events was reported in every trial.

Fatal and non-fatal events were reported combined.

Data from REIN-2 are missing because they did not report the

number of specific serious adverse events separately.

1.3.1 Myocardial infarction

Only 3 trials reported the rates for myocardial infarction. To main-

tain homogeneity with the other trials for the purpose of this anal-

ysis, data extracted from HOT do not include silent myocardial

infarctions. The meta-analysis showed no difference in the inci-

dence of myocardial infarction: RR 0.84, 95% CI (0.74, 1.09),

p= 0.15.

Furthermore, the incidence of silent myocardial infarctions re-

ported in the HOT trial was not different between the lower

(89/12526) and the traditional target groups (43/6264): RR 1.04,

99% CI (0.64, 1.67), p= 0.9.

1.3.2 Stroke

The information on stroke is available from only 3 trials. Data

from ABCD (H) was provided by the BPLTTC.

A lower incidence of stroke was reported in ABCD (N), but not

in the other trials. There was no difference in the pooled analysis

for this outcome: RR 0.99, 95% CI (0.79, 1.25), p= 0.96.

1.3.3 Congestive heart failure

The only trial reporting data on congestive heart failure was the

ABCD (N) trial. It was defined as congestive heart failure requiring

hospital admission. Data from ABCD (H) and HOT was provided

by BPLTTC 2003. There was no difference in the pooled analysis

for this outcome: RR 0.88, 95% CI (0.59, 1.32), p= 0.55



1.3.4 End-stage renal disease

End-stage renal disease, defined as the requirement of dialysis or

kidney transplantation, was reported in the AASK trial, in the

trial by Toto et al, and in the REIN-2 trial. An additional 106

patients included in the MDRD trial developed end-stage renal

disease, but they could not be included in this analysis because

their distribution between “usual” or “lower” blood pressure was

not provided. An additional publication of the trial (Sarnak 2005)

reported kidney failure during long term follow-up (7 years after

the end of the trial), but it was not included because no specific

target blood pressure was recommended after completion of the

trial.

The incidence of end-stage renal disease was similar between pa-

tients randomized to “lower” or “standard” blood pressure targets:

RR 1.01, 95% CI (0.81, 1.27), p= 0.92

1.3.5 Major cardiovascular events

Information regarding major cardiovascular events, a compos-

ite outcome including myocardial infarction, stroke, heart fail-

ure or any cardiovascular death, was available from 4 trials. The

BPLTTC’s authors provided additional information for this out-

come in the AASK, ABCD (H) and ABCD (N) trials. The HOT

trial reported major cardiovascular events, but did not include hos-

pital admissions due to heart failure. As mentioned before, that

information was provided by BPLTTC 2003. The effect size does

not change whether or not the HOT trial is included in the anal-

ysis.

There was no difference between the lower or standard target blood

pressure for this outcome: RR 0.94, 95% CI (0.83, 1.07), p= 0.35.

1.3.6 All other serious adverse events

None of the trials reported the number of other serious adverse

events.

2. Secondary outcomes

Some secondary outcomes were not available in several trials. Each

of the outcomes is briefly described below.

2.1 Systolic blood pressure achieved

Six trials reported the mean systolic blood pressure achieved. The

MDRD trial was not included in the analysis because it reported

mean arterial pressure, but not systolic blood pressure achieved.

In HOT, achieved blood pressure was defined as the mean of all

blood pressures from 6 months of follow-up to end of study. In

ABCD (N) and in ABCD (H), the achieved blood pressure was de-

fined as the average blood pressure for the last four years of follow-

up. AASK included blood pressure measurements after 3 months

of follow-up. REIN-2 considered blood pressure throughout fol-

low-up. Toto et al did not describe the method used to estimate

achieved blood pressure.

Heterogeneity between trials for this outcome was high. However,

using the random effects model the achieved BP was statistically

significantly lower in the lower target group than the standard tar-

get group: p= 0.003. The fixed effects model provides the best es-

timate of average magnitude of the difference between the systolic

BP in the two groups, 3.9 mmHg lower in the lower target group

(see Analysis 1.10).

2.2 Diastolic blood pressure achieved

Six trials reported the mean diastolic blood pressure achieved, as

defined above. The MDRD trial was not included because it re-

ported mean arterial pressure achieved, but not diastolic blood

pressure. Using the fixed effects model as the best estimate of the

weighted mean change, the weighted mean diastolic blood pres-

sure was 3.4 mmHg lower in the lower target group. Heterogeneity

was also high for this outcome; the random effects model demon-

strated that the blood pressure was statistically significantly lower

in the lower target group p = 0.001.

2.3 Proportion of patients not achieving the blood pressure

targets

Only three trials, the AASK, the HOT and the MDRD trials,

reported the number of patients who did not achieve the tar-

get blood pressure levels. Data from the HOT trial was obtained

from an interim analysis reporting results on blood pressure at 24

months of follow-up (Hansson 1997). AASK was excluded from

this analysis, as in AASK the higher target was a range of values

rather than as any value below the target. In the other two trials

there was a statistically significantly larger proportion of patients

not achieving the lower blood pressure target: RR 2.36, 99% CI

(2.17, 2.56), p<0.00001.

2.4 Withdrawals due to adverse effects

Only the REIN-2 trial reported the total number of withdrawals

specifically due to the treatment adverse effects in each treatment

arm, and there was no statistical difference between the groups:

RR 2.00, 99% CI (0.33, 12.10), p=0.32.

Only fragmented information regarding adverse effects was pro-

vided in 3 of the remaining 6 trials. For example, in the MDRD

trial, in 14 (3.2%) of patients in the lower blood pressure group

and in 3 (0.7%) of patients in the higher blood pressure group,

a reduction in antihypertensive medications was required due to

persistent symptoms of hypotension (p=0.01 for the comparison

between groups) (Lazarus 1997). Furthermore, the blood pressure

had to be raised because of persistent symptoms of hypotension in

17 patients, but their distribution according to blood pressure tar-

get was not provided (MDRD). However, the authors mentioned

that no patient reached a stopping point in the study because of

complications of hypotension (MDRD). The main report of the

HOT trial did not provide information regarding withdrawals due

to adverse effects. A preliminary publication of the same trial (



Hansson 1997) described tolerability at 24 months and reported

that there was no difference in overall incidence of side effects be-

tween the three target groups. However, according to the protocol,

treatment was titrated in up to five steps, and the already cited pre-

liminary publication mentioned that “more patients needed step

5 medication in the less than or equal to 80 mmHg target group

than in the less than or equal to 90 mmHg target group”, and

“with increasing dose titration steps there was a gradual increase

in the total number of side effects” (Hansson 1997). In the AASK

trial it is stated that “proportions of patients reporting adverse

symptoms, including hypotensive symptoms, were similar in the

2 blood pressure groups”. However, according to Table 5 in the

same report, cough occurred more frequently in patients assigned

to the lower blood pressure target (54.6% vs 47.0, p<0.05).

2.5 Number of antihypertensive drugs needed per patient

Only the MDRD and the AASK trials reported the number of

drugs needed in each group in order to try to achieve the target

blood pressure. When those trials were combined 0.53 99% CI

(0.22, 0.84) more pharmacological antihypertensive agents were

needed per patient in the groups randomized to the lower blood

pressure target (p= 0.00001).

The following information from the HOT trial was estimated from

a figure provided in an interim publication reporting results after

24 months of follow-up (Hansson 1997). Due to these limitations,

the data were not combined with the other trials. The estimated

mean number of antihypertensive drugs per patient was 1.87 in the

lower target groups combined (DBP < 80 mmHg and < 85 mmHg)

and 1.68 in the traditional target group (DBP < 90 mmHg): p<

0.00001. The proportion of patients requiring a high dose of one

or more antihypertensive drugs (step 3 or higher), was larger in

the lower target groups (44.9%) than in the standard target group

(31.4%): p< 0.0001.

D I S C U S S I O N

The objective in the treatment of patients with elevated blood pres-

sure is to reduce morbidity and mortality and not simply to lower

blood pressure. Many epidemiological studies have shown a con-

tinuous direct linear relationship between blood pressure and the

incidence of cardiovascular events. The lower threshold for this re-

lationship has not been established (MacMahon 1990, Prospective

Studies). More aggressive treatment in patients with elevated blood

pressure aiming at lower blood pressure targets assumes that the

benefits of attempting to achieve lowering blood pressure targets

using antihypertensive drugs outweigh the harms caused by the

drugs. This hypothesis needs to be tested and validated by specif-

ically designed randomized controlled trials (Gueyffier 2001).

This systematic review and meta-analysis of randomized controlled

trials summarizes the presently available evidence from the trials

that have tested blood pressure targets and includes more than

22,000 patients, with a mean follow-up period of 3.8 years. It in-

cludes all trials measuring clinical outcomes in patients random-

ized to “lower blood pressure targets” as compared with “standard

blood pressure targets”, according to our definitions. The impor-

tant observations from this systematic review are as follows.

Summary of main results

In patients randomized to the “lower targets” the weighted mean

systolic blood pressure was 3.9 mmHg lower and the weighted

mean diastolic blood pressure was 3.4 mmHg lower than pa-

tients randomized to the “standard target” (139.3 mmHg vs 143.2

mmHg systolic, and 81.7 mmHg vs 85.1 mmHg diastolic respec-

tively). However, despite these clinically significant reductions in

blood pressure over a 4 year period, trying to achieve the “lower

targets”, instead of the “standard target”, did not result in any

change in total, cardiovascular or non-cardiovascular mortality. In

addition it did not result in any change in cardiovascular or re-

nal morbidity expressed as the incidence of myocardial infarction,

stroke, congestive heart failure, the composite outcome of major

cardiovascular events, or end-stage renal disease. Thus at present

there is no randomised controlled trial evidence justifying blood

pressure targets lower than standard targets.

The lack of a difference in mortality and morbidity is robust as

evidenced by the two most important measures: total mortality

(RR=1.0, 95% CI 0.86 to 1.16) and total major cardiovascular

events (RR= 0.95, 95% CI 0.84 to 1.08). Those numbers mean

that we have acceptable confidence that the relative risk for total

mortality is between a 14% decrease and a 16% increase, and that

the relative risk for major cardiovascular events is between a 16%

decrease and 8% increase. As can be appreciated, these ranges rule

out a ≥20% reduction or ≥20% increase. They do not, however,

exclude the possibility of a small benefit or small harm associated

with attempting to achieve lower diastolic blood pressure targets.

One possible argument against the findings of this review is that the

minimum difference in the targets chosen in this review, 5 mmHg,

was not great enough to demonstrate mortality and morbidity

benefits. This argument can be tested in this meta-analysis by

including only those trials where the difference in the targets was at

least 10 mmHg. In fact placing this restriction on the review only

excludes the middle group ( lower than 85 mmHg) of the HOT

trial. A re-analysis with exclusion of the < 85 mmHg diastolic blood

pressure group leads to a greater weighted mean difference in target

diastolic blood pressure (10.3 mmHg) between the two groups and

a greater difference in the mean achieved blood pressures of 5/4

mmHg. More importantly it led to no appreciable changes in the

RR for mortality nor for any of the primary morbidity outcomes,

and the conclusions remain the same as described above.

SENSITIVITY ANALYSIS IN PATIENTS WITH DIABETES

MELLITUS



The main meta-analysis in this review combines all trials per-

formed in all types of patients. Doing it in this way makes the as-

sumption that there are no significant differences in blood pressure

targets for the different subgroups of the populations included.

This is a reasonable assumption and in fact it would be unex-

pected if lower targets were beneficial in one subgroup of patients

and not beneficial or harmful in another. However, as mentioned

previously, experts preparing guidelines for patients with diabetes

mellitus or chronic renal disease have suggested that lower blood

pressure targets are indicated in these groups. Therefore, we have

performed sensitivity analyses in these two subgroups of patients.

Diabetes was an exclusion criterion in the trial by Toto et al, and

AASK. In the MDRD trial, diabetic patients were excluded if they

required insulin; 25 of the included patients had Type 2 diabetes

mellitus, but they could not be included in this analysis because

outcomes were not reported separately for the diabetics. There-

fore, this sensitivity analysis is limited to two trials in which all

patients had diabetes mellitus at baseline, ABCD (H) and ABCD

(N), and a sub-group analysis of the HOT trial, which separately

reported outcomes in patients with diabetes mellitus at baseline.

Several issues regarding the design and the characteristics of these

3 trials must be mentioned. Although not clearly specified, the

subgroup analysis of diabetic patients in the HOT trial appears to

be a post-hoc analysis, because it was not mentioned in any of the

preliminary descriptions or reports of the trial published in 1993,

1994, 1995 and 1997 (HOT). In terms of baseline diastolic blood

pressure, one of the trials, ABCD (N), included only normoten-

sive diabetic patients, defined as a diastolic blood pressure between

80 and 89 mmHg. Twenty-six patients (5.4%) with isolated sys-

tolic hypertension (systolic blood pressure > 160 mmHg and di-

astolic blood pressure between 80 and 89 mmHg) were enrolled

during the first year of recruitment, but none thereafter. On the

other hand, both ABCD (H) and HOT only included patients

with elevated blood pressure, but the criteria for inclusion were

different. In ABCD (H), patients had a baseline diastolic blood

pressure equal to or higher than 90 mmHg, whereas the blood

pressure inclusion criterion in HOT was a baseline diastolic blood

pressure between 100 mmHg and 115 mmHg. Finally, it must be

mentioned that when these three trials were performed the diag-

nostic criterion for diabetes mellitus was two fasting plasma glu-

cose levels, measured on different days, higher than 7.7 mmol/L

(140 mg/dL), instead of greater than 7.0 mmol/L (126 mg/dL) as

currently defined.

The analysis in diabetics demonstrates a statistically significant re-

duction in blood pressure of 5/5 mmHg but no statistically sig-

nificant difference p < 0.01, for any of the mortality and mor-

bidity outcomes in diabetics randomized to “lower target” ( ≤85

mmHg for diastolic blood pressure) as compared with a “standard

target” (≤ 90 mmHg). The results for the two composite out-

comes, mortality RR = 0.72 [99%CI, 0.47, 1.10] and total car-

diovascular events RR = 0.80 [99%CI, 0.59, 1.09] demonstrates

a trend towards a benefit for the lower target and wide confidence

intervals. This provides a strong rationale for performing further

trials comparing lower blood pressure targets with standard targets

in patients with diabetes mellitus. It does not provide sufficient

evidence for recommending lower blood pressure targets in this

patient population.

SENSITIVITY ANALYSIS IN PATIENTS WITH CHRONIC

RENAL DISEASE

Four trials were included in this sensitivity analysis. Clinical trials

commonly define chronic renal disease based solely on a glomeru-

lar filtration rate lower than 70 mL/min/1.73 m2 of body sur-

face area. Using that definition alone, three trials were included:

MDRD, Toto et al, and AASK. REIN-2 required patients with

proteinuria 1-3 g per 24 hours if their creatinine clearance was less

than 45 mL/min per 1.73 m2 and patients with proteinuria of 3 g

per 24 hours or more if their creatinine clearance was less than 70

mL/min per 1.73 m2. Derangement in renal function was not an

exclusion criterion in the HOT trial; however, HOT data could

not be included because no outcomes in patients with chronic re-

nal disease were reported. ABCD (H) and ABCD (N) excluded

patients receiving hemodialysis, peritoneal dialysis or with a serum

creatinine concentration greater than 265 mol per liter (3 mg/dL).

Many outcomes were not reported, because the reports focused

mainly on surrogate markers of renal function. Most of the infor-

mation comes from the AASK and REIN-2 trials.

Toto et al, the AASK trial and the REIN-2 trial reported achieved

systolic and diastolic blood pressures. The MDRD trial could not

be included because it only reported achieved mean arterial pres-

sure. The weighted mean blood pressure was substantially lower,

128.6 /78.3 mmHg, in the “lower target” group than in the “stan-

dard target” group, 139.2/84.5 mmHg.

In order to achieve the greater reduction in blood pressure, 0.5

more pharmacological antihypertensive agents were needed per

patient in the lower blood pressure target group. Despite the lower

achieved blood pressure no statistically significant reductions in

any of the mortality and morbidity outcomes was found for the

lower blood pressure target group as compared to the standard

blood pressure target group. The two outcomes where it was pos-

sible to pool data from three trials were total mortality RR 0.89

[99%CI 0.52, 1.52] and end stage renal disease RR 1.01 [99%CI

0.75, 1.36].

Although it is a surrogate marker, we also pooled the mean de-

cline in glomerular filtration rate (GFR), because it was the main

objective of the four trials included in this sensitivity analysis, and

also because preserving renal function is promoted as one of the

main benefits from lower target blood pressures in patients with

chronic renal disease. There was no difference in mean annual de-

cline in GFR between patients randomized to lower as compared

with traditional blood pressure targets: WMD -0.09, CI 95% (-

0.51, 0.32), p= 0.55. Therefore, at present there is no evidence for



any benefits associated with trying to achieve lower than standard

blood pressure targets in patients with chronic renal disease.

Overall completeness and applicability of evidence.

All of the identified trials assessed diastolic or mean blood pressure

targets, and none of the trials compared different targets for sys-

tolic blood pressure. Therefore, at present we have no information

regarding the benefits or harms of trying to achieve “lower systolic

blood pressure targets” as compared with “standard systolic blood

pressure targets”. The ACCORD trial, which is currently under-

way, is comparing clinical outcomes in patients with diabetes ran-

domized to systolic targets of lower than 120 mmHg or systolic

targets of lower than 140 mmHg (ACCORD 2007).

Although mean arterial blood pressure (MAP), was used as the

target in some trials included in this review, MAP is not a good

estimate of systolic blood pressure because every single value of

MAP can be the result of many different combinations of systolic

and diastolic blood pressure values. For example, defining MAP

as equal to 2/3 diastolic blood pressure plus 1/3 systolic blood

pressure, a MAP equal to 107 mmHg could be the result of both

140/90 mmHg and 180/70 mmHg, among many other possi-

ble combinations of systolic/diastolic values. The assumption that

the mortality and morbidty implications of blood pressure mea-

surements of 140/90 mmHg and 180/70 mmHg are the same

based on the same estimated mean arterial pressure is likely to be

wrong. Observational data suggest that pulse pressure is an in-

dependent and better predictor of cardiovascular risk than either

systolic or diastolic blood pressure (Franklin 1999, Millar 1999,

Benetos 2000).

Six of the seven included RCTs compared diastolic or estimated

diastolic BP targets of less than or equal to 85 mmHg with a

diastolic or estimated diastolic BP target of less than or equal

to 90 mmHg. In the only exception (Toto et al) the “standard

target” diastolic blood pressure was less than or equal to 95 mmHg,

but still within the range of “standard targets” specified in this

systematic review. This trial was small and a sensitivity analysis

excluding it does not change the results. Therefore, the results of

this systematic review are generalizable to physicians prescribing

antihypertensive drugs to attempt to achieve diastolic targets.

The mean reduction in achieved diastolic blood pressure of 3.4

mmHg was not as great as the weighted mean difference in tar-

get goals in the 7 trials, a reduction of 8.2 mmHg diastolic blood

pressure. This inability to achieve the difference in target probably

reflects a real limitation in the ability to achieve the lower targets

plus a possible flaw in the design of the trials. By defining each BP

target as less than or equal to a particular number, physicians may

tend to over-treat the higher target group, while experiencing dif-

ficulty achieving the targets in the lower target groups. This possi-

ble flaw could be corrected if the targets were defined as a range of

blood pressure for each group, in which case a greater difference

in blood pressure between the groups may be achievable. What is

clear is that an increased number of antihypertensive drugs, and

consequently increased inconvenience and economic costs to the

patient or society, were a consequence of using the lower blood

pressure target as a goal of therapy.

Potential biases in the review process

The main potential bias in this meta-analysis is inevitable because

the intervention of trying to achieve a target blood pressure can-

not be blinded. Such open trials are subject to investigator bias for

both efficacy and safety outcomes. In this particular case the bias

would be in favour of the lower blood pressure target intervention

as most of the trials were funded by drug companies and the lower

blood pressure target would lead to increased sales of antihyper-

tensive drugs. In 4 of the trials attempts to minimize this potential

bias was done by ensuring that the outcomes were well defined

and that investigators performing the outcome evaluation were

blinded to the randomized group (Hansson 1992). In that regard,

it is noteworthy that in the HOT trial the blinded Clinical Event

Committee rejected 24% of all investigator-reported events.

Another limitation of this meta-analysis is the fact that one single

trial (HOT) provides most of the participants and outcomes. Oth-

ers have expressed concern regarding performing a meta-analysis

in such cases, especially when the results from the pooled small

trials and the large trial are contradictory (Borzak 1995). This is

not the case in this meta-analysis since the results are congruent

whether or not the large trial is included.

The differences between trials in the definition of outcomes are

also a source of bias. For example, the HOT trial did not include

congestive heart failure in the definition of major cardiovascular

events. HOT, but not the remaining trials, also reported silent my-

ocardial infarctions. Silent myocardial infarcts were not included

in this meta-analysis. However, their inclusion would not change

any of the estimates of treatment effect nor any of the conclusions.

Selective reporting bias is a significant source of bias in this meta-

analysis, as in some trials certain outcomes were not reported. The

magnitude of this bias can be appreciated in the metaview. None

of the outcomes included data from all 7 trials. The information

on mortality and on end-stage renal disease from the MDRD trial

could not be included for the reasons already mentioned. The most

blatant example of potential selective reporting bias is total serious

adverse events, which was reported in only one trial. If results from

this trial were supplemented by data likely to have been collected

during the other trials, it would be possible to test whether total

SAEs are increased or decreased by lower BP targets. In spite of

repeated specific requests to the trials’ main authors, the missing

SAE information was not provided.

Agreements and disagreements with other studies or reviews



This review was originally completed and published as a Master’s

Thesis (Arguedas 2004). Despite the potential biases in the RCTs

making up this review, the results do not demonstrate evidence

of benefit for attempting to acheive a blood pressure target that

is lower than the accepted standard blood pressure target in any

patient population. This conclusion leads to a recommendation

that physicians aim for standard blood pressure targets and this

differs from recommendations provided by several currently used

clinical guidelines for the treatment of high blood pressure. Why

is that the case? We suggest the main reason for this difference it

that the guidelines are based either on the results of observational

cohort studies or on the interpretation of results in randomized

controlled trials (RCT) as if they were observational studies. Due

to the prevalent misunderstanding of this issue, it deserves a more

detailed explanation.

Although observational studies can provide very interesting and

useful information, these studies have limitations (Gueyffier

2001). Observational studies are always subject to confounding by

variables that cannot be accounted for because they are unknown.

They are also susceptible to selection bias, which means that there

is differential assignment of subjects to treatment groups based

on subject characteristics (MacMahon 2001). This is particularly

true for treatment targets. Therefore, findings from observational

studies must be limited to generation of hypotheses, which can

be tested in properly designed, conducted and reported RCTs (

MacMahon 2001).

The HOT trial is an excellent example to demonstrate how ob-

servational data can lead to wrong conclusions. This trial was de-

signed as a randomized trial to measure outcomes based on 3 dif-

ferent target diastolic blood pressures. Mortality and cardiovascu-

lar morbidity were not different in the 3 different target groups.

However, instead of accepting the findings of the randomized trial

as designed, the authors did a further analysis of the trial, as if it

was a prospective observational study and made the bulk of their

conclusions based on that analysis. In this design they combined

all randomized groups into one and reported outcomes based on

the blood pressures achieved during follow-up. That analysis led

to an interpretation and conclusions that were the opposite of the

interpretation and conclusions from the randomized trial. The

achieved blood pressure approach is inappropriate, confounded

and biased. It is surprising that this flawed approach, interpreta-

tion and conclusions passed the peer review and editorial process

of the Lancet (Kunz 1998). The following explanation may help

to better understand this important concept. The cohort of pa-

tients with low blood pressure as identified by achieved blood pres-

sure selects for patients who did not have sustained elevated blood

pressure in the first place (incorrectly identified as having baseline

BP > 100 mmHg), for patients in whom the blood pressure is

most easily reduced with low doses of antihypertensive drugs, for

patients with the lowest baseline blood pressure, and for patients

who are most compliant with drug and non-drug therapy to lower

blood pressure (healthy user effect, Dormuth 2009). All of these

factors are also most likely associated with a lower risk of having an

adverse cardiovascular event. The approach is thus heavily biased

for finding less cardiovascular events in the patients with lower

blood pressure, and thus must not be encouraged. The biases men-

tioned above are prevented when results from a RCT are analyzed

according to intention-to-treat principle, such as we used in this

meta-analysis, because then the only difference between groups

is the treatment strategy under consideration. Consequently any

difference in outcomes can be attributed to the allocated treatment

strategy (Peto 1995).

The results of this systematic review also differ from those re-

ported in another meta-analysis performed by the Blood Pressure

Lowering Treatment Trialists’ Collaboration (BPLTTC 2003). In

their study, the BPLTTC compared “less intensive” with “more

intensive” blood pressure lowering regimens, without defining any

specific blood pressure target values for that grouping. The most

important difference between BPLTTC analysis and this one is

the handling of the UKPDS-38 trial (UKPDS). They included

it and we excluded it. The BPLTTC meta-analysis showed a de-

creased incidence in stroke and major cardiovascular events, and

no significant difference in the incidence of coronary heart disease,

congestive heart failure, death due to cardiovascular causes, or to-

tal mortality with “more intensive” blood-pressure-lowering reg-

imens compared with “less intensive” regimens. However, it was

possible to demonstrate from detailed information available at the

BPLTTC web site ( http:/ / www.iih.org/ bplttc) that the reduc-

tion in stroke and major cardiovascular events was due to the in-

clusion of the UKPDS-38 trial. As mentioned before, the reasons

for excluding UKPDS-38 in this review were two-fold. Firstly, the

target for the “low target” group was 150/85 mmHg. This target

is in the mid-range for the “traditional target” for systolic blood

pressure. Secondly, the blood pressure target in the less intensive

treatment group was initially < 200/105 mmHg, and after 5 years

it was reduced to < 180/105 mmHg. These high targets are very

similar to the safety cutoffs for the no treatment group in trials

comparing treatment with no treatment. For these reasons, it is

clear that this trial is not relevant to a comparison between “lower”

and “standard” blood pressure treatment targets. The inclusion

of UKPDS-38 by BPLTTC to suggest benefits of more intensive

blood pressure lowering regimens is misleading and inappropriate.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

1. The optimal target for systolic blood pressure has not been

tested in randomized controlled trials. This is particu-

larly important because current trends in clinical prac-

tice emphasize the control of elevated systolic blood

pressure. In the absence of any evidence, systolic blood



http://www.iih.org/bplttc




pressure targets should be the standard targets that have

been demonstrated to be better than placebo or no

treatment in randomized controlled trials (≤ 140 - 160

mmHg).

2. The optimal target for diastolic blood pressure was ad-

equately tested in this review and demonstrated that

“lower targets” of ≤ 85 mmHg achieved lower blood

pressures but were not associated with a reduction in

mortality or morbidity when compared with the stan-

dard target of ≤ 90 - 100 mmHg. The same conclusion

is true if one limits the lower target group to trials with a

target of ≤ 80 mmHg. Therefore, for the general popu-

lation of patients with elevated blood pressure, the dias-

tolic target should be equal to or lower than 90 mmHg

and there is no RCT evidence supporting attempting

to treat to lower targets.

3. This review was not designed to test subgroups of pop-

ulations, but sensitivity analyses in patients with dia-

betes mellitus and chronic renal disease did not demon-

strate statistically significant benefits for treating to tar-

gets lower than 135/85 mm Hg. However, in these

two populations the evidence for a lack of benefit is less

robust. We are going to perform separate systematic

reviews in these two populations to test, as suggested in

clinical guidelines, if targets lower than 130/80 mm Hg

change morbidity or mortality as compared to standard

targets.

4. Because of the paucity of reported data on harms (non-

fatal serious adverse events and withdrawals due to ad-

verse effects) in this review, it is possible that the failure

to demonstrate harms associated with “lower targets”,

is due to selective reporting bias.

5. Conclusions and recommendations for blood pressure

targets based on achieved blood pressures whether from

randomized controlled trials or observational studies are

misleading and inappropriate.

Implications for research

1. Properly conducted randomized controlled trials are needed

comparing lower systolic blood pressure targets with

standard blood pressure targets in the general popula-

tion of patients with elevated blood pressure and in sub-

groups of patients (see below). The ongoing ACCORD

2007 trial represents one of many needed trials.

2. Because guidelines are presently recommending un-

proven lower systolic and diastolic blood pressure targets

in the following subgroups of patients: diabetes melli-

tus, chronic renal disease, coronary artery disease, cere-

brovascular disease, peripheral arterial disease and ab-

dominal aortic aneurysm, RCTs comparing the benefits

and harms associated with recommended lower targets

as compared to standard targets are urgently needed in

those subgroups.

A C K N O W L E D G E M E N T S

We are very grateful to the following persons and institutions:

Dr. Fiona Turnbull, from the Blood Pressure Lowering Treatment

Trialists’ Collaboration, for providing useful additional informa-

tion not available from the published reports of the trials.

The Therapeutics Initiative, Department of Pharmacology &

Therapeutics, University of British Columbia.

Department of Clinical Pharmacology and Toxicology, School of

Medicine, Faculty of Medicine, University of Costa Rica.

CONICIT, Ministerio de Ciencia y Tecnología, Costa Rica.

R E F E R E N C E S

References to studies included in this review

AASK {published data only}

Wright JT, Bakris G, Greene T, et al.for the African American Study

of Kidney Disease and Hypertension Study Group. Effect of blood

pressure lowering and antihypertensive drug class on progression of

hypertensive kidney disease. JAMA 2002;288(19):2421–31.

ABCD (H) {published data only}

Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood pres-

sure control on diabetic complications in patients with hypertension

and type 2 diabetes. Diabetes Care 2000;23(suppl 2):B54–B64.

ABCD (N) {published data only}

Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive

blood pressure control in normotensive type 2 diabetic patients on

albuminuria, retinopathy and strokes. Kidney Int 2002;61:1086–

1097.

HOT {published data only}

Hansson L. The Hypertension Optimal Treatment study and the

importance of lowering blood pressure. J Hypertens 1999;17(suppl

1):S9–S13.

Hansson L, for the HOT Study Group. The Hypertension Optimal

Treatment Study (The HOT Study). Blood Pressure 1993;2:62–68.∗ Hansson L, Zanchetti A, Carruthers SG, et al.for the HOT Study

Group. Effects of intensive blood-pressure lowering and low-dose

aspirin in patients with hypertension: principal results of the Hyper-

tension Optimal Treatment (HOT) randomized trial. Lancet 1998;



351:1755–62.

Hansson L, Zanchetti A, for the HOT Study Group. The Hyper-

tension Optimal Treatment (HOT) Study: 12-month data on blood

pressure and tolerability with special reference to age and gender.

Blood Pressure 1995;4:313–319.



pressure and tolerability. Blood Pressure 1997;6:313–317.

Hansson L, Zanchetti A for the HOT Study. The Hypertension

Optimal Treatment (HOT) Study. Patient characteristics: random-

ization, risk profiles, and early blood pressure results. Blood Pressure

1994;3:322–327.

Zanchetti A, Hansson L, Clement D, et al on behalf of the HOT

Study Group. Benefits and risks of more intensive blood pressure

lowering in hypertensive patients of the HOT study with different

risk profiles: does a J-shaped curve exist in smokers?. J Hypertens

2003;21:787–804.

Zanchetti A, Hansson L, Dahlof B, on behalf of the HOT Study

Group. Effects of individual factors on the incidence of cardiovas-

cular events in the treated hypertensive patients of the Hypertension

Optimal Treatment Study. J Hypertens 2001;19:1149–1159.

MDRD {published data only}

Klahr S, Levey AS, Beck GJ, et al.for the Modification of Diet in Renal

Disease Study Group. The effects of dietary protein restriction and

blood-pressure control on the progression of chronic renal disease..

N Eng J Med 1994;330(13):877–84.

Lazarus JM, Bourgoignie JJ, Buckalew VM et al for the Modification

of Diet in Renal Disease Study Group. Achievement and safety of a

low blood pressure goal in chronic renal disease. Hypertension 1997;

29:641–650.

Peterson JC, Adler S, Burkart KM et al for the Modification of Diet

in Renal Disease (MDRD) Study Group. Blood Pressure Control,

Proteinuria, and the Progression of Renal Disease: The Modification

of Diet in Renal Disease Study. Ann Intern Med 1995;123:754–762.

Sarnak MJ, Greene T, Wang X, et al.The effect of a lower target blood

pressure on the progression of kidney disease: long-term follow-up

of the Modification of Diet in Renal Disease study. Ann Intern Med

2005;142:342–351.

REIN-2 {published data only}

Ruggenenti P, Perna A, Loriga G, et al for the REIN-2 Study Group.

Blood-pressure control for renoprotection in patients with non-dia-

betic chronic renal disease (REIN-2): multicentre, randomised, con-

trolled trial. Lancet 2005;365:939–46.

Toto {published data only}

Toto RD, Mitchell HC, Smith RD, et al.“Strict” blood pressure con-

trol and progression of renal disease in hypertensive nephrosclerosis.

Kidney Int 1995;48:851–9.

References to studies excluded from this review

BBB {published data only}∗ Hansson L for the BBB Study Group. The BBB Study Group:

the effect of intensified antihypertensive treatment on the level of

blood presure, side-effects, morbidity and mortality in “well treated”

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

AASK

Methods Randomized 3 x 2 factorial trial. Participants were randomly assigned to 1 of 2 mean arterial pressure goals, and to

initial treatment with a beta-blocker, an ACE inhibitor or a dihydropyridine calcium channel blocker. Open-label

agents were added sequentially to achieve the blood pressure goal.

3 consecutive seated blood pressure readings were measured with a sphygmomanometer after at least 5 minutes rest,

with the mean of the last 2 readings recorded.

All cardiovascular events, including cardiovascular deaths and hospitalizations for myocardial infarctions, strokes,

heart failure, revascularization procedures, and other hospitalized cardiovascular events were reviewed and classified

by a blinded end points committee.

The follow-up was 3 to 6.4 years.

Participants 1094 participants, self-identified as African-Americans, with diastolic blood pressure higher than 94 mmHg, who were

aged 18 to 70 years, with a glomerular filtration rate between 20 and 65 ml/min per 1.73 m2, and no other identified

cause of renal disease. Exclusion criteria included diastolic blod pressure of less than 95 mmHg, known history of

diabetes mellitus, urinary protein to creatinine ratio of more than 2.5, accelerated or malignant hypertension within

6 months, secondary hypertension, evidence of non-BP-related causes of chronic kidney disease, serious systemic

disease, clinical congestive heart failure, or specific indication for or contraindication to a study drug procedure.

Interventions Participants were randomized equally to a usual mean arterial pressure goal of 102 to 107 mm Hg or to a lower mean

arterial pressure goal of 92 mm Hg or lower.

Outcomes The primary analysis in the trial was based on the rate of change in glomerular filtration rate (GFR slope).

The protocol also designated a main secondary composite outcome, which included any of the following: a confirmed

reduction in GFR by 50% or by 25 mL/min per 1.72 m2 from the mean of the two baseline GFRs; end stage renal

disease (dialysis or transplantation); or death.

Notes Patients were also randomized to treatment with 1 of 3 antihypertensive drugs (metoprolol, ramipril, amlodipine).



ABCD (H)

Methods Randomized, open label clinical trial. Patients were randomized to intensive versus moderate blood pressure control.

They were also allocated to either nisoldipine or enalapril as the initial antihypertensive medication. If the target

blood pressure was not achieved with increasing doses, then open-labeled antihypertensive medications were added

in a step-wise fashion, initially with metoprolol, then hydrochlorothiazide or additional drugs, but not a calcium

channel blocker or ACE inhibitor.

Blood pressure recordings were obtained at peak drug levels and were an average of three seated readings obtained at

each visit.

An independent end point committee, which was blinded to the study intervention arms, reviewed all cardiovascular

events.


Participants 470 patients, between the ages of 40 and 74 years, with diabetes mellitus type 2 diagnosed. All of them had a diastolic

blood pressure equal to or higher than 90 mm Hg without taking antihypertensive medications. They could not have

had a myocardial infarction or a cerebrovascular accident within the previous 6 months, had coronary artery bypass

surgery within the previous 3 months, had unstable angina pectoris within the previous 6 months, had congestive

heart failure NYHA class III or IV, demonstrated an absolute need for ACE inhibitors or CCB, and/or had a serum

creatinine level > 3 mg/dl.

Interventions Patients were randomized into two treatment arms consisting of intensive treatment with a diastolic blood pressure

goal of 75 mmHg, and moderate treatment with a diastolic blood pressure goal of 80-89 mmHg.

Outcomes The primary end point was the change in 24-hour creatinine clearance. Secondary end points included cardiovascular

events, retinopathy, clinical neuropathy, and urinary albumin excretion

Notes Patients were also randomized to either nisoldipine or enalapril as the initial antihypertensive medication.

ABCD (N)

Methods Randomized, open label clinical trial. Patients were randomized to intensive (10 mm Hg below the baseline diastolic

blood pressure) versus moderate (80-89 mm Hg) diastolic blood pressure control. Patients in the moderate therapy

were given placebo, while patients randomized to intensive therapy received either nisoldipine or enalapril in a blinded

manner as the initial antihypertensive medication. If the target blood pressure was not achieved with increasing doses,

then open-labeled antihypertensive medications were added in a step-wise fashion, initially with metoprolol, then

hydrochlorothiazide or additional drugs, but not a calcium channel blocker or ACE inhibitor.

Blood pressure recordings were obtained at peak drug levels and were an average of three seated readings obtained at

each visit.

An independent end point committee, which was blinded to the study intervention arms, reviewed all cardiovascular

events.


Participants 480 patients, between the ages of 40 and 74 years, with diabetes mellitus type 2 diagnosed. All of them had a diastolic

blood pressure between 80 and 89 mm Hg and were not receiving antihypertensive medications at the randomization

visit.

They could not have had a myocardial infarction or a cerebrovascular accident within the previous 6 months, had

coronary artery bypass surgery within the previous 3 months, had unstable angina pectoris within the previous 6



ABCD (N) (Continued)

months, had congestive heart failure NYHA class III or IV, demonstrated an absolute need for ACE inhibitors or

CCB, and/or had a serum creatinine level > 3 mg/dl.

Interventions Patients were randomized into two treatment arms consisting of intensive treatment (diastolic blood pressure decrease

of 10 mmHg below baseline DBP), and moderate treatment (diastolic blood pressure goal of 80-89 mmHg).

Outcomes The primary end point was the change in 24-hour creatinine clearance. Secondary end points included cardiovascular

events, retinopathy, clinical neuropathy, and urinary albumin excretion

Notes Patients randomized to intensive therapy received either nisoldipine or enalapril in a blinded manner as the initial

antihypertensive medication. Patients in the moderate group were given placebo. However, by the end of the study,

117 (48%) of patients initially randomized to moderate therapy became hypertensive (systolic blood pressure > 159

and/or diastolic blood pressure > 89 mmHg on two consecutive visits), requiring either nisoldipine or enalapril

according to randomization at entry into the study with the goal of maintaining the systolic blood pressure < 160

mmHg and diastolic blood pressure < 90 mmHg.

HOT

Methods Randomized, open label, controlled trial, with blinded endpoint evaluation (PROBE) design. An Independent

Clinical Event Committee, masked to the group allocation, evaluated all clinical events. Patients were randomly

assigned to one of three diastolic blood pressure target groups: less or equal than 90 mmHg, less or equal than 85

mmHg, or less or equal than 80 mmHg. Randomization took into consideration the following baseline variables:

age, sex, previous antihypertensive therapy, smoking, previous myocardial infarction, previous coronary heart disease,

previous stroke and diabetes mellitus.

Blood pressure was measured three times, by an oscillometric semiautomatic device, with the patient in the sitting

position after 5 minutes of rest.

All patients were given the same therapeutic approach, organized in the following steps in order to achieve the target

blood pressure:

1-starting therapy was felodipine 5 mg once a day

2-angiotensin enzyme (AEC) inhibitors or beta-blockers were added

3-increased dose of felodipine to 10 mg once a day

4-doubling the dose of the ACE inhibitor o beta-blocker

5-adding a diuretic

The average follow-up was 3.8 years.

Participants 19193 hypertensive patients, aged 50-80 years, were initially included, but the study population was composed by

18790 patients because 403 of them were excluded early in the trial because of the suspicion of incorrect inclusion.

Baseline diastolic blood pressure between 100 mmHg and 115 mmHg was an inclusion criterion. 1501 non-insulin

treated diabetic patients were included and the event rates were reported separately in them.

Main exclusion criteria were malignant hypertension, secondary hypertension, diastolic blood pressure > 115 mmHg,

stroke or myocardial infarction within 12 months prior to randomization, decompensated congestive heart failure,

other serious concomitant diseases which could affect survival during the next 2-3 years, patients who required a

beta-blocker, ACE inhibitor or diuretic for reasons other than hypertension, patients who required antiplatelet or

anticoagulant therapy, and insulin treated diabetics.



HOT (Continued)

Interventions Patients were randomly assigned to one of three diastolic blood pressure target groups: less or equal than 90 mmHg,

less or equal than 85 mmHg, or less or equal than 80 mmHg.

Outcomes The outcomes measured were: total and cardiovascular mortality, all (fatal and non-fatal) myocardial infarctions

including silent infarctions, all (fatal and non-fatal) strokes, and major cardiovascular events (all myocardial infarctions

plus all strokes plus other cardiovascular deaths).

Notes Patients were also randomly assigned to acetylsalicylic acid 75 mg daily or placebo.

24% of all investigators-reported events were rejected by the Clinical Event Committee.

MDRD

Methods Randomized, open label, controlled trial. Patients were randomized to two different targets and also to two different

protein diets.

Blood pressure was measured monthly. The same nurse or technician took the sitting blood pressure three times in a

quiet room, and the average of the last two was used as the blood pressure for the visit.

The recommended antihypertensive regimen was an ACE inhibitor with or without a diuretic agent. A calcium

channel blocker and other medications were added as needed.

The mean follow-up was 2.2 years.

Participants 840 patients with various chronic renal diseases were included. Chronic renal disease was established as a creatinine

clearance of less than 70 ml per minute per 1.73 m2 of body surface area. To be included the participants had to be

between 18 and 70 years old, and a mean arterial pressure of 125 mmHg or less. Mean arterial pressure was calculated

as two thirds of systolic blood pressure plus one third of diastolic blood pressure. Arterial hypertension was not an

inclusion criterion, but 86% of included participants had elevated blood pressure.

The main exclusion criteria were pregnancy, insulin requiring diabetes mellitus, severe under or overweight, and

urinary protein excretion exceeding 10 grams per day.

Interventions Patients were randomly assigned to a usual- or low-blood pressure group. Usual blood pressure was defined as a mean

arterial pressure equal to or less than 107 mmHg (approximately 140/90 mmHg), whereas low blood pressure was

established as a mean arterial pressure lower than or equal to 92 mmHg (approximately 125/75 mmHg).

Outcomes The rate of change in glomerular filtration rate was the primary outcome measured. Other recorded outcomes were

death, end-stage renal disease requiring dialysis or transplantation, and other serious medical conditions.

Notes Patients were also randomized to usual- or low-protein diet. The effects of the blood pressure intervention were

similar in the two diet groups.



REIN-2

Methods Multicentre, randomized, controlled trial. Before randomization, patients were treated with antihypertensive drugs

(apart from ACE inhibitors, angiotensin-II-receptor antagonists, and dihydropyridine calcium-channel blockers)

to maintain diastolic blood pressure at less than 90 mm Hg. Participants were then randomly assigned to either

conventional blood-pressure control (diastolic < 90 mm Hg, irrespective of systolic blood pressure) or intensified

blood-pressure control . To achieve the intensified blood-pressure level, patients received add-on therapy with the

dihydropyridine calcium-channel blocker felodipine 5 mg/day, and up-titrated the dose after a week to 10 mg/day

according to blood -pressure response. In both arms up- and down-titration of concomitant drugs was allowed to

maintain the target blood pressure and to avoid symptomatic hypotension.

Blood pressure was measured 1 week, 2 weeks, and 3 weeks after randomization, and every 3 months thereafter.

Additional measurements were done within 1 week after any change in antihypertensive therapy.

The blood pressure was the mean of three values taken 2 minutes apart, after 5 minutes rest in the sitting position.

on the same arm by a standard sphygmomanometer. The time of day when blood pressure was measured was not

reported.

The median follow-up was 19 months.

Participants Three hundred and thirty eight patients, who had non-diabetic nephropathy and persistent proteinuria, and who

had not received ACE-inhibition therapy for at least 6 weeks. Persistent proteinuria was defined as urinary protein

excretion exceeding 1 g per 24 h for at least 3 months without evidence of urinary-tract infection or overt heart failure

(NYHA class III-IV). Patients with proteinuria of 1-3 g per 24 h were included if their creatinine clearance was less

than 45 mL/min per 1.73 m2; those with a proteinuria of 3 g per 24 h or more were included if their creatinine

clearance was less than 70 mL/min per 1.73 m2.

Exclusion criteria were treatment with corticosteroids, non-steroidal antiinflammatory drugs, or immunosupressive

drugs; acute myocardial infarction or cerebrovascular accident in the previous 6 months, severe uncontrolled hyper-

tension, evidence or suspicion of renovascular disease, obstructive uropathy, type 1 diabetes mellitus, collagen disease,

cancer, higher serum aminotransferase concentrations, or chronic cough, history of allergy, or poor tolerance to ACE

inhibitors or dihydropiridine calcium-channel blockers, pregnancy, breastfeeding.

Interventions Participants were randomly assigned to either “conventional” (diastolic < 90 mm Hg) or intensified (systolic/diastolic

< 130/80 mm Hg) blood-pressure control.

Outcomes The primary outcome was progression to end-stage renal disease. Other outcomes were GFR decline, residual

proteinuria, fatal and non-fatal cardiovascular events.

Notes After the first interim analysis, done as per protocol, an independent adjudicating panel stated that the study had to be

stopped for futility because the outcomes were similar in both arms despite more effective blood-pressure reduction

in the intensified blood-pressure control arm.



Toto

Methods The study was a 2 X 2 factorial, randomized controlled trial. Patients were randomized to either placebo or enalapril

and to either “strict” or “conventional” blood pressure ranges. Before randomization, diastolic blood pressure was

lowered to 80 mmHg or less over a 3 to 6 months initial assessment period. Patients able to achieve that target were

randomized and included in the study.

To achieve the target diastolic blood pressure, a stepped-care approach with antihypertensive medications was used: a

diuretic was the initial drug, followed by a beta-blocker, hydralazine or minoxidil, and clonidine, alpha-methyldopa

or a alpha-1 blocker. With the exception of the diuretic, the maximum dose of each agent was used before moving to

the next step. In patients assigned to “conventional” group, diastolic blood pressure was allowed to increase to the 85

to 95 mmHg range, whereas in patients assigned to the “strict” group the intention was to maintain diastolic blood

pressure in the 65 to 80 mmHg range.

Blood pressure was measured in the supine position with a mercury sphygmomanometer after a minimum of 5

minutes rest. Three measurements were taken at 2-minute intervals. The mean of those measurements was used.

Mean follow-up was 40.5 ± 1.8 months in the “strict” group, and 42.2 ± 2.1 months in the “conventional” group.

Participants 87 patients with hypertensive nephrosclerosis were initially considered for the trial. Their age ranged from 25

to 73 years. The inclusion criteria were a diastolic blood pressure higher than or equal to 95 mmHg, a serum

creatinine greater than 1.6 mg/dl but lower than 7.0 mg/dl and a glomerular filtration rate less than or equal to 70

ml/min/1.73m2, history of long-standing hypertension, an inactive urine sediment, a protein excretion rate lower

than 2 grams per day, no physical or biochemical evidence for a humoral-mediated cause for hypertension. Exclusion

criteria were diabetes mellitus, a recent history (in the previous 4 months) of malignant hypertension, stroke or

myocardial infarction, acute renal failure of any cause, analgesic abuse, polycystic kidney disease, systemic lupus

erythematosus, scleroderma, rapidly progressive glomerulonephritis, evidence of significant hepatic impairment (AST

and ALT greater than 2.5 X normal, or serum total bilirrubin > 1.5 mg/dl), mental incapacity, pregnancy or lactation,

primary aldosteronism, renovascular hypertension, pheochromocytoma.

Based on the initial assessment period, 77 patients were classified as “responders” and 10 patients were “non-

responders”. Since they were not randomized, “non-responder” patients were not included in this study.

Interventions “Responder” patients were randomized to either placebo or enalapril, in a double-blind design. They were also

randomized to either “strict” or “conventional” blood pressure ranges. “Strict” was defined as a diastolic blood pressure

lower than 80 mm Hg, whereas “conventional” was defined as a diastolic pressure between 85 and 95 mm Hg.

After randomization, the blinded study drug was titrated to maximum allowable dose and the unblinded antihyper-

tensive agents were back-titrated as needed to achieve and maintain blood pressure control.

Outcomes The primary outcome was the rate of decline in glomerular filtration rate, measured by the renal clearance of 125I-

iothalamate. Other outcomes were death, end-stage renal disease and 50% decline in glomerular filtration rate or

doubled serum creatinine (from baseline).

Notes Assignment to enalapril versus placebo did not change the results of the blood pressure control.



Characteristics of excluded studies [ordered by study ID]

BBB The number of patients randomised to each treatment target was not reported and not provided by the authors.

HDS The higher blood pressure target in this trial (aiming for systolic < 180 mmHg and diastolic < 105 mmHg) was much

higher than the standard target interval defined in our protocol.

Lewis No usable data for any of the outcomes defined in this systematic review were reported

SANDS This trial used a dual intervention, lower blood pressure and lower LDL cholesterol plus both systolic blood pressure

targets were within the values considered as “lower targets” in this systematic review.

Steno-2 The multifactorial intervention in the two treatment groups prevented any inference as to whether any difference in

clinical outcomes could be attributed to a lower blood pressure target or to any of the other combined interventions

UKPDS The higher blood pressure target in this trial (aiming for systolic < 180 mmHg and diastolic < 105 mmHg) was much

higher than the standard target interval defined in our protocol.

Characteristics of ongoing studies [ordered by study ID]

ACCORD 2007

Trial name or title Action to Control CardiOvascular Risk in Diabetes trial

Methods Randomized factorial 2 X 2 design

Participants Type 2 Diabetes Mellitus

Interventions Systolic BP <120 mmHg versus Systolic BP <140 mmHg

Outcomes Mortality, myocardial infarction, stroke, CHF

Starting date February 2003

Contact information http://www.accordtrial.org.

Notes



D A T A A N D A N A L Y S E S

Comparison 1. BP < 135/85 vs BP < 140-160/90-100

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Total Mortality 6 21249 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.86, 1.15]

2 Cardiovascular mortality 5 21172 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.83, 1.28]

3 Non-CV mortality 5 21172 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.78, 1.18]

4 Total serious adverse events 1 338 Risk Ratio (M-H, Fixed, 95% CI) 1.39 [0.90, 2.15]

5 Myocardial infarction 3 19740 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.74, 1.09]

6 Strokes 3 19740 Risk Ratio (M-H, Fixed, 95% CI) 0.99 [0.79, 1.25]

7 Congestive heart failure 3 19740 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.59, 1.32]

8 Major CV events 4 20834 Risk Ratio (M-H, Fixed, 95% CI) 0.94 [0.83, 1.07]

9 End-stage renal disease 3 1509 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.81, 1.27]

10 Achieved systolic blood

pressure

6 21249 Mean Difference (IV, Random, 95% CI) -6.81 [-12.26, -1.36]

11 Achieved diastolic blood

pressure

6 21249 Mean Difference (IV, Random, 95% CI) -5.46 [-8.22, -2.69]

12 Patients not achieving the

target blood pressure

2 19630 Risk Ratio (M-H, Random, 95% CI) 4.16 [0.82, 20.97]

13 Withdrawals due to adverse

effects

1 338 Risk Ratio (M-H, Fixed, 95% CI) 2.0 [0.33, 12.10]

14 Number of antihypertensive

drugs needed

2 1934 Mean Difference (IV, Fixed, 95% CI) 0.54 [0.41, 0.67]



Analysis 1.1. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 1 Total Mortality.

Review: Treatment blood pressure targets for hypertension

Comparison: 1 BP < 135/85 vs BP < 140-160/90-100

Outcome: 1 Total Mortality

Study or subgroup BP < 135/85 BP < 140-160/90-100 Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

AASK 37/540 43/554 12.5 % 0.88 [ 0.58, 1.35 ]

ABCD (H) 10/237 22/233 6.6 % 0.45 [ 0.22, 0.92 ]

ABCD (N) 18/237 20/243 5.8 % 0.92 [ 0.50, 1.70 ]

HOT 401/12526 188/6264 74.0 % 1.07 [ 0.90, 1.27 ]

REIN-2 2/169 3/169 0.9 % 0.67 [ 0.11, 3.94 ]

Toto 1/42 0/35 0.2 % 2.51 [ 0.11, 59.79 ]

Total (95% CI) 13751 7498 100.0 % 0.99 [ 0.86, 1.15 ]

Total events: 469 (BP < 135/85), 276 (BP < 140-160/90-100)

Heterogeneity: Chi2 = 6.21, df = 5 (P = 0.29); I2 =19%

Test for overall effect: Z = 0.09 (P = 0.93)

0.1 0.2 0.5 1 2 5 10

Lower target Higher target



Analysis 1.2. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 2 Cardiovascular mortality.



Outcome: 2 Cardiovascular mortality



AASK 14/540 16/554 10.3 % 0.90 [ 0.44, 1.82 ]

ABCD (H) 6/237 11/233 7.2 % 0.54 [ 0.20, 1.43 ]

ABCD (N) 13/237 9/243 5.8 % 1.48 [ 0.65, 3.40 ]

HOT 186/12526 87/6264 75.4 % 1.07 [ 0.83, 1.38 ]

REIN-2 1/169 2/169 1.3 % 0.50 [ 0.05, 5.46 ]

Total (95% CI) 13709 7463 100.0 % 1.03 [ 0.83, 1.28 ]


Heterogeneity: Chi2 = 3.02, df = 4 (P = 0.55); I2 =0.0%


0.1 0.2 0.5 1 2 5 10


Analysis 1.3. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 3 Non-CV mortality.



Outcome: 3 Non-CV mortality



AASK 23/540 27/554 14.5 % 0.87 [ 0.51, 1.50 ]

ABCD (H) 4/237 11/233 6.0 % 0.36 [ 0.12, 1.11 ]

ABCD (N) 5/237 11/243 5.9 % 0.47 [ 0.16, 1.32 ]

HOT 215/12526 101/6264 73.1 % 1.06 [ 0.84, 1.35 ]

REIN-2 1/169 1/169 0.5 % 1.00 [ 0.06, 15.86 ]

Total (95% CI) 13709 7463 100.0 % 0.96 [ 0.78, 1.18 ]




0.1 0.2 0.5 1 2 5 10




Analysis 1.4. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 4 Total serious adverse events.



Outcome: 4 Total serious adverse events

Study or subgroup <135/85 mm Hg <140-160/90-100 mm H Risk Ratio Weight Risk Ratio


REIN-2 39/169 28/169 100.0 % 1.39 [ 0.90, 2.15 ]

Total (95% CI) 169 169 100.0 % 1.39 [ 0.90, 2.15 ]

Total events: 39 (<135/85 mm Hg), 28 (<140-160/90-100 mm H)

Heterogeneity: not applicable


0.1 0.2 0.5 1 2 5 10

Lower target Traditional target

Analysis 1.5. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 5 Myocardial infarction.



Outcome: 5 Myocardial infarction



ABCD (H) 16/237 14/233 7.1 % 1.12 [ 0.56, 2.25 ]

ABCD (N) 19/237 15/243 7.5 % 1.30 [ 0.68, 2.49 ]

HOT 214/12526 127/6264 85.4 % 0.84 [ 0.68, 1.05 ]

Total (95% CI) 13000 6740 100.0 % 0.90 [ 0.74, 1.09 ]




0.1 0.2 0.5 1 2 5 10




Analysis 1.6. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 6 Strokes.



Outcome: 6 Strokes



ABCD (H) 9/237 9/233 6.2 % 0.98 [ 0.40, 2.43 ]

ABCD (N) 4/237 13/243 8.7 % 0.32 [ 0.10, 0.95 ]

HOT 200/12526 94/6264 85.1 % 1.06 [ 0.83, 1.36 ]

Total (95% CI) 13000 6740 100.0 % 0.99 [ 0.79, 1.25 ]




0.1 0.2 0.5 1 2 5 10


Analysis 1.7. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 7 Congestive heart failure.



Outcome: 7 Congestive heart failure



ABCD (H) 9/237 9/233 18.9 % 0.98 [ 0.40, 2.43 ]

ABCD (N) 12/237 11/243 22.7 % 1.12 [ 0.50, 2.49 ]

HOT 32/12526 21/6264 58.4 % 0.76 [ 0.44, 1.32 ]

Total (95% CI) 13000 6740 100.0 % 0.88 [ 0.59, 1.32 ]




0.1 0.2 0.5 1 2 5 10




Analysis 1.8. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 8 Major CV events.



Outcome: 8 Major CV events

Study or subgroup BP <135/85 BP <140-160/90-100 Risk Ratio Weight Risk Ratio


AASK 51/540 60/554 12.5 % 0.87 [ 0.61, 1.24 ]

ABCD (H) 36/237 39/233 8.3 % 0.91 [ 0.60, 1.37 ]

ABCD (N) 37/237 39/243 8.1 % 0.97 [ 0.64, 1.47 ]

HOT 483/12526 253/6264 71.1 % 0.95 [ 0.82, 1.11 ]

Total (95% CI) 13540 7294 100.0 % 0.94 [ 0.83, 1.07 ]

Total events: 607 (BP <135/85), 391 (BP <140-160/90-100)



0.1 0.2 0.5 1 2 5 10


Analysis 1.9. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 9 End-stage renal disease.



Outcome: 9 End-stage renal disease



AASK 81/540 90/554 71.1 % 0.92 [ 0.70, 1.22 ]

REIN-2 38/169 34/169 27.2 % 1.12 [ 0.74, 1.69 ]

Toto 7/42 2/35 1.7 % 2.92 [ 0.65, 13.15 ]

Total (95% CI) 751 758 100.0 % 1.01 [ 0.81, 1.27 ]




0.1 0.2 0.5 1 2 5 10




Analysis 1.10. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 10 Achieved systolic blood

pressure.



Outcome: 10 Achieved systolic blood pressure

Study or subgroup BP < 135/85 BP < 140-160/90-100 Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

AASK 540 128 (12) 554 141 (12) 17.9 % -13.00 [ -14.42, -11.58 ]

ABCD (H) 237 132 (11.75) 233 138 (11.34) 17.4 % -6.00 [ -8.09, -3.91 ]

ABCD (N) 237 128 (12.31) 243 137 (10.91) 17.4 % -9.00 [ -11.08, -6.92 ]

HOT 12526 140.55 (11.7) 6264 143.7 (11.3) 18.2 % -3.15 [ -3.50, -2.80 ]

REIN-2 169 129.6 (10.9) 169 133.7 (12.6) 17.1 % -4.10 [ -6.61, -1.59 ]

Toto 42 133 (19.4) 35 138 (11.8) 11.9 % -5.00 [ -12.05, 2.05 ]

Total (99% CI) 13751 7498 100.0 % -6.81 [ -12.26, -1.36 ]

Heterogeneity: Tau2 = 24.57; Chi2 = 202.26, df = 5 (P<0.00001); I2 =98%


-20 -10 0 10 20




Analysis 1.11. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 11 Achieved diastolic blood

pressure.



Outcome: 11 Achieved diastolic blood pressure


N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

AASK 540 78 (8) 554 85 (7) 17.3 % -7.00 [ -7.89, -6.11 ]

ABCD (H) 237 78 (5.17) 233 86 (5.24) 17.2 % -8.00 [ -8.94, -7.06 ]

ABCD (N) 237 75 (4.61) 243 81 (4.68) 17.4 % -6.00 [ -6.83, -5.17 ]

HOT 12526 82.15 (5.05) 6264 85.2 (5.1) 17.8 % -3.05 [ -3.20, -2.90 ]

REIN-2 169 79.5 (5.3) 169 82.3 (7.1) 16.7 % -2.80 [ -4.14, -1.46 ]

Toto 42 81 (6.48) 35 87 (5.92) 13.6 % -6.00 [ -8.77, -3.23 ]

Total (99% CI) 13751 7498 100.0 % -5.46 [ -8.22, -2.69 ]


Test for overall effect: Z = 5.08 (P < 0.00001)

-10 -5 0 5 10


Analysis 1.12. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 12 Patients not achieving the

target blood pressure.



Outcome: 12 Patients not achieving the target blood pressure


n/N n/N M-H,Random,95% CI M-H,Random,95% CI

HOT 4259/12526 940/6264 51.6 % 2.27 [ 2.13, 2.42 ]

MDRD 168/432 20/408 48.4 % 7.93 [ 5.09, 12.36 ]

Total (99% CI) 12958 6672 100.0 % 4.16 [ 0.82, 20.97 ]




0.1 0.2 0.5 1 2 5 10




Analysis 1.13. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 13 Withdrawals due to adverse

effects.



Outcome: 13 Withdrawals due to adverse effects



REIN-2 6/169 3/169 100.0 % 2.00 [ 0.51, 7.87 ]

Total (99% CI) 169 169 100.0 % 2.00 [ 0.33, 12.10 ]


Heterogeneity: not applicable


0.1 0.2 0.5 1 2 5 10


Analysis 1.14. Comparison 1 BP < 135/85 vs BP < 140-160/90-100, Outcome 14 Number of antihypertensive

drugs needed.



Outcome: 14 Number of antihypertensive drugs needed


N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

AASK 540 3.04 (1.14) 554 2.39 (1.18) 54.0 % 0.65 [ 0.51, 0.79 ]

MDRD 432 1.91 (1.1) 408 1.5 (1.1) 46.0 % 0.41 [ 0.26, 0.56 ]

Total (99% CI) 972 962 100.0 % 0.54 [ 0.41, 0.67 ]


Test for overall effect: Z = 10.47 (P < 0.00001)

-10 -5 0 5 10




A P P E N D I C E S

Appendix 1. Search Strategy

1. Randomized controlled trial.pt

2. Randomized controlled trials.mp

3. Randomized controlled trial.mp

4. Controlled clinical trial.pt

5. Controlled clinical trials.mp

6. Controlled clinical trial.mp

7. random allocation.mp

8. or/1-7

9. exp animal/

10. 8 not 9

11. Clinical trial.pt

12. Clinical trials.mp

13. Clinical trial.mp

14. Exp clinical trials/

15. (clin$ adj25 trial$).mp

16. Random$.mp

17. Exp research design/

18. Research design.mp

19. Or/11-18

20. 19 not 9

21. 20 not 10

22. Comparative studies.mp

23. Comparative study.mp

24. Exp evaluation studies/

25. Evaluation studies.mp

26. Evaluation study.mp

27. Follow up studies.mp

28. Follow up study.mp

29. Prospective studies.mp

30. Prospective study.mp

31. (control$ or prospective$ or volunteer$).mp

32. 0r 22-31

33. 32 not9

34. 33 not (10 or 21)

35. 10 or 21 or 34

36. Arterial hypertension.mp

37. Hypertension.mp

38. High blood pressure.mp

39. Elevated blood pressure.mp

40. Hypertensive patients.mp

41. Or/36-40

42. Target level.mp

43. Target blood pressure.mp

44. Target systolic blood pressure.mp

45. Target diastolic blood pressure.mp

46. Intensive treatment.mp

47. Intensive blood pressure treatment.mp

48. Intensive antihypertensive treatment.mp

49. Intensive control.mp



50. Intensive blood pressure control.mp

51. Tight control.mp

52. Tight blood pressure control.mp

53. Strict control.mp

54. Strict blood pressure control.mp

55. Or/42-54

56. 41 and 55

57. 35 and 56

H I S T O R Y

Protocol first published: Issue 3, 2003

Review first published: Issue 3, 2009

12 August 2008 Amended Converted to new review format.

11 November 2003 Amended minor changes included in the protocol

C O N T R I B U T I O N S O F A U T H O R S

Jose Arguedas developed the basis for the protocol. He was primarily responsible for searching, identifying and assessing studies, data

extraction and analyses and writing the review.

Marco Pérez independently verified the trials for inclusion and the data entry.

James Wright formulated the idea for the review and assisted in methodologic issues and writing the review.

D E C L A R A T I O N S O F I N T E R E S T

None.

S O U R C E S O F S U P P O R T

Internal sources

• Departments of Anesthesiology, Pharmacology & Therapeutics and Medicine, Faculty of Medicine, University of British

Columbia, Canada.

• Canadian Institutes of Health Research, Canada.



External sources

• British Columbia Ministry of Health Grant to the Therapeutics Initiative, Canada.

• Universidad de Costa Rica, Costa Rica.

• CONICIT, Ministerio de Ciencia y Tecnologia, Costa Rica.



Arguedas JA, Perez MI, Wright JM - PRIMARY CARE TIPS · Contact address: Jose Agustin Arguedas,...

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