1472-6963-6-47 1472-6963 Research article <p>Methods underpinning national clinical guidelines for hypertension: describing the evidence shortfall</p> Campbell Fiona fiona.campbell@ncl.ac.uk Dickinson O Heather heather.dickinson@ncl.ac.uk Cook VF Julia j.v.f.cook@ncl.ac.uk Beyer R Fiona fiona.beyer@ncl.ac.uk Eccles Martin martin.eccles@ncl.ac.uk Mason M James j.m.mason@durham.ac.uk

University of Newcastle upon Tyne, Centre for Health Services Research, 21 Claremont Place, Newcastle upon Tyne, NE2 4AA, UK

University of Durham, School for Health, Wolfson Research Institute, Queen's Campus, University Boulevard, Stockton-on-Tees, TS17 6BH, UK

 BMC Health Services Research 1472-6963 2006 6 1 47 http://www.biomedcentral.com/1472-6963/6/47 16597334 10.1186/1472-6963-6-47 31 8 2005 05 4 2006 05 4 2006 2006 Campbell et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background

To be useful, clinical practice guidelines need to be evidence based; otherwise they will not achieve the validity, reliability and credibility required for implementation.

Methods

This paper compares the methods used in gathering, analysing and linking of evidence to guideline recommendations in ten current hypertension guidelines.

Results

It found several guidelines had failed to implement methods of searching for the relevant literature, critical analysis and linking to recommendations that minimise the risk of bias in the interpretation of research evidence. The more rigorous guidelines showed discrepancies in recommendations and grading that reflected different approaches to the use of evidence in guideline development.

Conclusion

Clinical practice guidelines as a methodology are clearly still an evolving health care technology.

Background

Clinical practice guidelines can provide building blocks for changing and improving health care 1 and are a useful means of bridging the gap between scientific research evidence and usual practice 2. They are defined as 'systematically developed statements to assist physicians and patients about appropriate health care for specific clinical circumstances' 3. To achieve their potential as effective tools for improving health care they need to maximise their validity, a feature related to the use of evidence within a guideline and development using a multidisciplinary process 4. However, despite an apparently explicit methodology there are variations in what guidelines say and how they relate this to underlying evidence 356. There is also concern that guideline development may be subject to external influence 78.

Like many other conditions hypertension has been the subject of many different international guidelines. The World Health Organisation (WHO) have described hypertension – defined as a blood pressure of greater than 140/90 mmHg – as one of the ten leading risk factors influencing the global burden of disease 9. It is a contributory factor in ischaemic heart disease and cerebrovascular disease accounting for 20% and 10% of all deaths in England and Wales respectively 10. Reducing blood pressure levels leads to significant reductions in cardiovascular and cerebrovascular morbidity and mortality 11. Nevertheless the management of hypertension remains suboptimal: for example, 40% of the adult population of England suffer from hypertension, but current levels of detection and treatment result in only 9% of sufferers having their hypertension controlled to <140/90 mm Hg 12. There is a clear need to improve the management of hypertension both in this country and worldwide. If guidelines, however, are to play a role in this improvement they will need to maximise their validity.

The aim of this study was to review how well 10 guidelines for hypertension addressed validity in terms of their methods and their use of published evidence.

Methods

Contributing guidelines

We reviewed the methods used in development and the key recommendations of ten current guidelines (see table 1) meeting the following criteria: they concerned the general management of hypertension, or the management of hypertension in specific populations; published in English and nationally or internationally recognised. Guidelines developed before 1994 were also excluded as they predated the publication and wide dissemination of the work by Field and Lohr which offered the first and seminal work on guideline methodology 1.

<p>Table 1</p>

Recent major guidelines for hypertension

Organisation

Publication Year

Acronym

Canadian Medical Association [13]

1999

CMA

World Health Organisation – International Society of Hypertension [14]

1999

WHO

Veterans Health Administration (US) [15]

2000

VHA

Scottish Intercollegiate Guidelines Network [18]

2001

SIGN

European Society of Hypertension[19]

2003

ESH

Institute for Clinical Systems Improvement (US) [16]

2003

ICSI

Joint National Committee VII (US)

2003

JNC

Southern African Hypertension Society [17]

2003

SA

British Hypertension Society [21]

2004

BHS

National Institute for Clinical Excellence [22]

2004

NICE

We used five guidelines (CMA 13, WHO 14, VHA 15, ICSI 16, SA 17) meeting these criteria retrieved by the comprehensive search strategy employed by the German Guideline Clearing Report 7, whose search strategy covered 1990–1999. We updated the strategy by searching MEDLINE, EMBASE and OMNI from 1999 onwards using the thesaurus heading HYPERTENSION and limiting to guidelines or practice guidelines in English. This retrieved a further five guidelines (SIGN 18, ESH 19, JNC 20, BHS 21, NICE 22) for consideration.

Evaluation of guideline development methods

We evaluated the methods used to develop each guideline with particular reference to three dimensions that relate to the use of research evidence, as found in the full published report of each guideline:

• the construction of the guideline development group and its component stakeholders.

• the use of published literature and the strategy used in screening for the primary evidence; in particular, the use of existing systematic reviews or the performance of a new systematic review explicitly to answer questions posed by the guideline.

• the grading of evidence and recommendations: in particular, an explicit link between recommendations and supporting evidence.

Evaluation of recommendations and their underlying evidence

We compared recommendations on four areas that were common to all the guidelines: diagnosis of hypertension, lifestyle modification, criteria for initiation of antihypertensive drug therapies and initial recommended drug therapy. We also explored links between recommendation grades and citations and looked at how these differed in recommendations for drug therapy and salt intake.

Results

Methods used to develop the guidelines

The measures used to assess the guideline development process are summarised in table 2.

<p>Table 2</p>

Methodological aspects of recent major guidelines for hypertension

Guideline

Development group describeda

New systematic reviewing

Used existing systematic reviewsc

Literature searchb

Grading of evidenced

Grading of recommendationsd

CMA

P

N

Y

Y

Y

Y

WHO

P

N

Y

N

N

N

VHA

P

N

N

Y

Y

Y

SIGN

Y

N

Y

Y

Y

Y

ESH

Y

N

Y

N

N

N

ICSI

N

N

y

N

Y

N

JNC

P

N

Y

N

Y

N

SA

P

N

y

N

N

N

BHS

P

N

Y

N

Y

Y

NICE

Y

Y

Y

Y

Y

Y

a Y/N: Includes/does not include description of stakeholders involved in the development process, including patient representatives and any conflicts of interest.

P: Partially – a list of names with institutional affiliations was provided.

b Y/N: Searches were/were not undertaken, at least through Medline.

c Y: Made extensive use of existing systematic reviews (referenced 7 or more).

y: Made partial use of existing systematic reviews (referenced 6 or less).

N: Did not use existing systematic reviews.

d Y/N: Reports/does not report explicit grading of the quality of the supporting evidence/recommendations.

Only three guidelines were constructed by multidisciplinary groups where the members' affiliations and conflicts of interest were described; these three guideline groups included patient representatives as well as key professional stakeholders. A further six guidelines provided only a list of names and institutional affiliations of members of the guideline development group. One further guideline gave no details of the guideline development group (see table 3).

Only one guideline conducted new systematic reviews to inform recommendations. Seven guidelines made extensive use of existing systematic reviews; three of these guidelines also stated that a search strategy based on MESH search terms was used for identifying relevant research evidence. A further two guidelines made limited use of existing systematic reviews.

<p>Table 3</p>

Methodological aspects of previously published guidelines

Guideline

Literature search

Grading of evidence

Development group

CMA

MEDLINE and Cochrane Collaboration searches; reference lists in retrieved articles. Requests to experts and panel members.

Recommendations were graded from A-D and were based on assessment of the studies using an algorithm.

A Grade assigned if recommendation was:

– based on an adequate RCT ie, with blinded assessment of outcomes, intention-to-treat analysis, adequate follow-up, and sufficient sample size to detect a clinically important difference with power greater than 80%.

– based on an adequate subgroup analysis

– based on a systematic review in which the comparison arms are derived from head-to head comparisons with the same RCT

A committee with a range of representatives from different bodies. Patient involvement unclear

WHO

None described

None described

Patient involvement unclear

VHA

MeSH terms covering key therapies, and study characteristics and design

Evidence was graded:

A RCT

B well-designed clinical studies

C panel consensus

Recommendations were rated:

I usually indicated; always acceptable; useful and effective

IIa acceptable, of uncertain effectiveness, and may be controversial. Weight of evidence in favour of usefulness/effectiveness

IIb acceptable, of uncertain effectiveness and may be controversial. Not well established by evidence, can be helpful and probably not harmful

Thirty-eight individuals. Roles not always clear.

SIGN

Systematic literature searches on MEDLINE, Healthstar, EMBASE, Cochrane Library. Based on a published Cochrane review

Evidence was graded when obtained from:

Ia: meta-analysis of RCTs Ib: at least 1 RCT

IIa: at least 1 well-designed controlled study without randomisation

IIb: at least one other type of well-designed quasi-experimental study

III: well-designed non-experimental descriptive studies

IV: expert committee reports and/or respected clinical opinion

Recommendations were rated:

A Evidence levels Ia, Ib

B Evidence levels IIa, IIb, III

C Evidence level IV.

Members' names and affiliations listed and conflicts of interest available. Specialist reviewer names given. Age Concern represented.

ESH

None described

Recommendations not classified upon strength of available evidence.

Members' names, affiliations, potential conflicts of interest given. Patient involvement unclear

ICSI

None described

Research reports were graded as follows:

Primary reports A (RCT) to D (case and cross sectional studies)

Reviews M (Meta-analysis, systematic reviews, decision analysis, cost-benefit analysis, cost-effectiveness study)

R: Narrative review, consensus statement or report

X: Medical opinion

In the 2002 update, some recommendations link to the evidence grade

No details

JNC

None described

Evidence supporting recommendations for prevention and treatment was classified:

M meta-analysis

Re retrospective analyses (case control)

RA RCT

F prospective follow-up – cohort study

Pr previous review

C clinical interventions (non-randomised)

X cross-sectional population studies (prevalence)

Nine individuals. Contributions were sought from multidisciplinary experts. No mention of patient involvement

SA

None described

Evidence not described or graded

Members' names and affiliation given. Patient involvement unclear

BHS

Not described

Strength of evidence: Ia (meta analysis of RCTs) to IV expert opinion Strength of recommendation

A Directly based on category I evidence

B Directly based on category II evidence or extrapolated recommendation from category I evidence

C Directly based on category III evidence or extrapolated recommendation from category I or II evidence.

D Directly based on category IV evidence or extrapolated recommendation from category I, II or III evidence

No details given

NICE

Search using MEDLINE, EMBASE and CENTRAL, previous systematic reviews, bibliographic seachs as well as contact with subject area experts.

Guideline Recommendation and Evidence Grading (GREG [34]) system applied.

Evidence Grade: Interpretation of Evidence

I High Plausible, precisely quantified and not vulnerable to bias.

II Intermediate Plausible but not quantified precisely or may be vulnerable to bias.

III Low Concerns about plausibility or vulnerability to bias.

Recommendation Grade Interpretation of recommendation

A Recommendation Robust evidence

B Provisional Recommendation Recommend with caution

C Consensus Opinion Recommended by consensus

Members names and affiliations given and any potential conflicts of interest. Contributions were sought from multidisciplinary experts. Group included patient representatives

There were different approaches used in the guidelines to assess the evidence available upon which to base a recommendation and upon the grading of the recommendation itself (see table 3 for a description of the grading systems used in the guidelines). Three guidelines did not grade either the evidence they cited or their recommendations. Two coded the evidence on the basis of study design but did not link this to the recommendations. In contrast, five guidelines graded the evidence and explicitly linked this to the recommendations. However, there were differences also between these grading systems with different criteria used to assess the contributing studies. The grading systems used by two guidelines (NICE, CMA) allowed for the quality of relevant randomised controlled trials and meta-analyses and the strength of their results to be analysed. The grading systems used by other guidelines did not allow for this more sensitive assessment of the evidence. Differences and shortcomings in these grading systems can be confusing and impede effective communication 23. The GRADE system was developed as a result of these shortcomings and recommends an approach which takes into account study design, quality, consistency and directness in judging the considers the benefit harm ratio, quality of evidence, applicability, and baseline risk when translating to recommendation 23.

Recommendations made by the guidelines

Diagnosis of hypertension

The guidelines were consistent in defining the threshold for hypertension as 140/90 mmHg and all agreed that blood pressure should be measured twice in a consultation on at least two separate occasions. The need for a full medical examination, clinical history and accurate blood pressure measurement was described in all of the guidelines. However, they differed on the recommended routine tests. All agreed that an electrocardiogram, blood chemistry, a complete blood cell count and urinalysis should be conducted during the initial assessment of hypertension, to assess broader cardiovascular risk. There was less agreement on the assessment of: total cholesterol, lipid profile, blood glucose, creatinine, blood calcium, thyroid stimulating hormone, gammaglutamyl transpeptidase and serum urate.

Lifestyle modifications

All of the guidelines addressed lifestyle modification as an integral part of the management of hypertension and as a first line treatment in mild hypertension, and made similar recommendations for weight loss, limiting alcohol and sodium intake, regular exercise and smoking cessation (see table 4). Guidelines typically recommended a target BMI of 18.5 – 25 kg/m2, restriction of salt intake to under 6 g/day and restriction of alcohol to 14 to 20 g (ethanol) per day for women and from 24 to 30 g (ethanol) per day for men. Differences in the daily limits for alcohol consumption may reflect the variations on guidance for sensible drinking in different countries. Most guidelines recommended a diet rich in fruit and vegetables with reduced saturated and total fats. Guidelines typically recommended 30–45 minutes of aerobic exercise three to five times per week. Although their recommendations were similar, guidelines lacked consistency in the estimations of the effect of lifestyle changes on blood pressure, possibly reflecting the different data sources used. Guidelines varied in the additional areas that they addressed: potassium, magnesium and calcium supplementation, management of stress and caffeine consumption were considered by some of the guidelines. This demonstrates one of the challenges facing guideline developers. Each clinical care pathway involving assessment, diagnosis, treatment and follow-up requires multiple complex decisions. A clinical guideline will be unable to offer guidance on every consideration that must be made by caregivers and patients. Guidelines will reflect this complexity and are likely to vary in their scope and coverage of the decisions involved in the care pathway.

<p>Table 4</p>

Recommendations for lifestyle interventions in recent major guidelines for hypertension

Guideline

Weight reduction

Diet

Salt restriction

Alcohol restriction

Smoking cessation

Exercise

Recommended weight

Reduce saturated fat

Increase fruit & vegetables

Other recommendations

Recommended max. daily intake

Recommended max. daily intake (ethanol)

CMA

Y

(BMI 20–25 kg/m2)

No specific recommendation

Y

(3–7 g/day)

≤17.4 g/day (women)

≤27.0 g/day (men)

Y

50–60 mins. aerobic exercise 3–4 times per week

WHO

Y if overweight

Y

Y

Increase fish consumption

Y

(≤ 6 g/day)

≤10–20 g/day (women)

≤ 20–30 g/day (men)

Y

30–45 mins. aerobic exercise 3–4 times /week

VHA

Y

(if > 10% of ideal body weight)

Y

Y

Increase cereal consumption

Y

(≤ 6 g/day)

≤14 g/day (women)

≤ 28 g/day (men)

Y

30–45 mins. aerobic exercise 3–5 times/week

SIGN

Y

(BMI < 25 kg/m2)

Y

Y

Y

(<5 g/day)

≤15.8 g/day (women)

≤ 23.7 g/day (men)

Y

30–45 mins. aerobic exercise most days

ESH

Y

Y

Y

Increase fish consumption

Y

(4.7–5.8 g/day)

≤10–20 g/day (women)

≤ 20–30 g/day (men)

Y

30–45 mins. aerobic exercise 3–5 times/week

ICSI

Y if overweight

Y

Y

Increase low fat dairy food consumption

Y

(<6 g/day)

≤14 g/day (women)

≤ 28 g/day (men)

Y

30–45 mins. aerobic exercise 3–4 times/week

JNC

Y

(BMI 18.5–25 kg/m2)

Y

Y

Increase low fat dairy food consumption

Y

(≤ 6 g/day)

≤14 g/day (women)

≤ 28 g/day (men)

Not discussed

≥30 mins. aerobic exercise most days

SA

Y

(BMI < 25 kg/m2)

Y

Y

Increase fibre, unrefined carbohydrates

Y

≤24 g/day

Y

30 mins. aerobic exercise 3–5 times per week

BHS

Y

(BMI 20–25 kg/m2)

Y

Y

Reduce total fat

Y

(< 6 g/day)

≤15.8 g/day

≤ 23.7 g/day (men)

Y

> 30 mins. aerobic exercise most days

NICE

Y

Healthy, low calorie diet

Y

(<6 g/day)

< 14 units/wk (women)

< 21 units/week (men)

Y

30–60 mins. 3–5 times/week

Criteria for initiation of antihypertensive drug therapy

Guidelines used a varying combination of blood pressure and other factors to establish a threshold for drug therapy (see Table 5). These factors included the presence of concomitant disease, target organ damage, cardiovascular risk factors, response to lifestyle changes and the patient's own personal preferences. For uncomplicated patients the relatively recent SA and JNC guidelines recommended lower thresholds. All guidelines (except CMA) recommended lower thresholds for patients with target organ damage, renal disease or diabetes. Some guidelines modified their recommendations for older age groups and specific ethnic groups.

<p>Table 5</p>

Recommended thresholds for drug treatment and initial drug therapy in recent major guidelines for hypertension

Thresholds for initiating drug treatment*

Initial drug therapy in uncomplicated patient (non-black patient aged over 55–60 years)†

Guideline

No target organ damage or risk factors

With risk factors (other than diabetes mellitus)

With target organ damage

With diabetes mellitus or renal disease

Recommendation

Grade of recommendation

CMA

≥160/90

≥160/90

≥160/90

≥140/90

Thiazides

A

WHO

≥150/95

≥140/90

≥140/90

≥130/85

Low dose monotherapy

VHA

>160 and/or>100

>160 and/or >100

≥130/85

≥130/85

Thiazides or β-blockers

SIGN

≥160/100

≥160/100

≥140/90

≥140/90

Thiazides

A

ESH

≥150/95

≥140/90

≥130/85

≥130/85

Low dose monotherapy or a combination

ICSI

≥160/100

≥140/90

≥130/85

≥130/85

Thiazides

JNC

≥140/90

≥140/90

≥130/80

≥130/80

Thiazides alone and/or combination ACE, ARB, β-blockers, CCB

SA

≥140/90

≥140/90

≥130/85

≥130/85

Thiazides

BHS

≥160/100

≥140/90

≥140/90

≥140/90

Thiazides or calcium channel blockers

C

NICE

≥160/100

≥160/100 or ≥ 140/90 if CHD§ risk ≥ 15% or CVDrisk ≥ 20%

≥140/90

Outside scope of guideline

Thiazides

A[34]

* Blood pressure threshold in mmHg

† Thiazides: low dose thiazide diuretics

ACE: angiotensin-converting enzyme inhibitors

ARB: angiotensin receptor blockers

CCB: calcium channel blocker

§CVD: cardiovascular disease

¶CHD: coronary heart disease

First line drug therapies

Variations existed in thresholds for initiating drug treatment and initial drug therapy in typical patients (table 5). Five guidelines recommended the use of thiazdes as initial therapy in non- black patients aged over 55–65 years (SIGN, CMA, ICSI, SA, NICE). The other five differed in their recommendations, one recommended thiazides or b-blockers (VHA), one recommended low dose monotherapy selecting from a broad range of antihypertensive agents (WHO), one recommended low dose monotherapy or a combination of low dose antihypertensive agents (ESH), one recommended thiazides or calcium channel blockers (BHS) and one recommended thiazides alone or in combination with a range of antihypertensive drugs (JNC). The pattern of variation in these recommendations did not follow publication date of the guideline or relate to the research sources used in the development of the guideline.

Grading recommendations and links to the evidence base

Salt intake

Although all guidelines recommended restriction of salt intake, four (SIGN, CMA, BHS, NICE) relied upon a similar and extensive body of work, either directly using the original data in a systematic review or indirectly sourcing the study via a previously published systematic review (see table 6). Nevertheless, these four guidelines were inconsistent in their grading of the recommendation: two guidelines (CMA, NICE) graded it 'B' suggesting that the pattern of care was recommended with caution and based upon research evidence subject to bias, while two graded it as 'A' (BHS, SIGN) indicating that the recommendation was based on strong research evidence not vulnerable to bias. Although the VHA guideline cited much less evidence than these four guidelines, it nevertheless graded salt restriction as 'I', equivalent to 'A' in other schemes. These disparities reflects the differences in the grading of recommendations in guideline development. Both the CMA and NICE guidelines adopted systems that required judgement about the quality of the RCT and the strength of its findings rather than a system that graded recommendations solely upon research design. The other five guidelines made similar recommendations about salt restriction, although they cited very limited evidence to support this.

<p>Table 6</p>

Reporting in guidelines of trials and systematic reviews of salt reduction

Reference

Year

CMA 1999

WHO 1999

VHA 1999

SIGN 2001

ESH 2003

ICSI 2003

JNC 2003

SA 2003

BHS 2004

NICE 2004

Randomised Controlled Trials

Silman [35]

1983

Y

SR[36]

Y

Fagerberg [37]

1985

SR[38]

SR[38]

SR[38]

Y

Chalmers [39]

1986

SR[38]

SR[40]

SR[38]

SR[38]

Y

Chalmers [41,42]

1989

SR[40]

Y

TOHPI

1992

Y

Y(ex)

Jula [43]

1994

SR[38]

SR[38]

SR[38]

Y

Whelton [44]

1998

Y

Y

Y(ex)

Appel [45]

2001

Y

Y(ex)

Sacks [46]

2001

Y

Y

Y(ex)

Systematic Reviews

Law [47]

1991

Y

Y

Y

Midgely [38]

1996

Y

Y

Y

Y

Cutler [40]

1997

Y

Y

Y

Hooper [36]

2002

Y

Y

Grade of recommendation

B

I

A

-

-

-

-

A

B[34]

Y Trial cited by guideline

SR Trial included in systematic review cited by guideline

Y(ex) Trial cited by guideline but excluded from meta-analysis

First line drug therapy

Overall the guidelines were relatively consistent in the studies that they cited as the evidence for the drug treatment recommendations (Table 7). One guideline (VHA) cited very little evidence; another (ICSI) did not cite any systematic reviews but referred to recent primary reports of trials, two guidelines (CMA, SA) relied almost exclusively on existing systematic reviews, whereas others (WHO, SIGN, ESH, JNC, BHS) supplemented citation of systematic reviews with citation of recent primary reports; one guideline (NICE) performed its own systematic review. Recommendations for use of thiazides and/or beta-blockers as initial drug therapy in typical patients were graded as 'A' by three guidelines (NICE, SIGN and CMA). One guideline (BHS) recommended thiazides or calcium channel blockers grading it 'C'. This recommendation was largely based on the ABCD algorithm which in turn is based upon an extrapolation of how different drugs work rather than RCT findings; hence the evidence was graded as category III (descriptive studies, or evidence extrapolated from RCTs or quasi experimental studies), leading to the grade of 'C' for the recommendation.

<p>Table 7</p>

Reporting in guidelines of trials of antihypertensive medication a

Triala

Yearb

CMA 1999

WHO 1999

VHA 1999

SIGN 2001

ESH 2003

ICSI 2003

JNC 2003

SA 2003

BHS 2004

NICE 2004

VA-II[48]

1970

SR[49, 50]

SR[49,51]

SR[49,51,52]

SR[51]

SR[53]

SR[51]

SR[49]

HSCSG[54]

1974

SR[50]

SR[51]

SR[51]

SR[51]

SR[53]

SR[51]

USPHS[55]

1977

SR[50]

SR[51]

SR[51]

SR[51]

SR[53]

SR[51]

VA-NHLBI[56]

1978

SR[50]

SR[51]

SR[51]

SR[51]

SR[53]

SR[51]

HDFP[57-59]

1979

SR[49]

SR[49,51]

SR[49,51,52,60]

SR[51,61]

SR[51]

SR[49]

ANBPS[62]

1980

SR[51]

SR[51,52,60]

SR[51,63]

SR

SR[51]

EWPHE[64,65]

1985

SR[49,50]

SR[49,51,66]

SR[51,61]

SR[53]

SR[51]

SR[49]

IPPPSH[67]

1985

MRC[68]

1985

SR[50]

SR[51]

SR[53]

SR[51]

Coope[69]

1986

SR[49]

SR[49,51,66]

SR[51,61]

SR[53]

SR[51]

SR[49]

OSLO[70]

1986

SR[50]

SR[51]

SR[51]

SR[51]

SR[53]

SR[51]

SHEP-P[71-73]

1986

SR[50]

SR[60]

SR[61]

SR[53]

HAPPHY[74]

1987

SR[50]

MAPHY[75]

1988

CAPPP[76,77]

1990

SHEP[78-81]

1991

STOP-H[82]

1991

SR[49]

SR[61]

SR[53]

SR[49]

SYST-EUR[83-86]

1991

SR[87]

MRC-O[88]

1992

SR[50]

SR[61]

SR[53]

SR[49]

STOP-H2[89-91]

1993

SR[92]

SR[63,87,93]

NICS-EH[94,95]

1994

SR[92]

SR[63,87,93]

SR[63,96]

HOT[97]

1995

PATS[98]

1995

ALLHAT[99,100]

1996

MIDAS[101,102]

1996

SR[50,92]

SR[63]

VHAS[103]

1997

SR[50,92]

SR[3,87,93]

SR[63,96]

ABCD[104]

1998

SR[92]

SR[87]

FACET[105]

1998

SR[92]

UKPDS[106]

1998

HOPE[107]

2000

INSIGHT[108,109]

2000

SR[92]

NORDIL[110]

2000

SR[92]

IDNT[111]

2001

SR[93]

SR[96]

PROGRESS[112]

2001

c

RENAAL[113]

2001

ELSA[114]

2002

SR[93]

SR[96]

LIFE[115]

2002

ANBP2[116,117]

2003

SR[93]

SR[96]

CONVINCE[118,119]

2003

SR[96]

SCOPE[120]

2003

SR[96]

JMIC-B[121]

2004

SR[96]

VALUE[122-124]

2004

a Trials post-dating the guidelines (indicated by the stepped line) were not available to the guideline developers.

b Year of earliest publication.

c Referred only to rationale and design.

Primary report of trial cited by guideline.

SR Trial included in systematic review cited by guideline; primary report not cited by guideline.

Discussion

Current guidelines are inconsistent in their handling of key methodologies that relate to the sourcing, interpretation and application of research evidence. Some cite a substantial body of evidence whereas others present little evidence. Some grade their recommendations – although the grading systems and grades used are not consistent – whereas others do not. These findings are consistent with other studies exploring the quality of guideline development 24252627. Methodological failings may affect the quality of the guideline in several ways. A search that is insufficiently thorough may introduce bias into the summary of the evidence 28. Systematic reviews have been described as the optimum method of summarising evidence of effectiveness within a clinical practice guideline 29. In this study we found that most of the guidelines relied on previously published systematic reviews, despite the possible problems with this strategy. Firstly, systematic reviews may date quickly and not incorporate newer evidence. Secondly, the scope of the published reviews may not always match the remit of the guideline and so may not be relevant to the target population of the guideline. Thirdly, up-to-date high quality systematic reviews may not be available in all the areas covered by a guideline.

Despite the inconsistent approach in the guidelines to sourcing the evidence, interpreting it and applying it to recommendations, and the great variation in the volume of supporting evidence cited, the areas of consensus are substantial. Different hypertension guidelines made similar recommendations for many areas of management, notably recommendations for lifestyle changes and their role as first line interventions for patients in certain categories of risk. This level of agreement suggests the possibility either that the published guideline did not cite all the evidence which influenced the recommendations, or that guideline groups may develop guidelines that are heavily influenced by previously published guidelines or an implicit international consensus. Guidelines generated without a systematic search of the literature and without systematic review of all the supporting evidence would be more likely to reflect the biases of developers and it would not be surprising if they were congruent with other guidelines in the same area.

Only five guidelines graded the recommendations made. Failure to grade research evidence and the subsequent recommendations means that the decision making process is not explicit and does not inform the guideline user of the strength of evidence underpinning a particular pattern of care.

The inconsistent grading of the same recommendation in different guidelines also indicates varying approaches to interpreting and applying research evidence in guideline development. The process of evaluating the quality of research evidence and applying this to guideline recommendations using a system of grading is clearly inconsistent and currently an evolving area of guideline methodology.

As well as seeking research evidence, guidelines seek to elicit and incorporate the views of clinical experts and various stakeholders in interpreting the evidence or in offering expert opinion where objective evidence is sparse. Indeed this is an important feature used to assess the quality of a guideline 30. Differences in guidelines, reflecting the differing views of individuals participating in the guideline development process, are therefore to be expected 2931. Herein lies a tension between the rigour needed to try and produce objective and unbiased statements and to also be responsive to the views of participants. It is clear from other reviews of clinical guidelines that the composition of the development group is reflected in the recommendations. Savoie et al 31 in their critical appraisal of guidelines for cholesterol testing found that the greater the involvement of clinical experts in the development process of the guideline, the less the recommendations reflected the research evidence. As only three of the guidelines which we considered fully reported the composition of the guideline development group, it is not possible to make inferences about its impact on recommendations for hypertension. Achieving evidence based guidelines while incorporating the views of the various stakeholders within the development group may create conflict and divergence that the final guideline may mask. The differences between the guidelines described here may reflect this tension.

Differences in recommendations may reflect not only differences in material sourced, differences in interpreting and grading the evidence but also different influences in moving from evidence to recommendations. Differing recommendations for first line drug therapy suggest this. The research base underpinning the recommendations for first line drug therapies is strong in terms of the number and quality of trials in the area (see table 6). Nevertheless, three guidelines (NICE, SIGN and CMA) recommended thiazides for the uncomplicated patient, grading this as 'A', while one (BHS) recommended thiazides or calcium channel blockers grading it 'C'. This suggests either a strong competing interest or the possibility that a less supported but broader recommendation is felt to hold greater clinical merit than older treatments which have accumulated a strong research base. This again may reflect a tension in the development of guidelines, between the restrictiveness of the conventional evidence based approach which inevitably relies on older, well researched therapies and the greater openness of an approach which allows newer, less well endorsed treatments.

Clinical guidelines are rarely based solely on the research evidence and incorporate the consensus views of experts. Raine et al. argue that current approaches to guideline development often lack a sufficient transparency and reliability concerning how such consensus opinions are formed 32. They highlight the possible influence of key individuals, unrepresentative decision making and the role of constraints of time and resources which limit the range of guidelines that can be generated and their need for updating. They propose an approach which makes reasons for disagreement and degree of consensus explicit and suggests the inclusion of a survey stage to enhance reliability.

The potential influence of external pressures in the formation of guideline recommendations highlights the need for transparency in the declarations of conflictions of interest by authors of clinical practice guidelines. One investigation of panels that write clinical guidelines found that more than one-third of authors declared financial links to relevant drug companies, with around 70% of panels being affected 33. Another study found that 87% of authors of clinical practice guidelines had some form of interaction with the pharmaceutical industry 7. If authors have relationships that pose a potential conflict of interest these need appropriate disclosure so that readers may evaluate the merit of those guidelines.

Conclusion

Many challenges exist to improve the use of evidence in all its forms in guideline development. Clinical practice guidelines remain a developing healthcare technology and if they are to fulfil their potential as a tool to improve standards of care these challenges need to be addressed. The requirements of future guidelines are clear if they are to inform clinicians and patients about appropriate healthcare. Authoritative and rigorously developed guidelines should (where possible) feature transparent and fully reported: guideline group methods and participation; involvement of stakeholders and sponsors; reporting and use of evidence and linking of recommendation to evidence; understanding of health care delivery, the policy context and narratives of patient experience.

Abbreviations

ACE angiotensin converting enzyme

ARB angiotensin receptor blocker

BMI body mass index

g gram

kg kilogram

m metre

mmHg millimetres of mercury

mins minutes

Competing interests

The authors contributed to the development of one of the guidelines reviewed 26.

Authors' contributions

FC, HOD and JMM wrote the manuscript.

ME critically revised the manuscript.

FC, JC, FRB, HOD and JMM performed data abstraction.

FC and FRB performed literature searches.

JMM designed the study.

Acknowledgements

This work was undertaken with funding from the National Institute for Clinical Excellence. However, the views expressed are those of the authors and not the funding body.

 Field MJ Lohr KN (eds) Guidelines for clinical practice: from development to use Washington DC, National Academy Press <p>Institute of Medicine Committee on Clinical Practice Guidelines</p> 1992 <p>Credibility, cookbook medicine, and common sense: guidelines and the college</p> Dans PE Annals of Internal Medicine 1994 120 966 968 8172442 Guidelines CCP Clinical practice guidelines: directions for a new program Washington, National Academy Press, Institute of Medicine Field MG LKN 1990 <p>Developing cost effectiveness guidelines</p> Eccles M Freemantle N Mason J BMJ 1997 27 27 <p>Development and validation of an interational appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project</p> Collaboration TAGREE Quality and Safety in Health Care 2003 12 18 23 10.1136/qhc.12.1.18 <p>International comparison of 19 clinical guideline programmes - a survey of the AGREE Collaboration</p> Burgers J Grol R Klazinga N Van Der Bij A Makela M Zaat J Ollenschlager G Grilli R Slutsky JPNC Bruun Madsen P Durieus P Brouwers M Jackson R Meulenberg F Ten Have P Fervers B Grimshaw J Burnand B Miller J Makela J Dosquet P Eccles M Silagy C Bowersox J Irwin P Dahlgren H Atkins D Zeitschrift fur Arzliche Fortbildung und Qualitatssicherung 2003 97 81 88 <p>Relationships between authors of clinical practice guidelines and the pharmaceutical industry</p> Choudhry NK Stelfox HT Detsky AS JAMA 2002 287 612 617 10.1001/jama.287.5.612 11829700 <p>Just how tainted has medicine become?</p> Editorial The Lancet 2002 359 1167 1167 10.1016/S0140-6736(02)08198-9 <p>The world health report 2002: reducing risks, promoting healthy life</p> WHO Geneva 2002 Statistics ON Key Health Statistics from General Practice 1998: analysis of morbidity and treatment data, including time trends, England and Wales London, National Statistics 2000 <p>Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies</p> Collaboration PS Lancet 2002 360 1903 1913 10.1016/S0140-6736(02)11911-8 12493255 <p>Improved hypertension management and control: results from the health survey for England 1998</p> Primatesta P Brookes M Poulter NR Hypertension 2001 38 827 832 11641294 <p>1999 Canadian recommendations for the management of hypertension including case-based applications of the recommendations</p> Task force for the Development of the 1999 Canadian recommendations for the management of hypertension Can Med Assoc J 1999 161 S1 S22 <p>1999 World Health Organization-International Society of Hypertension Guidelines for the Management of Hypertension. Guidelines Subcommittee</p> WHO J Hypertens 1999 17 151 183 10067786 <p>VHA/DOD Clinical Practice Guideline for diagnosis and management of hypertension in the primary care setting</p> Workgroup TH USA, Veteran's Health Administration and Department of Defense 1999 http://www.va.gov/health/hypertension/HTN.doc <p>Hypertension diagnosis and treatment</p> Improvement ICS ICSI 2003 1 46 <p>South African Hypertension Guideline 2003 update</p> Southern Africa Hypertension Society Hypertension Guideline Working Groups 2000 and 2003 South Africa, Southern Africa Hypertension Society 2003 i 32 <p>Hypertension in older people</p> Network SIG Edinburgh, SIGN 2001 1 50 <p>2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension</p> Committee G J Hypertens 2003 21 1011 1053 12777938 <p>The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.</p> Chobanian AV Bakris GL Black HR Cushman WC Green LA Izzo JL Jones DW Materson BJ Oparil S Wright JTJ Roccella EJ National Heart LBIJNCPDETHBP National High Blood Pressure Education Program Coordinating Committee. JAMA 2003 289 2560 2572 10.1001/jama.289.19.2560 12748199 <p>The BHS Guidelines Working Party Guidelines for Management of Hypertension: Report of the Fourth Working Party of the British Hypertension Society, 2004 - BHS IV</p> Williams B Poulter N Brown MJ Davis M McInnes GT Poulter N Potter JP J Hum Hypertens 2004 18 139 185 10.1038/sj.jhh.1001683 14973512 <p>Essential hypertension: managing adult patients in primary care</p> North of England Hypertension Guideline Development Group Newcastle, Centre for Health Services Research, University of Newcastle 2004 <p>Systems for grading the quality of evidence and the strength of recommendations I: critical appraisal of existing approaches The Grade Working Group</p> Atkins D Eccles M Flottorp S Guyatt GH Henry D Hill S Liberati A O'Connell D Oxman AD Phillips B Schunemann H Tan-Torres Edejer T Vist GE Williams Jr JW Group TGW BMC Health Services Research 2004 4 545647 15615589 <p>Practice guidelines developed by specialty societies: the need for a critical appraisal</p> Grilli R Magrini N Penna A Mura G Liberati A Lancet 2000 355 103 106 10.1016/S0140-6736(99)02171-6 10675167 <p>Guidelines on anticoagulant treatment in atrial fibrillation in Great Britain: variation in content and implications for treatment</p> Thomson R McElroy H Sudlow M BMJ 1998 316 509 513 9501712 <p>The relation between methods and recommendations in clinical practice guidelines for hypertension and hyperlipidemia.</p> Fretheim A Williams JWJ Oxman AD Herrin J J Fam Pract 2002 51 963 968 12485552 <p>The 2001 Canadian recommendations for the management of hypertension: Part two--Therapy</p> McAlister FA Zarnke KB Campbell NR Feldman RD Levine M Mahon J Grover SA Lewanczuk R Leenen F Tobe S Lebel M Stone J Schiffrin EL Rabkin SW Ogilvie RI Larochelle P Jones C Honos G Fodor G Burgess E Hamet P Herman R Irvine J Culleton B Wright JM Group. CHRW Can J Cardiol 2002 18 625 641 12107420 <p>Systematic reviews: identifying relevant studies for systematic reviews</p> Dickersin K Scherer R Lefebvre C BMJ 1994 309 1286 1291 7718048 <p>Using systematic reviews in clinical guideline development</p> Eccles M Freemantle N Mason J Systematic Reviews in Health Care BMJ publishing group M E, G DS and DG A 2001 400 409 <p>Appraisal Instrument for Clinical Guidelines</p> Cluzeau F Littlejohns P Grimshaw J Feder G London, St George's Hospital Medical School 1997 <p>Do clinical practice guidelines reflect research evidence?</p> Savoie I Kazanjian A Bassett K J health Serv Res Policy 2000 5 76 82 10947551 <p>Developing clinical guidelines: a challenge to current methods.</p> Raine R Sanderson C Black N British Medical Journal 2006 331 631 633 <p>Cash interests taint drug advice.</p> Taylor R Giles J Nature 2005 437 1070 1071 10.1038/4371070a 16237402 <p>Guideline recommendation an evidence grading (GREG): a new grading method for clinical guideline development groups</p> Mason J Eccles M Newcastle upon Tyne, Centre for Health Services Research, University of Newcastle upon Tyne 2003 Report 109 <p>Evaluation of the effectiveness of a low sodium diet in the treatment of mild to moderate hypertension</p> Silman AJ Locke C Mitchell P Humpherson P Lancet Silman AJ 1983 1 1179 1182 10.1016/S0140-6736(83)92463-7 6133987 <p>Systematic review of long term effects of advice to reduce dietary salt in adults</p> Hooper L Bartlett C Davey Smith G Ebrahim S BMJ 2002 325 628 636 126303 12242173 10.1136/bmj.325.7365.628 <p>Reactivity to norepinehrine and effect of sodium on blood pressure during weight loss</p> Fagerberg B Andersson OK Persson B Hedner T Hypertension 1985 7 586 592 3891615 <p>Effect of reduced dietary sodium on blood pressure: a meta-analysis of randomized controlled trials</p> Midgley JP Matthew AG Greenwood CM Logan AG JAMA 1996 275 1590 1597 10.1001/jama.275.20.1590 8622251 <p>Australian National Health and Medical Research Council dietary salt study in mild hypertension</p> Chalmers J Morgan T Doyle A Dickson B Hopper J Mathews J Matthews J Moulds R Myers J Nowson C Scoggins B Stebbing M J Hypertens Chalmers J 1986 4 S629 S637 <p>Randomized trials of sodium reduction: an overview</p> Cutler JA Follmann D Allender PS Am J Clin Nutr 1997 65 643S 651S 9022560 <p>Effects of replacing sodium intake in subjects on a low sodium diet: a crossover study</p> Australian National Health and Medical Research Council Dietary Salt Study Management Committee Clin Exp Hypertens Chalmers JP 1989 A11 1011 1024 <p>Fall in blood pressure with modest reduction in dietary salt intake in mild hypertension</p> Australian National Health and Medical Research Council Dietary Salt Study Management Committee Lancet Chalmers JP 1989 1 399 402 2563786 <p>Effects on left-ventricular hypertrophy of long-term nonpharmacolgical treatment with sodium restriction in mild-to-moderate essential hypertension</p> Jula AM Karanko HM Circulation 1994 89 1023 1031 8124787 <p>Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled Trial of Nonpharmacologic Interventions in the Elderly (TONE)</p> Whelton PK Appel LJ Espeland MA Applegate WB Ettinger WH Kostis JB al JAMA 1998 279 839 846 10.1001/jama.279.11.839 9515998 <p>Effects of reduced sodium intake on hypertension control in older individuals: results from the Trial of Nonpharmacologic Interventions in the Elderly (TONE)</p> Appel LJ Espeland MA Easter L Wilson AC Folmar S Lacy CR Arch Intern Med 2001 161 685 693 10.1001/archinte.161.5.685 11231700 <p>Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet</p> Sacks FM Svetkey LP Vollmer WM Appel LJ Bray GA Harsha D Group DASHSCR N Engl J Med 2001 344 3 10 10.1056/NEJM200101043440101 11136953 <p>III Analysis of data from trials of salt reduction</p> Law MR Frost CD Wald NJ BMJ 1991 302 819 824 1827353 <p>Effects of treatment on morbidity in hypertension: II results in patients with diastolic blood pressure averaging 90 through 114 mm Hg</p> Veterans Administration Cooperative Study Group on Antihypertensive Agents JAMA 1970 213 1143 1152 10.1001/jama.213.7.1143 4914579 <p>Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review.</p> Messerli FH Grossman E Goldbourt U JAMA 1998 279 1903 1907 10.1001/jama.279.23.1903 9634263 <p>Systematic review of antihypertensive therapies</p> Wright JM C. L G.K C Canadian Medical Associataion Journal 1999 161 <p>Blood pressure, stroke and coronary heart disease: Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiology context</p> Collins R Peto R MacMahon S Herbert P Fiebach NH Eberlein KA Godwin J Qizilbash N Taylor JO Hennekens CH Lancet 1990 335 827 838 10.1016/0140-6736(90)90944-Z 1969567 <p>Drug Treatment of Hypertension in the Elderly. A Meta-Analysis</p> Insua JT H.S. S Lau T.Lau J.Reitman D.Pagano D.Chalmers T.C. Ann Intern Med 1994 121 355 362 7726892 <p>Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis</p> Psaty BM Smith NL Siscovick DS Koepsell TD Weiss NS Heckbert SR Lemaitre RN Wagner EH Furberg CD JAMA 1997 277 739 745 10.1001/jama.277.9.739 9042847 <p>Effect of antihypertensive treatment on stroke recurrence</p> Group HSCS JAMA 1974 229 409 418 10.1001/jama.229.4.409 4599980 <p>Treatment of mild hypertension: results of a ten-year intervention trial</p> Smith WM Circ Res 1977 40 98 105 830442 <p>Evaluation of drug treatment in mild hypertension: VA-NHLBI feasibility trial. Plan and preliminary results of a two-year feasibility trial for a multicenter intervention study to evaluate the benefits versus the disadvantages of treating mild hypertension.</p> Prepared for the Veterans Administration-National Heart LBISGETMH Ann N Y Acad Sci 1978 304 267 288 360921 <p>Five-year findings of the hypertension detection and follow-up program: I reduction in mortality of persons with high blood pressure, including mild hypertension</p> Hypertension Detection and Follow-up Program Cooperative Group JAMA 1979 242 2562 2571 10.1001/jama.242.23.2562 490882 <p>Five-year findings of the Hypertension Detection and Follow-up Program: III reduction in stroke incidence among persons with high blood pressure</p> Hypertension Detection and Follow-up Program Cooperative Group JAMA 1982 247 633 638 10.1001/jama.247.5.633 7033578 <p>Effect of stepped care treatment on the incidence of myocardial infarction and angina pectoris: 5-year findings of the Hypertension Detection and Follow-up Program</p> Hypertension Detection and Follow-up Program Cooperative Group Hypertension 1984 6 I-198 I-206 <p>Does Antihypertenive Treatment of the Elderly prevent Cardiovascular Events or Prolong Life?: A Meta-analysis of Hypertension Treatment Trials</p> Pearce KA C.D F J R Arch Fam Med 1995 4 943 950 10.1001/archfami.4.11.943 7582060 <p>Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men: a meta-analysis of individual patient data from randomized controlled trials</p> Gueyffier F Boutitie F Boissel JP Pocock S Coope J Cutler J Ekbom T al Ann Intern Med 1997 126 761 767 9148648 <p>The Australian Therapeutic Trial in Mild Hypertension</p> Australian National Blood Pressure Management Committee: Lancet 1980 1 1261 1267 6104081 <p>Cardiovascular protection and blood pressure reduction: a meta-analysis</p> J.A S J W L T The Lancet 2001 358 1305 1315 10.1016/S0140-6736(01)06411-X <p>An international trial of antihypertensive therapy in elderly patients: objectives protocol and organization</p> European Working Party on High Blood Pressure in the Elderly (EWPHE) Arch Int Pharmacodyn Ther 1985 275 300 334 3896176 <p>Relation between mortality and treated blood pressure in elderly patients with hypertension: report of the European Working Party on High Blood Pressure in the Elderly</p> Staessen J Bulpitt C Clement D de Leeuw P Fagard R Fletcher A Forette F Leonetti G Nissinen A O'Malley K Tuomilehto J Webster J Williams BO BMJ 1989 298 1552 1556 2503114 <p>The Effects of Blood Pressure Reduction in Older Patients: an overview of Five Randomized Controlled Trials in Elderly Hypertensives.</p> MacMahon S Rodgers A Clin Exp Hypertens 1993 15 967 978 8268901 <p>Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH)</p> Group IPPPSHC J Hypertens 1985 3 379 392 2864374 <p>MRC trial of treatment of mild hypertension: principal results</p> Party MRCW BMJ 1985 291 97 104 2861880 <p>Randomized trial of treatment of hypertension in elderly patients in primary care</p> Coope J Warrender TS BMJ 1986 293 1145 1152 3094811 <p>Treatment of mild hypertension: a five year controlled drug trial: The Oslo Study</p> Helgeland A Am J Med 1980 69 725 732 10.1016/0002-9343(80)90438-6 7001898 <p>Systolic Hypertension in the Elderly Program (SHEP): antihypertensive efficacy of chlorthalidone</p> Hulley SB Furberg CD Gurland B McDonald R Perry HM Schnaper HW Am J Cardiol 1985 56 913 920 10.1016/0002-9149(85)90404-7 4072925 <p>Systolic Hypertension in the Elderly Program. Pilot Study (SHEP-PS): morbidity and mortality experience</p> Perry HM McDonald RH Hulley SB Smith WM Furberg CD Greenlick MR J Hypertens 1986 4 S21 S23 <p>Morbidity and mortality in the Systolic Hypertension in the Elderly Program (SHEP) Pilot Study</p> Perry HM Smith WM McDonald RH Black D Cutler JA Furberg CD Stroke 1989 20 4 13 2911834 <p>Beta Blockers versus diuretics in hypertensive men: main results from the HAPPHY Trial</p> Wilhelmsen L Berglund G Elmfeldt D Fitzsimons T Holzgreve H Hosie J Hörnkvist PE Pennert K Tuomilehto J Wedel H J Hypertens 1987 5 561 572 2892881 <p>Primary prevention with Metoprolol in patients with hypertension: mortality results from the MAPHY study</p> Wikstrand J Warnold I Olsson G Tuomilehto J Elmfeldt D Berglund G JAMA 1988 259 1976 1982 10.1001/jama.259.13.1976 3346979 <p>Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial</p> Hansson L Lindholm LH Niskanen L Lanke J Hedner T Niklason A Luomanaki K Dahlöf B de Faire U Morlin C Karlberg BE Wester PO Bjorck JE Lancet Hansson PL 1999 353 611 616 10.1016/S0140-6736(98)05012-0 10030325 <p>The Captopril Prevention Project: a prospective intervention trial of angiotensin converting enzyme inhibition in the treatment of hypertension</p> group TCAPPP J Hypertens 1990 8 985 990 1981218 <p>Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP)</p> Perry HM Davis BR Price TR Applegate WB Fields WS Guralnik JM Kuller L Pressel S Stamler J Probsfieldt JL JAMA 2000 284 465 471 10.1001/jama.284.4.465 10904510 <p>Rationale and design of a randomized clinical trial on prevention of stroke in isolated systolic hypertension</p> Group SHEPCR J Clin Epidemiol 1988 41 1197 1208 10.1016/0895-4356(88)90024-8 2905387 <p>Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP)</p> Group SHEPCR JAMA 1991 265 3255 3264 10.1001/jama.265.24.3255 2046107 <p>Pulse pressure and risk of cardiovascular events in the systolic hypertension in the elderly program</p> Vaccarino V Berger AK Abramson J Black HR Setaro JF Davey JA Krumholz HM Am J Cardiol 2001 88 980 986 10.1016/S0002-9149(01)01974-9 11703993 <p>Morbidity and mortality in the Swedish Trial in Old Patients With Hypertension (STOP-Hypertension)</p> Dahlöf B Lindholm LH Hansson L Scherstén B Ekbom T Wester P Lancet 1991 338 1281 1285 10.1016/0140-6736(91)92589-T 1682683 <p>Syst-Eur: a multicenter trial on the treatment of isolated systolic hypertension in the elderly objectives, protocol, and organisation</p> Amery A Birkenhager W Bulpitt CJ Clement D de Leeuw P Dollery CT Ageing 1991 3 287 302 <p>Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension</p> Staessen JA Fagard R Thijs L Celis H Arabidze GG Birkenhager WH Bulpitt CJ de Leeuw P Dollery CT Fletcher AE Forette F Leonetti G Nachev C O'Brien ET Rosenfeld J Rodicio JL Tuomilehto J Zanchetti A Lancet 1997 350 757 764 10.1016/S0140-6736(97)05381-6 9297994 <p>Withdrawal from treatment in the Syst-Eur Trial</p> Bulpitt CJ Beckett NS Fletcher AE Thijs L Staessen JA Dumitrascu DL Forette F Leonetti G Nachev C Tuomilehto J Fagard RH investigators TSE J Hypertens 2002 20 339 346 10.1097/00004872-200202000-00026 11821721 <p>Update on the Systolic Hypertension in Europe (Syst-Eur) Trial</p> Staessen JA Thijs L Birkenhager WH Bulpitt CJ Fagard R Hypertension 1999 33 1476 1477 10373236 <p>Effects of different blood-pressure-lowering regimens on major cardiovascular events: Results of prospectively-designed overviews of randomised trials</p> Blood Pressure Lowering Treatment Trialists' Collaboration Lancet 2003 362 1527 1535 10.1016/S0140-6736(03)14739-3 14615107 <p>Medical Research Council Trial of treatment of hypertension in older adults: principal results</p> Party MRCW BMJ 1992 304 405 412 1445513 <p>STOP-Hypertension-2: a prospective intervention trial of newer versus older treatment alternatives in old patients with hypertension</p> Dahlöf B Hansson L Lindholm LH Schersten B Wester PO Ekbom T Hedner T de Faire U Blood Press 1993 2 136 141 8180726 <p>Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study</p> Hansson L Lindholm LH Ekbom T Dahlöf B Lanke J Schersten B Wester PO Hedner T Lancet Hansson PL 1999 354 1751 1756 10.1016/S0140-6736(99)10327-1 10577635 <p>Results of the STOP-Hypertension-2 trial</p> Hansson L Blood Press 2000 9 17 20 10.1080/080370500439326 <p>Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a meta-analysis of randomised controlled trials</p> Pahor M Psaty BM Alderman MH Applegate WB Williamson JD Cavazzini C Furberg CD Lancet 2000 356 1949 1954 10.1016/S0140-6736(00)03306-7 11130522 <p>Cardiovascular prevention and blood pressure reduction: A quantitative overview updated until 1 March 2003</p> Staessen JA Wang JG Thijs L J Hypertens 2003 21 1055 1076 10.1097/00004872-200306000-00002 12777939 <p>Tolerability and safety of a calcium channel blocker in comparison with a diuretic in the treatment of elderly patients with hypertension: Secondary analysis of the NICS-EH</p> Kuwajima I Kuramoto K Ogihara T Iimura O Abe K Saruta T al Hypertens Res 2001 24 475 480 10.1291/hypres.24.475 11675939 <p>Randomized double-blind comparison of a calcium antagonist and a diuretic in elderly hypertensives</p> National Intervention Cooperative Study in Elderly Hypertensives Study Group Hypertension 1999 34 1129 1133 10567194 <p>Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials</p> Blood Pressure Lowering Treatment Trialists' Collaboration Lancet 2000 356 1955 1964 10.1016/S0140-6736(00)03307-9 11130523 <p>Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial.</p> Hansson L Zanchetti A Carruthers SG Dahlöf B Elmfeldt D Julius S Menard J Rahn KH Wedel H Westerling S Lancet 1998 351 1755 1762 10.1016/S0140-6736(98)04311-6 9635947 <p>Post-stroke antihypertensive treatment study: a preliminary result</p> Group PATSC Chin Med J (Engl) 1995 108 710 717 8575241 <p>Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)</p> Davis BR Cutler JA Gordon DJ Furberg CD Wright JTJ Cushman WC Grimm RH LaRosa J Whelton PK Perry HM Alderman MH Ford CE Oparil S Francis C Proschan M Pressel S Hawkins CM Am J Hypertens 1996 9 342 360 10.1016/0895-7061(96)00037-4 8722437 <p>Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic</p> The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) JAMA - Express 2002 288 2981 2997 <p>Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS)</p> Borhani NO Mercuri M Borhani PA Buckalew VM Canossa-Terris M Carr AA Kappagoda MD Rocco MV Schnaper HW Sowers JR Bond MG JAMA 1996 276 785 791 8769587 10.1001/jama.276.10.785 <p>Isradipine in prediabetic hypertensive subjects</p> Byington RP Furberg CD Craven TE Pahor M Sowers JR Diabetes Care 1998 21 2103 2110 9839101 <p>Clinical results of the Verapamil in Hypertension and Atherosclerosis Study</p> Rosei EA Dal Palú C Leonetti G Magnani B Pessina A Zanchetti A J Hypertens 1997 15 1337 1344 10.1097/00004872-199715110-00019 9383184 <p>The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension</p> Estacio RO Jeffers BW Hiatt WR Biggerstaff SL Gifford N Schrier RW N Engl J Med 1998 338 645 652 10.1056/NEJM199803053381003 9486993 <p>Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial (FACET) in patients with hypertension and NIDDM</p> Tatti P Pahor M Byington RP Di M Guarisco R Strollo G Diabetes Care 1998 21 597 603 9571349 <p>Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39</p> Group UKPDS BMJ 1998 317 713 720 28660 9732338 <p>Effects of an angiotensin-converting-enzyme inhibitor, Ramipril, on cardiovascular events in high-risk patients</p> The Heart Outcomes Prevention Evaluation Study Investigators N Engl J Med 2000 342 145 153 10.1056/NEJM200001203420301 10639539 <p>Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: Intervention as a Goal in Hypertension Treatment (INSIGHT)</p> Brown MJ Palmer CR Castaigne A de Leeuw PW Mancia G Rosenthal T Lancet 2000 356 366 372 10.1016/S0140-6736(00)02527-7 10972368 <p>Principal results from the International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT)</p> Brown MJ Palmer CR Castaigne A de Leeuw PW Mancia G Rosenthal T Eur Heart J Brown PMJ 2001 3 B20 B26 <p>Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study</p> Hansson L Hedner T Lund-Johansen P Kjeldsen SE Lindholm LH Syvertsen JO Lanke J de Faire U Dahlöf B Karlberg BE Lancet Hansson PL 2000 356 359 365 10.1016/S0140-6736(00)02526-5 10972367 <p>Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy</p> Berl T Hunsicker LG Lewis JB Pfeffer MA Porush JG Rouleau JL Drury PL Esmatjes E Hricik D Parikh CR Raz I Vanhille P Wiegmann TB Wolfe BM Locatelli F Goldhaber SZ Lewis EJ Irbesartan Diabetic Nephropathy Trial.Collaborative Study Group. Ann Intern Med 2003 138 542 549 12667024 <p>Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack</p> Group PROGRESSC Lancet 2001 358 1033 1041 10.1016/S0140-6736(01)06178-5 11589932 <p>Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy</p> Brenner BM Cooper ME de Zeeuw D Keane WF Mitch WE Parving H Remuzzi G Snapinn SM Zhang Z Shahinfar S N Engl J Med 2001 345 861 869 10.1056/NEJMoa011161 11565518 <p>Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial</p> Zanchetti A Bond MG Hennig M Neiss A Mancia G Dal Palu C Hansson L Magnani B Rahn KH Reid JL Rodicio J Safar M Eckes L Rizzini P European Lacidipine Study on Atherosclerosis investigators. Circulation 2002 106 2422 2427 10.1161/01.CIR.0000039288.86470.DD 12417537 <p>Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol</p> Dahlöf B Devereux RB Kjeldsen SE Julius S Beevers G de Faire U Fyhrquist F Ibsen H Kristiansson K Lederballe-Pedersen O Lindholm LH Nieminen M Omvik S Wedel H Lancet Dahlöf PB 2002 359 995 1003 10.1016/S0140-6736(02)08089-3 11937178 <p>Australian comparative outcome trial of angiotensin-converting enzyme inhibitor-and diuretic-based treatment of hypertension in the elderly (ANBP2): objectives and protocol</p> Management Committee on behalf of the High Blood Pressure Research Council of Australia Clin Exp Pharmacol Physiol 1997 24 188 192 9075595 <p>A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertrension in the elderly</p> Wing LMH Reid CM Ryan P Beilin LJ Brown MA Jennings GLR Jonston CI McNeil JJ Macdonald GJ Marley JE TO M West MJ N Engl J Med 2003 348 583 592 10.1056/NEJMoa021716 12584366 <p>Rationale and design for the controlled ONset Verapamil INvestigation of Cardiovascular Endpoints (CONVINCE) Trial</p> Black HR Elliott WJ Neaton JD Grandits G Grambsch P Grimm RH Hansson L Lacourciere Y Muller J Sleight P Weber MA White WB Williams G Wittes J Zanchetti A Fakouhi TD Control Clin Trials 1998 19 370 390 10.1016/S0197-2456(98)00013-0 9683312 <p>Principal results of the controlled onset verapamil investigation of cardiovascular end points (CONVINCE) trial</p> Black HR Elliott WJ Grandits G Grambsch P Lucente T White WB Neaton JD Grimm RH Hansson L Lacourciere Y Muller J Sleight P Weber MA Williams G Wittes J Zanchetti A Anders RJ JAMA 2003 289 2073 2082 10.1001/jama.289.16.2073 12709465 <p>The study on cognition and prognosis in the elderly (SCOPE): principal results of a randomized double-blind intervention trial</p> Lithell H Hansson L Skoog I Elmfeldt D Hofman A Olofsson B Trenkwalder P Zanchetti A J Hypertens 2003 21 875 886 10.1097/00004872-200305000-00011 12714861 <p>Comparison of nifedipine retard with angiotensin converting enzyme inhibitors in Japanese hypertensive patients with coronary artery disease: the Japan Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) Randomized Trial</p> Yui Y Sumiyoshi T Kodama K Hirayama A Nonogi H Kanmatsuse K Origasa H Iimura O Ishii M Saruta T Arakawa K Hosoda S Kawai C for the Japanese Multicenter Investigation for Cardiovascular Diseases-B (JMIC-B) Study Group Hypertens Res 2004 27 181 191 10.1291/hypres.27.181 15080377 <p>Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial</p> Julius S Kjeldsen SE Weber M Brunner HR Ekman S Hansson L Hua T Laragh J McInnes GT Mitchell L Plat F Schork A Smith B Zanchetti A group* VALUE Lancet 2004 363 2022 2031 10.1016/S0140-6736(04)16451-9 15207952 <p>Characteristics of 15,314 hypertensive patients at high coronary risk. The VALUE trial. The Valsartan Antihypertensive Long-term Use Evaluation</p> Kjeldsen SE Julius S Brunner H Hansson L Henis M Ekman S Laragh J McInnes G Smith B Weber M Zanchetti A Blood Press 2001 10 83 91 10.1080/08037050152112069 11467764 <p>The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial of cardiovascular events in hypertension. Rationale and design</p> Mann J Julius S Blood Press 1998 7 176 183 10.1080/080370598437394 9758088

Pre-publication history

The pre-publication history for this paper can be accessed here:

http://www.biomedcentral.com/1472-6963/6/47/prepub