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Base de datos Cochrane de Revisiones Sistemáticas Protocolo - Intervención

Pharmacological interventions for essential hypertension in children

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Versión publicada: 07 octubre 2009 Historial de versiones

https://doi.org/10.1002/14651858.CD008117

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

Primary Objectives

To determine dose related effects of different classes of antihypertensive medications as compared to placebo on systolic and/or diastolic blood pressure in children with essential/primary hypertension.

The different classes of antihypertensive medications include diuretics, calcium channel blockers, beta‐blockers, alfa‐blockers, alfa and beta‐blockers, angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), vasodilators etc.

Secondary Objectives

To determine effects of monotherapy with one class of antihypertensive medications as compared to monotherapy with drugs from other antihypertensive class on systolic and/or diastolic blood pressure in children with essential/primary hypertension.

To determine effects of combination therapy of antihypertensive medications as compared to placebo or monotherapy of the drugs included in the combination therapy on systolic and/or diastolic blood pressure in children with essential/primary hypertension.

To determine and compare effects of drugs within the same antihypertensive drug class on systolic and/or diastolic blood pressure in children with essential/primary hypertension.

To determine effects of different classes of antihypertensive medications on target end organ disease such as left ventricular hypertrophy, cardiac function, nephropathy and retinopathy.

To determine withdrawals due to adverse events.

To determine adverse biochemical effects of antihypertensive drug therapy on serum potassium, uric acid, creatinine, glucose and lipid profile.

To determine the adherence of different antihypertensive medications among children with primary hypertension by pill count, self report or any other method used in a trial.

Background

Description of the condition

Hypertension is a major risk factor for cardiovascular disease and increases the risk for myocardial infarction, stroke, congestive heart failure, peripheral vascular disease and end stage renal disease (Chobanian 2003).  In children, hypertension is defined as an average systolic blood pressure (SBP) and/or diastolic blood pressure (DBP) that is >/= 95th percentile for gender, age, and height on at least 3 separate occasions.  Average SBP or DBP levels that are >90th percentile but <95th percentile have been designated as “high normal”.  As with adults, adolescents with BP levels >120/80 mm of Hg but <95th percentile should be considered pre‐hypertensive (National High Blood Pressure Group 2004).  The prevalence of paediatric pre‐ hypertension and hypertension is approximately 10% and 4% respectively Din‐Dzietham 2007.  In recent years, this prevalence is rising which may be due to the increased prevalence of obesity and overweight, both in the developed world as well as in developing nations (Din‐Dzietham 2007, Ogden 2006, Bovet 2006). 

Essential or primary hypertension is defined as hypertension in the absence of cardiovascular, renal, rheumatologic, and endocrine causes or the use of drugs or chemicals that lead to hypertension. The natural history of primary hypertension is not as clear in children as it is in adults.  Overt morbid cardiovascular events are rare in the majority of hypertensive children. Consequently recent publications have focused on markers of hypertensive end organ damage including left ventricular mass index, increased carotid intima‐media thickness, hypertensive retinopathy and early renal injury (Laird 1981, McNiece 2007, Sorof 2003, Lande 2006, Daniels 1991, Assadi 2007). 

The National High Blood Pressure Education Program Working group on High Blood Pressure in Children and Adolescents (The Fourth Report) has provided guidelines for the diagnosis, evaluation, and treatment of hypertension (National High Blood Pressure Group 2004). Non‐pharmacologic measures including weight reduction, regular physical activity and dietary modification have been recommended as first‐line therapy for children with primary hypertension. This is particularly applicable for obese children. The indications for pharmacological intervention are secondary hypertension, symptomatic hypertension, hypertensive children with established end organ damage, and failure of non‐pharmacologic measures. Comprehensive programs incorporating therapeutic lifestyle changes can be successful in reducing weight and elevated blood pressure (Couch 2008, Denzer 2004).  However, because of the intensive nature and variable success of non‐pharmacologic measures, a significant proportion of children still require anti‐hypertensive medications.   

Why it is important to do this review

A systematic review of randomised controlled trials evaluating safety and dosing of the anti‐hypertensive agents currently in use in children as compared to placebo control has not been performed.  The information derived from this review should assist physicians in informed decision making.

Objectives

Primary Objectives

To determine dose related effects of different classes of antihypertensive medications as compared to placebo on systolic and/or diastolic blood pressure in children with essential/primary hypertension.

The different classes of antihypertensive medications include diuretics, calcium channel blockers, beta‐blockers, alfa‐blockers, alfa and beta‐blockers, angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), vasodilators etc.

Secondary Objectives

To determine effects of monotherapy with one class of antihypertensive medications as compared to monotherapy with drugs from other antihypertensive class on systolic and/or diastolic blood pressure in children with essential/primary hypertension.

To determine effects of combination therapy of antihypertensive medications as compared to placebo or monotherapy of the drugs included in the combination therapy on systolic and/or diastolic blood pressure in children with essential/primary hypertension.

To determine and compare effects of drugs within the same antihypertensive drug class on systolic and/or diastolic blood pressure in children with essential/primary hypertension.

To determine effects of different classes of antihypertensive medications on target end organ disease such as left ventricular hypertrophy, cardiac function, nephropathy and retinopathy.

To determine withdrawals due to adverse events.

To determine adverse biochemical effects of antihypertensive drug therapy on serum potassium, uric acid, creatinine, glucose and lipid profile.

To determine the adherence of different antihypertensive medications among children with primary hypertension by pill count, self report or any other method used in a trial.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) (parallel group as well as cross‐over trials), using different classes of antihypertensive agents  in children with essential hypertension will be included.  Duration of treatment should be at least 2 weeks with blood pressure measurements reported at baseline (following washout) and at one or more time points post baseline.               

Types of participants

Inclusion Criteria

Children 1‐18 yrs with primary/essential hypertension.         

Exclusion Criteria

Children less than 1 year old will be excluded as the etiology and course of hypertension is different in this group as compared to older children. We will also exclude children with secondary hypertension, i.e. hypertension from renal, endocrine, neurologic and rheumatic diseases or a result of medications.          

Types of interventions

All pharmacological interventions are potentially eligible.  Interventions which will be considered include:

  1. Blood pressure lowering medications versus placebo

  2. Combination drugs versus placebo

  3. Combination drugs versus single medication

  4. Comparison between different doses of same antihypertensive medications versus placebo 

  5. Comparison of two different classes of antihypertensive medications (either as indirect comparison of each drug with placebo or directly if an RCT using two drugs from two different classes with a placebo control group as well in the same trial)

  6. Comparison of two different medications within the same antihypertensive class (either as indirect comparison of each drug within the same drug class with placebo or directly if an RCT using two drugs from the same class with a placebo control group as well in the same trial)

Types of outcome measures

Primary outcomes

  1. Dose related change in office measurement of systolic BP.

  2. Dose related change in office measurement of diastolic BP. 

  3. Dose related change in 24 hour ambulatory blood pressure monitoring (ABPM) systolic BP. 

  4. Dose related change in 24 hour ambulatory blood pressure monitoring (ABPM) diastolic BP.

Ambulatory blood pressure monitoring (ABPM) can more precisely characterize changes in BP throughout daily activity and is increasingly gaining acceptance as useful modality for BP evaluation in both clinic and research setting (Urbina 2008). Changes in office blood pressure readings and ABPM will be pooled and analysed separately.  

Secondary outcomes

  1. Change in night time dipping and blood pressure load on ABPM.

  2. Regression of left ventricular hypertrophy or left ventricular wall thickness.

  3. Change in kidney function (by creatinine) or proteinuria or albuminuria.

  4. Change in retinopathy.

  5. Change in heart rate, cardiac output, and systemic vascular resistance as measured by standardised bio‐impedance methods.

  6. Change in levels of serum potassium, serum uric acid, blood glucose, serum cholesterol and triglycerides.

  7. The number of medication withdrawals due to adverse events.

  8. Average percent adherence to medications during the trial as reported in the trials.

Search methods for identification of studies

The Database of Abstracts of Reviews of Effectiveness (DARE) and the Cochrane Database of Systematic Reviews will be searched for related reviews.

The following electronic databases will be searched for primary studies:

  1. The Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Renal Group specialised register

  2. English language databases, including MEDLINE (2005‐) and EMBASE (2007‐)

Electronic databases will be searched using a strategy combining a variation of the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐maximizing version (2008 revision) with selected MeSH terms and free text terms relating to children and hypertension.  No language restrictions will be used.  The MEDLINE search strategy (Appendix 1) will be translated into the other databases using the appropriate controlled vocabulary as applicable.

Other sources:

  • International Clinical Trials Registry Platform (WHO ICTRP)

  • OpenSIGLE (System for Information on Grey Literature in Europe)

  • Reference lists of nephrology textbooks, review articles and all papers and relevant reviews identified

  • Authors of relevant papers will be contacted regarding any further published or unpublished work

  • Authors of trials reporting incomplete information will be contacted to provide the missing information

  • ISI Web of Science will be searched for papers which cite studies included in the review

Data collection and analysis

Selection of studies

The initial search of all databases will be performed to identify citations with potential relevance. Two reviewers SC and RP will initially screen abstracts and will exclude articles whose titles and/or abstracts are clearly irrelevant.  The full text of the remaining articles will be retrieved. The bibliographies of pertinent articles, reviews and texts will be searched for additional citations. SC and RP will independently assess the eligibility of the trials using a trial selection form. CL and JC will resolve discrepancies.

Data extraction and management

Data will be extracted independently by SC and RP using a standard form. 

Measures of treatment effect

The position of the patient during blood pressure measurement may affect the blood pressure lowering effect.  When blood pressure measurement is available in more than one position, sitting blood pressure is the first preference.  However, in order not to lose valuable data if BP is taken in any other position (lying or standing), data from that position will be collected.  If the position during blood pressure measurement is not stated, effort will be made to collect the missing information by contacting the authors.

Assessment of risk of bias in included studies

Risk of bias will be assessed using the Risk of Bias Tables for each trial as outlined in the Cochrane Handbook.        

Dealing with missing data

In case of missing information in the included studies, investigators will be contacted (using e‐mail, letter and/or fax) to obtain missing information. 

In the case of missing values for standard deviation of the change in blood pressure, the standard deviation will be imputed based on the information in the same trial or from other trials using the same dose. The following hierarchy (listed from high to low preference) will be used to impute standard deviation values: 

  1. Pooled standard deviation calculated either from the t statistic corresponding to an exact p‐value reported or from the 95% confidence interval of the mean difference between treatment group and placebo. 

  2. Standard deviation of blood pressure/heart rate at the end of treatment. 

  3. Standard deviation of blood pressure/heart rate at baseline (except if this measure was used for entry criteria). 

  4. Standard deviation of change in blood pressure from other trials using the same class of drug (at any dose).

Assessment of heterogeneity

Test for heterogeneity of treatment effect between trials will be made using a standard chi‐square statistic for heterogeneity.  The random effect model will be applied to obtain summary statistics of pooled trials. 

Data synthesis

Data synthesis and analysis will be performed using Cochrane Review Manager Software, RevMan 5. Data for changes in blood pressure (systolic BP, diastolic BP), serum levels of potassium, uric acid, creatinine, glucose, cholesterol,  triglycerides and other continuous variables, e.g. LVH, will be combined using a weighted mean difference method (WMD) or the standardised mean difference (SMD) if different scales have been used. Dichotomous outcomes will be assessed as relative risk (RR) with 95% confidence intervals (CI).  In addition the drop outs due to adverse effects will be analysed using relative risk ratio (RR), risk difference (RD), absolute risk increase (ARI) = risk difference x 100 and number needed to harm (NNH) = 1/ (risk difference).

Subgroup analysis and investigation of heterogeneity

If possible subgroup analysis will include variability in blood pressure response in relation to age, sex, ethnicity, body mass index (BMI) and severity of initial hypertension.

Sensitivity analysis

The robustness of the results will be tested using several sensitivity analyses including:

  1. Trials of high quality versus poor quality

  2. Trials which are industry sponsored versus non‐industry sponsored.