Cochrane in context: pharmacological interventions for hypertension in children

Hypertension is a major risk factor for stroke, coronary artery disease and kidney damage in adults. There is a paucity of data on the long-term sequelae of persistent hypertension in children, but it is known that children with hypertension have evidence of end-organ damage and are at risk of hypertension into adulthood. The prevalence of hypertension in children is increasing, most likely owing to a concurrent rise in obesity. In children with hypertension, nonpharmacological measures are often recommended as first-line therapy, but a significant proportion of children will eventually require pharmacological treatment to reduce blood pressure, especially those with evidence of end-organ damage at presentation or during follow-up. A systematic review of the effects of antihypertensive agents in children has not previously been conducted.

To determine the dose-related effects of different classes of antihypertensive medications, as monotherapy compared with placebo; as combination therapy compared with placebo or as a single medication; or in comparisons of various doses within the same class on systolic or diastolic blood pressure (or both) in children with hypertension.

We searched the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2013,Issue 9), Ovid MEDLINE (1946 to October 2013), Ovid EMBASE (1974 to October 2013) and bibliographic citations.

The selection criteria were deliberately broad as there are only few clinical trials in children. We included randomized controlled trials of at least 2 weeks duration comparing antihypertensive agents either as monotherapy or as combination therapy with either placebo or another medication, or comparing different doses of the same medication, in children with hypertension. Hypertension was defined as an average (over a minimum of three readings) systolic or diastolic blood pressure (or both) on the 95th percentile or above for age, height and gender.

Two authors independently selected relevant studies, extracted data and assessed risk of bias. We summarized data, where possible, using a random-effects model. Formal assessment of heterogeneity was not possible because of insufficient data.

A total of 21 trials evaluated antihypertensive medications of various drug classes in 3454 hypertensive children with periods of follow-up ranging from 3 to 24 weeks. There were five randomized controlled trials comparing an antihypertensive drug directly with placebo, 12 dose-finding trials, two trials comparing calcium channel blockers with angiotensin receptor blockers, one trial comparing a centrally acting ..-blocker with a diuretic and one trial comparing an angiotensin-converting enzyme inhibitor with an angiotensin receptor blocker. No randomized trial was identified that evaluated the effectiveness of antihypertensive medications on target end-organ damage. The trials were of variable quality and most were funded by pharmaceutical companies. Among the angiotensin receptor blockers, candesartan (one trial, n=240), when compared with placebo, reduced systolic blood pressure by 6.50 mmHg (95% confidence interval .9.44 to .3.56) and diastolic blood pressure by 5.50 mmHg (95% confidence interval .9.62 to .1.38) (low-quality evidence). High dose telmisartan (one trial, n=76), when compared with placebo, reduced systolic blood pressure by .8.50 (95% confidence interval .13.79 to .3.21) but not diastolic blood pressure (.4.80, 95% . .9.50 to 0.10) (low-quality evidence). ..-Blocker (metoprolol, one trial, n=140), when compared with placebo, significantly reduced systolic blood pressure by 4.20 mmHg (95% confidence interval .8.12 to .0.28) but not diastolic blood pressure (.3.20 mmHg 95% confidence interval .7.12 to 0.72) (low-quality evidence). ..-Blocker-diuretic combination (bisoprolol/hydrochlorothiazide, one trial, n=94) when compared with placebo did not result in a significant reduction in systolic blood pressure (.4.0 mmHg, 95% confidence interval .8.99 to .0.19), but did have an effect on diastolic blood pressure (.4.50 mmHg, 95% confidence interval .8.26 to .0.74) (low-quality evidence). Calcium channel blocker (extended-release felodipine, one trial, n=133) was not effective in reducing systolic blood pressure (.0.62 mmHg, 95% confidence interval .2.97 to 1.73) or diastolic blood pressure (.1.86 mmHg, 95% confidence interval .5.23 to 1.51) when compared with placebo. Further, there was no consistent dose-response observed among any of the drug classes. The adverse events associated with the antihypertensive agents were mostly minor and included headaches, dizziness and upper respiratory infections. AUTHORS'

Overall, there are sparse data informing the use of antihypertensive agents in children, with outcomes reported limited to blood pressure and not end-organ damage. Most data are available for candesartan, for which there is low-quality evidence of a modest lowering effect on blood pressure. We did not find evidence of a consistent dose–response relationship for escalating doses of angiotensin receptor blockers, calcium channel blockers or angiotensin-converting enzyme inhibitors. All agents appear safe, at least in the short term.