Hypertension
The drug trials conducted were based on the US Food and Drug Administration Modernization Act 199752
reduction. The most commonly studied classes of antihypertensive medication were angiotensin receptor blockers (ARBs),37–43 channel blockers,43–45 (ACEIs),46–48 agonists.51
beta-blockers,49,50 calcium
angiotensin-converting enzyme (ACE) inhibitors thiazide diuretics50,51
and α-2 adrenergic and the clinical trials
were conducted in children to determine efficacy and safety with short-term use and not specifically to study long-term cardiovascular benefit in children. Important data on the effectiveness of drugs that paediatricians require for clinical practice, such as age-appropriate drug formulations and dosing regimens for children with differing severities of hypertension, could not be evaluated in these trials.52 Additionally, the limited number of trials in each drug class prohibits the comparison between the effects of different drugs within a drug class – for example, the various calcium channel blockers.
Among ARBs, the drugs valsartan, irbesartan, olmesartan, candesartan and losartan were studied;38–44
all of them, with the
exception of valsartan, were studied in patients aged 6–18 years; the valsartan and candesartan studies included younger children aged 1–5 years. On average, the ARBs decreased systolic blood pressure by 6–13 mmHg and diastolic blood pressure by 5.2–11.1 mmHg from baseline. ACE inhibitors, including fosinopril, lisinopril and enalapril, decreased systolic and diastolic blood pressure among children aged 6–16 years by 5.4–15.2 mmHg and 4.2–16.4 mmHg, respectively, from baseline.46–48
The calcium channel blockers amlodipine and felodipine (extended- release) were studied in children aged 6–18 years. In the three studies examining amlodipine, a decrease in systolic blood pressure of 0.1–12 mmHg from baseline was found; the change in diastolic blood pressure ranged from an increase of 0.8 mmHg to a decrease of 7 mmHg, depending on the study.39,41,44
Felodipine was reported to
produce no change in systolic blood pressure and a placebo-adjusted decrease in diastolic blood pressure of 4.6 mmHg from baseline (95 % confidence intervals [CI] -9.2 and -0.1, respectively).45
Two beta-blockers were studied in patients aged 6–16 years. Extended-release metoprolol resulted in a decrease from baseline of 5.2–7.7 mmHg in systolic blood pressure and 3.1–7.5 mmHg in diastolic blood pressure.49
Bisoprolol in combination with
Since diuretics alone have not been studied, it is unclear how much of a blood pressure lowering effect they have on children.50 Diuretics are often not considered as first-line agents in children. Nevertheless, they are potent adjuvant agents when combined with ACEIs/ARBs, beta-blockers or calcium channel blockers. Clonidine, an a-2 adrenergic agonist, was found to decrease systolic and diastolic blood pressure from baseline by 10 mmHg and 8 mmHg, respectively, in adolescents aged 13–19 years. The effect, however, was modest and the study contained limited data.51
hydrochlorothiazide resulted in a decrease from baseline of 9.3 mmHg in systolic blood pressure and 7.2 mmHg in diastolic blood pressure49,50
Most of the short-term trials do show effective blood pressure lowering; the greatest effect was seen with ACEIs, ARBs and beta-blockers, and only a moderate effect was seen with calcium channel blockers. In the Antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT) in adults, diuretics were superior in cardiovascular risk reduction compared with ACEIs and calcium channel blockers.53,54
Similar studies have never been 130
This trial studied the effect of blood pressure control on the progression of kidney disease in children aged 3–18 years over a five-year period. Children received 10 mg per day of the ACEI ramipril, adapted for their body size. Children with chronic kidney disease who received the intensified blood pressure control showed delays in the progression of renal disease (29.9 % versus 41.7 %, hazard ratio 0.65 [95 % CI 0.44–0.94], p=0.02) compared with children who received conventional treatment. However, most of the children in the study were on an average of two or more antihypertensive medications to achieve optimal blood pressure control.55
In the
future, with the increasing prevalence of hypertension and obesity worldwide, clinical trials in children will need to be considered to determine optimal medication interventions.
Six of the 16 paediatric trials included an open-label extension period lasting up to 52 weeks and designed to collect safety information.37,38,40,41,46,49
conducted in children, whether with diuretics or other medications. We are thus limited in our ability to make specific antihypertensive medication recommendations to treat primary hypertension in children. Based on prior diagnosis of diabetes, chronic kidney disease or heart disease, however, the use of specific drug classes such as ACEIs/ARBs has been studied, with improved blood pressure, lowering of proteinuria and decreased rates of kidney disease progression. There has only been one study in children, the Effect of strict blood pressure control and ACE-inhibition on progression of chronic renal failure in pediatric patients (ESCAPE) trial.55
Most of the medications were well tolerated and
only minor side effects were reported, including headache, dizziness, upper respiratory tract infections, abdominal pain and diarrhoea. However, further research is needed to improve our understanding of the long-term outcomes and benefits of antihypertensive medications beyond short-term blood pressure reduction. Further research is also necessary on the reversal of markers of target organ damage, such as left ventricular hypertrophy and albuminuria, which have not been systematically studied in children.
Target Levels of Blood Pressure
High blood pressure has been shown to carry over into adulthood, with resultant increases in cardiovascular risk.56–58
In treating
paediatric hypertension, there are no guidelines for the specific threshold for blood pressure lowering, other than lower than the 90th percentile. The ESCAPE trial demonstrated that lowering blood pressure with intensive therapy to the 50th percentile for age, gender, and height delays the progression to end-stage renal disease among children with chronic kidney disease and proteinuria.55
At this point in time, the optimal lowering is suggested to be lower than the 90th percentile for age, gender and height in children with essential or primary hypertension. If there is evidence of end-organ damage, a lower blood pressure may need to be considered, especially in case of end-organ impairment, such as chronic kidney disease, left ventricular hypertrophy or albuminuria.
Summary
Hypertension in childhood is exceedingly common and screening should start as early as the age of 3. The mainstay of treatment should be dietary and lifestyle modifications, with pharmacological therapy used in those patients who show evidence of sustained elevated blood pressure, end-organ damage, secondary causes of hypertension or symptomatic hypertension. The choice of the antihypertensive often
EUROPEAN NEPHROLOGY
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