PEDIATRICS Vol. 107 No. 3 March 2001, pp. 558-561

SPECIAL ARTICLE:
The Testing of Antihypertensive Medications in Children: Report of the Antihypertensive Agent Guidelines Subcommittee of the Pediatric Pharmacology Research Units

Russell W. Chesney, MD^*, Peter Adamson, MD, Thomas Wells, MD^§, John T. Wilson, MD, and Philip D. Walson, MD^#

From the ^* University of Tennessee College of Medicine, Department of Pediatrics, Memphis, Tennessee;  Children's Hospital of Philadelphia, Department of Pediatrics, Division of Clinical Pharmacology and Therapeutics, Philadelphia, Pennsylvania; ^§ Arkansas Children's Hospital Research Center, Inc, Section of Clinical Pharmacology, Little Rock, Arkansas;  Louisiana State University Medical School, Department of Pediatrics, Shreveport, Louisiana; and the ^# Section of Pharmacology and Toxicology, Children's Hospital Research Foundation, Columbus, Ohio.

The testing of antihypertensive medications in children is timely because physicians caring for hypertensive childrenespecially pediatric nephrologists, cardiologists, endocrinologists, and adolescent medicine physicians, as well as clinical pharmacologistshave as therapeutic options almost no approved drugs for children, and somewhat outdated official recommendations.^1,2 In the balance of this need lie the problems inherent in using pediatric populations for clinical trialsa problem that has been recognized by leaders in the pharmaceutical industry. A representative of the pharmaceutical industry concurred that a particularly difficult pediatric population are hypertensives. The incidence (and prevalence) of hypertension in childhood is low, between 2% and 5% in some series.¹ Even in many of the population groups in which numerous epidemiologic studies have shown that adult hypertension is frequentparticipants with diabetes mellitus, obesity, certain racial groups (black, Native American, Latino), and in families with essential hypertensionthe prevalence of hypertension during childhood is low, but blood pressure values may progress over time to be hypertensive.^2,3 Placebo control and placebo arm of treatment trials are problematic because the only children in whom recommendations for therapy exist are those whose blood pressures are above the 95th percentile.^2,3

The identification of hypertension is further beset by a considerable number of technical issues, including white coat hypertension, appropriate cuff size for arm length or weight, height related norms, current paucity of validation of ambulatory blood pressure measurements, and measurement devices in North American children, which Korotkoff sounds to evaluate (4th or 5th) and at which ages, and whether the 4th or 5th sound is more relevant in children under 13-years of age.⁴ Studies in children who are the offspring of adult hypertensive participants have shown that reproducible stress testing (eg, playing a video game at an accelerating speed) may unmask a tendency for blood pressure elevation for chronological age.⁵ The blood pressure reactivity does not predict the nocturnal fall in blood pressure, and therefore, is probably not a good surrogate.⁶

A second issue raised by the pharmaceutical industry is the suitability of studying children whose blood pressure lies between the 90th and 95th percentile. These children are candidates for management by salt restriction and/or weight reduction, but this approach is primarily unsuccessful, especially in adolescents. Enrolling children with blood pressure in the 90th to 95th percentile remains controversial within the Pediatric Pharmacology Research Units (PPRU). One approach is to limit inclusion of such children to those with evidence of target organ damage (eg, eye ground changes, electrocardiogram findings, or renal damage) or family history of hypertension. It has also been suggested that 24-hour ambulatory blood pressure recording, rather than casual readings, should be considered the current gold standard.⁶

Our PPRU subcommittee recommends that several well-studied procedures could better define hypertensive children.³

1. Ambulatory blood pressure measurements over 24 hours that at times exceed the 95th percentile.
2. Abnormal response to a clearly established stress test.
3. A failure of the normal decline in nocturnal blood pressure as monitored by ambulatory blood pressure devices. Although norms for this procedure are not well established, certain publications are relevant.^7,8

Another issue raised by the PPRU subcommittee was that long-term follow upover several yearscould better demonstrate the utility of including this group of children with borderline hypertension (ie, 90th-95th percentile). Nevertheless, several large longitudinal studies indicate that an appreciable percentage of these children will become hypertensive over time.^9,10

A third major concern raised by industry involves the pharmacokinetic components of the Federal Drug Administration (FDA) Pediatric Drug Initiative. The FDA cardiorenal group has recommended trials in the following 4 age groups: infants and toddlers (1-24 months old); preschoolers (2-6 years old); children (7-12 years old); and adolescents (13-18 years old). Ford states that these 2 younger groups will be problematic; we concur that pharmacokinetic studies in children <6 years old would be difficult. The prevalence of hypertension in children in this age range is extremely low, unless the child has a history of prematurity, vascular abnormalities, bronchiopulmonary dysplasia, or structural renal disease. In addition, children with chronic obstructive renal disease, including posterior urethral valves or other forms of congenital obstruction, may demonstrate renal salt wasting and be volume depleted or resistant to the action of aldosterone (ie, type IV renal tubular acidosis). Indeed this subset of children usually remains normotensive until late in the course of their renal disease.¹¹

	OTHER KEY ISSUES IN THE TESTING OF ANTIHYPERTENSIVE AGENTS IN CHILDREN

Issue 1

Should investigators focus on primary (essential) or secondary (renal, cardiovascular, endocrine) causes of hypertension?

Should guidelines for each etiologic form of hypertension be developed?

Although essential hypertension is found less commonly in series of hypertensive children than in adult series, it can be identified in a certain percentage of children, especially those from families with hypertension. In these families, the percentage of hypertensive children may be as high as 10% and signs of end organ damage may be evident.³ These signs of end organ damage could include funduscopic changes in the retina, evidence of left ventricular hypertrophy (electrocardiogram, echocardiogram), and factors predictive of stroke and other relevant findings. Children with secondary hypertension are detected during the evaluation of their underlying condition; eg, renal failure, coarctation of the aorta, adrenal disorders, etc. The caveats listed above regarding ambulatory blood pressure measurements, stress testing, and nocturnal measurements are especially pertinent here. Although the type of hypertension should be identified, the indication for therapy is consistent for all patients. Any of these children should be considered for trials. Guidelines developed by the American Academy of Pediatrics and American Heart Association represent the consensus views of experts in childhood hypertension and should be carefully considered in any or all trials.^2,3

Issue 2

Which class of antihypertensive agent used should be examined in trials?

The subcommittee arrived at a consensus view in this area and identified several import factors. It was expressed that the PPRU should focus its resources on the following:

1. Drugs should be ranked by pharmacologic class. High priority should be given to novel classes of agents.
2. We should prioritize agents based on longer dosing intervals and simplicity of usage for the child and family.
3. We should prioritize agents based on child-appropriate formulations.
4. After testing several agents (3-5) in a class, any additional agent for potential study will have a lower priority unless there are dosing, formulations, or other unique characteristics.
5. We should survey different subspecialty groups (eg, nephrology, cardiology, and endocrinology) treating hypertension to determine which classes of hypertensives are used. The ideal dose of each agent used should be sought. Also, it is not known whether dose differences are related to diagnosis.
6. New classes of agents and/or new agents with attributes that enhance their child-therapeutic utility should receive high priority.

Issue 3

The Issue of Compensation for Participants <7 Years Old, for Whom Assent Cannot Be Obtained Institutional review boards (IRBs) nationwide have differing perspectives regarding the type and degree of compensation for children who participate in clinical trials. Opinions range from allowing only for parental reimbursement of actual expense incurred to significant monetary or material rewards. Monetary compensation for children <7 years old is particularly problematic because of a lack of appreciation of the value of money and because parents may take or spend these funds for something other than the child's needs/wants. Appropriate items for compensation at many centers includes book store coupons, video games, coupons valid in toy stores, coupons valid for children's apparel, etc. IRBs at certain sites may not permit any inducement.

Issue 4

On What Type (or Class) of Trial Should the PPRU or Other Testing Groups Focus Their Resources? This issue was extensively discussed and a consensus view was reached:

1. Phase I and pharmacokinetic studies
2. Phase II trials that are better designed, child friendly, and applicable to agents with high priority scores. We are strongly concerned that the safety and efficacy trials proposed by the FDA are primarily repeats of trials in adult participants, which are problematic in children as participants.¹² Among the problems identified are:
   • Length of trialIs the trial long enough to show efficacy and to permit evaluation of safety?
   • Forced titration trialsThis standard method in adult trials may be inappropriate in children of different ages and sizes.
   • Mandatory randomization to placebo withdrawalThis technique is widely used in adult trials. The achievement of a safe and effective dose of the agent in a hypertensive child should be the goal of the study.
   • Overlapping data in adults should not be overlooked, especially if the mode of action of a given class of agent in adults and children is essentially similar. The mechanism of action is the same for all age groups, but the physiologic effect may be greater for patients in whom maintenance of renal blood flow is highly renin-dependent (especially neonates and those children with bilateral renal artery stenosis).
   • Multiple dosage schedulesThese are difficult for children and for their families. Moreover, in school-aged children multidosing is cumbersome in a classroom setting for teachers, aides, school nurses, etc.
   • Difficulties in formulation, (ie, palatability).

Issue 5

Industry Relationships The relationship between the pediatric investigators and the pharmaceutical industry is complex and fluid. The importance of a close working relationship with interested companies is critical. The needs of pharmaceutical companies are clear; they need to be able to get a drug or device tested, evaluated, and then approved. The PPRU strives to be accurate in the network's ability to conduct trials in a timely manner to provide input into optimizing pediatric trial design.

Issue 6

The Use of Healthy Children The subcommittee is concerned about the use of healthy children and the permission by the FDA to use healthy children in clinical trials for whom benefits are uncertain.

Issue 7

The Setting of the Study of Antihypertensive Therapy Antihypertensive agents should be examined in clinically relevant settings. For example, hypertension is an issue in children receiving cyclosporine after solid organ transplant; these children require therapy regardless of underlying cause. Drug trials that exclude children with diabetes, chronic renal disease, and/or organ transplantation will be missing patients in whom these antihypertensive agents will be used and in whom a clear-cut therapeutic benefit is evident. To explore drug-drug interactions, children in these categories where exclusion might be considered should actually receive a higher priority. Because many of these children are treated and followed in academic medical centers, entry into studies at PPRU sites would be advantageous.

	CONCLUSION

Top Conclusion References

The use of children in antihypertensive trials is highly complex, relating, in part, to a relatively low incidence and prevalence, the lability of blood pressure values, and technical problems in measurement of blood pressure. Conventional approaches to antihypertensive agent trials that have benefited adult participants may not be relevant in children. The current surge in interest by the pharmaceutical industry to study antihypertensive agents in children will provide the opportunity to derive important data. However, the use of healthy children is problematic because many of the side-effects of antihypertensive agents are related to rapid lowering of blood pressure. Moreover, the exclusion of certain groups of children with complex diseases resulting in secondary hypertension may preclude the intelligent, well-informed use of agents in children in these diagnostic categories. An interactive relationship between the PPRU and interested companies, and the PPRU and the FDA are paramount in the appropriate labeling of antihypertensive drugs in children.

	FOOTNOTES

Gregory Harshfield, PhD, is a consultant from Medical College of Georgia, Augusta, Georgia, and Bruce Apert, MD, is a consultant from the University of Tennessee College of Medicine, Department of Pediatrics, Division of Cardiology, Memphis, Tennessee.

Received for publication May 11, 2000; accepted Jul 21, 2000.

Reprint requests to (R.W.C.) Department of Pediatrics, University of Tennessee, 50 N Dunlap, Rm 306-307, Memphis, TN 38103. E-mail: rchesney{at}utmem.edu

	ABBREVIATIONS

PPRU, Pediatric Pharmacology Research Units; FDA, Federal Drug Administration; IRB, Internal Review Board.

	REFERENCES

Top Conclusion References

1. McCrory WW. Definition, prevalence, and distribution of causes of hypertension. In Loggie J, ed. Pediatric and Adolescent Hypertension. Cambridge, MA; 1992:104-111
2. Task Force on Blood Pressure in Children Report of the Second Task Force on Blood Pressure in Children1987. Pediatrics 1987; 79:1-25 [Abstract/Free Full Text]
3. National High Blood Pressure Education Program Working Group Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: A Working Group Report from the National High Blood Pressure Education Program. Pediatrics 1996; 98:649 [Abstract/Free Full Text]
4. Harshfield GA, Alpert BS, Murphy JK, Willey ES, Dupaul LM, Somes GW. Hyperreactive adolescents have elevated casual and ambulatory blood pressures. Paper presented at: Proceedings of the Society of Behavioral Medicine; September 15, 1990; Chicago, IL. Abstract 3A
5. Harshfield GA, Alpert BS, Willey ES, Somes GW, Murphy JK, Dupaul LM Race and gender influence ambulatory blood pressure patterns of adolescents. Hypertension 1989; 14:598-603 [Abstract/Free Full Text]
6. Harshfield GA, Alpert BS, Pullman DA, Ambulatory blood pressure readings in children and adults. Pediatrics 1994; 94:180 [Abstract/Free Full Text]
7. Soergel M, Kirschstein M, Busch C, Oscillometric twenty-four-hour ambulatory blood pressure in healthy children and adolescents: a multicenter trial including 1411 subjects. J Pediatr 1997; 130:178-184 [CrossRef][Medline]
8. Harshfield GA, Hanevold CD Ambulatory blood pressure monitoring in the evaluation of pediatric disorders. Pediatr Ann 1998; 27:491-494 [Medline]
9. Lauer RM, Clarke WR, Beaglehole R Level, trend, and variability of blood pressure during childhood: the Muscatine study. Circulation 1984; 69:242-249 [Abstract/Free Full Text]
10. Berenson GS. Causation of Cardiovascular Risk Factors in Children-Perspectives on Cardiovascular Risk in Early Life. New York, NY: Raven Press; 1986
11. Chesney, RW. Renal Osteodystrophy in Children With Chronic Renal Disease: Causes, Complications & Treatment. New York, NY: Plenum Medical Book Company; 1985:321-331
12. Template for Sample Written Request for Oral Hypertensives. Available at: http://www.GOV/CDER/Pediatric/Index