A Comparison of Compliance Between Clonidine Patch and Methyldopa for the Treatment of Chronic Hypertension in Pregnancy

Purpose of the Study:

The purpose of this of open-label randomized clinical trial is to compare clonidine patch
(Catapres-TTS®) and orally administered methyldopa (Aldomet®) over a 4-week period for
compliance in pregnant women between 14 and 28 weeks of gestation. In addition, this study
will evaluate blood pressure (BP) control, patient tolerability, and development of side
effects to each medication. Patients will be alternately randomized to receive methyldopa
(standard of care) or clonidine patch.

Hypothesis:

Clonidine is an effective antihypertensive agent with similar mechanism of action to
methyldopa. Transdermal clonidine may provide a better compliance profile, adequate BP
control and, therefore, may be used as an alternative to methyldopa for the treatment of CHTN
in pregnancy.

Primary outcome of the study is patient compliance. Compliance will be measured via patient
diary, promptness of keeping appointments, and pill/patch counts at each visit. Overall
compliance will be calculated over a 4 week study period by adding compliance points for each
visit as outlined in the data sheet.

Secondary outcomes are:

1. Change in mean arterial BP at weeks 1,2,3,4 in comparison to baseline BP at the initial
visit (It will be used in patients newly started on medications or in patients with
uncontrolled BP at baseline).

2. Side effects to each medication as reported by the patients.

Background and Significance

Chronic hypertension (CHTN) affects 1-5% of pregnancies. It is defined as BP of 140/90 or
higher before the 20th week of gestation or beyond 12 weeks postpartum. CHTN is associated
with an increased risk of preeclampsia, preterm delivery, intrauterine growth restriction,
intrauterine fetal demise, placental abruption and cesarean delivery. Mild hypertension is
defined as BP < 150/100 mm Hg and severe hypertension as BP > 160/110 mm Hg. There is a
direct correlation of adverse perinatal outcomes with duration and severity of CHTN in
pregnancy. Treatment of mild CHTN in pregnancy does not improve perinatal outcomes, and
therefore, antihypertensive therapy is reserved for moderate to severe hypertension only.

Methyldopa is used as a first line therapy for CHTN in pregnancy. It is a central
alpha-adrenergic agonist that decreases peripheral sympathetic outflow and thus results in a
decrease in peripheral resistance and BP. It does not impact uteroplacental blood flow and
fetal hemodynamics. Methyldopa is a weak antihypertensive agent and often times there is a
need for increase in dose, frequency and/or addition of another medication to optimize BP
control with advancing gestational age. Side effects of methyldopa include sedation,
orthostatic hypotension, edema, weight gain, bradycardia, and dry mouth. Rarely, aggravation
of angina, congestive heart failure, pancreatitis, colitis, hyperprolactinemia, bone marrow
depression, hemolytic anemia, false positive anti-nuclear antibodies and rheumatoid factor
may be seen.

The use of various classes of antihypertensive medications in pregnancy is limited due to
potential teratogenic effects. Angiotensin converting enzyme inhibitors are contraindicated
in pregnancy. The use of beta-blockers and diuretics is controversial, and there is limited
data on calcium channel blockers in pregnancy.

Clonidine is an effective antihypertensive treatment and is available in oral, parenteral,
and transdermal dosage forms. Although oral and parenteral forms are commonly employed for
short-term use in hypertensive urgencies, data regarding its use in pregnancy are lacking. It
acts by stimulating α2-adrenergic receptors in the central nervous system (CNS), which
depresses peripheral sympathetic nervous system outflow, and thus lowering BP. Clonidine is
not associated with teratogenic effects in the fetus. Reproduction studies performed in
rabbits at doses up to 3 times the maximum recommended daily human dose (MRDHD) of clonidine
hydrochloride have revealed no evidence of teratogenic or embryotoxic potential. The
pharmacokinetics of clonidine in pregnancy has been studied. Clonidine crossed placenta and
fetal concentration is 0.89 of the maternal level. No neonatal side effects have been
reported. Clonidine is metabolized by the liver and is excreted unchanged in the urine.

Therapeutic levels of orally administered drugs are affected by the transit time through
small intestines and the presence of food and liquid in the gastrointestinal tract.
Transdermal administration of drugs by passes the first-pass metabolism through the liver,
requires smaller dose to achieve therapeutic effects, and promotes patient compliance. In
addition, the drug is absorbed through the skin at a constant rate eliminating peak and
troughs associated with oral administration. This may result in steadier BP control with
transdermal clonidine administration. This may be of benefit in pregnancy as the
gastrointestinal transit time is significantly prolonged due to progesterone effects and
nausea vomiting in the first trimester may limit the use of orally administered drugs. In
addition, one would expect improved patient compliance be avoiding repeated dosing such as
four times a day schedule for methyldopa.

Transdermal clonidine (Catapres-TTS®) is a preparation of clonidine hydrochloride that can be
released and absorbed transdermally over a 7-day period. Its side effect profile is similar
to methyldopa including tiredness, lethargy, drowsiness, constipation and dry mouth.
Orthostatic hypotension occurs in 3% patients with oral administration and has not been
reported with the transdermal form. Skin reactions including redness, itching, and darkening
of the skin may occur with clonidine patches. Rarely, angioedema, atrioventricular block,
chest pain, congestive heart failure, hepatitis, thrombocytopenia, or urinary retention may
occur.

A study of hypertension in non-pregnant individuals from United Kingdom showed that only 40%
of patients who were started on a new antihypertensive drug were compliant six months later.
There are no data available on compliance with antihypertensive medications in pregnancy,
although our anecdotal experience is of improved compliance with medications in pregnancy
compared to a non-pregnant state.

Our study will determine differences in compliance between the two antihypertensive drugs,
and will provide additional comparisons of patient tolerability and adequacy of BP control.
This may be of particular value in pregnant women who are unable to tolerate oral feeds e.g.
those with hyperemesis gravidarum, or in immediate postoperative period. In addition, it will
provide information on an alternate option for BP control, which has not been described in
obstetrical literature.

1. National High Blood Pressure Educational Program Working Group. Report on High Blood
Pressure in Pregnancy. Am J Obstet Gynecol 1990;163:1691-1712.

2. Report of the National High Blood Pressure Education Program Working Group on High Blood
Pressure in Pregnancy. Am J Obstet Gynecol 2000;183:S1-S22.

3. Chronic Hypertension in Pregnancy. ACOG Practice Bulletin No. 29. American College of
Obstetricians and Gynecologists. Obstet Gynecol 2001;98:177-185.

4. Montan S, Anandakumar C, Arulkumaran S, Ingemarsson I, Ratnam SS. Effects of Methyldopa
on Uteroplacental and Fetal Hemodynamics in Pregnancy Induced Hypertension. Am J Obstet
Gynecol 1993;168:152-6.

5. Horrath JS, Phippard A, Korda A, Hendersen-Sart DJ, Child A, Tiller DJ. Clonidine
Hydrochloride - A Safe and Effective Antihypertensive in Pregnancy. Obstet Gynecol
1985;66:634-8.

6. Turnbull AC, Ahmad S. Catapress in the Treatment of Hypertension in Pregnancy, A
Preliminary Study. In Hypertension. Symposium of the Royal College of Surgeons, London
1970:237-45

7. Hartikainen-Sorri AL, Heikkinen JE, Koivisto M. Pharmacokinetics of Clonidine During
Pregnancy and Nursing. Obstet Gynecol 1987;69:598-600.

8. Ala-Kokko TI, Pienimaki P, Lampela E, Hollmen AI, Pelkonen O, Vahakangas K. Transfer of
Clonidine and Dexmedetrmidine Across the Isolated Perfused Human Placenta. Acta
Anesthesiol Scand 1997;41(2):313-19.

9. Jones JK, Gorkin L, Lian JF, Staffa JA, Fletcher AP. Discontinuation of and Changes in
Treatment after start of new courses of Antihypertensive Drugs: A Study of a United
Kingdom Population. BMJ 1995;311:293-5

Inclusion Criteria:

1. Intrauterine pregnancy between 14 - 28 weeks of gestation

2. Chronic hypertension requiring antihypertensive therapy (BP < 180/110)

3. Subjects who consent to the study

4. No evidence of fetal compromise (i.e. intrauterine growth restriction)

Exclusion Criteria:

1. Evidence or suspicion of preeclampsia

2. Known cardiac disease

3. Known renal dysfunction (creatinine > 1 mg/dl)

4. Known hepatic disease

5. Known cerebrovascular disease

6. Allergy to clonidine patch