Does PO clonidine have utility in ambulatory practice?

Does PO clonidine have utility in ambulatory practice?

Comment by InpharmD Researcher

There appears to be limited data detailing the appropriateness of prescribing oral clonidine for ambulatory care management of hypertension. While some older studies suggest that short-acting agents like clonidine can lower blood pressure in the outpatient setting, other findings indicate that gradual reduction over time may be safer and more effective than rapid, in-office lowering. Additionally, the effect of clonidine can be unpredictable as it can cause excessive hypotension (see Table 3). As a result, some experts suggest caution with the use of rapid-acting agents, including oral clonidine, in outpatient management.

Background

A 2018 systematic review evaluated pharmacologic treatment of hypertensive urgency (HU) in the outpatient setting and identified a total of 20 double-blind randomized controlled trials and 12 cohort studies, encompassing 262 participants in prospective controlled trials. The authors noted that the studies were too heterogeneous to allow pooling of results, and that comorbidities and their potential impact on long-term management were inadequately addressed. However, among centrally acting antihypertensives, clonidine was evaluated in six trials, including four randomized controlled trials, one prospective cohort, and one retrospective cohort. Oral doses of clonidine ranging from 0.1 to 0.6 mg lowered systolic blood pressure from approximately 204-196 mmHg to 165-155 mmHg within two hours. Reported side effects included hypotension, orthostatic symptoms, sedation, mild transient drowsiness, dry mouth, impotence, and a modest decrease in heart rate averaging 6.2 beats per minute. In general, most medications evaluated in the review were short-acting, and the authors emphasized that rapid reductions in blood pressure may be harmful in patients with hypertensive urgency. Furthermore, some findings suggest that lowering blood pressure over a six-month period may be a safer and more effective approach. Accordingly, the authors of the review suggested that the use of rapid-acting agents, such as oral clonidine and nifedipine, should generally be avoided in outpatient management of hypertensive urgency. [1]

Relevant Prescribing Information

Indication and Usage: Clonidine hydrochloride tablets, USP are indicated in the treatment of hypertension. Clonidine hydrochloride tablets, USP may be employed alone or concomitantly with other antihypertensive agents. [2]

Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Does PO clonidine have utility in ambulatory practice?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-3 for your response.

Implementing a Policy and Protocol on Managing Patients With Hypertensive Urgencies
Design	Observational cohort study N= 179
Objective	To achieve decreased rates of ordering clonidine for the immediate treatment of hypertensive urgency in the office and to determine if reduced use led to a decline in poor outcomes
Study Groups	Preintervention group (n= 106) Postintervention group (n= 73)
Inclusion Criteria	Patients seen at either of the 2 federally qualified health centers (FQHCs) where clinical pharmacists were located and had given the in-service, with clonidine ordered according to the report
Exclusion Criteria	Patients presenting with signs or symptoms of hypertensive emergency (ie, chest pain, shortness of breath, and vision or mental status changes)
Methods	An institution-wide protocol and algorithm were developed to guide providers in managing hypertensive urgency, avoiding short-acting antihypertensives like clonidine. Preintervention and postintervention reports were generated to determine clonidine orders. Electronic health charts were reviewed for documentation of poor outcomes related to clonidine administration within 1 week of the hypertensive urgency visit date
Duration	9 months preintervention and 9 months postintervention
Outcome Measures	Primary: Decreased rates of clonidine orders Secondary: Decline in poor outcomes (ED referrals and adverse events associated with clonidine administration)
Baseline Characteristics		Preintervention Group (n = 106)	Postintervention Group (n = 73)	P Value
	Female, n (%)	61 (57.5)	41 (56.2)	0.854
	Age, mean ± SD	54.3 ± 13.7	53.4 ± 10.7	0.646
	Hispanic or Latino, n (%)	26 (24.5)	17 (23.3)	0.849
	Systolic blood pressure, mean ± SD	194 ± 22	189 ± 27	0.160
	Diastolic blood pressure, mean ± SD	110 ± 16	111 ± 16	0.860
	Home anti-HTN medications - ACE inhibitor/ARB	58 (54.7)	44 (60.3)	0.461
	Home anti-HTN medications - Diuretic	48 (45.3)	28 (38.4)	0.357
	Home anti-HTN medications - CCB	41 (38.7)	38 (52.1)	0.077
	Home anti-HTN medications - BB	34 (32.1)	26 (35.6)	0.622
	Home anti-HTN medications - Clonidine	8 (7.5)	14 (19.2)	0.020
	Number of home anti-HTN medications, mean ± SD	1.86 ± 1.4	2.08 ± 1.4	0.301
	None, n (%)	25 (23.6)	13 (17.8)	0.353
	More than one, n (%)	63 (59.4)	52 (71.2)	0.106
	Patient-reported signs and symptoms at encounter - Headache	16 (15.1)	15 (20.5)	0.343
	Patient-reported signs and symptoms at encounter - Dizziness	8 (7.5)	5 (6.8)	0.860
	Patient-reported signs and symptoms at encounter - Anxiety	4 (3.8)	0 (0)	0.093
	Existing HTN diagnosis	75 (70.8)	41 (56.2)	0.045
Results	Endpoints	Preintervention Group (n = 106)	Postintervention Group (n = 73)	P Value
	Clonidine orders, n (%)	106 (17.4)	73 (10.6)	0.001
	ED referrals, n (%)	7 (6.8)	9 (12.5)	0.198
	Hospitalizations, n	2	0
Adverse Events	No adverse effects were documented from in-office clonidine administration in either cohort of patients
Study Author Conclusions	The hypertensive urgency protocol and education reduced the number of clonidine orders and hospital admissions. The increase in ED referrals needs further assessment.
Critique	The study effectively demonstrated a reduction in clonidine orders and hospital admissions through protocol implementation. However, the study was limited by its focus on clonidine orders only, without reviewing all patients with asymptomatic hypertension or comparing ED rates in patients who received clonidine with those who did not. Additionally, the lack of documentation on why patients presented with hypertensive urgency and what medication regimen was given to those who went to the ED limits the understanding of the full impact of the protocol.

References:

Chim C, Dimitropoulos E, Ginzburg R. Implementing a Policy and Protocol on Managing Patients With Hypertensive Urgencies. Ann Pharmacother. 2016;50(7):548-554. doi:10.1177/1060028016644756

Transdermal and Oral Clonidine
Design	Double blind, randomised cross over trial N= 26
Objective	To compare the antihypertensive efficacy and side effects of transdermal clonidine (Catapres-TTS) and oral clonidine in equivalent doses on a weight basis
Study Groups	Transdermal clonidine (n= 13) Oral clonidine (n= 13)
Inclusion Criteria	Patients with mild to moderate WHO I hypertension, previously untreated or treated with drugs other than clonidine
Exclusion Criteria	Patients who had received clonidine before
Methods	Patients received placebo for four weeks, followed by six weeks of active treatment with either transdermal clonidine (0.2 mg/day) or oral clonidine (0.1 mg twice daily), with a one-week placebo washout period in between. Blood pressure and heart rate were measured weekly
Duration	Four weeks placebo run-in, six weeks active treatment, one-week placebo washout, six weeks active treatment
Outcome Measures	Reduction in supine and standing blood pressures and heart rates
Baseline Characteristics		All patients (n= 16)
	Age, years	43
	Female	6
	Weight, kg	80
Results		Transdermal (n= 13)	Oral (n= 13)	p-value
	Supine systolic BP reduction, mmHg	13	11	<0.01
	Supine diastolic BP reduction, mmHg	7	-	<0.01
	Standing systolic BP reduction, mmHg	14	-	<0.01
	Standing diastolic BP reduction, mmHg	9	-	<0.01
	Heart rate reduction, beats/min	9	8	<0.05
Adverse Events	Dry mouth and tiredness were common but mild, with no significant difference between treatments. Mild erythema occurred in some patients during transdermal treatment
Study Author Conclusions	Transdermal clonidine is similar in effect to oral clonidine for mild to moderate hypertension and may improve patient compliance due to less frequent dosing.
Critique	The study's strengths include its double-blind, cross-over design and direct comparison of transdermal and oral clonidine. Limitations include the small sample size and short duration, which may not capture long-term effects or rare adverse events.

References:

Lilja M, Juustila H, Sarna S, Jounela AJ. Transdermal and oral clonidine. Ann Med. 1991;23(3):265-269. doi:10.3109/07853899109148058

Hypertensive Urgency
Design	Case series
Case 1	A 74-year-old man presented to a routine clinic appointment with a moderate posterior cervical headache persisting for several days. He had no significant medical history and rarely visited physicians, with no record of previous blood pressure readings. His headache had fluctuated over the past months but intensified recently. He was self-medicating with over-the-counter ibuprofen. He reported no chest discomfort or respiratory issues, and he was a nonsmoker and nondrinker. His family history included maternal hypertension. During examination, his blood pressure was critically high at 224/120 mm Hg, with a heart rate of 72 bpm. Physical examination revealed an S4 gallop, trace bipedal edema, slightly reduced cervical range of motion without tenderness, normal lung sounds, and no murmurs or bruits. After an initial blood pressure reading, he was administered 0.2 mg of clonidine orally. An hour later, he experienced severe dizziness accompanied by a precipitous drop in systolic blood pressure to 60 mm Hg. In the emergency department, he received intravenous normal saline, which improved his blood pressure to 92/72 mm Hg, though dizziness persisted. Laboratory results were largely unremarkable, showing blood urea nitrogen at 13 mg/dL, creatinine at 0.7 mg/dL, potassium at 3.8 mEq/L, normal urinalysis, and a normal 12-lead ECG. He was observed overnight in the hospital and felt better the next morning, with a blood pressure of 156/88 mm Hg. Upon discharge, he was prescribed hydrochlorothiazide 25 mg daily. At a follow-up appointment one week later, his blood pressure had improved to 142/84 mm Hg, but he continued to experience occipital headaches. This case highlights the challenges of managing hypertensive crises and the need for careful monitoring and appropriate medication adjustments in such situations.
Case 2	A 72-year-old woman with a five-year history of poorly controlled hypertension, despite compliance with a regimen of lisinopril/hydrochlorothiazide and extended-release verapamil, presented to the Hypertension Clinic. Additionally, she had polymyalgia rheumatica, managed with prednisone. Due to episodes of high systolic blood pressure (SBP) at home (>180 mm Hg), she was taking clonidine, averaging two tablets daily. The patient experienced side effects like dry mouth, anxiety, fatigue, and dizziness. Her clinic BP was 162/82 mm Hg with a heart rate of 62 bpm, and physical examination revealed an S4 gallop and a soft left femoral bruit. Initial self-monitoring of BP was incorrect due to an unsupported arm and an inadequate cuff size. Following a proper BP monitoring demonstration and adjustments, including adding felodipine 5 mg daily, reducing home BP checks to once daily, and discontinuing clonidine for elevated readings, her home SBP readings improved with no further recordings over 180 mm Hg. After two weeks, the clinic BP improved to 148/78 mm Hg, leading to an increase in felodipine dosage to 10 mg daily. This regimen was well tolerated, resulting in a subsequent clinic BP of 136/72 mm Hg.
Study Author Conclusions	Clonidine loading, particularly sequential clonidine loading for asymptomatic or minimally symptomatic BP elevations in the absence of target organ damage, is overused; as noted, patient instructions for as-needed unobserved usage of clonidine based on home BP determinations poses risks. In his review, Vidt16 best sums up the evidence when he states “No data currently exist to show immediate benefit from acutely lowering BP in asymptomatic patients with severe hypertension, but data do suggest that an aggressive approach may be harmful.” Probably the most urgent instruction to provide such “urgency” patients is a confirmed clinic follow-up appointment within a few days following an advance in daily antihypertensive therapy directed at the time of their evaluation.

References:

Handler J. Hypertensive urgency. J Clin Hypertens (Greenwich). 2006;8(1):61-64. doi:10.1111/j.1524-6175.2005.05145.x