Download Managing Calcium Channel Blocker

Case
Joel
Stu dies
Handl er,
MD,
in
H y p e r t e n s i o n
S ec tio n
E d i t o r
Managing Calcium Channel BlockerRelated Peripheral Edema
Joel Handler, MD
A
69-year-old woman was referred to the hypertension clinic with refractory stage 2 hypertension.
She had been taking a diuretic for 20 years. Mild pedal
edema occurred a year previously but had gotten worse
following prescription of nifedipine 2 months before
the initial hypertension clinic visit. The patient denied
exertional dyspnea or paroxysmal nocturnal dyspnea.
She complained of dry mouth and fatigue. Past medical history included transient ischemic attacks with a
normal brain computed tomography scan and echocardiogram, hemiparkinsonism with a right-sided tremor,
and hypothyroidism. Both of the patient’s parents, her
two brothers, and her two sisters had hypertension.
Medications at the time of her first hypertension clinic
visit were levothyroxine 0.075 mg q.d., pramipexole
dihydrochloride 1.5 mg t.i.d., clonidine 0.3 mg t.i.d.,
clopidogrel 75 mg q.d., losartan 50 mg b.i.d., amantadine 100 mg b.i.d., nifedipine extended release 30 mg
q.d., and furosemide 40 mg q.d. Blood pressure (BP)
was 184/92 mm Hg in both arms supine and 168/94
mm Hg in the left arm standing. Creatinine was 1.2 mg/
dL (normal range 0.7–1.3 mg/dL), potassium 4.0 mEq/
L (normal range 3.5–5.0 mEq/L), thyroid-stimulating
hormone 3.3 IU/mL (normal range 0.4–4.0 IU/mL),
and urinalysis was negative for protein. Twenty-fourhour urine collections for vanilmandelic acid, catecholamine, and metanephrine were normal.
Initial hypertension clinic plans were to switch the
furosemide to chlorthalidone 25 mg q.d. and to wean
her from clonidine. Fatigue and dry mouth resolved,
but pedal edema continued to be bothersome; a followup BP was 144/94 mm Hg. She refused to try a β blockFrom Kaiser Permanente, Anaheim, CA
Address for correspondence:
Joel Handler, MD, Kaiser Permanente, 411 Lakeview
Avenue, Anaheim, CA 92807
www.lejacq.com
400
THE JOURNAL OF CLINICAL HYPERTENSION
ID: 2863
er due to fear of alopecia. Nifedipine was changed to
diltiazem extended release 120 mg q.d., and when seen
in the hypertension clinic about 6 weeks later, her pedal
edema had resolved and BP was 132/82 mm Hg.
CASE TWO
A 57-year-old man was referred to the hypertension
clinic with refractory stage 2 hypertension. Four
years previously, when hypertension was diagnosed,
atenolol 50 mg q.d. had been initiated followed by the
addition of hydrochlorothiazide 25 mg q.d. and lisinopril 40 mg q.d. Systolic BP had been running in the
150–160+ mm Hg range and in the prior few months
had gone up to the 170+ mm Hg range. He had a
childhood right-sided head injury that he blamed for
chronic right-sided headaches responsive to ibuprofen
200 mg q.d., and he complained of new posterior
cervical headaches that he attributed to elevated BP.
Creatinine was 0.9 mg/dL, and an echocardiogram
revealed mild left ventricular hypertrophy.
Hypertension clinic BP was 176/84 mm Hg supine
and 174/88 mm Hg standing; heart rate was 64
bpm. His posterior cervical headaches were attributed to cervical osteoarthritis. Nifedipine extended
release 30 mg q.d. was added as a fourth antihypertensive drug, and 6 weeks later his BP had improved
to 148/84 mm Hg. A walking program was advised,
but another 6 weeks later his BP was 144/74 mm
Hg and 1+ pedal edema was noted on exam. With
the patient expressing belief that his edema predated
the nifedipine, the dose was increased to 60 mg q.d.
Edema worsened and the patient stopped the nifedipine on his own followed by nearly complete resolution of edema. Felodipine 5 mg q.d. was initiated
in addition to the hydrochlorothiazide, lisinopril,
and atenolol. Eight weeks later the patient’s BP had
improved to 134/88 mm Hg, and he maintained a
heart rate of 68 bpm without edema.
VOL. VI NO. VII JULY 2004
The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No
part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing
from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please
contact Sarah Howell at [email protected] or 203.656.1711 x106.
Table. Incidence of Edema and Other Adverse Events With Calcium Channel Blockers (CCBs)
EDEMA
STUDY
Papavassiliou et al.1
Papavassiliou et al.1
McMahon et al.2
Papavassiliou et al.1
McMahon et al.2
Papavassiliou et al.1
Papavassiliou et al.1
Leonetti et al.3
Papavassiliou et al.1
Leonetti et al.3
Papavassiliou et al.1
Russell4
Papavassiliou et al.1
Russell4
CCB
Nitrendipine
Amlodipine
Amlodipine
Felodipine
Felodipine
Nifedipine
Isradipine
Lercanidipine
Lacidipine
Lacidipine
Diltiazem
Diltiazem
Verapamil
Verapamil
N
37
78
%
28.9
22.0
69
16.2
42
13
14.2
8.2
9.3
5.7
14
10
9
2.4
6.1
1.7
4.9
DISCUSSION
Calcium channel blockers (CCBs) are potent agents
and may be useful additions to the regimen of patients
with resistant hypertension, as they were in the two
cases presented here. The most common class-specific
side effect responsible for intolerance and patient nonadherence to therapy is peripheral edema. Peripheral
edema is more likely to occur with dihydropyridine
CCBs. One study noted 272/2000 (13.6%) patients
reporting edema with CCB monotherapy, slightly
but not significantly more common in women than
men (15.6% vs. 11.8%),1 with the varying prevalence
according to the specific agent (Table). Two major
hypertension trials involving CCBs have reported
edema rates: the second Swedish Trial in Old Patients
with Hypertension (STOP-2) noted that 25.5% of
patients treated with either felodipine or isradipine had
edema;5 and Intervention as a Goal in Hypertension
Treatment (INSIGHT) study patients reported a 28%
incidence of edema while taking nifedipine long-acting GastroIntestinal Transport System (GITS), 8% of
whom discontinued that drug due to this side effect.6
Additionally, CCB edema rates are both dose and
duration related. In the Leonetti et al. study,3 increasing edema incidence was noted past 3 months of samedose administration of a CCB.
CCB edema is unlike fluid retention, which
occurs with the nonspecific vasodilators minoxidil
and hydralazine and is not diuretic responsive.
CCBs are natriuretic, a property that has been
attributed to a direct tubular effect.7 A water
displacement study demonstrated simultaneously
increased foot volume and sodium excretion with
nifedipine.8 The CCB edema mechanism is attributed to direct precapillary arteriolar dilatation leadVOL. VI NO. VII JULY 2004
HEADACHE
N
%
20
15.6
15
4.2
19.0
29
6.8
10.0
10
3.4
11
6.9
4.8
11
4.5
4.3
2.0
9
5.5
1.8
10
5.4
FLUSHING
N
%
15
11.7
7
2.0
2.5
13
3.1
10.0
18
6.1
14
8.8
2.9
5
2.0
3.9
DISCONTINUATION DUE
TO ADVERSE EVENT
N
%
42
32.8
33
9.3
2.5
59
13.8
10.0
52
17.6
24
15.1
21
8.6
2.9
5
3.1
23
14
1
0.5
37
20
ing to increased hydrostatic pressure and fluid shift
into the interstitial compartment of gravitationally
dependent sites.9 This mechanism is described as
creating a hypertensive state at the arteriocapillary
connection in the absence of compensatory postcapillary venous dilation resulting in a leak syndrome.10
This pathophysiology accounts for the observation
of dependent edema, which is often asymmetrical
due to variable local arteriolar and venous anatomic
features in older hypertensive populations. CCB
effects on lymphatic return or arteriolar vascular
permeability may play lesser roles.9,10
Both patients described preexisting dependent
edema, which worsened with nifedipine, and in
case 2 was not initially thought to be a drug effect.
Whereas the spectrum of non–drug-related dependent edema in older persons due to venous insufficiency is most often mild, CCB-related edema
may be more severe and painful. CCB-associated
peripheral edema may also be warm, erythematous,
and petechial as a result of red blood cell transudation.11 The severity may be more pronounced in
patients with preexisting venous insufficiency, but
there has not as yet been a prospective study looking at venous insufficiency as a risk factor for CCBrelated edema. Edema on CCB agents also merits
consideration of alternative etiologies such as heart,
renal, or hepatic failure, sleep apnea,9 or concurrent
use of nonsteroidal antiinflammatory agents. Most
often a clinical rather than a test-driven approach
suffices to obviate these conditions.
Treatment options for CCB-related peripheral
edema include reducing the dose; switching preferably to a nondihydropyridine CCB, or to another
dihydropyridine CCB; or providing a venodilator
THE JOURNAL OF CLINICAL HYPERTENSION
401
The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No
part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing
from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please
contact Sarah Howell at [email protected] or 203.656.1711 x106.
drug to reduce the venous hypertension that characterizes the phenomenon.9 The incidence of CCB
edema is dose related and a dose decrease may lead
to patient tolerability. As indicated in the Table,
variable edema rates for individual CCBs merit an
attempt with an alternative agent in a patient with
refractory hypertension. Third-generation lipophilic
CCBs (lercanidipine, lacidipine, manidipine) are
marked by their cell membrane domain with sustained site of action access and long receptor halflife.12 An associated dilatory effect upon efferent
arterioles appears to explain the reduced incidence
of edema compared with first- and second-generation CCBs. The Leonetti et al. study3 specifically
examined comparative CCB tolerability and looked
at examiner-verified edema in addition to less reproducible patient-reported complaints (Figure).
Venodilator drugs include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and nitrates. Reports indicate
that concomitant ACE inhibitor use can ameliorate
CCB-related edema.9 Most of the time the edema is
reduced rather than resolved. Occasionally, an ACE
inhibitor-associated BP decrease may permit dose
reduction of the CCB and therefore improve edema
in this fashion. One report stated that the incidence
of CCB edema was “improved in 85% of patients
experiencing the problem.”13 The Safety of Lotrel vs.
Amlodipine in a Comparative Efficacy (SOLACE)
trial showed that patients randomized to the combination tablet Lotrel (Novartis Pharmaceuticals Corp.,
East Hanover, NJ) containing both the ACE inhibitor
benazepril and amlodipine experienced peripheral
edema significantly less frequently than those randomized to amlodipine alone ( 12.6% vs. 23.0%,
p=0.01).14 ARBs and nitrates have not been as well
studied in this area.
Both patients presented here had resistant
hypertension despite taking four antihypertensive
drugs and were referred to a hypertension clinic. Nifedipine-related dependent edema occurred
despite an ACE inhibitor or an ARB in addition to
a diuretic leading to patient intolerance and discontinuation. The second patient stopped nifedipine on
his own without notifying a physician. Both patients
also observed a gradual worsening of prenifedipine
venous insufficiency edema becoming more prominent over several months at the same nifedipine
dosage (case 1) or following a dose increase (case 2).
Exchanging the nifedipine for extended-release diltiazem (case 1) or felodipine (case 2) led to patient
tolerability and BP control. Learning to be a CCB
jockey may occasionally enhance the management
of difficult hypertension.
402
THE JOURNAL OF CLINICAL HYPERTENSION
Edema
20
Legend
Amlodipine
15
Lercanidipine
Lacidipine
10
5
0
0
1 mo
2 mo 3 mo
6 mo Study end
Figure. Incidence of peripheral edema after 1, 2, 3,
and 6 months of treatment and at study end (N=828).
Adapted from Am J Hypertens. 2002;15:932–940.4
REFERENCES
1 Papavassiliou MV, Vyssoulis GP, Karpanov EA, et al. Side
effects of antihypertensive treatment with calcium channel
antagonists [abstract]. Am J Hypertens. 2001;14:114A.
2 McMahon FG. Management of Essential Hypertension.
The New Low-Dose Era. 2nd Ed. Mt Kisco, NY: Futura
Publishing; 1984:393–424.
3 Leonetti G, Magnani B, Pessina AC, et al. Tolerability of
long-term treatment with lercanidipine versus amlodipine
and lacidipine in elderly hypertensives. Am J Hypertens.
2002;15:932–940.
4 Russell RP. Side effects of calcium channel blockers.
Hypertension. 1988;11(suppl II):II42-II44.
5 Hansson L, Lindholm LH, Ekbom T, et al. Randomized
trial of old and new antihypertensive drugs in elderly
patients: cardiovascular mortality and morbidity. Swedish
trial in old patients with hypertension-2 study. Lancet.
1999;354:1751–1756.
6 Brown MJ, Palmer CR, Castaigne A, et al. Morbidity and
mortality in patients randomized to double-blind treatment
with a long-acting calcium channel blocker or diuretic
in the international nifedipine GITS study: intervention
as a goal in hypertension treatment (INSIGHT). Lancet.
2000;356:366–372.
7 Damasceno A, Santos A, Postana M, et al. Acute hypotensive, natriuretic, and hormonal effects of nifedipine in saltsensitive and salt-resistant black normotensive and hypertensive subjects. J Cardiovasc Pharmacol. 1999;34:346–353.
8 Van Hamersvelt HW, Kloke HJ, De Jong DJ, et al. Oedema
formation with the vasodilators nifedipine and diazoxide: direct local effect or sodium retention? J Hypertens.
1996;14:1041–1045.
9 Sica DA. Calcium channel blocker-related peripheral
edema: Can it be resolved? J Clin Hypertens (Greenwich).
2003;5:291–297.
10 Weir MR. Incidence of pedal edema formation with dihydropyridine calcium channel blockers: issues and practical significance. J Clin Hypertens (Greenwich). 2003;5:330–335.
11 Sirker A, Missouris CG, MacGregor GA. Case report:
dihydropyridine calcium channel blockers and peripheral
side effects. J Hum Hypertens. 2001;15:745–746.
12 Messerli FH, Grossman E. Pedal edema – not all dihydropyridine calcium antagonists are created equal. Am J
Hypertens. 2002;15:1019–1020.
13 Weber MA. How should combination therapy be started?
[abstract]. Am J Hypertens. 2003;16:265A.
14 Materson BJ. Rationale for initial therapy with combination
antihypertensive agents. Am J Hypertens. 2004;17:246A.
VOL. VI NO. VII JULY 2004
The Journal of Clinical Hypertension (ISSN 1524-6175) is published monthly by Le Jacq Communications, Inc., Three Parklands Drive, Darien, CT 06820-3652. Copyright ©2004 by Le Jacq Communications, Inc., All rights reserved. No
part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing
from the publishers. The opinions and ideas expressed in this publication are those of the authors and do not necessarily reflect those of the Editors or Publisher. For copies in excess of 25 or for commercial purposes, please
contact Sarah Howell at [email protected] or 203.656.1711 x106.