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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.