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High-Output Heart Failure Associated With Anagrelide Therapy for Essential Thrombocytosis

Posted on: Saturday, 20 August 2005, 03:00 CDT

CLINICAL OBSERVATIONS

TO THE EDITOR: Background: Congestive heart failure (CHF) is usually associated with disorders causing low cardiac output; disorders associated with high cardiac output rarely cause CHF (1, 2). Medications have not previously been thought to cause high- output heart failure. New-onset CHF and cardiovascular death have rarely been associated with therapy with anagrelide (3-5), a novel treatment for essential thrombocytosis. The mechanism of cardiac dysfunction related to anagrelide has not previously been reported.

Objective: To report a case of high-output heart failure associated with anagrelide use in a patient with essential thrombocytosis.

Case Report: A 34-year-old man was referred for evaluation of pulmonary hypertension. He had received a diagnosis of essential thrombocytosis at age 25 years, and his course was marked by recurrent gastrointestinal bleeding and arterial thromboembolic disease. Four years before the evaluation reported here, he began treatment with anagrelide. In the year before the patient's cardiac evaluation, the dose of anagrelide was titrated upward to 8 mg/d, with a subsequent reduction in platelet count from 1800 10^sup 9^ cells/L to 400 10^sup 9^ cells/L. Over the next several months, he noted palpitation, pedal edema, increasing abdominal girth, exertional dyspnea, and muscle wasting. Furosemide was given with a subsequent 20-pound weight loss, but the palpitations, dyspnea, and ascites persisted. Echocardiography performed after onset of symptoms revealed mild left ventricular dilatation (5.9 cm) and moderate left atrial dilatation (5.3 cm) and right atrial dilatation. Left ventricular wall motion and ejection fraction were normal. There was mild tricuspid regurgitation with a peak jet velocity of 3.5 m/s. Cardiac catheterization revealed moderate pulmonary hypertension and prompted referral to a subspecialty pulmonary hypertension clinic. Physical examination revealed a blood pressure of 120/60 mm Hg, a pulse of 80 beats/min, oxygen saturation of 97% on room air, moderate elevation of jugular venous pressure, no S^sub 3^ or murmur, a moderately enlarged pulsatile liver, and 2+ pedal edema. Leukocyte count was 18.4 10^sup 9^ cells/L, hemoglobin level was 11%, hematocrit was 0.34, platelet count was 962 10^sup 9^ cells/L, brain natriuretic peptide level was 326 ng/L, and thyroid-stimulating hormone level was 3.29 mU/L (within normal range). Results of serologic tests for HIV infection were negative. Electrocardiography showed first-degree atrioventricular block. A pulmonary ventilation-perfusion scan showed low probability of pulmonary embolism, and computed tomography of the pulmonary arteries yielded negative results with no evidence of acute or chronic pulmonary embolism. Repeated rightheart catheterization showed evidence of CHF related to high cardiac output (Figure, Table).

After a discussion with the patient's hematologist, anagrelide therapy was discontinued. Within 1 week, symptoms had improved dramatically and signs of CHF regressed. Diuretics were withdrawn. Repeated right-heart catheterization 6 weeks later revealed resolution of all hemodynamic abnormalities (Figure, Table). Six months later, the patient was asymptomatic and taking hydroxyurea therapy for essential thrombocytosis.

Figure. Intracardiac pressure tracings before and after discontinuation of anagrelide.

Discussion: High-output heart failure is an uncommon syndrome that has been described in association with anemia, thyrotoxicosis, systemic arteriovenous fistulas, Paget disease, and nutritional deficiencies, such as beriberi heart disease (1, 2). High cardiac output is also known to occur in association with certain types of renal and hepatic disease, pregnancy, and treatment with certain vasodilators (for example, epoprostenol), but the clinical syndrome of CHF is rarely seen under these circumstances.

Anagrelide, a thrombocytopenic agent, is a quinazoline derivative that inhibits cyclic nucleotide phosphodiesterase type IV and is approved for use in essential thrombocytosis and for control of thrombocytosis associated with polycythemia vera. In some studies, commonly reported cardiovascular side effects included palpitations, tachycardia, and fluid retention or edema (3). In a study of 577 patients treated with anagrelide, 14 developed CHF; of these, 2 died suddenly (4). In another study of 942 patients taking anagrelide for thrombocytosis, 15 died of cardiac causes (5). None of the heart failure cases in either of these studies was studied in detail.

Table. Serial Hemodynamic Findings*

The present case is remarkable for 2 major features: marked elevation of cardiac output and normal left ventricular ejection fraction in the setting of clinical CHF, and nearly immediate resolution of clinical and hemodynamic abnormalities after withdrawal of anagrelide. The observation of high cardiac output as a part of the pathophysiologic characteristics of this case is not entirely unexpected. Anagrelide is known to have positive inotropic activity in animals (4). As a phosphodiesterase inhibitor, it may have actions in common with such drugs as amrinone, milrinone, and enoximone, phosphodiesterase type 3 inhibitors known for their positive inotropic effects and for their adverse effect on mortality when used over the long term in patients with heart failure (6).

Cardiac disease is a major cause of death (including sudden death) in patients treated with anagrelide. Since the adverse hemodynamic effects were reversible in our case, clinicians should consider discontinuing anagrelide therapy when even mild cardiac side effects are noted.

References

1. Braunwald E, Zipes D, Libby P. Heart Disease-A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders; 2001.

2. Anand IS, Florea VG. High output cardiac failure. Curr Treat Options Cardiovasc Med. 2001;3:151-159. [PMID: 11242561]

3. Silverstein MN, Petitt RM, Solberg LA Jr, Fleming JS, Knight RC, Schacter LP. Anagrelide: a new drug for treating thrombocytosis. N Engl J Med. 1988;318:1292-4. [PMID: 3362187]

4. Anagrelide, a therapy for thrombocythemic states: experience in 577 patients. Anagrelide Study Group. Am J Med. 1992;92:69-76. [PMID: 1731512]

5. Petitt RM, Silvetstein MN, Petrone ME. Anagrelide for control of thrombocythemia in polycythemia and other myeloproliferative disorders. Semin Hematol. 1997;34: 51-4. [PMID: 9025162]

6. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. 1991;325:1468-75. [PMID: 1944425]

Peter J. Engel, MD

Heide Johnson, RN

The Ohio Heart Health Center and The Lindner Center for Research and Education

Cincinnati, OH 45219

Robert P. Baughman, MD

University of Cincinnati Medical Center

Cincinnati, OH 45267

Arthur I. Richards, MD

Oncology Hematology Care, Inc.

Cincinnati, OH 45219

Potential Financial Conflicts of Interest: None disclosed.

Copyright American College of Physicians Aug 16, 2005

Source: Annals of Internal Medicine

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