- Email: [email protected]
Bradycardia during therapy for multiple myeloma with thalidomide
after landing. Any significant main effects were further examined using the Tukey post hoc test. The significance level was set at p ⬍0.05, and the power level achieved was ⬎0.80. Flights of ⬍10 days did not alter PR or QTc intervals, and RR intervals decreased significantly 2 days after landing compared with previous days (Figure 1). Six astronauts had increased and 5 had decreased QTc intervals during spaceflight, suggesting individual variability. The largest change was 0.02 second. Interestingly, 3 astronauts had QTc intervals ⱖ0.44 second before spaceflight. Of these 3, the QTc interval increased during spaceflight in 1 and decreased in the others. Mean QTc intervals from the 3 long-duration astronauts reported previously1 were identical before spaceflight compared with our present study (0.41 ⫾ 0.01 second) but increased significantly after 30 days (0.46 ⫾ 0.02 second), 60 days (0.48 ⫾ 0.02 second), and 90 days (0.49 ⫾ 0.02 second) of spaceflight. •••
In this study, QTc intervals did not increase significantly during the first 9 days of spaceflight. Based on our previous work demonstrating prolongation of QTc intervals in astronauts on long-duration spaceflights, we speculate that QTc interval prolongation occurs sometime between 9 and 30 days of spaceflight. Perhaps after the longer exposure to a reduced workload in flight, the heart begins to remodel. Interestingly, this group of astronauts
had longer QTc intervals than a previously reported group of astronauts who underwent short-duration spaceflight,1 and several had QTc intervals that were at or near the clinical threshold of prolonged QTc (QTc ⱖ0.44 second) before spaceflight. Future studies should examine this time-dependent effect of spaceflight on QTc intervals. Acknowledgment: We express our appreciation to the astronauts who volunteered for this study and to L. Christine Ribeiro, MS, for assistance with data analysis.
1. D’Aunno DS, Dougherty AH, DeBlock HF, Meck JV. Effect of short- and long-duration spaceflight on QTc intervals in healthy astronauts. Am J Cardiol 2003;91:494 –497. 2. Rossum AC, Ziegler MG, Meck JV. Effect of spaceflight on cardiovascular responses to upright posture in a 77-year-old astronaut. Am J Cardiol 2001;88: 1335–1337. 3. Fritsch-Yelle JM, Leuenberger UA, D’Aunno DS, Rossum AC, Brown TE, Wood ML, Josephson ME, Goldberger AL. An episode of ventricular tachycardia during long-duration spaceflight. Am J Cardiol 1998;81:1391–1392. 4. Golubchikova ZA, Alferova IV, Liamin VR, Turchaninova VF. Dynamics of some electrocardiographic parameters in cosmonauts during long-term Mir mission. Aviakosm Ekolog Med 2003;37:41–45. 5. Hoffler GW, Wolthuis RA, Johnson RL. Apollo space crew cardiovascular evaluations. Aerosp Med 1974;45:807–820. 6. Romanov EM, Artamonova NP, Golubchikova ZA, Zavadovskii AF, Korotaev MM. Results of long-term electrocardiographic examinations of cosmonauts. Kosm Biol Aviakosm Med 1987;21:10 –14. 7. Fritsch-Yelle JM, Charles JB, Jones MM, Wood ML. Microgravity decreases heart rate and arterial pressure in humans. J Appl Physiol 1996;80:910 –914. 8. Bazett HC. An analysis of the time relation of electrocardiograms. Heart 1920;7:353–370.
Bradycardia During Therapy for Multiple Myeloma With Thalidomide Ibrahim Elias Fahdi, MD, Venkat Gaddam, MD, Jorge F. Saucedo, MD, Channarayapatna V. Kishan, MD, Keyur Vyas, MD, Matthew G. Deneke, MD, Hani Razek, MD, Brett Thorn, MS, Joseph K. Bissett, MD, Elias Anaisse, MD, Bart Barlogie, MD, and Jawahar L. Mehta, MD, PhD We studied the medical records of 96 patients who received thalidomide and 104 patients who made up a control group. We found that 53% of patients (52 patients) using thalidomide had a heart rate of <60 beats/min at some point during follow-up and 19% of thalidomide patients (10 patients) developed symptom-related bradycardia. Reducing the thalidomide dose appeared to alleviate symptoms in most patients. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:1052–1055) From the Division of Cardiovascular Medicine, the Department of Internal Medicine, and the Multiple Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Dr. Mehta’s address is: Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, #532, Little Rock, Arkansas 72205. E-mail: [email protected]. Manuscript received August 27, 2003; revised manuscript received and accepted December 18, 2003.
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©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 April 15, 2004
halidomide (␣-N-phthalimidoglutarimide) was initially manufactured in West Germany and was T marketed as an antiemetic and sedative until 1960. Thalidomide functions as a potent immunosuppressive and antiangiogenic agent1–3 by inhibiting the phagocytic ability of inflammatory cells and the production of cytokines, such as tumor necrosis factor-␣ (TNF␣). It has been shown to be effective in the treatment of inflammatory diseases,4 – 6 in conditions associated with human immunodeficiency virus (HIV) infection,7 and in various cancers.8 –10 Vogelsang et al11 showed improved survival in patients with refractory chronic graft-versus-host reaction who received thalidomide. One-third of patients with advanced and refractory multiple myeloma, in whom salvage therapy failed after single and even tandem autotransplants, responded markedly to this drug.10,12 Thalidomide represents only the third independently active compound in the treatment of myeloma since the introduction of melphalan and prednisone 4 decades ago. Thalido0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.12.061
nosed patients with multiple myeloma. In this study, patients were Control Thalidomide treated with combination chemotherapy and were randomized to receive Heart Rate With Heart Rate With either thalidomide or placebo. All Time Point (beats/min) Bradycardia (beats/min) Bradycardia p Value patients were randomized to receive Baseline 80.7 ⫾ 1.5 9.1% 77.9 ⫾ 1.5 9.4% 0.146 oral thalidomide at a dose of 400 4–12 weeks 82.9 ⫾ 2.4 8.3% 67.2 ⫾ 1.7 38.8% ⬍0.001 mg/day throughout the induction 13–32 weeks 84.3 ⫾ 2.0 6.3% 68.7 ⫾ 1.8 35.3% ⬍0.001 33–52 weeks 86.6 ⫾ 1.9 5.0% 70.6 ⫾ 2.0 29.7% ⬍0.001 phase. They received 200 mg every other day for the first year of maintenance and 100 mg/day orally. Treatment cycles were as follows: (1) vincristine (0.5 mg/day) administered by continuous infusion along with adriamycin (10 mg/m2/day) for 4 days and oral dexamethasone (40 mg/day); dexamethasone was repeated on days 9 to 12 and again on days 17 to 20; (2) after 5 weeks, dexamethasone (40 mg/day) was administered orally with continuous infusion of cyclophosphamide (400 mg/m2/day), etoposide (40 mg/m2/day), and cisplatin (15 mg/m2/day); and (3) after 4 weeks, continuous infusion of cyclophosphamide (750 mg/m2/day), adriamycin (15 mg/ m2/day), and oral dexamethasone (40 mg/day) was admininstered with stem cell collection; this cycle was repeated if needed. Six independent reviewers performed the data review. Medical records of all patients were available and were reviewed. The data were obtained at baseline (before randomization), at first follow-up (4 to 12 weeks after randomization), at second follow-up (13 to 32 weeks after randomization), and at third follow-up (33 to 52 weeks after randomization). Data were recorded in Microsoft Excel and Access (Microsoft, Redmond, Washington) and analyzed using SAS version 8.2 software (SAS Institute, Inc., Cary, North Carolina) to detect statistically significant differences in the variables. Two-way analyses, Fisher’s exact test, and t tests were used to check randomization results. This was necessary because this study was randomized for the purposes of the cancer component and not the electrocardiographic component. The same tests were used to analyze the impact of FIGURE 1. (A) The reduction in heart rate in the thalidomide prior drug intake. Also, the impact of age, race, and group began almost immediately after starting the medication gender was analyzed at baseline as a covariate repeatand was sustained throughout the treatment course. Follow-up visit 1 was at 4 to 12 weeks, visit 2 was at 13 to 32 weeks, and ed-measures analysis and found not to be significant. visit 3 was at 33 to 52 weeks. (B) Heart rate reduction in the Hence, we chose to present the results with the simthalidomide group is shown as a percentage change from baseplest interpretation: the Kruskal-Wallis, distributionline. free, 1-way analysis of the raw heart rate data based on treatment group over the follow-up times. Of the 200 patients enrolled in the study, 96 pamide is currently undergoing investigation in combination with dexamethasone and chemotherapy during in- tients received thalidomide and the remaining 104 duction and for maintenance of remission. Side effects patients received placebo. We collected data on painclude peripheral neuropathy, sometimes irreversible, tient demographics, the presence of known cardiac hypothyroidism,13 and thrombotic events.14,15 We have risk factors such as hypertension (systolic blood presrecently observed a high incidence of bradyarrhythmias sure ⱖ140 mm Hg, ⱖ90 mm Hg), current and past in these patients and, therefore, systematically studied smoking, alcohol intake (ⱖ3 drinks/day), and diabetes the frequency at which bradyarrhythmias appear and if mellitus (need for dietary control or intake of antidithere are predictors of bradyarrhythmias in patients re- abetic drugs). We also gathered data on the use of cardiac drugs before randomization and at follow-up ceiving thalidomide. visits, particularly the use of  blockers, diuretics, ••• We studied the charts of 200 consecutive patients digitalis, nondihydropyridine calcium channel blockenrolled in an ongoing phase III study of newly diag- ers, and antiarrhythmics. Patients were questioned for TABLE 1 Heart Rates and Patients With Bradycardia
BRIEF REPORTS
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history of syncope or presyncope at all visits. An echocardiogram was recorded at each visit. Echocardiograms were computer-interpreted and were subsequently confirmed by a staff cardiologist. The data on heart rate, PR interval, QRS duration, and QTc interval were recorded. Demographics revealed an equal distribution of genders in the 2 groups of patients. There were no statistically significant differences in age (50 ⫾ 3 years in both groups), gender, race, prevalence of cardiac risk factors, such as presence of hypertension (33% in placebo group and 23% in thalidomide group), diabetes (5% in placebo group and 4% in thalidomide group), or use of medications. Importantly, only a small number of patients were taking  blockers, diuretics, digitalis, nondihydropyridine calcium channel blockers, antiarrhythmics, or antihistaminics. None of the patients in the thalidomide group had a history of syncope, but 1 patient in the placebo group had a history suggestive of presyncope at baseline. Cardiac rhythm characteristics of patients showed that the 2 groups had similar heart rates at baseline (Table 1). Two patients (2.4%) in the placebo group and 3 patients (4%) in the thalidomide group had bradycardia (defined as a heart rate of ⬍60 beats/min) at baseline. At 3-month follow-up, there was a marked reduction in average heart rate in the thalidomide group compared with the placebo group, which persisted over the next year. The decrease in heart rate and its persistence over the next year in the thalidomide group is shown in Figure 1. Among patients taking thalidomide, 52 patients (53%) developed bradycardia at some point during follow-up. All patients had sinus bradycardia with heart rates ranging from 30 to 60 beats/min, but none developed atrial flutter or fibrillation. Eight patients had a heart rate as low as 30 beats/min. There was no statistically significant difference in the PR interval, QRS duration, and QTc interval of the thalidomide and control groups at any time over the 12 months of follow-up. The most common symptoms among patients taking thalidomide were weakness, fatigue, dizziness, and syncope. These symptoms resolved or decreased in severity after either discontinuing or reducing the dose of thalidomide. Five patients had severe bradycardia and needed permanent pacemaker implantations; we checked to see if use of certain negative chronotropic medications predicted the development of bradycardia.15 There was no correlation between development of bradycardia and the intake of  blockers, calcium channel blockers, digoxin, or antiarrhythmic drugs. Next, we checked to see if metabolic parameters, such as thyroid function abnormality, influenced the development of bradycardia. There was no difference in the plasma levels of thyroid-stimulating hormone or free thyroxine levels in patients in either group. We also checked to see if renal function correlated with the use of thalidomide. Renal function, as assessed by serum creatinine and blood urea nitrogen values, did not differ in the 2 patient groups. •••
Our data suggest that thalidomide causes signifi1054 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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cant bradycardia with heart rates as low as 30 beats/ min, resulting in symptoms including but not limited to severe weakness and hypotension. Thalidomideinduced bradycardia often required the placement of a pacemaker to remedy the associated symptoms. Bradycardia in our study was not associated with prolongation of the intracardiac intervals, such as PR, QRS, and QTc intervals, suggesting that there is no interruption of the ionic currents in the conduction system. We did not identify any obvious factors, such as impaired thyroid or renal function, which would cause some patients to develop bradycardia. Also, we found no association of the development of bradycardia with any of the known drugs that impair sinus node function. Our observations suggest that sinus bradycardia is perhaps due to a reduction in the generation of the impulse by the sinus node. Sympathetic nervous system and parasympathetic nervous system balance maintain a hemodynamically stable heart rate according to the needs of the body. Most of the physiologically identified dorsal motor neurons, which are a part of the nucleus of vagus nerve, are rapidly and completely inhibited by exposure to TNF-␣.16 Because thalidomide inhibits TNF-␣ expression and activity, it could lead to overactivity of the parasympathetic system. Bradycardia was decreased by a reduction in dose or discontinuation of thalidomide, suggesting a reversible effect on sinus node function. We propose that thalidomide-related bradycardia may be due to reversible changes in autonomic balance. In conclusion, our findings indicate that treatment of patients who have multiple myeloma with thaliodmide results in significant bradycardia in a large number of patients. Precise identification of symptoms related to heart rate was not possible due to the retrospective nature of our data acquisition. 1. Barnhill RL, Doll NJ, Millikan LE, Hastings RC. Studies on the anti-inflam-
matory properties of thalidomide: effects on polymorphonuclear leukocytes and monocytes. J Am Acad Dermatol 1984;11:814 –819. 2. Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G. Thalidomide exerts its inhibitory action on TNF-␣ by enhancing the mRNA degradation. J Exp Med 1993;177:1675–1680. 3. D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994;91:4082–4085. 4. Grinspan D. Significant response of oral aphthosis to thalidomide treatment. J Am Acad Dermatol 1985;12:85–90. 5. Hamuryudan V, Mat C, Saip S, Ozyazgan Y, Siva A, Yurdakul S, Zwingenberger K, Yazici H. Thalidomide in the treatment of the mucocutaneous lesions of Behc¸ et’s syndrome: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;128:443–459. 6. Knop J, Bonsmann G, Happle R, Ludolph A, Matz DR, Mifsud EJ, Macher E. Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus. Br J Dermatol 1983;108:461–466. 7. Moreira AL, Corral LG, Ye W, Johnson B, Stirling D, Muller GW, Freedman VH, Kaplan G. Thalidomide and thalidomide analogs reduce HIV type 1 replication in human macrophages in vitro. AIDS Res Hum Retroviruses 1997;13: 857–863. 8. Soler RA, Howard M, Brink NS, Gibb D, Tedder RS, Nadal D. Regression of AIDS-related Kaposi’s sarcoma during therapy with thalidomide. Clin Infect Dis 1996;23:501–505. 9. Nguyen M. Thalidomide and chemotherapy combination: preliminary results of pre-clinical and clinical studies. Int J Oncol 1997;10:965–969. 10. Barlogie B, Desikan R, Eddlemon P, Spencer T, Zeldis J, Munshi N, Badros A, Zangari M, Anaissie E, Epstein J, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001;98:492–494. 11. Vogelsang GB, Farmer ER, Hess AD, Altamonte V, Beschorner WE, Jabs
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DA, Corio RL, Levin LS, Colvin OM, Wingard JR. Thalidomide for the treatment of chronic graft-versus-host disease. N Engl J Med 1992;326:1055–1058. 12. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, et al. Anti-tumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341:1565–1571. 13. Badros AZ, Siegel E, Bodenner D, Zangari M, Zeldis J, Barlogie B, Tricot G. Hypothyroidism in patients with multiple myeloma following treatment with thalidomide. Am J Med 2002;112:412–413. 14. Zangari M, Anaissie E, Barlogie B, Badros A, Desikan R, Gopal AV, Morris
C, Toor A, Siegel E, Fink L, et al. Increased risk of deep vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 2001;98:1614 –1615. 15. Zangari M, Siegel E, Barlogie B, Anaissie E, Saghafifar F, Fassas A, Morris C, Fink L, Tricot G. Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy. Blood 2002;100:1168 –1171. 16. Emch GS, Herman GE, Rogers RC. Tumor necrosis factor-␣ inhibits physiologically identified dorsal motor nucleus neurons in vivo. Brain Res 2002;951: 311–315.
Relation of Anemia to Diastolic Heart Failure and the Effect on Outcome Steffen Brucks, MD, William C. Little, MD, Tania Chao, MD, Ronald L. Rideman, PharmD, Bharathi Upadhya, MD, Deborah Wesley-Farrington, RN, BSN, CCRC, and David C. Sane, MD We evaluated the frequency and importance of anemia in 137 patients with heart failure and a normal ejection fraction (diastolic heart failure). We found that anemia is common in these patients and is associated with greater elevations in serum B-type natriuretic peptide, more severe diastolic dysfunction, and a worse prognosis. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:1055–1057)
substantial portion (ⱖ40%) of patients with heart failure (HF) have a normal ejection fracA tion and have been considered to have diastolic HF. 1
2
Patients with diastolic HF have similar, but frequently less severe, exercise limitations and neurohormonal activation than patients with HF and a reduced ejection fraction (i.e., systolic HF).3 Because anemia is common in patients with systolic HF, we hypothesized that anemia may also be common in patients with diastolic HF. However, the frequency of anemia in patients with diastolic HF and its association with the severity of HF and prognosis are not known. We have tried to answer these questions. •••
We performed this study under a protocol approved by the institutional review board. The study population was derived from patients who were evaluated for the presence of HF by a cardiologist at Wake Forest University School of Medicine between November 1, 2001 and August 1, 2002, and who had a contemporaneous (0.7 ⫾ 1.9 days) Doppler echocardiographic examination and determination of hemoglobin and serum B-type natriuretic peptide (BNP). The study population consisted of 137 consecutive From the Cardiology Section, Wake Forest University School of Medicine, Winston-Salem, North Carolina; and Amgen, Incorporated, Thousand Oaks, California. This study was supported in part by an unrestricted research grant from Amgen, Incorporated, Thousand Oaks, California. Dr. Little’s address is: Cardiology Section, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1045. E-mail: wlittle@ wfubmc.edu. Manuscript received November 6, 2003; revised manuscript received and accepted December 24, 2003. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 April 15, 2004
patients with clinical HF and a left ventricular (LV) ejection fraction ⱖ50%. No patients with hemodynamically significant valve disease, prosthetic valve replacement, active myocardial ischemia, myocardial infarction, malignancy, or dialysis-dependent renal failure were included. The frequency of anemia in diastolic HF was compared with 101 patients with HF and ejection fraction ⬍50% (systolic HF) evaluated at the same time. The clinical evaluation was made without knowledge of the hemoglobin or Doppler echocardiographic results. HF was clinically diagnosed using previously published criteria.3 Anemia was defined using the World Health Organization criteria as follows: hemoglobin ⬍12 g/dl in women and ⬍13 g/dl in men.4 Serum BNP levels were measured using the Triage BNP Test (Biosite Diagnostics, San Diego, California). The Doppler echocardiographic examination was performed and analyzed using standard techniques, as previously described.5 LV volumes were measured from the apical 4-chamber view, by the area–length method, and used to calculate the ejection fraction. Tissue Doppler imaging of the lateral mitral annulus was used to determine the peak systolic velocity of the annulus (SM) and the peak early diastolic lengthening rate (EM). The Doppler mitral inflow velocities and EM were used to classify the diastolic function as normal, mild (impaired relaxation pattern), or severe (pseudonormalized or restricted patterns).6 This classification was performed by consensus of 2 observers who were blinded to the hemoglobin or clinical evaluations. Up to 2 years’ follow-up (330 ⫾ 200 days) was obtained in 132 of 137 patients (96%) by review of medical records, a death registry, and by direct telephone contact; 5 patients could not be located. All hospitalizations were considered cardiovascular related unless due to a clear noncardiac cause (trauma, scheduled admission for a noncardiovascular procedure, or malignancy). Data are summarized as mean ⫾ SD. Variables are compared using unpaired t tests. Because BNP values are not normally distributed, statistical testing was performed after natural logarithmic transformation. 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.12.062
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In this study, QTc intervals did not increase significantly during the first 9 days of spaceflight. Based on our previous work demonstrating prolongation of QTc intervals in astronauts on long-duration spaceflights, we speculate that QTc interval prolongation occurs sometime between 9 and 30 days of spaceflight. Perhaps after the longer exposure to a reduced workload in flight, the heart begins to remodel. Interestingly, this group of astronauts
had longer QTc intervals than a previously reported group of astronauts who underwent short-duration spaceflight,1 and several had QTc intervals that were at or near the clinical threshold of prolonged QTc (QTc ⱖ0.44 second) before spaceflight. Future studies should examine this time-dependent effect of spaceflight on QTc intervals. Acknowledgment: We express our appreciation to the astronauts who volunteered for this study and to L. Christine Ribeiro, MS, for assistance with data analysis.
1. D’Aunno DS, Dougherty AH, DeBlock HF, Meck JV. Effect of short- and long-duration spaceflight on QTc intervals in healthy astronauts. Am J Cardiol 2003;91:494 –497. 2. Rossum AC, Ziegler MG, Meck JV. Effect of spaceflight on cardiovascular responses to upright posture in a 77-year-old astronaut. Am J Cardiol 2001;88: 1335–1337. 3. Fritsch-Yelle JM, Leuenberger UA, D’Aunno DS, Rossum AC, Brown TE, Wood ML, Josephson ME, Goldberger AL. An episode of ventricular tachycardia during long-duration spaceflight. Am J Cardiol 1998;81:1391–1392. 4. Golubchikova ZA, Alferova IV, Liamin VR, Turchaninova VF. Dynamics of some electrocardiographic parameters in cosmonauts during long-term Mir mission. Aviakosm Ekolog Med 2003;37:41–45. 5. Hoffler GW, Wolthuis RA, Johnson RL. Apollo space crew cardiovascular evaluations. Aerosp Med 1974;45:807–820. 6. Romanov EM, Artamonova NP, Golubchikova ZA, Zavadovskii AF, Korotaev MM. Results of long-term electrocardiographic examinations of cosmonauts. Kosm Biol Aviakosm Med 1987;21:10 –14. 7. Fritsch-Yelle JM, Charles JB, Jones MM, Wood ML. Microgravity decreases heart rate and arterial pressure in humans. J Appl Physiol 1996;80:910 –914. 8. Bazett HC. An analysis of the time relation of electrocardiograms. Heart 1920;7:353–370.
Bradycardia During Therapy for Multiple Myeloma With Thalidomide Ibrahim Elias Fahdi, MD, Venkat Gaddam, MD, Jorge F. Saucedo, MD, Channarayapatna V. Kishan, MD, Keyur Vyas, MD, Matthew G. Deneke, MD, Hani Razek, MD, Brett Thorn, MS, Joseph K. Bissett, MD, Elias Anaisse, MD, Bart Barlogie, MD, and Jawahar L. Mehta, MD, PhD We studied the medical records of 96 patients who received thalidomide and 104 patients who made up a control group. We found that 53% of patients (52 patients) using thalidomide had a heart rate of <60 beats/min at some point during follow-up and 19% of thalidomide patients (10 patients) developed symptom-related bradycardia. Reducing the thalidomide dose appeared to alleviate symptoms in most patients. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:1052–1055) From the Division of Cardiovascular Medicine, the Department of Internal Medicine, and the Multiple Myeloma Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Dr. Mehta’s address is: Division of Cardiovascular Medicine, University of Arkansas for Medical Sciences, 4301 West Markham Street, #532, Little Rock, Arkansas 72205. E-mail: [email protected]. Manuscript received August 27, 2003; revised manuscript received and accepted December 18, 2003.
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©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 April 15, 2004
halidomide (␣-N-phthalimidoglutarimide) was initially manufactured in West Germany and was T marketed as an antiemetic and sedative until 1960. Thalidomide functions as a potent immunosuppressive and antiangiogenic agent1–3 by inhibiting the phagocytic ability of inflammatory cells and the production of cytokines, such as tumor necrosis factor-␣ (TNF␣). It has been shown to be effective in the treatment of inflammatory diseases,4 – 6 in conditions associated with human immunodeficiency virus (HIV) infection,7 and in various cancers.8 –10 Vogelsang et al11 showed improved survival in patients with refractory chronic graft-versus-host reaction who received thalidomide. One-third of patients with advanced and refractory multiple myeloma, in whom salvage therapy failed after single and even tandem autotransplants, responded markedly to this drug.10,12 Thalidomide represents only the third independently active compound in the treatment of myeloma since the introduction of melphalan and prednisone 4 decades ago. Thalido0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.12.061
nosed patients with multiple myeloma. In this study, patients were Control Thalidomide treated with combination chemotherapy and were randomized to receive Heart Rate With Heart Rate With either thalidomide or placebo. All Time Point (beats/min) Bradycardia (beats/min) Bradycardia p Value patients were randomized to receive Baseline 80.7 ⫾ 1.5 9.1% 77.9 ⫾ 1.5 9.4% 0.146 oral thalidomide at a dose of 400 4–12 weeks 82.9 ⫾ 2.4 8.3% 67.2 ⫾ 1.7 38.8% ⬍0.001 mg/day throughout the induction 13–32 weeks 84.3 ⫾ 2.0 6.3% 68.7 ⫾ 1.8 35.3% ⬍0.001 33–52 weeks 86.6 ⫾ 1.9 5.0% 70.6 ⫾ 2.0 29.7% ⬍0.001 phase. They received 200 mg every other day for the first year of maintenance and 100 mg/day orally. Treatment cycles were as follows: (1) vincristine (0.5 mg/day) administered by continuous infusion along with adriamycin (10 mg/m2/day) for 4 days and oral dexamethasone (40 mg/day); dexamethasone was repeated on days 9 to 12 and again on days 17 to 20; (2) after 5 weeks, dexamethasone (40 mg/day) was administered orally with continuous infusion of cyclophosphamide (400 mg/m2/day), etoposide (40 mg/m2/day), and cisplatin (15 mg/m2/day); and (3) after 4 weeks, continuous infusion of cyclophosphamide (750 mg/m2/day), adriamycin (15 mg/ m2/day), and oral dexamethasone (40 mg/day) was admininstered with stem cell collection; this cycle was repeated if needed. Six independent reviewers performed the data review. Medical records of all patients were available and were reviewed. The data were obtained at baseline (before randomization), at first follow-up (4 to 12 weeks after randomization), at second follow-up (13 to 32 weeks after randomization), and at third follow-up (33 to 52 weeks after randomization). Data were recorded in Microsoft Excel and Access (Microsoft, Redmond, Washington) and analyzed using SAS version 8.2 software (SAS Institute, Inc., Cary, North Carolina) to detect statistically significant differences in the variables. Two-way analyses, Fisher’s exact test, and t tests were used to check randomization results. This was necessary because this study was randomized for the purposes of the cancer component and not the electrocardiographic component. The same tests were used to analyze the impact of FIGURE 1. (A) The reduction in heart rate in the thalidomide prior drug intake. Also, the impact of age, race, and group began almost immediately after starting the medication gender was analyzed at baseline as a covariate repeatand was sustained throughout the treatment course. Follow-up visit 1 was at 4 to 12 weeks, visit 2 was at 13 to 32 weeks, and ed-measures analysis and found not to be significant. visit 3 was at 33 to 52 weeks. (B) Heart rate reduction in the Hence, we chose to present the results with the simthalidomide group is shown as a percentage change from baseplest interpretation: the Kruskal-Wallis, distributionline. free, 1-way analysis of the raw heart rate data based on treatment group over the follow-up times. Of the 200 patients enrolled in the study, 96 pamide is currently undergoing investigation in combination with dexamethasone and chemotherapy during in- tients received thalidomide and the remaining 104 duction and for maintenance of remission. Side effects patients received placebo. We collected data on painclude peripheral neuropathy, sometimes irreversible, tient demographics, the presence of known cardiac hypothyroidism,13 and thrombotic events.14,15 We have risk factors such as hypertension (systolic blood presrecently observed a high incidence of bradyarrhythmias sure ⱖ140 mm Hg, ⱖ90 mm Hg), current and past in these patients and, therefore, systematically studied smoking, alcohol intake (ⱖ3 drinks/day), and diabetes the frequency at which bradyarrhythmias appear and if mellitus (need for dietary control or intake of antidithere are predictors of bradyarrhythmias in patients re- abetic drugs). We also gathered data on the use of cardiac drugs before randomization and at follow-up ceiving thalidomide. visits, particularly the use of  blockers, diuretics, ••• We studied the charts of 200 consecutive patients digitalis, nondihydropyridine calcium channel blockenrolled in an ongoing phase III study of newly diag- ers, and antiarrhythmics. Patients were questioned for TABLE 1 Heart Rates and Patients With Bradycardia
BRIEF REPORTS
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history of syncope or presyncope at all visits. An echocardiogram was recorded at each visit. Echocardiograms were computer-interpreted and were subsequently confirmed by a staff cardiologist. The data on heart rate, PR interval, QRS duration, and QTc interval were recorded. Demographics revealed an equal distribution of genders in the 2 groups of patients. There were no statistically significant differences in age (50 ⫾ 3 years in both groups), gender, race, prevalence of cardiac risk factors, such as presence of hypertension (33% in placebo group and 23% in thalidomide group), diabetes (5% in placebo group and 4% in thalidomide group), or use of medications. Importantly, only a small number of patients were taking  blockers, diuretics, digitalis, nondihydropyridine calcium channel blockers, antiarrhythmics, or antihistaminics. None of the patients in the thalidomide group had a history of syncope, but 1 patient in the placebo group had a history suggestive of presyncope at baseline. Cardiac rhythm characteristics of patients showed that the 2 groups had similar heart rates at baseline (Table 1). Two patients (2.4%) in the placebo group and 3 patients (4%) in the thalidomide group had bradycardia (defined as a heart rate of ⬍60 beats/min) at baseline. At 3-month follow-up, there was a marked reduction in average heart rate in the thalidomide group compared with the placebo group, which persisted over the next year. The decrease in heart rate and its persistence over the next year in the thalidomide group is shown in Figure 1. Among patients taking thalidomide, 52 patients (53%) developed bradycardia at some point during follow-up. All patients had sinus bradycardia with heart rates ranging from 30 to 60 beats/min, but none developed atrial flutter or fibrillation. Eight patients had a heart rate as low as 30 beats/min. There was no statistically significant difference in the PR interval, QRS duration, and QTc interval of the thalidomide and control groups at any time over the 12 months of follow-up. The most common symptoms among patients taking thalidomide were weakness, fatigue, dizziness, and syncope. These symptoms resolved or decreased in severity after either discontinuing or reducing the dose of thalidomide. Five patients had severe bradycardia and needed permanent pacemaker implantations; we checked to see if use of certain negative chronotropic medications predicted the development of bradycardia.15 There was no correlation between development of bradycardia and the intake of  blockers, calcium channel blockers, digoxin, or antiarrhythmic drugs. Next, we checked to see if metabolic parameters, such as thyroid function abnormality, influenced the development of bradycardia. There was no difference in the plasma levels of thyroid-stimulating hormone or free thyroxine levels in patients in either group. We also checked to see if renal function correlated with the use of thalidomide. Renal function, as assessed by serum creatinine and blood urea nitrogen values, did not differ in the 2 patient groups. •••
Our data suggest that thalidomide causes signifi1054 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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cant bradycardia with heart rates as low as 30 beats/ min, resulting in symptoms including but not limited to severe weakness and hypotension. Thalidomideinduced bradycardia often required the placement of a pacemaker to remedy the associated symptoms. Bradycardia in our study was not associated with prolongation of the intracardiac intervals, such as PR, QRS, and QTc intervals, suggesting that there is no interruption of the ionic currents in the conduction system. We did not identify any obvious factors, such as impaired thyroid or renal function, which would cause some patients to develop bradycardia. Also, we found no association of the development of bradycardia with any of the known drugs that impair sinus node function. Our observations suggest that sinus bradycardia is perhaps due to a reduction in the generation of the impulse by the sinus node. Sympathetic nervous system and parasympathetic nervous system balance maintain a hemodynamically stable heart rate according to the needs of the body. Most of the physiologically identified dorsal motor neurons, which are a part of the nucleus of vagus nerve, are rapidly and completely inhibited by exposure to TNF-␣.16 Because thalidomide inhibits TNF-␣ expression and activity, it could lead to overactivity of the parasympathetic system. Bradycardia was decreased by a reduction in dose or discontinuation of thalidomide, suggesting a reversible effect on sinus node function. We propose that thalidomide-related bradycardia may be due to reversible changes in autonomic balance. In conclusion, our findings indicate that treatment of patients who have multiple myeloma with thaliodmide results in significant bradycardia in a large number of patients. Precise identification of symptoms related to heart rate was not possible due to the retrospective nature of our data acquisition. 1. Barnhill RL, Doll NJ, Millikan LE, Hastings RC. Studies on the anti-inflam-
matory properties of thalidomide: effects on polymorphonuclear leukocytes and monocytes. J Am Acad Dermatol 1984;11:814 –819. 2. Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G. Thalidomide exerts its inhibitory action on TNF-␣ by enhancing the mRNA degradation. J Exp Med 1993;177:1675–1680. 3. D’Amato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 1994;91:4082–4085. 4. Grinspan D. Significant response of oral aphthosis to thalidomide treatment. J Am Acad Dermatol 1985;12:85–90. 5. Hamuryudan V, Mat C, Saip S, Ozyazgan Y, Siva A, Yurdakul S, Zwingenberger K, Yazici H. Thalidomide in the treatment of the mucocutaneous lesions of Behc¸ et’s syndrome: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1998;128:443–459. 6. Knop J, Bonsmann G, Happle R, Ludolph A, Matz DR, Mifsud EJ, Macher E. Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus. Br J Dermatol 1983;108:461–466. 7. Moreira AL, Corral LG, Ye W, Johnson B, Stirling D, Muller GW, Freedman VH, Kaplan G. Thalidomide and thalidomide analogs reduce HIV type 1 replication in human macrophages in vitro. AIDS Res Hum Retroviruses 1997;13: 857–863. 8. Soler RA, Howard M, Brink NS, Gibb D, Tedder RS, Nadal D. Regression of AIDS-related Kaposi’s sarcoma during therapy with thalidomide. Clin Infect Dis 1996;23:501–505. 9. Nguyen M. Thalidomide and chemotherapy combination: preliminary results of pre-clinical and clinical studies. Int J Oncol 1997;10:965–969. 10. Barlogie B, Desikan R, Eddlemon P, Spencer T, Zeldis J, Munshi N, Badros A, Zangari M, Anaissie E, Epstein J, et al. Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients. Blood 2001;98:492–494. 11. Vogelsang GB, Farmer ER, Hess AD, Altamonte V, Beschorner WE, Jabs
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DA, Corio RL, Levin LS, Colvin OM, Wingard JR. Thalidomide for the treatment of chronic graft-versus-host disease. N Engl J Med 1992;326:1055–1058. 12. Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, et al. Anti-tumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999;341:1565–1571. 13. Badros AZ, Siegel E, Bodenner D, Zangari M, Zeldis J, Barlogie B, Tricot G. Hypothyroidism in patients with multiple myeloma following treatment with thalidomide. Am J Med 2002;112:412–413. 14. Zangari M, Anaissie E, Barlogie B, Badros A, Desikan R, Gopal AV, Morris
C, Toor A, Siegel E, Fink L, et al. Increased risk of deep vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy. Blood 2001;98:1614 –1615. 15. Zangari M, Siegel E, Barlogie B, Anaissie E, Saghafifar F, Fassas A, Morris C, Fink L, Tricot G. Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy. Blood 2002;100:1168 –1171. 16. Emch GS, Herman GE, Rogers RC. Tumor necrosis factor-␣ inhibits physiologically identified dorsal motor nucleus neurons in vivo. Brain Res 2002;951: 311–315.
Relation of Anemia to Diastolic Heart Failure and the Effect on Outcome Steffen Brucks, MD, William C. Little, MD, Tania Chao, MD, Ronald L. Rideman, PharmD, Bharathi Upadhya, MD, Deborah Wesley-Farrington, RN, BSN, CCRC, and David C. Sane, MD We evaluated the frequency and importance of anemia in 137 patients with heart failure and a normal ejection fraction (diastolic heart failure). We found that anemia is common in these patients and is associated with greater elevations in serum B-type natriuretic peptide, more severe diastolic dysfunction, and a worse prognosis. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:1055–1057)
substantial portion (ⱖ40%) of patients with heart failure (HF) have a normal ejection fracA tion and have been considered to have diastolic HF. 1
2
Patients with diastolic HF have similar, but frequently less severe, exercise limitations and neurohormonal activation than patients with HF and a reduced ejection fraction (i.e., systolic HF).3 Because anemia is common in patients with systolic HF, we hypothesized that anemia may also be common in patients with diastolic HF. However, the frequency of anemia in patients with diastolic HF and its association with the severity of HF and prognosis are not known. We have tried to answer these questions. •••
We performed this study under a protocol approved by the institutional review board. The study population was derived from patients who were evaluated for the presence of HF by a cardiologist at Wake Forest University School of Medicine between November 1, 2001 and August 1, 2002, and who had a contemporaneous (0.7 ⫾ 1.9 days) Doppler echocardiographic examination and determination of hemoglobin and serum B-type natriuretic peptide (BNP). The study population consisted of 137 consecutive From the Cardiology Section, Wake Forest University School of Medicine, Winston-Salem, North Carolina; and Amgen, Incorporated, Thousand Oaks, California. This study was supported in part by an unrestricted research grant from Amgen, Incorporated, Thousand Oaks, California. Dr. Little’s address is: Cardiology Section, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157-1045. E-mail: wlittle@ wfubmc.edu. Manuscript received November 6, 2003; revised manuscript received and accepted December 24, 2003. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 April 15, 2004
patients with clinical HF and a left ventricular (LV) ejection fraction ⱖ50%. No patients with hemodynamically significant valve disease, prosthetic valve replacement, active myocardial ischemia, myocardial infarction, malignancy, or dialysis-dependent renal failure were included. The frequency of anemia in diastolic HF was compared with 101 patients with HF and ejection fraction ⬍50% (systolic HF) evaluated at the same time. The clinical evaluation was made without knowledge of the hemoglobin or Doppler echocardiographic results. HF was clinically diagnosed using previously published criteria.3 Anemia was defined using the World Health Organization criteria as follows: hemoglobin ⬍12 g/dl in women and ⬍13 g/dl in men.4 Serum BNP levels were measured using the Triage BNP Test (Biosite Diagnostics, San Diego, California). The Doppler echocardiographic examination was performed and analyzed using standard techniques, as previously described.5 LV volumes were measured from the apical 4-chamber view, by the area–length method, and used to calculate the ejection fraction. Tissue Doppler imaging of the lateral mitral annulus was used to determine the peak systolic velocity of the annulus (SM) and the peak early diastolic lengthening rate (EM). The Doppler mitral inflow velocities and EM were used to classify the diastolic function as normal, mild (impaired relaxation pattern), or severe (pseudonormalized or restricted patterns).6 This classification was performed by consensus of 2 observers who were blinded to the hemoglobin or clinical evaluations. Up to 2 years’ follow-up (330 ⫾ 200 days) was obtained in 132 of 137 patients (96%) by review of medical records, a death registry, and by direct telephone contact; 5 patients could not be located. All hospitalizations were considered cardiovascular related unless due to a clear noncardiac cause (trauma, scheduled admission for a noncardiovascular procedure, or malignancy). Data are summarized as mean ⫾ SD. Variables are compared using unpaired t tests. Because BNP values are not normally distributed, statistical testing was performed after natural logarithmic transformation. 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.12.062
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