Correspondence
Further Cases of Valvular Heart Disease Associated with Fenfluramine–Phentermine
N Engl J Med 1997; 337:635August 28, 1997
- Article
To the Editor:
In this issue of the Journal is a report of 24 cases of valvular heart disease in women treated with a combination of fenfluramine and phentermine.1 On the basis of prepublication notification of this finding, the Food and Drug Administration issued a Public Health Advisory on July 8 in which it requested that other cases be reported. We now describe an additional 28 patients from the United States with similar disease. Excluded from this series were a handful of reports describing isolated tricuspid insufficiency in the presence of primary pulmonary hypertension or isolated mitral-valve prolapse.
The reports came from 18 different states. The patients' median age was 45 years (range, 28 to 61); all were women. The median daily dose of fenfluramine was 60 mg (range, 10 to 120), and of phentermine, 30 mg (range, 15 to 60). The median duration of therapy before diagnosis of valvular disease was 10 months (range, 2 to 36). Six patients (21 percent) underwent valve-replacement surgery, of whom one died. Most of the patients were symptomatic, usually with dyspnea or evidence of congestive heart failure. However, four (14 percent) were asymptomatic, usually with a new murmur on routine examination that prompted the performance of echocardiography. Antidepressants of the selective serotonin-reuptake inhibitor class were used by two patients.
In all cases, valvular insufficiency was noted. The mitral valve was affected in 24 (86 percent), the aortic valve in 19 (68 percent), the tricuspid valve in 11 (39 percent), and the pulmonary valve in 1 (4 percent). A left-sided valve was involved in all cases, and two or more valves were affected in 78 percent. Severity was graded as moderate or severe in 18 of the 23 patients (78 percent) for whom we had measurements. Pulmonary hypertension was reported in 10 patients, 4 of whom had left-sided valvular lesions only.
In general, the patients took appetite suppressants until symptoms developed and valvular disease was diagnosed. Valvular disease was not noted to resolve in any of the patients after stopping appetite suppressants, although several reported controlling symptoms of heart failure with various medications. In two patients there was progression from the discovery of a new heart murmur to valve-replacement surgery within 1.5 years.
We analyzed the reports to identify potential risk factors. A fenfluramine dose of more than 30 mg per day was associated with multivalvular disease (P = 0.015), with involvement of both right- and left-sided valvular lesions (P = 0.05), and with pulmonary hypertension (P = 0.06). A dose of phentermine of 30 mg or more per day was also associated with multivalvular disease (P = 0.02). The association between the duration of therapy and various measures of severity could not be addressed, because only three cases were reported involving therapy of three months or less. Age did not appear to be a factor.
In addition to the above, we have received reports of valvular disease with fenfluramine alone (two patients), dexfenfluramine alone (four patients), and dexfenfluramine with phentermine (two patients). We do not have sufficient data to study the effects of fenfluramine alone as compared with in combination with phentermine.
This case series suggests that cardiac valvulopathy is a separate entity from primary pulmonary hypertension, which has been described previously with appetite suppressants. Both disorders may be end-organ responses to the same underlying pathophysiology. Distinctive features of our cases were involvement of the left side of the heart, the tendency to involve multiple valves, rapid onset, and the absence of pulmonary hypertension in most patients.
1 ReferencesDavid J. Graham, M.D., M.P.H.
Lanh Green, R.Ph., M.P.H.
Food and Drug Administration, Rockville, MD 208571
Connolly HM ,Crary JL ,McGoon MD , et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337:581-588
Full Text | Web of Science | Medline
- Citing Articles (28)
Citing Articles
1
A. Boudes, C. Lavoute, J.-F. Avierinos, Y. Le Dolley, C. Villacampa, A. Salem, A. D. Loundou, N. Michel, S. Renard, G. Habib. (2011) Valvular heart disease associated with benfluorex therapy: high prevalence in patients with unexplained restrictive valvular heart disease. European Journal of Echocardiography 12:9, 688-695
CrossRef2
Robert O. Bonow, Blase A. Carabello, Kanu Chatterjee, Antonio C. de Leon, David P. Faxon, Michael D. Freed, William H. Gaasch, Bruce W. Lytle, Rick A. Nishimura, Patrick T. O'Gara, Robert A. O'Rourke, Catherine M. Otto, Pravin M. Shah, Jack S. Shanewise, Rick A. Nishimura, Blase A. Carabello, David P. Faxon, Michael D. Freed, Bruce W. Lytle, Patrick T. O'Gara, Robert A. O'Rourke, Pravin M. Shah. (2008) 2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease. Journal of the American College of Cardiology 52:13, e1-e142
CrossRef3
L D Whigham, N V Dhurandhar, P S Rahko, R L Atkinson. (2006) Comparison of combinations of drugs for treatment of obesity: body weight and echocardiographic status. International Journal of Obesity
CrossRef4
Robert O. Bonow, Blase A. Carabello, Kanu Chatterjee, Antonio C. de Leon, David P. Faxon, Michael D. Freed, William H. Gaasch, Bruce Whitney Lytle, Rick A. Nishimura, Patrick T. O’Gara, Robert A. O’Rourke, Catherine M. Otto, Pravin M. Shah, Jack S. Shanewise, Sidney C. Smith, Alice K. Jacobs, Cynthia D. Adams, Jeffrey L. Anderson, Elliott M. Antman, David P. Faxon, Valentin Fuster, Jonathan L. Halperin, Loren F. Hiratzka, Sharon A. Hunt, Bruce W. Lytle, Rick Nishimura, Richard L. Page, Barbara Riegel. (2006) ACC/AHA 2006 Practice Guidelines for the Management of Patients With Valvular Heart Disease: Executive Summary. Journal of the American College of Cardiology 48:3, 598-675
CrossRef5
Robert O. Bonow, Blase A. Carabello, Kanu Chatterjee, Antonio C. de Leon, David P. Faxon, Michael D. Freed, William H. Gaasch, Bruce Whitney Lytle, Rick A. Nishimura, Patrick T. O’Gara, Robert A. O’Rourke, Catherine M. Otto, Pravin M. Shah, Jack S. Shanewise, Sidney C. Smith, Alice K. Jacobs, Cynthia D. Adams, Jeffrey L. Anderson, Elliott M. Antman, David P. Faxon, Valentin Fuster, Jonathan L. Halperin, Loren F. Hiratzka, Sharon A. Hunt, Bruce W. Lytle, Rick Nishimura, Richard L. Page, Barbara Riegel. (2006) ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease. Journal of the American College of Cardiology 48:3, e1-e148
CrossRef6
Lisa L Ioannides-Demos, Joseph Proietto, Andrew M Tonkin, John J McNeil. (2006) Safety of Drug Therapies Used for Weight Loss and Treatment of Obesity. Drug Safety 29:4, 277-302
CrossRef7
2006. Fenfluramines. , 1333-1344.
CrossRef8
R. Sonia Batra, Jeffrey S. Dover, Kenneth A. Arndt. (2005) Adverse event reporting for botulinum toxin type A. Journal of the American Academy of Dermatology 53:6, 1080-1082
CrossRef9
Amalia M Issa. (2003) Pharmacogenomic profiling in postmarketing surveillance: prospects and challenges. Pharmacogenomics 4:5, 647-655
CrossRef10
A. Halpern, M. C. Mancini. (2003) Treatment of obesity: an update on anti-obesity medications. Obesity Reviews 4:1, 25-42
CrossRef11
Kenneth Lyons Jones, Kathleen A. Johnson, Lyn M. Dick, Robert J. Felix, Kelly K. Kao, Christina D. Chambers. (2002) Pregnancy outcomes after first trimester exposure to phentermine/fenfluramine. Teratology 65:3, 125-130
CrossRef12
Vivian M. Dickerson. (2001) Focus on Primary Care Evaluation, Management, and Treatment of Obesity in Women. Obstetrical and Gynecological Survey 56:10, 650-663
CrossRef13
Evangelos D. Michelakis, E. Kenneth Weir. (2001) Anorectic Drugs and Pulmonary Hypertension from the Bedside to the Bench. The American Journal of the Medical Sciences 321:4, 292-299
CrossRef14
VA Barvaux, G Aubert, DO Rodenstein. (2000) CLINICAL REVIEW ARTICLE: Weight loss as a treatment for obstructive sleep apnoea. Sleep Medicine Reviews 4:5, 435-452
CrossRef15
Joseph Proietto, Barbara C Fam, Deborah A Ainslie, Anne W Thorburn. (2000) Novel anti-obesity drugs. Expert Opinion on Investigational Drugs 9:6, 1317-1326
CrossRef16
Sridharan Rajamani, Christian Studenik, Rosa Lemmens-Gruber, Peter Heistracher. (2000) Cardiotoxic effects of fenfluramine hydrochloride on isolated cardiac preparations and ventricular myocytes of guinea-pigs. British Journal of Pharmacology 129:5, 843-852
CrossRef17
Bonnie E. Gould Rothberg, Tennore M. Ramesh, Catherine E. Burgess. (2000) Integrating expression-based drug response and SNP-based pharmacogenetic strategies into a single comprehensive pharmacogenomics program. Drug Development Research 49:1, 54-64
CrossRef18
Richard W. Asinger. (1999) The Fen-Phen Controversy: Is Regression Another Piece of the Puzzle?. Mayo Clinic Proceedings 74:12, 1302-1304
CrossRef19
D D Hensrud, H M Connolly, M Grogan, F A Miller, K R Bailey, M D Jensen. (1999) Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine.. Mayo Clinic Proceedings 74:12, 1191-1197
CrossRef20
Donald J. Willison, Stuart M. MacLeod. (1999) The role of research evidence in pharmaceutical policy making: evidence when necessary but not necessarily evidence. Journal of Evaluation in Clinical Practice 5:2, 243-249
CrossRef21
Laura E. Derby, Marian W. Myers, Hershel Jick. (1999) Use of dexfenfluramine, fenfluramine and phentermine and the risk of stroke. British Journal of Clinical Pharmacology 47:5, 565-569
CrossRef22
RobertO. Bonow, Blase Carabello, AntonioC. de Leon, L.Henry Edmunds, BradleyJ. Fedderly, MichaelD. Freed, WilliamH. Gaasch, CharlesR. McKay, RickA. Nishimura, PatrickT. O’Gara, RobertA. O’Rourke, ShahbudinH. Rahimtoola, JamesL. Ritchie, MelvinD. Cheitlin, KimA. Eagle, TimothyJ. Gardner, Arthur Garson, RaymondJ. Gibbons, RobertA. O’Rourke, RichardO. Russell, ThomasJ. Ryan, SidneyC. Smith. (1998) ACC/AHA guidelines for the management of patients with valvular heart disease. Journal of the American College of Cardiology 32:5, 1486-1582
CrossRef23
P Godeau, P Cherin, P Tellier. (1998) Hypertension artérielle pulmonaire et valvulopathies induites par les fenfluramines? Hypothèses ou certitudes? Mythe ou réalité?. La Revue de Médecine Interne 19:10, 700-703
CrossRef24
Jick, Hershel, Vasilakis, Catherine, Weinrauch, Larry A., Meier, Christoph R., Jick, Susan S., Derby, Laura E., . (1998) A Population-Based Study of Appetite-Suppressant Drugs and the Risk of Cardiac-Valve Regurgitation. New England Journal of Medicine 339:11, 719-724
Full Text25
Melvin A. Shiffman. (1998) ANESTHESIA RISKS IN PATIENTS WHO HAVE HAD ANTIOBESITY MEDICATION. Plastic & Reconstructive Surgery 102:3, 927-928
CrossRef26
Kassirer, Jerome P., Angell, Marcia, . (1998) Losing Weight — An Ill-Fated New Year's Resolution. New England Journal of Medicine 338:1, 52-54
Full Text27
&NA;. (1997) Anorectics: do the benefits outweigh the risks?. Reactions Weekly &NA;:668, 3-4
CrossRef28
Curfman, Gregory D., . (1997) Diet Pills Redux. New England Journal of Medicine 337:9, 629-630
Full Text
