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NEWSLETTER 15: VALVULAR HEART DISEASE AND FEN-PHEN  Mitral Valve Stenosis What is mitral valve stenosis? Mitral valve stenosis is a narrowing of the opening of the mitral valve in the heart. The mitral valve is 1 of 4 valves in your heart. It is located between the upper left heart chamber (left atrium) and lower left heart chamber (left ventricle). The mitral valve has 2 flaps, or leaflets, which open and close like a door with each heartbeat and normally permit blood to flow in only 1 direction. Stenosis of the mitral valve prevents the valve from opening normally. A narrowed (stenotic) mitral valve reduces the amount of blood that can flow through your heart. Over time, the stenosis can cause high blood pressure in the left atrium and the lungs. The left atrium gets bigger, your lungs become congested with fluid, and breathing becomes difficult. How does it occur? Rheumatic fever is the most common cause of mitral valve stenosis. This infection caused by strep bacteria may damage all the heart valves, but it affects the mitral valve most often. Rheumatic fever causes scarring of the heart valves, which forces the heart to work harder. Over several years the scarring joins the leaflets together and prevents complete opening of the valve. Calcium may be deposited in the valve, making it hard and stiff rather than flexible. Mitral valve stenosis caused by childhood rheumatic fever usually doesn't show symptoms until early or mid-adulthood. Mitral valve stenosis is sometimes a birth defect. Other causes include some rheumatoid diseases. What are the symptoms? Symptoms may include:
Your health care provider will ask about your symptoms and examine you. He or she will listen to your heart with a stethoscope. Mitral valve stenosis causes a specific type of heart murmur. Your provider will also listen to your lungs and may hear sounds of fluid congestion. Your provider may order the following tests:
How is it treated? If the narrowed valve is not causing any symptoms, no treatment may be needed. For mild symptoms, your health care provider may prescribe a low-salt diet or medicine to help get rid of excess body water (diuretics). If your symptoms worsen over time, you will need other medicines to help your heart pump more efficiently. Mitral valve stenosis can cause abnormal heart rhythms. If this occurs, your health care provider may prescribe medicines. If the heart rhythm does not return to normal, you will need to take a blood thinner (anticoagulant) to prevent small blood clots that could cause a stroke. In some cases you may need to be sedated and an electric shock used to change your heart rhythm to normal. Your symptoms may gradually worsen. It may become harder for you to do your normal activities. If this happens, you may need to have the valve opening widened. In some cases, a procedure called a balloon valvotomy can be done. During the procedure, a catheter with a deflated balloon at the end is inserted into a vein. The catheter is then positioned across the valve in your heart, and the balloon is inflated. As the balloon expands, the mitral valve is stretched and forced open. Another option may be open-heart surgery. This kind of surgery is usually needed if the valve is very deformed or has calcium deposits on it. The surgeon decides either to separate the fused leaflets of the valve or to replace the valve with an artificial heart valve, depending on the condition of your valve. Your surgeon will discuss the options with you before surgery. How long will the effects last? You may have mitral valve stenosis with few or no symptoms for a long time. When your symptoms worsen, permanent heart damage can occur if you don't get treatment. See your health care provider as often as recommended so you can get treatment when you need it. How can I take care of myself? Follow the treatment your health care provider prescribes. In addition:
Mitral stenosis is often a result of rheumatic fever, which is caused by the same bacteria that cause strep throat. Go to your health care provider for a throat culture if you have a sore throat. If you have strep throat, take antibiotics as prescribed by your provider. If you have had rheumatic fever in the past, your doctor may recommend that you take penicillin on a regular basis.
Mitral Valve Regurgitation What is mitral valve regurgitation? The mitral valve lies on the left side of the heart between the left upper chamber (atrium) and lower chamber (ventricle). The valve has 2 flaps called leaflets that normally close every time the ventricle squeezes to pump blood out of the heart. When the mitral valve doesn't close properly, some of the blood from the ventricle is forced back up (regurgitated) into the left atrium instead of flowing out to the rest of the body. The added workload on the heart and the increased blood pressure in the lungs may eventually cause problems. How does it occur? Rheumatic fever can damage valve leaflets and cause scarring. The scars can deform the leaflets so that they don't close properly. A condition called mitral valve prolapse can also cause mitral regurgitation. In mitral valve prolapse one or both of the leaflets bulge (prolapse) into the upper left chamber (atrium) of the heart. A small amount of mitral regurgitation (MR) is common with mitral valve prolapse. If one or more of the cordlike structures attaching the leaflets to the heart muscle breaks, the valve may leak. Heart attacks, diseases of the heart muscle, or other heart valve abnormalities may cause the whole heart to enlarge. The enlargement stretches the mitral valve ring and muscular attachments, pulling the valve leaflets apart. When the leaflets no longer meet, leaking of the mitral valve (mitral regurgitation) results. Over time, the added workload on the heart may cause heart failure. Heart failure occurs when the heart can't pump enough blood to keep the lungs or other body tissues from filling with fluid. Mitral regurgitation may cause both the left ventricle and left atrium to get larger. If the left atrium becomes big enough, an irregular heart rhythm called atrial fibrillation may result. What are the symptoms? People with mild to moderate MR may have no symptoms. Over time, the added workload on the heart may cause shortness of breath with exercise or an abnormal rhythm. This abnormal rhythm feels like your heart is pounding, racing, or skipping in your chest. If a valve leaflet cord breaks, the sudden MR may quickly cause heart failure. The main symptoms of heart failure are:
Most MR causes a heart murmur that can be heard through a stethoscope and easily recognized. Enlargement of the heart may be discovered during a physical examination. The echocardiogram uses ultrasound waves to make pictures of the heart. The pictures show the size of the heart chambers, the thickness of the heart muscle, and the movement of the heart valves. Doppler echo is a special kind of ultrasound that shows the backflow of blood through a valve. The echocardiogram can measure the amount of MR. How is it treated? If you have MR with a normal-sized heart and no symptoms, you need no treatment except for antibiotics before having dental work or procedures that involve the rectum, bladder, or vagina. The antibiotics prevent infections from starting on the mitral valve. Moderate to severe MR eventually results in heart enlargement and symptoms. Most people with symptoms will need valve repair or replacement. If you delay treatment for too long, your heart muscle may already be seriously damaged. Surgery is often needed. If the valve is not too badly deformed, it may be possible for the surgeon to repair it instead of replacing it. Surgeons repair the existing valve by narrowing the valve ring and tailoring the valve leaflets. A plastic support ring is stitched around the valve to bring the leaflets closer together. An advantage of this kind of surgery is that long-term use of blood-thinning drugs is not needed. Sometimes the mitral valve leaflets are damaged so badly that they must be replaced. Artificial heart valves made of human or pig tissue work well but may not last as long as man-made valves. They don't require long-term blood thinners after surgery. Artificial mechanical valves also work very well. These valves last longer without wearing out, but blood thinners must be taken for life. Other than surgery, drugs that expand (dilate) blood vessels and slightly lower blood pressure are the only medicines known to be helpful in treating MR. They work best for those who are very ill, because they help them feel better. Though the drugs work well at first, they don't seem to be the answer for the long term. How can I take care of myself?
Weight Loss Drugs like Fen-Phen And Leaky Heart Valves Valvular Heart Disease (VHD) By the time fenfluramine and its sister drug, dexfenfluramine, were recalled, an estimated 6 million Americans and an estimated 77 million people worldwide had used one drug or the other.1 In 1996 alone, it is estimated that over 18 million prescriptions were written for fenfluramine and phentermine - the two drugs that comprise the "Fen-Phen."2 The litigation that has grown out of this recall is massive, especially as it relates to the pharmaceutical defendants, although increasing numbers of healthcare providers are also being sued. Eventually, the "recall could grow into one of the biggest medical-liability cases in history, perhaps exceeding the anticipated $2.4 billion from silicone breast implants."3 What is Fen-Phen? "Fen-Phen" is the term given to the combined use of the drugs fenfluramine (a.k.a "fen") (or the use of dexfenfluramine, a.k.a. "Redux")) and phentermine (a.k.a. "phen"). Fenfluramine and dexfenfluramine were developed by a French company called Les Laboratories Servier ("LLS"). LLS sold the United States licensing rights of fenfluramine to A.H. Robin, which sold it under the trade name "Pondimin" (also "Ponderol"). Additionally, Wyeth-Ayerst Laboratories, a division of American Home Products, sold fenfluramine in the United States. LLS sold the United States licensing rights of dexfenfluramine to Interneuron Pharmaceuticals Inc., a Lexington, Massachusetts company. Interneuron, in turn, licensed Wyeth-Ayerst Laboratories to sell dexfenfluramine under the trade name "Redux." Phentermine has been sold by various manufacturers/distributors (and under various trade names), including Smith-Kline Beecham Pharmaceuticals (Fastin), Gate Pharmaceuticals (Adipex), Goldline Laboratories (generic Fastin), ION Laboratories (Zantryl), Richwood Pharmaceuticals (Oby-Cap), Abana Pharmaceuticals (Obenix), and Medeva Pharmacology Inc. (Ionamin).4 Fenfluramine and phentermine were sold separately but prescribed in combination. Phentermine was approved by the Food and Drug Administration ("FDA") in March 1959; fenfluramine in June 1973; and dexfenfluramine in April 1996.5 What is the Void that Fen-Phen filled? Most researchers estimate that as many as 35% of Americans are overweight by accepted standards. Additionally, as many as one in four women and one in six men can be classified as obese. Other estimates of the percentage of obese Americans vary, but usually fall within the range of 20% to 30%.6. The treatment of obesity is a multibillion-dollar industry: Americans spend over $30 billion yearly in weight loss efforts.7 Numerous treatments have been attempted for obesity, including the individual prescription use of phentermine, fenfluramine, or dexfenfluramine. Phentermine and fenfluramine were approved for short-term (a few weeks) obesity therapy. Dexfenfluramine was approved for long-term use in order to maintain weight loss, but was only to be prescribed for those who were diagnosed as obese.8 How do the Individual Components of Fen-Phen Work? Fenfluramine (and similarly, dexfenfluramine) triggers the release of serotonin - one of the many natural chemicals stored in the nerves which facilitate a nerve cell's ability to send messages to another nerve cell - into the system. Drugs which enhance serotonin levels are thought to provide a feeling of fullness. One of the common side effects associated with fenfluramine is the feeling of lethargy and, at times, depression. As an appetite suppressant, phentermine works by releasing norepinephrine, similar to adrenalin, into the system. Norepinephrine acts as a stimulant and also leaves the user with the feeling of fullness. Neither fenfluramine nor phentermine individually garnered large market shares as appetite suppressants, primarily because of their disappointing results in achieving weight loss by users. No formal drug studies were ever done to prove their combination was safe and effective. The dawn of the Fen-Phen Phenomena? While the combination of fenfluramine and phentermine was probably in use prior to May 1992, it was the publication of a study by Michael Weintraub, MD (then at the University of Rochester School of Medicine, now a director of Drug Evaluation at the FDA) entitled "Longterm Weight Control Study" in the May 1992 issue of Clinical Pharmacology and Therapeutics that is recognized as the spark that started the wide spread use of Fen-Phen. Dr. Weintraub tested the combined use of fenfluramine and phentermine in 121 subjects who started on a weight-reduction diet program. After six weeks, the subjects were divided into two groups, the control group and the Fen-Phen group. After seven months, the group receiving the Fen-Phen showed significant weight loss in 80% of subjects compared to the control group still using conventional weight-reduction measures. The average weight loss for the Fen-Phen group was three times as large as the control group. Dr. Weintraub continued the study and placed all participants on Fen-Phen. Significant weight loss was reported. When subjects were randomly selected to be given a placebo instead of the Fen-Phen, they regained weight. Some participants who showed little or no weight loss on the original dosage schedule started to lose weight at a higher dose. By the end of the study, Dr. Weintraub reported that 80% of the participants who had been on the Fen-Phen diet for four years had lost 16% of their total body weight (an average of 34 pounds each).9 According to Dr. Weintraub, "the idea of giving the two drugs together was that each would balance out the adverse effects of the other. Fenfluramine was well-known to give those taking it a feeling of malaise, whereas phentermine alone often gave patients the jitters."10 The attraction of Fen-Phen was that this combination had a positive effect on appetite control as well as on mood. With the publication of Dr. Weintraub's study the combination of Fen-Phen quickly became one of the drug industry's hottest sellers. In 1996 alone, the sale of Redux and Pondimin (a trade name for fenfluramine) brought over $305 million in revenue. It is estimated that at the height of its usage, 200,000 prescriptions for Redux and Pondimin were being filled each week.11 The Recall of Fen-Phen? The downfall of the Fen-Phen craze began on July 8, 1997, when Doctor Heidi M. Connolly of the Mayo Clinic reported, in a speech, a "new clinical observation of a possible relationship between heart valve disease and the weight loss medications Phentermine and Fenfluramine, commonly known as Phen-Fen [sic]."12 This culminated in the voluntary recall of fenfluramine and dexfenfluramine from the market just two months later, on September 15, 1997. The Mayo Clinic study identified 24 previously healthy women with an average age of 43 who were treated with the Fen-Phen combination for approximately 12 months. According to the study, all developed the same unusual form of heart valve disease. Even though the findings of the study were to be published in the New England Journal of Medicine in August 1997, Dr. Connolly felt the need to report her findings earlier because of the "potential public health implications...." Id. On the same day that Dr. Connolly delivered her speech, the FDA issued a news release alerting physicians to the reports of valvular heart disease in women treated with a combination of fenfluramine and phentermine. The FDA stated that "[t]hese are drugs that should be taken only by obese patients in conjunction with a weight loss regimen that includes a reduced-calorie diet and an exercise program, in accordance with approved labeling."13 In addition to the women cited in the Mayo Clinic study, the FDA noted that it had received reports of 33 cases of unusual abnormalities in mitral, aortic, and tricuspid heart valves in women between the ages of 30 and 72 who had been taking fenfluramine and phentermine for one month to 28 months. The FDA pointed out, however, that there was no conclusive evidence of a cause-effect relationship between use of the drugs and the development of valvular disease. On August 27, 1997, researchers from the National Institute of Mental Health published an article entitled "Brain Serotonin Neurotoxicity and Primary Pulmonary Hypertension From Fenfluramine and Dexfenfluramine" published in The Journal of the American Medical Association (August 27, 1997). The researchers stated that fenfluramine and dexfenfluramine "have been demonstrated to damage brain serotonin neurons in animal studies." They also pointed out that it "is not known if such damage occurs in humans or if there are clinical consequences." Id. On August 28, 1997, the New England Journal of Medicine published Dr. Connolly's article entitled "Valvular Heart Disease Associated with Fenfluramine-Phentermine", New England Journal of Medicine 337: 581-588 (1997). In the article, Dr. Connolly postulated that "the combination of fenfluramine and phentermine may potentiate the effect or concentration of circulating serotonin and result in valvular injury ... However, the precise process by which this might occur is not known." Id. Also on August 28, 1997, the FDA issued a press release stating that it was requesting that manufacturers of phentermine, fenfluramine, and dexfenfluramine stress the potential risk of combining fenfluramine and phentermine, and state the possible link between the use of these drugs and the development of cardiac valvular disease, in a black boxed warning at the beginning of the drug labels. On September 2, 1998, researchers from the Massachusetts College of Pharmacy and Allied Health Sciences (MCP/AHS) and the Massachusetts Institute of Technology (MIT) stated at the International Congress of Obesity that the combination of "Fen-Phen" was potentially toxic because the two drugs taken together destroy the body's ability to control the amount of serotonin in blood plasma. According to the researchers, "too much serotonin damages blood vessels, particularly in the lungs, and may also harm heart valves." The researchers stressed that "[e]ach of these drugs has not caused these problems when taken alone." Finally, on September 15, 1997, the FDA announced that it had asked manu-facturers to voluntarily withdraw fenfluramine and dexfenfluramine from the market, and that the manufacturers had agreed. This action was apparently taken based on findings from doctors who had evaluated patients taking these two drugs by means of echocardiograms; such findings indicated that approximately 30 percent (a much higher than expected percentage) of patients who were evaluated had abnormal echocardiograms, even though they had no symptoms. In a Question and Answer Sheet accompanying the FDA press release, the FDA stated that phentermine was not being withdrawn because "no case of heart valve disease meeting FDA's case definition have been reported with phentermine alone." According to the FDA, "[a]nalysis of the data points to an association of heart valve disease with fenfluramine and dexfenfluramine." The Fen-Phen Litgation Flood Following the withdrawal of fenfluramine and dexfenfluramine from the market, plaintiffs around the nation began to flood courts with complaints alleging that they had suffered injuries as a result of taking these drugs, or required medical monitoring to see if they developed any of the injuries which were allegedly caused by taking the drugs. The majority of the Fen-Phen litigation has been directed at the above-referenced manufacturers/distributors of the components of Fen-Phen, accusing them, among other things, of failing to warn users of health risks about which they knew or should have known. Increasingly, doctors and weight loss centers are also being drawn into the Fen-Phen suits, based on allegations of medical malpractice.
Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCTI, CCRC, CCRP Member, ACFEI (American College of Forensic Examiners Institute of Forensic Science) Expert Medical Witness, ExpertMD PI (Principal Investigator), DSI (Drug Study Institute) Board Certified Internist, JPMC (Jupiter Preventive Medicine Center) DABIM (Diplomat American Board of Internal Medicine) FACP (Fellow American College of Physicians) CPI (Certified Physician Investigator) by the APPI (American Academy of Pharmaceutical Physicians) CCTI (Certified Clinical Trial Investigator) by the ACRP (Association of Clinical Research Professionals) CCI (Certified Clinical Investigator) by the DIA (Drug Information Association) CCRC (Certified Clinical Research Coordinator) by the ACRP (Association of Clinical Research Professionals) CCRP (Certified Clinical Research Professional) by SoCRA (Society of Clinical Research Associates) Member, SIMPD (Society for Innovative Medical Practice Design) Member, ACPM (American College Preventive Medicine) Ethics Committee Member, Jupiter Medical Center IRB Member, Jupiter Medical Center Founder, CertifiedResearchers.com |