The following expert witness report alleges that a woman developed the fatal disease PPH after using Fen-Phen products for less than two months.
6. As it was formerly called, Primary Pulmonary Hypertension (PPH) is a progressive, incurable and often fatal disease, characterized by elevated pulmonary vascular resistance. This increased PVR results in a progressive loss of cardiac output due to increased right ventricular after load. Pulmonary hypertension is clinically defined as a mean pulmonary arterial pressure (mean PA) of more than 25 mm Hg at rest or 30 mm Hg during exercise. (Rubin, ACCP Consensus Statement: Primary Pulmonary Hypertension. Chest 1987; 104:236-50.) Prior to 2003, pulmonary hypertension was usually classed as either primary or secondary. A diagnosis of Primary Pulmonary Hypertension was made when all types of secondary pulmonary hypertension had been excluded on clinical grounds (Gaine & Rubin, Seminar: Primary Pulmonary Hypertension. Lancet 1998; 352:719-25) Following the consensus WHO conference in 2003, most experts in the field now refer to primary pulmonary hypertension as idiopathic pulmonary arterial hypertension; disease states which would formerly have been noted as secondary pulmonary hypertension are now called associated pulmonary arterial hypertension. Prior to 2003, cases involving diet drugs were called primary pulmonary hypertension when it was the opinion of the treating clinician that diet drugs were the only risk factor for the disease. In the current classification we would recognize anorexigens as a definite risk factor for the development of pulmonary arterial hypertension (much like scleroderma or congenital heart disease.) Therefore, pulmonary arterial hypertension related to diet drugs would be classified as associated pulmonary arterial hypertension (the association being diet drugs). Thus, for the purpose of this affidavit, the terms primary pulmonary hypertension (PPH) and pulmonary arterial hypertension (PAH, either idiopathic or anorexigen-associated) are synonymous. Patients suffering from PAH generally have a progressive pruning of the pulmonary vascular tree (resulting from occluded pulmonary arterioles), elevated pulmonary vascular resistance, and eventual loss of the cardiac output and death. The most recent survival data in the prostanoid era comes from Columbia Presbyterian Hospital where consecutive patients were followed between 1994 and 2002 (Kawut, et al. New Predictors of Outcome in Idiopathic Pulmonary Arterial Hypertension. Am. J. Cardiol. 2005; 95:199-203.) This is the era in which patients should have benefited from advanced pulmonary vasodilator therapy. Despite this, the survival for patients was only 75% at 3 years and 60% at five years.
7. Estimates of the incidence of idiopathic PAH are in the range of 1 to 2 cases per million in the general population for those who have not ingested diet drugs. This incident rate greatly increases for people who have a history of certain diet drugs, especially Pondimin(R) and ReduxTM.
16. According to Becky's deposition [at 115-16] and the history I took, she took Pondimin for two months (she estimates she had 5 left, hence, 58 of 63 pills). Given that her clinical history points to no other identifiable cause that would account for her pulmonary hypertension, elevated PVR and low cardiac output; and because exposure to the fenfluramines are among the most powerful known risk factors for developing PPH, I would consider her to have PAH associated with anorexigens even if she took fenfluramine for a month. There are discordant histories of Ms. Wright's length of use (one week [BW 18], one month [BW 469] and a prescription for 63 pills [BW 2]), but on the sole occasion Dr. Murphy ever discussed fen-phen with Becky, he recorded that she was “extraordinarily nervous”, “very nervous” and that “[s]he feels very pressured at the moment because of the rapid pace of events”. [BW 18-19]. Physician documentation is not infallible, and Dr. Murphy conceded that his entry of a left to right shunt on the same page is in error, but rather that Ms. Wright's echo demonstrated a right to left shunt. In my experience it is common for patients to be anxious and imprecise about historical details; this is all the more true for first time patients at a major referral center learning they have an incurable and deadly disease called PPH. This especially true when they are not given reason to believe that a particular piece of history is pertinent to their care and treatment. Given that Dr. Murphy never followed up with Ms. Wright regarding her fen-phen usage as the source of PPH, I do not think that his single piece of documentation should take precedence over the other data which I have seen. Dr. Scott has a sworn affidavit regarding how much he prescribed, prescription records show what was dispensed, and Becky has consistently testified that she stopped taking the drugs due to the onset of shortness of breath and chest pain [BW 22 & 469]. I am compelled to conclude that we have a more accurate history in 2007 than that recorded by Dr. Murphy in 2002.
My name is R. James White, M.D., Ph.D.
1. I have personal knowledge of the facts stated herein by virtue of my care and treatment of Becky J. Wright and by my review of her pertinent medical records. All of the opinions expressed in this report and declaration are based on a reasonable degree of medical certainty. My opinions are also based upon my professional experience and scientific training. My experience and training includes formal education, clinical experience, bench and clinical research, participation in scientific conferences, and service as a consultant to pharmaceutical companies. My opinions are also based upon my review of and contribution to the published medical and scientific literature.
2. I hold the rank of Assistant Professor of Medicine and Pharmacology & Physiology at the University of Rochester Medical Center (URMC); I am a fully employed physician scientist in the Pulmonary and Critical Care division of the Department of Medicine. I am admitted to practice medicine in New York and currently practice at the URMC in Rochester, NY. I am Board-certified in Internal Medicine, Pulmonary Disease, and Critical Care Medicine. A true copy of my curriculum vitae (C.V.), including a list of my publications, is attached hereto as Exhibit A. A summary of my professional experience follows below.
3. From 1990-1997, I was a National Institute of Health Medical Scientist Training Program Scholar graduating with the degrees doctor of medicine and doctor of philosophy. From 1997 to 2000, I was a resident in internal medicine at the University of Rochester. From 2000 to 2003, I was an instructor and fellow obtaining my clinical and research training in Pulmonary and Critical Care Medicine at the URMC. From 2003 to the present, I have been a member of the full-time faculty doing scientific work at the Cardiovascular Research Institute and clinical work in the Pulmonary division of the URMC.
4. I have conducted scientific research and published articles regarding various aspects of pulmonary hypertension. My focus is on the vascular biology which leads to the development of plexiform lesions and concentric luminal obliteration in the lungs of patients with pulmonary arterial hypertension. I have a Parker B. Francis Fellowship to support this work. I am also the site principal investigator for clinical trials in the treatment of pulmonary arterial hypertension. I have served as a consultant to the major pharmaceutical manufacturers with regard to novel therapeutic options in pulmonary arterial hypertension.
5. The vascular biology, diagnosis, treatment, and epidemiology of pulmonary arterial hypertension (formerly “primary” and “secondary”) occupies the vast majority of my professional efforts. University of Rochester Medical Center is now a nationally recognized pulmonary hypertension center with me as the lead physician. My outpatient practice is exclusively focused on the diagnosis and treatment of patients with pulmonary hypertension of varying severity. I am currently treating between 125-150 individuals with selective vasodilators for pulmonary arterial hypertension. I routinely see 8-12 new patients each month, most of whom do not have pulmonary arterial hypertension but rather have echocardiographic evidence for pulmonary hypertension. I am well-qualified to distinguish patients who have echocardiogram estimated pulmonary hypertension from those who have pulmonary arterial hypertension of any cause.
6. As it was formerly called, Primary Pulmonary Hypertension (PPH) is a progressive, incurable and often fatal disease, characterized by elevated pulmonary vascular resistance. This increased PVR results in a progressive loss of cardiac output due to increased right ventricular after load. Pulmonary hypertension is clinically defined as a mean pulmonary arterial pressure (mean PA) of more than 25 mm Hg at rest or 30 mm Hg during exercise. (Rubin, ACCP Consensus Statement: Primary Pulmonary Hypertension. Chest 1987; 104:236-50.) Prior to 2003, pulmonary hypertension was usually classed as either primary or secondary. A diagnosis of Primary Pulmonary Hypertension was made when all types of secondary pulmonary hypertension had been excluded on clinical grounds (Gaine & Rubin, Seminar: Primary Pulmonary Hypertension. Lancet 1998; 352:719-25) Following the consensus WHO conference in 2003, most experts in the field now refer to primary pulmonary hypertension as idiopathic pulmonary arterial hypertension; disease states which would formerly have been noted as secondary pulmonary hypertension are now called associated pulmonary arterial hypertension. Prior to 2003, cases involving diet drugs were called primary pulmonary hypertension when it was the opinion of the treating clinician that diet drugs were the only risk factor for the disease. In the current classification we would recognize anorexigens as a definite risk factor for the development of pulmonary arterial hypertension (much like scleroderma or congenital heart disease.) Therefore, pulmonary arterial hypertension related to diet drugs would be classified as associated pulmonary arterial hypertension (the association being diet drugs). Thus, for the purpose of this affidavit, the terms primary pulmonary hypertension (PPH) and pulmonary arterial hypertension (PAH, either idiopathic or anorexigen-associated) are synonymous. Patients suffering from PAH generally have a progressive pruning of the pulmonary vascular tree (resulting from occluded pulmonary arterioles), elevated pulmonary vascular resistance, and eventual loss of the cardiac output and death. The most recent survival data in the prostanoid era comes from Columbia Presbyterian Hospital where consecutive patients were followed between 1994 and 2002 (Kawut, et al. New Predictors of Outcome in Idiopathic Pulmonary Arterial Hypertension. Am. J. Cardiol. 2005; 95:199-203.) This is the era in which patients should have benefited from advanced pulmonary vasodilator therapy. Despite this, the survival for patients was only 75% at 3 years and 60% at five years.
7. Estimates of the incidence of idiopathic PAH are in the range of 1 to 2 cases per million in the general population for those who have not ingested diet drugs. This incident rate greatly increases for people who have a history of certain diet drugs, especially Pondimin(R) and ReduxTM.
8. In 1998, the World Symposium on Primary Pulmonary Hypertension sponsored by the World Health Organization (WHO) identified fenfluramine as a “definite” risk factor for PPH. According to the Symposium Summary, “ ‘Definite’ indicates an association based on several concordant observations, including a major controlled study or a clear epidemic. Definite risk factors are considered to play a causal role in the development of the disease.” (Rich S, ed. Executive Summary from the World Symposium on Primary Pulmonary Hypertension, 1998; September 6-10, 1998; cosponsored by the World Health Organization, Evian, France) This statement expresses the consensus of scientific and medical opinion that fenfluramine and dexfenfluramine cause PPH; this conclusion was reaffirmed at the WHO convention in Venice in 2003. (Simonneau, et al. Clinical classification of pulmonary hypertension. J. Amer. Coll. Cardiol. 2004; 43:5S-12S.) I agree with this consensus view.
9. The epidemiological data support the conclusion that there is a dose response relationship between exposure to the anorexigen dexfenfluramine and PAH and that longer exposures are associated with greater risk. (Simonneau, et al., Primary Pulmonary Hypertension Associated with the Use of Fenfluramine Derivatives. Chest, 1998 Suppl., 114 (3): 195S-199S.) However, to underscore our lack of understanding regarding exactly how fenfluramine causes pulmonary arterial hypertension, even brief exposures in a susceptible person can result in fatal PAH. (Mark, et al., Fatal Pulmonary Hypertension Associated with Short Term Use of Fenfluramine and Phentermine. New England Journal of Medicine 1997; 337:602-605.) According to a study published in 1996, exposure to anorexigens (fenfluramine and dexfenfluramine) resulted in an adjusted odds ratio of 6.3 for developing PAH. (Abenhaim, et al., Appetite-Suppressant Drugs and the Risk of Primary Pulmonary Hypertension. New England Journal of Medicine, 1996; 335(9): 609-616, 612.) A more recent French registry enrolling 674 patients over one year beginning in October 2002 confirms the prevalence of anorexigen associated pulmonary arterial hypertension at nearly 10% of all those enrolled (Humbert, et al., Pulmonary Arterial Hypertension in France: Results from a National Registry. Am J Respir Crit Care Med 2006; 173:1023-1030.) Thus, exposure to fenfluramine and dexfenfluramine is among the most powerful known risk factors for developing PAH.
10. Patients suffering from WHO Group 1 PAH generally have a progressive pruning of the pulmonary vascular tree (resulting from occluded pulmonary arterioles) and elevated pulmonary vascular resistance. The heart becomes unable to pump against the increased resistance of the diseased blood vessels in the lungs. The right ventricle needs to pump blood through the lungs to be oxygenated before oxygenated blood is pumped to systemic arteries by the left ventricle.
11. The elevated resistance caused by diseased vessels in the lungs eventually damages the heart's right ventricle. The right ventricle increases in size and worsens in function until it can no longer pump. Unless treatment is given, the patient will suffer right heart failure and die.
12. In the absence of treatment, the NIH/NHLBI PPH registry documented a median survival of 2.8 years after diagnosis. Although medications can generally improve symptoms and life span as described above, there is no cure for PAH.
13. Patients with PAH are at risk of sudden death or dying from progressive right heart failure. Regardless of how well patients respond to treatment, medications cannot eliminate the risk that these patients can deteriorate within a matter of hours or days. This risk is unpredictable and real for every PAH patient.
14. It is my opinion to a reasonable degree of medical certainty and probability that Becky J. Wright suffers from PPH (now PAH associated with anorexigen use) caused by her ingestion of fenfluramine.
15. A present list of materials I have reviewed that are specific to Becky J. Wright are listed below.[FN1]
FN1. 1) Becky Wright's CT and X-ray images generated at Mayo; 2) medical records marked BW 001 through 752; 3) the medical records generated from and my letter report to Drs. Nabhane and Frantz from my February 8, 2007, evaluation, care and treatment of Ms. Wright [BW 753 - 769]; 4) Becky Wright's deposition of 12.4.06; 5) Dr. Stanley R. Horner's deposition of 2.19.07; 6) Dr. Joseph G. Murphy's deposition of 4.10.07; 7) Dr. Robert P. Frantz' deposition of 4.10.07; 8) Dr. E. David Scott's affidavit of 8.24.06; and 9) Becky's daughter, Amanda Braman's deposition of 4.13.07.
16. According to Becky's deposition [at 115-16] and the history I took, she took Pondimin for two months (she estimates she had 5 left, hence, 58 of 63 pills). Given that her clinical history points to no other identifiable cause that would account for her pulmonary hypertension, elevated PVR and low cardiac output; and because exposure to the fenfluramines are among the most powerful known risk factors for developing PPH, I would consider her to have PAH associated with anorexigens even if she took fenfluramine for a month. There are discordant histories of Ms. Wright's length of use (one week [BW 18], one month [BW 469] and a prescription for 63 pills [BW 2]), but on the sole occasion Dr. Murphy ever discussed fen-phen with Becky, he recorded that she was “extraordinarily nervous”, “very nervous” and that “[s]he feels very pressured at the moment because of the rapid pace of events”. [BW 18-19]. Physician documentation is not infallible, and Dr. Murphy conceded that his entry of a left to right shunt on the same page is in error, but rather that Ms. Wright's echo demonstrated a right to left shunt. In my experience it is common for patients to be anxious and imprecise about historical details; this is all the more true for first time patients at a major referral center learning they have an incurable and deadly disease called PPH. This especially true when they are not given reason to believe that a particular piece of history is pertinent to their care and treatment. Given that Dr. Murphy never followed up with Ms. Wright regarding her fen-phen usage as the source of PPH, I do not think that his single piece of documentation should take precedence over the other data which I have seen. Dr. Scott has a sworn affidavit regarding how much he prescribed, prescription records show what was dispensed, and Becky has consistently testified that she stopped taking the drugs due to the onset of shortness of breath and chest pain [BW 22 & 469]. I am compelled to conclude that we have a more accurate history in 2007 than that recorded by Dr. Murphy in 2002.
17. On February 8, 2007, I evaluated and made treatment recommendations for Becky J. Wright at the Mary Parkes Center for Asthma, Allergy and Pulmonary Care at URMC. We performed full pulmonary function testing, a standardized six minute walk test and a VQ scan. I wrote a letter to to Gracia Nabhane, MD and copied Robert P. Frantz, MD, regarding my history, physical, evaluation, testing, diagnoses, impressions, and suggestions, as summarized in my February 8, 2007, letter that I incorporate herein by this reference to avoid restating it in full. [BW 759-63] In rendering opinions in this report, it is noteworthy that in substance what I have done in reviewing Ms. Wright's prior medical history before her office visit in February, 2007, is precisely what I do in my every day clinical practice: I completely review all prior pertinent tests, evaluations, histories, diagnoses, medical opinions and conclusions. Accordingly, in reviewing Ms. Wright's prior medical records in order to evaluate and assess her myself, I have (as I would in my ordinary clinical practice) focused predominantly on her nearly five year history at Mayo.
18. A widely accepted and appropriate method of confirming Mrs. Wright's diagnosis of PPH (now PAH associated with anorexigen use) is to follow the algorithm for investigation of suspected pulmonary hypertension, outlined in the peer-reviewed article co-authored by Lewis Rubin and Sean P. Gaine, M.D., entitled Seminar: Primary Pulmonary Hypertension. Lancet 1998; 352:719-25 at 720. This algorithm included the following steps:
19. Review of Catheterizations: The principal method of diagnosing PAH is right heart catheterization, which allows for accurate measures of hemodynamics, including the pulmonary artery pressure, at rest and with exercise, if warranted.
20. Mrs. Wright had a right heart catheterization at the Mayo Clinic on 7/15/02 [BW 311-12] which found severe pulmonary hypertension (PH) at rest. It showed a baseline PA pressure (PAP) of 137/60 mmHg with a mean (PAM) of 63 mm Hg; her measured pulmonary capillary wedge pressure (PCW) was 3, and thus she meets the diagnostic criteria for PPH and PAH. Her pulmonary vascular resistance (PVR) was significantly elevated at about 14 Woods units (WU). Her 7/18/2004 right heart catheterization [BW 309-10] continued to demonstrate severe PH with a mean baseline PAP of 67 mmHg and a PCW of 15 mmHg.
21. Her 10/28/2004 right heart catheterization [BW 308-09] documented ongoing severe PH with a mean PAP of 43 mmHg against a PCW of 5 mmHg despite aggressive therapy with a continuous intravenous prostanoid.
22. Review of Echocardiography: Echocardiography is useful to exclude left heart problems as a potential cause of elevated pulmonary artery pressures and to evaluate right ventricular morphology and function. Mrs. Wright had a transthoracic echocardiogram (TTE) on (ECHO #1) 12/4/1998 [BW 530] which showed a normal left ventricular function and did not reveal evidence for pulmonary hypertension.
23. On 12/17/2001 immunologist and allergist Dr. Stanley R. Homer referred Mrs. Wright to a cardiologist for further assessment [BW 402]. A TTE was performed that day and reported RVSP to be “extremely high” at 114 mmHg. (ECHO #2) BW 379.
24. On 6/13/2002 (ECHO #3) an additional TTE was performed at the Mayo Clinic. BW 327-28. There was no significant mitral or aortic regurgitation reported. There was mild tricuspid regurgitation, moderate inferior vena cava (IVC) dilatation, and an extremely high estimated RVSP of 141 mmHg. They found right ventricular enlargement and reduced right ventricular function. They used agitated saline to assess for a shunt, and they found a large right to left shunt through a patent foreman ovale. The left atrium was said to be normal in size although no formal measurement was provided. The diastolic left ventricular size was normal, and the estimated left ventricular ejection fraction was normal.
25. The Mayo Clinic started Ms. Wright on continuous Flolan treatment for what they diagnosed as PPH on 7/18/2002 (BW 36 & 38.) For reasons explained in greater detail below I agree with this diagnosis and the treatment as instituted in 2002.
26. A TTE on 10/17/2002 (ECHO # 4) at the Mayo Clinic continued to show a severely elevated estimated RVSP of 98 mmHg, with moderate to severe right ventricular hypertrophy (RVH) (BW 325.)
27. The following is a pertinent summary of her fifth through tenth echocardiograms all done at Mayo:
ECHO # 5) TTE 4/15/2003 [BW 323-24]: LV ejection fraction (EF) 63%; left atrium (LA) and left ventricle (LV) within normal limits (WNL); Moderate right ventricular hypertrophy (RVH) and decreased function; Increased RV wall thickness; Moderate RA enlarge; Mild TV regurge; Trivial PV regurge; estimated RVSP of 74 mmHg.
ECHO # 6) TTE 10/6/2003 [BW 321-22]: Moderate RV enlargement and decreased function; Normal LV; Trivial TV regurge; estimated RVSP of 71 mmHg.
ECHO # 7) TTE 4/5/2004 [BW 319-20]: RVSP 71 mmHg, assuming RA 10 mm Hg; EF 69%; Normal LV; Increased RV wall thickness; RA WNL; Trivial pericardial effusion.
ECHO # 8) TTE 6/23/2005 [BW 317-19]: RVSP 81 mm Hg assuming RA 10 mm Hg; LVEF 65%; Increased RV size and decreased function since 4/5/04.
ECHO # 9) TTE 12/19/2005 [BW 315-17]: RVSP 84 mm Hg assuming RA 10; LVEF 68%; No significant changes since 6/23/05.
ECHO # 10) TTE 5/18/2006 [BW 312-14]: No significant changes from 12/19/2005; estimated RVSP of 87 mmHg.
Based on these echocardiogram reports, Mrs. Wright has never had left-sided ventricular disease nor has she had substantive valvular disease. Thus she has never had any evidence for pulmonary venous hypertension but continues to display right ventricular dysfunction despite continuous Flolan therapy.
28. Review of Chest Radiography: Chest radiography may be used to exclude various lung diseases, such as interstitial lung disease (ILD) and emphysema which might cause WHO Group 3 PH. Mrs. Wright had chest X-rays performed on 6/11/2002, 7/17/2002, 10/17/2002, 4/15/2003, 10/6/2003, 4/6/2004, 7/7/2004 and 5/18/2006. BW 304-07. In December, 2001, cardiologist Dr. James F. Tritz raised the possibility of sarcoidosis or underlying fibrotic lung disease [BW 589] based on a CAT scan which reported “[r]edemonstration indeterminate 4 mm x 7 mm nodule left mid lung posteriorly .. [o]therwise negative with no evidence of pulmonary emboli”; it was also negative for pneumonia and pleural effusion (BW 332). Mrs. Wright's various CT's report a pulmonary nodule largely consistent with this 2001 report. I examined in detail the individual images from three different CT scans of Mrs. Wright's chest obtained at the Mayo. I conclude that she does not have radiographic findings typical for sarcoidosis. Concern was also raised early in the course of Mrs. Wright's evaluation for ILD or pulmonary veno-occlusive disease (PVOD). The CT scans do not show progressive interstitial lung disease. Furthermore, her clinical response to treatment is not at all consistent with a diagnosis of PVOD. In fact, the administration of Flolan is potentially deadly for a person who has PVOD. Becky J. Wright's serial clinical evaluation and her response to therapy would be unusual for PVOD but are entirely typical for PAH associated with anorexigens.
29. In April 2004, she was evaluated by Dr. Michael McGoon, arguably one of the leading authorities in PAH. He was concerned about the slight decrement in her lung function as assessed by spirometry and diffusing capacity. He planned an appropriate evaluation for this with a follow-up CT scan in 3 months. Her follow-up visit with Dr. McGoon in July 2004 (immediately before second catheterization BW 117, 309) is quite interesting. In this visit, Dr. McGoon reports that he personally reviewed the images of a high-resolution CT scan with a leading authority in pulmonary vascular disease, Dr. Michael Krowka. They agreed that there was no change in the radiographic abnormalities previously present on her CT scan. Importantly, Dr. McGoon was sufficiently confident in the diagnosis of WHO Group 1 pulmonary arterial hypertension that he felt comfortable enrolling her in a clinical trial adding sildenafil to her regimen of epoprostenol. Investigators are held to a very high standard in terms of their diagnostic certainty when enrolling patients in a clinical trial. In fact, there are severe penalties for protocol violations both with institutional review boards as well as with the FDA for physicians who are careless in their diagnostic certainty. It seems clear to me that Dr. McGoon, an authority in the field, felt very comfortable with this patient's diagnosis at the time that he enrolled her in this controlled clinical trial.
30. I reviewed CT scans in relation to my evaluation of Ms. Wright as well. The mosaic attenuation or ground glass appearance (which can be an early sign of some interstitial lung diseases) on Becky Wright's serial CT scans do not increase in overall distribution. Furthermore, although she has had small areas of linear scarring, she has not demonstrated progressive scarring and she has not developed honeycombing. These CT scans were collected over years, and she never had CT scan changes anywhere near sufficient to explain the severe hemodynamic derangements found at her first RHC. According to my report to Dr. Nabhane [BW 761-62] and Dr. Frantz' testimony, PVOD was ruled out as a cause of Becky Wright's PPH. Based on my review of Ms. Wright's chest radiography from Mayo, I agree with the Mayo physicians who have ruled out PVOD as a cause of Becky's PPH. I note with interest the colorful description of her disease by Dr. Murphy as “rip roaring pulmonary hypertension in spades”. [Murphy Dep. @ 154:19-20] Dr. Murphy's illustrative description contrasts the severity and chronicity of her invasive hemodynamic derangements with much more mild and stable abnormalities in her chest radiography.
31. As further explained below, the most likely cause of Mrs. Wright's severe PH is not PVOD (which was considered and eliminated as a cause of her PH) but is her ingestion of fenfluramine. A number of her CT images evidenced dilated central pulmonary vessels, a finding that is is compatible with PPH. Also a 7/13/2002 CT angiogram had no evidence of a pulmonary embolism. Additionally, my 2.8.07 VQ scan showed remarkably normal perfusion images, not at all compatible with chronic thromboembolic disease to explain her PH. Accordingly, when assessed in conjunction with all of her other studies and her clinical profile, Mrs. Wright's chest imaging lends support to a diagnosis of PPH, or more accurately, PAH associated with diet drugs.
32. Pulmonary Function Tests: Pulmonary function tests can assist in diagnosing restrictive lung disease and obstructive lung diseases such as emphysema which can cause PH. Mrs. Wright has had routine spirometry on 12/5/01 [BW 385-88] which reported forced vital capacity (FVC) =94% predicted; forced expiratory volume in the 1st second of exhalation (FEV1) = 88% predicted; the ratio, FEV1/FVC, provides an index of the severity of the obstructive physiology, and her FEV1/FVC ratio was 66%. Full pulmonary functions tests were completed at Mayo on 6/13/2002. They found her to have a total lung capacity of 3.7-L (88% predicted); her vital capacity was 2.0 L (74% predicted); her FEV1 was 1.6-L (68% predicted). The vital capacity is reduced; in reviewing the flow volume loop, I would think that her reduction in FEV1 was consistent with very mild obstructive lung disease. Especially since her total lung capacity was in the normal range, I would interpret this as consistent with mild obstructive lung disease. The diffusing capacity of her lungs for carbon dioxide (DLCO) was 51% predicted.
33. On 6/14/2002 [BW 18] Dr. Joseph G. Murphy's assessment was “[h]er pulmonary function tests are compatible with primary pulmonary hypertension”. I agree. He also reported “Mrs. Wright has evidence of significant pulmonary hypertension, which is almost certainly primary.”
34. The PFT's I obtained at URMC revealed [BW 765] FVC=62% predicted; FEV1=60% predicted and FEV1/FVC=75%, which is moderate restrictive physiology by ATS criteria. Further, her TLC was 79% predicted and DLCO was 32% predicted. As I reported, her TLC is at the lower limit of normal, and this suggests that her reduction in FVC might be more related to deconditioning than ILD. Certainly, these modest levels of restriction would never be associated with the severity of Becky's hemodynamic changes including her severely high mean pulmonary pressure, her marginal CO, and her very elevated PVR.
35. Although one must always give consideration to WHO Group 3 diseases (respiratory disorders and hypoxemia) when evaluating patients with PH, Ms. Wright has at worst mild interstitial lung disease (others might use the term “fibrosis “), which couldn't possibly cause her degree of PH. She has a total lung capacity in the normal range measured on two different occasions by plethysmography. It is inconceivable that someone would have a mean pulmonary artery pressure greater than 60 mm Hg with a total lung capacity in the normal range if their disease was related to interstitial lung disease. Furthermore, her measured lung function abnormalities are stable (diffusing capacity and total lung capacity), and yet clinically she has improved. If her pulmonary hypertension was related to interstitial lung disease, it would be difficult to understand how she had improved so dramatically with no change in her lung function. She has improved markedly on selective pulmonary vasodilators directed at her Group 1 pulmonary arterial hypertension; these sorts of changes have not been recorded in patients with pulmonary hypertension related to interstitial lung disease (WHO Group 3), and the drugs are not widely used in such patients. Her disease is not related to hypoxemia since it persisted even when the patient was placed on supplemental oxygen. There are repeated evaluations of her oxyhemoglobin saturation with values greater than 90%, and yet her follow-up catheterizations continue to show severe PAH. I agree with Dr. Murphy's description stating that Ms. Wright's PPH is like the elephant in the room while any mild degree of pulmonary fibrosis couldn't cause this degree of PH. Further, as I reported to Dr. Nabhane [BW759] and in accordance with Dr. Frantz' testimony, I agree with the investigators at Mayo who concluded that Becky Wright either has no or such mild pulmonary fibrosis that she was appropriately enrolled in the sildenafil * epoprostenol study. She would have been initially excluded if she had WHO Group 3 PH, and furthermore, the investigators would generally be required to exclude someone at follow-up if they ever deemed her to have developed significant interstitial lung disease. To a reasonable degree of medical certainty, she does not have WHO Group 3 PH, that is she doesn't PH associated with disorders of the respiratory system or hypoxemia.
36. Sleep Study (Polysomnography) is recommended for patients with sleep breathing problems and/or significant daytime sleepiness, which are not problems for Mrs. Wright. Nonetheless, her providers were complete in the evaluation and Mrs. Wright did undergo facility based nocturnal polysomnogram (NPSG) on 11/12/2000 [BW 367]. I often order such tests on my patients even when my suspicion is low. She did not have a respiratory disturbance index that was concerning, and she had only trivial oxyhemoglobin saturation. Dr. Rebecca Lueckenhoff described the sleep study as “negative for sleep apnea” and I agree (BW 368.) Mrs. Wright next had overnight oximetry on 6/13/2002 [BW 6, 13-14], on room air and Alprazolam. In contrast to her facility based study, she had marked oxyhemoglobin desaturations. However, because it was not a laboratory based NPSG, this study can't differentiate obstructive sleep apnea from nighttime hypoxemia attributable to intrinsic cardiopulmonary disease (ie, advanced PAH). She had previously had a negative NPSG, and so her physicians wisely prescribed oxygen to manage her nocturnal hypoxemia and improve her long term outcome. She has not had symptoms of sleep apnea while on chronic oxygen. Obstructive sleep apnea has been appropriately considered and eliminated as a possible contributor to Mrs. Wright's severe PH. Having said that, obstructive sleep apnea without obesity hypoventilation (even if the apnea is severe) is never associated with hemodynamic derangements as severe as Mrs. Wright's and is more commonly associated with marked elevations in the PCW (an abnormality which she does not have).
37. Ventilation-Perfusion Scan (VQ Scan): On 2.8.07 I performed a VQ scan which showed remarkably normal perfusion images and thus eliminated chronic thromboembolic disease (WHO Group 4) as a possible cause of Becky's PH. The VQ scan I ordered was apparently the first VQ scan performed on Ms. Wright. Mrs. Wright's numerous CT scans reveal no evidence to suggest acute or chronic pulmonary embolism. In addition, she underwent a pulmonary angiogram on 6/13/2002 [BW 307] which was normal and only served to further confirm her diagnosis of PAH.
38. Autoimmune Blood tests: Blood tests may also be useful to rule out collagen vascular disease or connective tissue disease as a possible cause of PH. Mrs. Wright has no evidence by history or physical exam of a significant autoimmune disorder of the kind associated with PH. Autoimmune blood testing was performed on 1/10/2002. The labs [BW 337-344] were negative for Smith Ab, Sjogren's Ab, Scleroderma Ab, Anti-DNA, and Antibody to PM-1. Anti -pANCA <6, cANCA <6. On 6/11/2002 she was negative for rheumatoid and ANA. These labs as well as her lab results on 7/17/2002, 10/17/2002, 4/15/2003, 10/6/2003, 7/7/2004, 7/9/2004, 10/28/2004, 3/1/2006, 5/18/2006 [BW 299-300] permit connective tissue disease to be excluded as a cause of Mrs. Wright's very significant pulmonary hypertension.
39. HIV Test: Mrs. Wright's HIV test was negative, she lacks signs or symptoms of HIV infection and lacks any significant risk factors for HIV disease.
40. Liver Function Tests: Liver function tests may be useful, if clinically indicated, to determine whether a patient might suffer from severe liver disease which can cause cirrhosis associated PAH. Mrs. Wright had liver function tests [BW 301-02] performed on 6/11/2002, 10/17/2002, 4/15/2003 reported “[l]iver function tests were good” [BW 83], 10/6/2003, 4/5/2004, 7/7/2004, 10/28/2004 and 3/1/2006 which were either WNL (bilirubin total & direct) or barely outside of the reference range (aspartate aminotransferase, AST of 33 in June, 2002). The sole exception to this would be her April, 2004, alkaline phosphatase (Alk) of 193, but she had four subsequent Alk labs WNL. Thus, based on all her labs addressed herein and the remainder of her clinical presentation, cirrhosis is ruled out as a cause of Mrs. Wright's severe pulmonary hypertension.
41. Personal and Family History: Mrs. Wright's personal and family history also shows that alternative causes of PAH are exceedingly unlikely in her case. Ms. Wright's smoking history which she testified was “at the most” 12 packs a year for three years between 1970 and 1973 is not the cause of her PPH. No one in her family has ever been known to have suffered from the disease, and thus familial PAH (FPAH) is ruled out.
42. Based upon the information described above, it is my opinion that Mrs. Wright suffers from PPH caused by taking AHP/Wyeth's diet drug sold to her as Pondimin; in 2007, we would make the diagnosis “PAH associated with anorexigen ingestion.”
43. According to Dr. Murphy's testimony [@ 40-41] and his chart, the only time he spoke of fen-phen with Becky Wright she was “extraordinarily nervous”, “very nervous” and “feels very pressured at the moment because of the rapid pace of events” [BW 18-19]. It appears that no Mayo Clinic physician ever revisited the issue of her fenfluramine exposure, and each subsequent treating physician based his/her subsequent histories on Dr. Murphy's (and Dr. Vlahakis') initial notations that the patient had had one week exposure. In 2006, Humbert, et al., published an article entitled Pulmonary Arterial Hypertension in France, Results from a National Registry. Am. J. Resp. Crit. Care Med. 2006 Vol. 173, pp. 1023-1030. Dr. Humbert and his colleagues concluded that the “registry highlights current practice and shows that PAH is detected late in the course of the disease”. Of the 674 patients with PAH studied, 9.5% of them had PAH secondary to anorexigen exposure and of that number 77% of the PAH cases corresponded to fenfluramine derivatives. The duration of exposure to fenfluramine derivatives ranged from 1 month to 300 months. Importantly, 15.3% of the persons with PAH secondary to fenfluramines were exposed for less than 3 months (p 1025).
44. The temporal relationship between Mrs. Wright's ingestion of fenfluramine and the onset of her symptoms supports the conclusion that fenfluramine caused her PAH. Mrs. Wright had her first symptoms while taking fenfluramine [BW 22, 469 and her deposition @ 117-19], and her daughter reported significant shortness of breath on a college-viewing trip within 3-6 months of Becky's cessation [Amanda Braman Dep. @ 94-95]. Mrs. Wright also complained of breathlessness in 1998 and these symptoms were sufficient for her to seek evaluation. Her symptoms were initially attributed to asthma, and Albuterol was prescribed. (BW 2, 333 & 530.)
45. Exposure to fenfluramine and dexfenfluramine are among the most powerful known risk factors for developing PPH/PAH and the risk factor has been recently characterized as “definite.” Simonneau, et al., Clinical Classification of Pulmonary Hypertension, Journal of American College of Cardiology, 2004, vol. 43, no. 12 Suppl. S., pp. 5S-12S, Table 2. Additionally AHP/Wyeth's April, 1994, “working list” of PH cases [AHP-Q-00078524-26] documented that at least 14 of the 74 cases (18.9%) associated with fenfluramine use occurred even though the drugs had been used for less than three months. Two of these less than 3-months use patients required lung transplantation (one in a 27 year old female and the other in a 41 year old male) and a third (52 year old female) died. This Wyeth working list of cases coupled with the other medical literature set forth herein constitute additional evidence that short term use of the fenfluramines can result in severe PPH.
46. It is my opinion, to a reasonable degree of medical certainty, that Mrs. Wright's severe PPH is due to her exposure to fenfluramine. This opinion is based on Mrs. Wright's clinical history, her comprehensive evaluation and response to treatment, the prescription records and Dr. Scott's affidavit, her first symptomatology, the pertinent medical literature, and the absence of any other identifiable contributing cause (PVOD and pulmonary fibrosis included). While it is clear that longer durations are associated with higher risks, even brief exposures to anorectic agents are associated with increased risk of PAH. According to the 1996 IPPHS, exposure to anorexigens (fenfluramine and dexfenfluramine) resulted in an adjusted odds ratio of 6.3 for contracting PPH/PAH. Abenhaim, et al., Appetite-Suppressant Drugs and the Risk of Pulmonary Hypertension, New England Journal of Medicine, August 29, 1996, vol. 335, no. 9, pp. 609-616.
47. As explained above, Mrs. Wright's heart catheterizations, echocardiograms, electrocardiograms, chest x-rays, pulmonary function tests, VQ scan, autoimmune blood tests, liver function tests, CT scans, and overnight oximetry rule out secondary factors as the most likely cause of her severe PAH.
48. In April, 2007, Dr. Joseph Murphy stated in relation to Ms. Wright that “I think we are keeping the devil at bay... her hemodynamics are still very abnormal. Her hemodynamics are still consistent with a significant reduction in life span and significant disability”. [Murphy Dep. @ 172:14] I agree with Dr. Murphy's assessment. Dr. Robert Frantz estimated that Becky's expected life span at five years (meaning April, 2012) was 60-70%. [Frantz Dep. @ 65:4] Dr. Murphy referenced studies by Drs. Sitbon and McLaughlin in 2002 and was likely referring to: Sitbon, et al, Long-Term Intravenous Epoprostenol Infusin in Primary Pulmonary Hypertension, JACC, Vol 40, No. 4, 780-88 (2002) and McLaughlin, Survival in Primary Pulmonary Hypertension: The Impact of Epoprostenol Therapy, Circulation, V. 106, 1477-82 (2002). I think that more recent data from Dr. Kawut argues for a more dire prognosis (Kawut, et al. New Predictors of Outcome in Idiopathic Pulmonary Arterial Hypertension. Am. J. Cardiol. 2005; 95:199-203.) Only 60% of patients diagnosed with PAH at one of the premier centers in the country were alive 5 years later. A reasonable conclusion would be that she is already on borrowed time since it has now been nearly 5 years since her diagnosis at the Mayo. Beyond Dr. Frantz and my good faith attempts to estimate Becky Wright's mortality considering the most recent literature, what remains clear is that I am near certain that Ms. Wright, now 56 years old, will die well before her 70th birthday as a result of her fenfluramine-induced PPH.
49. Not only will her life span be shorter than if she had not taken fen-phen, whatever life she has enjoyed has required a cumbersome, continuous infusion of Flolan through the associated catheter. The inconvenience and morbidity of this chronic infusion cannot be overstated, and Mrs. Wright has already endured the terrifying experience of drug interruption carrying the real possibility of death. Other drugs may be appropriate for her treatment in the future, but she will require pulmonary vasodilators for life since this disease has no known cure. It's also highly likely that she will die wearing oxygen (continuously in the home and office). Oxygen and vasodilators will ultimately have been a losing battle “to keep the [PPH] devil at bay” as Dr. Murphy aptly and correctly described. [Murphy Dep. @ 172:14]
50. As a person who has devoted my professional career to the diagnosis, care and treatment of persons suffering from PAH or what was called PPH, I am deeply troubled by the limitations which these patients experience during their dramatically attenuated lifespans. Treatments including Flolan have improved survival, and we hope to make further gains. However, we in the field of clinical PAH research are necessarily excited about ridiculously small gains in objective patient function when evaluating the efficacy of new drugs. While many 56 year olds would be sailing, biking, or otherwise playing happily with their grandchildren, Mrs. Wright is pleased that she can ascend a single flight of steps carrying laundry without stopping. That's a “good day.” Even with the best available therapy, many of our patients (including Mrs. Wright) walk about 1/2 the distance walked by a healthy adult in six minutes.
51. Hence, my letter to Dr. Nabhane of 2.8.07 stated that Becky is “stoic and tough” and the fact that she has only missed about a month of work since starting on Flolan in July, 2002 “is nothing short of amazing.” Beyond what I stated above, the basis of that statement is that only a very small percentage of my patients who require prostanoid infusion (like Flolan) are able to work full time. Frequently, patients who work miss days for increased breathlessness, infections or discomfort associated with the drug infusion. Many patients find that work utilizes all of the energy that they have in a given day leaving them nothing for the maintenance of their home, preparation of meals, and/or relationship with friends or family. Finally, their medical care is time consuming. Daily mixing of medication, cleaning and care of a chronic infusion catheter, frequent laboratory blood work, routine and unexpected physician office visits all require time. It is a rare patient who can care for her catheter, make breakfast, go to work, do laundry, prepare dinner, clean the dishes, and mix the next day's drug. Sadly, Becky is probably working at the expense of any recreational time and likely at the expense of important personal relationships with friends or family. She told me in the office that she would travel more freely if she were not ill.
52. It became clear to me in spending time with Becky that while she has personally invested greatly in attempting to fight her disease, she is also interested in determining whether physicians concur in potentially providing her an alternative to Flolan. Flolan, no doubt, after 4 months, let alone over 4 years, as with Becky, has taken an enormous physical, emotional and familial toll. Hence, as reported, we spent considerable time talking about a potential alternative drug, subcutaneous Remodulin. It is my understanding that Becky has been appropriately assessing possible alternatives to Flolan and will follow up with Dr. Frantz and perhaps others regarding their opinions.
53. I've been provided the understanding that to fulfill the rules and procedures of the Court in this case I am to list all publications that I have authored in the preceding ten years (all such publications are listed on my attached CV); state the compensation to be paid for my care, evaluation and treatment of Becky J. Wright (all of same not covered by insurance will be at the rate of $500 per hour; $750 per hour for oral testimony); and provide a list of cases in which I have testified as an expert in the past four years (Becky Wright is the first patient I have seen in relation to a medical and legal proceeding where I was not the treating physician to begin with. I was a treating physician who believed that my patients Kathy Mahar and Jodi Burgholzer both developed PAH after ingestion of AHP/Wyeth's diet drugs, and I was deposed in those matters). I declare under penalty of perjury under the laws of Missouri, New York, Pennsylvania and the United States, that the foregoing is true and correct and this declaration was executed in Rochester, NY on the date noted below.
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