Report From the 93rd Cardiovascular and Renal Drugs Advisory Committee Meeting, August 9–10, 2001
Two new drugs for the treatment of pulmonary hypertension received tentative approval at the 93rd meeting of the US Food and Drug Administration’s (FDA) Advisory Committee Meeting on August 9 to 10, 2001. Although the committee can recommend that the FDA approve the drugs, it is not mandatory that the agency accept that recommendation.
The first drug, Remodulin (trepostinil sodium), which is manufactured by United Therapeutics, was approved by a vote of 6 to 3 in the committee after an animated discussion of the fact that there was no trend toward reduced mortality or need for transplantation after Remodulin treatment. The approval was based on an improvement in perceived quality of life. Although dyspnea, syncope, and fatigue were side effects of the drug’s administration, the committee thought its safety profile warranted approval.
Remodulin, or UT-15, is a structural analogue of prostacyclin, which acts as a vasodilator in the pulmonary and systemic circulation. Its terminal half-life is 2 to 4 hours. It is administered as a continuous subcutaneous infusion.
There were two pivotal, placebo-controlled trials considered by the committee. A total of 470 patients with primary or secondary pulmonary hypertension and functional class II to IV symptoms were entered into the 2 studies.
Investigators hoped that after 3 months of therapy, patients in the studies would be able to walk 55 meters more in 6 minutes than they had before the study. However, the treatment group was able to walk only an average of 10 meters more after therapy, less than the prespecified objective. Nor did the studies reach the level of statistical significance for which the researchers had hoped.
The committee voted 10 to 0 to approve a second drug for pulmonary hypertension, bosentan (Tracleer), which is manufactured by Actelion Pharmaceuticals. It is the first orally active, nonpeptide antagonist of endothelin receptors developed to treat the disorder.
In 2 placebo-controlled trials, 246 class III to IV patients with pulmonary hypertension achieved the primary end point of a 44-meter difference in a 6-minute walk between the treatment and placebo groups. The difference was statistically significant, with P=0.0002. In addition, patients experienced significant improvements in dyspnea, functional class, and time to worsening symptoms.
The first study involved 32 patients who were randomized in a 2:1 manner to 125 mg of bosentan twice a day or placebo. In the second study, 213 patients were randomized equally to 3 groups. One group took 125 mg BID; a second took 250 mg BID, and a third took placebo. The bosentan groups received 62.5 mg BID for the first 4 weeks of therapy.
The drug did have safety issues, including potential teratogenicity, which requires exclusion of pregnancy before treatment; decreased hemoglobin of unknown cause; liver toxicity with a dose-related increase of liver enzymes in as many as 11% of patients; and many potential interactions with other drugs.
The sponsor will implement a monitoring/surveillance program and identify drugs that should be either avoided or undergo dose adjustment if patients are treated with bosentan.
Information for this article was obtained from the following persons: Paul Armstrong, MD, Chairman, Department of Medicine, University of Alberta; Raymond Lipicky, FDA Director of the Cardio-Renal Drug Products Division; Thomas Fleming, PhD, Professor and Chair, Department of Biostatistics, University of Washington; and JoAnn Lindenfeld, MD, Professor of Medicine, Division of Cardiology, University of Colorado Health Science Center.
Finding Uncontrolled Hypertensives
Although most clinicians are aware that many people in the United States have uncontrolled high blood pressure, the findings of David J. Hyman, MD, MPH, an associate professor of medicine, and Valory N. Pavlik, PhD, an assistant professor of family and community, at Baylor College of Medicine cast doubt on speculation about the reasons for the lack of treatment.
Their analysis of the data from the third National Health and Nutrition Examination Survey demonstrated that most of the patients had isolated, mild systolic hypertension and were covered by health insurance. Most of them came into relatively frequent contact with physicians.
They studied the records of >16 000 patients and found that only 23% of those with high blood pressure were taking medications to control their condition (N Engl J Med. 2001;345:479–486).
Their analysis revealed 4 important characteristics of the population and the condition they were studying. (1) Undiagnosed and treated but uncontrolled hypertension occurred mostly in people who had frequent or regular contact with their doctors or the healthcare system; (2) lack of awareness of hypertension and lack of adequate control are factors that affect mostly older members of society; (3) lack of control is not a problem confined to the poor, the uninsured, or minorities; and (4) the pattern of an elevation in systolic blood pressure with a diastolic blood pressure <90 mm Hg predominates in the middle-aged and the elderly. “These findings dispel the stereotype that the typical patient with uncontrolled hypertension is a young man (often a non-Hispanic black) who does not visit the physician or who will not take antihypertensive drugs regularly,” the authors wrote.
In an accompanying editorial, Aram V. Chobanian, MD, of Boston University School of Medicine, said, “Clearly a shift needs to occur in clinical practice to focus more on the management of systolic rather than diastolic hypertension. The National High Blood Pressure Education Program, sponsored by the National Heart, Lung, and Blood Institute recently recognized the urgency of this change and released a clinical advisory statement recommending that systolic blood pressure become the major end point for the detection, evaluation, and treatment of hypertension.”
“Intensified efforts to alter modifiable cardiovascular risk factors such as blood pressure, lipoprotein levels, smoking, blood glucose levels, weight, and physical activity levels must become a national priority,” Dr Chobanian wrote (N Engl J Med. 2001;345:534–535).
Lung-Volume Reduction Surgery Poses Significant Mortality Risks to the Sickest Patients
Caution is the watchword in performing lung-volume reduction surgery on patients with emphysema who have a low forced expiratory volume in 1 second (FEV1) and either homogeneous emphysema or a very low carbon monoxide diffusing capacity, according to a report from the National Emphysema Treatment Trial Research Group in a report appearing online in the New England Journal of Medicine on August 14, 2001. The printed report will appear in the October 11, 2001, issue of the Journal.
In their study, the investigators randomly assigned patients to undergo lung-volume reduction surgery or to receive medical treatment. An outside data and safety monitoring board monitored patient outcomes. By June 2001, 1033 patients had been entered into the study. For 69 patients with a FEV1 that was ≤20% of the predicted value who also had either a homogeneous distribution of emphysema on computed tomography or a carbon monoxide diffusing capacity of ≤20% of the predicted value, the 30-day mortality rate after surgery was 16%. In these high-risk patients, the overall mortality rate was higher in surgical patients than medical patients. When compared with patients who received only medical treatment, survivors who had the surgery had small improvements in maximal workload, distance walked in 6 minutes, and FEV1 in 6 months. However, the health-related quality-of-life for both groups was similar, and researchers concluded that the functional outcomes in this group did not favor either treatment.
In an accompany editorial that was also published online on August 14, 2001, Jeffrey M. Drazen, MD, the Journal’s editor-in-chief wrote that, given the dearth of treatments for emphysema and, in particular, hyperinflated lung, it was not surprising that lung-volume reduction surgery had been hailed as an advance. However, he noted, as the operation began to be performed more routinely, 2 problems emerged. The first was that the operation was not as effective as had been expected on the basis of previous published reports. “In fact, after surgery, many patients languished in intensive care units—not sick enough to die but without adequate lung function to breathe on their own.” The second problem was economic. The nation’s burden of emphysema was substantial, and if everyone with moderately advanced emphysema demanded the operation, there would be a shortage of surgeons to perform the operation and a shortage of funds to pay for it. These dual problems demanded a creative solution.
The solution was this trial. “One key factor set this trial apart: Medicare would no longer pay for the operation if it was performed outside the trial,” Dr Drazen noted. “Thus, prospective patients who were also Medicare recipients had only 2 choices if they wanted lung-volume reduction surgery: participate in the trial or pay for the operation themselves. The decision to participate in the trial was thus complicated because of the long wait for the operation in the 50% of patients who were assigned to the medically managed control group.”
The trial was designed to identify who would and would not benefit from the surgery. When the results were in, about 1 in 8 of the study subjects were in the group for which surgery represented a risk that was higher than medical therapy. “The operation harmed some patients and did not benefit those who survived,” Dr Drazen noted.
The study is continuing, but those patients who fall into the group that runs a greater risk with surgery will no longer be considered eligible for the study. “These findings are important. They demonstrate, through the use of data from a controlled clinical trial, that rational bounds can be placed on clinical practice,” Dr Drazen concluded. “For now, we can prevent iatrogenic suffering by not performing lung-volume reduction surgery in patients with emphysema whose FEV1 is ≤20% of their predicted value and who have a low carbon monoxide diffusing capacity (≤20% of their predicted value) or whose disease appears radiographically uniform. In evaluating the appropriateness of surgery for emphysema, we would do well to remember that sometimes doing nothing is the best approach.”