Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with chronic obstructive pulmonary disease: a randomised, dose-ranging study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common, progressive respiratory disease that causes great morbidity and mortality despite treatment. There is evidence for airway inflammation in COPD. Cilomilast is an orally active, potent, selective phosphodiesterase type 4 inhibitor, which in vitro can affect cells thought to be of clinical importance in COPD. Our aim was to assess the safety, efficacy, and dose response of cilomilast in the treatment of patients with this disease. METHODS: We did a 6-week, randomised, dose-ranging study in 424 patients with COPD (forced expiratory volume in 1 s [FEV(1)] 46.8% of predicted, FEV(1)/forced vital capacity [FVC] 54.6%, and postsalbutamol reversibility 5.4%). We randomly assigned individuals at 60 European centres to receive cilomilast 5 (n=109), 10 (n=102), or 15 (n=107) mg twice daily, or placebo (n=106). The main outcome measure was trough FEV(1) before and after use of a bronchodilator. Analyses were by intention to treat. FINDINGS: Cilomilast 15 mg twice daily significantly improved FEV(1) compared with placebo (mean 130 mL vs -30 mL [95% CI 90-240] at week 6, p<0.0001). FVC and peak expiratory flow were also improved (p=0.001 and p<0.0001, respectively). Quality of life measures did not differ significantly between the groups. There were no significant differences in serious adverse events between the groups. INTERPRETATION: Cilomilast 15 mg twice daily might be an effective maintenance treatment for COPD. Further clinical studies are underway.

Health care costs associated with escalation of drug treatment in type 2 diabetes mellitus.

The cost of different intensities of therapy in HMO patients with type 2 diabetes mellitus was studied. Health care utilization data from 1995 were obtained for 12,200 registrants from the Kaiser Permanente Northwest Diabetes Registry who had type 2 diabetes mellitus. The data were used to determine costs associated with the escalation of antidiabetic therapies in persons with type 2 diabetes mellitus. The total annual costs (in 1993 dollars) associated with no drug therapy, a sulfonylurea only, metformin, a sulfonylurea plus insulin, and insulin alone were $4400, $4187, $4838, $8856, and $7365, respectively. Per patient total costs were higher for patients who had received antidiabetic therapy in 1995 or previously than for those who had not ($5303 versus $4365) and for patients who had received insulin therapy than for those who had not ($7379 versus $4117). Macrovascular complications accounted for 62-89% of the cost associated with inpatient treatment of diabetes-related complications. The total cost of treating patients with type 2 diabetes mellitus at an HMO increased as antidiabetic therapies escalated.

Direct medical cost of chronic obstructive pulmonary disease in the U.S.A.

The aim of this study was to estimate the direct medical costs of chronic obstructive pulmonary disease (COPD) in the United States using a public-payor perspective. Cost estimates were derived separately for 10 components of care using national survey databases and valued using Medicare and Medicaid reimbursement rates. COPD affects 15 million people in the U.S.A. and the total annual U.S. payment for care is $6.6 billion. Approximately one-third ($2.3 billion) is due to the cost of long-term oxygen therapy, one-quarter is attributed to hospitalizations and inpatient physician services ($1.9 billion), and one-seventh ($942 million) is due to nursing home stays. Other annual costs are outpatient physician visits ($480 million), prescription medications ($462 million), home healthcare ($309 million), emergency department visits ($148 million), outpatient diagnostic procedures ($55 million) and hospice care ($28 million). The cost of COPD is therefore considerable. The significant expenditure for long-term oxygen therapy indicates that disease severity is a major driver of costs. However, the cost of hospitalizations, nursing home stays, emergency department and physician visits are not insignificant.

American translation, modification, and validation of the St. George's Respiratory Questionnaire.

BACKGROUND: The St. George's Respiratory Questionnaire (SGRQ) is a 50-item health status survey specific for chronic obstructive pulmonary disease (COPD) and other respiratory diseases that is available in British English but not American English. The SGRQ's symptom-reporting component requires a 1-year reporting period, which may be too long for reliable and accurate patient recall. OBJECTIVES: The objectives of the present study were to translate the SGRQ from British to American English, modify the reporting period of the symptom-reporting component from 1 year to 1 month, and assess the reliability, validity, and sensitivity to change of this translated modified version in a sample of patients with COPD. METHODS: Based on input from American patients with COPD and health professionals, the SGRQ was translated into American English (SGRQ-A) and then translated back to British English. For SGRQ-A reliability and validity studies, patients were asked to report symptoms experienced over 1 year (reporting period in the original SGRQ) and 1 month (modification made to SGRQ-A). We evaluated 102 patients with COPD (50% female; mean age, 68 years; mean forced expiratory volume in 1 second [FEV1], 1.01 L) at an administrative session before and after completion of a pulmonary rehabilitation program. The SGRQ-A, Chronic Respiratory Disease Questionnaire (CRQ), 36-Item Short Form Health Survey (SF-36), 6-minute walk (6MW), Medical Research Council (MRC) Dyspnea scale, and pulmonary function tests (FEV1 and % predicted FEV1) were used in the assessment battery. RESULTS: The SGRQ-A showed good agreement with the original SGRQ when translated back to British English. Internal reliability (Cronbach alpha) was > 0.70 for all SGRQ-A components except the 1-year symptom-reporting component. Test-retest intraclass correlations were 0.795 to 0.900. Construct validity was strengthened when all SGRQ-A components (except 1-year symptoms and most 1-month symptoms) correlated (P < or = 0.01) with the MRC Dyspnea scale, 6MW, all SF-36 concept scores, and 80% of CRQ domains (r = 0.30-0.72). Discriminate validity was demonstrated when all components of the SGRQ-A with the modified 1-month symptom-reporting period were shown to discriminate better between disease-severity groups (based on patient self-reports of disease severity) than did pulmonary function tests and the 6MW. Responsiveness of the SGRQ-A to change in health status was demonstrated when scores on the Symptoms-1 month and Total-1 month components detected significant improvements in patients' health status (P = 0.02 and P = 0.04, respectively). CONCLUSION: The SGRQ-A with a modified 1-month symptom-reporting period demonstrated reliability and validity in this sample of patients with COPD. Key words: chronic obstructive pulmonary disease, St. George's Respiratory Questionnaire, American translation, reliability, validity, symptom recall.

A comparison of three approaches for attributing hospitalizations to specific diseases in cost analyses.

OBJECTIVES: Calculations of healthcare costs rarely disclose the specific approach used to allocate the cost of hospitalizations by diagnosis. However, the type of approach used can have a major impact on the findings in the case of significant comorbidities. The present analyses compared three approaches for attributing Medicare DRG reimbursements (which were used as surrogates for average costs) for hospitalization by diagnosis. METHODS: Medical resource utilization data from the National Hospital Discharge Survey were analyzed using each of three allocation approaches: a) attributing 100% of the cost of hospitalization to the disease when it was the first-listed diagnosis; b) attributing a portion of the cost of hospitalization to the disease, depending on its position in the list of diagnoses and the relevance of any comorbidities; and c) an incremental analysis of cost based upon the hospitalization experiences of an age and gender matched cohort. These three approaches were applied to the cost of hospitalization for chronic obstructive pulmonary disease (COPD). RESULTS: The first approach projected 206,098 hospitalizations at $3,449 per hospitalization for a projected U.S. annual total of $711 million. The second approach projected 681,547 hospitalizations at $3,205 per hospitalization for a projected U.S. annual total of $2.2 billion. The third approach also projected 681,547 hospitalizations, but at $2,361 per hospitalization, for a projected U.S. annual total of $1.6 billion. CONCLUSIONS: Expanding from the example on COPD, the limitations of each approach are described and their applications to other conditions are presented.

High K(+)-induced membrane depolarization attenuates endothelium-dependent pulmonary vasodilation.

Impairment of endothelium-dependent pulmonary vasodilation has been implicated in the development of pulmonary hypertension. Pulmonary vascular smooth muscle cells and endothelial cells communicate electrically through gap junctions; thus, membrane depolarization in smooth muscle cells would depolarize endothelial cells. In this study, we examined the effect of prolonged membrane depolarization induced by high K(+) on the endothelium-dependent pulmonary vasodilation. Isometric tension was measured in isolated pulmonary arteries (PA) from Sprague-Dawley rats, and membrane potential was measured in single PA smooth muscle cells. Increase in extracellular K(+) concentration from 4.7 to 25 mM significantly depolarized PA smooth muscle cells. The 25 mM K(+)-mediated depolarization was characterized by an initial transient depolarization (5-15 s) followed by a sustained depolarization that could last for up to 3 h. In endothelium-intact PA rings, ACh (2 microM), levcromakalim (10 microM), and nitroprusside (10 microM) reversibly inhibited the 25 mM K(+)-mediated contraction. Functional removal of endothelium abolished the ACh-mediated relaxation but had no effect on the levcromakalim- or the nitroprusside-mediated pulmonary vasodilation. Prolonged ( approximately 3 h) membrane depolarization by 25 mM K(+) significantly inhibited the ACh-mediated PA relaxation (-55 +/- 4 vs. -29 +/- 2%, P < 0.001), negligibly affected the levcromakalim-mediated pulmonary vasodilation (-92 +/- 4 vs. -95 +/- 5%), and slightly but significantly increased the nitroprusside-mediated PA relaxation (-80 +/- 2 vs. 90 +/- 3%, P < 0. 05). These data indicate that membrane depolarization by prolonged exposure to high K(+) concentration selectively inhibited endothelium-dependent pulmonary vasodilation, suggesting that membrane depolarization plays a role in the impairment of pulmonary endothelial function in pulmonary hypertension.

Continuous intravenous epoprostenol therapy for pulmonary hypertension in Gaucher's disease.

Gaucher's disease is a rare disorder characterized by a deficiency of lysosomal beta-glucosidase. Pulmonary hypertension, the etiology of which is unclear, has been reported to occur in association with Gaucher's disease. We report the use of continuous intravenous epoprostenol (prostacyclin), which has been used to treat other forms of pulmonary hypertension, in a patient with pulmonary hypertension associated with Gaucher's disease. Although its mechanism of action remains unknown, epoprostenol may be an effective form of therapy for chronic pulmonary hypertension due to a variety of conditions, one of which is Gaucher's disease.

The progressive cost of complications in type 2 diabetes mellitus.

BACKGROUND: A substantial proportion of the costs of diabetes treatment arises from treating long-term complications, particularly cardiovascular and renal disease. However, little is known about the progressive cost of these complications. Firmer knowledge would improve diabetes modeling and might increase the financial and organizational support for the prevention of diabetic complications. METHODS: We analyzed 9 years of clinical data on 11 768 members of a large group-model health maintenance organization who had probable type 2 diabetes mellitus. We ascertained the presence of cardiovascular and renal complications, staged the members progression, and estimated their incremental costs by stage. RESULTS: We found no significant differences between men and women in the prevalence or staging of complications. Per-person costs increased over baseline ($2033) by more than 50% ($1087) after initiation of cardiovascular drug therapy and/or use of a cardiologist, and by 360% ($7352) after a major cardiovascular event. Abnormal renal function increased diabetes treatment costs by 65% ($1337); advanced renal disease, by 195% ($3979); and end-stage renal disease, by 771% ($15 675). Both cardiovascular and renal diseases were more common among older subjects, but age did not affect the additional costs of these complications. Women had substantially higher medical care costs after controlling for age and presence of complications. Incremental cost estimates based solely on "labeled" events significantly underestimate true incremental cost. CONCLUSIONS: In an aggregate population, the greatest cost savings would be achieved by preventing major cardiovascular events. For individuals, the greatest savings would be achieved by preventing progression to stage 3 renal disease.

Ten-year follow-up of antidiabetic drug use, nonadherence, and mortality in a defined population with type 2 diabetes mellitus.

Studies performed for drug registration provide little insight into the long-term use and effectiveness of drugs in "real world" populations and settings. To obtain such insight, we used 10 years of electronic medical-record data from Kaiser Permanente Northwest Division, a large, group-model health maintenance organization in the United States, to study drug transitions, lapses in drug therapy, and mortality among 693 persons with newly diagnosed type 2 diabetes mellitus in 1988. We also studied an equivalently defined cohort of 1071 persons with new diagnoses in 1994, for whom the availability of laboratory results via electronic data permitted additional analyses. Cumulative mortality in the 1988 cohort increased steadily to 207 of 571 patients (36%) by 1997 (year 10). In 1988, 548 of 693 patients (79%) received initial monotherapy with a sulfonylurea. Insulin use rose as the use of sulfonylureas declined. Over this period, 504 of 693 patients (73%) discontinued or added drug therapy. Eight percent to 10% of both sulfonylurea users and insulin users discontinued drug use during the study period. In the 1994 cohort, two thirds of the subjects who discontinued therapy and were tested for glycosylated hemoglobin (Hb A1c) (n = 86) maintained good-to-excellent glycemic control. However, 78 discontinuers (38%) were not tested for Hb A1c, and, among this subset, 32% failed to visit a primary care clinician. The results of this study suggest that 5% to 10% of persons with type 2 diabetes mellitus avoid contact with the medical care system. Avoidance persists for at least the first 10 years after diagnosis but is more common in the first year after diagnosis. In addition, secondary failure of sulfonylureas begins within 1 year of diagnosis and continues at a steady pace. Almost 80% of patients initially treated with sulfonylureas added or switched to metformin or insulin within 10 years of diagnosis.

Type 2 diabetes: incremental medical care costs during the first 8 years after diagnosis.

OBJECTIVE: To describe and analyze the time course of medical care costs caused by type 2 diabetes, from the time of diagnosis through the first 8 postdiagnostic years. RESEARCH DESIGN AND METHODS: From electronic health maintenance organization (HMO) records, we ascertained the ongoing medical care costs for all members with type 2 diabetes who were newly diagnosed between 1988 and 1995. To isolate incremental costs (costs caused by the diagnosis of diabetes), we subtracted the costs of individually matched HMO members without diabetes from costs of members with diabetes. RESULTS: The economic burden of diabetes is immediately apparent from the time of diagnosis. In year 1, total medical costs were 2.1 times higher for patients with diabetes compared with those without diabetes. Diabetes-associated incremental costs (type 2 diabetic costs minus matched costs for people without diabetes) averaged $2,257 per type 2 diabetic patient per year during the first 8 postdiagnostic years. Annual incremental costs varied relatively little over the period but were higher during years 1, 7, and 8 because of higher-cost hospitalizations for causes other than diabetes or its complications. CONCLUSIONS: For the first 8 years after diabetes diagnosis, patients with type 2 diabetes incurred substantially higher costs than matched nondiabetic patients, but those high costs remained largely flat. Once the growth in costs due to general aging is controlled for, it appears that diabetic complications do not increase incremental costs as early as is commonly believed. Additional research is needed to better understand how diabetes and its diagnosis affect medical care costs over longer periods of time.

Initial and long-term results with the CrossFlex stent--data from a national registry.

The Cordis CrossFlex trade mark stent is a balloon expandable helical coil made of stainless steel. OBJECTIVE: To assess the short- and long-term safety and efficacy of this stent by conducting a multi-center national registry. METHODS: One hundred and sixteen stents were implanted in 109 patients (mean age 59 3 10 years, 95 males). The lesions were classified as type B2 or C in 56 patients (51%). Successful deployment was achieved in 103 patients (94.5%). Failure was due to damage to the stent (two patients) or inability to reach the lesion (four patients). High-pressure deployment (>14 atm) was used in 68% of cases. RESULTS: Edge dissections occurred in nine patients after high-pressure deployment and necessitated implantation of a second stent. One patient with a large acute myocardial infarction died during hospitalization. Side branch occlusion occurred in five patients (4.6%). Subacute thrombosis occurred in two patients (1.8%) during the first four weeks. During a six-month follow-up period, 18 patients (16.5%) were rehospitalized with recurrent angina. Fifteen patients had coronary angiography and 13 (12.1%) needed additional target lesion revascularization (TLR). Twelve patients required a second PTCA for in-stent restenosis, and one needed a coronary artery bypass graft operation. CONCLUSIONS: The CrossFlex coronary stent can successfully be used in complex coronary lesions, with few short-term complications and a low TLR rate. Operators should be aware of the possibility of edge dissection during high-pressure implantation.

Transient bradycardia induced by carotid sinus pressure increases outflow obstruction in hypertrophic obstructive cardiomyopathy but not in valvular aortic stenosis.

BACKGROUND: The murmur of hypertrophic obstructive cardiomyopathy (HOCM) increases in intensity in about 80% of those patients in whom carotid sinus pressure (CSP) slows the heart rate. This does not occur in valvular aortic stenosis (AS). STUDY OBJECTIVES, DESIGN, AND PATIENTS: It was hypothesized that left ventricular (LV) obstruction increases with CSP in HOCM and not in AS. Furthermore, it was not clear whether it was the sudden bradycardia or CSP itself that was responsible for the effect noted. Therefore, studies were performed using two different interventions: (1) Doppler echocardiography was performed before and during CSP in 36 HOCM patients and 21 AS patients; (2) two patients with DDD pacemakers and HOCM were examined before and after pacemaker rate slowing. Finally, atrial pacing was performed in three HOCM patients at catheterization, and atrial pacing was either slowed or stopped (without CSP). RESULTS: LV outflow velocity and pressure gradient increased in 28 of 30 HOCM patients (92%) in whom heart rate decreased with CSP. The peak instantaneous pressure gradient increased from 45+/-37 to 77+/-53 mm Hg (p<0.005), and the velocity contour became more typical of HOCM. The pressure gradient increased from 30 mm Hg to 64 and 81 mm Hg, respectively, in the two patients with DDD pacemakers after pacemaker rate slowing. Similar results were seen with slowing or cessation of atrial pacing at catheterization. In contrast, the pressure gradient increased in only three of 21 AS patients (14%), to 44+/-28 from 41+/-25 mm Hg, and remained unchanged in the other 18. CONCLUSION: This study shows that LV outflow velocity and pressure gradient increase markedly in most HOCM patients (92%) if CSP succeeds in slowing the heart rate, but not in patients with valvular AS. A similar effect is obtained by simply decreasing the atrial rate in patients with DDD or atrial pacemakers. This increase in outflow tract obstruction is sufficient to account for the increase in murmur intensity. Decreased afterload (secondary to greater aortic decompression with the longer diastole), increased intrinsic force of contraction with the bradycardia (the Woodworth effect), and Starling's law may play independent roles in the dynamic increase in obstruction observed during CSP in patients with HOCM. Worsening of mitral regurgitation was not clearly shown to contribute to the increase in murmur, but it cannot readily be ruled out.

Infection in surgical patients: effects on mortality, hospitalization, and postdischarge care.

In-hospital mortality, length of stay (LOS), and level of postdischarge care in infected and noninfected surgical patients were studied. An analysis was conducted of a database that included diagnostic, procedure, and drug data collected when surgical patients were discharged from the hospital. Hospitals consisted of 90 nongovernment, nonspecialty, teaching, and nonteaching acute care hospitals of more than 100 beds. Patients in the database included 288,906 patients of all ages hospitalized between July and September 1994. Patients selected of those who had undergone procedures likely to pose a moderate to high risk of infection. Of the 288,906 patients, 12,384 had undergone a moderate- to high-risk procedure; of these, 1,479 (11.9%) had had an infection during their hospitalization. Infection rates ranged from 1.9% to 25.4%, depending on the procedure. The in-hospital mortality rate in infected patients was 14.5%, versus 1.8% for noninfected patients. Similarly, LOS in infected patients (median, 14 days) was substantially greater than in noninfected patients (4 days). About 24% of infected patients required additional professional care after discharge, compared with 7% of noninfected patients. Infection occurs in a substantial portion of surgical patients and is associated with a higher death rate, longer hospitalization, and more intense postdischarge care.

Pharmacoeconomics and the formulary decision-making process.

What is pharmacoeconomics and why is there growing interest in this concept by those who work in or serve the medical community? This article provides a brief explanation of this concept and its importance from an institutional perspective. Additionally, the tasks typically associated with the position of a pharmacoeconomist in the hospital setting are defined. Also described are the types of cost analyses that can be used, the relationship between pharmaceutical care and pharmacoeconomics, and finally, two examples of how pharmacoeconomic principles are actually being used in the formulary decision-making process at a major tertiary care center--The Cleveland Clinic Foundation.

Balloon aortic valvuloplasty in the elderly: useful when there is no alternative.

Of 63 elderly patients with calcific aortic stenosis in whom balloon aortic valvuloplasty was performed, 26 treated with the new technique of Cribier and Letac are the subject of this report. Patients were referred for the procedure because they were at high surgical risk, or were not candidates for surgery. Seven matched patients who fit the criteria for balloon valvuloplasty but refused the valvuloplasty procedure served as controls. Aortic gradient decreased from 78 +/- 27 mm Hg to 35 +/- 20 mm Hg and aortic valve area increased from 0.47 +/- 0.16 cm2 to 0.83 +/- 0.38 cm2 (P < 0.0001). Symptomatic improvement was immediately obtained in each patient. Complications were rare, with only one patient needing vascular repair for femoral artery occlusion. Three patients died during the initial hospitalization (none during the procedure). Valvuloplasty patients were followed for a mean period of 9.6 +/- 9.4 months. Three months survival was 87%, 6 months survival was 76%, and 12 months survival was 61%. Four of seven patients in the control group (57%) died within 3 months after initial referral. Balloon aortic valvuloplasty is a useful treatment in elderly patients who are poor surgical candidates. It may have a positive influence on short-term survival.

Effects of the dipyridamole test on left ventricular function in coronary artery disease.

The dipyridamole stress test is used with thallium-201 to detect areas of inhomogeneity of blood flow that point to coronary artery disease (CAD). It is unclear whether dipyridamole produces inhomogeneous perfusion only or whether it actually decreases net flow in the obstructed vessels and produces true ischemia. It is also unclear what effect dipyridamole has on global and segmental left ventricular function. Therefore, ejection fraction, segmental wall motion and ventricular volume equivalents were measured before and after dipyridamole in 113 patients and 32 normal subjects. Ejection fraction responded in an abnormal fashion in 98 patients (87%), decreasing from 49 +/- 11% to 43 +/- 13% (p less than 0.0001), whereas it increased in 29 normal subjects (90%) from 57 +/- 6% to 64 +/- 10% (p less than 0.0001). Wall motion worsened distinctly in 75 patients (66%), and pressure/volume ratio deteriorated in 72%. The effect of dipyridamole lasted between 10 and 25 minutes, but was promptly reversed by aminophylline. These findings indicate that dipyridamole generally induces true ischemia in CAD. Furthermore, the degree of dysfunction is related to the angiographically assessed severity of CAD. The shortness of breath (seen in 10% of patients) may be partially explained by the findings, and it seems advisable to give aminophylline to every patient in order to promptly correct left ventricular dysfunction.

Alternate delivery methods for morphine sulfate in cancer pain.

New routes of opioid administration that have become available in recent years can be managed by the primary care physician or the oncologist in an attempt to improve pain control and the quality of life. Although oral morphine sulfate is the standard treatment for cancer patients with chronic pain, these novel methods of delivering morphine have enabled some patients whose pain is refractory to traditional methods of drug administration to obtain satisfactory control of their symptoms. The authors review some of these innovative methods.