Insurance coverage, physician recommendations, and access to emerging treatments: growth hormone therapy for childhood short stature

CONTEXT: There is concern in both the medical community and the general public about mechanisms of medical decision making and the interplay of physician and insurer decisions in determining access to care. OBJECTIVE: To examine the medical process influencing access to growth hormone (GH) therapy for childhood short stature by comparing coverage policies of US insurers with the treatment recommendations of US physicians. DESIGN AND PARTICIPANTS: Independent national representative surveys were mailed to insurers (private, Blue Cross/Blue Shield, health maintenance organizations, programs for Children with Special Health Care Needs, and Medicaid programs, n=113), primary care physicians (n=1504), and pediatric endocrinologists (n=534) with response rates of 75%, 60%, and 81%, respectively. Each survey included identical case scenarios. Primary care physicians were asked decisions about referrals to pediatric endocrinologists. Endocrinologists were asked GH treatment recommendations. Insurers were asked coverage decisions for GH therapy. MAIN OUTCOME MEASURES: Insurer coverage decisions for GH in specific case scenarios were compared with the recommendations of primary care physicians and pediatric endocrinologists. RESULTS: Physician recommendations and insurance coverage decisions differed strikingly. For example, while 96% of pediatric endocrinologists recommended GH therapy for children with Turner syndrome, insurer policies covered GH therapy for only 52% of these children. Overall, referral and treatment decisions by physicians resulted in recommendations for GH therapy in 78% of children with GH deficiency, Turner syndrome, or renal failure; of those recommended for treatment, 28% were denied coverage by insurers. Similarly, GH therapy would be recommended by physicians for only 9% of children with idiopathic short stature, but insurers would not cover GH for the vast majority of these children. Furthermore, the data indicated considerable variation among insurers regarding coverage policies for GH (P<.01). CONCLUSIONS: Access to GH therapy differs depending on the type of insurance coverage. The deep discord between physician recommendations and insurance coverage decisions, exemplified by these findings, represents a major challenge to mechanisms of health care decision making, access, and costs.     

Short and long-term cardiovascular effects of growth hormone therapy in growth hormone deficient adults

OBJECTIVE: Since GH substitution therapy is now available for adult GH deficient patients, information on the cardiovascular effects of GH substitution has assumed major clinical interest. We have therefore assessed cardiovascular effects of short and long-term growth hormone substitution therapy in these patients. PATIENTS AND MEASUREMENTS: Doppler echocardiography was performed in 21 GH deficient patients after 4 months placebo and 4 months GH therapy, in a double blind cross-over study. In an open design study, 13 patients were reinvestigated following 16 months and 9 patients following 38 months of GH therapy. Twenty-one age and sex-matched normal control subjects were also investigated. RESULTS: Heart rate was increased in placebo treated patients as compared to controls. After 4 months of GH treatment, heart rate showed a further increase (10%, P < 0.01) and seemed to remain elevated after 16 months of GH therapy. Systolic and diastolic blood pressures were significantly lower in placebo treated patients than in controls, and did not change significantly after GH treatment. The left ventricular diastolic diameter was reduced in patients as compared to controls, but increased after 4 months GH therapy (P > 0.05) and seemed to increase further during prolonged GH treatment. Cardiac index was at the same level in controls and in placebo-treated patients, but increased by 20% following GH therapy and remained elevated after 16 and 38 months (P < 0.05) of GH substitution. CONCLUSION: Following GH substitution in GH deficient adult patients, left ventricular diastolic dimensions increased and seemed to normalize, while heart rate and cardiac output were found to be increased to supranormal levels.     

Moral assessment of growth hormone therapy for children with idiopathic short stature

Subjects ranging in age from 50 to 89 years old, either with or without dementia were studied by both ELISA for anti-human T-cell lymphotropic virus type I (HTLV-I) gag 100-130 antibody and by cranial CT in order to clarify the relationship between HTLV-I infection and dementia. The frequency of anti-HTLV-I antibody was found to be significantly higher in the patients with dementia (24/130, 18.5%) than in those without dementia (11/139, 7.9%) (P=0.0169). Among the various types of dementia, HTLV-I seropositivity was found to be significantly associated with vascular dementia (11/48, 23%) (P=0.0087), but not with Alzheimer type dementia. In addition, HTLV-I seropositivity was also associated with Babinski sign, and the severity of cerebral infarction, ventricular dilatation and periventricular lucency on CT. The presence of HTLV-I therefore appears to be one of the risk factors for vascular dementia in HTLV-I endemic areas.     

Short stature associated with high circulating insulin-like growth factor (IGF)-binding protein-1 and low circulating IGF-II: effect of growth hormone therapy

We report a case of short stature associated with high circulating levels of insulin-like growth factor (IGF)-binding protein-1 (IGFBP-10 and low levels of IGF-II responsive to pharmacological treatment with GH. Our patient suffered severe growth failure from birth (2.06 SD below the mean for normal full-term boys, and 5.2 and 7.3 SD below the mean at 5 and 10 months). Studies carried out before referral to our pediatric unit included normal 46,XY karyotype and normal encephalic imaging. Other endocrine and metabolic alterations and other systemic diseases were excluded. At 1.7 yr of age (length, 6.1 SD; weight, 4.6 SD; head circumference, 1.4 SD below the mean, respectively) the patient was referred to our pediatric unit. The baseline GH concentration was 31 microg/L, and the peak after an arginine load was 59.6 microg/L. In the same samples GH bioactivity was nearly superimposable (RIA/Nb2 bioactivity ratio = 0.9). Fasting insulin and glucose concentrations were 7.4 microU/mL and 65 mg/dL, respectively, both normally responsive to an oral glucose load. GH insensitivity was excluded by a basal IGF-I concentration (64 ng/mL) in the normal range for 0- to 5-yr-old boys and its increase after 2 IU/day hGH administration for 4 days. IGFBP-3 (0.5 microg/mL) was slightly reduced, whereas IGFBP-1 (2218 and 1515 ng/mL in two different basal samples) was well above the normal values for age and was suppressible by GH (maximum suppression, -77% at 84 h) and glucose load (maximum suppression, -46% at 150 min). The basal IGF-II concentration was below the normal range (86 ng/mL), whereas IGFBP-2 was normal (258 ng/mL). Analysis of the promoter region of IGFBP-1 and IGF-II failed to find major alterations. Neutral gel filtration of serum showed that almost all IGF-I activity was in the 35- to 45-kDa complex, coincident with IGFBP-1 peak, while the 150-kDa complex was absent, although the acid-labile subunit was normally represented. At 2.86 yr (height, 65.8 cm; height SD score, -7.3; height velocity SD score, -5) the patient underwent treatment with 7 IU/week human GH; after 4 months, the patient's height was 68.5 cm (height SD score, -6.9) corresponding to a growth velocity of 8.3 cm/yr (0.3 height velocity SD score). IGFBP-1 was reduced (216 ng/mL), although still in the high range, whereas IGF-I (71 ng/mL), IGFBP-3 (0.62 microg/mL), and IGF-II (111 ng/mL) were only slightly increased. The IGF-I profile showed activity in the 150-kDa region. In conclusion, we speculate that the increased IGFBP-1 values found in this patient produce 1) inhibition of IGF-I biological activity and, therefore, a resistance to IGF-I not due to a receptor defect for this hormone; 2) inhibition of formation of the circulating 150-kDa ternary complex and, therefore, an accelerated clearance rate of IGF peptides; 3) inhibition of the feedback action on GH, leading to increased GH levels, which could suggest the diagnosis of GH insensitivity syndrome; and 4) inhibition of body growth.     

A hypopituitary patient who attained tall stature without growth hormone

In this report, incidence and clinical characteristics of Kaposi's sarcoma (KS) were retrospectively analyzed among renal transplant recipients who were being followed-up in the outpatient clinic of the Istanbul School of Medicine. Between October 1983 and December 1997, 17 cases of KS were diagnosed among 557 patients (3%). Of the total 25 post-transplant malignancies, KS was the most common tumor, representing a rate of 68%. Diagnosis was suspected with typical skin lesions and was confirmed by biopsy. Gastroduodenal endoscopy was applied to 7 patients in order to assess gastrointestinal tract involvement. Of the total number of patients diagnosed with KS 14 were male and 3 female, with the mean age of 40 +/- 15 (range 13-68) yr. The mean duration between the date of transplantation and diagnosis of KS was 15.9 +/- 20.3 (range 1-65) months. The lesions were limited to the skin in 13 patients, while skin and gastrointestinal tract were involved in 2 patients and generalized disease was noted in 2 patients. The initial therapeutic approach was to withdraw cyclosporine and to reduce azathioprine. In the case of progression of the lesions azathioprine was also stopped. Besides, surgical excision of the lesions, radiotherapy and/or chemotherapy were performed according to the clinical picture. Remission was observed in 14 patients after this therapy protocol. The 2 patients with gastrointestinal involvement and 1 patient with generalized KS died in spite of the above-mentioned therapeutic interventions. One of the patients on remission died of pneumonia. It was concluded that KS carried a high risk of morbidity and mortality in renal transplant recipients, and tapering of immunosuppression, especially withdrawal of cyclosporine, affected the prognosis favorably.     

Short stature due to a partial idiopathic deficiency of the growth hormone. The role of the TW2 method in assessing treatment with r-hGH

The purposes of this study were: (1) to determine whether peripheral arterial occlusive disease (PAOD) patients who smoked had more severe claudication pain, reduced peripheral circulation, and poorer cardiopulmonary measurements at peak exercise than non-smoking patients, and (2) to determine whether the differences between the smoking and non-smoking patients persisted after controlling for the resting ankle/brachial systolic pressure index (ABI). Thirty-eight PAOD patients (ABI = 0.59 +/- 0.15, mean +/- SD) who smoked an average of 1.5 packs of cigarettes per day over 42 years and 100 PAOD patients (ABI = 0.74 +/- 26) who had quit smoking for an average of 7 years were recruited. Smokers refrained from smoking on the day of testing. Claudication pain times, oxygen uptake, ventilation, leg oximetry, and ankle systolic pressure responses to peak exercise were recorded. The smoking group had more severe claudication pain, as maximal pain occurred 1:37 min:s sooner during exercise (p < 0.05), and the pain took 2:21 min:s longer to subside (p < 0.01) compared to the non-smoking group. Additionally, at peak exercise the smoking group had a lower oxygen uptake (12.8 +/- 2.6 vs 13.9 +/- 2.4 ml/kg/min, p < 0.01), a higher ventilation (31.7 +/- 9.2 vs 27.9 +/- 7.1 liters/min, p < 0.05), and a higher oximeter electrode power (409 +/- 55 vs 385 +/- 37 mW, p < 0.01) than the non-smoking group. Differences between the groups persisted (p < 0.05) after adjusting for resting ABI. It is concluded that cigarette smokers with PAOD had more severe claudication pain, reduced peripheral circulation, and poorer cardiopulmonary measurements at peak exercise than non-smoking patients. These differences were independent of resting ABI. Thus, cigarette smoking reduces the exercise capacity of claudicants, placing patients who smoke at an even greater risk of living a functionally dependent lifestyle.     

Biosynthetic growth hormone in the treatment of low stature in Turner syndrome

BACKGROUND AND STUDY AIMS: The presumptive diagnosis of Candida esophagitis has been included in the Centers for Disease Control (CDC) case definition for full-blown AIDS since 1987. Endoscopic examination should be reserved for patients showing symptoms despite treatment. The purpose of this study was to assess the degree of diagnostic accuracy of the CDC presumptive clinical criteria and to determine the usefulness of upper digestive endoscopy in the diagnosis of Candida esophagitis in patients infected with HIV-1, with and without a previous AIDS-defining event. PATIENTS AND METHODS: A total of 144 HIV-1 infected patients who had undergone an upper digestive endoscopy were studied retrospectively. To determine the risk and the predictive value of the clinical markers, only the 84 patients without prior antimycotic therapy were included. RESULTS: Of the 84 patients without previous treatment, 34 (41%) had a history of an AIDS-defining illness. Candida esophagitis was found on endoscopy in 11 of the AIDS and 28 of the non-AIDS cases. Oral thrush, either alone (relative risk [R.R.] 9.4; 95% C.I. 2.4-36.4; p < 0.01; positive predictive value [PPV] 82%) or in combination with esophageal symptoms (R.R. 7.4; 95% C.I. 2.5-21.9; p < 0.01; PPV 89%), was a reliable marker of Candida esophagitis only in patients with a previous AIDS-defining event. The diagnostic value of the CDC presumptive pattern was confirmed by a multivariate analysis after controlling for the CD4 cell count (R.R. 9.3; 95% C.I. 2.3-25.3; p < 0.01). On the other hand, in HIV-1 positive patients without a previous AIDS-defining event, the diagnostic accuracy of oral candidiasis, either alone (R.R. 1.4; 95% C.I. 0.8-2.4; p n.s.; PPV 64%) or in combination with esophageal symptoms (R.R. 1.1; 95% C.I. 0.7-1.8; p n.s.; PPV 60%), was too low to allow a reliable diagnosis of Candida esophagitis. CONCLUSIONS: A presumptive diagnosis of Candida esophagitis on the basis of the CDC clinical criteria is a valid diagnostic method only in HIV-1 infected patients with a previous diagnosis of full-blown AIDS. Upper digestive endoscopy should be performed in symptomatic patients with no history of an AIDS-defining illness, especially if the diagnosis of esophageal candidiasis is important for surveillance purposes.     

Short stature and failure of pubertal development in thalassaemia major: evidence for hypothalamic neurosecretory dysfunction of growth hormone secretion and defective pituitary gonadotropin secretion

In patients with beta-thalassaemia major, frequent blood transfusions combined with desferrioxamine chelation therapy lead to an improved rate of survival. Endocrine disorders related to secondary haemosiderosis such as short stature, delayed puberty and hypogonadism are major problems in both adolescent and adult patients. A total of 32 patients with beta-thalassaemia major undergoing treatment at the Children's Hospital, University of G?ttingen were examined. Fourteen of these were short in stature. Growth hormone (GH) secretion was investigated in 13 patients exhibiting either a short stature or reduced growth rate. The stimulated GH secretion of 10 patients in this subgroup lay within the normal range. Studies of their spontaneous GH secretion during the night revealed that these patients had a markedly reduced mean GH and reduced amplitudes in their GH peaks. Low insulin-like growth factor (IGF)-I levels were seen in the growth-retarded thalassaemic patients. Eight were subjected to an IGF generation test and showed a strong increase in both IGF-I and insulin-like growth factor binding protein (IGFBP)-3 levels indicating intact IGF-I generation by the liver. Hypogonadotropic hypogonadism was found to be present in both the male and female patients with impaired sexual development. After priming with LH-releasing hormone (GnRH) per pump in 2 female and 5 male patients, no change in either their serum oestradiol or testosterone levels or in LH/FSH response to GnRH was observed suggesting that they were suffering from a severe pituitary gonadotropin insufficiency. Three male patients at the age of puberty but exhibiting short stature. low GH, low IGF-I and hypogonadism received low dose long-acting testosterone. After 3 12 months of therapy there was a marked growth spurt, higher nocturnal GH levels and an increase in both IGF-I and IGFBP-3. CONCLUSION: Reduced GH secretion and low IGF-I in thalassaemic patients are related to a neurosecretory dysfunction due to iron overload rather than to liver damage. Hypogonadotropic hypogonadism is caused by the selective loss of pituitary gonadotropin function. In patients with both GH deficiency and hypogonadism, low dose sexual steroid treatment should be considered either as an alternative or an additional treatment before starting GH therapy.     

The treatment with biosynthetic growth hormone (GH) of familial short stature

The effect of growth hormone (GH) treatment in non-GH deficient subjects has been amply studied over the past few years. Although the results of these studies are encouraging, there are still no definitive data since the findings are not comparable due to the different characteristics of the populations examined. In the present study the authors examined the following parameters: stature, height SDS, growth rate, bone age and final height prediction according to Tanner, pubertal stage, before and after treatment with biosynthetic GH at a dose of 1.4 IU/kg of bodyweight for 12 months. The population treated consisted of 10 subjects (5 males and 5 females) aged between 7.3 and 9.5 years old, all prepubertal, with "familial short stature", selected according to the following criteria: stature below the 3rd centile, normal growth rate, normal GH response to stimuli using clonidine and insulin, correlation with parental stature between 25th and 75th centile, bone age correlated to chronological age, absence of other pathologies. After 12 months height SDS moved from -2.75 +/- 0.26 to -2.23 +/- 0.25 (p < 0.5); the growth rate changed from 5.75 +/- 0.63 to 6.66 +/- 0.56 (p < 0.05). No abnormal acceleration of bone age as observed: it moved from 8.2 +/- 0.62 to 9.5 +/- 0.72; all subjects continued to be prepubertal. The expected final stature changed from 154 +/- 2.38 to 159 +/- 0.7 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of growth hormone therapy on bone metabolism of growth hormone deficient children

The effects of human growth hormone (hGH) therapy on biochemical markers of bone metabolism were studied in 17 children (10 boys and 7 girls, aged 3.7-13.1 years old) with idiopathic GH deficiency, before and 1 and 6 months after GH therapy (0.5 0.7 IU/kg weekly SC). Serum levels of calcium, phosphate, alkaline phosphatase osteocalcin, parathyroid hormone, 1,25 dihydroxyvitamin D, insulin-like growth factor I (IGF-I) and renal phosphate per 100 ml glomerular filtrate (TPO4/GFR) were assessed. During therapy with hGH a significant decrease of serum calcium levels and increases of phosphate, osteocalcin, parathyroid hormone 1,25 dihydroxyvitamin D and IGF-I were observed. TPO4/GFR was also significantly increased. Growth response (increment in HV) was positively related with changes in alkaline phosphatase and IGF-I levels after 6 months of hGH therapy. There was also a significant positive correlation between increment in HV and increment in TPO4/GFR after 1 month of GH therapy, whereas no correlation between HV and changes in osteocalcin levels was found. CONCLUSION: GH treatment significantly influences mineral metabolism and the measurement of TPO4/ GFR after 1 month of GH therapy may serve as a useful predictor of growth response to hGH therapy in GH-deficient children.     

Compliance with hormone replacement therapy in postmenopausal women. A comparative study

OBJECTIVE: To assess compliance with hormone replacement therapy in postmenopausal women. METHOD: Two groups were compared prospectively: 100 women who sought treatment for menopausal symptoms, and 82 women who had undergone a total abdominal hysterectomy with bilateral salpingo-oophorectomy and were using estrogen replacement therapy. RESULTS: Compliance rates after 6 months were 81.0% and 84.1% in the two groups, respectively, and after 12 months, 73.0% and 80.5%. CONCLUSIONS: The high rates are attributed to our investment in patient education of the benefits of treatment and repeated and close follow-up.     

Dental maturity in children of short stature, with or without growth hormone deficiency

Macrophages are important constituents of the immune system by exerting phagocytosis on invading pathogens as well as secreting various immunoregulatory factors. Generation of human macrophage hybridoma has not been possible so far due to the lack of an appropriate fusion partner cell line. In the present study, an 8'-azaguanine resistant cell line, termed HL-60R, was established by drug selection of the promyelocytic cell line HL-60. This novel cell line showed resistance to high concentrations of 8'-azaguanine and was sensitive to aminopterin. These characteristics make it suitable for serving as a potential fusion partner cell line in the development of macrophage hybridoma. Cell-surface analysis by FACS revealed that HL-60R cells per se do not express MHC-class II molecules or the macrophage marker, CD11b. PEG-mediated fusion of HL-60R was performed with PBMC-derived human macrophages. Fluorescence labelling of ex vivo isolated macrophages prior to fusion and subsequent FACS analysis showed that PEG-4000 is a more effective fusion agent than PEG-1500. The generation of this novel fusion partner cell line opens the possibility for development of human macrophage hybridoma or other cell lines from myelocytic origin. Such hybridoma clones will not only enable a more convenient study of these cell but will also provide an excellent host site for the proper production and expression of various recombinant proteins from myelocytic origin in vitro.     

Complications of growth hormone therapy in children

The introduction of human growth hormone (GH) prepared by recombinant DNA technology has resulted in increased numbers of children and adults receiving treatment. This trend has led to questions concerning the safety of GH, particularly when used for indications other than GH deficiency. This review discusses the effects of GH on fluid, lipid, and carbohydrate metabolism; the risk of intracranial hypertension or pseudotumor cerebri; the effects on the skeletal system; the risk of malignancy; and the effects on the immune system. At present, GH treatment appears to be safe, although long-term follow-up of GH-treated patients is necessary.     

Individual growth in stature: a comparison of four growth studies in the U.S.A

Patterns of growth in stature of subjects from the four major U.S. longitudinal growth studies are compared by means of a two-component model for individual growth. Problems inherent in the comparison of data from independent growth studies, such as those arising from different methods of sampling subjects and scheduling measurements and the occurrence of atypical subjects, are considered and solutions are offered. Statistical tests of the individual growth parameters revealed significant, but small, differences among the samples in the magnitude of the contributions of prepubertal and adolescent growth to mature stature and in the velocity of growth. No differences between samples in the timing of the adolescent component were detected.     

Civic engagement patterns and transitions over 8 years: The AmeriCorps national study.

Latent transition analysis was used to examine civic engagement transitions across 2 waves spanning 8 years in a sample of AmeriCorps participants and a comparison group (N = 1,344; 77% female). Latent indicators of civic engagement included volunteering, community participation, civic organizational involvement, local and national voting, civic consciousness, and perceptions of civic knowledge. Three latent statuses were identified; inactive, voting involved, and highly committed. Consistent with life cycle theories of political engagement, the inactive status was most prevalent at Wave 1 and the voting-involved status most prevalent at Wave 4. AmeriCorps members were less involved in voting at Wave 1 but, among voters, were more likely to become highly committed by Wave 4. Compared with those who did not attend college, those who did had higher levels of civic engagement initially and over time. Young participants and Asian youths demonstrated lower levels of involvement initially compared with older participants or White youths. Findings suggest that national service programs geared toward young people who are not in college may hold promise for addressing gaps in civic engagement. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Brief therapy prevalence and training: A national survey of psychologists.

Psychologists find themselves ill-prepared to meet the increasing demand for briefer and briefer therapies. Members of APA Divisions 12 (Clinical Psychology) and 29 (Psychotherapy) were surveyed (N?=?1,250; return rate?=?57%) regarding their practice of and training in brief therapy. Results indicate that almost all (89%) of the respondents perform some brief therapy and, on average, spend half their time doing it. With regard to training, however, half of those conducting brief therapy have never taken any brief therapy courses. Additional findings indicate theoretical orientation, gender, region, practice site, and setting are significantly related to the amount of brief therapy delivered. Overall, the amount and helpfulness of brief therapy training are significantly related to one's skill, satisfaction, and positive attitude toward brief therapy. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A history of growth hormone

After the debacle of Brown-Séquard testicular extracts, hormone replacement therapy proper began in 1891 with the use of sheep thyroid extract to treat myxoedema. The second success in the field was "bovine' insulin to treat human diabetes in 1992. In contrast, the first successful use of growth hormone in a human pituitary dwarf did not come until 1958. Growth hormone preparations of reasonable purity had been made in the 1920s and were shown to be effective in rats and dogs, but the need for primate growth hormone in primates was not recognised until the late 1940s.     

A placebo-controlled study of growth hormone in patients with congestive heart failure

AIM: Experimental data in heart failure models and an open trial of seven patients with idiopathic dilated cardiomyopathy have suggested beneficial effects of growth hormone on cardiac function. The aim of the present study was to evaluate growth hormone effects on cardiac function in a placebo-controlled study. METHODS: Twenty two patients with congestive heart failure of different aetiologies in NYHA II and III and an echocardiographic ejection fraction <0.45 were studied in a 3 month double-blind placebo-controlled study with growth hormone added to optimal heart failure therapy. Patients received either placebo (n=11) or recombinant human growth hormone (n=11) in an initial dose of 0.1 IU x kg(-1) week(-1) for 1 week, and thereafter 0.25 IU x kg(-1) week(-1) for the rest of the treatment period. Cardiac function was assessed by equilibrium radionuclide angiography and Doppler echocardiography. Functional capacity was evaluated by computerized bicycle exercise electrocardiography. RESULTS: Recombinant human growth hormone had no significant effect on systolic or diastolic cardiac function, exercise capacity or neuroendocrine activation. In addition, there was no overall improvement in functional class or dyspnoea grade. Insulin-like growth factor-I significantly increased demonstrating that the growth hormone had an endocrine effect. CONCLUSION: This is the first double-blind and placebo-controlled study of the administration, over 3 months, of recombinant human growth hormone in patients with congestive heart failure of different aetiologies. The treatment was safe and without serious side effects. However, no beneficial effects on cardiac function or structure could be detected.