Healthcare consumption decreases in parallel with improvements in quality of life during GH replacement in hypopituitary adults with GH deficiency.

The morbidity associated with GH deficiency (GHD) in adults is now well established. Furthermore, many controlled clinical trials have demonstrated the efficacy of GH replacement therapy. The aim of the present study was to determine whether the effects of GH replacement in adults are reflected in a reduced use of healthcare resources, in addition to improving quality of life (QoL). Data concerning visits to the doctor, number of days in hospital, and amount of sick leave were obtained from patients included in KIMS (Pharmacia International Metabolic Database), a large pharmacoepidemiological survey of hypopituitary adults with GHD, for 6 months before GH treatment and for 6-12 months after the start of treatment. Assistance required with normal daily activities was recorded at baseline and after 12 months of GH therapy. QoL (assessed using a disease-specific questionnaire, QoL-Assessment of GHD in Adults) and satisfaction with physical activity during leisure time were also assessed. For the total group (n = 304), visits to the doctor, number of days in hospital, and amount of sick leave decreased significantly (P < 0.05) after 12 months of GH therapy. Patients also needed less assistance with daily activities, although this was significant (P < 0.01) only for the men. QoL improved after 12 months of GH treatment (P < 0.001), and both the amount of physical activity and the patients' satisfaction with their level of physical activity improved after 12 months (P < 0.001). In conclusion, GH replacement therapy, in previously untreated adults with GHD, produces significant decreases in the use of healthcare resources, which are correlated with improvements in QoL.

The influence of growth hormone deficiency, growth hormone replacement therapy, and other aspects of hypopituitarism on fracture rate and bone mineral density. .

To assess the influence of factors affecting fracture risk and bone density in adult hypopituitary patients with growth hormone deficiency (GHD), data from a large-scale pharmacoepidemiological survey (the Pharmacia & Upjohn International Metabolic Database [KIMS]) were analyzed and compared with data from a control population (the European Vertebral Osteoporosis Study [EVOS]). The KIMS group consisted of 2084 patients (1112 men and 972 women) with various types of pituitary disease and EVOS consisted of 1176 individuals (581 men and 595 women). Fracture and bone mineral density (BMD) data were available from 2024 patients from the KIMS group and 392 patients from EVOS. The prevalence of fractures in patients with hypopituitarism was 2.66 times that in the non-GH-deficient EVOS population. Adult-onset hypopituitarism with GHD was associated with a higher fracture risk than childhood-onset disease, and patients with isolated GHD had a similar prevalence of fractures to those with multiple pituitary hormone deficiencies. Hormonal replacement therapy with L-thyroxine, glucocorticoids, and sex steroids did not affect the risk of fracture in KIMS patients. In addition, fracture rates in KIMS were independent of body mass index (BMI) and the country of origin. However, smoking was associated with a higher fracture rate in this group. In summary, this is the first large-scale analysis to support the hypothesis of an increased fracture risk in adult patients with hypopituitarism and GHD. This increased risk appears to be attributable to GHD alone, rather than to other pituitary hormone deficiencies or to their replacement therapy.

Growth hormone deficiency and replacement in elderly hypopituitary adults. KIMS Study Group and the KIMS International Board. Pharmacia and Upjohn International Metabolic Database.

OBJECTIVE: Although elderly hypopituitary adults demonstrate an increase in total and central fat compared with age-matched controls and are distinguishable from control subjects in terms of growth hormone (GH) responsiveness on dynamic testing, there are few data available on response to GH replacement. The objective of this study was to compare the baseline characteristics and longitudinal response to GH replacement in patients aged > 65 years with that observed in younger patients enrolled in KIMS (Pharmacia and Upjohn International Metabolic Database). KIMS is a physician-managed, open, long-term surveillance study of adult GH-deficient patients receiving GH replacement. Patients were entered and data provided by interested physicians. PATIENTS: Baseline characteristics were studied in 109 patients (66 males) aged > 65 years commencing GH replacement at time of entry into KIMS and the effects of GH replacement on blood pressure, lipids and quality of life in 64 patients who had completed at least 6 months of GH replacement. Data were compared with baseline data on 863 patients aged < 65 years with adult onset GH deficiency, who had not received GH for at least 6 months prior to entry into KIMS, 220 of whom went on to complete > 6 months GH therapy in KIMS. RESULTS: Blood pressure, cholesterol and LDL cholesterol were positively correlated with age, particularly in females, and older patients had a predictably higher prevalence of diabetes mellitus and history of hypertension. The frequency of previous fractures was increased in females but not in males aged > 65 years. Body mass index, waist/hip ratio and quality of life (AGHDA score) was similar in both groups prior to commencement of GH therapy. GH replacement doses were similar in younger and older patients and the percentage of patients with serum IGF-I of > 2SD above the age-related normal mean was not significantly different between the groups (< 65 years, 20%; > 65 years, 11%). After 6 months of GH replacement significant improvements were evident in waist circumference, waist/hip ratio, diastolic blood pressure, total and LDL cholesterol and AGHDA score in patients aged < 65 years. Similar significant reductions in total and LDL cholesterol were evident in patients > 65 years. In addition, male patients aged > 65 years demonstrated significant reductions in diastolic blood pressure and AGHDA score but no change in waist circumference whereas females aged > 65 years demonstrated a trend to reduction in waist circumference and AGHDA score. CONCLUSIONS: These data, derived from the largest series of GH-treated hypopituitary patients published to date, confirm similar baseline characteristics and positive benefit from GH replacement in older compared with younger hypopituitary patients particularly in relation to quality of life.

The effects of treatment and the individual responsiveness to growth hormone (GH) replacement therapy in 665 GH-deficient adults. KIMS Study Group and the KIMS International Board.

Data from 665 adults with GH deficiency (GHD; 332 women; 169 childhood-onset GHD; mean age, 44 yr) were analyzed to determine the efficacy of and individual responsiveness to GH replacement therapy. GH replacement was started at enrolment into KIMS (Pharmacia & Upjohn, Inc. International Metabolic Database). Mean maintenance doses of GH after 6 and 12 months were 0.43 and 0.53 mg/day (1.3 and 1.6 IU/day) for men and women, respectively. Serum insulin-like growth factor I (IGF-I) SD score increased from -2.2 and -4.2 in men and women, respectively, to 1.8 and -0.9 at 6 months and 0.8 and -0.7 at 12 months. The waist/hip ratio decreased after 6 and 12 months, with the changes more pronounced in men. The waist/hip ratio was not influenced by age of onset of GHD, severity of hypopituitarism, or gonadal status. Total cholesterol decreased significantly in men, and high density lipoprotein cholesterol increased in women. Systolic blood pressure was unchanged during GH therapy, but diastolic blood pressure decreased in women. Quality of life, determined by a specific questionnaire for assessment of GHD in adults, improved after 6 and 12 months of GH therapy; this was more pronounced in adult-onset than in childhood-onset GHD, but was not influenced by gender, severity of hypopituitarism, or gonadal status. In 80% of patients, the starting dose of GH was 0.27 mg/day or less. This and the absence of a correlation between body weight and change in IGF-I were consistent with a dose-titration approach, which would tend to obscure individual variations in responses (determined by IGF-I levels). Nonetheless, the increase in IGF-I was significantly higher in men than in women on similar mean GH doses. Weak correlations were observed between the maintenance dose of GH and the change in IGF-I in men and women receiving sex steroid replacement, but not in patients with untreated hypogonadism or an intact gonadotropin reserve. Similarly, the increment in IGF-I was not related to the severity of GHD, as determined by the number of additional pituitary hormone deficiencies. Differences in IGF-I generation may partly explain the gender differences in reduction of central adiposity. These data highlight the value of large longitudinal surveillance databases in defining the optimum dose regimen for GH replacement and indicate that women may need a higher replacement dose of GH than men.

Felodipine once daily in elderly hypertensives. Binational MC Study Group (United Kingdom and Netherlands).

In this monotherapy study, 102 elderly hypertensive patients aged 65-80 years with a diastolic blood pressure (DBP) greater than or equal to 100 mmHg were randomized to double-blind treatment with felodipine 5 mg as an extended release (ER) formulation or placebo once daily. In patients with a DBP greater than 95 mmHg after two weeks the dose was doubled. Total treatment time was four weeks. Blood pressure and heart rate were measured 24 hours after dose intake. At the end of the study, supine BPs were reduced in comparison with values at randomization by 14/13 mmHg in the felodipine group and by 4/8 mmHg in the placebo group (P = 0.005/P = 0.007, felodipine vs. placebo). The proportion of responders was also significantly greater on felodipine than on placebo, 75% and 42%, respectively (response was defined as a reduction in supine DBP to less than or equal to 95 mmHg and/or a reduction by greater than or equal to 10 mmHg). A dose increase was performed in 41% of the patients on felodipine and in 50% on placebo. The proportion of patients reporting adverse events was low and of the same magnitude in both groups.

Felodipine extended release in mild to moderate hypertension.

A multi-centre study was carried out to examine the antihypertensive effect and adverse event profile of felodipine in an extended-release (ER) formulation given once daily as monotherapy. Doses of 5 mg, 10 mg or 20 mg felodipine ER were compared with placebo in 183 patients with mild or moderate hypertension. All antihypertensive medication was discontinued on entering a 4-week placebo run-in period. If, at the end of the run-in period, supine diastolic blood pressure was in the range greater than 95 less than 120 mmHg, patients were randomly allocated to double-blind treatment with felodipine, 5 mg, 10 mg or 20 mg, or placebo, to be taken once daily for 4 weeks. Supine and standing blood pressure, heart rate and body weight were measured every 2 weeks during the trial. Assessments were made 24 hours after intake of the study drug. Adverse events were recorded at each review. Over the 4-week treatment period, a dose-related decrease in supine diastolic blood pressure was observed, this reduction occurring already during the first 2 weeks of active treatment. In the placebo group and the felodipine 5 mg, 10 mg and 20 mg groups, supine blood pressure (systolic/diastolic) decreased by 7/6 mmHg, 9/8 mmHg, 12/10 mmHg and 14/11 mmHg, respectively. Supine diastolic blood pressure reduction in the felodipine 10 mg group and both systolic and diastolic blood pressure reductions in the 20 mg group were significantly greater than with placebo. Standing diastolic blood pressure reduction was significantly greater in all three dose groups on felodipine compared with placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacy and tolerability of long-term felodipine treatment in hypertension. The Scandinavian Multicenter Group.

The antihypertensive effect of felodipine and hydrochlorothiazide, both given in addition to beta-blockers, were compared in this double-blind multicenter study in 103 patients. To all patients concluding the study (n = 92), felodipine was given openly, and the antihypertensive effect and tolerability was studied for 1 year. Patients with a diastolic blood pressure greater than or equal to 100 mmHg, despite beta-blocker treatment, were randomized to treatment with felodipine 5 mg twice daily (n = 51) or hydrochlorothiazide 25 mg (n = 52) once daily for 4 weeks. The dose was then doubled in all patients for a second 4-week period. During open follow-up, all patients were given felodipine 5-15 mg (starting dose 5 mg) twice daily in addition to the beta-blocker. Hydrochlorothiazide could also be added. Reductions in systolic and diastolic blood pressure were significantly greater with felodipine than with hydrochlorothiazide at both the low and high dose levels. There were significantly more responders (diastolic blood pressure less than or equal to 90 mmHg or fall of greater than or equal to 10 mmHg) in the felodipine group. Felodipine and hydrochlorothiazide were both well tolerated. Hydrochlorothiazide treatment was accompanied by a decrease in serum potassium and an increase in serum uric acid. One year of treatment felodipine therapy resulted in a blood pressure fall from baseline of 34/23 mmHg. The most commonly reported adverse event was ankle edema. No clinically important changes in blood tests were seen during felodipine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Felodipine extended-release tablets once daily are equivalent to plain tablets twice daily in treating hypertension. Dutch Hospital Multicentre Group.

The efficacy of and tolerance to felodipine given as extended-release (ER) tablets once daily (o.d.) and the plain tablets twice daily (b.i.d.) were compared in this study. After a 4-week period on placebo and a beta-blocker, 102 patients who had a diastolic blood pressure (DBP) in the supine position greater than 95 mm Hg were randomized to treatment with felodipine ER tablets 10 mg o.d. (n = 50) or plain tablets 5 mg b.i.d. (n = 52). If the DBP was greater than 90 mm Hg after 2 weeks, the dose was doubled. The total treatment time on felodipine was 6 weeks. Blood pressure (BP) was measured 2 h after the dose and at the end of the dosing interval, i.e., 24 h after ER and 12 h after plain tablets. Both formulations reduced BP significantly (15/12 mm Hg in the ER and 13/11 mm Hg in the plain tablet group, at the end of the dosing interval). No differences in BP reduction were seen between the groups. The proportion of responders was 71% on ER and 65% on plain tablets 24 and 12 h, respectively, after dose intake, and greater than 90% in both groups, when measured 2 h after dose. Ankle swelling and flushing were the most frequently reported adverse events. Eight patients (three on ER) were withdrawn, most of them due to vasodilatory side effects. Felodipine ER once daily was as effective and tolerable as plain tablets b.i.d.

The treatment of high blood pressure in the elderly: a multi-centre evaluation of a fixed combination of metoprolol and hydrochlorothiazide ("Co-Betaloc") in general practice.

A post-marketing surveillance programme was carried out in general practice to evaluate the efficacy and tolerability of a fixed-dose combination of 100 mg metoprolol and 12.5 mg hydrochlorothiazide in the treatment of mild to moderate hypertension, with particular reference to elderly patients. Patients received a single daily dose over a period of 3 months. The results of the analysis of data from 1446 patients showed that, although the initial blood pressure was higher in the elderly, both the systolic and diastolic pressures were reduced by the same degree after 3-months' treatment, regardless of age. The incidence of side-effects was similar in all age groups, although a higher proportion of these side-effects led to treatment withdrawal in the elderly, possibly reflecting an increasing overall intolerance to drugs with age. The results suggest that treatment with the metoprolol/hydrochlorothiazide combination is effective and well tolerated in the majority of hypertensive patients, irrespective of age or previous antihypertensive therapy.