Clinical trial NCT00615004: Cardiovascular Outcome After Surgery or Somatostatin Analogues
Official title: An Observational, Retrospective, Comparative Study to Investigate Differential Outcome on Cardiomyopathy Following Control of Acromegaly After Surgery or Somatostatin Analogues Given as First-Line Therapy
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Acromegaly
Keywords: Acromegaly
GH
IGF-I
Octreotide-LAR
Lanreotide
Transsphenoidal surgery
Lead sponsor: Federico II University
Sponsor class: OTHER
First posted: 2008-02-14
Enrollment: 215
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: We will review all files from consecutive patients with active acromegaly coming to the Units of Endocrinology or Neurosurgery of the "Federico II" University of Naples from Jan 1st 1997 to December 31st 2006, primarily treated with either surgery or depot SSA, i.e. lanreotide (LAN) or slow-release octreotide (LAR), and with an available follow-up of at least 12 months. Due to the study design, this is a non ran-domized study. However, our routine procedure generally considers first-line treatment with SSA for 6-12 months, unless the tumors are clearly non invasive on Magnetic Resonance Imaging (MRI) and/or the patients who do not present any surgical or anesthesiological risk.

Brief summary: A direct comparison between the results of surgery or somatostatin analogues (SSA) on cardiovascular complication in acromegaly has never been performed.

Our objective is to investigate whether first-line surgery or SSA have a different outcome on cardiomyopathy after 12 months. The design of the study is retrospective, comparative, non randomized, because of ethical problems.

Setting University Hospital. All patients treated with SSA \[either octreotide-LAR (10-40 mg/q28d), or lanreotide (30-120 mg/q28d); dosages up-titrated to control GH and IGF-I levels\] or operated on by transsphenoidal approach. For the purposes of this study only controlled patients will be included.

Measurements Primary outcome measures were changes in left ventricular mass index (LVMi), diastolic \[early to atrial mitral flow velocity (E/A)\] and systolic perform-ance \[LV ejection fraction (LVEF)\]. Secondary outcome measures were reduction of total/HDL-cholesterol ratio, as a cardiovascular (CV) risk parameter, improvement of glucose profile and pituitary function, as indirect causes of CV improvement.

Expected results: SSA and surgery groups should have similar results in terms of improvement of cardiomyopathy. However, recent data suggest that SSA reduce directly heart rate and cardiomyocytes performance: clinical implications of these evidences suggest that SSA will improve cardiovascular outcome more than surgery. Moreover, after surgery, replacement therapy already stabilised or of new onset, has never been considered so far in this setting.

Detailed description: We will review all files from consecutive patients with active acromegaly coming to the Units of Endocrinology or Neurosurgery of the "Federico II" University of Naples from Jan 1st 1997 to December 31st 2006, primarily treated with either surgery or depot SSA, i.e. lanreotide (LAN) or slow-release octreotide (LAR), and with an available follow-up of at least 12 months. Due to the study design, this is a non randomized study. However, our routine procedure generally considers first-line treatment with SSA for 6-12 months, unless the tumors are clearly non invasive on Magnetic Resonance Imaging (MRI) and/or the patients who do not present any surgical or anesthesiological risk.

Cure criteria are considered according with Giustina et al. Acromegaly is considered to be controlled if mean fasting GH levels were ≤2.5 μg/liter in presence of normal IGF-I levels for sex and age. Nadir GH after oral glucose load (oGTT) ≤1 μg/liter is also an option to evaluate disease control according with the 2000 Consensus Statement. However, oGTT is generally not routinely performed in patients receiving SSA, since GH-induced glucose suppression is likely to be mediated by the endogenous somatostatin tone. To avoid ascertainment bias, disease control after surgery and SSA will be only based on fasting GH and IGF-I levels. The diagnosis of acromegaly is defined as previously reported, by high serum GH levels during a 6 hr time course, not suppressible \<1 µg/l after oGTT and high plasma IGF-I levels for age \[expressed as value upper limit of normal range (ULN)\].

For the purpose of this study only the patients with controlled acromegaly will be included to provide a period of follow-up long enough to investigate changes in cardiomyopathy parameters.

Study protocol: As for our routine procedure, at diagnosis all the patients undergo a complete metabolic and endocrine screening. After an overnight fasting, serum IGF-I levels are assayed twice in a single sample at the time 0 of the GH profile; GH levels are calculated as the mean value of at least 5 (up to 8) samples drawn every 30 min over a period of three-six hours and the average value will be considered for the statistical analysis; fasting total cholesterol, HDL cholesterol, glucose and insulin levels are also measured. The total/HDL-cholesterol ratio, index of cardiovascular risk, is calculated.

Eligibility criteria: Inclusion Criteria:

* Patients treated with first-line surgery via trans-sphenoidal route by microscopic and/or endoscopic approach or with first-line depot SSA treatment
* Achieving control of the disease; AND
* With available follow-up after 12 months of treatment

Exclusion Criteria:

* Patients receiving second surgery within 3 months from first surgery
* Requiring combined dopamine-agonists and SSA because of a mixed GH/PRL-secreting tumor
* Receiving the s.c. octreotide for longer than 15 days; OR
* Requiring surgery or SSA as second-line treatment before the completion of the 12 months or with a follow-up shorter than 6 months after surgery or pharmacotherapy

Primary outcomes:
measure: Changes of left ventricular mass index (LVMi), as measure of LV hypertrophy, early to atrial mitral flow velocity (E/A), as measure of diastolic function, and left ventricular ejection fraction (LVEF), as measure of systolic function.
timeFrame: 12 months
Secondary outcomes:
measure: Changes in the total/HDL cholesterol ratio, glucose tolerance, measured as fasting glucose levels and HOMA reduction, and improvement of pituitary function
timeFrame: 12 months
Other outcomes:
Locations:
city: Naples
country: Italy
facility: Department of Molecular and Clinical Endocrinology and Oncology, University Federico II of Naples
Study officials:
affiliation: Federico II University
name: Annamaria Colao, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Colao A, Lombardi G. Growth-hormone and prolactin excess. Lancet. 1998 Oct 31;352(9138):1455-61. doi: 10.1016/S0140-6736(98)03356-X.
citation: Melmed S. Medical progress: Acromegaly. N Engl J Med. 2006 Dec 14;355(24):2558-73. doi: 10.1056/NEJMra062453. No abstract available.
citation: Melmed S, Casanueva F, Cavagnini F, Chanson P, Frohman LA, Gaillard R, Ghigo E, Ho K, Jaquet P, Kleinberg D, Lamberts S, Laws E, Lombardi G, Sheppard MC, Thorner M, Vance ML, Wass JA, Giustina A. Consensus statement: medical management of acromegaly. Eur J Endocrinol. 2005 Dec;153(6):737-40. doi: 10.1530/eje.1.02036.
citation: Sheppard MC. Primary medical therapy for acromegaly. Clin Endocrinol (Oxf). 2003 Apr;58(4):387-99. doi: 10.1046/j.1365-2265.2003.01734.x.
citation: Giustina A, Barkan A, Casanueva FF, Cavagnini F, Frohman L, Ho K, Veldhuis J, Wass J, Von Werder K, Melmed S. Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab. 2000 Feb;85(2):526-9. doi: 10.1210/jcem.85.2.6363.
citation: Colao A, Martino E, Cappabianca P, Cozzi R, Scanarini M, Ghigo E; A.L.I.C.E. Study Group. First-line therapy of acromegaly: a statement of the A.L.I.C.E. (Acromegaly primary medical treatment Learning and Improvement with Continuous Medical Education) Study Group. J Endocrinol Invest. 2006 Dec;29(11):1017-20. doi: 10.1007/BF03349217. No abstract available.
citation: Cappabianca P, Alfieri A, Colao A, Ferone D, Lombardi G, de Divitiis E. Endoscopic endonasal transsphenoidal approach: an additional reason in support of surgery in the management of pituitary lesions. Skull Base Surg. 1999;9(2):109-17. doi: 10.1055/s-2008-1058157.
citation: Galderisi M, Vitale G, Bianco A, Pivonello R, Lombardi G, Divitiis Od, Colao A. Pulsed tissue Doppler identifies subclinical myocardial biventricular dysfunction in active acromegaly. Clin Endocrinol (Oxf). 2006 Apr;64(4):390-7. doi: 10.1111/j.1365-2265.2006.02475.x.
citation: Colao A, Pivonello R, Rosato F, Tita P, De Menis E, Barreca A, Ferrara R, Mainini F, Arosio M, Lombardi G. First-line octreotide-LAR therapy induces tumour shrinkage and controls hormone excess in patients with acromegaly: results from an open, prospective, multicentre trial. Clin Endocrinol (Oxf). 2006 Mar;64(3):342-51. doi: 10.1111/j.1365-2265.2006.02467.x.
citation: Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev. 2004 Feb;25(1):102-52. doi: 10.1210/er.2002-0022.
citation: Colao A, Auriemma RS, Savastano S, Galdiero M, Grasso LF, Lombardi G, Pivonello R. Glucose tolerance and somatostatin analog treatment in acromegaly: a 12-month study. J Clin Endocrinol Metab. 2009 Aug;94(8):2907-14. doi: 10.1210/jc.2008-2627. Epub 2009 Jun 2.
citation: Colao A, Pivonello R, Galderisi M, Cappabianca P, Auriemma RS, Galdiero M, Cavallo LM, Esposito F, Lombardi G. Impact of treating acromegaly first with surgery or somatostatin analogs on cardiomyopathy. J Clin Endocrinol Metab. 2008 Jul;93(7):2639-46. doi: 10.1210/jc.2008-0299. Epub 2008 Apr 29.