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No Greater Incidence or Worsening of Cardiac Valve Regurgitation with Somatostatin Analog Treatment of Acromegaly

Department of Molecular and Clinical Endocrinology and Oncology (A.C.), Federico II University of Naples, 80131 Naples, Italy; 1st School of Medicine (J.M.), Charles University, Prague 12108, Czech Republic; Division of Endocrinology (M.I.G.), Department of Medicine, National Medical Center, Budapest 1135, Hungary; Department of Endocrinology and Metabolic Diseases (P.C.), Centre Hospitalier Universitaire Larrey, Toulouse 31059, France; Institut National de la Santé et de la Recherche Médicale 0204 (J.M.K.), Hôpital Centre d’Investigation Clinique, Charles Nicolle, Rouen 76031, France; Department of Endocrinology and Metabolism (F.M.M.), University of Genova, 16132 Genova, Italy; and Cardiovascular Research Institute/Washington Hospital Center (N.J.W.), Washington, DC 20010

Address all correspondence and requests for reprints to: Annamaria Colao M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, via S. Pansini 5, 80131 Napoli, Italy. E-mail: colao{at}unina.it.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: Excess GH and IGF-I in acromegaly are associated with reduced life expectancy due to cardiovascular complications.

Objective: The objective of the study was to investigate the prevalence, incidence, and severity of cardiac valve regurgitation before and after somatostatin-analog treatment in acromegaly.

Design: This was a prospective, observer-blinded, multicenter, 12-month study.

Setting: The study was conducted at 33 specialist centers.

Patients: The study population consisted of 225 adult patients with acromegaly without significant cardiac valve abnormalities or prior valve-replacement surgery, matched for age, sex, and center/country/study.

Interventions: Interventions included initiation/continuation of lanreotide (n = 107) or octreotide treatment (n = 118), tailored for optimal disease control.

Main Outcome Measures: Relative risk of new/worsening regurgitation in any valve at 12 months compared with baseline, was measured.

Results: At baseline, almost 80% of patients had some degree of cardiac valve regurgitation, although none was severe. The risk of developing new/worsening regurgitation in any valve at 12 months was nonsignificant and similar for the cohorts [adjusted odds ratio 0.86; 95% confidence interval (CI) 0.41–1.82; P = 0.694; relative risk 1.04; 95% CI 0.67–1.60; risk difference 0.01; 95% CI –0.13 to 0.16]. For 54% of patients, the severity of regurgitation stayed the same during the study. At baseline, significant valve regurgitation occurred in 18% of patients (lanreotide cohort) and 13% (octreotide cohort) and at 12 months in 18% of each cohort.

Conclusions: The incidence of valve regurgitation did not change over 12 months of treatment with somatostatin analogs, and most cases were physiologic or mild in severity. There was no significant difference between somatostatin analogs in the risk of developing new/worsening valve regurgitation or significant regurgitation after 1 yr.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
Acromegaly is a chronic disease characterized by excess GH and IGF-I, which, if not effectively managed by somatostatin analog treatment, results in reduced life expectancy because of cardiovascular complications (1). One study of lanreotide in patients with acromegaly noted abnormalities of cardiac valves on some echocardiograms taken to evaluate cardiomyopathy. Subsequent centralized reanalysis of all echocardiograms revealed a higher level of background valve disease than previously reported for acromegaly, although Lie (2) found morphological mitral and aortic abnormalities in 19% of a series of autopsies. In one study, a high prevalence of mitral and aortic valve dysfunction was demonstrated in patients with active or surgically cured acromegaly (3), and cardiac valve abnormalities were associated with persistence of left ventricular hypertrophy (3, 4). Patients with uncontrolled acromegaly were reported to have aggravation of mitral valve regurgitation after a median follow-up of 1.9 yr (5).

There are no large studies assessing cardiac valve regurgitation in patients with acromegaly or the effect of somatostatin analog treatment on cardiac valve disease. This prospective study was designed to compare the prevalence and incidence of new/worsening cardiac valve regurgitation over a 12-month treatment period in patients receiving either of the somatostatin analogs, lanreotide or octreotide.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

This prospective, observer-blinded, phase IV, multicenter study enrolled patients from 33 centers across 10 European countries. All patients gave written informed consent. The study (registration number NCT00234520) was approved by the institutional ethics committee of each study center and conducted in accordance with the Declaration of Helsinki, adhering to all local regulatory guidelines.

Patients were aged 18 yr or older, had been diagnosed with acromegaly, and were already receiving lanreotide or octreotide in any dose form at the selection visit or were de novo patients, i.e. had never received somatostatin analog treatment. Patients were excluded from the lanreotide cohort if they had previously received octreotide for more than 3 months and vice versa. Clinical exclusion criteria included known significant cardiac valve abnormalities before treatment and prior valve replacement surgery. Patients were matched at study entry by age, sex, and center/country/study. De novo patients were included irrespective of matching.

Lanreotide and octreotide doses had been tailored for optimal disease control as part of the patient’s normal care by their physician.

Blood samples were taken at baseline and 6 and 12 months for GH and IGF-I assessment to monitor control of acromegaly. General safety was assessed using vital signs, physical examination, standardized electrocardiography, and adverse event (AE) reporting.

Echocardiography

Heart valve function was assessed by echocardiography performed according to American Society of Echocardiography recommendations (6) at baseline and 6 and 12 months. Echocardiographic results were analyzed independently in an observer-blinded fashion at a central specialized laboratory. Valve regurgitation was classified as none, physiologic/trace, mild, moderate, or severe, depending on the extent to which retrograde flow filled the chamber (7).

Biochemical assay

A sample for IGF-I analysis was taken in the morning before each monthly injection, and IGF-I levels were assayed centrally in duplicate using a commercially available immunoradiometric kit (Nichols Institute Diagnostics, San Juan Capistrano, CA), with a lower limit of quantification of 30 µg/liter.

Statistical analyses

The intention-to-treat (ITT) population comprised all patients with an evaluable assessment of valve regurgitation at two or more time points on the same valve or an assessment of none/severe valve regurgitation at one postbaseline time point. The ITT-matched population comprised those for whom both patient and match were included.

The primary end point was the relative risk of new/worsening regurgitation in any valve at 12 months, compared with baseline for both cohorts in the ITT-matched population. This was adjusted for potentially confounding factors. Any category increase (e.g. mild to moderate) was defined as worsening, any decrease as improvement. The degree of worsening/improvement was also assessed by the category change from baseline, derived using a last observation carried forward approach.

According to published definitions (8, 9), moderate or worse-than-moderate mitral regurgitation and aortic regurgitation graded as mild or worse were classified as significant. Although no established significance levels exist for tricuspid and pulmonic regurgitation, moderate or worse regurgitation was considered significant for these valves. Secondary end points included the risk of developing new/worsening regurgitation in individual valves and the relative risk of significant regurgitation in the mitral or aortic valves at 12 months, compared with baseline for both cohorts in the ITT-matched population.

To provide a measure of disease control, IGF-I levels were reviewed according to whether a patient had new/worsening or significant valve regurgitation.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Study population

The safety population comprised 225 patients (lanreotide, n = 107; octreotide, n = 118). Eight patients in the lanreotide cohort withdrew due to AEs (n = 2), lack of efficacy (n = 2), lost to follow-up (n = 2), or other reasons (n = 2). In the octreotide cohort, 16 patients withdrew due to AEs (n = 4), lack of efficacy (n = 1), protocol deviation (n = 1), consent withdrawn (n = 7), death (n = 1), or other reasons (n = 2).

Mean age was 50.3 yr (range 24–79; ITT population). The lanreotide cohort comprised 84 previously treated patients (23 had previously received lanreotide Autogel in other clinical studies) and 12 de novo patients; for octreotide there were 87 and 13 patients, respectively. Demographic data for de novo and pretreated patients were comparable between cohorts.

Similar acromegaly disease history characteristics and GH/IGF-I levels at baseline were noted between both ITT-matched cohorts.

Valve regurgitation

The risk of developing new/worsening regurgitation in any valve at 12 months was nonsignificant and similar between cohorts [adjusted odds ratio 0.86, 95% confidence interval (CI) 0.41–1.82; P = 0.694] for the ITT-matched population. The corresponding relative risk (1.04; 95% CI 0.67–1.60) and risk difference (0.01; 95% CI –0.13 to 0.16) supported the odds ratio conclusion. Similarly, there was no significant difference between cohorts in the relative risk of developing new/worsening valve regurgitation in each heart valve at 12 months.

At baseline, the majority of patients in each cohort had valve regurgitation, but none was severe; most cases affected the mitral or tricuspid valves; fewest cases affected the aortic valve (Table 1).

For 54% of patients (88 of 164), severity of valve regurgitation remained constant throughout the study. The numbers of patients who showed worsening or improvement by one level were similar between cohorts, and the proportion of patients worsening was balanced by the proportion improving in each cohort (Fig. 1). Improvements by one level in the degree of aortic, tricuspid, and pulmonic regurgitation were noted at similar incidences in each cohort. An improvement in mitral regurgitation of one level was noted for a higher proportion of the lanreotide [20 of 75 (27%)] than the octreotide [10 of 75 (13%); P = 0.04] cohort.

View larger version (20K): [in this window] [in a new window]   FIG. 1. Worsening or improvement in valve regurgitation between baseline and 12 months in patients receiving lanreotide or octreotide in the ITT-matched population. –3, Improvement by 3 points (e.g. moderate to none or severe to physiologic); –2, improvement by 2 points; –1, improvement by 1 point; 0, did not worsen; 1, worsening by 1 point; 2, worsening by 2 points; 3, worsening by 3 points. *, Excluding patients with nonevaluable data.

At 12 months, the numbers of patients with nonevaluable data for regurgitation (ITT-matched population) were 11 (7%), 10 (6%), and 27 (16%) for the mitral, aortic, and tricuspid valves, respectively, and 86 (52%) for the pulmonic valve; proportions were similar between cohorts. Sensitivity analyses showed that the nonevaluable data did not affect study outcomes.

Valve regurgitation was analyzed by patients’ IGF-I level status at baseline and 12 months (Table 2). Control of IGF-I levels at 12 months did not appear to influence the proportion of patients reported to have new/worsening or significant valve regurgitation. Of the patients in the lanreotide cohort, 33% (7/21) and 36% (21/58) of those with high (> mean + 2 SD) or normalized ( mean + 2 SD) IGF-I levels at 12 months, respectively, experienced new/worsening valve regurgitation. Significant regurgitation occurred in 14% (3/21) and 21% (12/58) of cases, respectively. Similarly, in the octreotide cohort, 28% (7/25) and 36% (20/55) of those with high or normalized IGF-I levels at 12 months, respectively, experienced new/worsening valve regurgitation, and significant regurgitation occurred in 16% (4/25) and 18% (10/55) of cases, respectively.

Other cardiac safety outcomes

ECG results were similar for the cohorts at baseline and 12 months. The cardiac AE profile was also similar (lanreotide: 10/107 [9%]; octreotide: 9/118 [8%]). The most common cardiac AEs were first-degree atrioventricular block (lanreotide, n = 2; octreotide, n = 3) and ventricular hypertrophy (lanreotide, n = 1; octreotide, n = 2).

IGF-I response

In both cohorts, IGF-I levels decreased at 12 months compared with baseline (Table 2). Of the 32 patients in the lanreotide cohort with high (> mean + 2 SD) IGF-I levels at baseline, 12 (38%) had low or normal ( mean + 2 SD) IGF-I results at 12 months, and of the 35 patients in the octreotide cohort with high IGF-I levels at baseline, 16 (46%) had low or normal levels at 12 months. In addition, of the 47 and 45 patients with low or normal IGF-I results at baseline in lanreotide and octreotide cohorts respectively, only 1 (2%) receiving lanreotide and 6 (13%) receiving octreotide had high IGF-I levels at 12 months.

The proportions of patients with high IGF-I levels at 12 months were similar for both cohorts: 26% for lanreotide and 30% for octreotide.

Noncardiac safety outcomes

The incidence of AEs was generally similar between treatment groups, except for a lower-than-expected incidence of diarrhea in the octreotide (2/118 [2%]) compared with the lanreotide group (12/107 [11%]). Other AEs reported in more than 1% of patients were cholelithiasis (lanreotide: 3/107 [3%]; octreotide: 4/118 [3%]), abdominal pain (lanreotide: 2/107 [2%]; octreotide: 2/118 [2%]) and nausea, (lanreotide: 0; octreotide: 2/118 [2%]).

The majority of AEs were mild or moderate in severity. Only three of the 20 reported serious AEs were considered possibly related to treatment (lanreotide: colitis and aortic aneurysm; octreotide: biliary colic) and none led to withdrawal.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients with acromegaly who are not suitable for, or have had unsuccessful, surgery require life-long depot somatostatin analog treatment. Therapy is known to control GH and IGF-I excess in two thirds of patients within 12 months and causes few side effects. Although cardiovascular disease is the most common cause of death in acromegaly (1), this is the first prospective study rigorously assessing cardiac valve disease in a large cohort of patients with acromegaly undergoing echocardiography at baseline and after 6 and 12 months of lanreotide or octreotide treatment.

Consistent with previous studies (3, 4), at baseline, more than three quarters of patients in the study population had a degree of cardiac valve regurgitation, although none was severe. There was no significant difference between the groups in the risk of developing new/worsening valve regurgitation after 12 months, and incidence of valve regurgitation changed little over 12 months. For 54% of patients, the severity of valve regurgitation remained constant during the study. The numbers of patients who showed worsening or improvement by one level were similar between cohorts, and the proportion of patients worsening was balanced by the proportion improving in each cohort.

This relatively stable picture was upheld by using published criteria to define significant valve regurgitations: these criteria reflect that regurgitation in the aortic valve is of greater concern than that in the other valves. The incidence of significant regurgitations in any valve was low and was the same in both ITT-matched treatment cohorts after 12 months (18%).

Because chronic excesses of GH and IGF-I levels are known to impair cardiac morphology and performance (10, 11, 12, 13), it might be expected that patients with new/worsening or significant regurgitation would have higher mean IGF-I values. However, an exploratory analysis performed to assess whether high IGF-I levels were associated with increased incidence of new/worsening or significant valve regurgitation did not show any statistically significant differences between patients with or without new/worsening or significant regurgitation in either cohort.

The cardiac AE profile observed in this study did not indicate any differences between lanreotide and octreotide. As expected (14, 15, 16), treatment was generally well tolerated in both cohorts. The most frequently reported AE was diarrhea, although the incidence of this was lower than expected in the octreotide cohort (2%), compared with previously reported data (10% persistent abdominal symptoms) (17).

After 12 months’ treatment, mild or moderate mitral regurgitation was reported for more patients receiving lanreotide, compared with octreotide; however, a trend for this difference was already present at baseline. One study demonstrated that the prevalence of mitral, but not aortic, regurgitation is increased in patients with active acromegaly, compared with those with controlled disease (5), suggesting that the mitral valve is particularly susceptible to elevated GH/IGF-I levels and should be carefully monitored in patients with active disease.

As expected based on previous reports of imaging difficulties, approximately half (52%) of the observations for the pulmonic valve were not evaluable at 12 months, presumably because of its anterior position. This low yield was similar between groups and therefore should not have adversely affected the results.

The ethical need for active treatment in acromegaly precludes the inclusion of a true control arm in clinical studies. Therefore, from this study, we can only speculate that the lack of deterioration in cardiac valve function is due to the action of somatostatin analogs improving cardiac valve function or at least preventing further deterioration. Results from this study need to be confirmed by follow-up over a longer period.

In this large population of patients with acromegaly, nearly 80% had a degree of cardiac valve regurgitation, although none was severe. Incidence did not change over 12 months of somatostatin analog treatment, and most cases of regurgitation were physiologic or mild in severity. The proportion of patients worsening was balanced by the proportion improving in each cohort. There was no significant difference in the risk of developing new or worsening valve regurgitation or significant regurgitation after 1 yr in patients treated with either somatostatin analog.

Study group

Investigators included: A. Beckers, M. Bex, D. Maiter (Belgium); J. áp (Czech Republic); U. Feldt-Rasmussen (Denmark); T. Brue, B. Delemer, P. Emy, A. Tabarin, G. Weryha (France); K. Rácz (Hungary); P. Beck-Peccoz, E. Degli Uberti, G. Pagani, G. Tamburrano (Italy); S. Zgliczynski (Poland); J. L. Herrera Pombo, T. Lucas Morante, A. M. Pico Alfonso (Spain); L. Fredstorp, C. Høybye, G. Johannsson (Sweden); S. Atkin, P. M. Bouloux, J. Newell-Price, P. Stewart, P. J. Trainer (United Kingdom).

	Acknowledgments

 
The authors take full responsibility for the content of the paper but thank Joanna Brown, D.Phil. (supported by Ipsen) for her assistance in preparing the initial draft of the manuscript and collating the comments of authors and other named contributors. We acknowledge the additional investigators who recruited patients into the study (see Study group) as well as M. Galderisi (Italy) and P. Massabuau (France), who both provided echocardiography technical assistance.

	Footnotes

 
This work was supported by Ipsen.

Disclosure Statement: A.C. receives unrestricted grants from Ipsen and Novartis for research in neuroendocrinology; she is part of international scientific advisory boards for Ipsen and Novartis and has received honoraria as a speaker in symposia sponsored by Ipsen and Novartis in the last 5 yr. J.M. received travel grants from Ipsen, Novartis, and Pfizer in the last 5 yr. M.I.G. is supported by an OKTA grant No. K68660. P.C. is part of an international scientific advisory board for Novartis and has received honoraria as a speaker in symposia sponsored by Ipsen and Novartis in the last 5 yr. J.M.K. has received grants from Ipsen (for this study) and Novartis for research in endocrinology. F.M.M. receives unrestricted grants from Ipsen and Novartis for research in neuroendocrinology and has received honoraria as a speaker in symposia sponsored by Pfizer in the last 5 yr. N.J.W. has received a grant from Ipsen (for this study).

First Published Online April 1, 2008

Abbreviations: AE, Adverse event; CI, confidence interval; ITT, intention to treat.

Received October 2, 2007.

Accepted March 25, 2008.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Colao, A. Articles by Weissman, N. J. Search for Related Content PubMed PubMed Citation Articles by Colao, A. Articles by Weissman, N. J. Related Collections Neuroendocrinology and Pituitary Cardiovascular Endocrinology Endocrine Oncology