ORIGINAL RESEARCH published: 30 November 2020 doi: 10.3389/fendo.2020.577173 Hypertension in Acromegaly in Relationship to Biochemical Control and Mortality: Global ACROSTUDY Outcomes Greisa Vila 1*, Anton Luger 1, Aart Jan van der Lely 2, Sebastian J. C. M. M. Neggers 2, Susan M. Webb 3, Beverly M. K. Biller 4, Srinivas Valluri 5 and Judith Hey-Hadavi 6 1Division of Endocrinology and Metabolism, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria, 2Pituitary Center Rotterdam, Endocrinology Section, Department of Internal Medicine, Erasmus University Medical Centre, Rotterdam, Netherlands, 3 IIB-Sant Pau and Service of Endocrinology, Department of Medicine, Centro de Investigacion Biomedica en Enfermedades Raras (CIBER-ER Unidad 747), Hospital Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain, 4 Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, United States, 5 Global Biometrics & Data Management, Pfizer Inc, New York, NY, United States, 6 Endocrine Care, Pfizer Inc, New York, NY, United States Edited by: Mô nica Gadelha, Federal University of Rio de Janeiro, Context: Hypertension is a major cardiovascular risk factor related to increased mortality Brazil in acromegaly. Surgical cure of acromegaly is associated with improvement in blood Reviewed by: pressure levels, however little is known about the effect of pegvisomant (PEGV) treatment Leandro Kasuki, in patients with hypertension. This analysis evaluates outcomes in patients with Instituto Estadual do Cé rebro Paulo Niemeyer (IECPN), Brazil hypertension and acromegaly included in ACROSTUDY. Odelia Cooper, Methods: ACROSTUDY is a global non-interventional surveillance study of long-term Cedars Sinai Medical Center, United States treatment with PEGV, monitoring its safety and efficacy. The cohort was retrospectively *Correspondence: divided in two subgroups: patients with and without hypertension. Stepwise logistic Greisa Vila regression and Kaplan-Meyer analyses were performed for testing predictors of mortality. greisa.vila@meduniwien.ac.at Results: The total cohort included 2,090 patients with acromegaly treated with PEGV Specialty section: who were followed for a median of 6.8 years (range up to 12.1 years). In ACROSTUDY This article was submitted to Pituitary Endocrinology, there were 1,344 patients with hypertension (52.3% males). This subgroup was older, had a section of the journal a higher BMI, and higher prevalence of diabetes, hyperlipidemia, and cardiovascular Frontiers in Endocrinology disease (CVD) when compared to patients without hypertension. During ACROSTUDY, Received: 28 June 2020 68 deaths were reported in the hypertension cohort, vs 10 in the cohort without Accepted: 20 October 2020 Published: 30 November 2020 hypertension. Both CVD (p<0.0001) and anterior pituitary deficiencies (p=0.0105) at Citation: study entry independently predicted mortality in patients with acromegaly and Vila G, Luger A, van der Lely AJ, hypertension; Kaplan-Meier analysis confirmed that CVD significantly impairs survival. Neggers SJCMM, Webb SM, Biller BMK, Valluri S and Hey-Hadavi J Conclusions: Hypertension is common in patients with acromegaly and significantly (2020) Hypertension in Acromegaly increases mortality, especially when there is concomitant CVD. These data suggest that in Relationship to Biochemical Control and Mortality: Global treatment goals should extend beyond IGF-I normalization, and include optimisation of ACROSTUDY Outcomes. substitution of pituitary deficiencies and scrutinous screening and treatment of CVD. Front. Endocrinol. 11:577173. doi: 10.3389/fendo.2020.577173 Keywords: hypertension, acromegaly, pegvisomant, prognosis, mortality, cardiovascular disease, hypopituitarism Frontiers in Endocrinology | www.frontiersin.org 1 November 2020 | Volume 11 | Article 577173 Vila et al. Hypertension in Acromegaly INTRODUCTION regulatory requirements; local ethical approval was obtained for each participating center and all patients were enrolled after Hypertension is a classical cardiovascular risk factor and the providing written informed consent. Patients were eligible for most prevalent cardiovascular comorbidity accompanying inclusion if they were on PEGV treatment, or if they were about acromegaly, reported in 15–60% of registry based acromegaly to start PEGV therapy. Exclusion criteria were participation in cohorts (1–7). The severity of hypertension in acromegaly is any interventional trial and/or tumor mass problems requiring related to GH-IGF-I excess, which is associated with enhanced surgical decompression. Study protocol details have been sodium- and water retention, expansion of plasma volume and described in previous publications (4, 22, 23). Importantly, increased systemic vascular resistance (8–10). decisions on acromegaly treatment were made by the Both GH hypersecretion and hypertension contribute to the investigators following the routine clinical practice of specific pathophysiology of cardiovascular changes accompanying clinics and countries. acromegaly, which include left ventricular hypertrophy, Follow-up visits were scheduled following the practice of the cardiomyopathy, valvular disease, arrhythmias, and heart treating physician, generally at least once yearly. Case report failure (5, 8). GH hypersecretion is considered the most forms were specially designed for capturing comorbidities and important causitive factor, as it has a strong impact on heart cardiovascular risk factors in addition to acromegaly-specific morphology and function, independent of blood pressure (5, 11, outcomes, and the following parameters were obtained at 12). Several studies reported that hypertension plays an additive baseline (entry in the ACROSTUDY) and during each follow- role aggravating the cardiomyopathy and increasing up visit: blood pressure, weight, height, GH, IGF-I, liver function cardiovascular risk in acromegaly (5, 13). Although cardiac tests, plasma glucose, HbA1c, comorbidities, current medication disease is highly prevalent in patients with acromegaly, with (including any changes and reasons for changing), and over 70% of cases in autopsy studies, and has even been found in information on pituitary imaging. At baseline and at each visit, asymptomatic patients, several studies have shown that the investigators were asked to confirm the presence or absence acromegaly per se is not specifically associated with an of the following cardiovascular risk factors: hypertension, increased incidence of coronary heart disease (10, 11, 14). smoking, obesity, diabetes, hyperlipidemia, as well as the Nevertheless, the atherogenic effects of most acromegaly presence of cardiovascular and cerebrovascular diseases. comorbidities such as hypertension, insulin resistance, diabetes, hyperlipidemia and sleep apnea, as well as the acromegaly Mortality cardiomyopathy, all contribute to the increased incidence of For the present study, we evaluated data from the 2nd interim cardiovascular and cerebrovascular diseases in this population analysis database freeze on the 12th of May 2016, which included (8, 10, 15). 2090 patients followed up for a median of 6.8 years with a Acromegaly is also associated with an excess in mortality, maximum of 12.1 years (23). Data on mortality during the study predominantly due to cardiovascular and cerebrovascular period were obtained from the adverse report forms, which were diseases, and several studies have confirmed that normalisation evaluated by two independent researchers for verifying the cause in GH/IGF-I ameliorates and even nearly normalizes mortality of death given by the investigator. rate (16–18). Mortality in patients with acromegaly is directly associated to IGF-I concentrations, older age, the presence of Hypertension Group hypertension and duration of symptoms prior to diagnosis (13, For this analysis, patients were retrospectively divided in two 19). Therefore, the optimal management of acromegaly includes cohorts: Hypertension and Normotension. Patients were the normalisation of GH/IGF-I levels and disease symptoms, as included in the Hypertension group if they were identified to well as the evaluation and treatment of comorbidities, aiming at have hypertension at any visit during the ACROSTUDY. The reducing morbidity and mortality (20, 21). presence of hypertension was determined when at least one of Here we prospectively studied patients with acromegaly the following three was present: 1) hypertension listed as included in ACROSTUDY™ receiving pegvisomant, aiming at comorbidity by the investigator, 2) antihypertensive characterising the cohort of patients with hypertension, their medication was used and 3) systolic blood pressure was biochemical control, comorbidities, and factors related >140 mm Hg and/or diastolic blood pressure was >90 mm Hg. to mortality. Comorbidities The presence of comorbidities at ACROSTUDY entry was evaluated by asking the investigators to fill in the study report PATIENTS AND METHODS form with “yes” or “no” for the presence of diabetes, hyperlipidemia, coronary heart disease, coronary angioplasty Study Protocol with or without stent implantation, coronary artery bypass ACROSTUDY™ is a global non-interventional surveillance surgery, arrhythmia, heart failure, myocardial infarction, study of long-term treatment with pegvisomant established in transient ischemic attack, cerebrovascular event, sleep apnea, 2004 for evaluating outcomes in patients with acromegaly (22, other respiratory disease, liver disease, gallstones, and cancer. 23). The study prospectively recruited patients in 204 centers Diabetes was diagnosed if at least one of the following was from 15 countries and adhered to all applicable local laws and present: 1) diabetes given as a comorbidity by the investigator, 2) Frontiers in Endocrinology | www.frontiersin.org 2 November 2020 | Volume 11 | Article 577173 Vila et al. Hypertension in Acromegaly concomitant intake of antidiabetic medication and 3) HbA1c assessed at all visits through case report forms and spontaneous ≥6.5% (48 mmol/mol), or random glucose >200 mg/dl (11.1 reports. Adverse events data were coded using the current mmol/L) as previously described (24). Hyperlipidemia was MedDRA version available at the time of reporting. All diagnosed if at least one of the following was present: 1) statistical analyses are performed using SAS version 9.4 (25). hyperlipidemia given as comorbidity by the investigator, 2) concomitant intake of lipid-lowering drugs. Patients were considered to have cardiovascular disease (CVD) RESULTS at baseline if any of the following was reported at ACROSTUDY entry: left ventricular hypertrophy, cardiomyopathy, aortic valvular Here we analyse data from 2,090 patients followed for a median disorders, mitral valvular disorders, tricuspid valvular disorders, of 6.8 years (range up to 12.1 yrs), in total, 7,687.5 patient years arrhythmias, myocardial ischaemia, myocardial infarction, heart (Figure 1). Data on acromegaly treatment outcomes were failure, cerebrovascular accident, transient ischaemic attack, already reported previously (23). haemorrhagic stroke and ischaemic stroke. Characteristics of the Statistical Analysis Hypertension Cohort Continuous measurements were summarized using descriptive The prevalence of hypertension in the ACROSTUDY cohort was statistics and discrete data by counts. Demographic and co- 56% at study entry and increased to 64% during the follow-up morbidities of acromegaly patients enrolled in the study are period, with 182 newly diagnosed patients with hypertension summarized descriptively by hypertensive and normotensive during the study (Figure 1). For this analysis, the entire groups. As this is a non-interventional study, all tests of ACROSTUDY population was divided in two groups: 1) significance provided (eg., p-values) are exploratory, not patients with hypertension at any time during the study (64% definitive and post-hoc in nature and should be interpreted of patients) and 2) patients with normotension at any time with caution. Stepwise logistic regression for mortality was during the study (36% of patients). Baseline demographic performed using independent predictors of demographic, characteristics of the cohorts with and without hypertension clinical and co-morbid risk factors. Odds ratios and 95% are shown in Table 1. At study entry, patients belonging to the confidence intervals for them are also provided. Kaplan-Meier hypertension group were older at initial diagnosis of acromegaly, analyses were performed for the significant predictors of older at study entry, had higher BMI and a higher prevalence of mortality and survival from the stepwise logistic regression all cardiovascular risk factors (Table 1). In addition, patients analysis for the total cohort of patients and within the with hypertension had significantly more pituitary deficiencies hypertensive sub-cohort. and received less pituitary surgery (Table 1). Patients who For the purposes of statistical analyses, baseline was defined started PEGV ≥5 years after diagnosis had a higher prevalence as the start of PEGV therapy upon entry in the ACROSTUDY. of hypertension. At baseline and at year 5, the average blood For adverse event (AE) reporting, including serious adverse pressure reduced from 137/84 to 134/81 mmHg in Hypertension events (SAEs), death and laboratory results, safety data were and 122/76 to 120/75 mmHg in Normotension groups, FIGURE 1 | ACROSTUDY flow chart. Frontiers in Endocrinology | www.frontiersin.org 3 November 2020 | Volume 11 | Article 577173 Vila et al. Hypertension in Acromegaly TABLE 1 | Differences in baseline characteristics, comorbidities and pituitary disease between patients with and without hypertension. Acromegaly Control Rates in the Hypertension Cohort Hypertension Normotension P-value At entry into the ACROSTUDY, IGF-I values evaluated as fold- n=1344 n=746 ULN were similar in both groups (Table 1). During the follow- Patient characteristics up period, the percentages of patients with IGF-I within the Age at diagnosis of acromegaly 46.0 (13.1) 37.1 (12.4) <0.0001 normal range continously increased in both groups, changing (years) from 52.2 to 59.5% in the Hypertension group and from 54.6 to Age at PEGV start (yrs) 53.9 (12.9) 44.0 (13.6) <0.0001 69.3% in the Normotension group, but were significantly higher Gender 47.7% ♀ 50.7% ♀ 0.1723 Ethnicity 92.9% 93.1% 0.1428 in the Normotension group when compared to the Hypertension caucasian caucasian group 1–5 years after starting PEGV (p<0.001 (Figure 2). CV risk factors and comorbidities Hypertensive patients received significantly higher PEGV doses Age at ACROSTUDY start (years) 55.6 (12.9) 45.6 (13.7) <0.0001 (p=0.014) for the first five years after the start of Somavert BMI (kg/m2) 30.5 (5.4) 28.3 (4.9) <0.0001 therapy ranging from 15 to 18.3 mg/day, when compared to 13.5 Smoking 27.7% 24.9% <0.0001 Cardiovascular disease 7.4% 2.5% <0.0001 to 16 mg/day in the Normotension group. Diabetes 20.2% 11.4% <0.0001 Hyperlipidemia 17.0% 5.6% <0.0001 Mortality in the Hypertension Cohort Pituitary disease All adverse effects observed in ACROSTUDY are shown in Table Pituitary surgery 73.7% 82.7% <0.0001 2. They were also previously reported for the overall population Radiotherapy 30.9% 30.8% 0.9606 Pituitary deficiencies 53% 47% 0.0224 by Buchfelder et al. (23). A total of 78 deaths (56% in males) were ACTH deficiency 24% 23% 0.7078 observed: 68 in the Hypertension group (5.1%) and 10 in the Baseline IGF-I (µg/L) 364 (283) 387 (278) 0.3265 Normotension group (1.3%), and mortality rate was 13.2 per IGF-I > ULN 88.9% 87.4% 0.3924 1,000 patient years in the Hypertension group and 4 per 1,000 IGF-I (foldULN = IGF-I/ULN) 1.54 (1.11) 1.39 (0.87) 0.0841 patient years in the Normotension group. The causes of death Data are shown as mean (SD) or percentage. CV, cardiovascular; CVD, cardiovascular were predominantly cardiovascular (31%), cerebrovascular disease; IGF-I, insulin-like growth factor-I; PEGV, pegvisomant; ULN, upper limit of normal. (18%), cancer (18%) and respiratory problems/sepsis (13%). For further analysis, both cardiovascular and cerebrovascular respectively. 20.4% of patients receiving PEGV monotherapy, causes of death are classified as cardiovascular deaths, and 19.7% of patients receiving PEGV + somatostatin receptor included cardiac arrest, ventricular fibrillation, myocardial ligands (SRL), 20.7% of patients receiving PEGV + dopamine infarction, heart failure, aortic aneurysm rupture, cardiogenic agonists (DA) and 24.1% of patients receiving tripple therapy shock, bilateral massive pulmonary embolism, stroke/ (PEGV + SRL + DA) developed novel hypertension during the cerebrovascular accident, basilar vein thrombosis and observation time in ACROSTUDY. subarachnoidal haemorrhage. The most common cause of A B FIGURE 2 | Number and proportion of patients with normal IGF-I (bar charts) and respective PEGV (pegvisomant) dose (blue boxes) in the subcohorts of patients with (A) and without (B) hypertension. Frontiers in Endocrinology | www.frontiersin.org 4 November 2020 | Volume 11 | Article 577173 Vila et al. Hypertension in Acromegaly TABLE 2 | Adverse events in patients with and without hypertension. Hypertension cohort, 34% of patients who died had already been Hypertension Normotension diagnosed with CVD at study entry. In the cohort of N (%) N (%) hypertensive patients who survived, CVD was present in less then 6%. Pituitary deficiency was present in 72% of hypertensive Adverse effects (AEs) patients who died, and in 51% of survivors. Traditional Subjects with AEs (all cause) 773 (57.5%) 364 (48.8%) Subjects with treatment-related AEs 206 (15.3%) 131 (17.6%) cardiovascular risk factors such as smoking, BMI and gender Serious adverse effects (SAEs) were not associated to mortality in acromegaly patients Subjects with SAEs (all cause) 343 (25.5%) 116 (15.5%) with hypertension. Subjects with treatment-related SAEs 35 (2.6%) 14 (1.9%) To further explore the importance of CVD and pituitary Deaths (all non-treatment related) 68 (5.1%) 10 (1.3%) deficiencies on mortality, we performed a Kaplan-Meyer analysis Drugs withdrawn due to SAEs Discontinued due to SAEs 116 (8.6%) 30 (4%) testing the differences in survival curves between hypertensive Discontinued due to treatment-related SAEs 19 (1.4%) 5 (0.7%) patients with and without pituitary deficiencies and CVD (Figure 3). Survival in patients with acromegaly and Data are shown as total numbers and respective percentages. Treatment=Pegvisomant. hypertension was not significantly influenced by concomitant death due to CVD was heart failure, which accounted for 9 cases. hypopituitarism (Figure 3A). The presence of CVD led to a Age of death ranged from 35.6 to 88.6 years (mean 68.4 years, SD remarkable reduction in survival (Figure 3B). 12.4). Two deaths occurred before the age of 40 and were caused by ventricular fibrillation in one patient and aortic aneurysm rupture in the other. Female patients died at an older age, with a DISCUSSION mean age at death of 71.8 years (SD 13.2) for females and 65.9 years (SD 11.3) for males. No gender differences were observed in Previous studies have identified hypertension as an independent the distribution of causes of death. factor related to an increased mortality in patients with For identifying which factors influenced the increased acromegaly (13, 26). Here we report the data from a large mortality in the hypertension cohort we performed a international cohort study of patients with a long history of univariate analysis testing the relationship between mortality acromegaly, necessitating long-term acromegaly-specific and baseline factors obtained at the ACROSTUDY entry visit. therapies. We observed a high prevalence of hypertension, Older age, the concomitant presence of pituitary deficiencies, which increases during the follow-up period, as patients get diabetes, hyperlipidemia, and CVD were all significantly related older. In this cohort, the presence of hypertension is associated to mortality (Table 3). Gender, BMI, smoking habits and IGF-I with ageing and with a higher prevalence of diabetes, levels were not associated with mortality. hyperlipidemia and other cardiovascular risk factors. After five Using step-wise logistic regression analyses with all-cause- years, blood pressure values decreased in the whole mortality as the outcome measure, we found that only age at ACROSTUDY cohort. In the subgroup of patients with diagnosis of acromegaly, the presence of CVD and pituitary acromegaly and hypertension, the presence of CVD was the deficiencies independently predicted mortality (Table 3). In the most robust independent predictor of mortality in both logistic regression and Kaplan-Meier analysis. Improvements in glucose metabolism and blood pressure TABLE 3 | Factors related to mortality in hypertensive patients with acromegaly. observed after successful treatment interventions of acromegaly Odds 95% confidence P-value with PEGV corroborate a direct link between GH-IGF-I excess Ratio limits for Odds and hypertension and diabetes (6, 15, 24, 27, 28). Indeed, long- Ratio term excess in GH/IGF-I plays an important role in the Univariate analysis development of hypertension, insulin resistance, diabetes and Age at diagnosis of acromegaly 1.008 0.982 1.034 <0.0001 obesity, which in turn also impact each other (8, 10, 15). As (years) PEGV is commonly used as a second- or third-line therapy in Age at ACROSTUDY start (yrs) 0.868 0.767 0.982 0.0247 Gender 0.797 0.487 1.304 0.3662 acromegaly, most patients included in ACROSTUDY were either BMI 0.972 0.929 1.016 0.2105 not adequately controlled with other treatment modalities or Smoking 0.963 0.568 1.633 0.8895 could not receive/tolerate other treatments. This may explain Diabetes 0.558 0.342 0.910 0.0194 why ACROSTUDY patients were older and had active disease Hyperlipidemia 3.263 1.014 10.500 0.0474 longer than other cohorts studied to date; this may also be the Cardiovascular disease 0.124 0.071 0.215 <0.0001 IGF-I at study entry (µg/L) 1.001 0.999 1.002 0.3252 reason that the ACROSTUDY population had a higher IGF-I at last visit (µg/L) 0.999 0.997 1.001 0.1997 prevalence of acromegaly-associated comorbidities at baseline Pituitary deficiencies 0.415 0.242 0.714 0.0015 when compared to other cohorts (4, 22, 23). The long follow-up ACTH deficiency 0.652 0.401 1.060 0.0844 period in the study extending to up to 12.2 years allowed us to Step-wise logistic regression analysis identify a large number of patients with hypertension, which Age at diagnosis of acromegaly 0.931 0.906 0.958 <0.0001 (years) reached 1,344 patients (64% of the cohort) at the time of the Cardiovascular disease 0.145 0.068 0.308 <0.0001 study data freeze for the second interim analysis. The high Pituitary deficiencies 0.378 0.179 0.796 0.0105 prevalence of arterial hypertension in the ACROSTUDY Frontiers in Endocrinology | www.frontiersin.org 5 November 2020 | Volume 11 | Article 577173 Vila et al. Hypertension in Acromegaly A B FIGURE 3 | Kaplan Meier plot survival curves in patients with acromegaly and hypertension in relation to the presence of (A) pituitary deficiencies and (B) cardiovascular disease at baseline visit (ACROSTUDY entry). cohort, which has a high frequency of IGF-I normalization, and the most significant difference was the fact that patients with its relationship to age, higher BMI, smoking and other hypertension had undergone significantly less pituitary surgery. comorbidities, corroborates the multifactorial pathophysiology Although the reason for this was not captured, it may be related of hypertension in patients with acromegaly, comparable to the to the older age and multiple comorbidities found in the general population. To our knowledge, this is the largest cohort hypertensive population and is in agreement with previous of patients with acromegaly and hypertension studied to date. reports on acromegaly in older patients (30). Based on already published reports and our clinical At entry in ACROSTUDY the prevalence of CVD reported in experience, hypertension in acromegaly is usually not very the sub-cohort of patients with acromegaly and hypertension severe, and can be effectively controlled with available was 7.4%. Cardiac disease in acromegaly was found by other antihypertensive medications (6). This is also confirmed by our investigators to depend on the amount and extent of GH observations on a small decrease in blood pressure values during hypersecretion, and was often partly reversible after ACROSTUDY. Nevertheless, hypertension plays an important normalization of GH levels via surgery or by blocking GH pathophysiological role in the development of acromegaly- action via PEGV (31). Hypertension plays an additive role, associated comorbidities, such as insulin resistance, diabetes aggravating GH/IGF-I-induced heart disease (5). A previous and CVD (6, 8). Indeed, in the present study we found study specifically analyzing all acromegaly patients for the significantly higher PEGV doses in patients with hypertension. presence of CVD reported that all patients with hypertension The main reasons for this might be the larger prevalence of and diabetes had echocardiographic abnormalities (8). In clinical diabetes and the higher BMI in patients with hypertension and practice, testing for the presence of CVD necessitates referrals to acromegaly, when compared to patients without hypertension, as other specialists and is not systematically done by the internist/ the presence of diabetes necessitates higher PEGV doses for endocrinologist. Patients with acromegaly were found to have achieving biochemical control (29). In terms of pituitary disease, morphological cardiac disease in the absence of signs and Frontiers in Endocrinology | www.frontiersin.org 6 November 2020 | Volume 11 | Article 577173 Vila et al. Hypertension in Acromegaly symptoms. So we cannot exclude that clinically silent but DATA AVAILABILITY STATEMENT functional or morphological CVD might be underdiagnosed in our population. Our data show that the prevalence of reported Upon request, and subject to certain criteria, conditions, and CVD in the subcohort of patients with acromegaly and exceptions (see https://www.pfizer.com/science/clinical-trials/ normotension is not higher than in the general normotensive trial-data-and-results for more information), Pfizer will provide population, while the prevalence of reported CVD in patients access to individual de-identified participant data from Pfizer- with acromegaly and hypertension is similar to the general sponsored global interventional clinical studies conducted for population with well-treated hypertension (32). This evidence medicines, vaccines, and medical devices (1.) for indications that supports the fact that arterial hypertension appears to be the have been approved in the US and/or EU or (2.) in programs that main factor contributing to the development of CVD in this have been terminated (i.e. development for all indications has cohort of patients with acromegaly, who have a high frequency of been discontinued). Pfizer will also consider requests for the IGF-I normalization. In addition, our data are in line with recent protocol, data dictionary, and statistical analysis plan. Data may studies finding a lower frequency of CVD in acromegaly than be requested from Pfizer trials 24 months after study completion. described in older cohorts, mainly attributed to better disease The de-identified participant data will be made available to control due to novel treatment modalities (10). researchers whose proposals meet the research criteria and The current guidelines for diagnosing and treating other conditions, and for which an exception does not apply, acromegaly promote screening all patients for the presence of via a secure portal. To gain access, data requestors must enter comorbidities, including CVD (20). Mortality in acromegaly has into a data access agreement with Pfizer. improved during the last decades and is considered to be similar to the normal population in well-controlled patients, and this is linked to the lower prevalence of CVD (10, 18, 33). Here we show that the presence of hypertension is associated with a 3.3 fold ETHICS STATEMENT increased mortality rate in patients with acromegaly, The studies involving human participants were reviewed and nevertheless mortality rate in the cohort of patients with approved by Ethics Committee of the Medical University of acromegaly and hypertension appears similar to the mortality Vienna and local Ethics Committees in each participating center. rate of the general population with hypertension (34). The patients/participants provided their written informed The strength of the present study is the prospective design for consent to participate in this study. capturing acromegaly comorbidities, and the inclusion of a large number of patients with uncontrolled acromegaly, which led to a high number of comorbidities and mortality events. Additional strengths are the long-term follow up, the real-world setting with AUTHOR CONTRIBUTIONS inclusion of patients that may not have been enrolled in clinical trials. Limitations include the retrospective classification of JH-H and GV conceived this study, which was approved by the Hypertension or Normotension groups, the investigator-based ACROSTUDY steering committee. All authors critically revised definition of cardiovascular disease, the lack of information on the study protocol. SV, JH-H, and GV collected and analyzed the how adequately pituitary deficiencies were treated and the fact data. GV wrote the initial version of the manuscript. All authors that all patients were on PEGV, so there was no treatment contributed to the article and approved the submitted version. comparator group. Additional strengths/limitations of ACROSTUDY overall were described in the previous publication (23). Taken together, here we report data on a very large cohort of FUNDING patients with acromegaly and hypertension, describing a higher ACROSTUDY was sponsored by Pfizer. prevalence of other comorbidities and cardiovascular risk factors and a 3.3 fold increased mortality when compared to patients with acromegaly without hypertension. Our findings indicate that hypertension significantly increases mortality in patients ACKNOWLEDGMENTS with acromegaly, especially in the presence of concomitant CVD, highlighting the importance of testing for and treating cardiac We thank all patients, study nurses and coordinators, as well as disease in hypertensive patients with acromegaly. all investigators, who participated in ACROSTUDY. REFERENCES 2. Arosio M, Reimondo G, Malchiodi E, Berchialla P, Borraccino A, De Marinis L, et al. Italian Study Group of Acromegaly. Predictors of morbidity and 1. 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Dekkers OM, Biermasz NR, Pereira AM, Romijn JA, Vandenbroucke JP. Chiasma and Novartis, and consultancy- and/or speakers fees from Pfizer, Mortality in acromegaly: a metaanalysis. J Clin Endocrinol Metab (2008) Novartis and Ipsen. AL has received lecture and/or consulting honoraria from 93:61–7. doi: 10.1210/jc.2007-1191 Ipsen, Novartis, and Pfizer; research grants to the Medical University of Vienna 18. Bolfi F, Neves AF, Boguszewski CL, Nunes-Nogueira VS. Mortality in from Ipsen and Pfizer. AJL has received grants, consultancy- and speaker’s fees acromegaly decreased in the last decade: a systematic review and meta- from Pfizer. SN has received research grants and speaker fees from Ipsen, Novartis, analysis. Eur J Endocrinol (2018) 179:59–71. doi: 10.1530/EJE-18-0255 and Pfizer, and consulting fees from Ipsen. SW has received honoraria as a 19. Tritos NA, Mattson AF, Vila G, Biller BMK, Klibanski A, Valluri S, et al. All- member of the Acrostudy Advisory Board, and lecture fees from Pfizer, Novartis cause mortality in patients with acromegaly treated with pegvisomant: an and Ipsen. BB has served as PI of research grants from Novartis, Crinetics and ACROSTUDY analysis. Eur J Endocrinol (2020) 182:285–92. doi: 10.1530/ Ionis to Massachusetts General Hospital and has received occasional consulting EJE-19-0794 honoraria from Novartis, Crinetics and Pfizer. SV and JH-H are Pfizer employees. 20. Katznelson L, Laws ERJr, Melmed S, Molitch ME, Murad MH, Utz A, et al. Endocrine Society. Acromegaly: An Endocrine Society Clinical Practice Copyright © 2020 Vila, Luger, van der Lely, Neggers, Webb, Biller, Valluri and Guideline. J Clin Endocrinol Metab (2014) 99:3933–51. doi: 10.1210/jc.2014-2700 Hey-Hadavi. This is an open-access article distributed under the terms of the Creative 21. Melmed S, Bronstein MD, Chanson P, Klibanski A, Casanueva FF, Wass JAH, Commons Attribution License (CC BY). The use, distribution or reproduction in et al. A Consensus Statement on acromegaly therapeutic outcomes. Nat Rev other forums is permitted, provided the original author(s) and the copyright owner(s) Endocrinol (2018) 14:552–61. doi: 10.1038/s41574-018-0058-5 are credited and that the original publication in this journal is cited, in accordance 22. Brue T, Castinetti F, Lundgren F, Koltowska-Häggström M, Petrossians P. with accepted academic practice. No use, distribution or reproduction is permitted ACROSTUDY investigators. Which patients with acromegaly are treated with which does not comply with these terms. Frontiers in Endocrinology | www.frontiersin.org 8 November 2020 | Volume 11 | Article 577173