Journal of Human Hypertension (2020) 34:673–681 https://doi.org/10.1038/s41371-020-0391-8 REVIEW ARTICLE Hypertension management in cardio-oncology 1 1 1 1,2 Hani Essa ● Rebecca Dobson ● David Wright ● Gregory Y. H. Lip Received: 16 June 2020 / Revised: 8 July 2020 / Accepted: 24 July 2020 / Published online: 3 August 2020 © The Author(s), under exclusive licence to Springer Nature Limited 2020 Abstract Cancer is one of the leading causes of death worldwide. During the last few decades prognosis has improved dramatically and patients are living longer and suffering long-term cardiovascular consequences of chemotherapeutic agents. Cardiovascular disease is a leading cause of morbidity and mortality in cancer survivors second only to recurrent cancer. In some types of cancer, cardiovascular disease is a more common cause of death than the cancer itself. This has led to a new sub-specialty of cardiology coined cardio-oncology to manage this specific population. Hypertension is one of the most common cardiovascular disease seen in this cohort. The aetiology of hypertension in cardio-oncology is complex and multifactorial based on the type of chemotherapy, type of malignancy and intrinsic patient factors such as age and pre- existing comorbidities. A variety of different oncological treatments have been implicated in causing hypertension. The effect can be transient whilst undergoing treatment or can be delayed occurring decades after treatment. A tailored 1234567890();,: 1234567890();,: management plan is recommended given the plethora of agents and their differing underlying mechanisms and speed of this mechanism in causing hypertension. Management by a multidisciplinary team consisting of oncology, general practice and cardiology is advised. There are currently no trials comparing antihypertensives in this specific cohort of patients. In the absence of evidence demonstrating otherwise, hypertension in cardio-oncology should be managed utilising the same treatment guidelines for the general population. Introduction overall lifetime risk of nearly 40% of developing cancer in the US. Cancer is one of the leading causes of death worldwide. In Cardio-oncology is a relatively new clinical field focus- the United States (US) cancer is the second most common ing on the diagnosis, prevention and treatment of the car- cause of death with an estimated toll of 606,520 in 2020. diovascular consequences of cancer and its treatment. Advances in oncological treatment have led to improved Approximately 75% of cancer survivors have chronic health survival of patients with a year on year decline in mor- problems [2]. CVD is the leading cause of morbidity and tality between 1991 and 2017 in the US [1]. The increase mortality in this population second only to recurrent in cancer survivors has been accompanied by increasing malignancy [2]. The risk of CVD in cancer survivors is cardiovascular disease (CVD) morbidity and mortality 800% higher than that of the general population [2]. The due to downstream side effects of treatment and an relative risk of coronary artery disease and heart failure is increasing age of patients due to improved survival. The over 1000% more in cancer survivors as compared with overall societal burden of CVD in oncology is likely to their cancer free sibling [2]. Cancer treatments in general increase with an increasing aging population and an share various detrimental effects in common, especially upregulation of cardiovascular risk factors [3]. This can lead to both short- and long-term cardiovascular complications. The increasing recognition of this resulted in the building of the world’s first cardio-oncology unit in the MD Anderson * Gregory Y. H. Lip Center in the US in 2000. Following this, the international [email protected] cardio-oncology society was born in 2009 [4]. fi 1 Liverpool Centre for Cardiovascular Science, University of Although the eld of cardio-oncology has received Liverpool, Liverpool Heart & Chest Hospital, Liverpool, UK increasing attention in recent years, many aspects of both 2 Aalborg Thrombosis Research Unit, Department of Clinical radiation-induced and cancer drug-induced CVD are still to Medicine, Aalborg University, Aalborg, Denmark be fully elucidated. As the field advances, insights into 674 H. Essa et al. fi Cancer patients is therefore dif cult to estimate given the hetero- treatment geneity present. However, retrospective data in patients without a prior diagnosis of hypertension have demon- strated that around 33% of patients will develop hyperten- sion [8]. This is particularly more profound in patients treated with angiogenesis inhibitors, where rates of hyper- tension close to 70% have been reported with some thera- Cancer cell pies [9]. The overall lack of data in prevalence suggests widespread under-diagnosis and undertreatment [10]. Death Table 1 grades the severity of hypertension occurring secondary to anticancer therapies based on the latest Hypertension Heart failure version of US Common Terminology Criteria for Adverse Accelerated atherosclerosis Valvular heart disease Thromboembolic disease Cardiac arrhythmias Events [11]. This rating system categorises “any unfa- Pulmonary hypertension Coronary artery disease Pericardial disease vourable symptom, sign or disease associated with the use of a medical treatment or procedure that may or may Fig. 1 Cancer treatment and its stigmata on the cardiovascular system. not be considered related to or caused by the medical treatment or procedure”. This rating system is often uti- lised in analysis of hypertension secondary to oncology mechanisms of cardiovascular toxicities and hypertension treatment. have become more evident. There are currently ten main The focus of this article is to review the literature with CVD stigmata of cancer treatments, these are (Fig. 1): regards to the development and management of hyperten- sion in cardio-oncology. Specifically, the article will focus ● Left ventricular systolic dysfunction on hypertension as a consequence of cancer therapy rather ● Arterial hypertension than hypertension induced by cancer. ● Pulmonary hypertension ● Valvular disease ● Cardiac arrhythmias Aetiology of hypertension in relation to ● Thromboembolic disease oncology treatments ● Peripheral vascular disease ● Stroke Table 2 demonstrates biologically plausible pathways for ● Coronary artery disease various agents in causing hypertension. ● Pericardial disease Angiogenesis inhibitors Essential hypertension is a leading cause of morbidity and mortality worldwide. The relationship between blood Angiogenesis is an essential process in the natural course of pressure (BP) and CVD is continuous, but for the sake of cancer, as it mediates tumour growth and metastasis. pragmatism hypertension is defined by the European Angiogenesis inhibitors generally exert their effect via Society of Cardiology (ESC) as a BP ≥ 140/90 [5]. The inhibition of a component of the vascular endothelial overall prevalence of hypertension in adults is around growth factor (VEGF) signalling pathway via two main 30–45% and this increases with increasing age, with a mechanisms. The first directly inhibit VEGF ligand’s ability prevalence of >60% in people aged >60 years [6]. to bind to its target receptor and includes bevacizumab and Hypertension has been reported to be the most common ramucirumab. These medications are classified as VEGF comorbidity in cancer patients [7]. Hypertension is a well- inhibitors. The second class inhibit tyrosine kinases which recognised cause of CVD morbidity and mortality and is would be activated by the VEGF ligand–receptor interac- implicated in strokes, coronary heart disease, peripheral tions and includes agents such as sunitinib and sorafenib. arterial disease, heart failure and renal disease. These medications are classified as tyrosine kinase The relationship between hypertension and cancer is inhibitors (TKI). multifaceted. Risk factors for hypertension can be risk Angiogenesis inhibitors are a well-recognised cause of factors for specific tumours e.g. smoking and lung cancer. CVD including hypertension. All commercially available Improving cancer survival is leading to an older population angiogenesis inhibitors have been implicated in the devel- at more risk of developing hypertension. In cancer patients, opment of hypertension to varying degrees [12]. VEGF specific treatments and some cancers lead to the develop- signalling inhibitor-induced elevation in BP appears to be ment of hypertension. The prevalence of hypertension in not an adverse event of the therapy, but rather a mechanism- Hypertension management in cardio-oncology 675 Table 1 Classification of the Grade 1 2 3 4 5 severity of hypertension occurring secondary to Description Systolic BP Systolic BP Systolic BP ≥ 160 Life-threatening Death anticancer therapies in adults for 120–139 mm Hg 140–159 mm Hg or mm Hg or consequences (e.g. based on the latest version of US hypertension or diastolic BP diastolic BP 90–99 diastolic BP ≥ 100 malignant Common Terminology Criteria 80–89 mm Hg mm Hg if mm Hg; medical hypertension, for Adverse Events [11]. previously within intervention transient or normal limits; indicated; more permanent change in baseline than one drug or neurologic deficit, medical more intensive hypertensive crisis); intervention therapy than urgent intervention indicated; recurrent previously used indicated or persistent (≥24 indicated h); symptomatic increase by >20 mm Hg (diastolic) or to >140/90 mm Hg; monotherapy indicated initiated [14]. Table 3