The interactions between antihypertensive drugs and novel anticancer therapy.

A nticancer therapy significantly developed over last 2 decades which significantly prolonged life of cancer patients, but also revealed new issue – a broad spectrum of toxicity reactions of which cardiotoxicity has the most important role in prognosis of cancer patients, aside to their primary disease. The revolution in anticancer therapy was achieved by immune checkpoint inhibitors (ICIs), which made a revolution in treatment of various hematologic and solid cancers (nonsmall-cell lung cancer, renal-cell carcinoma, melanoma, hepatocellular carcinoma, malignant pleural mesothelioma, colorectal cancer). Several ICIs have been developed to restore the T-cell-mediated immune response and improve the efficacy of antitumor treatments: inhibitors of the programmed cell death protein 1 (nivolumab and pembrolizumab), inhibitors of programmed cell death-ligand 1 (atezolizumab, avelumab and durvalumab), and inhibitors of cytotoxic T lymphocyte-associated antigen-4 (ipilimumab and tremelimumab). Immune-mediated toxicities may affect any organ or tissue including the skin, endocrine or gastrointestinal system, lung, liver or heart. The majority of these side effects can be controlled by glucocorticoid therapy [1]. ICIs can be associated with myocardial damage (myocarditis, heart failure, infarction, Takotsubo syndrome), pericardial disease (pericarditis, effusion, tamponade), arrhythmias and vascular injury [2]. A SEER-medicare study included 5730 patients who received chemotherapy and 675 patients who received chemotherapy and ICIs [3]. Findings showed that overall cardiovascular toxicity was significantly lower in ICIstreated patients than in participants with chemotherapy. The risk for heart failure, cardiac arrhythmia and heart blocks was significantly lower among cancer patients treated with ICIs than those who received chemotherapy [3]. There was no difference in acute coronary syndrome, cardiomyopathy, pericarditis and myocarditis between the two cohorts [3]. Patients older than 75 years, with comorbidities and preexisting heart disease, were at higher risk for cardiovascular toxicity. These results show that the addition of ICI therapy to chemotherapy is safe and does not increase, but in fact decrease, cardiotoxicity in cancer patients [3]. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-II receptor blockers (ARB) alone or in combination with beta-blockers are recommended for treatment of anticancer therapy-induced cardiac damage or for cardiac protection during anticancer treatment [4]. However, effect of ACEI/ARB during ICI therapy is controversial because these agents may favor a proinflammatory state within the tumor, which induces an immunosuppressive milieu [5]. Recently published animal study showed that captopril therapy moderates the immune response by infiltration and modification the phenotypical composition of T lymphocytes and may be an important additional mechanism for tumor control [6]. Captopril significantly decreased tumor viability and slowed growth of colorectal liver metastases in mice. Therefore, the concomitant use of ACEI/ARB might enhance the therapeutic efficacy of ICI. Study that investigated the effect of concomitant ACEI and ICIs treatment showed worse outcome in patients with advanced nonsmall-cell lung cancer [7]. This association was independent of typical prognostic factors. This underlined an immunosuppressive state in ACEI group. In the current issue of the Journal, Kichenadasse et al. [8] reported that concomitant use of antihypertensive patients including ACEI and ARB was not related with survival and immune-related safety outcomes during ICI (atezolizumab) therapy for solid cancers. The authors included 3695 cancer patients from seven published trials of whom 2539 were treated with atezolizumab and the rest with chemotherapy. There was no difference in overall survival (OS), progression-free survival or immune adverse events between atezolizumab-managed patients who were not treated with antihypertensive medication or concomitantly treated with ACEI/ARB [8]. Other classes of antihypertensive patients were also not related with survival. Potential confounding variables (age, sex, race, performance status, BMI, the number of sites of tumor metastases, comorbidities – diabetes, cardiovascular disease, hypertension and renal failure) were included in multivariable analysis. The Journal of Hypertension 2021, 39:1303–1305 Department of Cardiology, University Clinical Hospital Center ‘Dr Dragisa MisovicDedinje’, Belgrade, Serbia and Clinica Medica, University of Milan-Bicocca, Milan, Italy