Dual Angiotensin Receptor-Neprilysin Inhibition With Sacubitril/Valsartan Attenuates Systolic Dysfunction in Experimental Doxorubicin-Induced Cardiotoxicity

Boutagy, Nabil E.; Fehér, Attila; Pfau, Daniel; Liu, Zhao; Guerrera, Nicole; Freeburg, Lisa; Womack, Sydney J.; Hoenes, Abigail; Zeiss, Caroline J.; Young, Lawrence H.; Spinale, Francis G.; Sinusas, Albert J.

doi:10.1016/j.jaccao.2020.09.007

Cited by 35 publications

(24 citation statements)

References 33 publications

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“…For instance, anthracycline-induced cardiomyopathy in rodents was reduced through stimulation of intracellular pathways activated by natriuretic peptides [ 17 , 18 ]. In a recent study, sacubitril/valsartan attenuated the decrease in left ventricular ejection fraction (LVEF) in a rodent model of progressive doxorubicin-induced cardiotoxicity [ 19 ]. Another in vitro study showed that administering sacubitril/valsartan during doxorubicin, trastuzumab and pertuzumab treatment prevents cardiotoxicity [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial

et al. 2021

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Background Recent advances in the treatment algorithms of early breast cancer have markedly improved overall survival. However, anthracycline- and trastuzumab-associated cardiotoxicity may lead to dose-reduction or halt in potentially life-saving adjuvant cancer therapy. Early initiated neurohormonal blockade may prevent or attenuate the cardiotoxicity-induced reduction in cardiac function, but prior studies have been inconclusive. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to be superior to traditional treatment in heart failure with reduced ejection fraction, but its cardioprotective effects in the cardio-oncology setting remains to be tested. Objective To assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction. Methods PRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations. Results The study is ongoing. Results will be published when the study is completed. Conclusion PRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy. Trial registration The trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588). Registered 30 November 2018.

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Section: Introductionmentioning

confidence: 99%

Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial

et al. 2021

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“… 23 Boutagy et al. 24 reported that sacubitril/valsartan offered greater protection against left ventricular remodeling and dysfunction by decreasing activation of matrix metalloproteinases in a rodent model of progressive doxorubicin-induced cardiotoxicity compared with standard ARB therapy.…”

Section: Discussionmentioning

confidence: 99%

“…22 Regarding the mechanisms of the benefits of sacubitril/valsartan in treating chemotherapy-induced HF, some preclinical/in vitro studies have reported their association with additional alleviation of dynamin-related protein 1-mediated mitochondrial dysfunction. 23 Boutagy et al 24 reported that sacubitril/valsartan offered greater protection against left ventricular remodeling and dysfunction by decreasing activation of matrix metalloproteinases in a rodent model of progressive doxorubicininduced cardiotoxicity compared with standard ARB therapy.…”

Section: Discussionmentioning

confidence: 99%

Time to switch angiotensin-converting enzyme inhibitors/angiotensin receptor blockers to sacubitril/valsartan in patients with cancer therapy-related cardiac dysfunction

Chen

et al. 2022

J Int Med Res

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Advances in cancer therapy have resulted in more cancer therapy-related cardiac dysfunction (CTRCD), which is the main cause of death in older female survivors of breast cancer. Traditionally, guideline-recommended medications for heart failure, such as beta-blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), are commonly used to prevent or attenuate CTRCD. However, sometimes their effectiveness is not satisfactory. Recently, the drug combination of sacubitril plus valsartan has been proven to be more beneficial for heart failure with reduced ejection fraction in the long term compared with an ACEI/ARB alone. However, there is a lack of evidence of the efficacy and safety of this drug combination in CTRCD. We report a case of worsening CTRCD, despite treatment with traditional medications, in which the patient improved after changing perindopril to sacubitril/valsartan. The patient’s heart function greatly improved after changing this ACEI to sacubitril/valsartan. Changing an ACEI/ARB to sacubitril/valsartan in patients with worsening chemotherapy-induced heart failure is appropriate. Further studies with a high level of evidence are required to assess the efficacy and safety of sacubitril/valsartan for CTRCD.

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“…Another study reported that valsartan prevented LV dysfunction at the end of the 3-week treatment of rats with DOX, but no benefit was detectable after a 2-week FU, while sacubitril-valsartan induced significant cardioprotection in both periods [52]. In the only nonrodent study [53], ANT cardiotoxicity was induced in dogs with DOX (1 mg/kg, weekly for 4 weeks), and the results were evaluated after 8 weeks of FU.…”

Section: Discussionmentioning

confidence: 99%

Primary prevention of chronic anthracycline cardiotoxicity with ACE inhibitor is temporarily effective in rabbits, but benefits wane in post-treatment follow-up

et al. 2022

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Angiotensin-converting enzyme inhibitors (ACEis) have been used to treat anthracycline-induced cardiac dysfunction, and they appear beneficial for secondary prevention in high-risk patients. However, it remains unclear whether they truly prevent anthracycline-induced cardiac damage and provide long-lasting cardioprotection. This study aimed to examine the cardioprotective effects of perindopril on chronic anthracycline cardiotoxicity in a rabbit model previously validated with the cardioprotective agent dexrazoxane with focus on post-treatment follow-up (FU). Chronic cardiotoxicity was induced by daunorubicin (3 mg/kg/week for 10 weeks). Perindopril (0.05 mg/kg/day) was administered before and throughout chronic daunorubicin treatment. After the completion of treatment, significant benefits were observed in perindopril co-treated animals, particularly full prevention of daunorubicin-induced mortality and prevention or significant reductions in cardiac dysfunction, plasma cardiac troponin T levels, morphological damage, and most of the myocardial molecular alterations. However, these benefits significantly waned during 3 weeks of drug-free FU, which was not salvageable by administering a higher perindopril dose. In the longer (10-week) FU period, further worsening of left ventricular function and morphological damage occurred together with heart failure-related mortality. Continued perindopril treatment in the FU period did not reverse this trend but prevented heart failure-related mortality and reduced the severity of the progression of cardiac damage. These findings contrasted with the robust long-lasting protection observed previously for dexrazoxane in the same model. Hence, in this study, perindopril provided only temporary control of anthracycline cardiotoxicity development, which may be associated with the lack of effects on anthracycline-induced and topoisomerase II beta-dependent DNA damage responses in the heart.

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Dual Angiotensin Receptor-Neprilysin Inhibition With Sacubitril/Valsartan Attenuates Systolic Dysfunction in Experimental Doxorubicin-Induced Cardiotoxicity

Cited by 35 publications

References 33 publications

Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial

Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial

Time to switch angiotensin-converting enzyme inhibitors/angiotensin receptor blockers to sacubitril/valsartan in patients with cancer therapy-related cardiac dysfunction

Primary prevention of chronic anthracycline cardiotoxicity with ACE inhibitor is temporarily effective in rabbits, but benefits wane in post-treatment follow-up

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