Disclaimer. The only uniformly effective treatment for ACE inhibitor-induced cough is the cessation of treatment with the offending agent. Blood pressure (BP) was equally well controlled with both medications. Cough is thought to originate from multiple mechanisms, bradykinin theory is the most commonly appealed hypothesis. Angiotensin-Converting Enzyme Inhibitor-Induced Cough: 62. Recent studies have shown improvements in QOL measures in patients switched from other classes of antihypertensive agents to ARBs. HHS Vulnerability Disclosure, Help Angioedema in the mouth or upper airways is a feared adverse reaction to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, which is used for . 2017;96(9):575-580. Expert Opin Pharmacother. 12. Effectiveness and adherence to treatment with perindopril/indapamide/amlodipine single-pill combination in a Greek population with hypertension. 2006;116(12):2108-2112. doi: 10.1097/01.mlg.0000244377.60334.e3, 30. Eur Respir J. Angioedema is a rare but potentially fatal side effect of ACEI therapy that is reported less frequently in patients using ARBs. 2000;34:526-528. Halum SL, Sycamore DL, McRae BR. Genome-wide association study of angioedema induced by - Nature Tolerability and Quality of Life in ARB-treated Patients - AJMC 2014;192(1):75-85. doi: 10.1007/s00408 013-9508-y, 7. Drug-induced chronic cough and the possible mechanism of action 7. The most common AEs included headache, dizziness, fatigue, andsomnolence.65,66, Other Agents Considered for Chronic CoughTreatment, Several other agents, such as esomeprazole, erythromycin, and ipratropium bromide, have been evaluated by CHEST guidelines for patients with chronic cough.2 However, due to various factors including small sample size, lack of results replication, and lack of efficacy, among others, they are not currently recommended for the treatment of chronic cough.2 Multiple other therapies are in various stages of investigation for their utility in the treatment of chronic cough, including TRPV4 antagonists, voltage-gated sodium channel blockers, -aminobutyric acid (GABA) B receptor agonists, nicotinic acetylcholine receptor 7-subunit agonists, and inhaled sodium cromoglycate.19. If a specific etiology is discovered, that condition should be optimally treated first before treating the chronic cough. TRPA1 is an environmental-sensing member of the transient receptor potential channel family.19 This channel family is activated by cold temperature (<17 C), cigarette smoke, cinnamaldehyde, acrolein, and other various cough irritants.36 Cold air is a common trigger observed clinically among patients with chronic cough, leading to optimism for this potential therapeutic target.37-39 An early-phase clinical trial investigating the potent TRPA1 antagonist GRC 17536 did not demonstrate a clinical benefit compared with placebo in patients with RCC.40 At the current time of writing, there are no other TRPA1 antagonist clinical trials underway within the United States. eCollection 2022. Respir Med. Updates in Treatment of Adults With Chronic Cough - AJMC 1. There is an inconclusive debate for selecting RAAS inhibitors, ACEI or ARBs based on the available evidence. 1995 Nov;40(5):423-9. Intern Med J. However, studies have reported disappearance of cough despite continuing treatment. Chest. Smith JA, Woodcock A. https://www.nice.org.uk/guidance/ng136/resources/hypertension-in-adults-diagnosis-and-management-pdf-66141722710213. Download PDF: Tolerability and Quality of Life in ARB-treated Patients, Hypertension in America: Overcoming Barriers to Blood Pressure Control. Cross-Reactivity of ACE Inhibitor-Induced Angioedema with ARBs Insights from 254,301 patients from randomized trials. Accessed September 9, 2020. clinicaltrials.gov/ct2/show/NCT02993822, 65. Effects of modulators of the renin-angiotensin-aldosterone system on cough. 2015;385(9974):1198-1205. doi:10.1016/s0140-6736(14)61255-1, 43. 2000;13(4 pt 1):418-426. Vasotec (enalapril) According to the pre-market studies, 2.5% of people treated with lisinopril for hypertension (high blood pressure) reported coughing as a side effect. There were 68 patients enrolled in the trial, and 52 completed the dosing trial.49 Topline results from the RELIEF trial are expected to be released sometime in 2020.52, The trial evaluating S-600918 is a phase 2b trial that is actively recruiting patients to determine the optimal dose of S-600918 in patients with RCC via a change in baseline in 24-hour cough frequency compared with placebo. The SAVE Investigators. Etiologic and physiopathologic aspects. Otsuka K, Niimi A, Matsumoto H, et al. 2004;8:1-14. Chronic Cough Guidelines for Adult Patients, Currently, 2 major treatment guidelines address the medical management of RCC and UCC: those of the American College of Chest Physicians (ACCP or CHEST) and the European Respiratory Society (ERS).2,3 Both guidelines recommend a thorough history and physical when evaluating patients who present with chronic cough.2,3 A CHEST guideline and expert panel also recommend focusing on the identification of red-flag symptoms (see Table14) and ruling out other conditions that either commonly or more rarely result in chronic cough.4, CHEST guidelines recommend that individuals with a known cause of their chronic cough have their therapy optimized for each diagnosis.2,3 Patients need to be assessed for adherence regularly, with frequent follow-up to monitor for barriers, efficacy of treatment, cough severity, and QOL. Sebastin G.Z., Roberto P. Cough and angioedema in patients receiving angiotensin-converting enzyme inhibitors. 2015 Dec;26(8):678-85. doi: 10.1097/MCA.0000000000000303. Lancet Respir Med. Goto N., Shirahase M., Hatta H. Influence of type of questionnaire on the prevalence of coughing in patients taking angiotensin converting enzyme inhibitors (ACEI). 2011;24(3):280-285. doi: 10.1016/j.pupt.2010.12.003, 34. Am J Respir Crit Care Med. The medicine relaxes blood vessels, so blood flows more freely. Chronic cough is a severely debilitating condition that results in individuals coughing hundreds to thousands of times per day. Cough induced by losartan with resolution after substitution with 2007;62(6):491-495. doi:10.1136/thx.2006.063982, 60. Gastroesophageal symptoms typically respond within 4 to 8 weeks but may take up to 3 months. Dry cough is a well known side effect of ACE inhibitors due to inhibition of metabolism of bradykinin and kallikren system by the same enzyme which converts Angiotensin I into Angiotensin II. Cough: Diagnosis and Management | AAFP 11 The incidence of ARB-induced cough is much lower (3.2% in controlled trials and 0.6% in cohort studies). Angiotensin-Converting Enzyme Inhibitors vs. Angiotensin - AAFP FOIA Recent advancements in the understanding of the chronic cough reflex and suspected neurobiology have led to the development of novel therapeutic targets to bridge this unmet treatment need. In their study, Ravid etal reported that the incidence of ACEI-induced cough was higher in HF patients compared to in those with hypertension.34 Given that HF itself can cause coughing, the true incidence of ACEI-induced cough is difficult to estimate in these patients, and rather ACEI treatment could cure the HF-associated cough may be via improvement in ventilation/perfusion imbalance, alveolar-capillary gas transfer, pulmonary congestion.15. sharing sensitive information, make sure youre on a federal As a class, ARBs are generally well tolerated. Although the intensity of cough is usually mild to moderate, it can be occasionally severe enough and require discontinuation of treatment. In a series of studies performed in real clinical practice, such as PAINT, PIANIST, PROOF, PETRA, the incidence of cough was reported to be very low (ranged from <0.001 to 0.8%)22, 23, 24, 25 even with the use of the maximum dose of perindopril (Table1). The US Food and Drug Administration (FDA)'s Adverse Event Reporting System (AERS) database is a resource for identifying areas of concern. Role of ACEI in maintaining overall homeostasis in the body. Yusuf S. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. Clipboard, Search History, and several other advanced features are temporarily unavailable. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association task force on practice guidelines, a. Nerenberg K.A., Zarnke K.B., Leung A.A. ACE inhibitor-induced angioedema | DermNet Cough is much less common with ARBs. Pharmacotherapeutic options for chronic refractory cough. There was also significant reduction in CV mortality with the ACEIs (HR: 0.88, 95%CI: 0.771.00, p=0.051) but no effect was observed with the ARBs (HR: 0.96, 95% CI:0.901.01, p=0.14) in the same dataset of patients with hypertension.37 Moreover, among the included ACEIs studies, the principal mortality benefits were shown in the HYVET, ASCOT-BPLA, and ADVANCE, all of which are the perindopril trials (HR: 0.87, 95% CI: 0.810.93, p<0.001).37 Another systematic review of 26 studies that included 61,264 patients with diabetes and normoalbuminuria showed that ACEIs reduced the risk of new-onset microalbuminuria, macroalbuminuria or both (RR: 0.71, 95% CI: 0.560.89), and mortality risk (RR: 0.84, 95% CI: 0.730.97) when compared to placebo. 2017;196(10):1255-1263. doi: 10.1164/rccm.201704-0769OC, 35. Katsumata U, Sekizawa K, Inoue H, Sasaki H, Takishima T. Inhibitory actions of procaterol, a beta-2 stimulant, on substance P-induced cough in normal subjects during upper respiratory tract infection. Angioneurotic edema. A study of the cough reflex in idiopathic pulmonary fibrosis. Orvepitant also significantly improved severity scores and QOL, with a favorable safety profile.63, VOLCANO-2 was a phase 2b, placebo-controlled trial (N = 275) conducted over 12 weeks in patients with RCC and a baseline awake cough frequency of at least 10 coughs/hour (ClinicalTrials.gov identifier NCT02993822).64,65 The primary cough frequency end point was not significant; however, an improved efficacy trend was observed among patients taking 30 mg orvepitant and a higher cough frequency (66.7 coughs/hour) compared with placebo (P = .066). Michaudet C, Malaty J. Mazzone SB, Chung KF, McGarvey L. The heterogeneity of chronic cough: a case for endotypes of cough hypersensitivity. Nedogoda S.V., Stojanov V.J. In this context, perindopril has been associated with a relatively low incidence of cough and has extensive evidence supporting its cardiovascular benefits and tolerability. Losartan Cough Study Group. Arch Intern Med. In all cases, the ARB was well tolerated. Shankar P.K., Vidyasagar S., Adiga S. Efficacy and tolerability of trandolapril in mild to moderate hypertension - a double blind comparative clinical trial with enalapril in Indian population. Accessed September 9, 2020. atsjournals.org/doi/abs/10.1164/ajrccm-conference.2020.201.1_MeetingAbstracts.A7648, 52. The investigators expect to enroll 372 participants who will receive 50 mg, 150 mg, or 300 mg of S-600918, or placebo for 28 days. Harle A, Blackhail F, Molassiotis A, et al. The lack of efficacy of traditional antitussive agents combined with an improved understanding of the neurobiology of the cough reflex has led to an increased focus on the development of new agents to address this treatment gap.30,31 The new chronic cough agents target specific receptors or channels in the peripheral sensory neurons with the goal of reduced central nervous system AEs and control of hypersensitivity while reserving the protective cough response.32, Transient Receptor Potential Receptor Vanilloid-1 (TRPV1) Antagonists, The TRPV1 channel was the first therapeutic target evaluated for chronic cough.32 TRPV1 channels are present in both peripheral neurons and nonneuronal cells.19 They are activated by hot temperatures (>43 C), acidic pH, or inflammatory mediators and recognize capsaicin.33 Two subsequent clinical trials in patients with chronic cough did not demonstrate that TRPV1 antagonists were clinically beneficial in the treatment of chronic cough.34,35 SB-705498, a highly selective and potent competitive antagonist for TRPV1 receptors, has shown to significantly affect the capsaicin cough reflex but had almost no effect on objective cough frequency, cough severity scores, or CQLQ scores.35 XEN-D0501, which is significantly more potent than SB-705498 in vivo, exhibited similar results and failed to significantly reduce cough frequency in patients with chronic cough compared with placebo (P = .41).34, Transient Receptor Potential Ankyrin-1 (TRPA1)Antagonist.
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