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Pathophysiology of cough with angiotensin-converting enzyme inhibitors: How to explain within-class differences?

Open AccessPublished:January 09, 2023DOI:https://doi.org/10.1016/j.ejim.2023.01.005

      Highlights

      • ACE-inhibitors are commonly used for the management of cardiovascular diseases.
      • They are usually well tolerated but can be responsible for a dry cough due to a bradykinin related mechanism of action.
      • The incidence of cough is influenced by age, gender, concomitant diseases, type of study and characteristics of single molecules within the class.
      • Cough should be carefully evaluated in the single patients to exclude any drug-independent cause.
      • Drugs more active at the levels of the tissue RAS (Perindopril, Zofenopril) could be less responsible for cough.

      Abstract

      Angiotensin converting enzyme inhibitors (ACEi) have consistently demonstrated improved survival and reduced risk of major cardiovascular events, across the spectrum of cardiovascular disease, including hypertension, coronary artery disease, myocardial infarction, and heart failure. The cardioprotective effects of ACEi result from inhibiting the conversion of angiotensin I to angiotensin II, and inhibition of bradykinin degradation. They are generally well tolerated but may cause the onset of a dry cough in some patients. This review presents current evidence on the incidence and mechanisms of cough associated with ACEi use, and then considers how to manage ACEi-related cough in clinical practice. The incidence of ACEi-induced cough in the published literature varies widely due to heterogeneity in the source data and lack of adequate controls. Incidence also varies among individual ACEi with agents such as perindopril, which has a high tissue ACE affinity, associated with a lower rate of cough. Evidence from real-world studies shows that the incidence of ACEi-associated cough is lower than rates reported in clinical trials. Patients who experience any dry cough are often switched to angiotensin- receptor blockers or other classes of antihypertensive drugs, regardless of cough severity. To avoid inappropriate discontinuation of ACEi in clinical practice, an alternative approach in patients with persistent cough is to perform a challenge/re-challenge to determine if re-introduction of ACEi is associated with recurrence of symptoms. Incidence of cough should not be considered a class effect for ACEi, and the patient may benefit by a switch from one ACEi to another. Every effort should be made to enable patients to continue ACEi therapy to reduce adverse cardiovascular outcomes and improve survival.

      Keywords

      1. Introduction

      Angiotensin-converting enzyme inhibitors (ACEi) are largely used for the prevention and treatment of cardiovascular and renal diseases [
      • Messerli F.H.
      • Bangalore S.
      • Bavishi C.
      • Rimoldi S.F.
      Angiotensin- converting enzyme inhibitors in hypertension: to use or not to use?.
      ]. The rationale supporting the use of ACEi is based on evidence of extensive activation of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of these diseases. The mechanism of action of ACEi ( Fig. 1) is based on blockade of ACE, the enzyme responsible for the conversion of angiotensin-I into angiotensin-II, as well as for the degradation of several hemodynamically active peptides including bradykinin (BK). The latter contributes to the overall benefit associated with ACEi treatment [
      • Messerli F.H.
      • Bangalore S.
      • Bavishi C.
      • Rimoldi S.F.
      Angiotensin- converting enzyme inhibitors in hypertension: to use or not to use?.
      ]. This mechanism of action differs from that or angiotensin-II receptor antagonists (ARB's) that directly inhibit the angiotensin-II receptors type-1 while the clinical relevance of type-2 stimulation has never been confirmed in humans [
      • Messerli F.H.
      • Bangalore S.
      • Bavishi C.
      • Rimoldi S.F.
      Angiotensin- converting enzyme inhibitors in hypertension: to use or not to use?.
      ,
      • Carey R.M.
      AT2 receptors: potential therapeutic targets for hypertension.
      ].
      Fig 1
      Fig. 1Physiological interactions between ACE, angiotensin-II and bradykinin . Ang = angiotensin, BP = blood pressure, Na+ = sodium, SNS = sympathetic nervous system, ACE = angiotensin-converting enzyme, BDK = bradykinin.
      The effectiveness of ACEi in reducing cardiovascular disease (CVD) risk has been demonstrated in many randomized clinical trials, involving a broad variety of patients with or without manifest CVD [
      • Pfeffer M.A.
      • Braunwald E.
      • Moye L.A.
      • et al.
      SAVE investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction and myocardial infarction: results of the survival and ventricular enlargement trial.
      ,
      The SOLVD investigators
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
      ,
      The Acute Infarction Ramipril Efficacy (AIRE) study investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.
      ,
      • Torp-Pedersen C.
      • Kober L.
      TRACE Study Group
      Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced left-ventricular function after acute myocardial infarction.
      ,
      The heart outcomes prevention evaluation study investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
      ,
      The PEACE Trial Investigators
      Angiotensin-converting-enzyme inhibition in stable coronary artery disease.
      ,
      The European trial on reduction of cardiac events with perindopril in patients with stable coronary artery disease investigators. Efficacy of perindopril in reduction of cardiovascular events in stable coronary artery disease: randomized, double-blind, placebo controlled, multicentre trial (the EUROPA study).
      ,
      • Brugts J.J.
      • Ferrari R.
      • Simoons M.L.
      Angiotensin-converting enzyme inhibition by perindopril in the treatment of cardiovascular disease.
      ]. ACEi are recommended by all guidelines addressing the treatment of CVD and renal disease both in the general population [
      • Unger T.
      • Borghi C.
      • Charchar F.
      • Khan N.A.
      • Poulter N.R.
      • Prabhakaran D.
      • Ramirez A.
      • Schlaich M.
      • Stergiou G.S.
      • Tomaszewski M.
      • Wainford R.D.
      • Williams B.
      • Schutte A.E.
      2020 international society of hypertension global hypertension practice guidelines.
      ,
      • Williams B.
      • Mancia G.
      • Spiering W.
      • et al.
      ESC/ESH Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European society of cardiology and the European society of hypertension: the task force for the management of arterial hypertension of the European society of cardiology and the European society of hypertension.
      ,
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • Casey Jr, D.E.
      • Collins K.J.
      • Dennison Himmelfarb C.
      • et al.
      ACC/AHA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults.
      ] and in patients with diabetes [
      • Thomopoulos C.
      • Parati G.
      • Zanchetti A.
      Effects of blood pressure lowering on outcome incidence in hypertension: 4. Effects of various classes of antihypertensive drugs – Overview and meta-analyses.
      ,
      • Cheng J.
      • Zhang W.
      • Zhang X.
      • Han F.
      • Li X.
      • He X.
      • Li Q.
      • Chen J.
      Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis.
      ]. They can be effectively combined with almost all other classes of cardiovascular drugs with a significant improvement in blood pressure control, vascular and renal function, and long-term cardiovascular prognosis [
      • Dahlöf B.
      • Sever P.S.
      • Poulter N.R.
      • et al.
      Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial.
      ,
      ADVANCE Collaborative Group
      Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial.
      ]. The use of ACEi is part of daily clinical practice in the management of patients with cardiovascular and renal diseases [
      • Pfeffer M.A.
      • Braunwald E.
      • Moye L.A.
      • et al.
      SAVE investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction and myocardial infarction: results of the survival and ventricular enlargement trial.
      ,
      The SOLVD investigators
      Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure.
      ,
      The Acute Infarction Ramipril Efficacy (AIRE) study investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.
      ,
      • Torp-Pedersen C.
      • Kober L.
      TRACE Study Group
      Effect of ACE inhibitor trandolapril on life expectancy of patients with reduced left-ventricular function after acute myocardial infarction.
      ]. The safety and tolerability profile of ACEi ranks highly among the large family of cardiovascular drugs. Side effects include dry cough, hypotension, hyperkalemia, headache, dizziness, and renal impairment, which occur more often in patients with more severe medical conditions or treated with multiple classes of drugs [
      • Poulter N.R.
      • Borghi C.
      • Parati G.
      • Pathak A.
      • Toli D.
      • Williams B.
      • Schmieder R.E.
      Medication adherence in hypertension.
      ]. The aim of this review was to summarize the available information about the relevance of cough in patients treated with ACEi, with a special focus on pathophysiology and its interaction with the pharmacological profile of the different ACEi.

      1.1 ACEi and cough

      A persistent dry cough is the most common adverse effect of ACEi and has been reported to occur in a variable proportion of patients depending on the source of the data (observational, spontaneous report, controlled clinical trial), age, race and the gender of the population [
      • Wu H.
      • Roks A.J.
      • Leijten F.P.
      • Garrelds I.M.
      • Musterd-Bhaggoe U.M.
      • van den Bogaerdt A.J.
      • de Maat M.P.
      • Simoons M.L.
      • Danser A.H.
      • Oeseburg H.
      Genetic variation and gender determine bradykinin type 1 receptor responses in human tissue: implications for the ACE-inhibitor-induced effects in patients with coronary artery disease.
      ]. ACEi-induced cough is usually described as a scratching sensation in the throat that generally disappears a few days after discontinuation of treatment. Dry cough usually develops in the first week or month after starting the drug and is reported to be more frequent in Asian people and in female patients probably because of some differences in the metabolism of bradykinin peptides [
      • Pinto B.
      • Jadhav U.
      • Singhai P.
      • Sadhanandham S.
      ShahN. ACEI-induced cough: a review of current evidence and its practical implications for optimal CV risk reduction.
      ]. The overall incidence of cough in patients treated with ACEi is reported between 1% and over 30% depending on data set and patient population. It is less common in patients with hypertension, and more common in patients with coronary artery disease, in particular in those with heart failure bearing disease-related causes of cough, such as pulmonary congestion and bronchiolar edema [
      • Vukadinović D.
      • Vukadinović A.N.
      • Lavall D.
      • Laufs U.
      • Wagenpfeil S.
      • Böhm M.
      The true rate of angiotensin converting enzyme inhibitors related cough in placebo-controlled trials: a meta-analysis.
      ,
      • Borghi C.
      • Veronesi M.
      Cough and ACE Inhibitors: the Truth Beyond Placebo.
      ,
      • Wyskida K.
      • Jura-Szołtys E.
      • Smertka M.
      • Owczarek A.
      • Chudek J.
      Factors that favor the occurrence of cough in patients treated with ramipril e a pharmacoepidemiological study.
      ]. In addition the incidence of dry cough has been reported as more frequent among diabetics than non-diabetic patients [
      • Aslam M.
      • Ahmad M.
      • Mobasher F.
      Efficacy and tolerability of antihypertensive drugs in diabetic and nondiabetic patients.
      ]. This large difference in the reported incidence of cough is mainly due to heterogeneity in the source of the clinical data. Only a minority of ACEi trials have included cough as a formal endpoint, and these studies were limited by small sample sizes and lack of long-term follow-up with a low number of events. This, in turn, has resulted in marked differences in reported incidences [
      • Bahl V.K.
      • Jadhav U.M.
      • Thacker H.P.
      Management of hypertension with the fixed combination of perindopril and amlodipine in daily clinical practice: results from the STRONG perspective, observational, multicenter study.
      ,
      • Mv P.
      • Kaul S.
      Incidence of recurrent stroke in primary care during preventive treatment based on perindopril with or without indapamide.
      ,
      • Brugts J.J.
      • Arima H.
      • Remme W.
      • Bertrand M.
      • Ferrari R.
      • Fox K.
      • DiNicolantonio J.
      • MacMahon S.
      • Chalmers J.
      • Zijlstra F.
      • Caliskan K.
      • Simoons M.L.
      • Mourad J.J.
      • Boersma E.
      • Akkerhuis A
      The incidence and clinical predictors of ACE-inhibitor induced dry cough by perindopril in 27,492 patients with vascular disease.
      ,
      • Yılmaz I.
      Angiotensin-converting enzyme inhibitors induce cough.
      ]. Moreover, the incidence of cough varies among individual ACEis, and only a few drugs from this class have real-world data to support findings from randomized trials in clinical practice. The paucity of evidence providing a link between controlled studies and real-life data has largely limited analysis of the actual incidence of cough in patients treated with ACEi and led to an increase in the “narrative” interpretation of symptoms of cough.
      The consequence is that patients who experience any dry cough are often directly switched to ARBs, or other classes of antihypertensive drugs, in agreement with recommendations from most of the guidelines [
      • Unger T.
      • Borghi C.
      • Charchar F.
      • Khan N.A.
      • Poulter N.R.
      • Prabhakaran D.
      • Ramirez A.
      • Schlaich M.
      • Stergiou G.S.
      • Tomaszewski M.
      • Wainford R.D.
      • Williams B.
      • Schutte A.E.
      2020 international society of hypertension global hypertension practice guidelines.
      ,
      • Williams B.
      • Mancia G.
      • Spiering W.
      • et al.
      ESC/ESH Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European society of cardiology and the European society of hypertension: the task force for the management of arterial hypertension of the European society of cardiology and the European society of hypertension.
      ,
      • Whelton P.K.
      • Carey R.M.
      • Aronow W.S.
      • Casey Jr, D.E.
      • Collins K.J.
      • Dennison Himmelfarb C.
      • et al.
      ACC/AHA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults.
      ]. This could significantly modify the overall preventive impact of RAAS inhibition, particularly in terms of total and cardiovascular mortality.

      1.2 Mechanism of ACEi-induced cough

      Although the exact mechanism of ACEi-induced cough remains incompletely understood, several possible mechanisms have been hypothesized for cough development. The most widely accepted theory is based on the capacity of ACEis to prevent the ACE-dependent degradation of BK and substance P, with a subsequent accumulation of these substances in the upper and lower respiratory tracts [
      • Poulter N.R.
      • Borghi C.
      • Parati G.
      • Pathak A.
      • Toli D.
      • Williams B.
      • Schmieder R.E.
      Medication adherence in hypertension.
      ]. BK acts through rapidly adapting stretch receptors and C-fiber receptors of airway sensory nerves that promote the release of neurokinin A and substance P. This causes airway smooth muscle to constrict, leading to bronchoconstriction and cough [
      • Kaufman J.
      • Casanova J.E.
      • Riendl P.
      • Schiuder D.P.
      Bronchial hyperreactivity and cough due to angiotensin-converting enzyme inhibitors.
      ].
      However, the most challenging point in terms of mechanism of cough is: why does cough not occur in all patients receiving ACEis? Many different mechanisms have been proposed including differences in individual bronchial reactivity or subclinical history of asthma [
      • Bucknall C.E.
      • Neilly J.B.
      • Carter R.
      • Stevenson R.D.
      • Semple P.F.
      Bronchial hyperreactivity in patients who cough after receiving angiotensin converting enzyme inhibitors.
      ,
      • Kaufman J.
      • Schmitt S.
      • Barnard J.
      • Busse W
      Angiotensin-converting enzyme inhibitors in patients with bronchial responsiveness and asthma.
      ], underlying lung congestion (e.g. patients with chronic heart failure), increased sensitivity of BK-dependent airway sensory nerve fibers, decreased capacity of BK degradation (aminopeptidase P-APP enzyme deficiency), and BK receptor gene polymorphism leading to differences in cough reflex sensitivity. Conversely, other studies have reported that previous asthma or history of bronchial hyper-reactivity does not pose a risk for developing ACEi-induced cough [
      • Wood R.
      Bronchospasm and cough as adverse reactions to the ACE inhibitors captopril, enalapril and lisinopril. A controlled retrospective cohort study.
      ,
      • Sala H.
      • Abad J.
      • Juanmiquel L.
      • et al.
      Captopril and bronchial reactivity.
      ].
      Genetic polymorphisms may influence the incidence of ACEi-induced cough. A recent meta-analysis including 26 studies showed a significant association between ACE I/D I carriers (ACE gene insertion) and ACEi-induced cough, with some racial (Asian) and age (elderly) differences [
      • Mu G.
      • Xiang Q.
      • Zhou S.
      • Xie Q.
      • Liu Z.
      • Zhang Z.
      • Cui Y.
      Association between genetic polymorphisms and angiotensin-converting enzyme inhibitor-induced cough: a systematic review and meta-analysis.
      ]. Another study investigated the polymorphisms of BK receptors as a genetic marker of ACEi-related cough in a Japanese hypertensive population [
      • Mukae S.
      • Itoh S.
      • Aoki S.
      • Iwata T.
      • Nishio K.
      • Sato R.
      • et al.
      Association of polymorphisms of the renin-angiotensin system and bradykinin B2 receptor with ACE-inhibitor-related cough.
      ]. The TT genotype and T allele of BK B2 receptors were identified at a significantly higher frequency in patients with cough than in those without, with a more evident effect in women. No relationship was observed for the polymorphisms of ACE (I/D) and angiotensin II receptors. These genetic findings appear to be involved in the occurrence of cough and may provide a valuable tool to detect patients at risk of developing this side effect of ACEi before drug administration. In general, a summary review of the evidence provided by studies evaluating these pathogenetic hypotheses suggests the involvement of two or more genetic mechanisms in the development of ACEi-induced cough [
      • Brugts J.J.
      • Arima H.
      • Remme W.
      • Bertrand M.
      • Ferrari R.
      • Fox K.
      • DiNicolantonio J.
      • MacMahon S.
      • Chalmers J.
      • Zijlstra F.
      • Caliskan K.
      • Simoons M.L.
      • Mourad J.J.
      • Boersma E.
      • Akkerhuis A
      The incidence and clinical predictors of ACE-inhibitor induced dry cough by perindopril in 27,492 patients with vascular disease.
      ].
      Despite all this sound evidence, the BK hypothesis has some drawbacks generated from studies of direct head-to-head comparisons between various ACEi with recognized differences in the level of interaction with BK metabolism. First, in a randomized double-blind study that used a de-challenge and re-challenge method, a twofold higher incidence of cough was seen in patients undergoing enalapril therapy (22%) compared with perindopril treatment (11%) [
      • Tumanan-Mendoza B.A.
      • Dans A.L.
      • Villacin L.L.
      • et al.
      Dechallenge and rechallenge method showed different incidences of cough among four ACE-Is.
      ]. Furthermore, a retrospective study reached the same conclusions with a threefold increase in the incidence of cough in patients with hypertension treated with enalapril (7%) vs. perindopril (2.2%) [
      • Tumanan-Mendoza B.A.
      • Dans A.L.
      • Villacin L.L.
      • et al.
      Dechallenge and rechallenge method showed different incidences of cough among four ACE-Is.
      ]. This observation is crucial as the lower incidence of cough with perindopril has been observed even though this ACEi exhibits the highest BK/angiotensin selectivity, but also the strongest interaction with the vascular RAAS ( Fig. 2) [
      • Reisin L.
      • Schneeweiss A.
      Spontaneous disappearance of cough induced by angiotensin-converting enzyme inhibitors (captopril or enalapril).
      ].
      Fig 2
      Fig. 2ACEi and affinity for tissue ACE (adapted from [
      • Ferrari R.
      Angiotensin-converting enzyme inhibition in cardiovascular disease: evidence with perindopril.
      ]) and circulating effects.
      These findings support the importance of the tissue binding of ACEi over their circulating effects, even in terms of adverse events ( Fig. 2). Treatment with perindopril can be expected to reduce ANG II and to increase BK levels, particularly at the level of cardiac and vascular tissues. This helps maintain vascular homeostasis, probably with minor interactions with the extravascular system (e.g. respiratory system). As explained earlier, among ACEi, tissue potentiation of BK is particularly pronounced for perindopril and may underlie the cardiovascular benefits offered by the drug with a low rate of extravascular adverse events. This evidence suggests that the incidence of cough cannot be considered a class effect for ACEi, supporting the idea that it may be reasonable to switch from one ACEi to another in case of cough leading to discontinuation of drug.

      1.3 How to manage ACEi-related cough in clinical practice?

      1.3.1 Clinical approach

      The decision on what is the best therapeutic strategy for patients who present with cough during ACEi treatment is dependent on the intensity of the symptom and the presence or not of concomitant CVD with a specific recommendation for ACEi treatment. Cough intensity is usually mild to moderate in most patients, and only occasionally is it severe enough to require drug discontinuation. Before deciding to remove an effective drug with well-established cardiovascular protection from the treatment plan, it is mandatory to discuss with the patient the actual cough severity, which must be weighed against the potential loss of cardiovascular protection. As far as the problem of concomitant diseases, the efficacy of ACEi has been proven in many patients, with significant reductions in cardiovascular mortality and morbidity. The decision about whether or not to remove the ACEi must be discounted against the expected clinical benefit, as prevention of cardiovascular events holding greater importance than any slight improvement in quality of life. Furthermore, Reisin and Schneeweiss reported in two different studies that cough spontaneously disappeared in 25% to 50% of hypertensive patients treated with ACEi (follow-up 2–8 months), despite continued and unchanged treatment [
      • Reisin L.
      • Schneeweiss A.
      Complete spontaneous remission of cough induced by ACE inhibitors during chronic therapy in hypertensive patients.
      ,
      • Sato A.
      • Fukuda S.
      A prospective study of frequency and characteristics of cough during ACE inhibitor treatment.
      ]. More recently, a Japanese study reported a reduced incidence of cough with continuous use of ACEi [
      • Charlon Dollow S.
      • Fidel J.
      • Hoglund C.
      • Honkanen T.
      • Kobrin I.
      • McEwan J.
      • McInnes G.
      • Viskoper J.R.
      • Woo K.S.
      • et al.
      Reproducibility of angiotensin converting enzyme inhibitor induced cough: a double-blind randomised study.
      ]. The risk of inappropriate ACEi removal can be reduced by performing a challenge and re-challenge of to test if the re-introduction of the ACEi induces cough after remission of symptoms [
      • Mackay F.J.
      • Pearce G.L.
      • Mann R.D.
      Cough and angiotensin II receptor antagonists: cause or confounding?.
      ]. In practical terms the current protocol is based on 4 weeks of withdrawal and if the cough disappear the drugs can be re-introduced in daily therapy.
      This strategy has been shown to effectively reduce the cumulative incidence of cough [
      • Smith J.A.
      • Woodcock A
      Chronic cough.
      ], and to preserve the preventive efficacy of ACE-inhibition. In the presence of cough, the current strategy suggested by most guidelines is to switch from an ACEi to an ARB. However, this strategy does not entirely abolish the risk of cough (about 3% of ARB-treated patients complain of cough) [
      • Franova S.
      • Nosal'Ova G.
      • Antosova M.
      • Nosal S
      Enalapril and diltiazem coadministration and respiratory side effects of enalapril.
      ], and it also reduces the extent of cardiovascular protection. A reduction in the rate of cough can be also achieved by shifting from average ACE-inhibitors to those drugs bearing lesser incidence of cough in clinical practice (perindopril and zofenopril). Additional studies/surveys focused on continuation of ACEi while monitoring the development of cough in patients belonging to different cardiovascular risk categories are warranted to reduce the rate of unjustified discontinuation of effective disease-modifying drugs.

      1.3.2 Role of concomitant medications to reduce incidence of cough

      ACEi are often combined with other classes of first-line cardiovascular drugs, particularly in the treatment of hypertension. Clinical studies have suggested that the incidence of cough can be significantly reduced by combination treatment, with the double benefit of improving blood pressure control and treatment adherence. In particular, some studies have reported that the addition of calcium channel blockers to ACEi can reduce cough acting through two possible mechanisms. First, by inhibiting prostaglandin synthesis, and second by inhibiting Ca-dependent release of glutamate, which plays an important role in the central transmission of the cough reflex [
      • Franova S.
      The influence of inhaled furosemide on adverse effects of ACEi-nhibitors in airways.
      ]. This finding is further supported by other studies that reported a lower incidence of cough with concomitant calcium channel blockers or diuretics compared to ACEi monotherapy ( Fig. 3) [
      • Mackay F.J.
      • Pearce G.L.
      • Mann R.D.
      Cough and angiotensin II receptor antagonists: cause or confounding?.
      ,
      • Dicpinigaitis P.V.
      Angiotensin-converting enzyme inhibitor induced cough.
      ,
      • Sebastian G.Z.
      • Roberto P.
      Cough and angioedema in patients receiving angiotensin-converting enzyme inhibitors. Are they always attributable to medication?.
      ].
      Fig 3
      Fig. 3Incidence of cough in patients with mono- or dual-therapy including an ACEi (Reproduced with permission from [
      • Sato A.
      • Fukuda S.
      A prospective study of frequency and characteristics of cough during ACE inhibitor treatment.
      ]).
      Several other treatments may also reduce the rate of cough in patients treated with ACEi including sodium cromoglycate, theophylline, sulindac, indomethacin, ferrous sulfate, and picotamide [
      • Sebastian G.Z.
      • Roberto P.
      Cough and angioedema in patients receiving angiotensin-converting enzyme inhibitors. Are they always attributable to medication?.
      ]. The administration of these agents may be complicated by the onset of drug-specific adverse events, and should not be considered in routine practice, but as a rescue treatment for those patients who cannot tolerate any other RAAS inhibitor.

      1.3.3 Importance of underlying disease

      ACEi are widely used for the treatment of patients with CVD ranging from uncomplicated hypertension to late stages of heart failure. The rate of cough in treated patients is significantly higher in those with coronary artery disease and heart failure, while the percentage is proportionally smaller in patients with hypertension. Vukadinovic et al. [
      • Vukadinović D.
      • Vukadinović A.N.
      • Lavall D.
      • Laufs U.
      • Wagenpfeil S.
      • Böhm M.
      The true rate of angiotensin converting enzyme inhibitors related cough in placebo-controlled trials: a meta-analysis.
      ] published a comprehensive review of more than 20 clinical trials reporting the placebo-adjusted rate of cough in different populations of patients treated with ACEi, and reported that cough cannot be related to active ACEi in over 60% of treated patients. They also identified a remarkable proportion of unreliable “ACEi related” coughers, particularly among patients treated for coronary artery disease and heart failure in whom the prevalence of non-drug related cough during ACEi treatment was 58% and 71%, respectively. These data suggest that the true proportion of patients in whom discontinuation of an ACEi is appropriate because of cough is smaller than expected. This is particularly true in the uncomplicated hypertensive population, where the absolute rate of cough is probably less than 5% [
      • Vukadinović D.
      • Vukadinović A.N.
      • Lavall D.
      • Laufs U.
      • Wagenpfeil S.
      • Böhm M.
      The true rate of angiotensin converting enzyme inhibitors related cough in placebo-controlled trials: a meta-analysis.
      ,
      • Borghi C.
      • Veronesi M.
      Cough and ACE Inhibitors: the Truth Beyond Placebo.
      ] when assessed by an accurate methodology excluding the narrative approach.

      1.3.4 Selection of type of ACEi and incidence of cough

      The incidence of cough varies based on the individual ACEi used. ACEi are categorized into three groups based on the presence of a sulfhydryl, carboxyl, or phosphoryl group, but the relevance of this structural difference in terms of cough remains unclear [
      • Sangole N.V.
      • Dadkar V.N.
      Adverse drug reaction monitoring with angiotensin converting enzyme inhibitors: a prospective, randomized, open-label, comparative study.
      ]. A previous study based on the incidence of adverse drug reactions showed that phosphoryl group-containing ACEi (fosinopril) were associated with a higher incidence of cough compared with carboxyl group-containing ACEi (enalapril, lisinopril, and ramipril) [
      • Mutolo D.
      • Bongianni F.
      • Evangelista S.
      • Cinelli E.
      • Pantaleo T.
      • et al.
      Effects of Zofenopril and Ramipril on cough reflex responses in anesthetized and awake rabbits.
      ]. These results are in agreement with experimental data comparing the rate of cough induced by two structurally different ACEi with a sulphydryl (zofenopril) or a carboxyl moiety (ramipril). An increase in the cough response to both mechanical and chemical stimulation was significantly enhanced in animals (rabbits) treated with ramiprilat without differences in the hemodynamic response. The frequency of coughs also increased in ramipril-treated animals from 21.1 + 2.6 to 34.9 + 3.5; P < 0.01) [
      • Cialdai C.
      • Giuliani S.
      • Valenti C.
      • Tramontana C.
      • Maggi C.A.
      Differences between zofenopril and ramipril, two ACE inhibitors, on cough induced by citric acid in guinea pigs: role of bradykinin and PGE2.
      ]. Similar data have been published in another animal model (guinea pig) with an increase in the rate of cough in response to citric acid that was observed only in ramipril-treated animals when compared to zofenopril or vehicle control groups [
      • Mancia G.
      • Parodi A.
      • Merlino L.
      • Corrao G.
      Heterogeneity in antihypertensive treatment discontinuation between drugs belonging to the same class.
      ]. These findings confirm that there are differences in the cough potentiation effect induced by different ACEi. The mechanism of the low rate of cough observed with zofenopril appears to be different from that proposed for perindopril and may be related to its ability to induce a lower accumulation of BK and prostaglandins in the lung. All this evidence supports a role for pharmacological heterogeneity within the ACEi class and suggests a lower rate of cough for those molecules more extensively bound to vascular tissue ACE, even though the mechanism of cough limitation does not seem to be unique across the different drugs.
      Whatever the impact of drug-specific characteristics, the use of ACEi in clinical practice should be based on medications that induce cough less frequently. In this context, perindopril has been associated with a relatively low incidence of cough combined with extensive evidence supporting its cardiovascular benefits and tolerability. Nevertheless, the lack of head-to-head comparison of data in humans does not allow a definite conclusion about the differences across ACE-inhibitors and we must rely on indirect comparison integrated by more convincing animal reports. On the other side, the paper of co-workers [
      • Brugts J.J.
      • Arima H.
      • Remme W.
      • Bertrand M.
      • Ferrari R.
      • Fox K.
      • DiNicolantonio J.
      • MacMahon S.
      • Chalmers J.
      • Zijlstra F.
      • Caliskan K.
      • Simoons M.L.
      • Mourad J.J.
      • Boersma E.
      • Akkerhuis A.
      The incidence and clinical predictors of ACE-inhibitor induced dry cough by perindopril in 27,492 patients with vascular disease.
      ] based on a large administrative data base, suggests a lower rate of discontinuation for patients treated with perindopril and zofenopril in the Italian population and this indirectly support a better tolerability for these two drugs probably due to the lesser incidence of dry cough, the most common adverse event of ACE-inhibitors.
      The incidence of cough in patients treated with perindopril has been estimated both from randomized trials (RCT's) and real-world data. Data from three, large, landmark randomized clinical trials based primarily on the ACEi perindopril (ADVANCE, EUROPA, and PROGRESS) have been investigated as a single database. This has enabled useful subgroup analyses focused on selected populations of patients with a common background of vascular disease or high risk of vascular disease, and a clinical indication for ACEi use according to guidelines [
      • Zhang X.S.
      • Ren J.H.
      • Lu J.P.
      • Fan Y.J.
      Atorvastatin protects against angiotensin II-induced injury and dysfunction in human umbilical vein endothelial cells through bradykinin 2 receptors.
      ]. The final analysis included about 28,000 patients with CVD and revealed a cough discontinuation rate of 3.9% over a mean follow-up of 4 years (3.5% EUROPA with perindopril 8 mg, 4.3% ADVANCE with perindopril 4–8 mg, and 4.4% PROGRESS with perindopril 4 mg). A clinical risk score that was defined by the three strongest predictors of cough (advanced age, female gender and use of lipid-lowering drugs) was associated with an odds ratio of 4.4 (95% CI 3.1–5.4) in the subjects with the highest score. Interestingly, racial background was not related to a differential incidence of cough in patients of Caucasian or Asian origin (OR 1.11 95% CI 0.92–1.39), and this has clinical relevance for decisions about the use of ACEi or ARBs in Asian patients. The relationship between the use of lipid-lowering drugs and cough in ACEi -treated patients might be explained by the potential effects of statins on the expression of BK receptors [
      • Kobalava Z.D.
      • Troitskaya E.
      • Tolkacheva V.
      Combined therapy of arterial hypertension with triple fixed-dose combination of amlodipine/indapamide/perindopril arginine in real clinical practice: the organization and the main results of the DOKAZATEL'STVO (Proof) study.
      ], which could be responsible for an increased sensitivity to tissue BK accumulation at the level of airways. In view of the large prevalence of patients with a specific clinical indication for ACEi in the general population, these data can be used to reduce the probability of cough and to increase the clinical impact of ACEi considering the lower-than-expected incidence of cough.
      In a series of perindopril-based studies performed in real clinical practice, including PAINT, PIANIST, PROOF, and PETRA [
      • Toth K.
      PIANIST Investigators: antihypertensive efficacy of triple combination perindopril/indapamide plus amlodipine in high-risk hypertensives: results of the PIANIST study (Perindopril-Indapamide plus AmlodipiNe in high rISk hypertensive patients).
      ,
      • Pall D.
      • SzantoI Szabo Z
      Triple combination therapy in hypertension: the antihypertensive efficacy of treatment with perindopril, amlodipine, and indapamide SR.
      ,
      • Abrah am G.
      • D ezsi C.A
      The antihypertensive efficacy of the triple fixed combination of perindopril, indapamide, and amlodipine: the results of the PETRA study.
      ,
      • Bahl V.K.
      • Jadhav U.M.
      • Thacker H.P.
      Management of hypertension with the fixed combination of perindopril and amlodipine in daily clinical practice: results from the STRONG perspective, observational, multicenter study.
      ], the incidence of cough was reported to be very low (ranging from <0.001% to 0.8%), even with the use of maximum dose perindopril ( Table 1). Similarly, data from three Indian studies (STRONG, MONOCOMB, and PROTECT) demonstrated a cough incidence of 1.5% to 4%, in agreement with the incidence reported in global perindopril studies [
      • Padma M.V.
      • Kaul S.
      Incidence of recurrent stroke in primary care during preventive treatment based on perindopril with or without indapamide.
      ,
      • Mv P.
      • Kaul S.
      Incidence of recurrent stroke in primary care during preventive treatment based on perindopril with or without indapamide.
      ,
      • Borghi C.
      • Omboni S.
      Zofenopril and incidence of cough: a review of published and unpublished data.
      ]. The difference between real life data and RCT's are probably dependent on the different approach to adverse events in real life studies in comparison to RCT that can be regarded as the golden standard. In particular, the real-life data mainly identify the patients stopping from treatment based on their personal perception of adverse events and this contribute to the proportion of poor adherence. Conversely, patients enroled in RCT are “pushed” to report any adverse event and to stay on treatment up to the end of the follow-up period. The clinical relevance of real-life data is supported by the pare of co-workers [
      • Brugts J.J.
      • Arima H.
      • Remme W.
      • Bertrand M.
      • Ferrari R.
      • Fox K.
      • DiNicolantonio J.
      • MacMahon S.
      • Chalmers J.
      • Zijlstra F.
      • Caliskan K.
      • Simoons M.L.
      • Mourad J.J.
      • Boersma E.
      • Akkerhuis A.
      The incidence and clinical predictors of ACE-inhibitor induced dry cough by perindopril in 27,492 patients with vascular disease.
      ] supporting a relevant difference in the rate of discontinuation among patients treated with different drugs belonging to the same drug class.
      Table 1Summary of incidence of cough with perindopril in clinical studies.
      Name of study/ authorType of studyPerindopril doseCough Incidence (%)
      PIANIST [
      • Toth K.
      PIANIST Investigators: antihypertensive efficacy of triple combination perindopril/indapamide plus amlodipine in high-risk hypertensives: results of the PIANIST study (Perindopril-Indapamide plus AmlodipiNe in high rISk hypertensive patients).
      ]
      ObservationalPerindopril 10 mg0.8
      PAINT [
      • Pall D.
      • SzantoI Szabo Z
      Triple combination therapy in hypertension: the antihypertensive efficacy of treatment with perindopril, amlodipine, and indapamide SR.
      ]
      ObservationalPerindopril 5 and 10 mg<0.1
      PETRA [
      • Abrah am G.
      • D ezsi C.A
      The antihypertensive efficacy of the triple fixed combination of perindopril, indapamide, and amlodipine: the results of the PETRA study.
      ]
      ObservationalPerindopril 5 and 10 mg0.04
      GREEK cohort [

      Tsioufis K, Douma S, Kallistratos MS, Manolis AJ. Effectiveness and adherence to treatment with perindopril/indapamide/amlodipine single-pill combination in a Greek population with hypertension. Clin Drug Invest. 2019;39:385–393.

      ]
      ObservationalPerindopril 5 and 10 mg0.001
      PROOF [
      • Kobalava Z.D.
      • Troitskaya E.
      • Tolkacheva V.
      Combined therapy of arterial hypertension with triple fixed-dose combination of amlodipine/indapamide/perindopril arginine in real clinical practice: the organization and the main results of the DOKAZATEL'STVO (Proof) study.
      ]
      ObservationalPerindopril 5 and 10 mg
      Nedogoda SV et al.

      Nedogoda SV, Stojanov VJ. Single-pill combination of perindopril/indapamide/ amlodipine in patients with uncontrolled hypertension: a randomized controlled trial. Cardiol therapy. 2017; 6:91–104.

      RandomizedPerindopril 5 mgNo cough (0)
      Mourad JJ et al.

      Mourad J-J, Amodeo C, de Champvallins M, Brzozowska-Villatte R, Asmar R.Blood pressure-lowering efficacy and safety of perindopril/indapamide/amlodipine single-pill combination in patients with uncontrolled essential hypertension: a multicenter, randomized, double-blind, controlled trial. J Hypertens. 2017; 35:1481–1495.

      RandomizedPerindopril 5 and 10 mg1.1
      PROTECT I

      Sampalis JS, Psaradellis E, Stutz M, Rickard J, Rampakakis E. Post Hoc Analysis of the CONFIDENCE II, PROTECT I, SHAKE THE HABIT I and SHAKE THE HABIT II observational studies in mild to moderate hypertensive patients treated with perindopril and atorvastatin concomitantly. Drugs R. 2018; 18:283–293.

      ObservationalPerindopril 4 and 8 mg4.3
      Bansai S et al. [
      • Bansal S.
      • Chauhan D.
      • Ramesh D.
      • Barmare S.
      • Chakraborty S
      Blood pressure control and acceptability of Perindopril and its fixed dose combinations with Amlodipine or Indapamide, in younger patients with hypertension.
      ]
      ObservationalPerindopril, N 1250Monotherapy: 3.6 Combination:1.8 and 4.3
      STRONG [
      • Bahl V.K.
      • Jadhav U.M.
      • Thacker H.P.
      Management of hypertension with the fixed combination of perindopril and amlodipine in daily clinical practice: results from the STRONG perspective, observational, multicenter study.
      ]
      ObservationalPerindopril, N 4273.2
      Padma MV et al. [
      • Padma M.V.
      • Kaul S.
      Incidence of recurrent stroke in primary care during preventive treatment based on perindopril with or without indapamide.
      ]
      ObservationalPerindopril, N 2984.0
      PIANIST, Perindopril-Indapamide plus AmlodipiNe in high rISk hyperTensive patients; PAINT, Perindopril-Amlodipine plus Indapamide combination for controlled hypertension Non-intervention Trial; PETRA, The Antihypertensive Efficacy of the Triple Fixed Combination of Perindopril, Indapamide, and Amlodipine; PROOF, Combined Therapy of Arterial Hypertension With a Triple Fixed-Dose Combination of Amlodipine/Indapamide/ Perindopril Arginine in Real Clinical Practice; PROTECT, Effectiveness of PeRindOpril in the management of hyperTension: idEntification of patient and physiCian determinants of response to Treatment; STRONG, SafeTy & efficacy analysis of coveRsyl amlodipine in uncOntrolled and Newly diaGnosed hypertension.
      The lower-than-expected rate of cough in patients treated with perindopril has been confirmed with other drugs with a high level of ACE tissue binding. In 23 studies conducted in hypertensive and post-myocardial infarction patients exposed for a median follow-up time of 3 months to treatment with zofenopril, doses of 7.5–60 mg once-daily were associated with an incidence of cough of 2.6% (range 0%–4.2%). The rate of cough was 2.4% in the hypertension trials (2.4% in the double-blind randomized studies and 2.4% in the open-label post-marketing studies) and 3.6% in the double-blind randomized post-myocardial infarction trials. The incidence of cough was dose dependent and more common in the first 3–6 months of treatment (3.0%) vs 0.2% at 9–12 months [
      • Borghi C.
      • Rossi F.
      Role of the Renin-Angiotensin-Aldosterone System and its pharmacological inhibitors in cardiovascular disease: complex and critical issues.
      ].
      A paper summarizing the incidence of cough with other ACE-inhibitors, reports the results of several randomized clinical trials involving ramipril (12%), benazepril (2.2%), Enalapril (2.2%) Lisinopril (3.5%), Trandolapril (1.9) [
      • Padma M.V.
      • Kaul S.
      Incidence of recurrent stroke in primary care during preventive treatment based on perindopril with or without indapamide.
      ] whose incidence of cough was already discounted by placebo [

      Tsioufis K, Douma S, Kallistratos MS, Manolis AJ. Effectiveness and adherence to treatment with perindopril/indapamide/amlodipine single-pill combination in a Greek population with hypertension. Clin Drug Invest. 2019;39:385–393.

      ].
      These properties are based on its individual pharmacological profile as well as its favorable plasma/tissue ratio of ACE-inhibition that is probably responsible for the extensive cardiovascular protection and low rate of adverse events including cough.

      2. Conclusions

      ACEi are probably the most popular and extensively studied drugs for the prevention and treatment of CVD. Their efficacy has been proven in patients with hypertension, coronary artery disease, and heart failure with and without concomitant diabetes and/or chronic kidney disease. They have a favorable tolerability profile with cough as the only relevant adverse event that occurs in a variable proportion of the treated population, and which is dependent on the underlying disease and pharmacological profile of the ACEi concerned. The incidence of cough has been reported to be less than expected in real life and in placebo-controlled studies, while the presence of gender and racial differences is still a matter of debate and not unanimously confirmed by available data. The pathophysiological mechanism of cough is complex and closely related to the activity of circulating BK, with a lesser contribution of tissue BK levels. This may explain the reduced rate of cough in patients treated with drugs that strongly inhibit tissue ACE, such as perindopril and zofenopril. In clinical terms, cough intensity is often minimal or mild and does not support the automatic removal or modification of treatment. Such a decision should be carefully considered and generally discouraged in patients responding to treatment with only minimal and tolerable symptoms of cough. To avoid inappropriate discontinuation of ACEi in clinical practice, a challenge/re-challenge should be performed in patients with incident cough to determine if re-introduction of ACEi is associated with recurrence of symptoms.

      Funding

      Open access fee was funded by Servier, France 49)

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