Angiotensin-converting Enzyme Inhibitor-induced Cough Research Articles

Association between angiotensin-converting enzyme inhibitor-induced cough and the risk of lung cancer: a Mendelian randomization study.

Background: Observational studies and meta-analyses have demonstrated a positive correlation between the use of angiotensin-converting enzyme inhibitors (ACEIs) and lung cancer. However, the findings remain controversial; furthermore, the relationship between ACEI-induced cough and lung cancer development remains unknown. We used Mendelian randomization (MR) to verify the association between ACEI use, ACEI-induced cough, and the risk of lung cancer. Methods: We performed a two-sample MR analysis to determine the unconfounded relationships between ACE inhibition, which mimics the effects of ACEIs, and genetic proxies for ACEI-induced cough and lung cancer. Single nucleotide polymorphisms that imitate ACE receptors and ACEI-induced cough were collected and integrated into a meta-analysis of existing genome-wide association studies for various lung cancers. The relationship was quantified using inverse variance weighting, weighted median, and MR-Egger methods. Results: A statistically significant association was observed between ACE inhibition and the risk of small cell lung cancer for Europeans (excluding rs118121655/rs80311894). Associations were identified between ACEI-induced cough and the risk of lung cancer for Europeans, although not for Asians, and between ACEI-induced cough and lung adenocarcinoma (excluding rs360206). Conclusion: Our findings reveal a relationship between ACE inhibition and lung cancer development, as well as a significant association between ACEI-induced cough and a higher risk of lung cancer for Europeans. Patients with hypertension who experience dry cough as a side effect of ACEI use should consider switching to an alternative antihypertensive treatment.

Incidence of angiotensin-converting enzyme inhibitor-induced cough in a Malaysian public primary care clinic: A retrospective cohort study

Introduction: The incidence of angiotensin-converting enzyme inhibitors (ACEi)-induced cough has been reported between 5% and 30% but is unknown in Malaysia. This study aimed to determine the incidence of ACEi-induced cough and its associated factors in a public primary care clinic in Malaysia. Methods: A retrospective review of electronic medical records of patients who were initiated ACEi between January 1, 2015, and December 31, 2015, and reviewed until July 31, 2016. A total of 1,091 patients were newly prescribed ACEi, and 394 patients were eligible for this study. We excluded patients who defaulted follow-ups with no further clinic visits before July 31, 2016, were transferred to the clinic without the recorded date of ACEi initiation, were transferred to other clinics during the study period, were followed up at other clinics and attended the study clinic for a short period, or were given only a stat dose of ACEi. Results: Among the 394 patients initiated on ACEi, 225 (57.1%) were male, 369 (93.7%) were Malay, 376 (95.4%) had hypertension, and 192 (48.7%) had diabetes. The incidence of ACEi-induced cough was 24.1%, and 42 (10.7%) patients developed cough on the day of therapy initiation. There was no association between age, gender, ethnicity, type of ACEi, and cough. Conclusion: Approximately one quarter of patients developed cough after ACEi initiation, and approximately half of them developed cough within 1 week of ACEi initiation. Doctors should consider early follow-up for patients initiated on ACEi therapy to ensure adherence, quality of life, and minimise unnecessary treatment.

Modest Association of Long-Term ACE Inhibitor Treatment With Lung Cancer: The Promise and Pitfalls of Epidemiological Drug-Safety Analyses.

Results of the carefully executed Evaluation of Treatment with Angiotensin Converting Enzyme Inhibitors and the Risk of Lung Cancer (ERACER) study, reported in this issue, echo those of several previous observational analyses of the association of long-term angiotensin-converting enzyme (ACE) inhibitor use with incident lung cancer. These epidemiological drug-safety analyses merit cautious interpretation. First, the number needed to harm (NNH) of 6667 reported in ERACER for ACE inhibitors compared with angiotensin-2 receptor blockers (ARBs) after approximately 12 years of follow-up should be balanced against therapeutic benefits. Previously reported meta-analyses of randomized controlled trials (RCTs) over a mean 4.3-year follow-up suggested number needed to treat (NNT) of 67 for all-cause mortality, 116 for cardiovascular mortality, and 86 for a composite of myocardial infarction (MI) and stroke for ACE inhibitors, compared with nonsignificant benefits for ARBs on the mortality outcomes and NNT of 157 for ARBs on the MI/stroke composite. Second, confounding by indication is possible because until 2013, ACE inhibitors, not ARBs, were first-line medications for heart failure, which is associated with incident lung cancer. Third, findings may be compromised by detection bias due to investigation of ACE inhibitor-induced cough, or by residual confounding due to influential factors not measurable in the available data, such as socioeconomic status (SES) or smoking history. The important questions raised by ERACER and similar drug-safety analyses should be addressed in long-term RCTs or in enhanced large-database pharmacoepidemiological analyses, measuring both NNH and NNT and controlling for SES, indication, medication, and dosage.

Angiotensin Converting Enzyme (ACE) Inhibitor-Induced Cough Resulting in Prescribing Cascade

Objective: Prescribing cascade usually results from the misdiagnosis of a drug-related adverse event or condition. Although the prevalence of prescribing cascade remains unknown, it likely increases the risks associated with polypharmacy (e.g., adverse drug events). Furthermore, consequences of prescribing cascade are more likely to be detrimental for the elderly population due to the presence of multiple chronic diseases and the complexity of the derived medication regimen. This case aims to shed light on a particular prescribing cascade due to angiotensinconverting enzyme (ACE) inhibitor-induced cough. Case: A 101-year-old male with a past medical hypertension, osteoarthritis, gastroesophageal reflux disease, atrial fibrillation, hyperlipidemia, muscle weakness, and mild intermittent asthma was experiencing worsening of cough. To manage his hypertension, the patient was previously prescribed lisinopril and amlodipine. To control the cough, the patient was then prescribed benzonatate (Tessalon Perles®) and budesonideformoterol (Symbicort®). Lisinopril-induced cough was postulated; after the discontinuation of lisinopril and the initiation of losartan, the cough resolved. However, the use of the benzonatate and budesonide-formoterol was not re-evaluated. Conclusion: This case is an example of prescribing cascade resulting from a misdiagnosis of an ACE inhibitor-induced cough. Misdiagnosis may result in inappropriate prescribing of medications that increase the risks resulting from polypharmacy, such as adverse drug events. Pharmacists are uniquely positioned to intercept and avoid such prescribing cascade.

Association between genetic polymorphisms and angiotensin-converting enzyme inhibitor-induced cough: a systematic review and meta-analysis.

Genetic polymorphisms may influence the incidence of angiotensin-converting enzyme (ACE) inhibitor-induced cough. This study aims to investigate this association. Ten electronic databases and PharmGKB were systematically searched. Pooled odds ratio values and their 95% CI were used to assess the association, using the random-effects model. A total of 26 studies were included in the review, 17 of them were included from two separated meta-analysis (ACE I/D or BDKRB2-58T/C). Significant association was found between ACE I/DI carriers (ACE gene insertion) and ACE inhibitor-induced cough, showing racial and age differences. This study demonstrated that ACE I/D but not BDKRB2-58T/C polymorphism could be a predictor for the risk of ACE inhibitor-induced cough, especially in east Asians and the aged.

Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough: a genome-wide association study in a Swedish population.

We conducted a genome-wide association study on angiotensin-converting enzyme inhibitor-induced cough and used our dataset to replicate candidate genes identified in previous studies. A total of 124 patients and 1345 treated controls were genotyped using Illumina arrays. The genome-wide significance level was set to p < 5 × 10-8. We identified nearly genome-wide significant associations in CLASP1, PDE11A, KCNMB2, TGFA, SLC38A6 and MMP16. The strongest association was with rs62151109 in CLASP1 (odds ratio: 3.97; p = 9.44 × 10-8). All top hits except two were located in intronic or noncoding DNA regions. None of the candidate genes were significantly associated in our study. Angiotensin-converting enzyme inhibitor-induced cough is potentially associated with genes that are independent of bradykinin pathways.

Abstract P123: Prevalence of Angiotensin Converting Enzyme Inhibitor-induced Cough and Impact on the Quality of Life of Hypertensive Patients in a Tertiary Health Institution in Nigeria: A Pilot Study

Background/Objective: Angiotensin Converting Enzyme (ACE) inhibitors have widespread use and have been shown to be cardio- and reno-protective. However they have a class side effect of dry persistent cough that has been shown to have a significant impact on the physical, social and psychological health of patients. This study was carried out to determine the prevalence of ACE inhibitor-induced cough and to assess its impact on the quality of life of hypertensive patients in Lagos University Teaching Hospital (LUTH), Nigeria. Method. The study was centered at the outpatient cardiology clinic of LUTH. It was a cross sectional descriptive study with the use of interviewer-administered validated structured questionnaires. The Leicester Cough Questionnaire (LCQ) was used to assess the effect of the cough on the patients quality of life while the Visual Analogue Scale assessed the severity of the cough. Ethical clearance was obtained from the Research and Ethics committee of LUTH and patients consent sought prior commencement of the study. The data obtained was analyzed using SPSS version 20.0 and represented as simple percentages and frequencies. Bivariate analysis was carried out using chi square test. A p-value &lt;0.05 was considered statistically significant. Result: Out of the 101 patients interviewed, 20 patients had experienced ACE inhibitor-induced cough giving a prevalence of 19.8%. The prevalence of the cough was also found to be higher in females (13.86%, 14 of 20) than in males (5.94%, 6 of 20). An LCQ mean score of 13.895 was obtained which showed an average quality of life of the patients. The cough symptom severity results also showed that 40% ( 8 of 20) of the patients had a mild cough, 35% ( 7 of 20) had a moderate cough and 25% ( 5 of 20) had a severe cough. Conclusion: Dry cough is a relatively common side effect associated with ACE inhibitor therapy. The cough induced had an average impact on quality of life and was not severe enough to lead to discontinuation of the ACE inhibitor therapy in most patients.

Rs495828 polymorphism of the ABO gene is a predictor of enalapril-induced cough in Chinese patients with essential hypertension.

ABO genetic polymorphisms have recently been associated with angiotensin-converting enzyme (ACE) activity and inflammation, which play a critical role in the pathogenic mechanism of ACE inhibitor-induced cough. Therefore, the current study determined the association of ABO genetic polymorphisms with enalapril-induced cough in Chinese patients with essential hypertension. A total of 450 essential hypertensive patients treated with 10 mg of enalapril maleate were genotyped for ABO genetic polymorphisms using the PCR-direct sequencing method. Cough was recorded when patients were bothered by cough and respiratory symptoms during enalapril treatment without an identifiable cause. The distribution of rs8176740 and rs495828 was different between the coughers and the controls [P=0.039; odds ratio (OR)=0.70, P=0.018; OR=1.41]. The risk of enalapril-induced cough in the rs495828 TT carriers was increased (P=0.008; OR=2.69), which remained significant after false discovery rate correction. The results for the rs8176740 polymorphism were significant in the female subgroup (P=0.027; OR=0.22). Haplotype analysis of the four ABO polymorphisms (rs8176746/rs8176740/rs495828/rs12683493) showed that the frequency of the GATC haplotype was higher in the coughers than those in the controls (26.6 vs. 18.8%, P=0.033; OR=1.43). The rs495828 polymorphism was associated with enalapril-induced cough and may serve as a useful pharmacogenomics marker of the safety of enalapril in Chinese patients with essential hypertension. The mechanism for the associations may involve the effects of the ABO gene or ABO blood type on ACE activity and inflammation.

NLA Task Force on Statin Safety--2014 update.

1933-2874/$ see front matter 2014 http://dx.doi.org/10.1016/j.jacl.2014.03 Statins are the most widely prescribed class of medications in the United States and their benefits for lowering lowdensity lipoprotein cholesterol (LDL-C) and reducing the risk for coronary heart disease (CHD) are well documented. Statins have been the cornerstone of pharmacotherapy for the management of high blood cholesterol levels virtually since their development. The American Heart Association /American College of Cardiology 2013 guidelines recently expanded the number of individuals eligible for statin therapy by recommending it for those with: (1) clinical atherosclerotic cardiovascular disease (ASCVD), (2) LDL-C $190 mg/dL, (3) type 2 diabetes and age between 40 and 75 years with LDL-C 70 to 189 mg/dL, and (4) an estimated 10-year risk of ASCVD $7.5% and age 40 to 75 years. Considering only those who qualify according to their estimated 10-year risk of ASCVD, it has been reported that of the 101 million people in the United States age 40 to 79 years who do not have cardiovascular disease, 33 million have an estimated 10-year risk of ASCVD $7.5%, and another 13 million have a risk between 5% and 7.4%. Using crude global estimates, 920 million people worldwide would be expected to be

Angiotensin converting enzyme (ACE) gene polymorphism (ACEI/D) in hypertensive adults with ACE inhibitor-induced cough

Angiotensin converting enzyme (ACE) gene polymorphism (ACEI/D) in hypertensive adults with ACE inhibitor-induced cough

What is a preferred angiotensin II receptor blocker-based combination therapy for blood pressure control in hypertensive patients with diabetic and non-diabetic renal impairment?

Hypertension has a major associated risk for organ damage and mortality, which is further heightened in patients with prior cardiovascular (CV) events, comorbid diabetes mellitus, microalbuminuria and renal impairment. Given that most patients with hypertension require at least two antihypertensives to achieve blood pressure (BP) goals, identifying the most appropriate combination regimen based on individual risk factors and comorbidities is important for risk management. Single-pill combinations (SPCs) containing two or more antihypertensive agents with complementary mechanisms of action offer potential advantages over free-drug combinations, including simplification of treatment regimens, convenience and reduced costs. The improved adherence and convenience resulting from SPC use is recognised in updated hypertension guidelines. Despite a wide choice of SPCs for hypertension treatment, clinical evidence from direct head-to-head comparisons to guide selection for individual patients is lacking. However, in patients with evidence of renal disease or at greater risk of developing renal disease, such as those with diabetes mellitus, microalbuminura and high-normal BP or overt hypertension, guidelines recommend renin-angiotensin system (RAS) blocker-based combination therapy due to superior renoprotective effects compared with other antihypertensive classes. Furthermore, RAS inhibitors attenuate the oedema and renal hyperfiltration associated with calcium channel blocker (CCB) monotherapy, making them a good choice for combination therapy. The occurrence of angiotensin-converting enzyme (ACE) inhibitor-induced cough supports the use of angiotensin II receptor blockers (ARBs) for RAS blockade rather than ACE inhibitors. In this regard, ARB-based SPCs are available in combination with the diuretic, hydrochlorothiazide (HCTZ) or the calcium CCB, amlodipine. Telmisartan, a long-acting ARB with preferential pharmacodynamic profile compared with several other ARBs, and the only ARB with an indication for the prevention of CV disease progression, is available in two SPC formulations, telmisartan/HCTZ and telmisartan/amlodipine. Clinical studies suggest that in CV high-risk patients and those with evidence of renal disease, the use of an ARB/CCB combination may be preferred to ARB/HCTZ combinations due to superior renoprotective and CV benefits and reduced metabolic side effects in patients with concomitant metabolic disorders. However, selection of the most appropriate antihypertensive combination should be dependent on careful review of the individual patient and appropriate consideration of drug pharmacology.

Pharmacogenetic predictors of angiotensin-converting enzyme inhibitor-induced cough

Dry cough is the most common reason for stopping angiotensin-converting enzyme inhibitors (ACEi) therapy. The role of ACE in the metabolism of bradykinin has been proposed as a pathogenic mechanism. This study included a complete analysis of the variability of the genes involved in bradykinin metabolism (ACE and XPNPEP2) and bradykinin receptors (BDKRB2). We included two polymorphisms in the ABO (related to ACE levels); two polymorphisms in the AGTR1, and one polymorphism in the BKRB1 (related to ACEi response). A total of 281 patients who had been treated with ACEi were retrospectively recruited [102 patients were considered as cases (cough) and 179 patients were considered as controls (no cough)], and 56 polymorphisms were tested for association. We found that genetic polymorphisms in BDKRB2 [rs8016905; P=0.003; odds ratio (OR)=2.21] and ABO (rs495828; P=0.001; OR=2.45) are associated with ACEi-induced cough after correction for multiple testing. The effect of polymorphisms in ABO was sex specific (female patients; P=0.0006; OR=3.26). When we analyzed the subgroup of patients homozygous GG for rs4343, two polymorphisms in the ACE were found to have protective properties (rs4459610 and rs4267385; P=0.005 and 0.004; OR=0.25). We also found a strong interaction between the ABO polymorphisms, rs495828 and rs8176746 (P<0.0001; OR=3.7). These results highlight the importance of genetic determinants of ACE levels as good predictors of the ACEi response, and provide ABO as a good candidate gene for pharmacogenetic studies of ACEi-related cough. Moreover, our results also confirm the importance of bradykinin in the pathogenesis of this adverse effect.

Zofenopril and incidence of cough: a review of published and unpublished data

ObjectiveCough is a typical side effect of angiotensin-converting enzyme (ACE) inhibitors, though its frequency quantitatively varies among the different compounds. Data on the incidence of cough with the lipophilic third-generation ACE inhibitor zofenopril are scanty and never systematically analyzed. The purpose of this paper is to give an overview on the epidemiology, pathophysiology, and treatment of ACE inhibitor-induced cough and to assess the incidence of cough induced by zofenopril treatment.MethodsPublished and unpublished data from randomized and postmarketing zofenopril trials were merged together and analyzed.ResultsTwenty-three studies including 5794 hypertensive patients and three studies including 1455 postmyocardial infarction patients exposed for a median follow-up time of 3 months to zofenopril at doses of 7.5–60 mg once-daily were analyzed. The incidence of zofenopril-induced cough was 2.6% (range 0%–4.2%): 2.4% in the hypertension trials (2.4% in the double-blind randomized studies and 2.4% in the open-label postmarketing studies) and 3.6% in the doubleblind randomized postmyocardial infarction trials. Zofenopril-induced cough was generally of a mild to moderate intensity, occurred significantly (P < 0.001) more frequently in the first 3–6 months of treatment (3.0% vs 0.2% 9–12 months), and always resolved or improved upon therapy discontinuation. Zofenopril doses of 30 mg and 60 mg resulted in significantly (P = 0.042) greater rate of cough (2.1% and 2.6%, respectively) than doses of 7.5 mg and 15 mg (0.4% and 0.7%, respectively). In direct comparison trials (enalapril and lisinopril), incidence of cough was not significantly different between zofenopril and other ACE inhibitors (2.4% vs 2.7%).ConclusionEvidence from a limited number of studies indicates a relatively low incidence of zofenopril-induced cough. Large head-to-head comparison studies versus different ACE inhibitors are needed to highlight possible differences between zofenopril and other ACE inhibitors in the incidence of cough.

Polymorphisms in the neurokinin-2 receptor gene are associated with angiotensin-converting enzyme inhibitor-induced cough

Treatment with angiotensin-converting enzyme (ACE) inhibitors can induce chronic cough in many patients. Genetic variations in the neurokinin 2 receptor gene (NK2R) are significantly associated with cough sensitivity to capsaicin. This study assessed the relationship between genetic polymorphisms in the NK2R gene and chronic cough in 91 patients taking ACE inhibitors. Patients included in the study did not have chest abnormalities, postnasal drip, gastroesophageal reflux or a recent history of upper respiratory infection. We detected two single nucleotide polymorphisms in the NK2R gene (i.e., Gly231Glu and Arg375His). The allelic frequencies at amino acid 231 were 36.3% for Gly/Gly, 49.5% for Gly/Glu and 14.3% for Glu/Glu. The allelic frequencies at amino acid 375 were 74.7% for Arg/Arg, 24.2% for Arg/His and 1.1% for His/His. The prevalence of chronic cough in patients with the amino acid 231 genotype was 33.3% in Gly/Gly homozygotes, 24.4% in Gly/Glu heterozygotes and 0% in Glu/Glu homozygotes. There was a statistically significant association between chronic cough and the Glu/Glu allele (P = 0.028) when the data were analyzed with a recessive model. In addition, there was a significant inverse linear association between the number of Glu231 alleles and ACE inhibitor-related cough (P = 0.026). The prevalence of chronic cough in patients with the amino acid 375 genotype was 22.1% in Arg/Arg homozygotes, 31.8% in Arg/His heterozygotes and 0% in His/His homozygotes, although none of these association were statistically significant. Our findings indicate that the Gly231Glu polymorphism is associated with a lower prevalence of ACE inhibitor-related cough.

Can aliskiren reduce the incidence of cough caused by ramipril?

reported results from a double-blind, multi-centre trial in which 837 patients with diabetes mellitus and hypertension were randomised to once-daily aliskiren (150 mg titrated to 300 mg after four weeks; n=282), ramipril (5 mg titrated to 10 mg; n=278) or the combination of aliskiren and ramipril for eight weeks. We are not commenting on the effects on blood pressures. We noticed that aliskiren significantly reduced plasma renin activity as monotherapy (by 66%) or in combination with ramipril (by 48%), despite large increases in plasma renin concentration in all treatment groups. Of particular interest was the reported rate of cough; 4.7% in patients receiving ramipril, but only 1.8% of patients receiving the aliskiren/ramipril combination and 2.1% of patients receiving aliskiren only. Although the difference between ramipril and combined ramipril/ aliskiren groups did not achieve significance (p=0.08), the authors noticed the possibility that aliskiren might reduce the incidence of angiotensinconverting enzyme (ACE) inhibitor-induced cough, a property of potential therapeutic value. No explanation for a possible mechanism by which aliskiren might reduce the incidence of ACE inhibitor-induced cough was presented. We would like to offer a theoretical explanation. Induction of cough by ACE inhibitors is believed to be linked to increased tissue accumulation of mainly bradykinin and possibly of other autacoids. ACE both generates angiotensin II from angiotensin I and degrades bradykinin. No ACE inhibitor can cause complete ACE inhibition, but there will always be some ‘escape’ from the inhibitory action. Aliskiren treatment is known to reduce plasma renin activity and plasma concentrations of angiotensin I, a major substrate of ACE. This would leave more active sites of ACE free to cleave bradykinin, which in turn would lead to less accumulation of bradykinin and to – less cough. Future studies will show whether aliskiren or other renin inhibitors may indeed reduce the incidence of cough in patients treated with ACE inhibitors. If true, this would offer possible advantages of combined drug treatment.

Angiotensin-Converting Enzyme Inhibitor-Induced Cough: ACCP Evidence-Based Clinical Practice Guidelines

A dry, persistent cough is a well-described class effect of the angiotensin-converting enzyme (ACE) inhibitor medications. The mechanism of ACE inhibitor-induced cough remains unresolved, but likely involves the protussive mediators bradykinin and substance P, agents that are degraded by ACE and therefore accumulate in the upper respiratory tract or lung when the enzyme is inhibited, and prostaglandins, the production of which may be stimulated by bradykinin. Data for this review were obtained from a National Library of Medicine (PubMed) search, which was performed in May 2004, of the literature published in the English language from 1985 to 2004, using the search terms "angiotensin-converting enzyme," "angiotensin converting enzyme inhibitors," and "cough." The incidence of ACE inhibitor-induced cough has been reported to be in the range of 5 to 35% among patients treated with these agents. However, a much lower incidence has been described in studies of patients presenting for the evaluation of chronic cough. The onset of ACE inhibitor-induced cough ranges from within hours of the first dose to months after the initiation of therapy. Resolution typically occurs within 1 to 4 weeks after the cessation of therapy, but cough may linger for up to 3 months. The only uniformly effective treatment for ACE inhibitor-induced cough is the cessation of treatment with the offending agent. The incidence of cough associated with therapy with angiotensin-receptor blockers appears to be similar to that of the control drug. In a minority of patients, cough will not recur after the reintroduction of ACE inhibitor therapy. In a patient with chronic cough, ACE inhibitors should be considered as wholly or partially causative, regardless of the temporal relation between the initiation of ACE inhibitor therapy and the onset of cough. Although the cessation of therapy is the only uniformly effective treatment for ACE inhibitor-induced cough, some pharmacologic agents have been shown to attenuate the cough.

Angiotensin-Converting Enzyme Inhibitors and Obstructive Sleep Apnea

Angiotensin-converting enzyme (ACE) inhibitors may induce cough and rhinopharyngeal inflammation. Obstructive sleep apnea (OSA) is characterized by upper airway inflammation. We describe a patient who, during enalapril treatment, developed cough, upper airway symptoms, and diurnal sleepiness, with an increased number of obstructive apnea-hypopnea episodes (apnea-hypopnea index [AHI], 25) during sleep. Her symptoms and AHI improved 1 month after enalapril was discontinued and diuretic therapy (hydrochlorothiazide-spironolactone) was initiated. Similar findings were observed in 4 other patients with OSA who had ACE inhibitor-induced cough. The mean +/- SD AHI was 33.8+/-21.0 during enalapril treatment and 20.0+/-17.0 after withdrawal of this drug (P = .04). Exhaled nitric oxide, a marker of airway inflammation, was increased during enalapril treatment (15.0 +/- 4.3 parts per billion) and decreased after discontinuation of this drug (9.0 +/- 2.6; P = .03). No significant difference in the AHI and exhaled nitric oxide was observed in 4 patients with OSA who did not experience cough, before or after withdrawal of ACE inhibitor treatment. These findings suggest that ACE inhibitor treatment may contribute to OSA by inducing upper airway inflammation.

An evaluation of risk factors for adverse drug events associated with angiotensin-converting enzyme inhibitors.

To identify potential factors leading to discontinuation of angiotensin-converting enzyme (ACE) inhibitors because of adverse drug events. Retrospective cohort study was conducted at outpatient clinics affiliated with an urban tertiary care hospital. ACE inhibitors were administered to 2225 consecutive outpatients. In 19% of the total cohort, ACE inhibitors were discontinued because of adverse drug events. Cox proportional hazard model identified the following independent risk factors for discontinuation because of adverse drug events: age, female gender, ethnicity other than African American or Latino, no history of previous ACE inhibitor use, history of cough caused by another ACE inhibitor, hypertension, anxiety or depression, no hemodialysis, and elevated creatinine. History of smoking was shown to be a risk factor for cough [hazard ratio (HR): 2.5; 95% confidence interval (CI): 1.1-5.7], angioedema (HR: 2.7; 95% CI: 1.1-7.0), and hyperkalaemia (HR: 5.4; 95% CI: 1.3-23.2). History of ACE inhibitor-induced cough was not only a risk factor for cough (HR: 12.9; 95% CI: 7.5-22.3) but also for angioedema (HR: 9.1; 95% CI: 2.1-39.9). Patients with creatinine > or = 1.6 mg dL(-1) were likely to discontinue ACE inhibitors because of renal dysfunction (HR: 4.7; 95% CI: 1.5-12.7) and hyperkalaemia (HR: 10.9; 95% CI: 3.1-39.0). East Asians were more likely to develop cough (HR: 2.5; 95% CI: 1.1-5.7) and hyperkalaemia (HR: 80.3; 95% CI: 5.4-1190) and African Americans to develop angioedema (HR: 3.5; 95% CI: 1.3-8.9). Although further validation is necessary, these risk factors should help doctors identify patients with elevated risk for adverse drug events because of ACE inhibitors.

Cough and angioedema from angiotensin-converting enzyme inhibitors: new insights into mechanisms and management.

Angiotensin-converting enzyme inhibitors are widely prescribed for hypertension and heart failure. These drugs are commonly associated with cough, and are less commonly associated with angioedema, which may be potentially life threatening. This review describes data that extend our understanding of the mechanisms of these reactions, and provides guidance about clinical management. For patients who develop angioedema from angiotensin-converting enzyme inhibitors, recent data are reassuring that the majority of such patients can tolerate angiotensin-II receptor blockers. These data support earlier conclusions that most patients with angiotensin-converting enzyme inhibitor-induced cough can tolerate angiotensin-II receptor blockers. Limited case reports suggest that in acute angioedema induced by angiotensin-converting enzyme inhibitors, patients refractory to standard treatment may benefit from the infusion of fresh frozen plasma. Although data are incomplete, it appears that angiotensin-converting enzyme inhibitors cause cough and angioedema through a cascade of effects that begins with the accumulation of kinins, and then involves arachidonic acid metabolism and nitric oxide generation. Most patients who develop either cough or angioedema from angiotensin-converting enzyme inhibitors can tolerate angiotensin-II receptor blocking agents.

Development and validation of a clinical prediction rule for angiotensin-converting enzyme inhibitor-induced cough.

Angiotensin-converting enzyme inhibitors are effective for many cardiovascular diseases and are widely prescribed, but cough sometimes necessitates their withdrawal. To develop and validate a model that predicts, by using information available at first prescription, whether a patient will develop cough within 6 months. Retrospective cohort study with derivation and validation sets. Outpatient clinics affiliated with an urban tertiary care hospital. Clinical data were collected from electronic charts. The derivation set included 1125 patients and the validation set included 567 patients. None. Angiotensin-converting enzyme inhibitor-induced cough assessed by predetermined criteria. In the total cohort, 12% of patients developed angiotensin-converting enzyme inhibitor-induced cough. Independent multivariate predictors of cough were older age, female gender, non-African American (with East Asian having highest risk), no history of previous angiotensin-converting enzyme inhibitor use, and history of cough due to another angiotensin-converting enzyme inhibitor. Patients with a history of angiotensin-converting enzyme inhibitor-induced cough were 29 times more likely to develop a cough than those without this history. These factors were used to develop a model stratifying patients into 4 risk groups. In the derivation set, low-risk, average-risk, intermediate-risk, and high-risk groups had a 6%, 9%, 22%, and 55% probability of cough, respectively. In the validation set, 4%, 14%, 20%, and 60% of patients in these 4 groups developed cough, respectively. This model may help clinicians predict the likelihood of a particular patient developing cough from an angiotensin-converting enzyme inhibitor at the time of prescribing, and may also assist with subsequent clinical decisions.