- Email: [email protected]
Cough induced by losartan with resolution after substitution with enalapril
Clinical Therapeutics/Volume 30, Number 3, 2008
Case Report
Cough Induced by Losartan with Resolution After Substitution with Enalapril Simin Dashti-Khavidaki, PharmD1; Toktam Faghihi1; Farrokhlegha Ahmadi, MD2; and Hossein Khalili, PharmD1 1Department
Iran; and
of Clinical Pharmacy, School of Pharmacy, Medical Sciences, University of Tehran, Tehran, Referral Hospital, Medical Sciences, University of Tehran, Tehran, Iran
2Imam
Abstract
INTRODUCTION
Introduction: Cough is an adverse event associated with the angiotensin-converting enzyme (ACE) inhibitor drugs. ACE inhibitor–induced cough is believed to be related to the accumulation of bradykinin, substance P, and prostaglandins resulting from the inhibition of ACE. Angiotensin-receptor blockers (ARBs) do not have any effect on ACE and theoretically might not cause cough. Therefore, a proposed option in patients suffering with ACE inhibitor–induced cough is to try an ARB. However, this report describes the reverse: a case of losartan-induced cough that completely resolved after it was substituted with an ACE inhibitor, enalapril. Case summary: A 23-year-old, nonsmoking white woman, weighing 73.5 kg, ACE inhibitor naive (before admission), presented to the emergency department at Imam Referral Hospital, Tehran, Iran, with hypertension, proteinuria, and hyperlipidemia. The patient was admitted to the nephrology ward. She was prescribed hydrochlorothiazide 12.5 mg/d, furosemide 20 mg BID, and simvastatin 20 mg/d. The patient had no respiratory illnesses. The patient experienced cough 3 days following the initiation of losartan treatment. The cough continued in this patient for the 2-week duration of losartan treatment; however, 1 week after substitution of losartan with enalapril (2.5 mg/d), the cough resolved completely. Conclusion: This report describes a young woman who developed cough while receiving losartan treatment, which resolved after substitution with the ACE inhibitor enalapril. (Clin Ther. 2008;30:548–551) © 2008 Excerpta Medica Inc. Key words: cough, losartan, enalapril, angiotensinconverting enzyme inhibitor, angiotensin-receptor blockers.
Cough is an adverse event (AE) associated with angiotensin-converting enzyme (ACE) inhibitor medications, with a prevalence rate of 10% per year of treatment.1 Among patients being treated with this class of agents, the prevalence is reported to be in the range of 5% to 35%.2 The characteristic of ACE inhibitor–induced cough is highly variable3 but is commonly a dry, tickly (ie, nonproductive) cough,4 with a varying range of onset from 1 week to 1 year after the start of ACE inhibitor treatment.3 The severity of cough is also variable, from a bothersome, dry tickle to a persistent hacking accompanied by insomnia and/ or vomiting. Research has found it more prevalent in females and with increasing age.3 After discontinuation of ACE inhibitor treatment, alleviation of cough is rapid, usually within 1 week,5 with a range of 1 to 26 days.3 However, in a subgroup of patients, the cough can last up to 3 months.2 The mechanism of cough is not clearly understood, but it is thought to be related to the accumulation of bradykinin, substance P, and prostaglandins (PGs).3 Angiotensin-receptor blockers (ARBs) block angiotensin (AT) subtype 1 angiotensin II receptors. They do not have an effect on the cough mediators bradykinin and substance P and theoretically should not be associated with cough.3,4 Studies3,4,6,7 have reported that the prevalence of cough is lower with several ARBs than with ACE inhibitors and is similar to that of placebo4,8 or the diuretic hydrochlorothiazide (HCTZ).7,9 In a multicenter, double-blind, parallel-group,
548
Accepted for publication January 24, 2008. doi:10.1016/j.clinthera.2008.03.003 0149-2918/$32.00 © 2008 Excerpta Medica Inc. All rights reserved.
Volume 30 Number 3
S. Dashti-Khavidaki et al. active- and placebo-controlled trial4 in 100 hypertensive patients with a history of ACE inhibitor–induced cough, lisinopril was found to have a statistically significant higher prevalence of dry cough than losartan and placebo (87.5% vs 36.7% and 31.4%, respectively; P < 0.001), and there was no statistically significant difference between losartan and placebo.4 In a randomized, double-blind, parallel-group study, Ramsay et al9 compared the prevalence of cough associated with the ARB losartan, the ACE inhibitor lisinopril, and the diuretic HCTZ in 135 hypertensive patients with a history of ACE inhibitor–induced cough. Their study reported a significantly lower prevalence of cough associated with losartan compared with lisinopril (29% vs 72%, respectively; P < 0.01) and similar to that of HCTZ (34%). Cough frequency was also significantly lower for losartan compared with lisinopril (P < 0.01) and similar to that of HCTZ. We report a case of losartan-induced cough with resolution after substitution with enalapril. A search of the literature was performed using the PubMed, OVID, and EMBASE databases for English-language original research, review articles, and case reports containing key terms angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, losartan, enalapril, and cough published between 1980 to December 2007. Our search did not identify any similar cases of cough associated with losartan treatment with resolution after switching to an ACE inhibitor.
CASE SUMMARY A 23-year-old, nonsmoking white woman, weighing 73.5 kg, ACE inhibitor naive (before admission), presented to the emergency department at Imam Referral Hospital, Tehran, Iran, with hypertension, proteinuria, and hyperlipidemia. The patient was subsequently admitted to the nephrology ward. She was prescribed HCTZ 12.5 mg/d to treat hypertension, losartan potassium 12.5 mg/d to treat hypertension and proteinuria, furosemide 20 mg BID to treat edema, and simvastatin 20 mg/d to treat hyperlipidemia concomitantly. The patient was not receiving any other medications and had no other documented diseases. She experienced a dry, irritating cough 3 days following the initiation of losartan potassium. The patient’s medical history did not reveal any food, drug, or other type of allergies, and she was ACE inhibitor naive on admission. Physical examination revealed that at the onset of cough, there was no evidence of respiratory infecMarch 2008
tion (eg, sinusitis, pneumonia), asthma, postnasal drip, bronchitis, heart failure, or gastroesophageal reflux. The patient was a nonsmoker. Her chest radiograph was normal and her purified protein derivative test was negative. There was no change in her environment (ie, exposure to molds or pets) or habit (ie, smoking) at the onset of cough. The patient was under the observation of her practitioner for the specified conditions. Losartan potassium along with the other medications being administered continued for 2 weeks. However, the cough persisted with no resolution in this patient. After 2 weeks and no resolve, losartan was substituted with an ACE inhibitor, enalapril (2.5 mg/d). Both ACE inhibitors and ARBs have been reported to have beneficial effects on proteinuric renal diseases, and there are no contraindications of ACE inhibitors after ARB-induced cough.10 After initiating enalapril, the cough resolved completely within 1 week. Because ARB-induced cough is a contraindication of rechallenge with the same class,10 the patient was not rechallenged with losartan. The patient was discharged after 3 weeks. Even after 6 months, the patient remained cough free. During this follow-up period, she was diagnosed with systemic lupus erythematosus.
DISCUSSION Cough associated with ACE inhibitor medication is a documented AE that is believed to be associated with their effects on increasing bradykinin levels. According to this mechanism of cough, ARBs would not be expected to produce cough. However, cough has been reported with ARB administration, resulting in further investigations which identified other endogenous pathways and chemicals that result in increased local concentrations of thromboxane A2 , substance P, and PGs. In addition, secondary stimulation of AT subtype 2 angiotensin II receptors and subsequent increase in tissue bradykinin levels have been proposed to explain cough associated with ARBs. In the setting of ARB-induced cough, changing to another class of antihypertensive drugs (eg, calcium channel blockers, β-blockers) should be attempted. In the present case, the relationship between losartan and cough without other obvious cause suggests losartan as the precipitating agent for this AE. The patient’s Naranjo Probability Scale11 score (Table) was a 6, which is defined as a probable relationship between cough and losartan treatment. Our patient did not experience any AEs while on enalapril. Although cough is 549
Clinical Therapeutics
Table. Naranjo Probability Scale11 score assessing the adverse drug reaction (ADR) in a case of cough in a female patient treated with losartan potassium (12.5 mg/d). Question Yes No
Don’t Know
Patient’s Score
0
+1
2. Did the ADR appear after the suspected drug was administered? +2 –1 0 3. Did the ADR improve when the drug was discontinued or after a specific antagonist? +1 –1 0 4. Did the ADR reappear after the drug was restarted? +2 –1 0 5. Are there alternative causes that could have caused the ADR on their own? –1 +2 0 6. Did the reaction reappear after placebo was administered? –1 0 0 7. Were blood levels of the drug in a range known to be toxic? +1 0 0 8. Was reaction more severe when dose was increased or less severe when dose was decreased? +1 0 0 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1 0 0 10. Was the ADR confirmed by objective evidence (ie, laboratory findings)? +1 0 0 Total score
+2
1. Are there previous conclusive reports on this reaction?
not mentioned as a possible AE of HCTZ in the drug information reference, Ramsay et al9 reported a 34% prevalence rate with HCTZ treatment compared with placebo. There are no reports of furosemide-induced cough, and there is 1 Japanese case report of simvastatininduced eosinophilic pneumonia. Our patient’s cough resolved after switching from losartan to enalapril while HCTZ was continued.
CoNCLUSION Although the mechanism of such effect is not known, here we report a case of probable cough induced by the ARB, losartan, that resolved after substitution with an ACE inhibitor, enalapril, in a patient with systemic lupus erythematosus.
REFERENCES 1. Nussberger J, Koike H. Antagonizing the angiotensin II subtype I receptor: A focus on olmesartan medoxomil. Clin Ther. 2004;26:A12–A20. 2. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitorinduced cough: ACCP evidence-based clinical practice guidelines. Chest. 2006;129;169S–173S.
550
+1
0
+1 0 +2 0 0 0 0 0 +6
3. Pylypchuk GB. ACE inhibitor- versus angiotensin II blockerinduced cough and angioedema. Ann Pharmacother. 1998; 32:1060–1066. 4. Paster RZ, Snavely DB, Sweet AR, et al. Use of losartan in the treatment of hypertensive patients with a history of cough induced by angiotensin-converting enzyme inhibitors. Clin Ther. 1998;20:978–989. 5. Sadeghi N, Panje W. Angiotensin-converting enzyme inhibitor therapy: Adverse effects encountered by otolaryngologist. Curr Opin Otolaryngol Head Neck Surg. 2001;9: 162–165. 6. Coca A, Calvo C, García-Puig J, et al, for the MAPAVEL Investigators. A multicenter, randomized, double-blind comparison of the efficacy and safety of irbesartan and enalapril in adults with mild to moderate essential hypertension, as assessed by ambulatory blood pressure monitoring: The MAPAVEL Study (Monitorizacíon Ambulatoria Presión Arterial APROVEL). Clin Ther. 2002;24:126–138. 7. Lacourcière Y, Brunner H, Irwin R, et al, for the Losartan Cough Study Group. Effects of modulators of the reninangiotensin-aldosterone system on cough. J Hypertens. 1994;12:1387–1393. 8. Goldberg AI, Dunlay MC, Sweet CS. Safety and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol,
Volume 30 Number 3
S. Dashti-Khavidaki et al. felodipine ER, and angiotensinconverting enzyme inhibitors for the treatment of systemic hypertension. Am J Cardiol. 1995;75:793–795. 9. Ramsay LE, Yeo WW, for the Losartan Cough Study Group. ACE inhibitors, angiotensin II antagonists and cough. J Hum Hypertens. 1995;9 (Suppl 5):S51–S54. 10. K-DOQI guidelines. http://www. kidney.org/professionals/kdoqi/ guidelines. Accessed December 26, 2007. 11. Naranjo CA, Busto O, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–245.
Address correspondence to: Simin Dashti-Khavidaki, PharmD, Department of Clinical Pharmacy, School of Pharmacy, Medical Sciences, University of Tehran, PO Box 14155/6451, Tehran, Iran, 14176-14411. E-mail: [email protected] March 2008
551
Case Report
Cough Induced by Losartan with Resolution After Substitution with Enalapril Simin Dashti-Khavidaki, PharmD1; Toktam Faghihi1; Farrokhlegha Ahmadi, MD2; and Hossein Khalili, PharmD1 1Department
Iran; and
of Clinical Pharmacy, School of Pharmacy, Medical Sciences, University of Tehran, Tehran, Referral Hospital, Medical Sciences, University of Tehran, Tehran, Iran
2Imam
Abstract
INTRODUCTION
Introduction: Cough is an adverse event associated with the angiotensin-converting enzyme (ACE) inhibitor drugs. ACE inhibitor–induced cough is believed to be related to the accumulation of bradykinin, substance P, and prostaglandins resulting from the inhibition of ACE. Angiotensin-receptor blockers (ARBs) do not have any effect on ACE and theoretically might not cause cough. Therefore, a proposed option in patients suffering with ACE inhibitor–induced cough is to try an ARB. However, this report describes the reverse: a case of losartan-induced cough that completely resolved after it was substituted with an ACE inhibitor, enalapril. Case summary: A 23-year-old, nonsmoking white woman, weighing 73.5 kg, ACE inhibitor naive (before admission), presented to the emergency department at Imam Referral Hospital, Tehran, Iran, with hypertension, proteinuria, and hyperlipidemia. The patient was admitted to the nephrology ward. She was prescribed hydrochlorothiazide 12.5 mg/d, furosemide 20 mg BID, and simvastatin 20 mg/d. The patient had no respiratory illnesses. The patient experienced cough 3 days following the initiation of losartan treatment. The cough continued in this patient for the 2-week duration of losartan treatment; however, 1 week after substitution of losartan with enalapril (2.5 mg/d), the cough resolved completely. Conclusion: This report describes a young woman who developed cough while receiving losartan treatment, which resolved after substitution with the ACE inhibitor enalapril. (Clin Ther. 2008;30:548–551) © 2008 Excerpta Medica Inc. Key words: cough, losartan, enalapril, angiotensinconverting enzyme inhibitor, angiotensin-receptor blockers.
Cough is an adverse event (AE) associated with angiotensin-converting enzyme (ACE) inhibitor medications, with a prevalence rate of 10% per year of treatment.1 Among patients being treated with this class of agents, the prevalence is reported to be in the range of 5% to 35%.2 The characteristic of ACE inhibitor–induced cough is highly variable3 but is commonly a dry, tickly (ie, nonproductive) cough,4 with a varying range of onset from 1 week to 1 year after the start of ACE inhibitor treatment.3 The severity of cough is also variable, from a bothersome, dry tickle to a persistent hacking accompanied by insomnia and/ or vomiting. Research has found it more prevalent in females and with increasing age.3 After discontinuation of ACE inhibitor treatment, alleviation of cough is rapid, usually within 1 week,5 with a range of 1 to 26 days.3 However, in a subgroup of patients, the cough can last up to 3 months.2 The mechanism of cough is not clearly understood, but it is thought to be related to the accumulation of bradykinin, substance P, and prostaglandins (PGs).3 Angiotensin-receptor blockers (ARBs) block angiotensin (AT) subtype 1 angiotensin II receptors. They do not have an effect on the cough mediators bradykinin and substance P and theoretically should not be associated with cough.3,4 Studies3,4,6,7 have reported that the prevalence of cough is lower with several ARBs than with ACE inhibitors and is similar to that of placebo4,8 or the diuretic hydrochlorothiazide (HCTZ).7,9 In a multicenter, double-blind, parallel-group,
548
Accepted for publication January 24, 2008. doi:10.1016/j.clinthera.2008.03.003 0149-2918/$32.00 © 2008 Excerpta Medica Inc. All rights reserved.
Volume 30 Number 3
S. Dashti-Khavidaki et al. active- and placebo-controlled trial4 in 100 hypertensive patients with a history of ACE inhibitor–induced cough, lisinopril was found to have a statistically significant higher prevalence of dry cough than losartan and placebo (87.5% vs 36.7% and 31.4%, respectively; P < 0.001), and there was no statistically significant difference between losartan and placebo.4 In a randomized, double-blind, parallel-group study, Ramsay et al9 compared the prevalence of cough associated with the ARB losartan, the ACE inhibitor lisinopril, and the diuretic HCTZ in 135 hypertensive patients with a history of ACE inhibitor–induced cough. Their study reported a significantly lower prevalence of cough associated with losartan compared with lisinopril (29% vs 72%, respectively; P < 0.01) and similar to that of HCTZ (34%). Cough frequency was also significantly lower for losartan compared with lisinopril (P < 0.01) and similar to that of HCTZ. We report a case of losartan-induced cough with resolution after substitution with enalapril. A search of the literature was performed using the PubMed, OVID, and EMBASE databases for English-language original research, review articles, and case reports containing key terms angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, losartan, enalapril, and cough published between 1980 to December 2007. Our search did not identify any similar cases of cough associated with losartan treatment with resolution after switching to an ACE inhibitor.
CASE SUMMARY A 23-year-old, nonsmoking white woman, weighing 73.5 kg, ACE inhibitor naive (before admission), presented to the emergency department at Imam Referral Hospital, Tehran, Iran, with hypertension, proteinuria, and hyperlipidemia. The patient was subsequently admitted to the nephrology ward. She was prescribed HCTZ 12.5 mg/d to treat hypertension, losartan potassium 12.5 mg/d to treat hypertension and proteinuria, furosemide 20 mg BID to treat edema, and simvastatin 20 mg/d to treat hyperlipidemia concomitantly. The patient was not receiving any other medications and had no other documented diseases. She experienced a dry, irritating cough 3 days following the initiation of losartan potassium. The patient’s medical history did not reveal any food, drug, or other type of allergies, and she was ACE inhibitor naive on admission. Physical examination revealed that at the onset of cough, there was no evidence of respiratory infecMarch 2008
tion (eg, sinusitis, pneumonia), asthma, postnasal drip, bronchitis, heart failure, or gastroesophageal reflux. The patient was a nonsmoker. Her chest radiograph was normal and her purified protein derivative test was negative. There was no change in her environment (ie, exposure to molds or pets) or habit (ie, smoking) at the onset of cough. The patient was under the observation of her practitioner for the specified conditions. Losartan potassium along with the other medications being administered continued for 2 weeks. However, the cough persisted with no resolution in this patient. After 2 weeks and no resolve, losartan was substituted with an ACE inhibitor, enalapril (2.5 mg/d). Both ACE inhibitors and ARBs have been reported to have beneficial effects on proteinuric renal diseases, and there are no contraindications of ACE inhibitors after ARB-induced cough.10 After initiating enalapril, the cough resolved completely within 1 week. Because ARB-induced cough is a contraindication of rechallenge with the same class,10 the patient was not rechallenged with losartan. The patient was discharged after 3 weeks. Even after 6 months, the patient remained cough free. During this follow-up period, she was diagnosed with systemic lupus erythematosus.
DISCUSSION Cough associated with ACE inhibitor medication is a documented AE that is believed to be associated with their effects on increasing bradykinin levels. According to this mechanism of cough, ARBs would not be expected to produce cough. However, cough has been reported with ARB administration, resulting in further investigations which identified other endogenous pathways and chemicals that result in increased local concentrations of thromboxane A2 , substance P, and PGs. In addition, secondary stimulation of AT subtype 2 angiotensin II receptors and subsequent increase in tissue bradykinin levels have been proposed to explain cough associated with ARBs. In the setting of ARB-induced cough, changing to another class of antihypertensive drugs (eg, calcium channel blockers, β-blockers) should be attempted. In the present case, the relationship between losartan and cough without other obvious cause suggests losartan as the precipitating agent for this AE. The patient’s Naranjo Probability Scale11 score (Table) was a 6, which is defined as a probable relationship between cough and losartan treatment. Our patient did not experience any AEs while on enalapril. Although cough is 549
Clinical Therapeutics
Table. Naranjo Probability Scale11 score assessing the adverse drug reaction (ADR) in a case of cough in a female patient treated with losartan potassium (12.5 mg/d). Question Yes No
Don’t Know
Patient’s Score
0
+1
2. Did the ADR appear after the suspected drug was administered? +2 –1 0 3. Did the ADR improve when the drug was discontinued or after a specific antagonist? +1 –1 0 4. Did the ADR reappear after the drug was restarted? +2 –1 0 5. Are there alternative causes that could have caused the ADR on their own? –1 +2 0 6. Did the reaction reappear after placebo was administered? –1 0 0 7. Were blood levels of the drug in a range known to be toxic? +1 0 0 8. Was reaction more severe when dose was increased or less severe when dose was decreased? +1 0 0 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1 0 0 10. Was the ADR confirmed by objective evidence (ie, laboratory findings)? +1 0 0 Total score
+2
1. Are there previous conclusive reports on this reaction?
not mentioned as a possible AE of HCTZ in the drug information reference, Ramsay et al9 reported a 34% prevalence rate with HCTZ treatment compared with placebo. There are no reports of furosemide-induced cough, and there is 1 Japanese case report of simvastatininduced eosinophilic pneumonia. Our patient’s cough resolved after switching from losartan to enalapril while HCTZ was continued.
CoNCLUSION Although the mechanism of such effect is not known, here we report a case of probable cough induced by the ARB, losartan, that resolved after substitution with an ACE inhibitor, enalapril, in a patient with systemic lupus erythematosus.
REFERENCES 1. Nussberger J, Koike H. Antagonizing the angiotensin II subtype I receptor: A focus on olmesartan medoxomil. Clin Ther. 2004;26:A12–A20. 2. Dicpinigaitis PV. Angiotensin-converting enzyme inhibitorinduced cough: ACCP evidence-based clinical practice guidelines. Chest. 2006;129;169S–173S.
550
+1
0
+1 0 +2 0 0 0 0 0 +6
3. Pylypchuk GB. ACE inhibitor- versus angiotensin II blockerinduced cough and angioedema. Ann Pharmacother. 1998; 32:1060–1066. 4. Paster RZ, Snavely DB, Sweet AR, et al. Use of losartan in the treatment of hypertensive patients with a history of cough induced by angiotensin-converting enzyme inhibitors. Clin Ther. 1998;20:978–989. 5. Sadeghi N, Panje W. Angiotensin-converting enzyme inhibitor therapy: Adverse effects encountered by otolaryngologist. Curr Opin Otolaryngol Head Neck Surg. 2001;9: 162–165. 6. Coca A, Calvo C, García-Puig J, et al, for the MAPAVEL Investigators. A multicenter, randomized, double-blind comparison of the efficacy and safety of irbesartan and enalapril in adults with mild to moderate essential hypertension, as assessed by ambulatory blood pressure monitoring: The MAPAVEL Study (Monitorizacíon Ambulatoria Presión Arterial APROVEL). Clin Ther. 2002;24:126–138. 7. Lacourcière Y, Brunner H, Irwin R, et al, for the Losartan Cough Study Group. Effects of modulators of the reninangiotensin-aldosterone system on cough. J Hypertens. 1994;12:1387–1393. 8. Goldberg AI, Dunlay MC, Sweet CS. Safety and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol,
Volume 30 Number 3
S. Dashti-Khavidaki et al. felodipine ER, and angiotensinconverting enzyme inhibitors for the treatment of systemic hypertension. Am J Cardiol. 1995;75:793–795. 9. Ramsay LE, Yeo WW, for the Losartan Cough Study Group. ACE inhibitors, angiotensin II antagonists and cough. J Hum Hypertens. 1995;9 (Suppl 5):S51–S54. 10. K-DOQI guidelines. http://www. kidney.org/professionals/kdoqi/ guidelines. Accessed December 26, 2007. 11. Naranjo CA, Busto O, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–245.
Address correspondence to: Simin Dashti-Khavidaki, PharmD, Department of Clinical Pharmacy, School of Pharmacy, Medical Sciences, University of Tehran, PO Box 14155/6451, Tehran, Iran, 14176-14411. E-mail: [email protected] March 2008
551