Zofenopril and incidence of cough: a review of published and unpublished data

Figures & data

Figure 1 Pathophysiology of angiotensin-converting enzyme inhibitor-induced cough.^71,72

Abbreviations: ACE, angiotensin-converting enzyme; PG, prostaglandin.

Table 1 Details of placebo or active drug controlled studies in which occurrence of cough with zofenopril was assessed in hypertensive and postmyocardial infarction patients

Study	Zofenopril daily dose (mg)	Associated drug and daily dose (mg)	n	Control drug and daily dose (mg)	Study design	Inclusion criteria	Age range (years)	Treatment duration (weeks)
Study no. 21974-23^Citation10	7.5, 15, 30, or 60	Hydrochlorothiazide 25	301	Placebo	DBR PL PG	DBP 95–110 mmHg	19–79	8
Study no. 21974-26^Citation10	7.5, 15, 30, or 60	Hydrochlorothiazide 25	260	Placebo (hydrochlorothiazide 25)	DBR ACT/PL PG	DBP 95–114 mmHg	23–86	8
Study no. SZQ02^Citation10	7.5, 15, or 30	None	141	Placebo	DBR PL PG	Elderly DBP 95–115 mmHg SBP 170–220 mmHg	65–86	8
Study no. SZQ03^Citation10	15 or 30	None	88	Nifedipine 80	DBR ACT PG	Elderly DBP 95–115 mmHg SBP 170–220 mmHg	63–92	8
Study no. SQZ05^Citation10	30 or 60	None	57	Placebo	DBR PL PG	DBP 95–110 mmHg	27–71	6
Study no. 21974-16^Citation10	30 or 60	Hydrochlorothiazide 25	192	Atenolol 50 or 100, hydrochlorothiazide 25	DBR ACT PG	DBP 95–110 mmHg	23–81	12
Study no. 21974-17^Citation10	30 or 60	Nadolol 40	166	Hydrochlorothiazide 25 or 50, nadolol 40	DBR ACT PG	DBP 95–110 mmHg	22–81	12
Study no. 21974-20^Citation10	30 or 60	Prazosin 2, chlorthalidone 25	133	Propranolol 80 or 160, prazosin 2, chlorthalidone 25	DBR PL PG	DBP 95–115 mmHg	24–77	12
Study no. 21974-18^Citation10	15, 30 or 60	None	41	Enalapril 2.5, 5, or 10	DBR PL PG	DBP 95–110 mmHg	27–79	12
Study no. 21974-11^Citation10	30 or 60	Chlorthalidone 25	373	Placebo	DBR PL PG	DBP 92–110 mmHg	19–84	48
Study no. 21974-28^Citation10	30 or 60	Chlorthalidone 25	185	Enalapril 5 or 10, chlorthalidone 25	DBR ACT PG	Renal impairment DBP 95–110 mmHg	21–76	52
Study no. ZOF01MEN^Citation10	7.5, 15, 30, or 60	None	168	Placebo	DBR PL PG	DBP 95–114 mmHg	26–66	6
Parati et al^Citation11	15, 30, or 60	Hydrochlorothiazide 12.5 or 25	282	None	DBR PG	DBP 95–110 mmHg	18–75	12
Omboni et al^Citation1	30	Hydrochlorothiazide 12.5	350	Hydrochlorothiazide 12.5	DBR ACT PG	DBP 95–115 mmHg	18–75	36
Omboni et al^Citation1	30	Hydrochlorothiazide 12.5	376	None	DBR PG	DBP 90–100 mmHg	18–70	8
Nilsson^Citation12	30 or 60	None	147	Atenolol 50 or 100 DBR	ACT PG	DBP 95–115 mmHg	18–75	12
Narkiewicz^Citation13	30 or 60	None	165	Losartan 50 or 100 DBR	ACT PG	DBP 95–110 mmHg	18–75	12
Mallion^Citation14	30 or 60	None	155	Enalapril 20 or 40	DBR ACT PG	DBP 95–115 mmHg	23–70	12
Farsang^Citation15	30 or 60	None	152	Amlodipine 5 or 10	DBR ACT PG	DBP 95–110 mmHg	18–75	14
Leonetti et al^Citation16	30 or 60	None	114	Candesartan 8 or 16	DBR ACT PG	DBP 90–109 mmHg SBP 140–179 mmHg	18–65	12
Malacco et al^Citation17	30 or 60	None	91	Lisinopril 10 or 20	DBR ACT PG	Elderly DBP 90–110 mmHg	65–90	12
Study no. PMS-1 (CRF23012)^Citation10	30 or 60	None	1,303	None	OL	DBP ≥ 90 mmHg	18–75	31
Study no. PMS-2 (CRF23022)^Citation10	30 or 60	None	554	None	OL	Diabetes mellitus DBP ≥ 90 mmHg	18–75	19
SMILE-1^Citation5	7.5, 15, 30, or 60	None	772	Placebo	DBR PL PG	<24 hours nonthrombolyzed acute myocardial infarction	18–80	6
SMILE-2^Citation6	7.5, 15, 30, or 60	None	504	Lisinopril 2.5 to 10 mg	DBR ACT PG	<48 hours thrombolyzed patients with acute myocardial infarction	18–75	6
SMILE-3^Citation7	30 or 60	None	179	Placebo	DBR PL PG	Postmyocardial infarction with preserved left ventricular ejection fraction (>40%)	18–75	24

Abbreviations: ACT, active control; DBP, diastolic blood pressure; DBR, double blind randomized; OL, open label; PG, parallel group; PL, placebo control; SBP, systolic blood pressure; SMILE, Survival of Myocardial Infarction Long-term Evaluation.

Figure 2 Prevalence (%) of cough under zofenopril in hypertensive patients (A) according to study design, age, and gender and (B) versus other drugs, including angiotensin II antagonists, other angiotensin-converting enzyme inhibitors, beta-blockers, and combination of zofenopril with hydrochlorothiazide.

Note: P values refer to between-group differences.^1,10–17
Abbreviations: ACE, angiotensin-converting enzyme; HCTZ, hydrochlorothiazide.

Figure 3 Incidence (%) of drug-related cough stratified by observation period during zofenopril treatment of 5794 hypertensive patients.

Note: Numbers in brackets refer to the number of patients evaluated per treatment period.^1,10–17

Figure 4 Prevalence (%) of drug-related cough by zofenopril dose in hypertensive patients.

Note: Numbers in brackets refer to the number of patients evaluated per treatment period.^1,10–17

Figure 5 Rate (%) of patients with zofenopril-related cough in the postinfarction Survival of Myocardial Infarction Long-term Evaluation (SMILE) studies.^5–7

Figure 6 Changes (%) in the inhibition of lung angiotensin-converting enzyme activity as a function of time (hours and days) after administration of equivalent oral doses of zofenopril (full circles), captopril (open circles), enalapril (open squares), ramipril (open triangles), lisinopril (open stars), and fosinopril (open diamonds) in 42 rats (ex vivo study).

Notes: Asterisks refer to the statistical significance at each time point versus control for zofenopril (**P < 0.01; *P < 0.05). Redrawn with permission.¹⁸
Abbreviations: ACE, angiotensin-converting enzyme; d, days; h, hours.

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