The Effect of Antihypertensive Drugs on Endothelial Function as Assessed by Flow-Mediated Vasodilation in Hypertensive Patients

Table 1

Clinical trials on FMD in patients with HTN.

Reference	Patients	Trial design	Intervention	Treatment period	FMD (%)	Notes
Muiesan et al., 1999 [16]	58	Single-arm	An ACEI or a dihydropyridine CCB or a diuretic, in combination with a β-blocker	6 months	3.1±3.0 → 6.5±4.5^∗	—
	10	RCT	Nifedipine	2 months	5.0±6.1 → 9.4±3.9^∗,a	^a𝑃<0.05 versus Hydrochlorothiazide
	10		Hydrochlorothiazide		5.1±5.2 → 4.6±4.3
Yavuz et al., 2003 [17]	9	RCT	Enalapril 5–40 mg/day	6 months	8.4±4.5 → 14.0±4.0^∗	—
	9		Losartan 50–100 mg/day		7.9±3.9 → 12.4±1.9^∗
Felmeden et al., 2003 [18]	76	Single-arm	Either Amlodipine and/or Perindopril, or Atenolol and/or Bendroflumethiazide	6 months	4.8±1.3 → 7.3±1.7^∗	Lipid-lowering treatment (+)
Tezcan et al., 2003 [19]	9	Single-arm	Enalapril 5–40 mg/day	6 months	7.3±3.1 → 16.0±2.9^∗	—
Munakata et al., 2003 [20]	12	CCT	ACEI (Temocapril/Cirazapril 2/0.5 mg/day)	12 months	12.4 (3.5) → 25.8 (6.3)*	—
	24		CCB (Amlodipine/Benidipine 2.5/4 mg/day)		18.8 (4.4) → 30.0 (5.1)
Ghiadoni et al., 2003 [21]	28	RCT	Perindopril 2–4 mg/day	6 months	5.1±2.0 → 6.4±2.4^∗,c	^c𝑃<0.05 versus all other intervention groups
	29		Telmisartan 80–160 mg/day		5.5±2.1 → 5.6±1.9
	28		Nifedipine 30–60 mg/day		5.2±2.1 → 4.8±1.9
	28		Amlodipine 5–10 mg/day		5.4±2.0 → 5.1±1.8
	29		Atenolol 50–100 mg/day		5.5±2.1 → 5.7±1.9
	28		Nebivolol 5–10 mg/day		5.3±2.2 → 5.6±2.4
Koh et al., 2004 [22]	47	RCT	Simvastatin 20 mg/day	2 months	4.8 (0.1) → 6.5 (0.1)*	Hypercholesterolemia (+)
			Simvastatin/Losartan 20/100 mg/day		4.7 (0.1) → 7.8(0.1)^∗,d,e	^d𝑃<0.05 versus Simvastatin
			Losartan 100 mg/day		4.7 (0.1) → 6.1 (0.1)*	^e𝑃<0.05 versus Losartan
Koh et al., 2004 [23]	31	RCT	Losartan 50–100 mg/day	2 months	4.9 (0.4) → 6.0(0.4)^∗,f	^f𝑃<0.05 versus placebo
	30		Irbesartan 150–300 mg/day		4.9 (0.3) → 6.6(0.3)^∗,f	No difference among groups
	31		Candesartan 8–16 mg/day		5.0 (0.2) → 6.3(0.2)^∗,f
Morimoto et al., 2006 [24]	22	RCT	Amlodipine 5 mg/day	24 weeks	4.2 (0.7) → 3.1 (0.9)	—
	21		Telmisartan 40 mg/day		2.7 (0.8) → 5.7(1.0)^∗,g	^g𝑃<0.05 versus Amlodipine
Souza-Barbosa et al., 2006 [25]	18	RCT	Hydrochlorothiazide 25–50 mg/day	12 weeks	7.3±2.0 → 12.8±3.1^∗	No difference among groups
	16		Irbesartan 150 mg/day		7.1±2.8 → 13.0±2.9^∗
	14		Quinapril 20 mg/day		7.2±2.8 → 13.2±2.1^∗
	15		Irbesartan/Quinapril 150/20 mg/day		7.5±1.9 → 12.8±3.0^∗
Mohler et al., 2006 [26]	33	RCT	Amlodipine/Benazepril 5/20–40 mg/day	12 weeks	8.1 [median only] → 10.3*	No difference between both groups
	37		Amlodipine 5–10 mg/day		7.0 [median only] → 8.6*
Oshima et al., 2006 [27]	20	RCT	Efonidipine 20 mg/day	12 weeks	9.6±3.3 → 9.5±2.9	FMD/NTG ratio was increased
	20		Nifedipine 20 mg/day		9.7±3.0 → 8.0±2.0^∗
Ghiadoni et al., 2007 [28]	46	RCT	Ramipril 5 mg/day	3 months	4.6±1.8 → 5.9±2.1^∗	Comparison of dosage
			Ramipril 10 mg/day		4.6±1.8 → 6.3±2.4^∗	No difference between dosages
Pasini et al., 2007 [29]	15	RCT	Zofenopril 15–30 mg/day	8 weeks	5.3±1.6 → 6.9±1.7^∗	—
	15		Ramipril 2.5–5 mg/day		5.4±2.0 → 5.7	The mean after the intervention is estimated by the figure (detailed data not presented)
	15		Atenolol 50–100 mg/day		5.3±1.8 → 5.4
Buus et al., 2007 [30]	15	RCT	Perindopril 4–8 mg/day	1 year	2.7 (0.3) → 3.4 (0.2)*	No difference between groups
	16		Atenolol 50–100 mg/day		3.3 (0.2) → 4.0 (0.2)*
Benndorf et al., 2007 [31]	12	RCT	Telmisartan 80 mg/day	6 weeks	5.4±3.3 → 10.9±4.6^∗	—
	13		Nisoldipine 20 mg/day		6.6±3.3 → 5.9±3.7
	12		Telmisartan/Nisoldipine 80/10 mg/day		4.5±1.6 → 10.8±4.7^∗
Flammer et al., 2007 [32]	13	RCT	Losartan 100 mg/day	4 weeks	2.6 → 3.4(0.4)^h	DM (+), The mean of baseline is estimated by the figure (detailed data not presented); ^h𝑃<0.05 versus Atenolol
			Atenolol 100 mg/day		2.6 → 2.5 (0.4)
Morimoto et al., 2007 [33]	25	RCT	Amlodipine 5 mg/day	24 weeks	4.4 (0.8) → 3.2 (0.9)	No difference between groups
	25		Cilnidipine 10 mg/day		4.2 (0.7) → 5.2 (1.0)
Morimoto et al., 2008 [34]	16	RCT	Amlodipine 5 mg/day	24 weeks	3.0 (0.6) → 2.0 (0.8)	Addition to ARB monotherapy
	16		Perindopril 4 mg/day		2.7 (0.8) → 5.2(0.9)^∗,i	^i𝑃<0.05 versus Amlodipine
Hirooka et al., 2008 [35]	9	CCT	Valsartan 80–160 mg/day	1 year	5.8 (1.2) → 10.7 (1.4)*	—
	9		Amlodipine 5–10 mg/day		8.6 → 7.7	The mean is estimated by the figure (detailed data not presented)
Korkmaz et al., 2008 [36]	27	CCT	Quinapril 20 mg/day	4 weeks	4.7±3.9 → 5.6±6.1	—
	27		Nebivolol 5 mg/day		3.7±4.2 → 8.5±6.3*	𝑃=0.06 versus Quinapril
Yamada et al., 2008 [37]	21	RCT	Azelnidipine 16 mg/day	8 weeks	Unknown → 4.2±0.7	No difference between groups
			Benidipine 4 mg/day		Unknown → 4.7±0.6
Farkas et al., 2008 [38]	53	Single-arm	Quinapril 40 mg/day	24 weeks	2.8±1.2 → 8.0±2.5*	Postmenopausal women
Rossi et al., 2008 [39]	180	CCT	Antihypertensive regimens	1 year	2.4±2.2 → 4.8±3.5*	Postmenopausal women with MS
	170	(lifestyle modification or drugs)	4.4±2.5 → 11.5±4.4^∗,j			Postmenopausal women without MS; ^j𝑃<0.05 versus the MS group
Jennings et al., 2008 [40]	20	RCT	Lisinopril 10–40 mg/day	1 year	4.4 (1.0) → 7.1 (1.0)*	No difference between groups
	23		Atenolol 25–100 mg/day		4.5 (0.8) → 7.0 (0.8)*
Pasini et al., 2008 [41]	20	RCT	Nebivolol 5 mg/day	4 weeks	5.9±1.9 → 7.5±2.2^∗,k	^k𝑃<0.05 versus Atenolol
	20		Atenolol 100 mg/day		5.8±2.1 → 6.1±2.3
Kosch et al., 2008 [42]	25	RCT	Valsartan 80–160 mg/day	12 weeks	3.5 → 6.1	No difference between groups
	27		Metoprolol 50–100 mg/day		3.9 → 11.2*	The mean is estimated by the figure (detail data not presented)
Merchant et al., 2009 [43]	33	Single-arm	Nebivolol 5–10 mg/day	8 weeks	3.4±0.4 → 11.0±1.3^∗	Obesity (+)
Jung et al., 2009 [44]	39	Single-arm	Telmisartan 80 mg/day	8 weeks	7.6±3.5 → 9.0±2.8^∗	—
Ubaid-Girioli et al., 2009 [45]	39	CCT	Spironolactone 25 mg/day	6 months	7 → 10*	Poorly controlled HTN; Added to multiple agents; The median is estimated by the figure (detailed data not presented)
Yamanari et al., 2009 [46]	14	RCT	Chlortalidone 25 mg/day	16 weeks	8.1±2.0 → 6.0±1.5^∗	Poorly controlled HTN
	14		Spironolactone 25 mg/day		8.1±2.0 → 8.8±2.7^l	Addition to both Amlodipine and Candesartan; ^l𝑃<0.05 versus Chlortalidone
Perrone-Filardi et al., 2009 [47]	13	RCT	Candesartan 16 mg/day	2 months	5.2±1.6 → 7.1±2.6^∗,m	Coronary artery disease (+), added to β-blocker; ^m𝑃<0.05 versus placebo
Ghiadoni et al., 2009 [48]	31	RCT	Perindopril/Indapamide 2–4/0.625–1.25 mg/day	24 weeks	5.0±2.1 → 6.0±1.7^∗	No difference between groups
	31		Atenolol 50–100 mg/day		5.1±1.8 → 5.5±1.8
Brandão et al., 2010 [49]	29	RCT	Perindopril 4 mg/day	12 weeks	7.3 [4.3–10.3] → 9.3 [6.3–11.2]*	No difference among groups
	33		Hydrochlorothiazide 25 mg/day		8.3 [5.8–10.1] → 9.0 [7.2–11.7]*
	32		Indapamide 1.5 mg/day		6.7 [5.0–10.2] → 9.2 [6.7–12.3]*
Yilmaz et al., 2010 [50]	37	RCT	Amlodipine 10 mg/day	12 weeks	6.7 [5.5–8.3] → 7.5 [5.0–8.7]*	DM (+), CKD stage 1
	35		Valsartan 160 mg/day		6.3 [5.5–8.0] → 7.8[6.0-9.3]^∗,n	^n𝑃<0.05 versus Amlodipine
	36		Valsartan/Amlodipine 160/10 mg/day		6.4 [5.5–7.3] → 8.0[6.9-9.3]^∗,n
Wago et al., 2010 [51]	35	Single-arm	Telmisartan 40 mg/day	1 year	4.0±2.2 → 5.9±2.2*	DM (+)
Takiguchi et al., 2011 [52]	31	RCT	Olmesartan 20–40 mg/day	12 weeks	3.9±3.0 → 6.1±3.1^∗,o	^o𝑃<0.05 versus Amlodipine
			Amlodipine 5–10 mg/day		3.9±3.0 → 4.6±2.6
Heffernan et al., 2011 [53]	24	RCT	Atenolol 50 mg/day	4 weeks	8.4 (1.1) → 9.1 (1.4)	No difference between groups
			Metoprolol 50 mg/day		8.4 (1.1) → 10.3 (1.4)

FMD: flow-mediated vasodilation; HTN: hypertension; ACEI: angiotensin converting enzyme inhibitor; CCB: calcium channel blocker; RCT: randomized controlled trial; COX-2: cyclooxygenase-2; CCT: controlled clinical trial; DM: diabetes mellitus; PDE5-I: phosphodiesterase type 5 inhibitor; NTG: nitroglycerin-induced vasodilation; ARB: angiotensin II receptor blocker; MS: metabolic syndrome; CKD: chronic kidney disease. Data are presented as the mean ± standard deviation, mean (standard error), or median (interquartile range or total range). *𝑃<0.05 compared with before intervention.