Introduction
Methods
Search, study inclusion criteria and quality assessment
Outcomes and data analysis
Results
Characteristics of eligible studies
First author | Year | Country | Active principle | Patient’s status | Mean age (years) | Follow-up durationa
| Design | Total sample (generics) | Extracted outcomes | Funding | Protocol registration |
---|---|---|---|---|---|---|---|---|---|---|---|
ACE inhibitors or ARBs
| |||||||||||
Portoles [33] | 2004 | Spain | Enalapril | Healthy | 23 | 5 h (36 h) | Crossover | 23 (23) | SBP (E), mAEs (S), sAEs (S) | Not reported | No |
Carranza [56] | 2005 | Mexico | Captopril | Hypertension | 58 | 24 h | Cross-over | 21 (21) | SBP (E) | Not reported | No |
Kim (A) [64] | 2009 | Korea | Ramipril | Hypertension | 50 | 8 weeks | Parallel-group | 89 (45) | SBP (E), mAEs (S), sAEs (S) | Generic manufacturer | No |
Spinola [69] | 2009 | Canada | Valsartan | Healthy | 37 | 36 h | Cross-over | 41 (41) | mAEs (S), sAEs (S) | Generic manufacturer | No |
Iqbal [63] | 2010 | India | Valsartan | Healthy | 25 | 24 h | Cross-over | 18 (18) | sAEs (S) | Generic manufacturer | No |
Jia [54] | 2010 | China | Losartan | Healthy | 24 | 24 h (36 h) | Cross-over | 27 (27) | SBP (E), mAEs (S), sAEs (S) | Generic manufacturer | No |
Li [67] | 2010 | China | Olmesartan | Healthy | 21 | 48 h | Cross-over | 21 (21) | sAEs (S) | Generic manufacturer | 2005L01077 |
Larouche 1 [65]b
| 2010 | USA | Losartan | Healthy | 42 | 2 weeks | Cross-over | 80 (80) | mAEs (S), sAEs (S) | Generic manufacturer | NCT01124162 |
Larouche 2 [66]b
| 2010 | USA | Losartan | Healthy | 45 | 2 weeks | Cross-over | 80 (80) | mAEs (S), sAEs (S) | Generic manufacturer | NCT01124175 |
Carlson 1 [61]b
| 2010 | USA | Losartan and HCT | Healthy | 42 | 2 weeks | Cross-over | 80 (80) | sAEs (S) | Generic manufacturer | NCT01149473 |
Carlson 2 [62]b
| 2010 | USA | Losartan and HCT | Healthy | 42 | 2 weeks | Cross-over | 20 (20) | mAEs (S), sAEs (S) | Generic manufacturer | NCT01149486 |
Oigman [68] | 2013 | Brazil | Ramipril and HCT | Hypertension | 57 | 8 weeks | Parallel-group | 102 (54) | SBP (E), mAEs (S), sAEs (S) | Generic manufacturer | ISRCTN 05051235 |
Anticoagulants
| |||||||||||
Handler [19] | 1998 | USA | Warfarin | Atrial fibrillation | 71 | 4 weeks | Cross-over | 55 (54) | % within INR range (E), Anticoagulation events (S), sAEs (S) | Generic manufacturer | No |
Neutel [28] | 1998 | USA | Warfarin | Atrial fibrillation | 70 | 5 weeks | Cross-over | 39 (39) | % within INR range (E) | Not reported | No |
Weibert [42] | 2000 | USA | Warfarin | Atrial fibrillation | 70 | 4 weeks | Cross-over | 104 (102) | mAEs (S), sAEs (S) | Generic manufacturer | No |
Lee [22] | 2005 | Taiwan | Warfarin | Heart Valves | 52 | 12 weeks | Cross-over | 35 (35) | % within INR range (E) Anticoagulation events (S), sAEs (S) | Industry (other) | No |
Pereira [31] | 2005 | Canada | Warfarin | Outpatients to be treated | 63 | 15 weeks | Cross-over | 7 (7) | % within INR range (E) | Not reported | No |
Antiplatelet agents
| |||||||||||
Rao [34] | 2003 | India | Clopidogrel | Healthy | 27 | 2 h (10 days) | Parallel-group | 20 (10) | Bleeding time (E), mAEs (S), sAEs (S) | Generic manufacturer | No |
Ashraf [9] | 2005 | Pakistan | Clopidogrel | CVD | 49 | 24 h | Cross-over | 30 (30) | Platelet aggr. inhibition (E), sAEs (S) | Non profit | No |
Mijares [73] | 2008 | Venezuela | Clopidogrel | Healthy | 30 | 2 weeks | Cross-over | 20 (20) | Platelet aggr. inhibition (E), mAEs (S), sAEs (S) | Industry (other) | No |
Kim (P) [55] | 2009 | Korea | Clopidogrel | Healthy | 24 | 7 days (13 days) | Cross-over | 44 (44) | Platelet aggr. inhibition (E), mAEs (S), sAEs (S) | Generic manufacturer | No |
Di Girolamo [70] | 2010 | Argentina | Clopidogrel | Healthy | 34 | 12 h | Cross-over | 24 (24) | sAEs (S) | Generic manufacturer | No |
Müller [74] | 2010 | Venezuela | Clopidogrel | Healthy | 23 | 7 days | Cross-over | 20 (20) | Platelet aggr. inhibition (E) | Not reported | No |
Shim [95] | 2010 | Korea | Clopidogrel | Healthy | 29 | 1 week | Cross-over | 29 (29) | Bleeding time (E), sAEs (S) | Generic manufacturer | No |
Khosravi [71] | 2011 | Iran | Clopidogrel | PCI | 59 | 6 months | Parallel-group | 442 (224) | MACE and death (E) | Generic manufacturer | IRCT 138712111723N1 |
Suh [96] | 2011 | Korea | Clopidogrel | CVD | 62 | 4 weeks | Parallel-group | 203 (100) | mAEs (S), sAEs (S) | Generic manufacturer | NCT00947843 |
Oberhänsli [75] | 2012 | Swiss | Clopidogrel | CVD | 69 | 10 days | Cross-over | 60 (60) | Platelet aggr. inhibition (E), sAEs (S) | Non profit | No |
Srimahachota [78] | 2012 | Thailand | Clopidogrel | CVD | NR | 6 h | Parallel-group | 49 (25) | Platelet aggr. inhibition (E), mAEs (S) | Not reported | No |
Tsoumani (A) [79] | 2012 | Greece | Clopidogrel | ACS | 70 | 6 months | Parallel-group | 86 (45) | Platelet aggr. inhibition (E) | Generic manufacturer | No |
Tsoumani (E) [80] | 2012 | Greece | Clopidogrel | ACS | 64 | 4 weeks | Parallel-group | 96 (51) | Platelet aggr. inhibition (E) | Non profit | No |
Zou [81] | 2012 | China | Clopidogrel | Healthy | 24 | 36 h | Cross-over | 20 (20) | sAEs (S) | Not reported | No |
Park (J) [76] | 2013 | Korea | Clopidogrel | CVD | 62 | 4 weeks | Parallel-group | 130 (65) | Platelet aggr. inhibition (E), MACE and death (E), mAEs (S), sAEs (S) | Generic manufacturer | NCT01584791 |
Komosa [72] | 2014 | Poland | Clopidogrel | CVD | 49 | 8 days | Parallel-group | 53 (28) | Platelet aggr. inhibition (E), mAEs (S) | Not reported | No |
Seo [77] | 2014 | Korea | Clopidogrel | ACS | 58 | 24 h (4 weeks for AEs and MACE) | Parallel-group | 95 (47) | Platelet aggr. inhibition (E), MACE and death (E), sAEs (S) | Generic manufacturer | NCT02060786 |
Beta-blockers
| |||||||||||
Biswas [82] | 1989 | India | Propranolol | Healthy | 26 | 7 days | Cross-over | 18 (18) | SBP (E) | Not reported | No |
Carter [13] | 1989 | USA | Propranolol | Hypertension | 46 | 4 weeks | Cross-over | 12 (12) | SBP (E) | Non profit | No |
el-Sayed [16] | 1989 | UK | Propranolol | Healthy | 20 | 2 h | Cross-over | 12 (12) | SBP (E) | Not reported | No |
Chiang [15] | 1995 | Taiwan | Atenolol | Hypertension | 59 | 4 weeks | Cross-over | 23 (23) | SBP (E) | Not reported | No |
Sarkar [35] | 1995 | USA | Atenolol | Healthy | NR | 12 h (24 h) | Cross-over | 29 (29) | SBP (E), sAEs (S) | Generic manufacturer | No |
Bongers [12] | 1999 | Germany | Metoprolol | Stable angina | 62 | 4 weeks | Cross-over | 51 (51) | SBP (E), mAEs (S), sAEs (S) | Brand-name manufacturer | No |
Cuadrado [53] | 2002 | Spain | Atenolol | Healthy | 23 | 24 h (30 h) | Cross-over | 24 (24) | SBP (E), mAEs (S), sAEs (S) | Generic manufacturer | No |
Mirfazaelian [26] | 2003 | Iran | Atenolol | Healthy | 36 | 24 h | Cross-over | 12 (12) | SBP (E), sAEs (S) | Not reported | No |
Portoles [32] | 2005 | Spain | Carvedilol | Healthy | 23 | 24 h | Cross-over | 24 (24) | sAEs (S) | Not reported | No |
Bus-Kwasnik [83] | 2012 | Poland | Bisoprolol | Healthy | 23 | 60 h | Cross-over | 24 (24) | mAEs (S), sAEs (S) | Generic manufacturer | EudraCT 2009 014861-20 |
Liu [84] | 2013 | China | Carvedilol | Healthy | 27 | 24 h | Cross-over | 23 (23) | mAEs (S), sAEs (S) | Generic manufacturer | No |
Calcium channel blockers
| |||||||||||
Usha [40] | 1997 | India | Diltiazem | Healthy | 27 | 12 h | Cross-over | 12 (12) | SBP (E) | Generic manufacturer | No |
Saseen [36] | 1997 | USA | Verapamil | Hypertension | 70 | 2 weeks | Cross-over | 8 (8) | SBP (E), sAEs (S) | Not reported | No |
Park [30] | 2004 | Korea | Amlodipine | Healthy | 22 | 7 h (6 days) | Cross-over | 18 (18) | SBP (E), sAEs (S) | Not reported | No |
Kim [21] | 2007 | Korea | Amlodipine | Hypertension | 53 | 8 weeks | Parallel-group | 188 (94) | SBP (E), mAEs (S), sAEs (S) | Generic manufacturer | No |
Mignini [25] | 2007 | Italy | Amlodipine | Healthy | 35 | 3 h (6 days) | Cross-over | 24 (24) | SBP (E), mAEs (S), sAEs (S) | Not reported | No |
Kim [85] | 2008 | Korea | Amlodipine | Hypertension | 53 | 8 weeks | Parallel-group | 124 (63) | SBP (E), mAEs (S), sAEs (S) | Generic manufacturer | No |
Liu [86] | 2009 | China | Amlodipine | Healthy | 21 | 5 days | Cross-over | 20 (20) | mAEs (S), sAEs (S) | Non profit | No |
Diuretics
| |||||||||||
Garg [17] | 1984 | India | Furosemide | Healthy | 33 | 6 h | Cross-over | 16 (16) | SBP (E), mAEs (S), sAEs (S) | Not reported | No |
Grahnen [18] | 1984 | Sweden | Furosemide | Healthy | 26 | 7 h | Cross-over | 8 (8) | Urine volume (E) | Not reported | No |
Martin [23] | 1984 | UK | Furosemide | Healthy | 30 | 24 h | Cross-over | 12 (12) | Urine sodium (E) | Non profit | No |
Pan [29] | 1984 | Hong Kong | Furosemide | CVD | NR | 8 h | Cross-over | 5 (5) | Urine sodium (E) | Not reported | No |
Meyer [24] | 1985 | S. Africa | Furosemide | Healthy | 29 | 6 h | Cross-over | 12 (12) | Urine volume (E) | Not reported | No |
Singh [38] | 1987 | India | Furosemide | Edema of renal origin | 36 | 6 h | Cross-over | 7 (7) | SBP (E), sAEs (S) | Not reported | No |
Sharoky [37] | 1989 | USA | HCT and Triamterene | Hypertension | 55 | 3 weeks | Cross-over | 30 (30) | SBP (E), sAEs (S) | Generic manufacturer | No |
Kaojarern [20] | 1990 | Thailand | Furosemide | Healthy | 32 | 8 h | Cross-over | 8 (8) | Urine sodium (E) | Brand-name manufacturer | No |
Awad [11] | 1992 | Jordan | Furosemide | Healthy | 27 | 8 h | Cross-over | 20 (20) | Urine sodium (E) | Not reported | No |
Murray [27] | 1997 | USA | Furosemide | CVD | 65 | 2 weeks | Cross-over | 17 (17) | Urine sodium (E) | Brand-name manufacturer | No |
Almeida [87] | 2011 | Portugal | Eplerenone | Healthy | 40 | 24 h | Cross-over | 27 (27) | mAEs (S), sAEs (S) | Generic manufacturer | No |
Kumar (India) [88] | 2014 | India | Losartan and HCT | Healthy | 33 | 48 h | Cross-over | 15 (15) | sAEs (S) | Generic manufacturer | No |
Kumar (Japan) [88] | 2014 | Japan | Losartan and HCT | Healthy | 30 | 48 h | Cross-over | 24 (24) | sAEs (S) | Generic manufacturer | No |
Statins
| |||||||||||
Assawawitoontip [10] | 2002 | Thailand | Simvastatin | Hypercholest. | 37 | 8 weeks | Cross-over | 48 (48) | LDL (E) | Generic Manufacturer | No |
Wiwanitkit [43] | 2002 | Thailand | Simvastatin | Healthy | 49 | 16 weeks | Cross-over | 37 (37) | LDL (E), sAEs (S) | Generic manufacturer | No |
Kim [91] | 2010 | Korea | Atorvastatin | CVD | 61 | 8 weeks | Parallel-group | 235 (119) | LDL (E), mAEs (S), sAEs (S) | Generic manufacturer | NCT01029522. |
Liu [93] | 2010 | China | Atorvastatin | Healthy | 24 | 48 h | Cross-over | 45 (45) | sAEs (S) | Brand-name manufacturer | CNR 2007L02512 |
Boh [89] | 2011 | Slovenia | Atorvastatin | Hypercholest. | 56 | 16 weeks | Parallel-group | 137 (66) | LDL (E), mAEs (S), sAEs (S) | Not reported | No |
Kim [92] | 2013 | Korea | Atorvastatin | Hypercholest. | 61 | 8 weeks | Parallel-group | 289 (143) | LDL (E), mAEs (S), sAEs (S) | Generic manufacturer | NCT01285544. |
Others
| |||||||||||
Tsai [39] | 2007 | Taiwan | Terazosin | Healthy | 64 | 6 weeks | Cross-over | 43 (43) | SBP (E), mAEs (S), sAEs (S) | Generic manufacturer | No |
Feng [90] | 2009 | China | Heparin | Healthy | 21 | 24 h | Cross-over | 22 (22) | sAEs (S) | Not reported | No |
Palmer [94] | 2014 | India | Ezetimibe | Healthy | 27 | 72 h | Cross-over | 51 (50) | sAEs (S) | Generic manufacturer | NCT01597700 |
Efficacy
Efficacy (soft outcomes) | I2 (%) | Mild or moderate adverse events | I2 (%) | |||
---|---|---|---|---|---|---|
n (N) | ES (95 % CI) | Upper (95 % CI) | n (N) | ES (95 % CI) | Upper (95 % CI) | |
Overall | 52 (2609) | 0.01 (−0.05; 0.08) | 0 (32) | 32 (2407) | 0.07 (−0.06; 0.20) | 15 (45) |
Drug class
| ||||||
ACE inhibitors or ARBs | 5 (262) | 0.07 (−0.15; 0.28) | 0 (79) | 8 (456) | 0.10 (−0.20; 0.41) | 38 (72) |
Anticoagulants | 4 (136) | 0.09 (−0.15; 0.33) | 0 (85) | 3 (196) | 0.19 (−0.12; 0.50) | 0 (90) |
Antiplatelet agents | 13 (732) | 0.01 (−0.12; 0.15) | 0 (57) | 7 (519) | −0.10 (−0.40; 0.19) | 0 (71) |
Beta-blockers | 8 (181) | 0.00 (−0.21; 0.21) | 0 (68) | 4 (123) | 0.23 (−0.10; 0.57) | 0 (85) |
Calcium channel blockers | 6 (374) | −0.03 (−0.22; 0.16) | 0 (75) | 4 (356) | 0.09 (−0.23; 0.42) | 0 (85) |
Diuretics | 10 (135) | −0.07 (−0.31; 0.17) | 0 (62) | 2 (43) | 0.27 (−1.81; 2.36) | 91 (–) |
Statins | 5 (746) | 0.04 (−0.10; 0.18) | 0 (79) | 3 (671) | −0.06 (−0.40; 0.27) | 16 (91) |
Others | 1 (43) | −0.06 (−0.37; 0.25) | – | 1 (43) | 0.05 (−0.43; 0.53) | – |
Health status
| ||||||
Healthy | 23 (488) | −0.06 (−0.19; 0.06) | 0 (45) | 17 (557) | 0.14 (−0.13; 0.40) | 38 (65) |
Non-healthy | 29 (2121) | 0.05 (−0.03; 0.13) | 0 (41) | 15 (1850) | 0.05 (−0.09; 0.19) | 0 (53) |
Continent
| ||||||
America | 11 (258) | 0.03 (−0.14; 0.21) | 0 (60) | 7 (402) | 0.11 (−0.16; 0.37) | 36 (73) |
Europe | 12 (586) | 0.02 (−0.13; 0.17) | 0 (60) | 8 (365) | 0.15 (−0.15; 0.46) | 24 (65) |
Asia | 27 (1651) | 0.01 (−0.07; 0.10) | 0 (44) | 16 (1545) | 0.02 (−0.16; 0.21) | 4 (52) |
Others | 2 (114) | −0.15 (−0.67; 0.37) | 49 (–) | 1 (95) | −0.22 (−0.67; 0.23) | – |
Funding | ||||||
Industry—generic | 20 (1721) | 0.01 (−0.08; 0.09) | 0 (47) | 22 (2009) | 0.05 (−0.08; 0.18) | 10 (44) |
Industry—brand-name | 2 (25) | −0.03 (−0.89; 0.83) | 55 (–) | 0 (0) | – | – |
Other funding | 7 (321) | 0.02 (−0.21; 0.24) | 0 (71) | 3 (75) | −0.35 (−0.99; 0.29) | 0 (90) |
Not reported | 22 (552) | −0.01 (−0.12; 0.14) | 0 (46) | 7 (323) | 0.48 (0.04; 0.92) | 28 (69) |
Follow-up duration
| ||||||
≤1 day | 22 (484) | 0.00 (−0.13; 0.14) | 0 (46) | 4 (115) | 0.23 (−0.72; 1.81) | 73 (91) |
2–27 days | 10 (299) | −0.02 (−0.19; 0.16) | 0 (62) | 14 (501) | 0.16 (0.09; 0.41) | 10 (48) |
≥28 days | 20 (1826) | 0.02 (−0.06; 0.11) | 0 (48) | 14 (1791) | 0.04 (−0.09; 0.18) | 0 (55) |
Study design
| ||||||
Parallel-group | 14 (1693) | 0.02 (−0.08; 0.12) | 0 (55) | 12 (1622) | −0.03 (−0.19; 0.14) | 0 (58) |
Cross-over | 38 (916) | 0.00 (−0.09; 0.10) | 0 (37) | 20 (805) | 0.15 (−0.04; 0.34) | 27 (58) |
Blinding
| ||||||
Open-label or single-blind | 30 (1557) | 0.01 (−0.07; 0.10) | 0 (40) | 25 (1452) | 0.09 (−0.05; 0.23) | 0 (44) |
Double-blind | 22 (1052) | 0.02 (−0.09; 0.12) | 0 (46) | 7 (955) | 0.07 (−0.22; 0.36) | 52 (80) |
Sample size
| ||||||
≤30 | 28 (512) | −0.01 (−0.14; 0.12) | 0 (42) | 11 (249) | 0.19 (−0.23; 0.60) | 46 (73) |
31–99 | 17 (892) | 0.06 (−0.05; 0.17) | 0 (51) | 13 (738) | 0.13 (−0.04; 0.30) | 0 (57) |
≥100 | 7 (1205) | −0.01 (−0.13; 0.10) | 0 (71) | 8 (1420) | −0.01 (−0.19; 0.18) | 10 (71) |