Table 4.
Outcomes of comparison group within included studies
| Off‐label | Author (reference) | Main outcome | Baseline vs. final outcome in comparison group | |
|---|---|---|---|---|
| Proteinuric kidney disease | Juarez et al. 20 | Geometric mean (95%CI) of UPCR (g g–1) | 1.33 (0.83–2.18) to 1.01 (0.69–1.80; P = NS) | |
| Mean and SD of GFR (ml min–1 1.73 m–2) | Baseline = 46 ± 16 and decreased with a median rate of 3.3 (95%CI, 1.8–4.7) | |||
| Menne et al. 18 | Mean UACR (mg mmol–1)‐ adjusted ratio | 9.1 to 4.5 | ||
| Laverman et al. 17 | Mean (95%CI) of total proteinuria (g 24‐h–1) | 4.5 (3.5, 6.4) to 2.2 (1.2, 4.8; P < 0.05) | ||
| Mean (95%CI) of creatinine clearance (ml/min) | 80 (66, 96) to 73 (59, 89) | |||
| Poulsen et al. 25 | Geometric mean ± tolerance factor E‐UAE (μg min–1) | 150.1 ± 3.7 to 213.6 ± 6.9 | ||
| Mogensen et al. 23 | Adjusted mean reduction in UACR [Geometric mean (tolerance factor)] | 24 (0 to 43) [Baseline = 5.9 (1.1)] (P = 0.05) | ||
| Tarnow et al. 27 | Mean (95%CI) albuminuria mg 24‐h–1 | Baseline = 1033 (760–1406) and increased by 12% (–10 to 40; P = NS) | ||
| Mean and SE of GFR (ml min–1 1.73‐m–2) | Baseline = 85 ± 6 and declined 0.5 ± 0.1 ml. min–1. month–1 (P < 0.001) | |||
| Crepaldi et al. 21 | Mean and SD of AER (μg/min) | 70 (28–174) to 58 (2–198; P < 0.03)≈ | 88 (21–187) to 119 (4–176)* | |
| Mean and SD of creatinine clearance (ml min–1 1.73‐m–2) | 105 ± 14 to 101 ± 15≈ | 110 ± 15 to 105 ± 15* | ||
| Mean and SD of urinary albumin concentration (g dl–1) | 4.4 ± 0.3 to 4.2 ± 0.4≈ | 4.4 ± 0.2 to 4.4 ± 0.3* | ||
| Mean (95%CI) reduction of risk of progression to macroalbuminuria | 41.4% (22.1–64.3%; P = 0.05)≈ | |||
| regression rate from macroalbuminuria to normoalbuminuria | 0%≈ | 4%* | ||
| Janssen et al. 16 | Mean ± SEM of GFR (ml min–1) | 45 ± 8 to 45 ± 8 (P = NS) | ||
| Mean ± SEM of FF (%) | 23 ± 2 to 25 ± 2 (P = NS) | |||
| Mean ± SEM of UPCR (g mmol–1) | 0.56 to 0.69 (P = NS) | |||
| Mitchell et al. 22 | Mean ± SEM (range) of GFR (ml min–1 1.73‐m–2) | 56 ± 5 (23–65) to 53 ± 7 (13–108; P = NS) | ||
| Mean ± SEM (range) of RPF rate (ml min–1 1.73‐m–2) | 282 ± 27 (130–456) to 319 ± 38 (160–594; P = NS) | |||
| Mean ± SEM (range) of FF (%) | 21 ± 2 (11–33) to 19 ± 3 (9–46) | |||
| Chaturvedi et al. 28 | Geometric mean (IQR) of AER (μg min–1) | 8 (4.7–14) to 9.4 | ||
| Rossing et al. 26 | Means ± antilog SE of urinary IgG (mg 24‐h–1h) | 71 ± 1.19 to 81 ± 1.19 (P = NS) | ||
| Means ± antilog SE of fractional clearance of albumin (× 10–6) | 215 ± 1.23 to 297 ± 1.29 (P < 0.05) | |||
| Means ± antilog SE of GFR (ml min–1 1.73‐m–2) | 85 ± 6 to 81 | |||
| albuminuria (mg 24‐h–1) | 1087 ± 1.2 to 1271 | |||
| Nielsen et al. 24 | Means ± antilog SE of GFR (ml min–1 1.73‐m–2) | 74 ± 8 and – 0.60 ± 0.11 decreased during the study | ||
| Geometric mean ± antilog SE of Albuminuria (mg 24‐h–1) | Baseline = 1578 ± –1.2 and reduced 15% (–13 to 34%; P = NS) | |||
| means ± SE of Fractional albumin clearance (×106) | 553 ± 1.0 and increased 6% (–31 to 31%) | |||
| Ranieri et al. 19 | Mean ± SD of GFR (ml min–1) | 133.06 ± 15.75 to 120.17 ± 11.84 (P = NS)† ‡ | 115.5 ± 1 to 116.94 ± 11.11 (P = NS)ϕ | |
| Mean ± SD of FF (%) | 18.39 ± 2.17 to 19.78 ± 2.44 (P = NS)† ‡ | 20.06 ± 3.81 to 19.72 ± 2.07 (P = NS)ϕ | ||
| Mean ± SD of UAE (mg 24‐h–1) | 44.7 ± 9.5 to 69.3 ± 6.4(P < 0.01)† ‡ | 76.6 ± 5.6 to 71.7 ± 7.5 (P = NS)ϕ | ||
| *placebo, ≈Nifedipine, ϕbaseline to first phase with amlodipine, ‡baseline to first phase of lisinopril, †end of first phase with lisinopril to second phase of amlodipine, ∥end of first phase with amlodipine to second phase of lisinopril | ||||
| Off‐label | Author (reference) | Main outcome | Baseline vs. final outcome in lisinopril group | P‐value lisinopril vs. comparison | |
|---|---|---|---|---|---|
| Proteinuric kidney disease | Juarez et al. 20 | Geometric mean (95%CI) of UPCR (g g–1) | 0.92 (0.52–1.66) to 0.68 (0.38–1.20; P = NS) | ||
| Mean and SD of GFR (ml min–1 1.73‐m–2) | 48 ± 14 and decreased with a median rate of 3.8 (95%CI, 1.8–6.3) | ||||
| Menne et al. 18 | Mean UACR (mg mmol–1)‐ adjusted ratio | 9.6 to 5.7 adjusted ratio: 76%, CI: 48–118% | 0.213 | ||
| Laverman et al. 17 | Mean (95%CI) of total proteinuria (g 24‐h–1) | 4.5 (3.5–6.4) to 1.4 (0.5–2.9; P < 0.05) | <0.05 | ||
| Mean (95%CI) of creatinine clearance (ml/min) | 80 (66–96) to 72 (52–92) | ||||
| Poulsen et al. 25 | Geometric mean ± tolerance factor E‐UAE (μg min–1) | 96.8 ± 1.8 to 48.3 ± 3.1 | 0.04 | ||
| Mogensen et al. 23 | Adjusted mean reduction in UACR [Geometric mean (tolerance factor)] | 39 (20 to 54) [Baseline = 6.6 (1.1)] (<0.001) | |||
| Tarnow et al. 27 | Mean (95%CI) albuminuria mg 24‐h–1 | Baseline = 1554 (980–2465) and reduced by 52% (95%CI 14–73) | <0.001 | ||
| Mean and SE of GFR (ml min–1 1.73‐m–2) | Baseline = 85 ± 5 and declined 0.5 ± 0.1 ml min–1 month–1 (P < 0.001) | NS | |||
| Crepaldi et al. 21 | Mean and SD of AER (μg/min) | 54 (20–128) to 29 (5–173; P < 0.003) | |||
| Mean and SD of creatinine clearance (ml min–1 1.73‐m–2) | 113 ± 16 to 109 ± 19 | ||||
| Mean and SD of Urinary albumin concentration (g/dl) | 4.4 ± 0.4 to 4.3 ± 0.3 | ||||
| Mean (95%CI) reduction of risk of progression to macroalbuminuria | 49.1% (26.8–63.4%; P < 0.03) | ||||
| Regression rate from macroalbuminuria to normoalbuminuria | 15% | < 0.001 | |||
| Janssen et al. 16 | Mean ± SEM of GFR (ml/min) | 55 ± 11 to 50 ± 10 (P < 0.01) | |||
| Mean ± SEM of FF (%) | 24 ± 2 to 21 ± 2 (P < 0.001) | ||||
| Mean ± SEM of UPCR (g/mmol) | 0.39 ± 0.17 to 0.26 ± 0.11 (P < 0.05) | <0.05 | |||
| Mitchell et al. 22 | Mean ± SEM (range) of GFR (ml min–1 1.73‐m–2) | 46 ± 6 (18–78) to 42 ± 6 (18–83; P = NS) | NS | ||
| Mean ± SEM (range) of RPF rate (ml min–1 1.73‐m–2) | 262 ± 37 (122–570) to 247 ± 42 (62–523; P = NS) | NS | |||
| Mean ± SEM (range) of FF (%) | 19 ± 2 (9–37) to 21 ± 4 (8–65; P = NS) | NS | |||
| Chaturvedi et al. 28 | Geometric mean (IQR) of AER (μg min–1) | 8 (4.4–14.8) to 7.3 | 0.03 | ||
| Rossing et al. 26 | Means ± antilog SE of Urinary IgG (mg 24‐h–1) | 101 ± 1.29 to 64 ± 1.38 (P < 0.05) | <0.05 | ||
| Means ± antilog SE of Fractional clearance of albumin (× 10–6) | 380 ± 1.29 to 213 ± 1.35 (P < 0.05) | <0.05 | |||
| Means ± antilog SE of GFR (ml min–1 1.73‐m–2) | 85 ± 5 to 73.5 | <0.05 | |||
| albuminuria (mg 24‐h–1) | 1513 ± 1.3 to 790 | 0.001 | |||
| Nielsen et al. 24 | Means ± antilog SE of GFR (ml min–1 1.73‐m–2) | 75 ± 6 and –0.67 ± 0.10 decreased during the study | 0.63 | ||
| Geometric mean ± antilog SE of Albuminuria (mg 24‐h–1) | Baseline = 963 ± 1.2 and reduced 55% (29–72%; P < 0.05) | 0.01 | |||
| means ± SE of Fractional albumin clearance (×106) | (323 ± – 1.2 and reduced 52% (8–75%) | 0.03 | |||
| Ranieri et al. 19 | Mean ± SD of GFR (ml min–1) | 116.94 ± 11.11 to 127.27 ± 18.89 (P < 0.01)∥ | 119.61 ± 16.01 to 133.06 ± 15.7 (P < 0.01)‡ | ||
| Mean ± SD of FF (%) | 19.72 ± 2.07 to 18.22 ± 2.3 (P < 0.01)∥ | 20.06 ± 2.01 to 18.39 ± 2.17 (P < 0.01)‡ | |||
| Mean ± SD of UAE (mg 24‐h−1) | 71.7 ± 7.5 to 54.3 ± 3 (P < 0.01)∥ | 77.1 ± 8.1 to 44.7 ± 9.5 (P < 0.01)‡ | <0.01 | ||
| *placebo, ≈Nifedipine, ϕbaseline to first phase with amlodipine, ‡baseline to first phase of lisinopril, †end of first phase with lisinopril to second phase of amlodipine, ∥end of first phase with amlodipine to second phase of lisinopril | |||||
| Off‐label use | Author (Ref) | Main outcome | Final outcome vs. baseline in comparison group | ||
|---|---|---|---|---|---|
| Atrial fibrillation | Van Den Berg et al. 30 | Mean ± SD of heart rate (beats min–1) | 83 ± 14 to 81 + 13 (P = NS) | ||
|
Median number of isolated premature ventricular beats h–1 (range) |
23 (5–340) to 109 (22–372) | ||||
| Haywood et al. 31 | New AF per 1000 | 16.3† | 22.4‡ | 20.9¥ | |
| Odds ratio for univariable logistic model | 1.346‡ | 1.073‡ | 1.000¥ | ||
| Odds ratio for multivariable logistic model | 1.326‡ | 1.083‡ | 1.000¥ | ||
| CM in patients with DMD | Allen et al. 32 | Mean EF (%) | 48.4 to 55.2 (P = 0.03) | ||
| Diabetic retinopathy | Mehlsen et al. 36 | Mean (95%CI) of diameter change of retinal artery after exercise + flicker (%) | 1.8 (0.1–3.5) to 2.0 (0.3–3.6) | ||
| Mean (95%CI) of diameter change of retinal vein after exercise + flicker (%) | 4.4 (2.6–6.1) to 5.3 (3.5–7.0) | ||||
| Chaturvedi et al. 37 | Incidence of retinopathy: odds ratio | 15/62 | |||
| Regression of retinopathy | 28/117 | ||||
| Myocardial fibrosis | Brilla et al. 34 | Myocardial hydroxyproline concentration (μg mg–1) | 9.5 ± 0.5 to 10.4 ± 0.6 (P = NS) | ||
| Collagen volume fraction (%) | 6.4 ± 0.8 to 6.5 ± 0.8 (P = NS) | ||||
| Inflammatory cystoid macular oedema | Kooij et al. 40 | Number (%) of patients with improvement of cystoid macular oedema | 9 of 40 (23%) | ||
| Left ventricular hypertrophy | Christian et al. 34 | LV mass index (g m–2.7) | 176 ± 17 to 145 ± 11 (P = 0.08) | ||
| Mean ± SD of Cornell voltage overall (μV) | 1451 ± 620 to 1427 ± 630 (P = 0.0045)‡ | 1440 ± 627 to 1434 ± 636 (P = 0.3438)¥ | |||
| Ernst et al. 33. | Prevalence (%) of LVH by Cornell voltage | 482/7151 (6.74) to 311/4753 (6.54)‡ | 783/12102 (6.47) to 488/7947 (6.14)¥ | ||
| Individuals experienced regression of their LVH (%) | 50.21 | 52.96 | |||
| Migraine | Schrader et al. 41 | Mean ± SD of h with headache | 162 ± 142 | ||
| Mean ± SD of days with migraine | 18.5 ± 10 | ||||
| Mitral valve regurgitation | Wong et al. 35 | Mean ± SD of change in mitral regurgitant fraction (%) | +3.7% ± 3.2 | ||
| Mean ± SD of change of MR jet to LA area ratio | –10.9% ± 2.4 | ||||
| Mean ± SD of LA dimension (mm) measured by M‐mode techniques | 45.4 ± 8 to 46.7 ± 8 (P = NS) | ||||
| Oligospermia and infertility | Mbah et al. 42 | Mean ± SD (95%CI) sperm cell count (106 ml–1) | 17.1 (12.0–2.2) to 12.8 (8.2–19.0; P ≤ 0.02)† | 7.43 ± 3.97 to 7.0 (4.2–10.1; P = NS)ϕ | |
| Mean ± SD (95%CI) sperm cells with good motility (%) | 41.1 (32.1–50.6) to 15.3 (12.2–17.7; P ≤ 0.008)† | 22.12 ± 4.4 to 22.2 (18.6–25.7; P = NS)ϕ | |||
| Mean ± SD (95%CI) sperm cells with abnormal morphology (%) | 15.3 (11.6–19.8) to 28.2 (22.5–33.9; P ≤ 0.03)† | 44.12 ± 2.6 to 44.1 (39.1–50.2; P = NS)ϕ | |||
| Prevention of diabetes | ALLHAT Group 39 | Number (%) of patients with FBS ≥ 126 mg dl–1 among baseline‐nondiabetics | 154 (9.8)‡ | 302 (11.6)¥ | |
| Fogari and Roberto 38 | Glucose infusion rate (mg min–1 kg–1) | 5.79 ± 0.33 to 6.21 ± 0.41 (P = NS) | |||
| Total glucose requirement (g) | 31.9 ± 3.4 to 33.8 ± 3.3 (P = NS) | ||||
| Prevention of pneumonia | Lee et al. 43 | Unadjusted OR (95%CI) of Pneumonia or death | |||
| The incidences of pneumonia (%) | 47.4 | ||||
| ¥Chlorthalidone, ‡Amlodipine, †Doxazosin, ϕbaseline to the first phase with placebo, ‡baseline to the first phase of lisinopril, †end of the first phase with lisinopril to the second phase of placebo, ∥end of the first phase with placebo to the second phase of lisinopril | |||||
| Off‐label use | Author (reference) | Main outcome | Final outcome vs. baseline in lisinopril group (P value) | P‐value lisinopril vs. comparison | |
|---|---|---|---|---|---|
| Atrial fibrillation | Van Den Berg et al. 30 | mean ± SD of heart rate (beats/min) | 92 ± 9 to 88 + 9 (P = NS) | ||
|
Median number of isolated premature ventricular beats/h (range) |
34 (2–228) to 27 (4–335) | 0.040 | |||
| Haywood et al. 31 | New AF per 1000 | 20.6 | |||
| Odds ratio for univariable logistic model | 0.987 | 0.90¥ | |||
| Odds ratio for multivariable logistic model | 0.939 | 0.59¥ | |||
| CM in patients with DMD | Allen et al. 32 | Mean EF (%) | 47.5 to 54.6 (P = 0.02) | NS | |
| Diabetic retinopathy | Mehlsen et al. 36 | Mean (95%CI) of diameter change of retinal artery after exercise + flicker (%) | 1.8 (0.1–3.5) to 1.0 (1.4–3.4) | 0.43 | |
| Mean (95%CI) of diameter change of retinal vein after exercise + flicker (%) | 4.4 (2.6–6.1) to 2.3 (0.2–4.8) | 0.02 | |||
| Chaturvedi et al. 37 | Incidence of retinopathy ‐Odds ratio | 13/72 OR = 0.69 (95%CI 0.30–0.59) | 0.4 | ||
| Regression of retinopathy | 33/103 OR = 1.48 (95%CI 0.82–2.68) | 0.2 | |||
| Myocardial fibrosis | Brilla et al. 34 | Myocardial hydroxyproline concentration (μg mg–1) | 9.9 ± 0.3 to 8.3 ± 0.4 (P = 0.001) | <0.00001 | |
| Collagen volume fraction (%) | 6.9 ± 0.6 to 6.3 ± 0.6 (P < 0.01) | <0.05 | |||
| Inflammatory cystoid macular oedema | Kooij et al. 40 | Number (%) of patients with improvement of cystoid macular oedema | 10 of 40 (25) | 0.79 | |
| Left ventricular hypertrophy | Christian et al. 34 | LV mass index lisinopril (g m–2.7) | 170 ± 16 to177 ± 15 (P = NS) | ||
| Mean ± SD of Cornell voltage overall (μV) | 1425 ± 615 to 1435 ± 637 (P = 0.24) | 0.9433¥ | |||
| Ernst et al. 33. | Prevalence (%) of LVH by Cornell voltage | 473/7123 (6.64) to 292/4494 (6.50) | NS¥ | ||
| Individuals experienced regression of their LVH (%) | 49.27 | NS¥ ‡ | |||
| Migraine | Schrader et al. 41 | Mean ± SD of hours with headache | 129 ± 125 | <0.05 | |
| Mean ± SD of days with migraine | 14.5 ± 11 | <0.05 | |||
| Mitral valve regurgitation | Wong et al. 35 | Mean ± SD of change in mitral regurgitant fraction (%) | –6.4% ± 3.5 | <0.05 | |
| Mean ± SD of change of MR jet to LA area ratio | –15.7% ± 3.7 | NS | |||
| Mean ± SD of LA dimension (mm) measured by M‐mode techniques | 44.3 ± 7 to 44.1 ± 8 (P = NS) | NS | |||
| Oligospermia and infertility | Mbah et al. 42 | Mean ± SD (95%CI) sperm cell count (106 ml–1) | 7.0 (4.2–10.1) to 13.9 (8.7–17.5; P < 0.004)∥ | 5.29 ± 2.6 to 17.1 (12.0–22.2; P < 0.03)‡ | |
| Mean ± SD (95%CI) sperm cells with good motility (%) | 22.2 (18.6–25.7) to 30.3 (26.0–35.1; P ≤ 0.005)∥ | 17.33 ± 3.2 to 41.1 (32.1–50.6; P < 0.05)‡ | |||
| Mean ± SD (95%CI) Sperm cells with abnormal morphology (%) | 44.1 (39.1–50.2) to 11.8 (6.0–17.2; P ≤ 0.03)∥ | 42.91 ± 5.1 to 15.3 (11.6–19.8; P ≤ 0.04)‡ | |||
| Prevention of diabetes | ALLHAT Group 39 | Number (%) of patients with FBS ≥ 126 mg dl–1 among baseline‐nondiabetics | 119 (8.1) | <0.001¥ | |
| Fogari and Roberto 38 | Glucose infusion rate (mg min–1 kg–1) | 5.74 ± 0.31 to 7.21 ± 0.39 (P = 0.05) | 0.05 | ||
| Total glucose requirement (g) | 32.5 ± 3.2 to 39.8 ± 3.6 | ||||
| Prevention of pneumonia | Lee et al. 43 | Unadjusted OR (95%CI) of Pneumonia or death | 1.80 (0.69, 4.72; P = 0.232) | ||
| The incidences of pneumonia (%) | 57.6 | 0.390 | |||
¥Chlorthalidone, ‡Amlodipine, †Doxazosin, ϕbaseline to the first phase with placebo, ‡baseline to the first phase of lisinopril, †end of the first phase with lisinopril to the second phase of placebo, ∥end of the first phase with placebo to the second phase of lisinopril
AER, albumin exertion rate; AF, atrial fibrillation; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; CI, confidence interval; CM, cardiomyopathy; DMD, Duchenne muscular dystrophy; ERPF, effective renal plasma flow; EF, ejection fraction; FF, filtration fraction; GFR, glomerular filtration rate; RPF, renal plasma flow; LA, left atrium; LAV, left atrium volume; LVH, left ventricular hypertrophy; MR, Mitral valve regurgitation; NS, non‐significant; SD, standard deviation; SEM, Standard Error of the Mean; UAE, urine albumin exertion; UACR, urine albumin: creatinine ratio; UPCR, urine protein: creatinine ratio