Overview of included trials
| Study, reference (location) . | Design (phase) . | Participants . | Duration of intervention . | Intervention vs comparator (n of randomly assigned patients) . | Risk of bias score . | Primary review outcomes . | Measure of effect . | |
|---|---|---|---|---|---|---|---|---|
| Main criteria . | Age, y; male sex, %; HU, % . | |||||||
| Anticoagulation | ||||||||
| Aspirin | ||||||||
| 51 (United States) | CT, crossover (phase 2) | HbSS, HbSβ0, children | Mean, 7.7; 37%; NA | 21 months (crossover at 6 and 18 months, no washout) | Aspirin 3-6 mg/kg in tablets of 81 mg bd (n = 49*) orally | 3/6 | Days per painful event, mean (SD): 3.9 (±1.4) during intervention phase vs 3.2 (±1.6) during placebo phase | NA† |
| Placebo (n = 49*), oral | ||||||||
| Cumulative n of crises: 43 during intervention phase vs 49 during placebo phase | NA† | |||||||
| Cumulative n of days in pain: 140 during intervention phase vs 153 during placebo phase | NA† | |||||||
| 49 (Brazil) | RCT, crossover (phase 2) | HbSS, HbSβ0 | Range, 4-31; NA; NA | 10 months (5 months per treatment, no washout) | Aspirin 17-45 mg/kg od (n = 29*) orally | 0/6 | Frequency of painful events: 40 events in 17 patients during aspirin vs 40 events in 16 patients during placebo treatment | NA† |
| Placebo (n = 29*) orally | ||||||||
| Ticlopidine | ||||||||
| 55 (Senegal, Cote d'Ivoire, Benin) | RCT (phase 2) | HbSS | Range, 15-45; NA; NA | 6 months | Ticlopidine 250 mg <45 kg bd, >45 kg td (n = 70) orally | 5/6 | Total n of crises during 6-month study observation: 42 crises in 70 patients in ticlopidine (1.2 crises per patient-year) vs 125 crises in 70 patients in placebo group (3.5 crises per patient-year) | P < .001‡ |
| Placebo (n = 70) orally | ||||||||
| Pentoxifylline | ||||||||
| 44 (Brazil) | RCT (phase 2) | HbSS | Mean, 17.7§; 67§; NA | 6 weeks | Pentoxifylline ≥18 years 400 mg td, <18 years 400-600 mg per day depending on body weight (n = 28*) orally | 1/6 | N of patients with pain events: | OR (CI): 0.18 (0.05-0.67); P < .01|| |
| Observation days 2-7: 15 (54%) of 28 patients in pentoxifylline group vs 25 (86%) of 29 patients in control group | ||||||||
| Placebo (n = 29*) orally | Observation days 8-42: 14 (50%) of 28 patients in intervention group vs 25 (86%) of 29 patients in placebo group | OR (CI): 0.09 (0.03-0.31); P < .01|| | ||||||
| N of pain events per group: | P < .05‡ | |||||||
| Observation days 2-7: 32 in pentoxifylline group vs 60 in placebo group | ||||||||
| Observation days 8-42: 57 in intervention group vs 219 in placebo group | P < .05‡ | |||||||
| Acenocoumarol | ||||||||
| 72 (Netherlands, Antilles) | RCT, crossover (phase 2) | HbSS, HbSC, HbSβ; age ≥16 years | Mean, 37 (HbSS group); NA; NA | 33 weeks (14 weeks per treatment, 5-week washout in between) | Acenocoumarol 1 mg, dosage based on targeted INR range of 1.6-2.0 (n = 22*) orally | 6/6 | Frequency of acute vaso-occlusive events: 3 events in acenocoumarol vs 5 events in placebo group | NS‡ |
| Placebo (n = 22*) orally | ||||||||
| Prasugrel | ||||||||
| 32, 33, 62 (United States, Canada) | RCT (phase 2) | HbSS, HbSC, HbSβ0/+; age 18-55 years | Mean, 32.9§; 49§; 44§ | 30 days (+ 30-day follow-up) | Prasugrel 5 mg od (n = 41) orally | 4/6 | Proportion of patients reporting no pain or infrequent pain: 50% in prasugrel vs 22% in placebo group | NS‡ |
| Placebo (n = 21) orally | N of patients having painful episodes: 9 (23%) of 40 patients in prasugrel vs 7 (37%) of 19 patients in placebo group | OR (CI): 0.50 (0.15-1.64); NS|| | ||||||
| Proportion of days with pain, least-squares mean: 42% in prasugrel vs 54% in placebo group | NS‡ | |||||||
| 60 (United States, United Kingdom, Ghana, Saudi Arabia, Lebanon, Kenya, Italy, Egypt, Canada, Belgium, Brazil, Turkey, Oman) | RCT (phase 3) | HbSS, HbSβ0; age 2-17 years; ≥2 crises in past yr | Mean, 10.6§; 49§; 45§ | 9-24 months | Prasugrel 0.04-0.12 mg/kg od (n = 171) orally | 6/6 | N of patients with painful crises: 113 (66%) of 171 patients in prasugrel vs 122 (72%) of 170 patients in placebo group | OR (CI): 0.77 (0.48-1.21); NS|| |
| Placebo (n = 170) orally | N of patients with VOCs: 115 (67%) of 171 patients in prasugrel vs 123 (72%) of 170 patients in placebo group | OR (CI): 0.78 (0.49-1.25); NS|| | ||||||
| N of patients with hospital admission: 69 (40%) of 171 patients in prasugrel vs 76 (45%) of 170 patients in placebo group | OR (CI): 0.84 (0.54-1.29); NS|| | |||||||
| Monthly rate of daily pain, mean (SD): 17.5 (NA) in prasugrel group vs 17.7 (NA) in placebo group | Mean difference (CI): 0.24 (4.6–4.1); NS‡ | |||||||
| Antioxidants | ||||||||
| ω-3 fatty acids | ||||||||
| 31, 65 (United States) | RCT (phase 2) | Any sickle-cell syndrome; adults; ≥3 pain episodes per year | NA; NA; 0 | 6-12 months | Fish oil 0.25 g/kg per day in 3 daily doses containing 0.1 g/kg per day ω-3 fatty acids (EPA and DHA; n = 5*) orally | 3/6 | Frequency of pain episodes per year, mean: 3.8 episodes in ω-3 fatty acids vs 7.1 episodes in placebo group | P < .01‡ |
| Placebo (n = 5*) orally | ||||||||
| 59 (Sudan) | RCT (phase 2) | HbSS; age 2-24 years | Mean, 8.1§; 59§; 0 | 1 year | ω-3 fatty acids (EPA and DHA) 25 mg/kg od (n = 70) orally | 6/6 | Annual VOC rate, median (IQR): | P < .01‡ |
| 2.7 (0.9-4.8) in ω-3 vs 4.6 (3.0-6.4) in placebo group | ||||||||
| Placebo (n = 70) orally | Annual clinical VOC rate, median (IQR): 0 (0-0.9) in ω-3 vs 1 (0-2.4) in placebo group | P < .001‡ | ||||||
| N of hospitalization days, median (IQR): 0 (6) in ω-3 vs 0 (6) in placebo group | P < .05‡ | |||||||
| N-acetylcysteine | ||||||||
| 64 (United States) | RCT (phase 2) | HbSS, HbSβ0; age ≥15 years; ≥2 VOCs per year in past 2 years | Mean, 18.1§; 60§; NA | 7 months | N-acetylcysteine in 3 daily doses orally: 600 mg (n = 5*), 1200 mg (n = 5*), 2400 mg (n = 6*) | 3/6 | N of acute VOC episodes per person-days, mean: 0.006 episodes in 2400 mg N-acetylcysteine vs 0.011 in 1200 mg vs 1.24 in 600 mg vs 0.017 in placebo group | NA† |
| Placebo (n = 5*) orally | ||||||||
| Vitamin C-E | ||||||||
| 57 (Brazil) | RCT (phase 2) | HbSS, HbSβ0; adults | Median, 28.3§; 34§; 57§ | 6 months | Vitamin C 1400 mg and vitamin E 800 mg od (n = 44*) orally | 3/6 | Incidence of acute SCD complications: 16 (36%) of 44 patients in vitamin C-E vs 12 (31%) of 39 patients in placebo group | OR (CI): 1.29 (0.51-3.21); NS|| |
| Placebo (n = 39*) orally | ||||||||
| l-glutamine | ||||||||
| 34, 61 (United States) | RCT (phase 3) | HbSS, HbSβ0; age ≥5 years; ≥2 crises in past 12 months | Range, 5-58; 46; HU+ (% NA, stratified) | 48 weeks (+ 3-week tapering + 2-week follow-up) | l-glutamine: 0.6g/kg per day in 2 doses (n = 152) orally | 1/6 | N of sickle cell crises, median: 3 in l-glutamine vs 4 in placebo group | P = .008‡ |
| Placebo (n = 78) orally | N of hospitalizations, median: 2 in l-glutamine group vs 3 in placebo group | P = .005‡ | ||||||
| Cumulative n of hospital days, median: 6.5 in l-glutamine group vs 11 in placebo group | P = .022‡ | |||||||
| Antiadhesion | ||||||||
| Crizanlizumab | ||||||||
| 58 (United States, Brazil, Jamaica) | RCT (phase 2) | Any SCD genotype (including HbSS, HbSC, HbSβ0/+); age 16-65 years; 2-10 VOCs in 12 months before enrollment | Median, 29§; 48§; 63§ | 52 weeks | Crizanlizumab, 2 loading doses 2 weeks apart, then every 4 weeks IV: high dose, 5 mg/kg (n = 67); low dose, 2.5 mg/kg (n = 66) | 6/6 | Annual rate of sickle-cell–related pain crises, median (IQR): 1.63 (0.00-3.97) in high-dose vs 2.01 (1.25-5.87) in low-dose vs 2.98 (1.25-5.87) in placebo group | High dose vs placebo: −45.3%; P = .01‡; low dose vs placebo: −32.6%; NS‡ |
| Annual rate of uncomplicated sickle-cell–related pain crises: 1.08 (0.00-3.96) in high-dose vs 2.00 (0.00-3.02) in low-dose vs 2.91 (1.00-5.00) in placebo group | High dose vs placebo: −62.9%; P = .02‡; low dose vs placebo: 31.3%; NS‡ | |||||||
| Annual rate of days hospitalized, median (IQR): 4.00 (0.00-25.72) in high-dose vs 6.87 (0.00-28.30) in low-dose vs 6.87 (0.00-28.30) in placebo group | High dose vs placebo: −41.8%; NS‡; low dose vs placebo: 0%; NS‡ | |||||||
| Placebo (n = 65) IV | ||||||||
| Antisickling | ||||||||
| Promazine hydrochloride | ||||||||
| 46 (United States) | RCT, crossover (phase 2) | HbSS, HbSC; ≥2 painful episodes in past 2 years | NA; 64; NA | 2 years (crossover every 3 months, no washout) | Promazine hydrochloride 25 mg, dosage based on body weight; 40-80 lb bd, 80-120 lb td, ≥120 lb daily (n = 14) orally | 3/6 | N of hospital admissions for painful episodes per patient-month: 0.09 admissions (based on 16 admissions over 180 patient-months) in promazine hydrochloride group vs 0.05 admissions (based on 8 admissions over 152 patient-months in placebo group) | NA† |
| Placebo (n = 14) orally | N of diary recorded painful episodes per patient-month: 0.22 episodes (based on 40 episodes over 180 patient-months) in promazine hydrochloride group vs 0.28 episodes (based on 42 episodes over 152 patient-months) in placebo group | NA† | ||||||
| Steroids (including oral contraceptives) | ||||||||
| 42 (Nigeria) | RCT, crossover (phase 2; preliminary report before crossover) | HbSS; ≥1 episode of moderately severe pain in 3 months | Range, 2-35; 36; NA | 4-6 months | Men, testosterone 10 mg once per week im; women, progesterone 10 mg once per week im (n = 35*) | 1/6 | Primary review outcome: NA | |
| Secondary review outcomes: | ||||||||
| Pain score, mean (range): 57 (0-330) in testosterone/progesterone vs 153 (130-200) in placebo group | NA† | |||||||
| Placebo (n = 9*) im | ||||||||
| 53 (Jamaica) | RCT, crossover (phase 2) | HbSS; female sex | Range, 20-40; 0; NA | 2 years (9 months per treatment, 6-month washout in between) | Medroxyprogesterone 150 mg every 3 months (n = 10*) im | 1/6 | Primary review outcome: NA | |
| Placebo (saline; n = 13*) im | Secondary review outcomes: | |||||||
| Bone pain episodes: 14 (61%) of 23 in medroxyprogesterone vs 20 (87%) of 23 in placebo group | OR (CI): 0.23 (0.05-1.01); NS|| | |||||||
| Severity score of bone pain episodes, mean: 2.0 in medroxyprogesterone vs 1.8 in placebo group | NA† | |||||||
| 54 (Panama) | CT (phase 2) | HbSS; 1 crisis per month; female sex; desire for reversible method of contraception | Range, 17-39; 0; NA | 12 months | Levonorgestrel 0.15 mg and ethinyl estradiol 0.03 mg od (n = 14) orally | 0/6 | Proportion of patients with painful crisis at end of study: 50% in control group vs 30% of progestogen-only group vs 45.5% of combined oral contraceptive group | NA† |
| Medroxyprogesterone acetate 150 mg, first 3 months monthly, last 9 months every 3 months (n = 13) im | ||||||||
| Surgically sterilized (n = 16) | ||||||||
| Sodium bicarbonate | ||||||||
| 43 (United Kingdom) | RCT, crossover (phase 2) | HbSS, HbSC, HbSβ0/+; age 5-17 years | Mean, 8.4; 33; NA | 2 years (crossover after 1 year, no washout) | Sodium bicarbonate 0.1-0.4 mg/kg od, dosage based on targeted urine alkalinization (n = 18) orally | 1/6 | N of crises per 50 patient-weeks, mean (SD): 2.2 (±1.8) in sodium bicarbonate vs 3.0 (±2.3) in routine group | Mean difference (CI): −0.8 (−2.2-0.6); NS|| |
| Routine care (n = 18) | ||||||||
| Urea | ||||||||
| 52 (Ghana) | RCT (phase 2) | HbSS | <5 years, 23%§; 5-14 years, 38%§; >14 years, 40%§; 47§; NA | Average, 13.7 months | Urea 0.266 g/kg (n = 40) orally: low dose twice per week; high dose daily | 5/6 | N of patients with >1 crisis: 18 (45%) of 40 of urea vs 15 (38%) of 40 of placebo group | OR (CI): 1.4 (0.6-3.3); NS|| |
| N of patients with >2 crises: 8 (20%) of 40 of urea vs 5 (13%) of 39 of placebo group | OR (CI): 1.7 (0.5-5.7); NS|| | |||||||
| Crisis rate per person-year in patients with >1 crisis, mean: 0.596 in urea vs 0.506 in placebo group | Crisis rate ratio, 0.849 (placebo vs urea); NS‡ | |||||||
| Placebo (n = 39) orally | Crisis rate per person-year in patients with >2 crises, mean: 0.189 in urea vs 0.136 in placebo group | Crisis rate ratio, 0.720 (placebo vs urea); NS‡ | ||||||
| Piracetam | ||||||||
| 45 (Lebanon) | RCT, crossover (phase 2) | Sickle-cell anemia; children | Range, 4-15; 44; NA | 10 months (5 months per treatment, no washout) | Piracetam 80 mg/kg per day in 4 daily doses (n = 9*) orally | 2/6 | N of pain crises per patient per month, average: 0.89 in piracetam group vs 1.85 in placebo | P < .05‡ |
| Placebo (n = 9*) orally | ||||||||
| 36, 37 (Saudi Arabia) | RCT (phase 2) | HbSS, HbSβ0, children | Range, 3-12; 57; NA | 1 year | Piracetam 160 mg/kg per day (n = 48*) orally; during admission 300 mg/kg per day IV | 2/6 | N of painful crisis per year, mean (SD): 2.4 (±1.9) in piracetam vs 4.3 (±3.1) in placebo group | Mean difference (CI): −1.9 (−3.0 to −0.8); P < .001|| |
| Placebo (n = 39*) orally; during admission IV | N of hospitalizations per year in total group, mean (SD): 2.07 (±2.4) in piracetam group vs 3.20 (±2.9) in placebo group | Mean difference (CI): −1.1 (−2.3-0.0); P < .05|| | ||||||
| 40, 41 (Brazil) | RCT, crossover (phase 2) | HbSS, HbSC, HbSβ0/+; age 5-20 years | Median, 12.1; 45; 0 | 13 months (6 months per treatment, 1-month washout in between) | Piracetam 4.8g/m2 per day in 4 daily doses (n = 73*) orally | 1/6 | Absolute n of painful VOCs, median: 3 in both groups | NS‡ |
| Placebo (n = 73*) orally | N of pain days per month, median: 1.47 in both groups | NS‡ | ||||||
| Hospitalization days: data NA | NS‡ | |||||||
| Niprisan | ||||||||
| 38, 39 (Nigeria) | RCT, crossover (phase 2) | HbSS; ≥3 crises in past year; age 2-45 years | Mean, 15.5; 45; NA | 12 months (6 months per treatment, no washout) | Niprisan 12 mg/kg od (n = 70*) | 3/6 | N of episodes of mild to moderate pain over first 6 months, mean (SD): 9.1 (±9.6) in niprisan vs 20.6 in placebo group (±32.9) | NS‡ |
| Placebo (n = 70*) | N of episodes of severe pain first 6 months, mean (SD): 7.9 (±8.4) in niprisan vs 22.1 (±32.9) in placebo group | P < .05‡ | ||||||
| N of painful crises first 6 months, mean (SD): 0.27 (±0.6) in niprisan vs 1.17 (±1.8) in placebo group | NS‡ | |||||||
| N of hospital admissions per month in first 6 months, mean (SD): 0.15 (±0.6) in niprisan vs 0.22 (±0.6) in placebo group | NS‡ | |||||||
| NB. No summary statistics possible because of skewed data | ||||||||
| Ciklavit | ||||||||
| 71 (Nigeria) | RCT (phase 2) | HbSS; age 1-15 years | Mean, 8.09§; 57§; NA | 6 months | Ciklavit ≤5 years 10 mL twice daily, >5 years 20 mL bd (n = 47*) | 3/6 | N of painful crises in 6 months, mean (SD): 4.2 (4.2) in Ciklavit vs 3.9 (4.3) in placebo group | Mean difference (CI): 0.30 (−1.49-2.09); NS|| |
| Placebo (n = 42*) | ||||||||
| Cromolyn sodium | ||||||||
| 74 (Iran) | CT, crossover (phase 2) | HbSS | Range, 5-34; 41; HU was part of intervention | 12 months (crossover every 3 months, unclear washout) | Subsequent treatment regimens 1-4 (n = 17*): (1) cromolyn sodium nasal spray 2%, 4 puffs each nostril, frequency NA; (2) placebo nasal spray; (3) as in 1, plus HU 10-15 mg/kg per day orally; and (4) as in 2, plus HU 10-15 mg/kg per day orally | 0/6 | Primary review outcome: NA | |
| Secondary review outcomes: | ||||||||
| Pain score: data NA, pain score in cromolyn sodium and HU group lower than cromolyn sodium–only group | P < .05‡ | |||||||
| Other comparisons between groups | NS‡ | |||||||
| Senicapoc | | | |||||||
| 66 (United States) | RCT (phase 2) | HbSS; age 18-60 years | Mean, 37.2§; 59§; 27 | 12 weeks | Senicapoc loading dose on day 1, subsequently: low dose, 6 mg od (n = 29) orally; high dose, 10 mg od (n = 31) orally | 6/6 | N of patients with painful crisis: 5 (17%) of 29 in low-dose senicapoc vs 5 (16%) of 31 in high-dose senicapoc vs 5 (17%) of 30 in placebo group | OR (CI): low dose vs placebo, 1.04 (0.27-4.06); NS||; high dose vs placebo, 0.96 (0.24-3.73); NS|| |
| Placebo (n = 30) orally | ||||||||
| 73 (United States, United Kingdom, Jamaica, Brazil, France, Trinidad) | RCT (phase 3) | HbSS, HbSC, HbSβ0/+; age 16-65 years; ≥2 crises in past 12 months | Mean, 28.5§; 43§; 58§ | 52 weeks | Senicapoc 1 mg od, initial loading dose 20 mg bd for 4 days (n = 145*) orally | 6/6 | N of patients with acute sickle-cell–related painful crises: 106 (73%) of 145 in senicapoc vs 89 (62%) of 144 in placebo group | OR (CI): 1.68 (1.02-2.76); P = .045|| |
| Placebo (n = 144*) orally | ||||||||
| Painful crisis rate, mean (SD): 0.38 (±0.36) in senicapoc group vs 0.31 (±0.48) in placebo group | Mean difference (CI): 0.07 (−0.03-0.17); NS|| | |||||||
| N of days in hospital per patient, mean: 18.6 in senicapoc group vs 15.1 in placebo group | P = .03‡ | |||||||
| Magnesium pidolate | ||||||||
| 68 (United States) | RCT (phase 2) | HbSC; age ≥2 years; ≥1 vaso-occlusive event in past 12 months | Mean, 13.6; 57; HU was part of intervention | 44 weeks | HU 20 mg/kg per day plus magnesium pidolate 0.3 mmol/kg per day bd orally | 2/6 | N of vaso-occlusive pain crises: no significant differences observed between treatment groups (data NA) | NA† |
| HU 20 mg/kg per day plus placebo orally | ||||||||
| Placebo plus magnesium pidolate 0.3 mmol/kg per day bd orally | ||||||||
| Placebo plus placebo orally | ||||||||
| N per group, NA (total N = 44) | ||||||||
| Lime juice | ||||||||
| 56 (Nigeria) | RCT (phase 2) | Sickle-cell anemia; children | Mean, 4.6§; 53§; 0 | 6 months | Lime juice td ≤10 kg 5 mL, 11-20 kg 10 mL, >20 kg 15 mL (n = 58*) | 1/6 | N of children with significant painful episodes: 29 (50%) of 58 in lime juice vs 51 (93%) of 55 in routine care group | OR (CI): 0.078 (0.02-0.24); P < .001|| |
| Routine care (n = 55*) | ||||||||
| N of children with hospitalizations: 2 (3%) of 58 in lime juice vs 19 (35%) of 55 in routine care group | OR (CI): 0.068 (0.01-0.3); P < .001|| | |||||||
| Frequency of significant painful episodes, mean (SD): 0.64 (±0.11) in lime juice vs 1.51 (±0.34) in routine care group | Mean difference (CI): −0.87 (−0.96 to −0.78); P < .001|| | |||||||
| Frequency of hospitalizations, mean (SD): 0.03 (±0.01) in lime juice vs 0.35 (±0.07) in routine care group | Mean difference (CI): −0.32 (−0.33 to −0.30); P < .001|| | |||||||
| HQK-1001 | ||||||||
| 63 (United States, Egypt, Jamaica, Canada, Lebanon) | RCT (phase 2) | HbSS, HbSβ0; age 12-60 years; ≥1 acute SCD-related event in past 12 months | Mean, 27.8§; 34§; 0 | 48 weeks | HQK-1001 15 mg/kg bd (n = 38*) orally | 4/6 | Patients with at least 1 pain crisis: 22 (58%) of 38 in HQK-1001 vs 19 (50%) of 38 in placebo group | OR (CI): 1.38 (0.56-3.40); NS|| |
| Placebo (n = 38*) orally | Patients with acute chest syndrome: 6 (16%) of 38 in HQK-1001 vs 2 (5%) of 38 in placebo group | OR (CI): 3.4 (0.6-17.9); NS|| | ||||||
| Annualized rate of pain crises, mean (SD): 3.5 (±5.2) in HQK-1001 group vs 1.7 (±2.2) in placebo group | Mean difference (CI): 1.80 (−0.03-3.63); NS|| | |||||||
| Other interventions | ||||||||
| Folate | ||||||||
| 48 (Jamaica) | CT (phase 2) | HbSS; age 0.5-4 years | Range, 0.5-4; 56; NA | 1 year | Folate 5 mg od (n = 59*) | 3/6 | Patients with painful episodes: 22 (37%) of 59 in folate vs 18 (32%) of 56 in placebo group | OR (CI): 1.26 (0.58-2.71); NS|| |
| Placebo (n = 56*) | ||||||||
| Zinc | ||||||||
| 50 (India) | RCT (phase 2) | HbSS; age >5 years | Mean, 16.4§; 71§; NA | 1.5 years | Zinc sulfate 220 mg td (n = 65*) | 4/6 | N of crisis episodes, mean (SD): 2.46 (±1.04) in zinc vs 5.29 (±2.58) in placebo group | Mean difference (CI): −2.83 (−3.51 to −2.15); P < .0001|| |
| Placebo (n = 65*) | ||||||||
| 47 (United States) | RCT, partial crossover (phase 2) | HbSS, HbSC, HbSβ; adults | Range, 19-49; 50; NA | 3 years (excluding 1-year follow-up prior) | Zinc acetate 50-75 mg daily (n = 11; zinc deficient) orally | 2/6 | Incidence of hospital admission, mean (SD): 6.90 (±3.60) in zinc vs 5.36 (±5.30) in routine care vs 8.00 (±5.2) in placebo group | Mean difference (CI): zinc vs routine care, 1.54 (−2.49-5.57); NS||; zinc vs placebo, −1.1 (−5.15-2.95); NS|| |
| Placebo with crossover to zinc acetate 50-75 mg daily after 1 year (n = 10; zinc deficient) orally | ||||||||
| Routine care (n = 11; zinc sufficient) | Incidence of VOCs, mean (SD): 6.72 (±3.60) in zinc vs 5.18 (±4.80) in routine care vs 7.6 (±5.4) in placebo group | Mean difference (CI): zinc vs routine care, 1.54 (−2.23-5.31); NS||; zinc vs placebo, −0.88 (−5.03-3.27); NS|| | ||||||
| 67 (United States) | RCT (phase 2) | HbSS; adults | Mean, 33.6§; 61§; 0 | 3 months | Zinc acetate 25 mg td (n = 18) orally | 4/6 | N of sickle pain episodes: 1 episode in 18 patients in zinc vs 3 episodes in 18 patients in placebo group | NA† |
| Placebo (n = 18) orally | ||||||||
| Antimalarials | ||||||||
| 70 (Nigeria) | RCT, open label (phase 2) | HbSS; age 1-16 years | Mean, 8.1§; 52§; NA | 9 months | Antimalarial prophylaxis | 4/6 | N of patients with bone pain crisis during study: 2 (3%) of 36 in pyrimethamine vs 0 (0%) of 32 in proguanil vs 5 (17%) of 29 in placebo group | OR (CI): pyrimethamine vs placebo, 0.28 (0.05-1.58); NS||; proguanil vs placebo, NA; Fisher’s exact P = .02||; pyrimethamine vs placebo, 0.09 (0.02-0.48); P = .001||; proguanil vs placebo, 0.30 (0.09-1.02); NS|| |
| Pyrimethamine 0.5 mg/kg once per week (n = 36*) orally | ||||||||
| Proguanil 1.5 mg/kg od (n = 32*) orally | N of patients with hospitalizations during study: 2 (6%) of 36 in pyrimethamine vs 5 (16%) of 32 in proguanil vs 11 (38%) of 29 in placebo group | |||||||
| Placebo (vitamin C 7 mg/kg od; n = 29*) orally | ||||||||
| 35, 69 (Senegal) | RCT (phase 2) | Sickle-cell anemia | Mean, 24.5§; 47§; NA | 2 months | Seasonal intermittent antimalarial treatment with sulfadoxine 25 mg/kg and pyrimethamine 1.25 mg/kg once per month (n = 30) orally | 6/6 | N of VOC per year, total: 5 in sulfadoxine-pyrimethamine vs 5 in placebo group | Relative risk (CI): 1.0 (0.3-3.1); NS‡ |
| Placebo (n = 30) orally | ||||||||
| N of hospitalizations, total: 5 in sulfadoxine-pyrimethamine vs 5 in placebo group | Relative risk (CI): 1.0 (0.3-3.1); NS‡ | |||||||
| Study, reference (location) . | Design (phase) . | Participants . | Duration of intervention . | Intervention vs comparator (n of randomly assigned patients) . | Risk of bias score . | Primary review outcomes . | Measure of effect . | |
|---|---|---|---|---|---|---|---|---|
| Main criteria . | Age, y; male sex, %; HU, % . | |||||||
| Anticoagulation | ||||||||
| Aspirin | ||||||||
| 51 (United States) | CT, crossover (phase 2) | HbSS, HbSβ0, children | Mean, 7.7; 37%; NA | 21 months (crossover at 6 and 18 months, no washout) | Aspirin 3-6 mg/kg in tablets of 81 mg bd (n = 49*) orally | 3/6 | Days per painful event, mean (SD): 3.9 (±1.4) during intervention phase vs 3.2 (±1.6) during placebo phase | NA† |
| Placebo (n = 49*), oral | ||||||||
| Cumulative n of crises: 43 during intervention phase vs 49 during placebo phase | NA† | |||||||
| Cumulative n of days in pain: 140 during intervention phase vs 153 during placebo phase | NA† | |||||||
| 49 (Brazil) | RCT, crossover (phase 2) | HbSS, HbSβ0 | Range, 4-31; NA; NA | 10 months (5 months per treatment, no washout) | Aspirin 17-45 mg/kg od (n = 29*) orally | 0/6 | Frequency of painful events: 40 events in 17 patients during aspirin vs 40 events in 16 patients during placebo treatment | NA† |
| Placebo (n = 29*) orally | ||||||||
| Ticlopidine | ||||||||
| 55 (Senegal, Cote d'Ivoire, Benin) | RCT (phase 2) | HbSS | Range, 15-45; NA; NA | 6 months | Ticlopidine 250 mg <45 kg bd, >45 kg td (n = 70) orally | 5/6 | Total n of crises during 6-month study observation: 42 crises in 70 patients in ticlopidine (1.2 crises per patient-year) vs 125 crises in 70 patients in placebo group (3.5 crises per patient-year) | P < .001‡ |
| Placebo (n = 70) orally | ||||||||
| Pentoxifylline | ||||||||
| 44 (Brazil) | RCT (phase 2) | HbSS | Mean, 17.7§; 67§; NA | 6 weeks | Pentoxifylline ≥18 years 400 mg td, <18 years 400-600 mg per day depending on body weight (n = 28*) orally | 1/6 | N of patients with pain events: | OR (CI): 0.18 (0.05-0.67); P < .01|| |
| Observation days 2-7: 15 (54%) of 28 patients in pentoxifylline group vs 25 (86%) of 29 patients in control group | ||||||||
| Placebo (n = 29*) orally | Observation days 8-42: 14 (50%) of 28 patients in intervention group vs 25 (86%) of 29 patients in placebo group | OR (CI): 0.09 (0.03-0.31); P < .01|| | ||||||
| N of pain events per group: | P < .05‡ | |||||||
| Observation days 2-7: 32 in pentoxifylline group vs 60 in placebo group | ||||||||
| Observation days 8-42: 57 in intervention group vs 219 in placebo group | P < .05‡ | |||||||
| Acenocoumarol | ||||||||
| 72 (Netherlands, Antilles) | RCT, crossover (phase 2) | HbSS, HbSC, HbSβ; age ≥16 years | Mean, 37 (HbSS group); NA; NA | 33 weeks (14 weeks per treatment, 5-week washout in between) | Acenocoumarol 1 mg, dosage based on targeted INR range of 1.6-2.0 (n = 22*) orally | 6/6 | Frequency of acute vaso-occlusive events: 3 events in acenocoumarol vs 5 events in placebo group | NS‡ |
| Placebo (n = 22*) orally | ||||||||
| Prasugrel | ||||||||
| 32, 33, 62 (United States, Canada) | RCT (phase 2) | HbSS, HbSC, HbSβ0/+; age 18-55 years | Mean, 32.9§; 49§; 44§ | 30 days (+ 30-day follow-up) | Prasugrel 5 mg od (n = 41) orally | 4/6 | Proportion of patients reporting no pain or infrequent pain: 50% in prasugrel vs 22% in placebo group | NS‡ |
| Placebo (n = 21) orally | N of patients having painful episodes: 9 (23%) of 40 patients in prasugrel vs 7 (37%) of 19 patients in placebo group | OR (CI): 0.50 (0.15-1.64); NS|| | ||||||
| Proportion of days with pain, least-squares mean: 42% in prasugrel vs 54% in placebo group | NS‡ | |||||||
| 60 (United States, United Kingdom, Ghana, Saudi Arabia, Lebanon, Kenya, Italy, Egypt, Canada, Belgium, Brazil, Turkey, Oman) | RCT (phase 3) | HbSS, HbSβ0; age 2-17 years; ≥2 crises in past yr | Mean, 10.6§; 49§; 45§ | 9-24 months | Prasugrel 0.04-0.12 mg/kg od (n = 171) orally | 6/6 | N of patients with painful crises: 113 (66%) of 171 patients in prasugrel vs 122 (72%) of 170 patients in placebo group | OR (CI): 0.77 (0.48-1.21); NS|| |
| Placebo (n = 170) orally | N of patients with VOCs: 115 (67%) of 171 patients in prasugrel vs 123 (72%) of 170 patients in placebo group | OR (CI): 0.78 (0.49-1.25); NS|| | ||||||
| N of patients with hospital admission: 69 (40%) of 171 patients in prasugrel vs 76 (45%) of 170 patients in placebo group | OR (CI): 0.84 (0.54-1.29); NS|| | |||||||
| Monthly rate of daily pain, mean (SD): 17.5 (NA) in prasugrel group vs 17.7 (NA) in placebo group | Mean difference (CI): 0.24 (4.6–4.1); NS‡ | |||||||
| Antioxidants | ||||||||
| ω-3 fatty acids | ||||||||
| 31, 65 (United States) | RCT (phase 2) | Any sickle-cell syndrome; adults; ≥3 pain episodes per year | NA; NA; 0 | 6-12 months | Fish oil 0.25 g/kg per day in 3 daily doses containing 0.1 g/kg per day ω-3 fatty acids (EPA and DHA; n = 5*) orally | 3/6 | Frequency of pain episodes per year, mean: 3.8 episodes in ω-3 fatty acids vs 7.1 episodes in placebo group | P < .01‡ |
| Placebo (n = 5*) orally | ||||||||
| 59 (Sudan) | RCT (phase 2) | HbSS; age 2-24 years | Mean, 8.1§; 59§; 0 | 1 year | ω-3 fatty acids (EPA and DHA) 25 mg/kg od (n = 70) orally | 6/6 | Annual VOC rate, median (IQR): | P < .01‡ |
| 2.7 (0.9-4.8) in ω-3 vs 4.6 (3.0-6.4) in placebo group | ||||||||
| Placebo (n = 70) orally | Annual clinical VOC rate, median (IQR): 0 (0-0.9) in ω-3 vs 1 (0-2.4) in placebo group | P < .001‡ | ||||||
| N of hospitalization days, median (IQR): 0 (6) in ω-3 vs 0 (6) in placebo group | P < .05‡ | |||||||
| N-acetylcysteine | ||||||||
| 64 (United States) | RCT (phase 2) | HbSS, HbSβ0; age ≥15 years; ≥2 VOCs per year in past 2 years | Mean, 18.1§; 60§; NA | 7 months | N-acetylcysteine in 3 daily doses orally: 600 mg (n = 5*), 1200 mg (n = 5*), 2400 mg (n = 6*) | 3/6 | N of acute VOC episodes per person-days, mean: 0.006 episodes in 2400 mg N-acetylcysteine vs 0.011 in 1200 mg vs 1.24 in 600 mg vs 0.017 in placebo group | NA† |
| Placebo (n = 5*) orally | ||||||||
| Vitamin C-E | ||||||||
| 57 (Brazil) | RCT (phase 2) | HbSS, HbSβ0; adults | Median, 28.3§; 34§; 57§ | 6 months | Vitamin C 1400 mg and vitamin E 800 mg od (n = 44*) orally | 3/6 | Incidence of acute SCD complications: 16 (36%) of 44 patients in vitamin C-E vs 12 (31%) of 39 patients in placebo group | OR (CI): 1.29 (0.51-3.21); NS|| |
| Placebo (n = 39*) orally | ||||||||
| l-glutamine | ||||||||
| 34, 61 (United States) | RCT (phase 3) | HbSS, HbSβ0; age ≥5 years; ≥2 crises in past 12 months | Range, 5-58; 46; HU+ (% NA, stratified) | 48 weeks (+ 3-week tapering + 2-week follow-up) | l-glutamine: 0.6g/kg per day in 2 doses (n = 152) orally | 1/6 | N of sickle cell crises, median: 3 in l-glutamine vs 4 in placebo group | P = .008‡ |
| Placebo (n = 78) orally | N of hospitalizations, median: 2 in l-glutamine group vs 3 in placebo group | P = .005‡ | ||||||
| Cumulative n of hospital days, median: 6.5 in l-glutamine group vs 11 in placebo group | P = .022‡ | |||||||
| Antiadhesion | ||||||||
| Crizanlizumab | ||||||||
| 58 (United States, Brazil, Jamaica) | RCT (phase 2) | Any SCD genotype (including HbSS, HbSC, HbSβ0/+); age 16-65 years; 2-10 VOCs in 12 months before enrollment | Median, 29§; 48§; 63§ | 52 weeks | Crizanlizumab, 2 loading doses 2 weeks apart, then every 4 weeks IV: high dose, 5 mg/kg (n = 67); low dose, 2.5 mg/kg (n = 66) | 6/6 | Annual rate of sickle-cell–related pain crises, median (IQR): 1.63 (0.00-3.97) in high-dose vs 2.01 (1.25-5.87) in low-dose vs 2.98 (1.25-5.87) in placebo group | High dose vs placebo: −45.3%; P = .01‡; low dose vs placebo: −32.6%; NS‡ |
| Annual rate of uncomplicated sickle-cell–related pain crises: 1.08 (0.00-3.96) in high-dose vs 2.00 (0.00-3.02) in low-dose vs 2.91 (1.00-5.00) in placebo group | High dose vs placebo: −62.9%; P = .02‡; low dose vs placebo: 31.3%; NS‡ | |||||||
| Annual rate of days hospitalized, median (IQR): 4.00 (0.00-25.72) in high-dose vs 6.87 (0.00-28.30) in low-dose vs 6.87 (0.00-28.30) in placebo group | High dose vs placebo: −41.8%; NS‡; low dose vs placebo: 0%; NS‡ | |||||||
| Placebo (n = 65) IV | ||||||||
| Antisickling | ||||||||
| Promazine hydrochloride | ||||||||
| 46 (United States) | RCT, crossover (phase 2) | HbSS, HbSC; ≥2 painful episodes in past 2 years | NA; 64; NA | 2 years (crossover every 3 months, no washout) | Promazine hydrochloride 25 mg, dosage based on body weight; 40-80 lb bd, 80-120 lb td, ≥120 lb daily (n = 14) orally | 3/6 | N of hospital admissions for painful episodes per patient-month: 0.09 admissions (based on 16 admissions over 180 patient-months) in promazine hydrochloride group vs 0.05 admissions (based on 8 admissions over 152 patient-months in placebo group) | NA† |
| Placebo (n = 14) orally | N of diary recorded painful episodes per patient-month: 0.22 episodes (based on 40 episodes over 180 patient-months) in promazine hydrochloride group vs 0.28 episodes (based on 42 episodes over 152 patient-months) in placebo group | NA† | ||||||
| Steroids (including oral contraceptives) | ||||||||
| 42 (Nigeria) | RCT, crossover (phase 2; preliminary report before crossover) | HbSS; ≥1 episode of moderately severe pain in 3 months | Range, 2-35; 36; NA | 4-6 months | Men, testosterone 10 mg once per week im; women, progesterone 10 mg once per week im (n = 35*) | 1/6 | Primary review outcome: NA | |
| Secondary review outcomes: | ||||||||
| Pain score, mean (range): 57 (0-330) in testosterone/progesterone vs 153 (130-200) in placebo group | NA† | |||||||
| Placebo (n = 9*) im | ||||||||
| 53 (Jamaica) | RCT, crossover (phase 2) | HbSS; female sex | Range, 20-40; 0; NA | 2 years (9 months per treatment, 6-month washout in between) | Medroxyprogesterone 150 mg every 3 months (n = 10*) im | 1/6 | Primary review outcome: NA | |
| Placebo (saline; n = 13*) im | Secondary review outcomes: | |||||||
| Bone pain episodes: 14 (61%) of 23 in medroxyprogesterone vs 20 (87%) of 23 in placebo group | OR (CI): 0.23 (0.05-1.01); NS|| | |||||||
| Severity score of bone pain episodes, mean: 2.0 in medroxyprogesterone vs 1.8 in placebo group | NA† | |||||||
| 54 (Panama) | CT (phase 2) | HbSS; 1 crisis per month; female sex; desire for reversible method of contraception | Range, 17-39; 0; NA | 12 months | Levonorgestrel 0.15 mg and ethinyl estradiol 0.03 mg od (n = 14) orally | 0/6 | Proportion of patients with painful crisis at end of study: 50% in control group vs 30% of progestogen-only group vs 45.5% of combined oral contraceptive group | NA† |
| Medroxyprogesterone acetate 150 mg, first 3 months monthly, last 9 months every 3 months (n = 13) im | ||||||||
| Surgically sterilized (n = 16) | ||||||||
| Sodium bicarbonate | ||||||||
| 43 (United Kingdom) | RCT, crossover (phase 2) | HbSS, HbSC, HbSβ0/+; age 5-17 years | Mean, 8.4; 33; NA | 2 years (crossover after 1 year, no washout) | Sodium bicarbonate 0.1-0.4 mg/kg od, dosage based on targeted urine alkalinization (n = 18) orally | 1/6 | N of crises per 50 patient-weeks, mean (SD): 2.2 (±1.8) in sodium bicarbonate vs 3.0 (±2.3) in routine group | Mean difference (CI): −0.8 (−2.2-0.6); NS|| |
| Routine care (n = 18) | ||||||||
| Urea | ||||||||
| 52 (Ghana) | RCT (phase 2) | HbSS | <5 years, 23%§; 5-14 years, 38%§; >14 years, 40%§; 47§; NA | Average, 13.7 months | Urea 0.266 g/kg (n = 40) orally: low dose twice per week; high dose daily | 5/6 | N of patients with >1 crisis: 18 (45%) of 40 of urea vs 15 (38%) of 40 of placebo group | OR (CI): 1.4 (0.6-3.3); NS|| |
| N of patients with >2 crises: 8 (20%) of 40 of urea vs 5 (13%) of 39 of placebo group | OR (CI): 1.7 (0.5-5.7); NS|| | |||||||
| Crisis rate per person-year in patients with >1 crisis, mean: 0.596 in urea vs 0.506 in placebo group | Crisis rate ratio, 0.849 (placebo vs urea); NS‡ | |||||||
| Placebo (n = 39) orally | Crisis rate per person-year in patients with >2 crises, mean: 0.189 in urea vs 0.136 in placebo group | Crisis rate ratio, 0.720 (placebo vs urea); NS‡ | ||||||
| Piracetam | ||||||||
| 45 (Lebanon) | RCT, crossover (phase 2) | Sickle-cell anemia; children | Range, 4-15; 44; NA | 10 months (5 months per treatment, no washout) | Piracetam 80 mg/kg per day in 4 daily doses (n = 9*) orally | 2/6 | N of pain crises per patient per month, average: 0.89 in piracetam group vs 1.85 in placebo | P < .05‡ |
| Placebo (n = 9*) orally | ||||||||
| 36, 37 (Saudi Arabia) | RCT (phase 2) | HbSS, HbSβ0, children | Range, 3-12; 57; NA | 1 year | Piracetam 160 mg/kg per day (n = 48*) orally; during admission 300 mg/kg per day IV | 2/6 | N of painful crisis per year, mean (SD): 2.4 (±1.9) in piracetam vs 4.3 (±3.1) in placebo group | Mean difference (CI): −1.9 (−3.0 to −0.8); P < .001|| |
| Placebo (n = 39*) orally; during admission IV | N of hospitalizations per year in total group, mean (SD): 2.07 (±2.4) in piracetam group vs 3.20 (±2.9) in placebo group | Mean difference (CI): −1.1 (−2.3-0.0); P < .05|| | ||||||
| 40, 41 (Brazil) | RCT, crossover (phase 2) | HbSS, HbSC, HbSβ0/+; age 5-20 years | Median, 12.1; 45; 0 | 13 months (6 months per treatment, 1-month washout in between) | Piracetam 4.8g/m2 per day in 4 daily doses (n = 73*) orally | 1/6 | Absolute n of painful VOCs, median: 3 in both groups | NS‡ |
| Placebo (n = 73*) orally | N of pain days per month, median: 1.47 in both groups | NS‡ | ||||||
| Hospitalization days: data NA | NS‡ | |||||||
| Niprisan | ||||||||
| 38, 39 (Nigeria) | RCT, crossover (phase 2) | HbSS; ≥3 crises in past year; age 2-45 years | Mean, 15.5; 45; NA | 12 months (6 months per treatment, no washout) | Niprisan 12 mg/kg od (n = 70*) | 3/6 | N of episodes of mild to moderate pain over first 6 months, mean (SD): 9.1 (±9.6) in niprisan vs 20.6 in placebo group (±32.9) | NS‡ |
| Placebo (n = 70*) | N of episodes of severe pain first 6 months, mean (SD): 7.9 (±8.4) in niprisan vs 22.1 (±32.9) in placebo group | P < .05‡ | ||||||
| N of painful crises first 6 months, mean (SD): 0.27 (±0.6) in niprisan vs 1.17 (±1.8) in placebo group | NS‡ | |||||||
| N of hospital admissions per month in first 6 months, mean (SD): 0.15 (±0.6) in niprisan vs 0.22 (±0.6) in placebo group | NS‡ | |||||||
| NB. No summary statistics possible because of skewed data | ||||||||
| Ciklavit | ||||||||
| 71 (Nigeria) | RCT (phase 2) | HbSS; age 1-15 years | Mean, 8.09§; 57§; NA | 6 months | Ciklavit ≤5 years 10 mL twice daily, >5 years 20 mL bd (n = 47*) | 3/6 | N of painful crises in 6 months, mean (SD): 4.2 (4.2) in Ciklavit vs 3.9 (4.3) in placebo group | Mean difference (CI): 0.30 (−1.49-2.09); NS|| |
| Placebo (n = 42*) | ||||||||
| Cromolyn sodium | ||||||||
| 74 (Iran) | CT, crossover (phase 2) | HbSS | Range, 5-34; 41; HU was part of intervention | 12 months (crossover every 3 months, unclear washout) | Subsequent treatment regimens 1-4 (n = 17*): (1) cromolyn sodium nasal spray 2%, 4 puffs each nostril, frequency NA; (2) placebo nasal spray; (3) as in 1, plus HU 10-15 mg/kg per day orally; and (4) as in 2, plus HU 10-15 mg/kg per day orally | 0/6 | Primary review outcome: NA | |
| Secondary review outcomes: | ||||||||
| Pain score: data NA, pain score in cromolyn sodium and HU group lower than cromolyn sodium–only group | P < .05‡ | |||||||
| Other comparisons between groups | NS‡ | |||||||
| Senicapoc | | | |||||||
| 66 (United States) | RCT (phase 2) | HbSS; age 18-60 years | Mean, 37.2§; 59§; 27 | 12 weeks | Senicapoc loading dose on day 1, subsequently: low dose, 6 mg od (n = 29) orally; high dose, 10 mg od (n = 31) orally | 6/6 | N of patients with painful crisis: 5 (17%) of 29 in low-dose senicapoc vs 5 (16%) of 31 in high-dose senicapoc vs 5 (17%) of 30 in placebo group | OR (CI): low dose vs placebo, 1.04 (0.27-4.06); NS||; high dose vs placebo, 0.96 (0.24-3.73); NS|| |
| Placebo (n = 30) orally | ||||||||
| 73 (United States, United Kingdom, Jamaica, Brazil, France, Trinidad) | RCT (phase 3) | HbSS, HbSC, HbSβ0/+; age 16-65 years; ≥2 crises in past 12 months | Mean, 28.5§; 43§; 58§ | 52 weeks | Senicapoc 1 mg od, initial loading dose 20 mg bd for 4 days (n = 145*) orally | 6/6 | N of patients with acute sickle-cell–related painful crises: 106 (73%) of 145 in senicapoc vs 89 (62%) of 144 in placebo group | OR (CI): 1.68 (1.02-2.76); P = .045|| |
| Placebo (n = 144*) orally | ||||||||
| Painful crisis rate, mean (SD): 0.38 (±0.36) in senicapoc group vs 0.31 (±0.48) in placebo group | Mean difference (CI): 0.07 (−0.03-0.17); NS|| | |||||||
| N of days in hospital per patient, mean: 18.6 in senicapoc group vs 15.1 in placebo group | P = .03‡ | |||||||
| Magnesium pidolate | ||||||||
| 68 (United States) | RCT (phase 2) | HbSC; age ≥2 years; ≥1 vaso-occlusive event in past 12 months | Mean, 13.6; 57; HU was part of intervention | 44 weeks | HU 20 mg/kg per day plus magnesium pidolate 0.3 mmol/kg per day bd orally | 2/6 | N of vaso-occlusive pain crises: no significant differences observed between treatment groups (data NA) | NA† |
| HU 20 mg/kg per day plus placebo orally | ||||||||
| Placebo plus magnesium pidolate 0.3 mmol/kg per day bd orally | ||||||||
| Placebo plus placebo orally | ||||||||
| N per group, NA (total N = 44) | ||||||||
| Lime juice | ||||||||
| 56 (Nigeria) | RCT (phase 2) | Sickle-cell anemia; children | Mean, 4.6§; 53§; 0 | 6 months | Lime juice td ≤10 kg 5 mL, 11-20 kg 10 mL, >20 kg 15 mL (n = 58*) | 1/6 | N of children with significant painful episodes: 29 (50%) of 58 in lime juice vs 51 (93%) of 55 in routine care group | OR (CI): 0.078 (0.02-0.24); P < .001|| |
| Routine care (n = 55*) | ||||||||
| N of children with hospitalizations: 2 (3%) of 58 in lime juice vs 19 (35%) of 55 in routine care group | OR (CI): 0.068 (0.01-0.3); P < .001|| | |||||||
| Frequency of significant painful episodes, mean (SD): 0.64 (±0.11) in lime juice vs 1.51 (±0.34) in routine care group | Mean difference (CI): −0.87 (−0.96 to −0.78); P < .001|| | |||||||
| Frequency of hospitalizations, mean (SD): 0.03 (±0.01) in lime juice vs 0.35 (±0.07) in routine care group | Mean difference (CI): −0.32 (−0.33 to −0.30); P < .001|| | |||||||
| HQK-1001 | ||||||||
| 63 (United States, Egypt, Jamaica, Canada, Lebanon) | RCT (phase 2) | HbSS, HbSβ0; age 12-60 years; ≥1 acute SCD-related event in past 12 months | Mean, 27.8§; 34§; 0 | 48 weeks | HQK-1001 15 mg/kg bd (n = 38*) orally | 4/6 | Patients with at least 1 pain crisis: 22 (58%) of 38 in HQK-1001 vs 19 (50%) of 38 in placebo group | OR (CI): 1.38 (0.56-3.40); NS|| |
| Placebo (n = 38*) orally | Patients with acute chest syndrome: 6 (16%) of 38 in HQK-1001 vs 2 (5%) of 38 in placebo group | OR (CI): 3.4 (0.6-17.9); NS|| | ||||||
| Annualized rate of pain crises, mean (SD): 3.5 (±5.2) in HQK-1001 group vs 1.7 (±2.2) in placebo group | Mean difference (CI): 1.80 (−0.03-3.63); NS|| | |||||||
| Other interventions | ||||||||
| Folate | ||||||||
| 48 (Jamaica) | CT (phase 2) | HbSS; age 0.5-4 years | Range, 0.5-4; 56; NA | 1 year | Folate 5 mg od (n = 59*) | 3/6 | Patients with painful episodes: 22 (37%) of 59 in folate vs 18 (32%) of 56 in placebo group | OR (CI): 1.26 (0.58-2.71); NS|| |
| Placebo (n = 56*) | ||||||||
| Zinc | ||||||||
| 50 (India) | RCT (phase 2) | HbSS; age >5 years | Mean, 16.4§; 71§; NA | 1.5 years | Zinc sulfate 220 mg td (n = 65*) | 4/6 | N of crisis episodes, mean (SD): 2.46 (±1.04) in zinc vs 5.29 (±2.58) in placebo group | Mean difference (CI): −2.83 (−3.51 to −2.15); P < .0001|| |
| Placebo (n = 65*) | ||||||||
| 47 (United States) | RCT, partial crossover (phase 2) | HbSS, HbSC, HbSβ; adults | Range, 19-49; 50; NA | 3 years (excluding 1-year follow-up prior) | Zinc acetate 50-75 mg daily (n = 11; zinc deficient) orally | 2/6 | Incidence of hospital admission, mean (SD): 6.90 (±3.60) in zinc vs 5.36 (±5.30) in routine care vs 8.00 (±5.2) in placebo group | Mean difference (CI): zinc vs routine care, 1.54 (−2.49-5.57); NS||; zinc vs placebo, −1.1 (−5.15-2.95); NS|| |
| Placebo with crossover to zinc acetate 50-75 mg daily after 1 year (n = 10; zinc deficient) orally | ||||||||
| Routine care (n = 11; zinc sufficient) | Incidence of VOCs, mean (SD): 6.72 (±3.60) in zinc vs 5.18 (±4.80) in routine care vs 7.6 (±5.4) in placebo group | Mean difference (CI): zinc vs routine care, 1.54 (−2.23-5.31); NS||; zinc vs placebo, −0.88 (−5.03-3.27); NS|| | ||||||
| 67 (United States) | RCT (phase 2) | HbSS; adults | Mean, 33.6§; 61§; 0 | 3 months | Zinc acetate 25 mg td (n = 18) orally | 4/6 | N of sickle pain episodes: 1 episode in 18 patients in zinc vs 3 episodes in 18 patients in placebo group | NA† |
| Placebo (n = 18) orally | ||||||||
| Antimalarials | ||||||||
| 70 (Nigeria) | RCT, open label (phase 2) | HbSS; age 1-16 years | Mean, 8.1§; 52§; NA | 9 months | Antimalarial prophylaxis | 4/6 | N of patients with bone pain crisis during study: 2 (3%) of 36 in pyrimethamine vs 0 (0%) of 32 in proguanil vs 5 (17%) of 29 in placebo group | OR (CI): pyrimethamine vs placebo, 0.28 (0.05-1.58); NS||; proguanil vs placebo, NA; Fisher’s exact P = .02||; pyrimethamine vs placebo, 0.09 (0.02-0.48); P = .001||; proguanil vs placebo, 0.30 (0.09-1.02); NS|| |
| Pyrimethamine 0.5 mg/kg once per week (n = 36*) orally | ||||||||
| Proguanil 1.5 mg/kg od (n = 32*) orally | N of patients with hospitalizations during study: 2 (6%) of 36 in pyrimethamine vs 5 (16%) of 32 in proguanil vs 11 (38%) of 29 in placebo group | |||||||
| Placebo (vitamin C 7 mg/kg od; n = 29*) orally | ||||||||
| 35, 69 (Senegal) | RCT (phase 2) | Sickle-cell anemia | Mean, 24.5§; 47§; NA | 2 months | Seasonal intermittent antimalarial treatment with sulfadoxine 25 mg/kg and pyrimethamine 1.25 mg/kg once per month (n = 30) orally | 6/6 | N of VOC per year, total: 5 in sulfadoxine-pyrimethamine vs 5 in placebo group | Relative risk (CI): 1.0 (0.3-3.1); NS‡ |
| Placebo (n = 30) orally | ||||||||
| N of hospitalizations, total: 5 in sulfadoxine-pyrimethamine vs 5 in placebo group | Relative risk (CI): 1.0 (0.3-3.1); NS‡ | |||||||
This table provides a summary of the characteristics, risks of bias, and primary review outcomes of included studies. The 6 risk-of-bias criteria were summarized into a single risk-of-bias score from 0 to 6; the higher this score, the more items were marked with a low risk of bias. The full results of the risk-of-bias assessment per study can be found in supplemental Table 2. A complete overview of the primary and secondary review outcomes and the outcome definitions per study is provided in supplemental Table 3.
bd, twice daily; CI, confidence interval; CT, controlled trial; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; im, intramuscularly; IQR, interquartile range; NA, not available; NS, not significant; od, once daily; OR, odds ratio; SD, standard deviation; td, three times per day.
Patients included in final analysis.
Data did not allow post hoc summary statistics or were not available in paper.
(Summary) statistic copied from paper.
In intervention group (the first stated in case of multiple intervention groups).
Summary statistic calculated post hoc with data from the original paper.