. 2021 Sep 12;38(10):5025–5045. doi: 10.1007/s12325-021-01900-w

Table 4.

Serotonin-norepinephrine reuptake inhibitor (SNRI) study results

Clinical trial	Trial design and key participant BL data	Key outcomes	Results (p values vs. placebo)
1 Evans et al Obstetrics and Gynecology (2005) [20]	12-week RCT: 1 US centre Mean age = 52.15 years 80 randomised (1:1) to venlafaxine XR (37.5 mg/day for 1 week, titrated to 75 mg/day for 11 weeks) vs. placebo	1°: # of mild, mod, severe, and very severe HFs/day Avg. HF severity 2°: Important AEs/SAEs Discontinuation due to AEs	1°: absolute or %↓ data not reported No sig. ↓ in HF # vs. placebo (p = 0.2) No sig. ↓ in mean HF severity (p value not given) 2°: AEs: ↑ in dry mouth (81% vs. 44%), ↑ in sleeplessness (88% vs. 47%) and ↓ appetite (81% vs. 53%) vs. placebo ↑ withdrawals [11 vs. 8 (p = ns)] due to difficulty sleeping, ↓ libido, nausea or anxiety
2 Speroff et al Obstetrics and Gynecology (2008) [21]	1° efficacy evaluations completed at 4 and 12 weeks Safety and tolerability data collected for 52 weeks 52 week DBRCT; dose-ranging trial: 37 US centres Mean age = 53 years (37–78) Mean BMI = 26.96 kg/m² 707 randomised (2:2:2:2:1) to desvenlafaxine 50, 100, 150, or 200 mg/day vs. placebo for 52 weeks 620 included in mITT analysis	1°: ∆ from BL in avg. daily # of mod/severe HFs at week 4 and 12 ∆ from BL in avg. daily HF severity score at week 4 and 12 2°: ∆ from BL in daily # of night-time awakenings due to HFs at week 4 and 12 Important AEs/SAEs Discontinuation due to AEs	1°: ↓ from BL in avg. daily # of mod/severe HFs vs. placebo (No ↓ with 50 mg or 200 mg) 100 mg ↓ at week 4 (− 6.62 vs. − 5.22; p = 0.013) and week 12 [− 7.23 (64%↓) vs. − 5.50 (51%↓); p = 0.005] 150 mg ↓ at week 12 [− 6.94 (60%↓) vs. − 5.50 (51%↓); p = 0.020], but not at week 4 ↓ from BL in avg. daily HF severity scores vs. placebo (No ↓ with 50 mg or 150 mg) 100 mg ↓ at week 12 [− 0.80 (31%↓) vs. − 0.47 (18%↓); p = 0.002], but not at week 4 200 mg ↓ at week 12 [− 0.74 (27%↓) vs. − 0.47 (18%↓); p = 0.013], but not at week 4 2°: ↓ daily # of night-time awakenings vs. placebo at week 12 (week 4 not reported) (No ↓ with 50 mg) 100 mg, 150 mg and 200 mg ↓ at week 12 [− 2.77/night (76.9%↓), p = 0.013; − 2.69/night (69%↓), p = 0.034 and − 2.68/night (70.5%↓), p = 0.043, respectively vs. − 2.21/night (63.1%↓)] AEs vs. placebo 150 mg and 200 mg ↑ AEs during week 1 only (both p < 0.05), most commonly, nausea, dry mouth, insomnia (No ↑ with 50 mg and 100 mg) 3 SAEs possibly Tx-related: 2 increased LFTs, 1 cholecystitis ↑ hypertension (5.9% overall vs. 1.3% placebo; p = ns). 5 vs. 0 CV events at 1 year (p = ns) ↑ discontinuations due to AEs 150 and 200 mg during week 1 only (both p < 0.001). (No ↑ with 50 mg and 100 mg)
3 Archer et al American Journal of Obstetrics and Gynecology (2009) [22]	12 week DBRCT: 34 US centres Mean age = 53.36 years (29–71) Mean BMI = 27.86 kg/m² (17.2–40.1) 458 randomised to desvenlafaxine 100 mg/day or 150 mg/day vs. placebo for 12 weeks [50 mg/day for 3 days, titrated to 100 mg/day on day 4 (titrated to 150 mg/day on day 8 for 150 mg/day group)] 2 week dose-tapering 436 included in mITT analysis	1°: ∆ from BL in avg. daily # mod/severe HFs at weeks 4 and 12 ∆ from BL in avg. daily HF severity score at weeks 4 and 12 2°: ∆ from BL in # of night-time awakenings at weeks 4 and 12 Important AEs/SAEs Discontinuation due to AEs	1°: ↓ daily # of HF from BL vs. placebo with 100 mg and 150 mg at week 4 (both p ≤ 0.012, no % given) and week 12 (65.4%↓, p = 0.005; and 66.6%↓, p = 0.012, respectively vs. 50.8%↓) ↓ daily HF severity score from BL vs. placebo with 100 mg and 150 mg at week 12 [− 0.65 (27%↓); and − 0.66 (27.5%↓), respectively vs. − 0.33 (13.75%↓); both p < 0.001], and at all other time points 2°: ↓ daily # of night-time awakenings from BL vs. placebo with 100 mg and 150 mg at week 4 (− 1.8 and − 1.6, respectively vs. − 1.2) and week 12 [− 2.0 (60.6%↓) and − 1.8 (58.1%↓), respectively vs. − 1.4 (43.8%↓)]; all p ≤ 0.048 ↑ AEs during week 1 only vs. placebo (84.1% vs. 69.5%; p = 0.002), most commonly nausea (25.2%), dry mouth, insomnia, constipation, asthenia 2 SAEs possibly Tx-related: hypertension (1 subject with 150 mg ↑ SBP by 4.52 mmHg at week 12 (p = 0.002), bronchospasm (1 subject but on placebo) Discontinuation due to AEs: no diff. [but numerically ↑ in 150 mg group (p = ns)]
4 Archer et al American Journal of Obstetrics and Gynecology (2009) [23]	26 week DBRCT: 32 US centres Mean age = 53.7 years Mean BMI = 27.1 kg/m² (15.9–40.4) 567 randomised to desvenlafaxine 100 mg/day or 150 mg/day vs. placebo for 26 weeks 484 included in mITT analysis	1°: ∆ from BL in avg. daily # of mod/severe HFs at weeks 4 and 12 ∆ from BL in avg. daily HF severity at weeks 4 and 12 2°: ∆ from BL in # of night-time awakenings due to HFs Important AEs/SAEs Discontinuation due to AEs	1°: ↓ daily # of HFs from BL vs. placebo at week 4 and 12 (week 12: 100 mg 60%↓, p = 0.002; 150 mg 66.6%↓, p < 0.001, vs. 47%↓) 150 mg maintained ↓ at week 26 (69%↓ vs. 51%↓, p = 0.001), whereas 100 mg did not (61%↓, p = 0.061) but study not powered for efficacy > 12 weeks ↓ daily HF severity from BL vs. placebo at week 4 and 12 (week 12: 100 mg 24%↓, p = 0.002; 150 mg 29%↓, p < 0.001 vs. 13%↓). 150 mg maintained ↓ at week 26 (p = 0.008, no % given) 2°: ↓ daily # of night-time awakenings from BL vs. placebo at week 4 (actual ↓ not given) and week 12 [100 mg − 2.0 (52.6%↓); 150 mg − 2.4 (68.6%↓) vs. − 1.6 (47.1%↓)]; all p ≤ 0.026 ↑ AEs during week 1 only vs. placebo (p < 0.05), most commonly nausea (44.6%), dizziness, insomnia, dry mouth, constipation ↑ SAE possibly Tx-related: hypertension (100 mg) ↑ discontinuations due to AEs during week 1 only vs. placebo (16.1% vs. 0.6%; p < 0.001)
5 Bouchard et al Climacteric (2012) [24]	12-week DBRCT: 35 European centres, 2 centres in South Africa, 1 centre in Mexico Mean age = 53.6 years (40–66 years) Mean BMI = 26 kg/m² (16–34) ≥ 485 randomised (1:1:1) to desvenlafaxine 100 mg/day, tibolone 2.5 mg/day, vs. placebo for 12 weeks 451 included in mITT analysis	1°: ∆ from BL in avg. daily # of mod/severe HFs at weeks 4 and 12 ∆ from BL in avg. daily HF severity at weeks 4 and 12 2°: Important AEs/SAEs Discontinuation due to AEs	1°: No ↓ in daily # of HFs from BL vs. placebo at week 4 (− 4.63 vs. − 4.38, p = 0.558) and week 12 (− 5.78 (57.7%↓) vs. –5.82 (57.5%↓), p = 0.921] No ↓ in daily HF severity from BL vs. placebo at week 4 (− 0.37 vs. − 0.31, p = 0.352) and week 12 [− 0.61 (26.8%↓) vs. − 0.61 (26.5%↓), p = 0.943] 2°: ↑ AEs with desvenlafaxine vs. tibolone and placebo (73.4% vs. 64.5% and 55.9%, respectively), most commonly nausea (31%), dizziness and constipation ↑ bleeding with tibolone vs. desvenlafaxine and placebo [23% vs. 12% (p = 0.024) and 9% (p = 0.001), respectively] ↑ discontinuations due to AEs during week 1 only vs. placebo (p < 0.001). Most commonly nausea (8.9%) and headache (3.8%)
6a Pinkerton et al Menopause (2013) [25]	52-week DBRCT: 122 US and Canadian centres Mean age = 54 years (45–71) Mean BMI = 26.45 kg/m² (16.9–35.3) 396 randomised (1:1) to desvenlafaxine 100 mg/day vs. placebo for 52 weeks (50 mg/day for 1 week, titrated to 100 mg/day for 51 weeks) 2 week dose-tapering 365 included in mITT analysis Pinkerton et al. (2013) [25] reports 12-week data from an efficacy substudy (part of a larger n = 2186 safety study)	1°: ∆ from BL in avg. daily # of mod and severe HFs at weeks 4 and 12 ∆ from BL in avg. daily HF severity scores at weeks 4 and 12 2°: Important AEs/SAEs Discontinuation due to AEs	1°: ↓ daily # of HFs vs. placebo at week 4 [− 6.5 HFs (55%↓) vs. − 3.6 (31%↓); p < 0.001] and week 12 [− 7.3 HFs (62%↓) vs. − 4.5 (38%↓); p < 0.001] ↓ daily HF severity score vs. placebo at week 4 [− 0.47 (20%↓) vs. − 0.19 (8%↓); p < 0.001] and week 12 [− 0.59 (25%↓) vs. − 0.28 (12%↓); p < 0.001] 2°: ↑ AEs vs. placebo during week 1 only (p < 0.001), mostly nausea, dry mouth, constipation (but no diff. in BP) 2 SAEs: 1 squamous cell carcinoma, 1 multi-event SAE (altered mental status with slurred speech, uncontrolled hypertension, resolved hypokalemia, polypharmacy) ↑ discontinuations due to AEs vs. placebo (10.0% vs. 3.7%; p = 0.016); rates similar after week 1
6b Pinkerton et al. Menopause (2013) [26]	Pinkerton et al. (2013) [26] reports 52-week data from the same efficacy substudy population See above	1°: ∆ from BL in avg. daily # of HFs at weeks 12, 26, 52 ∆ from BL in avg. daily HF severity scores at weeks 12, 26, 52 2°: Important AEs/SAEs Discontinuation due to AEs	1°: ↓ in daily # of HFs at 12 weeks [− 7.5 HFs (64%↓) vs. –5.0 (43%↓); p < 0.001], 26 weeks [− 8.6 HFs (74%↓) vs. − 6.3 (54%↓); p < 0.001 and 52 weeks [− 7.7 HFs (66%↓) vs. − 4.8 (41%↓); p < 0.001] ↓ in daily HF severity score at 12 weeks [− 0.63 (27%↓) vs. − 0.3 (13%↓); p < 0.001], 26 weeks [− 0.85 (36%↓) vs. − 0.53 (22%↓); p = 0.001] and 52 weeks [− 0.75 (32%↓) vs. − 0.44 (19%↓); p = 0.003] 2°: includes efficacy substudy (n = 365) and larger safety population (n = 2186) ↑ AEs vs. placebo (84% vs. 79%; p = 0.006), most commonly nausea (21%), headache, dry mouth and insomnia. Rates of new-onset AEs were similar by week 3 SAEs: No excess CV ischaemic events vs. placebo over 52 weeks ↑ discontinuations due to AEs vs. placebo (18.3% vs. 9.7%; p < 0.001); rates highest during week 1
7a Joffe et al JAMA Internal Medicine (2014) [27]	DBRCT: 3 US centres Mean age = 54.6 years Mean BMI = 28.3 kg/m² 339 randomised (2:2:3) to venlafaxine XR 75 mg/day (37.5 mg/day titrated to 75 mg/day over 1 week), oral 17-beta-oestradiol (ET) 0.5 mg/day or placebo for 8 weeks Venlafaxine followed by 2-week dose-tapering 330 included in mITT analysis	1°: Mean daily # of HFs at weeks 4 and week 8 2°: HF severity at week 8 Important AEs/SAEs Discontinuation due to AEs	1°: ↓ # of HFs from BL vs. placebo at week 4 (48%↓ vs. 25%↓; p = 0.005) and week 8 (48%↓ vs. 29%; p = 0.005) 2°: baseline or %↓ data not reported ↓ HF severity vs. placebo at week 8 (mean diff. vs. placebo: − 0.2, p = 0.02) ↑ AEs vs. ET and placebo (69% vs. 56% and 62%, respectively; p = ns), most commonly fatigue 12 developed SBP > 165 mmHg or DBP > 95 mmHg (10.4% venlafaxine, 2.1% ET, 0 placebo), but all had BL SBP or DBP > study population mean. Vaginal bleeding 8.2% ET, 0% venlafaxine, and 1.6% placebo ↑ discontinuations due to AEs vs. placebo (5 venlafaxine, 4 ET, 2 placebo; p = ns)
7b Cann et al Menopause (2015) [28]	Cann et al. [28] reports questionnaire endpoints from Joffe et al. [27]	MENQoL total and domain scores Measure of pain (PEG), depression (PHQ-9) and anxiety (GAD-7) Perceived stress (PSS)	↓ (improved) mean total MENQoL score from BL vs. placebo at week 4 and week 8 (week 8: − 0.9 vs. − 0.7, p = 0.042) Only sig. diff. vs. placebo in psychosocial domain (week 8: − 1.5 vs. − 1.3, p = 0.008) No improvements vs. placebo with respect to changes in pain (PEG), depressive symptoms (PHQ-9) or anxiety (GAD-7) at weeks 4 and 8 ↓ (improved) perceived stress vs. placebo at week 4 and week 8 (week 8: − 3.4 vs. − 2.0, p = 0.02)

Clinical trial

Trial design and key participant BL data

Key outcomes

Results (p values vs. placebo)

Evans et al

Obstetrics and Gynecology (2005) [20]

12-week RCT: 1 US centre

Mean age = 52.15 years

80 randomised (1:1) to venlafaxine XR (37.5 mg/day for 1 week, titrated to 75 mg/day for 11 weeks) vs. placebo

1°:

# of mild, mod, severe, and very severe HFs/day

Avg. HF severity

2°:

Important AEs/SAEs

Discontinuation due to AEs

1°: absolute or %↓ data not reported

No sig. ↓ in HF # vs. placebo (p = 0.2)

No sig. ↓ in mean HF severity (p value not given)

2°:

AEs: ↑ in dry mouth (81% vs. 44%), ↑ in sleeplessness (88% vs. 47%) and ↓ appetite (81% vs. 53%) vs. placebo

↑ withdrawals [11 vs. 8 (p = ns)] due to difficulty sleeping, ↓ libido, nausea or anxiety

Speroff et al

Obstetrics and Gynecology

(2008) [21]

1° efficacy evaluations completed at 4 and 12 weeks

Safety and tolerability data collected for 52 weeks

52 week DBRCT; dose-ranging trial: 37 US centres

Mean age = 53 years (37–78)

Mean BMI = 26.96 kg/m²

707 randomised (2:2:2:2:1) to desvenlafaxine 50, 100, 150, or 200 mg/day vs. placebo for 52 weeks

620 included in mITT analysis

1°:

∆ from BL in avg. daily # of mod/severe HFs at week 4 and 12

∆ from BL in avg. daily HF severity score at week 4 and 12

2°:

∆ from BL in daily # of night-time awakenings due to HFs at week 4 and 12

Important AEs/SAEs

Discontinuation due to AEs

1°:

↓ from BL in avg. daily # of mod/severe HFs vs. placebo (No ↓ with 50 mg or 200 mg)

100 mg ↓ at week 4 (− 6.62 vs. − 5.22; p = 0.013) and week 12 [− 7.23 (64%↓) vs. − 5.50 (51%↓); p = 0.005]

150 mg ↓ at week 12 [− 6.94 (60%↓) vs. − 5.50 (51%↓); p = 0.020], but not at week 4

↓ from BL in avg. daily HF severity scores vs. placebo (No ↓ with 50 mg or 150 mg)

100 mg ↓ at week 12 [− 0.80 (31%↓) vs. − 0.47 (18%↓); p = 0.002], but not at week 4

200 mg ↓ at week 12 [− 0.74 (27%↓) vs. − 0.47 (18%↓); p = 0.013], but not at week 4

2°:

↓ daily # of night-time awakenings vs. placebo at week 12 (week 4 not reported) (No ↓ with 50 mg)

100 mg, 150 mg and 200 mg ↓ at week 12 [− 2.77/night (76.9%↓), p = 0.013; − 2.69/night (69%↓), p = 0.034 and − 2.68/night (70.5%↓), p = 0.043, respectively vs. − 2.21/night (63.1%↓)]

AEs vs. placebo

150 mg and 200 mg ↑ AEs during week 1 only (both p < 0.05), most commonly, nausea, dry mouth, insomnia

(No ↑ with 50 mg and 100 mg)

3 SAEs possibly Tx-related: 2 increased LFTs, 1 cholecystitis

↑ hypertension (5.9% overall vs. 1.3% placebo; p = ns). 5 vs. 0 CV events at 1 year (p = ns)

↑ discontinuations due to AEs 150 and 200 mg during week 1 only (both p < 0.001). (No ↑ with 50 mg and 100 mg)

Archer et al

American Journal of Obstetrics and Gynecology (2009) [22]

12 week DBRCT: 34 US centres

Mean age = 53.36 years (29–71)

Mean BMI = 27.86 kg/m² (17.2–40.1)

458 randomised to desvenlafaxine 100 mg/day or 150 mg/day vs. placebo for 12 weeks [50 mg/day for 3 days, titrated to 100 mg/day on day 4 (titrated to 150 mg/day on day 8 for 150 mg/day group)]

2 week dose-tapering

436 included in mITT analysis

1°:

∆ from BL in avg. daily # mod/severe HFs at weeks 4 and 12

∆ from BL in avg. daily HF severity score at weeks 4 and 12

2°:

∆ from BL in # of night-time awakenings at weeks 4 and 12

Important AEs/SAEs

Discontinuation due to AEs

1°:

↓ daily # of HF from BL vs. placebo with 100 mg and 150 mg at week 4 (both p ≤ 0.012, no % given) and week 12 (65.4%↓, p = 0.005; and 66.6%↓, p = 0.012, respectively vs. 50.8%↓)

↓ daily HF severity score from BL vs. placebo with 100 mg and 150 mg at week 12 [− 0.65 (27%↓); and − 0.66 (27.5%↓), respectively vs. − 0.33 (13.75%↓); both p < 0.001], and at all other time points

2°:

↓ daily # of night-time awakenings from BL vs. placebo with 100 mg and 150 mg at week 4 (− 1.8 and − 1.6, respectively vs. − 1.2) and week 12 [− 2.0 (60.6%↓) and − 1.8 (58.1%↓), respectively vs. − 1.4 (43.8%↓)]; all p ≤ 0.048

↑ AEs during week 1 only vs. placebo (84.1% vs. 69.5%; p = 0.002), most commonly nausea (25.2%), dry mouth, insomnia, constipation, asthenia

2 SAEs possibly Tx-related: hypertension (1 subject with 150 mg ↑ SBP by 4.52 mmHg at week 12 (p = 0.002), bronchospasm (1 subject but on placebo)

Discontinuation due to AEs: no diff. [but numerically ↑ in 150 mg group (p = ns)]

Archer et al

American Journal of Obstetrics and Gynecology (2009) [23]

26 week DBRCT: 32 US centres

Mean age = 53.7 years

Mean BMI = 27.1 kg/m² (15.9–40.4)

567 randomised to desvenlafaxine 100 mg/day or 150 mg/day vs. placebo for 26 weeks

484 included in mITT analysis

1°:

∆ from BL in avg. daily # of mod/severe HFs at weeks 4 and 12

∆ from BL in avg. daily HF severity at weeks 4 and 12

2°:

∆ from BL in # of night-time awakenings due to HFs

Important AEs/SAEs

Discontinuation due to AEs

1°:

↓ daily # of HFs from BL vs. placebo at week 4 and 12 (week 12: 100 mg 60%↓, p = 0.002; 150 mg 66.6%↓, p < 0.001, vs. 47%↓)

150 mg maintained ↓ at week 26 (69%↓ vs. 51%↓, p = 0.001), whereas 100 mg did not (61%↓, p = 0.061) but study not powered for efficacy > 12 weeks

↓ daily HF severity from BL vs. placebo at week 4 and 12 (week 12: 100 mg 24%↓, p = 0.002; 150 mg 29%↓, p < 0.001 vs. 13%↓). 150 mg maintained ↓ at week 26 (p = 0.008, no % given)

2°:

↓ daily # of night-time awakenings from BL vs. placebo at week 4 (actual ↓ not given) and week 12 [100 mg − 2.0 (52.6%↓); 150 mg − 2.4 (68.6%↓) vs. − 1.6 (47.1%↓)]; all p ≤ 0.026

↑ AEs during week 1 only vs. placebo (p < 0.05), most commonly nausea (44.6%), dizziness, insomnia, dry mouth, constipation

↑ SAE possibly Tx-related: hypertension (100 mg)

↑ discontinuations due to AEs during week 1 only vs. placebo (16.1% vs. 0.6%; p < 0.001)

Bouchard et al

Climacteric (2012) [24]

12-week DBRCT: 35 European centres, 2 centres in South Africa, 1 centre in Mexico

Mean age = 53.6 years (40–66 years)

Mean BMI = 26 kg/m² (16–34)

≥ 485 randomised (1:1:1) to desvenlafaxine 100 mg/day, tibolone 2.5 mg/day, vs. placebo for 12 weeks

451 included in mITT analysis

1°:

∆ from BL in avg. daily # of mod/severe HFs at weeks 4 and 12

∆ from BL in avg. daily HF severity at weeks 4 and 12

2°:

Important AEs/SAEs

Discontinuation due to AEs

1°:

No ↓ in daily # of HFs from BL vs. placebo at week 4 (− 4.63 vs. − 4.38, p = 0.558) and week 12 (− 5.78 (57.7%↓) vs. –5.82 (57.5%↓), p = 0.921]

No ↓ in daily HF severity from BL vs. placebo at week 4 (− 0.37 vs. − 0.31, p = 0.352) and week 12 [− 0.61 (26.8%↓) vs. − 0.61 (26.5%↓), p = 0.943]

2°:

↑ AEs with desvenlafaxine vs. tibolone and placebo (73.4% vs. 64.5% and 55.9%, respectively), most commonly nausea (31%), dizziness and constipation

↑ bleeding with tibolone vs. desvenlafaxine and placebo [23% vs. 12% (p = 0.024) and 9% (p = 0.001), respectively]

↑ discontinuations due to AEs during week 1 only vs. placebo (p < 0.001). Most commonly nausea (8.9%) and headache (3.8%)

Pinkerton et al

Menopause (2013) [25]

52-week DBRCT: 122 US and Canadian centres

Mean age = 54 years (45–71)

Mean BMI = 26.45 kg/m² (16.9–35.3)

396 randomised (1:1) to desvenlafaxine 100 mg/day vs. placebo for 52 weeks (50 mg/day for 1 week, titrated to 100 mg/day for 51 weeks)

2 week dose-tapering

365 included in mITT analysis

Pinkerton et al. (2013) [25] reports 12-week data from an efficacy substudy (part of a larger n = 2186 safety study)

1°:

∆ from BL in avg. daily # of mod and severe HFs at weeks 4 and 12

∆ from BL in avg. daily HF severity scores at weeks 4 and 12

2°:

Important AEs/SAEs

Discontinuation due to AEs

1°:

↓ daily # of HFs vs. placebo at week 4 [− 6.5 HFs (55%↓) vs. − 3.6 (31%↓); p < 0.001] and week 12 [− 7.3 HFs (62%↓) vs. − 4.5 (38%↓); p < 0.001]

↓ daily HF severity score vs. placebo at week 4 [− 0.47 (20%↓) vs. − 0.19 (8%↓); p < 0.001] and week 12 [− 0.59 (25%↓) vs. − 0.28 (12%↓); p < 0.001]

2°:

↑ AEs vs. placebo during week 1 only (p < 0.001), mostly nausea, dry mouth, constipation (but no diff. in BP)

2 SAEs: 1 squamous cell carcinoma, 1 multi-event SAE (altered mental status with slurred speech, uncontrolled hypertension, resolved hypokalemia, polypharmacy)

↑ discontinuations due to AEs vs. placebo (10.0% vs. 3.7%; p = 0.016); rates similar after week 1

Pinkerton et al. Menopause (2013) [26]

Pinkerton et al. (2013) [26] reports 52-week data from the same efficacy substudy population

See above

1°:

∆ from BL in avg. daily # of HFs at weeks 12, 26, 52

∆ from BL in avg. daily HF severity scores at weeks 12, 26, 52

2°:

Important AEs/SAEs

Discontinuation due to AEs

1°:

↓ in daily # of HFs at 12 weeks [− 7.5 HFs (64%↓) vs. –5.0 (43%↓); p < 0.001], 26 weeks [− 8.6 HFs (74%↓) vs. − 6.3 (54%↓); p < 0.001 and 52 weeks [− 7.7 HFs (66%↓) vs. − 4.8 (41%↓); p < 0.001]

↓ in daily HF severity score at 12 weeks [− 0.63 (27%↓) vs. − 0.3 (13%↓); p < 0.001], 26 weeks [− 0.85 (36%↓) vs. − 0.53 (22%↓); p = 0.001] and 52 weeks [− 0.75 (32%↓) vs. − 0.44 (19%↓); p = 0.003]

2°: includes efficacy substudy (n = 365) and larger safety population (n = 2186)

↑ AEs vs. placebo (84% vs. 79%; p = 0.006), most commonly nausea (21%), headache, dry mouth and insomnia. Rates of new-onset AEs were similar by week 3

SAEs: No excess CV ischaemic events vs. placebo over 52 weeks

↑ discontinuations due to AEs vs. placebo (18.3% vs. 9.7%; p < 0.001); rates highest during week 1

Joffe et al

JAMA Internal Medicine

(2014) [27]

DBRCT: 3 US centres

Mean age = 54.6 years

Mean BMI = 28.3 kg/m²

339 randomised (2:2:3) to venlafaxine XR 75 mg/day (37.5 mg/day titrated to 75 mg/day over 1 week), oral 17-beta-oestradiol (ET) 0.5 mg/day or placebo for 8 weeks

Venlafaxine followed by 2-week dose-tapering

330 included in mITT analysis

1°:

Mean daily # of HFs at weeks 4 and week 8

2°:

HF severity at week 8

Important AEs/SAEs

Discontinuation due to AEs

1°:

↓ # of HFs from BL vs. placebo at week 4 (48%↓ vs. 25%↓; p = 0.005) and week 8 (48%↓ vs. 29%; p = 0.005)

2°: baseline or %↓ data not reported

↓ HF severity vs. placebo at week 8 (mean diff. vs. placebo: − 0.2, p = 0.02)

↑ AEs vs. ET and placebo (69% vs. 56% and 62%, respectively; p = ns), most commonly fatigue

12 developed SBP > 165 mmHg or DBP > 95 mmHg (10.4% venlafaxine, 2.1% ET, 0 placebo), but all had BL SBP or DBP > study population mean. Vaginal bleeding 8.2% ET, 0% venlafaxine, and 1.6% placebo

↑ discontinuations due to AEs vs. placebo (5 venlafaxine, 4 ET, 2 placebo; p = ns)

Cann et al

Menopause

(2015) [28]

Cann et al. [28] reports questionnaire endpoints from Joffe et al. [27]

MENQoL total and domain scores

Measure of pain (PEG), depression (PHQ-9) and anxiety (GAD-7)

Perceived stress (PSS)

↓ (improved) mean total MENQoL score from BL vs. placebo at week 4 and week 8 (week 8: − 0.9 vs. − 0.7, p = 0.042)

Only sig. diff. vs. placebo in psychosocial domain (week 8: − 1.5 vs. − 1.3, p = 0.008)

No improvements vs. placebo with respect to changes in pain (PEG), depressive symptoms (PHQ-9) or anxiety (GAD-7) at weeks 4 and 8

↓ (improved) perceived stress vs. placebo at week 4 and week 8 (week 8: − 3.4 vs. − 2.0, p = 0.02)

DBRCT double-blind, randomised, placebo-controlled trial, XR extended release, mod moderate, # number, HFs hot flushes/flashes, VMS vasomotor symptoms, ≥ greater than or equal to, ≤ less than or equal to, > greater than, < less than, mg/d milligrams/day, (m)ITT (modified) intention-to-treat, BL baseline, 1° primary, 2° secondary, avg. average, ∆ change, sig. significant, ns not significant, ↑ increase, ↓ reduced, diff. difference, Tx treatment, (S)AEs (serious) adverse events, (S) or (D) BP (systolic) or (diastolic) blood pressure, LFTs liver function tests, ALT alanine aminotransferase, AST aspartate aminotransferase, NASH non-alcoholic steatohepatitis, ULN upper limit of normal, MENQoL Menopause-Specific Quality of Life questionnaire, HFRDIS Hot Flash-Related Daily Interference Scale, PEG The Pain Enjoyment of Life and General Activity scale, PHQ-9 9-item Patient Health Questionnaire, GAD-7 7-item Generalized Anxiety Disorder questionnaire, PSS Perceived stress scale