Nonsteroidal anti‐inflammatory drugs for heavy menstrual bleeding

Anne Lethaby; Cristina Augood; Kirsten Duckitt; Cindy Farquhar

doi:10.1002/14651858.CD000400.pub2

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Analysis 1.1

Comparison 1 NSAIDs versus placebo, Outcome 1 Menstrual blood loss (ml per cycle).

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Analysis 1.2

Comparison 1 NSAIDs versus placebo, Outcome 2 Proportion with no subjective improvement in MBL.

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Analysis 1.3

Comparison 1 NSAIDs versus placebo, Outcome 3 Adverse events.

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Study
Mefenamic acid versus placebo
Fraser 1981	Mean menstrual blood loss (SD) on placebo: 70.7 (24.9) mls Mean menstrual blood loss (SD) on mefenamic acid: 47.3 (21.7) mls p<0.001, n=28, paired t test, t=6.56 Other outcomes were not given for this subgroup.
Muggeridge 1983	Mean menstrual blood loss (SD) on placebo: 161 (78.5) mls Mean menstrual blood loss (SD) on mefenamic acid: 128.3 (78.1) mls No significant difference between placebo and MFA cycles, n=15, Wilcoxon Sum Rank Test Mean score of dysmenorrhoea symptoms (SD) in 2nd placebo cycle: 2.1 (2.1) Mean score of dysmenorrhoea symptoms (SD) in 2nd MFA cycle: 1.3 (1.6) No significant difference between placebo and MFA cycles,n=15, Wilcoxon Sum Rank Test
Tsang 1987	Mean menstrual blood loss (SD) on placebo: 156.5 (105.9) Mean menstrual blood loss (SD) on MFA: 140.0 (109) p<0.05, n=10, t test comparing MFA cycles with combined placebo and control cycles
Naproxen versus placebo
Rybo 1981	Mean menstrual blood loss (SD) on placebo: 144 (26) mls Mean menstrual blood loss (SD) on naproxen: 107 (154) mls p<0.02, n=4, statistical method not given
Ylikorkala 1986	Mean menstrual blood loss (SD) on placebo: 150.7 (34) mls Mean menstrual blood loss (SD) on naproxen: 96.8 (27.3) mls p<0.001, n=14, paired t test Proportion of patients with side effects on placebo: 7% Proportion of patients with side effects on naproxen: 0% Not tested
Ibuprofen versus placebo
Makarainen 1986	Median menstrual blood loss (range) on placebo: 146 (71‐374) mls Median menstrual blood loss (range) on ibuprofen 600mg: 123 (23‐319) Median menstrual blood loss (range) on ibuprofen 1200mg: 110 (30‐288) p<0.01, n=13, Wilcoxon paired test, ibuprofen 1200 vs placebo

Analysis 1.4

Comparison 1 NSAIDs versus placebo, Outcome 4 Menstrual blood loss and other outcomes (descriptive results).

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Analysis 2.1

Comparison 2 NSAIDs versus tranexamic acid, Outcome 1 Menstrual blood loss (ml per cycle).

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Analysis 2.2

Comparison 2 NSAIDs versus tranexamic acid, Outcome 2 Proportion with no subjective improvement in MBL.

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Analysis 2.3

Comparison 2 NSAIDs versus tranexamic acid, Outcome 3 Duration of menstruation (days).

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Analysis 2.4

Comparison 2 NSAIDs versus tranexamic acid, Outcome 4 Proportion with no improvement in quality of life and or dysmenorrhoea.

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Analysis 2.5

Comparison 2 NSAIDs versus tranexamic acid, Outcome 5 Proportion who find treatment unacceptable.

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Study
Andersch 1988	Mean menstrual blood loss (SD) on tranexamic acid: 154.8 (127.8) mls Mean menstrual blood loss (SD) on flurbiprofen: 223 (168.5) mls p<0.01, n=15, student's t test Proportion of patients with side effects on tranexamic acid: 47% Proportion of patients with side effects on flurbiprofen: 27% DIfference not tested

Analysis 2.6

Comparison 2 NSAIDs versus tranexamic acid, Outcome 6 Menstrual blood loss and other outcomes (descriptive results).

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Analysis 3.1

Comparison 3 NSAIDs versus ethamsylate, Outcome 1 Menstrual blood loss at Rx (ml per cycle).

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Analysis 3.2

Comparison 3 NSAIDs versus ethamsylate, Outcome 2 Menstrual blood loss 1 ‐ 6 months after Rx (ml per cycle).

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Analysis 3.3

Comparison 3 NSAIDs versus ethamsylate, Outcome 3 Proportion with no subjective improvement in MBL.

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Analysis 3.4

Comparison 3 NSAIDs versus ethamsylate, Outcome 4 Duration of menstruation (days).

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Analysis 3.5

Comparison 3 NSAIDs versus ethamsylate, Outcome 5 Proportion with no improvement in quality of life and or dysmenorrhoea.

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Analysis 3.6

Comparison 3 NSAIDs versus ethamsylate, Outcome 6 Proportion who find treatment unacceptable.

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Analysis 4.1

Comparison 4 NSAIDs versus danazol, Outcome 1 Menstrual blood loss (ml per cycle).

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Analysis 4.2

Comparison 4 NSAIDs versus danazol, Outcome 2 Duration of menstruation (days).

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Analysis 4.3

Comparison 4 NSAIDs versus danazol, Outcome 3 Proportion with no improvement in quality of life and or dysmenorrhoea.

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Analysis 4.4

Comparison 4 NSAIDs versus danazol, Outcome 4 Proportion who find treatment unacceptable.

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Analysis 4.5

Comparison 4 NSAIDs versus danazol, Outcome 5 Adverse events.

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Analysis 5.1

Comparison 5 NSAIDs versus oral progestagens, Outcome 1 Menstrual blood loss (ml per cycle).

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Analysis 5.2

Comparison 5 NSAIDs versus oral progestagens, Outcome 2 Duration of bleeding (days).

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Analysis 5.3

Comparison 5 NSAIDs versus oral progestagens, Outcome 3 Proportion with non‐adherence.

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Analysis 5.4

Comparison 5 NSAIDs versus oral progestagens, Outcome 4 Total adverse events.

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Analysis 5.5

Comparison 5 NSAIDs versus oral progestagens, Outcome 5 Adverse events ‐ headache.

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Analysis 5.6

Comparison 5 NSAIDs versus oral progestagens, Outcome 6 Adverse events ‐ abdominal pain.

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Analysis 5.7

Comparison 5 NSAIDs versus oral progestagens, Outcome 7 Adverse events ‐ nausea.

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Analysis 6.1

Comparison 6 NSAIDs versus progesterone releasing intra‐uterine system, Outcome 1 Menstrual blood loss (mls per cycle).

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Analysis 6.2

Comparison 6 NSAIDs versus progesterone releasing intra‐uterine system, Outcome 2 Duration of menstruation (days).

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Analysis 6.3

Comparison 6 NSAIDs versus progesterone releasing intra‐uterine system, Outcome 3 Adverse events.

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Study	Outcomes	Results (NSAIDs)	Results (LNG IUS)	Significance test	Comment
Reid 2005	Menstrual blood loss (alkaline hematin method Total menstrual fluid loss: PBAC score:	3 months: Median (range): 94 (29‐219) 6 months: Median (range): 100 (46‐168) 3 months: Median (range) 151 (57‐280) 6 months: Median (range): 157 (76‐319) 3 months: Median (range): 161 (77‐262) 6 months: Median (range): 159 (50‐307)	3 months: Median (range): 12 (0‐240) 6 months: Median (range): 5 (0‐45) 3 months: Median (range): 53 (0‐459) 6 months: Median (range) 27 (0‐156) 3 months: Median (range): 49 (0‐286) 6 months: Median (range) 25 (0‐402)	Wilcoxon rank sum test: p<0.001 for all comparisons

Analysis 6.4

Comparison 6 NSAIDs versus progesterone releasing intra‐uterine system, Outcome 4 Menstrual blood loss and other outcomes (descriptive results).

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Analysis 7.1

Comparison 7 NSAIDs versus oral contraceptive pill, Outcome 1 Menstrual blood loss (ml per cycle).

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Analysis 8.1

Comparison 8 Mefenamic acid versus naproxen, Outcome 1 Menstrual blood loss (ml per cycle).

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Analysis 8.2

Comparison 8 Mefenamic acid versus naproxen, Outcome 2 Duration of menstruation (days).

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Analysis 8.3

Comparison 8 Mefenamic acid versus naproxen, Outcome 3 Total adverse events.

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Analysis 8.4

Comparison 8 Mefenamic acid versus naproxen, Outcome 4 Gastrointestinal adverse events.

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Analysis 8.5

Comparison 8 Mefenamic acid versus naproxen, Outcome 5 Central nervous system adverse events.

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Table 1. Quality of included studies

Study	Design	Randomisation method	Allocation concealment	Blinding	Power calc	ITT analysis	Dropouts	B.line comparability
Andersch 1988	Crossover	Not stated	B	No	No	?	Not reported	Not stated
Bonnar 1996	Parallel	Computer generated list	B	No	Yes	No	5/81 (2 from mefenamic acid group, 2 from ethamsylate group and 1 from tranexamic acid group)	Yes
Cameron 1987	Parallel	Not stated	B	No	No	?	Not reported	No
Cameron 1990	Parallel	Not stated	B	No	No	?	Not reported	Yes
Chamberlain 1991	Parallel	Taves method of minimisation	B	double	No	No	6/42 (not clear from which group: 5 for fibroids and 1 because of IUCD)	No
Dockeray 1989	Parallel	Randomisation code	B	No	No	No	1/40 (from mefenamic acid group because of side effects)	Yes
Fraser 1981	Crossover	Not stated	B	double	No	No	16/85	Not stated
Fraser 1991	Parallel	Not stated	B	No	No	No	7/45	Not stated
Grover 1990	Parallel	Not stated	B	double	No	Not stated	Not stated	Yes
Hall 1987	Crossover	Fisher's table of random numbers	B	double	No	No	15/50 (9 women excluded post randomisation for not meeting inclusion criteria; 6 withdrawn during treatment)	Yes
Makarainen 1986	Crossover	Tables of random numbers	B	double	No	?	Not reported	Not stated
Muggeridge 1983	Crossover	Not stated	B	double	No	No	5/20 (not clear from which group: 1 for heavy bleeding, 1 irregular bleeding, 1 nausea, 2 left the area)	Not stated
Reid 2005	Parallel group	Random permuted blocks by computer	A	No	Yes	Yes	8/51 (4 from MFA group: 1 for non compliance, 2 for diarrhoea, 1 because Rx ineffective; 4 from LNGIUS group: 2 for partial expulsion, 2 for full expulsion)	Yes
Rybo 1981	Crossover	Not stated	B	double	No	Yes		Not stated
Tsang 1987	Crossover	Not stated	B	double	No	No	4/14	Yes
van Eijkeren 1992	Parallel	Randomisation list controlled by pharmacy	A	double	No	No	7/19 (postponed hysterectomy, fibroids at operation, postmenstrual phase, premenstrual phase, side effects of MFA	Yes
Ylikorkala 1986	Crossover	Not stated	B	double	No	No		Yes

Table 1. Quality of included studies

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Comparison 1. NSAIDs versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Menstrual blood loss (ml per cycle) Show forest plot	1	11	Mean Difference (IV, Fixed, 95% CI)	‐124.0 [‐186.36, ‐61.64]

1.1 Mefenamic acid versus placebo	1	11	Mean Difference (IV, Fixed, 95% CI)	‐124.0 [‐186.36, ‐61.64]
2 Proportion with no subjective improvement in MBL Show forest plot	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.08 [0.03, 0.18]

2.1 Mefenamic acid versus placebo	1	80	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.08 [0.03, 0.18]
3 Adverse events Show forest plot	1	11	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.77 [0.07, 8.09]

3.1 Mefenamic acid versus placebo	1	11	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.77 [0.07, 8.09]
4 Menstrual blood loss and other outcomes (descriptive results) Show forest plot			Other data	No numeric data

4.1 Mefenamic acid versus placebo			Other data	No numeric data
4.2 Naproxen versus placebo			Other data	No numeric data
4.3 Ibuprofen versus placebo			Other data	No numeric data

Comparison 1. NSAIDs versus placebo

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Comparison 2. NSAIDs versus tranexamic acid

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Menstrual blood loss (ml per cycle) Show forest plot	1	48	Mean Difference (IV, Fixed, 95% CI)	73.0 [21.66, 124.34]

2 Proportion with no subjective improvement in MBL Show forest plot	1	49	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.44 [0.45, 4.61]

3 Duration of menstruation (days) Show forest plot	1	49	Mean Difference (IV, Fixed, 95% CI)	0.40 [‐0.47, 1.27]

4 Proportion with no improvement in quality of life and or dysmenorrhoea Show forest plot	1	49	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.13 [0.27, 4.73]

5 Proportion who find treatment unacceptable Show forest plot	1	49	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.17 [0.32, 4.27]

6 Menstrual blood loss and other outcomes (descriptive results) Show forest plot			Other data	No numeric data

Comparison 2. NSAIDs versus tranexamic acid

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Comparison 3. NSAIDs versus ethamsylate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Menstrual blood loss at Rx (ml per cycle) Show forest plot	2	82	Mean Difference (IV, Fixed, 95% CI)	‐42.88 [‐86.25, 0.50]

2 Menstrual blood loss 1 ‐ 6 months after Rx (ml per cycle) Show forest plot	1	31	Mean Difference (IV, Fixed, 95% CI)	‐70.3 [‐158.88, 18.28]

3 Proportion with no subjective improvement in MBL Show forest plot	1	50	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.70 [0.23, 2.12]

4 Duration of menstruation (days) Show forest plot	1	46	Mean Difference (IV, Fixed, 95% CI)	‐0.40 [‐1.56, 0.76]

5 Proportion with no improvement in quality of life and or dysmenorrhoea Show forest plot	1	50	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.83 [0.18, 3.72]

6 Proportion who find treatment unacceptable Show forest plot	1	50	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.20 [0.07, 0.61]

Comparison 3. NSAIDs versus ethamsylate

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Comparison 4. NSAIDs versus danazol

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Menstrual blood loss (ml per cycle) Show forest plot	3	79	Mean Difference (IV, Fixed, 95% CI)	45.06 [18.73, 71.39]

2 Duration of menstruation (days) Show forest plot	2	53	Mean Difference (IV, Fixed, 95% CI)	1.03 [0.26, 1.80]

3 Proportion with no improvement in quality of life and or dysmenorrhoea Show forest plot	1	28	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.19 [0.20, 7.05]

4 Proportion who find treatment unacceptable Show forest plot	1	40	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.82 [0.24, 2.80]

5 Adverse events Show forest plot	1	40	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.17 [0.05, 0.59]

Comparison 4. NSAIDs versus danazol

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Comparison 5. NSAIDs versus oral progestagens

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Menstrual blood loss (ml per cycle) Show forest plot	2	48	Mean Difference (IV, Fixed, 95% CI)	‐22.97 [‐46.57, 0.62]

2 Duration of bleeding (days) Show forest plot	2	48	Mean Difference (IV, Fixed, 95% CI)	‐0.41 [‐0.95, 0.13]

3 Proportion with non‐adherence Show forest plot	1	32	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.88 [0.05, 14.78]

4 Total adverse events Show forest plot	1	32	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.54 [0.13, 2.26]

5 Adverse events ‐ headache Show forest plot	1	32	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.63 [0.14, 2.86]

6 Adverse events ‐ abdominal pain Show forest plot	1	32	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.86 [0.15, 4.96]

7 Adverse events ‐ nausea Show forest plot	1	32	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.79 [0.17, 18.65]

Comparison 5. NSAIDs versus oral progestagens

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Comparison 6. NSAIDs versus progesterone releasing intra‐uterine system

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Menstrual blood loss (mls per cycle) Show forest plot	1	16	Mean Difference (IV, Fixed, 95% CI)	‐4.0 [‐31.23, 23.23]

2 Duration of menstruation (days) Show forest plot	1	16	Mean Difference (IV, Fixed, 95% CI)	‐5.0 [‐6.08, ‐3.92]

3 Adverse events Show forest plot	1		Peto Odds Ratio (Peto, Fixed, 95% CI)	Subtotals only

3.1 Headache	1	51	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.94 [0.31, 2.86]
3.2 Abdominal pain	1	51	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.22 [0.06, 0.87]
3.3 Ovarian cyst	1	51	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.43 [0.10, 1.80]
3.4 Breast pain	1	51	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.30 [0.07, 1.33]
3.5 Nausea	1	51	Peto Odds Ratio (Peto, Fixed, 95% CI)	2.01 [0.37, 10.86]
3.6 Diarrhoea	1	51	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.53 [0.57, 21.98]
3.7 Upper respiratory infection (URI)	1	51	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.95 [0.24, 3.75]
4 Menstrual blood loss and other outcomes (descriptive results) Show forest plot			Other data	No numeric data

Comparison 6. NSAIDs versus progesterone releasing intra‐uterine system

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Comparison 7. NSAIDs versus oral contraceptive pill

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Menstrual blood loss (ml per cycle) Show forest plot	1	26	Mean Difference (IV, Fixed, 95% CI)	25.25 [‐22.34, 72.84]

Comparison 7. NSAIDs versus oral contraceptive pill

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Comparison 8. Mefenamic acid versus naproxen

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Menstrual blood loss (ml per cycle) Show forest plot	2	61	Mean Difference (IV, Fixed, 95% CI)	21.00 [‐5.85, 47.85]

2 Duration of menstruation (days) Show forest plot	1	35	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

3 Total adverse events Show forest plot	1	35	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.12 [0.01, 2.00]

4 Gastrointestinal adverse events Show forest plot	1	35	Peto Odds Ratio (Peto, Fixed, 95% CI)	0.24 [0.06, 0.87]

5 Central nervous system adverse events Show forest plot	1	35	Peto Odds Ratio (Peto, Fixed, 95% CI)	1.40 [0.34, 5.73]

Comparison 8. Mefenamic acid versus naproxen

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