Management of Menorrhagia Associated With Chemotherapy-Induced Thrombocytopenia in Women With Hematologic Malignancy

Jill S. Bates, Pharm.D., M.S.; Larry W. Buie, Pharm.D.; C. Brock Woodis, Pharm.D.

Disclosures

Pharmacotherapy. 2011;31(11):1092-1110. 

In This Article

Treatment of Menorrhagia

Unfortunately, it is possible that a patient may experience menorrhagia despite use of preventive therapies or in the absence of a preventive therapy. Many patients with hematologic malignancies will have thrombocytopenia at presentation, and menorrhagia may be a symptom on initial diagnosis. For these patients, treatment options may include platelet transfusions, antifibrinolytic therapy, continuous high-dose oral contraceptives, cyclic progestins, or other therapies for refractory patients including danazol, desmopressin, and recombinant factor VIIa (rFVIIa).[7,8,18] It is important to note that trial data are not restricted to only patients with cancer and menorrhagia secondary to chemotherapy-induced thrombocytopenia. Much of the limited data that are available for refractory treatment are reported only in patients with nonmalignant hematologic disorders such as von Willebrand's disease. Whenever possible, all patient populations are reviewed so that useful clinical decisions are possible.

Tranexamic Acid

Tranexamic acid has been evaluated in a multicenter, randomized, double-blind, parallelgroup study of women with heavy menstrual bleeding.[59] Women aged 18–49 years were included if they had a history of at least 3 consecutive days of heavy menstrual flow during at least four of their last six menstrual cycles, with an average blood loss of at least 80 ml/cycle. All women included had normal pelvic examinations. Exclusion criteria were extensive and included women with history of thromboembolic disorders, known coagulopathies, severe anemia, pelvic or cervical abnormalities, anovulatory uterine bleeding, metrorrhagia, and pregnancy or lactation. Other exclusion criteria included visual abnormalities, glaucoma, ocular hypertension, and macular degeneration. Of importance, this trial did not include patients with cancer.

Patients were randomly assigned to treatment with tranexamic acid or matching placebo. Randomization occurred in blocks of eight participants, with five receiving treatment with tranexamic acid and three receiving placebo. Treatment consisted of tranexamic acid 1.3 g 3 times/day for 5 days during menstruation. Study participants were not allowed to use anticoagulants, aminocaproic acid, or hydroxychloroquine; NSAIDs were permitted only during the premenstrual portion of the cycle. Oral iron therapy was required for women with a hemoglobin concentration of less than 11 g/dl.

The primary efficacy end point was the mean reduction in menstrual blood loss. There were three components to this end point, the first being overall reductions in menstrual blood flow between the two groups. The second and third components evaluated specific blood volumes (> 50 ml and at least 36-ml reductions in menstrual flow from baseline, respectively). The 36 ml was chosen to be an important reduction in menstrual flow to measure because this has been the amount proven to be a meaningful reduction in healthrelated quality of life trials. The volume of blood loss was objectively measured by using an alkaline hematin method. Secondary end points included change from baseline in health-related quality of life (using the MIQ),[20] occurrence of large blood stains, measurement of hemoglobin and ferritin concentrations, and drug safety and adherence.

Of the 196 randomized participants, 189 were the intent-to-treat population (117 received tranexamic acid and 72 received placebo). Of those enrolled, 94 women in the tranexamic group and 54 women in the placebo group completed the study. Two patients in the placebo group and no patients in the tranexamic acid group discontinued because of perceived failed response. Baseline characteristics were similar between the groups, but menstrual blood loss was higher, although not statistically significant (p=0.11), in the group randomly assigned to receive tranexamic acid versus placebo (mean ± SD 172 ± 95.6 vs 153 ± 66.6 ml/cycle).

Women receiving treatment with tranexamic acid achieved all of the prespecified portions of the primary efficacy outcome. Reductions in menstrual blood loss were statistically significant for the women receiving tranexamic acid (−69.6 ml, 40.4% reduction) compared with those receiving placebo (−12.6 ml, 8.2% reduction, p<0.001). This reduction from baseline was greater than 50 ml and exceeded 36 ml, the reduction considered meaningful to women based on health-related quality of life data. The reductions achieved in the first cycle were achieved on future cycles as well. Overall, menstrual blood loss declined to less than 80 ml in 43% of cycles measured for women receiving treatment with tranexamic acid compared with 17% of all measured cycles for women receiving placebo (p<0.001).[21,59]

The proportion of women with a clinically meaningful reduction in menstrual blood loss of 36 ml or more was greater in the tranexamic acid group than the placebo group (69% vs 29%, p<0.001). Reductions of at least 50 ml occurred in 56% of those treated with tranexamic acid. Reductions of 50% or greater were much more frequent in the tranexamic acid treatment group compared with placebo (35% vs 7%, p<0.001).

Improvements in scores for limitations on social or leisure activities, as well as improvements on physical activities were greater in the tranexamic acid group (p<0.001). The proportion of women with reductions in blood stains was higher in the tranexamic acid group, but this reduction was not statistically significant when compared with placebo (p=0.45). Women receiving tranexamic acid had overall improvement of their score for limitations on social, leisure, or physical activities from "moderate impairment" at baseline to "slight impairment" after treatment. Because this study used a validated tool to measure impact on healthrelated quality of life, these findings are significant for women with heavy menstrual bleeding. Changes from baseline in hemoglobin and ferritin concentrations were not statistically significantly different for either group. The fact that there was no significant change in hemoglobin or ferritin levels is not surprising as supplementation was started in patients with severe anemia at baseline, and the anemia is likely to take longer to correct with oral supplementation given the study duration of 6 months.

Adverse events were mild in the tranexamic acid group. Most commonly reported adverse events included menstrual discomfort, cramps, headache, and back pain. The only incident of VTE occurred in the placebo group and was unrelated to study treatment. No patients died during the treatment period, and there were no significant cardiovascular changes noted. Two of the patients treated with tranexamic acid did have ocular-related events that were considered to be possibly related to tranexamic acid therapy, but five patients treated with placebo also had similar ocular events. Gastrointestinal adverse effects were low, which may be due to the newer tranexamic acid formulation administered that delivers the drug more slowly to the gastric mucosa. In this study, the rate of gastrointestinal adverse effects in the tranexamic acid group was similar to that in the placebo group. Drugs that could have confounded the effects on menstruation were not allowed to be coadministered with tranexamic acid; however, this may have also masked potential adverse events associated with concomitant use of other drugs with tranexamic acid (e.g., NSAIDs, oral contraceptives, progestins).

The same group of authors performed a prospective study to determine the minimal reduction in menstrual blood flow that would be considered meaningful in women with heavy menstrual bleeding, an objective measure correlating to a woman's perception of improved quality of life.[21] Women with at least an average blood loss of 80 ml/cycle were eligible to participate. Randomization occurred in a 2:2:1 ratio to oral tranexamic acid 1.3 or 0.65 g 3 times/day or placebo. End points included both objective (primary efficacy end point) and subjective (secondary) improvements in menstrual blood flow. Health-related quality of life was measured by using the MIQ within 1–4 days of each menstrual cycle.

There were six specific measures relating to the most recent menses. One of the items was directly related to the patient's estimation of the amount of blood flow (scale of 1–4, light to heavy). Three items related to limitations on social, physical, or leisure activities (scale of 1–5, not at all limiting to extremely limiting). One item delineated activities affected by the menstrual bleeding, and one item measured the effect of change in menstrual blood loss. For the global assessment, bleeding improvement was noted on a scale from 1–7 (almost the same to much improved).

Of the 304 women enrolled in the study, 297 received study drug and were included in the sensitivity and specificity analysis. Receiver operating curve analysis revealed that 36 ml/cycle was the threshold identified as a meaningful reduction for most of the women included in the study. Maintaining reductions of at least 31 ml/cycle was associated with 1-point increases in the scales for limitations of physical activity.

Because of the association between antifibrinolytics (e.g., tranexamic acid) and VTE, researchers performed a study to investigate whether tranexamic acid increased the risk of deep vein thrombosis or pulmonary embolism.[60] Using the General Practice Research Database, women aged 15–49 years with a diagnosis of menorrhagia were eligible for study inclusion. Cases were defined by diagnosis of deep vein thrombosis or pulmonary embolism. Women with known risk factors for VTE such as surgery, prescription oral contraceptive use, diagnosis of cancer before or after the event, lupus erythematosus, multiple sclerosis, or Crohn's disease were excluded. Up to eight control subjects were chosen for each of the cases, with the same exclusion criteria applied. Cases and controls were considered exposed to tranexamic acid or other treatment for menorrhagia if they had a prescription for treatment within 90 days before the index date. The risk of VTE among women exposed was compared with those unexposed, and odds ratios (ORs) were calculated.

Of the women with menorrhagia, 134 cases and 552 matched controls met inclusion criteria. Fifty-two (39%) of the cases had a pulmonary embolism, whereas 82 cases (61%) had a deep vein thrombosis. Twenty-three (17%) of the cases and 33 (6%) of the controls had been exposed to tranexamic acid or another treatment option for menorrhagia. Tranexamic acid was associated with an increased risk of VTE (adjusted OR 3.20, 95% confidence interval [CI] 0.65–15.78); however, this association was not significant. Anemia, smoking, and obesity (body mass index of ≥ 30 kg/m2) were all associated with increased risk of VTE. The increased risk with anemia was of interest, with an adjusted OR of 2.23 (95% CI 1.02–4.86). This increase in the risk of VTE was seen after adjustment for the drugs used to treat menorrhagia, indicating that menorrhagia itself may be a risk factor for VTE. The authors do acknowledge that the study may have had inadequate numbers to associate VTE risk with patients receiving tranexamic acid. The ORs associated with treatment may have also been underestimated, given potential misclassifications of disease or outcomes. The correlation between VTE and menorrhagia would be impossible to assess in a hypercoagulable cancer population with thrombocytopenia and anemia.

Pharmacokinetics and tolerability of tranexamic acid were evaluated for both modified–immediaterelease (MIR) and delayed-release formulations.[61] Dosages of 1.3 g 3 times/day were used to achieve therapeutic concentrations of 5–15 μg/ml. Evaluations occurred in both the fed and fasted state and after single and multiple doses. The minimum effective plasma concentration (≥ 5 μg/ml) was achieved within 1.5 hours of administration of the MIR product and within 3 hours of the delayed-release product. The delayed-release formulation was greatly affected by food, with a 4.3-hour increase in time to maximum concentration, and a 24% decrease in maximum concentration. Steady-state concentrations were achieved by using both formulations, with average plasma concentrations reaching 9 μg/ml for the MIR and 6.5 μg/ml for the delayed-release formulation. Adverse effects were reported for both formulations and were similar, with headache being the most common. No adverse effects were severe or could be probably or definitely associated with therapy. Tranexamic acid has been shown to have no impact on cardiac ventricular repolarization (QTc prolongation).[61,62]

Hormonal Manipulation

A retrospective review of data from 33 women undergoing hematopoietic stem cell transplantation was performed.[29] Women were treated according to practice-based guidelines, which allowed use of oral contraceptives containing ethinyl estradiol with progestin, medroxyprogesterone alone, or another oral contraceptive pill if they were already taking this at home. Platelet transfusions were also routinely given for platelet counts less than 20 × 103/mm3, or 50 × 103/mm3 if menorrhagia developed.

Before gynecologic consultation, 21 patients (64%) had been taking oral contraceptives, 3 (9%) were receiving medroxyprogesterone, and 9 (27%) had no previous hormonal exposure started by the transplant team. In total, 97% of patients had complete resolution of menorrhagia, and 75% achieved resolution with only one hormonal manipulation. Hormonal therapies consisted of high-dose oral contraceptive pills (ethinyl estradiol ≥ 50 μg), standard-dose oral contraceptive, medroxyprogesterone, or transdermal estrogen. Seven patients required more than one hormonal therapy, but menorrhagia was controlled and the patients were ultimately switched to an oral contraceptive. Patients not tolerating oral contraceptives were given transdermal estrogen therapy. Table 5 shows the sequential hormonal therapy that was successful in alleviating menorrhagia.

Four patients in this study did receive intravenous conjugated estrogen therapy dosed at 25 mg every 6 hours for 24 hours. The first three patients required intravenous estrogen because of the severity of their menorrhagia at the time of consultation. After 24 hours, they were changed to high-dose oral contraceptives. Another patient experienced menorrhagia after transplantation. She was initially escalated from standard-dose to high-dose oral contraceptive, but the bleeding persisted and intravenous conjugated estrogens were recommended. This patient ultimately died from multiple system organ failure secondary to infection, and her renal dysfunction was thought to be associated with the platelet dysfunction that was propagating her menorrhagia. There were no significant differences noted in this very small study between standard-dose and high-dose oral contraceptives, monophasic and phasic oral contraceptives, or oral and transdermal estrogen therapy.

Progestins make up 55% of the prescriptions used to treat menorrhagia, although there is little clinical data to support their use. A Cochrane review was performed to determine if oral progestin therapy was effective at reducing menstrual blood flow in women of reproductive age.[63] Other goals of the review were to determine if oral progestins were more efficacious than other medical therapies, if progestins had a better adverse-effect profile than other therapies, if progestins were more cost-effective, and if progestins increased quality of life for women with heavy menstrual bleeding. All randomized comparisons of oral progestin therapy versus placebo or other medical therapy used to treat menorrhagia were reviewed. Variable doses and lengths of therapy were included. Progestins can be given as late luteal phase support on days 19–26 or 15–25, as a longer course of therapy from days 5–26 of the menstrual cycle, or continuously until bleeding is controlled followed by maintenance suppression. Women were included with either subjective symptoms of menorrhagia or proven objective assessments by means of the alkaline hematin method (> 80 ml/cycle).

Outcomes included objective and subjective measures of blood loss. Secondary outcomes were number of days of bleeding during the intervention menstrual cycle, quality of life, compliance, acceptability of therapy, adverse events, mortality, and cost. The review was not able to support the hypothesis that treatment with progestins was more effective than other medical therapies. Luteal administration of progestins offered no advantage, whereas longer courses did reduce menstrual blood loss.

Summary and Recommendations

Tranexamic acid, dosed as 1.3 g orally 3 times/day, has been shown in a randomized controlled trial to reduce menstrual blood flow to a level that has been shown to significantly improve quality of life indexes for women with menorrhagia.[21,59] Adverse events have been mild, with the most significant being menstrual cramping. Studies have been performed that prove that tranexamic acid does not increase the risk of VTE or cardiac arrhythmia.[60–62] However, the VTE data were reported in a patient population that did not include patients with cancer, and the rates of VTE may be higher in a hypercoagulable patient population.

For bleeding that persists beyond tranexamic acid, oral progestin therapy can be started, with continuous daily therapy most likely to induce amenorrhea. Doses can be started as low as 5 mg/day or increased to a maximum of 40 mg/day in divided doses. Patients receiving continuous therapy with medroxyprogesterone will need to be monitored for the development of VTE, since progestin therapy increases this risk. If the bleeding is so significant (use of at least one pad/hr) or if patients are nonresponsive to progestin therapy, then conversion to high-dose oral contraceptive therapy can occur after menses suppression with intravenous estrogen 25 mg every 6 hours. For patients maintained with an oral contraceptive, a reduction to a moderate– estrogen content oral contraceptive, ethinyl estradiol 30–40 μg/day, should be attempted to minimize the long-term risk of VTE in patients with cancer (a hypercoagulable population).[64]

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