Nuevas alternativas en el manejo de los miomas uterinos.
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Nuevas alternativas en el manejo de los miomas uterinos.

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Ponencia: Nuevas alternativas en el manejo de los miomas uterinos.

Ponencia: Nuevas alternativas en el manejo de los miomas uterinos.
Dr. Francisco Vázquez Fernández. Director Clínica CEOGA. Lugo.

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Nuevas alternativas en el manejo de los miomas uterinos. Nuevas alternativas en el manejo de los miomas uterinos. Presentation Transcript

  • Francisco Vázquez,MD,PhD CEOGA LUGO Ulipristal Acetate: A new medical treatment for uterine fibroids. Pearl I & II Clinical Studies
  • EDITORIAL Uterine Fibroids and Evidence-Based Medicine — Not an Oxymoron Elizabeth A. Stewart, M.D N Engl J Med 2012; 366:471-473 February 2, 2012
  • PEARL I RANDOMISED, DOUBLE-BLIND PHASE III TRIAL OF ULIPRISTAL ACETATE (UPA) VS PLACEBO 3 months Patients with symptomatic uterine fibroids and anaemia R A N D O M I S A T I O N 6 months Once-daily oral UPA 5 mg + concomitant iron n=95 Once-daily oral UPA 10 mg + concomitant iron n=94 S U R G E R Y Follow-up Period Once-daily oral Placebo + concomitant iron n=48 ITT Population ITT, intent-to-treat; UPA, ulipristal acetate Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20
  • PEARL I BASELINE CHARACTERISTICS Key Inclusion Criteria ● Excessive uterine bleeding PBAC score >100 during Days 1–8 of menstruation ● Anaemia Haemoglobin ≤10.2 g/dL Baseline medical status Mean PBAC (range) Mean haemoglobin Mean haematocrit Placebo (N=48) UPA 5 mg (N=95) UPA 10 mg (N=94) 460 (119–1284) 487 (118–1645) 411 (102–1570) 9.55 g/dL 9.32 g/dL 9.46 g/dL 32.5% 32.1% 32.4% ITT Population ITT, intent-to-treat; PBAC, Pictorial Bleeding Assessment Chart; UPA, ulipristal acetate Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20
  • PRIMARY AND SECONDARY STUDY OBJECTIVES PEARL I Primary objectives • Demonstrate superior efficacy of UPA + iron versus placebo + iron for: – Reducing excessive uterine bleeding prior to surgery – Reducing total fibroid volume prior to surgery Secondary objectives • Demonstrate improvements in fibroid-related symptoms, eg. QoL, pain • Assess the capacity of UPA to decrease uterine volume • Demonstrate superior efficacy of UPA + iron versus placebo + iron at correcting anaemia caused by uterine fibroids Assess overall safety of UPA in subjects with uterine fibroids UPA, ulipristal acetate (ESMYA®) Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20
  • PEARL I BLEEDING CONTROL IN MORE THAN 90% OF WOMEN TREATED WITH UPA (PRIMARY ENDPOINT) WEEK 13 *p<0.001 vs. placebo * Patients * Patients with PBAC <75 at the EOT (Week 13; ITT) Placebo EOT, end of treatment; ITT, intent-to-treat; PBAC, Pictorial Bleeding Assessment Chart; UPA, ulipristal acetate UPA 5 mg UPA 10 mg Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20
  • PEARL I TIME TO CONTROL OF BLEEDING UPA 10 mg PBAC <75 UPA 5 mg Placebo 100 Patients (%) 80 Bleeding was controlled 7 days from treatment initiation, in ● 75.9% of UPA 5 mg patients and ● 82.7% of patients in the UPA 10 mg group 60 40 20 0 0 10 7 days 20 PBAC, Pictorial Bleeding Assessment Chart; UPA, ulipristal acetate 30 40 50 60 70 80 90 100 Time (days) Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20
  • PEARL I HIGHER NUMBER OF PATIENTS WITH CORRECTED ANAEMIA IN UPA GROUPS ANAEMIA CORRECTION AT WEEK 13 • (all patients had Hb ≤10.2 g/dL at screening) Hb >12.0 g/dL 89.4% Patients (%) 85.3% 77.1% Placebo + iron UPA, ulipristal acetate UPA 5 mg + iron UPA 10 mg + iron Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20
  • PEARL I. EFFECT ON FIBROID VOLUME (MEASURED WITH CENTRALISED BLINDED MRI READING) WEEK 13 Difference in Median Total Fibroid Volume Reduction vs Placebo Median Placebo Reduction 3.0% UPA 5 mg -21.22% ∆ -22.61% UPA 10 mg -12.31% ∆ -18.19% Placebo ● UPA 5 mg UPA 10 mg The results include reduction of all fibroids captured with the MRI scan UPA, ulipristal acetate (ESMYA®) Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20
  • The effect of medical therapy on myoma size (MRI scan) Before therapy After therapy
  • PEARL I. QUALITY OF LIFE (DISCOMFORT DUE TO UTERINE FIBROIDS) UPA SIGNIFICANTLY IMPROVED DISCOMFORT DUE TO UTERINE FIBROIDS 18 • Discomfort due to uterine fibroids (median): • 7 questions (0–4)* • Bleeding • Abdominal pressure • Urination frequency • Daily activity • Fatigue • Mood • Sexual activity * lower = better 16 BL, Baseline W13, Week 13 16.0 14 14.1 14.0 12 10 14.7 8 6 4 4.0 2.9 2 0 BL W13 BL W13 Placebo UPA, ulipristal acetate (ESMYA®) BL W13 UPA 5 mg UPA 10 mg Donnez J ,Tatarchuk TF, Bouchard P et al. N Engl J Med 2012;366:409−20
  • PEARL I. EFFECT ON PAIN (SF-MCGILL SHORT FORM PAIN QUESTIONNAIRE*) ● ● UPA resulted in a clinically meaningful reduction of pain This reduction (7 points) is comparable to the reduction of post operative pain obtained with narcotic or non-narcotic analgesics UPA, ulipristal acetate (ESMYA®) *Melzack R. The short-form McGill pain questionnaire. Pain 1987;30:191–197 Donnez J, et al. N Engl J Med 2012;366:409−420 (PEARL I)
  • PEARL II RANDOMISED, DOUBLE-BLIND PHASE III TRIAL OF ULIPRISTAL ACETATE (UPA) VS GnRHa 3 months Patients with symptomatic uterine fibroids R A N D O M I S A T I O N 6 months Once-daily oral UPA 5 mg n=97 Once-daily oral UPA 10 mg n=103 S U R G E R Y Follow-up Period Intramuscular leuprorelin 3.75 mg once every 4 weeks n=101 ITT Population GnRHa, gonadotrophin-releasing hormone agonist UPA, ulipristal acetate Donnez J, Tomaszewski J, Vázquez F et al. N Engl J Med 2012;366:421−32
  • PEARL II Study - Spanish Participants 40 35 Treatment completed 30 Early termination 25 20 15 19 10 14 5 8 4 0 2 8 6 5 2 3
  • PEARL II BASELINE CHARACTERISTICS* Key Inclusion Criteria ● Excessive uterine bleeding PBAC score >100 during Days 1–8 of menstruation ● Anaemia not required ● Eligible for surgical procedure Hysterectomy, myomectomy, uterine artery embolisation or endometrial ablation Baseline medical status Mean PBAC (range) UPA 5 mg (N=93) UPA 10 mg (N=95) Lupron 3.75 mg (N=93) 379 328 404 (109–1984) (120–1809) (102–2104) *PP Population PBAC, Pictorial Bleeding Assessment Chart; PP, per protocol; UPA, ulipristal acetate Donnez J, Tomaszewski J, Vázquez F et al. N Engl J Med 2012;366:421−32
  • PRIMARY AND SECONDARY STUDY OBJECTIVES PEARL II Primary objectives • Demonstrate non-inferior efficacy of UPA versus GnRHa for reducing excessive uterine bleeding due to uterine fibroids prior to surgery • Demonstrate superior safety and tolerability of UPA versus GnRHa for hot flushes and estradiol levels Secondary objectives • Demonstrate improvements in fibroid-related symptoms, eg. QoL, pain • Assess the capacity of UPA to: – Decrease the volume of the 3 largest fibroids – Decrease uterine volume Assess overall safety of UPA in subjects with uterine fibroids GnRHa, gonadotrophin-releasing hormone agonist QOL, quality of life; UPA, ulipristal acetate (ESMYA®) Donnez J, Tomaszewski J, Vázquez F et al. N Engl J Med 2012;366:421−32
  • PEARL II UPA IS AS EFFECTIVE AS GnRHa IN CONTROLLING BLEEDING AT THE END OF THERAPY WEEK 13 Patients with PBAC <75 Primary efficacy endpoint (non-inferiority) Week 13 ● UPA 5 mg GnRHa, gonadotrophin-releasing hormone agonist; PBAC, Pictorial Bleeding Assessment Chart; PP, per protocol; UPA, ulipristal acetate UPA 10 mg >90% of patients have normalised bleeding (PP) Lupron 3.75 mg Donnez J, Tomaszewski J, Vázquez F et al. N Engl J Med 2012;366:421−32
  • PEARL II TIME TO CONTROL OF BLEEDING PBAC<75 100 Patients (%) 80 UPA 5 mg UPA 10 mg Lupron 3.75 mg 60 40 ● UPA normalised bleeding faster than GnRHa (7 days vs 30 days) 20 0 0 10 7 days 20 30 30 days GnRHa, gonadotrophin-releasing hormone agonist; PBAC, Pictorial Bleeding Assessment Chart; UPA, ulipristal acetate 40 50 60 70 80 90 100 Time (days) Donnez J, Tomaszewski J, Vázquez F et al. N Engl J Med 2012;366:421−32
  • UPA STOPS HEAVY BLEEDING FASTER AND MORE CONSISTENTLY THAN GnRHa (INDIVIDUAL PATIENT DATA) GnRHa Daily PBAC score UPA 5 mg Daily PBAC score PEARL II Planned timepoint (days) Daily PBAC score UPA 10 mg 7 days 28 days ● After first menstruation, most UPA patients are in amenorrhoea, while many GnRHa patients have further bleeds during the next 3 weeks due to flare-up effect Planned timepoint (days) 7 days GnRHa, gonadotrophin-releasing hormone agonist; PBAC, Pictorial Bleeding Assessment Chart; UPA, ulipristal acetate Donnez J, Tomaszewski J, Vázquez F et al. N Engl J Med 2012;366:421−32
  • PEARL II. EFFECT ON FIBROID VOLUME REDUCTION WEEK 13 Median % volume reduction in the largest fibroids 0 UPA 5 mg UPA 10 mg Change from baseline at Week 13 (%) (PP population) Lupron -10 -20 -30 -35.55 -40 -50 -42.05 -53.45 ● No significant difference between GnRHa and UPA -60 GnRHa, gonadotrophin-releasing hormone agonist; UPA, ulipristal acetate (ESMYA®) Donnez J, Tomaszewski J, Vázquez F et al. N Engl J Med 2012;366:421−32
  • PEARL II. MEDIAN % VOLUME REDUCTION IN 3 LARGEST FIBROIDS AT WEEK 13, 26 & 38 Follow-up 0 Follow-up Follow-up EOT 3 mo 6 mo EOT 3 mo 6 mo EOT 3 mo 6 mo -10 -16.5 EOT (Week 13) mo (months) -20 -30 -40 -50 -43.3 -44.8 -45.5 -50.0 -56.7 -60 ● -54.8 Subpopulation of subjects where no surgery/UAE was performed -55.7 -62.5 UPA 5 mg UPA 10 mg Lupron -70 Change from EOT (Wk 13) to 6 mo follow up for UPA 5 mg and UPA 10 mg vs Lupron: p< 0.05 UAE, uterine artery embolisation; UPA, ulipristal acetate (ESMYA®) Donnez J, Tomaszewski J, Vázquez F et al. N Engl J Med 2012;366:421−32
  • PEARL II. UPA HAS A SUPERIOR SAFETY PROFILE TO GnRHa AS IT DOES NOT INDUCE MENOPAUSAL SYMPTOMS 70 60 50 Coprimary Safety endpoints (superiority) 40 30 20 10 0 ● ● Oestradiol UPA 5 mg UPA 10 mg Lupron UPA shows a superior safety profile to GnRHa UPA does not induce menopausal symptoms GnRHa, gonadotrophin-releasing hormone agonist; UPA, ulipristal acetate (ESMYA®) Patients with moderate and severe hot flushes (%) Median serum oestradiol (pg/mL) SAFETY, WEEK 13 45 Hot flushes 40 35 30 25 20 15 10 5 0 UPA 5 mg UPA 10 mg Lupron
  • PEARL II. EFFECT OF TREATMENT ON HRQOL USING VALIDATED UFS-QOL QUESTIONNAIRE* HRQoL The higher the score the better; score is specific to uterine fibroids and is not a measure of overall QoL 80.5 76.4 77.1 BL 73.2 72.2 56.5 55.4 53.3 54.2 50.149.4 W13 UPA 5 mg HRQoL, health-related quality of life; UPA, ulipristal acetate (ESMYA®) BL, Baseline W13, Week 13 PP population 81.5 Mean HRQoL score s Six Domains 1- Concern 2- Activities 3- Energy / mood 4- Control 5- Self consciousness 6- Sexual function BL W13 UPA 10 mg BL W13 Lupron *Spies et al. Obstet.Gynecol 2002;99:290–300 Donnez J,Tomaszewski J, Vázquez F, et al. N Engl J Med 2012;366:421−432 (PEARL II)
  • PEARL II. EFFECT OF TREATMENT ON SYMPTOM SEVERITY USING UFS-QOL QUESTIONNAIRE* Symptom severity score 1- Bleeding 2- Abdominal pressure 3- Urination frequency 4- Fatigue The lower the score the better; score is specific to uterine fibroids and is not a measure of overall QoL ● ● Median symptom severity score SYMPTOM SEVERITY SCORE UPA significantly improved QOL The level of symptom severity score at end of treatment corresponds to typical healthy subject scores QoL, quality of life; UPA, ulipristal acetate (ESMYA®) *Spies et al. Obstet.Gynecol 2002;99:290–300 Donnez J,Tomaszewski J, Vázquez F, et al. N Engl J Med 2012;366:421−432 (PEARL II)
  • PEARL II. EFFECT ON PAIN (SF-MCGILL SHORT FORM PAIN QUESTIONNAIRE*) ● ● UPA resulted in a clinically meaningful reduction of pain This reduction (7 points) is comparable to the reduction of post-operative pain obtained with narcotic or non-narcotic analgesics UPA, ulipristal acetate (ESMYA®) *Spies et al. Obstet.Gynecol 2002;99:290–300 Donnez J,Tomaszewski J, Vázquez F, et al. N Engl J Med 2012;366:421−432 (PEARL II)
  • PEARL I & II SAFETY
  • SPRMS EFFECT ON ENDOMETRIUM Key Features of PAEC Novel and benign endometrial changes represent a new morphological category which has been referred to as PRM Associated Endometrial Change (PAEC) Distinguished features of PAEC are 1) low mitotic activity in both glands and stroma 2) abortive subnuclear vacuoles 3) apoptosis 4) absence of stromal breakdown and glandular crowding 5) the cystically dilated glands are lined by flattened epithelium without nuclear pseudostratification PAEC disappeared 2 months after the end of therapy Images courtesy of Professor A. Williams. Edinburgh University Medical School SPRM, selective progesterone receptor modulator
  • PEARL II. UPA EFFECT ON BONE Serum Markers ● P1NP (epiotope of type 1 N terminal propeptide) ● Reflects bone forming activity ● Elevated levels indicate an increase in bone formation ● BSAP (bone specific alkaline phosphatase) ● Elevated levels indicate increased rate of turnover & bone modeling Median CTX (ug/mmol Cr) • • Urine Markers ● DpD (deoxypyridinoline) ● Released into the circulation during bone resorption ● CTX (C-Terminal telopeptide of type I collagen) ● Elevated levels may indicate bone resorption
  • PEARL I & PEARL II CONCLUSIONS (1) ● UPA rapidly stops excessive bleeding (within a week), normalises ● ● ● menstrual bleeding in 90−98% of patients (PBAC <75) and induces amenorrhea in 75% of patients (Pearl II) UPA reduces significantly the volume of the three largest fibroids (by 35% and 42% for UPA 5 mg and 10 mg, respectively) and the effect on fibroid volume reduction seems to be maintained for up to 6 months after treatment cessation (Pearl II) UPA restores patients’ QoL scores to the level of healthy women (Pearl I & II) Majority of patients resume menstruation and ovulation within one month after treatment cessation (Pearl I & II)
  • PEARL I & PEARL II CONCLUSIONS (2) ● Pearl II shows that, compared to GnRHa, UPA 5 mg and 10 mg: ● ● ● Appear to control bleeding faster and more consistently (7 days vs 30 days) Maintain fibroid volume reduction for up to 6 months (-44.8% and -54.8% for UPA 5 mg and 10 mg respectively vs -16.5% for GnRHa) Have a superior safety profile as oestradiol levels are maintained in mid-follicular range