LISBON – The aromatase inhibitor letrozole was associated with roughly a 42% increase in the pregnancy rate, compared with clomiphene citrate in infertile women with polycystic ovary syndrome in a double-blind, randomized study.

In an intention-to-treat analysis, the pregnancy rate was 61.2% with letrozole (Femara) versus 43% with clomiphene (P = .022). There also was a trend toward more live births with letrozole (48.8% vs. 35.4%; P = .089).

The per-protocol results were similar for pregnancy (61% vs. 43.2%; P = .029) and live births (48.1% vs. 35.1%; P = .108).

“We now have convincing evidence that letrozole is better than clomiphene and we should seriously consider moving on to letrozole,” principle investigator Dr. Saad Amer said at the annual meeting of the European Society of Human Reproduction and Embryology.

The results are consistent with the most recent Cochrane meta-analysis, which called for further research comparing letrozole with clomiphene as a primary ovulation induction agent in polycystic ovary syndrome (PCOS) because of low-quality evidence (Cochrane Database Syst. Rev. 2014 Feb. 24;2:CD010287).

A recent robust U.S. study (N. Engl. J. Med. 2014;371:119-29) showed higher live-birth and ovulation rates with letrozole vs. clomiphene in women with PCOS, but it included a markedly obese population with a mean body mass index (BMI) of 35 kg/m² and thus does not reflect clinical practice worldwide, Dr. Amer said.

The current results are more generalizable, especially in Europe, because the patients fulfilled the widely accepted Rotterdam diagnostic criteria for PCOS and had a median BMI of 27.7 kg/m² in the clomiphene group and 27.5 kg/m² in the letrozole group, said Dr. Amer of the University of Nottingham in Derby, England.

The phase IV study evenly randomized 159 anovulatory women, aged 18-39 years, with a diagnosis of PCOS to one tablet of letrozole 2.5 mg or clomiphene 50 mg daily for 5 days, continuing until pregnancy or up to 6 cycles. If there was no response in the first cycle, the dose was increased to two tablets. If there was still no response, the patient was crossed over to the other treatment arm after a 6-week washout. Cycles were initially monitored with ultrasound follicle tracking, then mid-luteal serum progesterone measurements.

Among the 159 women in the intention-to-treat analysis, four conceived before treatment and four dropped out. The remaining 151 women included 77 given letrozole and 74 given clomiphene.

For the 60 women who crossed over, there was no significant difference in pregnancy and live birth rates between groups in either the intention-to-treat or per-protocol analyses.

Notably, however, 70.1% of women who started treatment with letrozole followed by clomiphene became pregnant vs. only 59.5% when the treatment strategy was reversed, while 56.2% started on letrozole and 49.4% started on clomiphene went on to a live birth.

“This tells us that if you take clomiphene first and then follow it with letrozole, you’re achieving almost the same result as just taking letrozole from the beginning,” Dr. Amer said.

The improved pregnancy rates, however, cannot be attributed to the effect of the endometrial factor, he said. Surprisingly, endometrial thickness was significantly greater in the clomiphene group than in the letrozole group (median, 9.0 mm vs. 8.4 mm; P = .002). Mono-follicular ovulation (83% vs. 85%) and multiple pregnancy (twins 0% vs. 6%) rates were similar.

No significant differences were observed between the clomiphene and letrozole groups in miscarriages (6 events vs. 9 events), ectopic pregnancies (0 vs. 1), or preterm births (2 vs. 4).

“Further research is required to investigate the mechanisms of increased pregnancy rates,” Dr. Amer said.

Serious adverse events included one hemorrhagic cyst in each group and a cholecystitis in the clomiphene group.

There was one fetal anomaly – a dilated left kidney – in the clomiphene group and none in the letrozole group, he said.

During a discussion of the results, reproductive medicine specialist Dr. Roy Homburg of Homerton University Hospital, London, said that it’s time for letrozole to recognized as the superior choice.

“Every study that has been done on the subject, every randomized controlled trial, every meta-analysis, every Cochrane database has shown exactly what you have shown – the superiority of letrozole over clomiphene,” Dr. Homburg said. “All this in addition to the fact that there are many more fetal abnormalities, congenital abnormalities with clomiphene rather than letrozole. I think it’s about time people start believing this and make sure letrozole is on-label rather than off-label.”

Dr. Amer agreed. “It’s now time for clomiphene to retire,” he said, receiving a round of applause from the audience.

The study was sponsored by Derby Hospitals NHS Foundation Trust. Dr. Amer reported having no financial disclosures.

pwendling@frontlinemedcom.com

On Twitter @pwendl

Letrozole bests clomiphene again in infertile women with PCOS