Scholarly Series No. 4: FASTT Trial

This clinical trial has been mentioned in some of the previous Scholarly Series  (here and here), so I had to look up the source itself. The attention it's been given by other researchers is primarily because it is one of the most recent and the largest, randomized control trials comparing different treatment models and has since been effective in changing policy in states that mandate insurance coverage. But I'm jumping ahead of myself with excitement.

Reindollar, R.H., Regan, M.M., Newman, P.J., Levine, B.S., Thornton, K.L., Apler, M.M., and Goldman, M.B. (2010). A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial. Fertility and Sterility, 94 (3), 888 - 899. 

Summary

This clinical trial randomized couples into one of two treatment strategies; standard approach versus an accelerated approach. In the standard approach, all couples initiated treatment with up to 3 trials of Clomid (100 mg, days 3-7) and IUI following a hCG "trigger shot". If this was not effective in three trials, they then received up to 3 cycles of gonadatropin/IUI, with the starting dose of 150 IU of FSH, which was adjusted based on the woman's response. If they were still not pregnant after these three cycles, the couples then received up to 6 cycles of IVF. In the accelerated approach, couples also initiated treatment with up to 3 trials of Clomid and IUI, in the same protocol as described above. Unlike the other group, if these couples were not pregnant after these three cycles, they then moved to directly to IVF for up to 6 cycles, skipping the FSH/IUI cycles completely.

All couples were considered unexplained infertility (i.e. no obvious tubal defects, regular ovulation, and normal sperm perameters) and were between the ages of 21-39. Couples were randomized into one of the two groups based on a stratified sample (<35 vs >/= 35) so that there would generally be consistency between these two age groups. A total of 493 couples initiated treatment cycles and underwent a total of 2,355 cycles.

The primary outcomes the study examined was "time to pregnancy" from initiating treatment and overall cost. They examined cost based on data from the insurance companies about how much was charged as well as adding in an estimated value of time lost from work ($17.43/hour based on 2007 national average wages).

In regards to time:

• They found a statistically significantly shorter time to pregnancy in the accelerated group, with the the median time to pregnancy in this group being 8 months, compared with the 11 months in the standard treatment group. 
• Per cycle pregnancy rates for Clomid/IUI, FSH/IUI, and IVF were 7.6%, 9.8%, and 30.7%, respectively, for each cycle. 
• Within each group, 20.6% of couples had a birth with one of the first three months of Clomid/IUI. An additional 25.4% of the remaining standard group couples (43 of 169 couples) had a live birth in one of the three FSH/IUI cycles, and then an average of 67.5% of the remaining couples in both groups had a live birth with the IVF cycles (73 of 111 standard group couples and 118 of 172 accelerated group couples). So total live birth rates by the end of the study was 74.9% for the standard group and 77.7% for the accelerated group. 
• Interestingly, 52 (14%) pregnancies occurred on cycles that couples were not receiving treatment. 
• Multiple birth rates did not differ significantly between the two arms (21% in the standard group vs. 23% in the accelerated group). 

In regards to cost effectiveness:

• The authors qualify themselves at the beginning of the article by stating that they would have needed approximately 800 couples to reach enough statistical power in order to detect meaningful differences. That being said, none of the differences that were discussed were statistically significant. 
• Total insurance charges for all of the couples analyzed was $9.4 million dollars. To be completely honest, the financially-oriented statistics are well beyond my scope of understanding, so I can't say that I completely understand the following results... 
• The authors looked at average total cost per delivery (i.e. they factored in improved success rates with accelerated track and divided the total cost for each group by the number of deliveries per group) and found that charges were $9,846 lower for the accelerated group (averaging $61,553) than the standard group (averaging $71,399). 
• When looking at the average cost per couple (not taking into account success of treatment), the difference was $2,624 less for the accelerated group (averaging $41,211) than the standard group (averaging $43,835). It's important to note that these differences were not considered statistically significant, but was definitely trending towards significance. 
• They also looked at the average amount of out-of-pocket costs, based on patient diaries and including time involvement, and found essentially no difference ($485 for the accelerated group vs. $495 for the conventional group*). 
• The authors used some fancy statistics to simulate cost differences based on different prices of treatment options and concluded that the cost of an IVF cycle would have to exceed $17,749 to have a lower cost per delivery. 

**I should note that this study was completed in MA, where insurance coverage for infertility is mandated. The out-of-pocket costs reflect time involvement and co-payments for drugs and physician visits. I appreciate that this cost is FAR BELOW what most of us have actually paid out-of-pocket and, frankly, sickens me a little.

Review

Phew, that was a long summary! Sorry. Or, you're welcome. I guess it depends if you find this as interesting as I do and are still reading this.

I have many reactions to this study and the implications, but first, some thoughts on the design of the study itself. Overall, it's a pretty solid study with a great design. The most optimal design is a randomized, double-blind, control trial and the only aspect that these authors were missing was the double-blinding. This is obviously understandable as it would be pretty impossible for people to be unaware of which treatment option they were giving or the doctors to be unaware of what treatment they were giving their patients (this is generally easier when it's just a simple pill and then you can give sugar pills and no one knows anything!). My only real beef with the study itself is that they had a lot of strong conclusions about the cost effectiveness based on statistics that were not significant at the 95th percentile. I completely understand why, that it would have been necessary to get an additional 300+ couples and that would have taken a lot of extra time, but I think that these results should be a little more cautioned.

Here are all of my other, random thoughts:

1. Eight months compared with 11 months is definitely a plus. No one can deny that. On the other hand, neither amount of time seems that exorbitant compared with what I hear about from others, or my current time-count for that manner. 
2. The accelerated group did have slightly better success overall, which is consistent with the research that suggests that the longer someone is in fertility treatment, the lower their success. This is also something for me to keep in mind. 
3. The fact that the authors concluded that the accelerated group had a (pretty significant) cost savings wasn't as important to me as just the knowledge that these two options are at least comparable. I had always assumed that IVF is so expensive so it would make sense to spend a lot of time and energy/expense on less expensive options before moving on. But this simplistic view doesn't account for the fact that IVF is also much more successful. I am reminded of the time that I went to an internist for migraines and she prescribed a sub-clinical dose of Imitrex. It helped a little, but when I finally sucked it up and went to a neurologist, I realized that there were WAY better options out there. 
4. Given these conclusions, I am still a little amazed at how many physicians still seem to encourage people to go through so many cycles of IUI before trying a more aggressive treatment option. I wonder if they think that this is what people want to hear. Or there is some other fatal flaw to this study that I'm not seeing. Ah!
5. I just have to bring this up again... couples with full insurance spent a total of $490 for their entire treatment! This makes me so angry at my state and place of employment and so jealous of the few people I know living in MA. I have honestly considered relocating to a state or at least company that offered infertility coverage. Not seriously, but I definitely did a mental pros/cons list on the issue. 

What are you reactions to this study? Will/would this influence your infertility decision making?