current thinking on low-dose aspirin (LDA)?

[expert@preeclampsia.org]

Can I get some new Expert commentary on the value of daily baby aspirin for women with a history of PE?

[expert@preeclampsia.org]

To date I still remain less than impressed, as these meta analyses have had to look at ~35,000 patients , the number to treat to avoid any real outcome problems are large, and there is reference that the effect is only in a high risk subgroup yet to be identified.

A final remark; all these re re re reviews of the aspirin data. Metaanalyses, including those seeking unpublished "negative studies", have flaws, the greatest being that the more endpoints you start analysing, the more subgroups you probe, the more like a significance will be a false positive. But I was never a statistical maven!

[expert@preeclampsia.org]

There are a substantial number of large, well designed clinical trials for the prevention of preeclampsia with ASA. While all suggest some trend towards a positive effect on the diagnosis of preeclampsia, the effect size is very small. At least one has a strong suggestion of an increased risk for clinically significant abruption. While I personally believe that the 0.01 P-value for this result is probably a type 1 error, it is hard to discount the 0.01 result and strongly endorse the weaker associations.

I am not sure there is a place for meta analysis when there are large trials that stand on their own. The very large resulting sample size will have the potential power to discern a statistically significant result that may have minimal clinical relevance.

I suspect that there is is a very small effect in the population treated, or, more likely in my mind, there is potential effect in a small number of individuals that drives the trends.

I think most of us have given up on the "single molecule cure" for preeclampsia. (ASA, Ca, antioxidants....) Preeclampsia is a complex, multifactorial constellation of clinical entities that are unified by an end stage condition manifest by a minimum of hypertension and proteinuria but with a broad spectrum of other findings.

[expert@preeclampsia.org]

Agree with ***** and *****. Great examples are the meta-analyses on Calcium (Br J Obstet Gynaecol 1994, JAMA, 1996) both suggesting very large benefits of Ca++ supplementation. Then comes CPEP (NEJM 1997) and no difference. Despite CPEP Ca++ remains in the Cochrane reviews as effective for preventing or ameliorating preeclampsia. Go figure. Maybe it really is a parasite.

[expert@preeclampsia.org]

I do not completely agree with the others. I do agree that metanalysis are problematic. Although, individual patient metanalysis (as was done in the PARIS study, and which I think must be what is being cited ( Askie LM, Duley L, Henderson-Smart DJ, Stewart LA, Group PC. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369(9575):1791-8)) gets around some of the issues of usual metanalysis by having the original data to standardize outcomes, diagnosis etc., they also are not perfect.

Nonetheless, the findings in the general metanalysis and individual metanalysis with a huge number of women (35,000 +) do indicate benefit to reduce preterm birth, the diagnosis of preeclampsia and serious adverse maternal outcome. Even with large numbers the reduction was small and if real would involve treating large numbers of low risk women (with an incidence of 2%. 500 women treated to prevent 1 case) to show benefit.

However, in high risk women the number to treat is reduced (for a 20% risk about 50 women treated to prevent 1 case) and I think an informed decision by care provider and patient about the benefits of treatment vs. the unknown long term risk (short term risk was pretty unlikely in the 35,00 women in the studies) is reasonable.

[expert@preeclampsia.org]

Even in high risk groups (except for the "diagnosis") the expected incidences for the outcomes to be decreased to those "not so bad NNTs" where I might prescribe ASA, are usually not present (except for the diagnosis PE, but not for the adverse outcomes). On the other hand the incidence for side affects or for bleeding (e.g., abruption ) is higher. Thus the dilemma is still there, and since I stopped active practice before the lancet Paris collaboration paper never suggested ASA, and still might not.

Again, and when I wrote previously mentioning the false significance with multiple outcomes.I was referring to that problem Klebenoff has brought up, time and time again; that as the number of endpoints surveyed increase, and both the the Paris approach and composite analyses may be guilty here, the probability of false statistical significance increases. The publication he has periodically sent us all on this is somewhere in the bowels of the computer., but if I find it will send it to everyone.

In essence I think everybody is saying about the same thing , the difference is having arrived at such shaky data some would and others would not prescribe low dose aspirin? In the last analysis, "some of my best friends" have spent so much time and effort (and at times meeting funds) re doing analyses on patients none of them ever actually examined (which is one definition of of a systematic analysis), that the strength of their recommendation to prescribe, quoted by *****, and reserved perhaps for some high risk situations, may be taken with a grain of aspirin!

[expert@preeclampsia.org]

I agree with *****, *****, ***** about metaanalysis. So far, at least 25 different metaanalysis and systematic reviews were written about low dose aspirin. The one by the Paris collaborative showed a reduction of 10%. The most recent one in the Green Journal does not have any new information, and used selected publications. Indeed, it excluded the first NICHD trial to show differences.

i believe that it is shameful for the reviewers and Editors of journals to continue publishing this nonsense. It is confusing the practicing physicians and doing more harm than good regarding improvement of outcomes for women with preeclampsia.

It is shameful that some are still in favor of recommending LDA despite 2 large multicenter trials conducted by the NICHD Network. Indeed we are ignoring the tax money used as well as the the women who volunteered for these trials.

I believe we should not waste any more time on this subject, and devote our times and resources to improve outcome of women with preeclampsia.

[expert@preeclampsia.org]

While I almost agree with the totality of your comments, the Paris collaboration would have been definitive had the NICHD data been shared - in my humble (non-US)) opinion, it would have been a better use of US tax dollars to have included those data in an individual patient meta-analysis as the sample sizes are so important and would have contributed so much.

Perhaps that issue could be re-visited within the network and the data shared with the Paris group so this can finally be put to bed one way or another, with the "GA at prescription" analysis from this study included in the analytical protocol.

[expert@preeclampsia.org]

This is news to me. I thought all that was settled years ago and the NIH data was made available to *****, or at least was promised. I remember some final chats with everyone happy. But then again, wishful thinking can lead to twisted memories!!!(that is I had thought I had done some groundwork on *****'s behalf)

However, no one seems to want to comment on what I am beginning to call the Klebenoff pronouncements. The more we dissect these data, the more endpoints we analyze, the less meaningful the findings become as the the propensity for false false positives rise. I am still waiting for a comment about that , a counter argument, or at least someone to find the article (maybe I will call Klebenoff!)

[expert@preeclampsia.org]

The dept librarian is back and I finally was able to get the whole article. Recall I had noted my surprise, and they did write a good article applying those very sophisticated tools of both statistics and metanalysis jargon. Also their discussion was appropriately circumspect (in contradistinction to their abstract), noting possible problems with the data, and their conclusion is the need for another large trial (Oh my God another expensive multicenter...!).

However the major problems here are as follows: The total participants in each subgroup ranged from 364-764 (thus picture the Ns of adverse reactions). None of the large trials were in this analysis, and despite the sanctity of mathematical formulas as well as the sophisticated science some worship called metaanalysis, we have seen several instances now where very promising metaanlyses proved erroneous when a very large , well designed, and well monitored multicenter trial was performed (after which some added
them to metaanalyses and continued to rave!).

There are other problems here, one of the trials was listed as ASA vs no treatment instead of placebo (minor). We know that the clinical diagnosis of preeclampsia is often wrong, especially in multipara, but here one supposes that might mask effects. However aspirin is known to decrease GFR in some patients with underlying renal disease, and I always worry that a little less GFR means a little less protein filtered, and ? Less in the urine. Finally, given the views in those articles I sent that critiqued subgroup analyses, the number of endpoints dictates that a p of 0.005 would be needed before one thinks of significance, and in fairness to the authors several are quoted as <0.001. However, as the article continues even here there would be false positives.

In the last analysis, there has always been a small effect in the aspirin trials, but is it much larger if started prior 16 wks? I do not think the data for a conclusion is there.

Again, it been a good exchange, and now to other things.