Medical Management of Marfan Syndrome
28:25-40:30
So a number of trials now were, were, were then undertaken and we then organized with the, with the investigators who, who did these trials. We put these trials all together to try to give a definitive answer because the trials were confusing, you know, when, when as the trials were coming out they, they started to say kind of slightly conflicting things and it was a confusing picture and it was only really when we put the data together that a, a clear picture at least to my, to my mind emerged and I think I can hopefully explain it in a way that at least makes sense to you and I want to share it with you in a way that hopefully will make sense to to you as well. Let me, let me take you through it.
ARBに関して、いくつかの臨床試験が実施されたことから、実施者らの協力のもと、試験結果をまとめ、確固たる解答を得る必要がありました。ですが、結果に対する主張の食い違いがあったり、誤解を招く図表だったりしたので、全てのデータをまとめるまでは、少なくとも私の中ではっきりとした答えは得られませんでした。皆さんには、できる限りわかりやすくこれらの結果を紹介したいと思います。
So let's, yeah, first of all I want to talk, talk you through these four trials, so there were four trials that essentially asked the same question. There was a trial from France, there was a trial from the Netherlands, there was the AIMS trial, which child was heavily involved with from the Marfan Trust and then there was the trial from Belgium, which, were all fundamentally trying to ask the same question, very similar question. What these trials were doing is they were comparing angiotensin receptor blockers with a placebo medication, so they were, they were comparing the same thing but is it better, you know, essentially they are asking the question, "Are angiotensin receptors blockers better than a, a sugar pill?" effectively.
実施された4例の臨床試験は、Marfan-Sartan（フランス）、COMPARE（オランダ）、AIMS（イギリス）、Ghent Marfan（ベルギー）です。AIMSは若者を主な対象とした試験で、Marfan Trustの協力で実施されました。これらの試験はいずれも、ARBとプラセボの比較という、ほぼ同一の目的で行われました。つまり、ARBはプラセボ（砂糖の塊）よりも効果が高いかどうかを調べたということです。
And they, they differed by size, so this trial had 299 patients, this trial had 233 patients, this trial had 192 and this trial had 22 patients and so you might say, "Okay, well, it's not fair to compare to, to include this trial with this trial because this trial was much bigger than this trial," and if you and, if you thought that then you understand meta-analysis because we didn't add those trials together in a, in a lump and just say, "Well, okay that's one trial, that's two trials, three trials, four trials." We weighted the trials according to the amount of information that they contained and this trial contained an awful lot more information than this trial, so this trial got given more emphasis in the meta-analysis than this trial and a lot of people didn't understand that, okay?
それぞれの試験で被験者の数が異なります。上から292、233、192、22名の参加者ですので、被験者の数が異なる試験同士を一緒するのはおかしいのではないか、という声があるかもしれません。こう考えておられるのであれば、メタアナリシスを正しく理解しているといえます。メタアナリシスでは、4つの試験を合わせて一つにすることはしません。それぞれの試験の情報量に基づいて重み付けをします。ある試験の情報量が他の試験よりも多いのであれば、その情報量の多い試験は他の試験よりも、より重視されるということです。この点を理解していない方が大勢いらっしゃいます。
There were certain trials that did very, very precise measurements of the aorta and there were other trials that did slightly less precise measurements. They just kind of, "Yeah, it's roughly there," and other trials really measured, it very precisely and some of the trialists said, "Well, I don't want my trial being mixed in with the guys who just kind of went, 'yeah it's roughly there'," and I said don't worry because we're going to weight the trials by the amount of information available, so if you did really precise measurements we know that and we're going to put more emphasis on your trials so that's the beauty of meta-analysis. We know which trials provide the most information and we can weight those trials accordingly, okay?
大動脈径を非常に正確に測定している試験もあれば、やや正確性に欠ける測定をしている試験もありますので、試験に参加した患者さんの中には「自分の試験結果を適当に計測された試験結果には混ぜて欲しくない」とおっしゃる方もおられるかもしれませんが、心配には及びません。メタアナリシスでは、情報量に応じて評価が決まりますので、正確に計測された結果であれば、それだけ評価も高くなります。これがメタアナリシスの素晴らしいところです。どの試験で最も多くの情報を得られたかはわかっていますので、それに応じて重要度が決まるということです。
So the trials bit frequent measurements, so we got lots of, we got huge amounts of information for every participant and they were measuring the aorta at exactly the place where the aorta tends to enlarge, okay? So that's the characteristics of those trials. I'm going to skip this trial and come back to it.
臨床試験では、何度も大動脈の計測をしたので、それぞれの患者さんから膨大なデータが集まりました。計測部位は拡張しやすい大動脈基部です。一旦こちらのスライドは飛ばし、後ほど戻ってきます。
We published the protocol before we knew what the trials were going to show so that there was no opportunity for us doing, you know, statistical jiggery-pokery. We, we said what we were going to do, we did it, we found the results. There was no opportunity for clever statistical messing around and we analyzed all eligible randomized trials that were done in the world that provided data to us. We used individual patient data and trials were weighted according to the information that they contain, okay.
研究を実施する前にプロトコルを公開していたので、統計的な不正はできないようになっていました。つまり、研究の方法を事前に発表し、その通りに実施して結果が得られたわけですので、悪いことはできなかったということです。また、世界中で実施されたランダム化比較試験で、今回の研究対象となり、かつデータを提供していただけたものに関しては全て分析を行いました。さらに、患者さん一人一人のデータを利用し、含まれる情報に応じて各臨床試験の重み付けを行いました。
The primary aims, that we wanted to estimate the effects of angiotensin receptor blockers and beta blockers on the change in aortic root size in patients with Marfan syndrome who had no prior aortic root surgery. There's no point in including patients with aortic root surgery because they've already had their aortas replaced with a piece of surgical material and, and so that would have affected the results in a way that was unhelpful.
主要目的は、大動脈基部置換未実施のマルファン患者さんにおける大動脈基部径の変化に対するARBおよびβ遮断薬の効果を評価することでした。大動脈基部手術を受けた患者さんを含めなかった理由としては、大動脈基部が人工血管に置換されている患者さんでは、薬の効果が得られないと思われたためです。
So and then we had various secondary aims as well to it, to look at different subgroups, the children benefit to do, that sort of thing, so we looked at various other secondary outcomes as well, okay.
副次的目的は、様々なサブグループや小児に対する薬の効果などを評価することであり、これらの目的に対する転帰も調べました。
So let's look at the results, so now this looks a little complex but it's really pretty simple, so I just want to spend a minute talking you through this, so these are the names of the trials that we just talked about here's the French trial, here's the Dutch trial, here's the UK AIMS study, some of you may have been participants in that trial, here's the Belgian trial, okay and these are the names of the trials.
では、結果を見ましょう。複雑に見えるかもしれませんが、実際は非常にシンプルです。左の列は試験の名前です。先ほど紹介した臨床試験名が並んでいます。
This is the annual change in the size of the aorta, so for each year that the participant was in the trial how much bigger did their aorta get. These are the participants who are on the drug treatment and these are the participants who are taking the sugar pill the placebo medication. If the patient, if the trial found that the angiotensin receptor blocker was better for the patient's aorta then the black dot here would be shifted over to the left hand side, side like this and if the trial found that it was actually better to be on the placebo medication then the black dot would be shifted over to this side.
Annual Changeが、大動脈径の年間変化です。臨床試験参加者の大動脈が毎年どの程度大きくなったかを示しています。ARBの列が薬物治療を受けた群で、Controlの列が、砂糖の塊を摂取した群です。ARB群が優れている場合には、黒い丸が左側に、プラセボ群が優れている場合には、右側に動きます。
And then the diamond represents the overall result, so when we looked at the results the first thing my eye went to is, "did this diamond fall on this side or did it fall on this side?" and if there was no difference the diamond would have fallen bang in the center, okay? and the further the diamond is to this side the more the ARBs work and the further to this side the more the, the controls work this side and if the diamond is completely on this side then we are, can be certain or more certain within certain confidence limits, that's a kind of statistical term, that the treatment works and what we can see is that the diamond falls completely on this side of the black line. If the diamond had been falling over the line, so half the diamonds on this side and half the diamonds on this side then it's a, it's a wash and the neither treatment works, you know, that just means the drugs do nothing.
ダイヤモンドのマークは全体的な結果を表しています。結果を見る場合にまず着目するのが、このダイヤモンドマークが左にあるのか、右にあるのかということです。もし、結果に違いがないとすると、このマークは中心にきます。ダイヤモンドが左にあればあるほどARBの効果が高く、右にあればあるほど、プラセボの効果が高いことになります。ダイヤモンド全体が黒のラインより左側にある場合には、一定の信頼限界（統計用語）で治療に効果があったということになります。また、黒のラインの両側に半分ずつダイヤモンドが出ていた場合には、プラマイゼロで、どちらの治療にも効果がなかったことを示します。
So what we can see is the diamond falls completely on this side of the line and that tells us that the ARB is better than the the no treatment and the fact that the diamond falls completely over the line means we can be 90, well, we can have 95% confidence that, that result is true, more or less, it's not entirely right but that's basically it so, so, so that was, that was the kind of key finding of the meta-analysis.
今回のケースでは、ダイヤモンドが完全に左側にありますので、ARBがプラセボよりも効果が高いことを意味します。これは95%の信頼度で結果が正しいことを示しています。完全に正しいということではないのですが、ほぼ正しいということです。これが、メタアナリシスで最も重要な結果です。
And then the, and then the next thing to, to look at is well what how big is this effect, you know, are we, are we saying that the angiotensin receptors reduce the rate of aortic enlargement a tiny bit or is it a lot, what does that mean? Well, let, let's look at this, so per year the aorta was enlarging by 0.13 units here and if you were on treatment it was 0.07 units. Here now 0.13 and 0.07, this is about half of that 0.1, you know, if you double, if you double 0.07 you get 0.14, don't you? So .03, .14 it's about the same, so effectively what's happening is the ARB is halving the rate of at which the aorta enlarges. That's huge, okay?
次に注目すべきは、ARBの効果です。ARBによって大動脈の拡張速度がどのくらい遅くなったか、ということです。プラセボ群の大動脈拡張は0.13で、ARB群では0.07ですので、約半分になっています。つまりARBによって大動脈の拡張速度は約半分になったということです。これは非常に大きな効果といえます。
So, you know, like if, if, if there was a, if there was a medication that would give me half my hair back I take it, okay? So, you know, that so, so halving the rate of hair loss would be huge for me, halving the rate of which my, a the aorta was expanding for, for you guys is really really big, okay? So that's a really big effect and I and I'm and, you know, on a statistical level I'm quite certain about it, okay? So that, that's what, that's, what that showed and then there's various different ways of, of, of looking at it in in terms of the statistics which I think I'm just going to jump over for the moment. I'll put that on there, so it's on the, on the YouTube video.
例えば、髪の毛を半分フサフサにしてくれる薬があったら、私は絶対に飲みます。髪の毛が抜ける速度を半分にしてくれるなんて、私にとってはありがたい薬です。それと同じで、大動脈の拡張速度が半分になるってすごいことですよね。統計レベルでは、確実に言えることです。統計的にはこのように別の表し方もできますが、ここでは飛ばします。後ほどYouTubeでご覧ください。
So now then the next question people always want to say is, "Oh, does it work for older people, does it work for children, does it work equally for men and for women, does it work if my parents had Marfan syndrome, did it work if I've got a big aorta to start with or a small aorta, does it work people have got high and low blood pressure, does it work if I also take a beta blocker?" These, these are all very good questions and the short answer is that we found, I'm gonna get, I'm got to get this right, otherwise my, my statistical colleagues will sort of raise an eyebrow at me and, and the correct way of saying this I think is, is to say that we explored the data for evidence of differences because of these things and we found no evidence that it made any difference at all for any of these things, okay? If I'm being properly statistically correct about it that it, that is the way I should should say it, okay? We found no evidence for any differences according to any of these subgroups. We, we looked for whether people were, you know, for children, young people under the age of 16 compared to over the 16 we found no evidence for any difference. We, we looked for whether it was different for men and for women, we found no difference, we looked for family history, we looked for people with big aorta compared to small aorta, we found no difference, okay?
次に皆さんが知りたいことは、高齢者や子どもおよび男女、親がマルファンであるかどうか、服薬開始時の大動脈の太さ、血圧の高低、β遮断薬を使用しているかどうか、といった要因で、ARBの効果に違いは出るかどうかということだと思います。端的にお答えすると、というか正確に回答しないと、統計を専門にしている同僚から白い目で見られてしまいますので、統計的に正しい回答をせざるを得ないのですが、上記の項目によって薬の効果に差が出ることを示すエビデンスとなるデータを探した結果、そのようなデータを見つけることはできなかった、という回答になります。つまり、上記のサブグループで違いがあることを示すエビデンスは見つからなかったのです。例えば、16歳以下の子どもと16歳以上の若者の比較で、差異を示すエビデンスは見つかりませんでしたし、男女別、家族歴、試験開始時の大動脈基部サイズの比較でも、ARBの効果に差は見られなかったということです。
I, I, I think what people would like me to say is to say that it makes no difference, that is going very slightly beyond what the data, what one can say from these types of data sets but I think I would I, I recommend these medications to men and women. I recommend it for children and for adults. I recommend it for people with high blood pressure, low blood pressure, big aortas, small aortas and if I fell into any of these categories I would be taking these meds. I'd be considering these medications for myself, for my children, for my sister, for me, my mom, my dad whether someone had a big or small aorta. That's how I would be approaching this and I've see no rational reason for denying these medications for certain people.
皆さんとしては、データよりも多少良い結果が出ることを期待していたかと思いますが、私としては、男性、女性、大人、子ども、高血圧の方、低血圧の方、大動脈基部の大きな方、小さな方、皆さんにARBを飲んでいただきたいと思っています。私自身これらのグループに属することになったとしてもやはりARBを飲むと思いますし、自分の子どもや妹、父母など、大動脈基部の大小に関わらず飲ませることを考えます。これが私の方針であり、一部の患者さんには飲ませないという妥当な理由はないと考えています。
Some colleagues say, "I like to individualize things, I like to tailor things to the individual patient," and with very limited number of exceptions what I like to ask those colleagues is on what rational basis do you do that because I can find no rational basis for doing it apart from one or two very limited exceptions.
同僚医師の中には、一人一人の患者さんに応じて薬を調整したい、という者もいますが、合理的な理由があるのか？と尋ねたい気持ちです。それだけ、ごく少数の例外を除いては、個別対応が必要な理由は見つからないということなのです。
The Marfan Foundation did not participate in the translation of these materials and does not in any way endorse them. If you are interested in this topic, please refer to our website, Marfan.org, for materials approved by our Professional Advisory Board.
The Marfan Foundation は、当翻訳には関与しておらず、翻訳内容に関してはいかなる承認も行っておりません。このトピックに興味をお持ちの方は、Marfan.org にアクセスし、当協会の専門家から成る諮問委員会が承認した内容をご参照ください。
