Regression or no progression, of coronary atheroma, in trials with non statin, intensive lipid lowering, injectable treatments.
Great claims but small results, about regression, despite impressive reduction of LDL cholesterol.
Waiting for immininent results of clinical outcomes trials:
Two regression trials, with IVUS imaging, were presented at the AHA 2016 congress, with different results:
- Milano pilot study, with Apo A1 Mi (HDL mimetic)
- Glagov trial, with Evolocumab (PCSK9 inhibitor)
Progressione e regressione dell’aterosclerosi
Circa venticinque anni fa, con l’introduzione delle statine si è avuto il primo trattamento efficace per ridurre sia il colesterolo LDL, sia gli eventi cardiovascolari sfavorevoli (1).
Da allora sono iniziati anche i tentativi per la dimostrazione di una regressione o mancata progressione dell’aterosclerosi coronarica (2), le cui complicazioni, atero-trombosi, sono la principale causa di morte al mondo.
In quegli anni il gold standard, per valutare un’eventuale regressione dell’ateroma, era la coronarografia. I risultati ottenuti con la coronarografia sono però risultati molto modesti per dimostrare in modo convincente una regressione della placca.
Il concetto di progressione della placca aterosclerotica venne radicalmente cambiato da S. Glagov, il patologo che nel 1987 dimostrò come la progressione della placca avvenga nello spessore della parete vasale, al contrario di quanto ritenuto fino ad allora, quando il progressivo accumulo di ateroma per deposizione nel lume coronarico era considerato il meccanismo responsabile delle forme ostruttive, in analogia alle incrostazioni di una tubatura idraulica.
La dilatazione compensatoria del vaso, “Glagov phenomenon”, consente l’accrescimento della placca esclusivamente all’interno della parete, senza interessare il lume, almeno fino ad una estensione del volume dell’ateroma superiore a 40%. (3)
Questo rimodellamento compensatorio non può essere rilevato da una coronarografia, che può valutare esclusivamente il lume del vaso, come sottolineato in un famoso articolo sulla “luminologia“, già nel 1995 da Topol e Nissen. (4)
In base a queste argomentazioni, S. Nissen indicò come nuovo riferimento per gli studi di progressione-regressione, l’ecografia intravascolare (IVUS) che permette di valutare non solo il lume ma soprattutto la parete del vaso.
Nel 2003 Nissen dimostrò per la prima volta (5) , con una valutazione IVUS, una regressione di placca dopo trattamento di cinque settimane con Apo A1 Milano, HDL mimetico.
Nel 2004 lo studio Reversal, evidenziò la mancata progressione nel gruppo trattato con atorvastatina 80 mg ripetto al controllo (6) e nel 2006 lo studio Asteroid dimostrò invece una regressione di placca dopo trattamento con 40 mg di rosuvastatina (7), risultato confermato anche nel recente studio IBIS-4 (8).
Tuttavia, nonostante l’impiego della tecnica IVUS per la valutazione del volume complessivo della placca, sia nella parete, sia nel lume, il trattamento con statine ha evidenziato solo una regressione di modesta entità, inferiore rispetto alle aspettative legate alla marcata riduzione degli eventi cardiovascolari ottenuta.
L’efficacia delle statine sembra infatti attribuibile non tanto ad una riduzione dell’effetto ostruttivo del volume della placca, quanto piuttosto ad un effetto di “stabilizzazione”. L’ipotesi, non ancora sufficientemente dimostrata, è quella di una modifica della composizione della placca, con una minor vulnerabilità alle complicazioni infiammatorie, come rottura ed erosione, che caratterizzano gli eventi atero-trombotici.
In attesa di conoscere i risultati degli studi di outcome clinico.
Al congresso AHA 2016 sono stati presentati due studi di imaging IVUS sulla regressione:
- Milano pilot study
con APO A1 Milano, è risultato negativo per regressione. L’attuale produttore, The Medicine Company, aveva rilevato la molecola da Pfizer, dopo questo studio ha sospeso la produzione e ulteriori ricerche su Apo A1 Mi; ha concentrato il suo impegno su un nuovo inibitore della sintesi di PCSK9. Il farmaco si chiama Inclisiran, agisce con un meccanismo denominato “RNA interference” sulla sintesi di PCSK9. All’AHA 2016 è stato presentato uno studio in fase 2, denominato Orion-1 (9).
- Glagov RCT, (10)
con Evolocumaub, ha evidenziato una regressione di placca di entità poco inferiore ad 1% del volume percentuale dell’ateroma (PAV). Riguardo a questo parametro, PAV, l’entità di regressione è risultata simile a quella degli studi sopra citati.
Downloaded From: http://jamanetwork.com/ on 11/15/2016
A fronte di un’efficacia così evidente sulla riduzione del colesterolo LDL, il risultato ottenuto sulla regressione della placca sembra invece piuttosto limitato, nonostante le positive considerazioni degli autori, tratte da una precedente metanalisi, sulla associazione lineare tra la riduzione, anche modesta, del parametro IVUS usato come endpoint primario, il PAV, e gli outcome. (11)
Precedentemente, nel 2014, lo studio Improve-it, aveva legittimato il paradigma “lower is better” riferito alla riduzione di LDL, ottenuta con aggiunta di Ezetimibe a Simvastatina. Ezetimibe ha però portato solo un modesto incremento di beneficio sugli outcome, in uno studio su 18000 trattati, ad un follow-up medio di sei anni. (12)
I nuovi trattamenti con anticorpi monoclonali anti PCSK9, hanno permesso di ottenere in poco tempo una riduzione della colesterolemia di entità precedentemente impensabile.
Si tratta di tre anticorpi monoclonali, due umani Evolocumab (Amgen) ed Alirocumab (Sanofi, Regeneron), ed uno non umano, Bococizumab. In questo novembre 2016 la Pfizer ha sospeso lo sviluppo del Bococizumab e degli studi clinici Spire, per scarsa efficacia a distanza, attribuita alla formazione di anticorpi.
Tra pochi mesi saranno disponibili i risultati dello studio Fourier sugli outcome clinici di Evolocumab. Le aspettative sono alte, in base al notevole abbattimento del colesterolo LDL.
Nel maggior studio clinico, finora effettuato con le statine, cioè l‘HPS (13), la riduzione di eventi cardiovascolari sfavorevoli, con Simvastatina, fu di circa un quarto rispetto ai controlli.
Una recentissima analisi post-hoc, su 10 studi Odyssey effettuati con l’anticorpo monoclonale, inibitore PCSK9, Alirocumab, ha complessivamente evidenziato una riduzione del rischio di eventi sfavorevoli del 24%, cioè meno di quanto ci si poteva aspettare, dopo aver ottenuto con Alirocumab una riduzione del colesterolo LDL nettamente superiore a quella ottenuta con le statine: fino a meno di 50 mg/dl. (14) Per Alirocumab i risultati dello studio Odyssey outcomes, sono attesi nel 2018.
In conclusione: nuovi farmaci iniettabili, aggiunti alle statine, hanno dimostrato una capacità, senza precedenti, di ridurre il colesterolo LDL.
I risultati dei mega trial di outcome, su decine di migliaia di pazienti, saranno disponibili nei prossimi mesi.
Sarà importante valutare se l’entità dell’eventuale aggiunto beneficio clinico (effect size) risulterà abbastanza ampia e proporzionale all’efficacia evidenziata nella riduzione del colesterolo LDL.
vedi anche:
References
- Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389
- Brown G., Albers J.J., Fisher L.D., et al. Regression of Coronary Artery Disease as a Result of Intensive Lipid-Lowering Therapy in Men with High Levels of Apolipoprotein B November 8, 1990, N Engl J Med 1990; 323:1289-1298
- Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987 May 28;316(22):1371-5.
- Topol EJ, Nissen SE. Our preoccupation with coronary luminology. The dissociation between clinical and angiographic findings in ischemic heart disease. Circulation 1995; 92:2333 – 2342.
- Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA. 2003;290(17):2292-2300.
- Nissen SE, Tuzcu EM, Schoenhagen P, et al; REVERSAL Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291(9):1071-1080.
- Nissen SE, Nicholls SJ, Sipahi I, et al; ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID JAMA. 2006;295(13):1556-1565.
- Räber L, Taniwaki M, Zaugg S, et al. IBIS 4 (Integrated Biomarkers and Imaging Study-4) Trial Investigators (NCT00962416). Effect of high-intensity statin therapy on atherosclerosis in non-infarct-related coronary arteries (IBIS-4): a serial intravascular ultrasonography study.Eur Heart J. 2015 Feb 21;36(8):490-500. doi: 10.1093/eurheartj/ehu373.
- Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9.N Engl J Med 2016; DOI:10.1056/NEJMoa1609243. Article
- Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, Koenig W, Somaratne R, Kassahun H, Yang J, Wasserman SM, Scott R, Ungi I, Podolec J, Ophuis AO, Cornel JH, Borgman M, Brennan DM, Nissen SE. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. JAMA. 2016 Nov 15.
- Nicholls SJ, Hsu A,Wolski K, et al. Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome. J Am Coll Cardiol. 2010;55(21):2399-2407.
- Cannon CP, Blazing MA, Giugliano RP, et al.(Improve-it) Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-2397
- Heart Protection Study Collaborative Group.MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial. (HPS) Lancet, 360 (2002), pp. 7–22
- Ray KK, Ginsberg HN, Davidson MH, Pordy R, Bessac L, Minini P, Eckel RH, Cannon CP.Reductions in Atherogenic Lipids and Major Cardiovascular Events: A Pooled Analysis of 10 ODYSSEY Trials Comparing Alirocumab to Control. Circulation. 2016 Oct 24. pii: CIRCULATIONAHA.116.024604. [Epub ahead of print] PMID:27777279
" Slow Medicine"
"Choosing wisely" .
Dissezione coronarica spontanea: sito europeo
Dissezione coronarica spontanea: sito US
Go red for women .
Il fatto alimentare.
Image Wisely
La più importante rivista di medicina.
Preventing Overdiagnosis.
theheartorg and Medscape.
dottorknock 
excellent post, very informative. I wonder why the other specialists of this sector do not notice this. You should continue your writing. I’m confident, you’ve a great readers’ base already!
"Mi piace""Mi piace"
Thank you for another wonderful article. Where else could anyone get that type of information in such an ideal way of writing? I have a presentation next week, and I am on the look for such info.
"Mi piace""Mi piace"
I simply had to say thanks again. I’m not certain the things that I might have gone through without the tactics provided by you on my situation. It previously was the fearsome matter in my circumstances, however , witnessing a new professional tactic you processed the issue made me to cry with contentment. Extremely happy for the assistance and believe you realize what a powerful job that you’re carrying out instructing many people by way of your site. I am sure you have never met all of us.
"Mi piace""Mi piace"
Thanks for one’s marvelous posting! I certainly enjoyed reading it, you may be a great author.I will be sure to bookmark your blog and definitely will come back later in life. I want to encourage you to definitely continue your great job, have a nice holiday weekend!
"Mi piace""Mi piace"
I really like your blog.. very nice colors & theme. Did you create this website yourself or did you hire someone to do it for you? Plz answer back as I’m looking to create my own blog and would like to know where u got this from. cheers
"Mi piace""Mi piace"
I’m not sure where you’re getting your information, but good topic. I needs to spend some time learning more or understanding more. Thanks for excellent info I was looking for this information for my mission.
"Mi piace""Mi piace"
I am continually searching online for tips that can assist me. Thx!
"Mi piace""Mi piace"
I’m still learning from you, but I’m improving myself. I certainly enjoy reading everything that is written on your website.Keep the information coming. I enjoyed it!
"Mi piace""Mi piace"
Simply desire to say your article is as astonishing. The clearness in your post is just spectacular and i could assume you’re an expert on this subject. Well with your permission allow me to grab your feed to keep updated with forthcoming post. Thanks a million and please continue the gratifying work.
"Mi piace""Mi piace"
Magnificent web site. Plenty of helpful info here. I am sending it to several friends ans also sharing in delicious. And obviously, thanks to your effort!
"Mi piace""Mi piace"
Usually I do not read article on blogs, but I wish to say that this write-up very forced me to try and do it! Your writing style has been amazed me. Thanks, very nice post.
"Mi piace""Mi piace"
I’ve been exploring for a little bit for any high quality articles or blog posts on this sort of area . Exploring in Yahoo I at last stumbled upon this web site. Reading this information So i am happy to convey that I’ve a very good uncanny feeling I discovered just what I needed. I most certainly will make certain to do not forget this web site and give it a glance on a constant basis.
"Mi piace""Mi piace"
Thank you for your entire labor on this website. Kim loves conducting investigation and it is easy to understand why. Most people learn all regarding the lively method you create useful items via this website and even foster contribution from other individuals about this issue and our simple princess has been discovering a whole lot. Take pleasure in the remaining portion of the new year. You are carrying out a wonderful job.
"Mi piace""Mi piace"
A powerful share, I simply given this onto a colleague who was doing slightly analysis on this. And he in actual fact purchased me breakfast as a result of I discovered it for him.. smile. So let me reword that: Thnx for the deal with! However yeah Thnkx for spending the time to debate this, I feel strongly about it and love reading extra on this topic. If possible, as you become expertise, would you thoughts updating your weblog with more details? It is highly useful for me. Huge thumb up for this weblog put up!
"Mi piace""Mi piace"
Nice read, I just passed this onto a friend who was doing a little research on that. And he actually bought me lunch because I found it for him smile Thus let me rephrase that: Thanks for lunch!
"Mi piace""Mi piace"
I’ve learn a few good stuff here. Certainly value bookmarking for revisiting. I surprise how a lot effort you put to make one of these great informative web site.
"Mi piace""Mi piace"
What’s Happening i’m new to this, I stumbled upon this I’ve found It positively useful and it has aided me out loads. I hope to contribute & help other users like its aided me. Good job.
"Mi piace""Mi piace"
Wow, fantastic blog layout! How long have you been blogging for? you make blogging look easy. The overall look of your web site is great, as well as the content!
"Mi piace""Mi piace"
Hi there very cool site!! Man .. Excellent .. Wonderful .. I will bookmark your site and take the feeds also…I am satisfied to seek out numerous helpful info here in the publish, we need work out extra techniques on this regard, thanks for sharing. . . . . .
"Mi piace""Mi piace"
I wish to get across my appreciation for your kindness giving support to those individuals that need help with in this topic. Your personal commitment to getting the message along turned out to be particularly important and have in every case helped professionals much like me to get to their desired goals. Your amazing useful key points entails this much a person like me and somewhat more to my mates. Warm regards; from all of us.
"Mi piace""Mi piace"
You should take part in a contest for probably the greatest blogs on the web. I will suggest this site!
"Mi piace""Mi piace"
Do you mind if I quote a couple of your posts as long as I provide credit and sources back to your website? My website is in the very same area of interest as yours and my visitors would definitely benefit from some of the information you provide here. Please let me know if this alright with you. Regards!
"Mi piace""Mi piace"
It’s actually a cool and useful piece of information. I’m glad that you shared this useful information with us. Please keep us informed like this. Thanks for sharing.
"Mi piace""Mi piace"
As I web site possessor I believe the content material here is rattling fantastic , appreciate it for your efforts. You should keep it up forever! Good Luck.
"Mi piace""Mi piace"
Hi! This is my first visit to your blog! We are a group of volunteers and starting a new initiative in a community in the same niche. Your blog provided us valuable information to work on. You have done a outstanding job!
"Mi piace""Mi piace"
I’m really enjoying the theme/design of your site. Do you ever run into any internet browser compatibility issues? A few of my blog readers have complained about my site not operating correctly in Explorer but looks great in Safari. Do you have any solutions to help fix this issue?
"Mi piace""Mi piace"
fantastic points altogether, you simply gained a new reader. What would you recommend about your post that you made a few days ago? Any positive?
"Mi piace""Mi piace"
Somebody essentially help to make critically posts I would state. This is the very first time I frequented your web page and up to now? I surprised with the analysis you made to create this actual put up amazing. Wonderful task!
"Mi piace""Mi piace"
Great site. Lots of helpful info here. I am sending it to several buddies ans additionally sharing in delicious. And naturally, thank you to your sweat!
"Mi piace""Mi piace"
Howdy would you mind letting me know which web host you’re utilizing? I’ve loaded your blog in 3 different browsers and I must say this blog loads a lot faster then most. Can you recommend a good internet hosting provider at a reasonable price? Many thanks, I appreciate it!
"Mi piace""Mi piace"
I want to express appreciation to you for rescuing me from this particular instance. Just after searching throughout the online world and coming across concepts which were not productive, I thought my life was done. Being alive without the approaches to the issues you’ve solved as a result of your good short post is a serious case, as well as the ones that would have in a wrong way affected my career if I hadn’t discovered your blog. Your expertise and kindness in playing with all the pieces was invaluable. I am not sure what I would have done if I hadn’t come upon such a thing like this. It’s possible to at this moment relish my future. Thanks a lot so much for your specialized and amazing help. I will not hesitate to propose your site to any person who requires guidelines on this matter.
"Mi piace""Mi piace"