Beyond atheroma regression: clinical outcomes and effect size.

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.

glagov

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.

pav-vs-ldl-reduction

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:

slides regressione

oltre le statine

Oltre il colesterolo

Statine nella tempesta

References

  1. 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
  2. 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
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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
  10. 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.
  11. 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.
  12. 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
  13. 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
  14. 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

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