Pathophysiology of atherosclerosis
Vascular modification | Characteristics |
---|---|
Intimal thickening | Layers of SMCs and extracellular matrix More frequent in coronary artery, carotid artery, abdominal aorta, descending aorta, and iliac artery |
Fatty streak | Abundant macrophage foam cells mixed with SMCs and proteoglycan-rich intima |
Pathologic intimal thickening | Layers of SMCs in proteoglycan-collagen matrix aggregated near the lumen Underlying lipid pool: acellular area rich in hyaluronan and proteoglycans with lipid infiltrates |
Fibroatheromas | Acellular necrotic core (cellular debris) Necrotic core is covered by a thick fibrous cap: SMCs in proteoglycan-collagen matrix |
Vulnerable plaque | ‘Thin-cap fibroatheroma’ Type I collagen, very few/absent SMCs Fibrous cap thickness is ≤65 µm |
Ruptured plaque | Ruptured fibrous cap Presence of luminal thrombus Larger necrotic core and increased macrophage infiltration of the thin fibrous cap |
Lipoprotein modification treatment
Current view
LDL-C-lowering therapy
Drug/Target | Clinical trial | Study size | Duration | CV endpoints | Results |
---|---|---|---|---|---|
Statins | 4 S [44] | 4444 patients with CHD | 5.4 y | Coronary death | 111 in the simvastatin group; 189 in the placebo group; (RR = 0.58, 95% CI: 0.46–0.73) |
WOSCOP [45] | 6595 men with hypercholesterolemia | 4.9 y | Combined nonfatal MI/coronary death | 174 in the pravastatin group; 248 in the placebo group; (RRR = 31%, 95% CI: 17–43%) | |
CARE [46] | 4159 subjects with high CV risk and normal LDL-C levels | 4.9 y | Combined coronary event/nonfatal MI | 10.2% in the pravastatin group; 13.2% in the placebo group; (RRR = 24%, 95% CI: 9–36%) | |
ASTEROID [47] | 349 patients on statin therapy with serial IVUS examinations | 2.0 y | IVUS change in PAV | −0.79% (−1.21 to −0.53%) in the rosuvastatin group | |
SATURN trial [48] | 1039 patients with CAD on intensive statin treatment | 2.0 y | IVUS change in PAV | −0.99% (−1.19 to −0.63%) in the atorvastatin group; −1.22% (−1.52 to −0.90%) in the pravastatin group | |
REGRESS [9] | 885 symptomatic male patients on pravastatin or placebo | 2.0 y | Change in lumen diameter | 0.10 mm decrease in the placebo group; 0.06 mm decrease in the pravastatin group (p = 0.019) | |
PROVE-IT TIMI 22 [10] | 4162 ACS patients on either intensive or standard statin therapy | 2.0 y | Combined death, MI, UAP, revascularization, stroke | 22.4% in intensive therapy group; 26.3% in standard statin therapy group; (HR 0.84, 95% CI: 0.74–0.95) | |
Ezetimibe | PRECISE-IVUS [14] | 246 patients undergoing PCI on statin alone or statin + ezetimibe | 9.9 m | IVUS change in PAV | −1.4% (−3.4 to −0.1%) in the dual lipid lowering group; −0.3% (−1.9 to 0.9%) in the statin monotherapy group |
IMPROVE-IT [15] | 18,114 ACS patients on statin + placebo or on statin + ezetimibe | 6.0 y | Combined death, MI, UAP, revascularization, stroke | 32.7% in simvastatin + ezetimibe group; 34.7% in the simvastatin + placebo group; (HR 0.94, 95% CI: 0.89–0.99) | |
Bile acid sequestrants | LRC-CPP [49] | 3806 men with hypercholesterolemia on cholestyramine resin or placebo | 7.4 y | Combined CAD death/nonfatal acute MI | 8.1% in cholestyramine group; 9.8% in the placebo group; (RR 0.81, 90% CI: 0.68–0.84) |
PCSK-9 inhibitors | OSLER [16] | 4465 patients on evolocumab + standard therapy or standard therapy alone | 11.1 m | %change LDL-C, cardiovascular events | −61% (−59 to −63%) LDL-C change in the evolocumab group, 0.95% event-rate in the evolocumab group; 2.18% in the standard therapy group; (HR 0.47, 95% CI 0.28–0.78) |
ODYSSEY LONG TERM [17] | 2341 high risk patients receiving in a 2:1 ratio alirocumab or placebo | 78 w | %change in LDL-C, combined death, MI, UAP, revascularization, stroke | −61% LDL-C change in the alirocumab group; 0.8% in the placebo group; (p < 0.001). 1.7% event-rate in the alirocumab group; 3.3% in the placebo group; (HR 0.52, 95% CI: 0.31–0.90) | |
GLAGOV [18] | 968 presenting for CAG randomized with either evolocumab or placebo | 76 w | IVUS change in PAV | −1.0% (−1.8 to −0.64%) in the evolocumab group |
Clinical trial | Mechanism of action | Molecules | Population | Phase | Endpoint | Expected/known results |
---|---|---|---|---|---|---|
ODYSSEY OUTCOME [19] | PCSK-9 antibodies | Alirocumab | 18,000 post ACS patients | 3 | Combined CAD death/nonfatal acute MI | 2017/2018 |
FOURIER [20] | PCSK-9 antibodies | Evolocumab | 27,564 high risk patients with LDL-C > 1.8 mmol/L | 3 | Combined CAD, death/nonfatal acute MI | Early 2017 |
SPIRE 1 + 2 [21] | PCSK-9 antibodies | Bococizumab | 28,000 patients on high residual risk | 3 | Combined death, MI, UAP, revascularization, stroke | Terminated due to the emerging clinical profile |
ORION [34] | siRNA against PCSK-9 | Inclisiran | 480 patients with ASCVD or ASCVD-risk equivalents | 2 | Change in LDL-C from baseline to Day 180 | −51% |
TG-lowering therapy
HDL-C increasing therapy
Future perspectives
LDL-C-lowering therapy
Other lipoprotein modification targets
Target | Clinical trial | Mechanism of action | Molecules | Population | Phase | Endpoint | Results/expected results |
---|---|---|---|---|---|---|---|
LDL-C | CLEAR Harmony [36] | ACL-inhibitor | Bempedoic acid | 1950 high CV risk patients | 3 | Safety, tolerability | 2018 |
MBX-8025 [37] | Selective PPARδ | MBX-8025 | 13 patients with HoFH | 2 | Effect on LDL-C | Full results – early 2017 | |
HDL-C | REVEAL [31] | CETP inhibitors | Anacetrapib | 30,624 patients with a history of MI stroke or PAD | 3 | Major coronary events (defined as coronary death, MI or coronary revascularisation) | Early 2017 |
MILANO-PILOT [38] | Apo A‑I mimetics | MDCO-216 | 120 ACS patients | 2 | Change in PAV | No significant effect | |
CARAT [39] | Apo A‑I mimetics | CER-001 | 301 ACS patients | 2 | Change in PAV | Early 2017 | |
AEGIS [40] | Apo A‑I mimetics | CSL-112 | 1258 ACS patients | 2b | Safety, tolerability, PK | Well tolerated and safe | |
Triglycerides | IONIS ANGPTL3-LRx [41] | Inhibition of LPL activity | IONIS ANGPTL3-LRx | 61 healthy volunteers | 1–2 | Safety, tolerability, PK/PD | June 2017 |
L(p) a | IONIS-APO(a)-Rx [43] | Antisense oligonucleotide targeting hepatic apo(a) mRNA | IONIS-APO(a)-LRx | 64 participants with high Lp(a) levels | 2 | %change in Lp(a) | −71.6% |
IONIS-APO(a)-LRx [43] | Ligand-conjugated antisense oligonucleotide | IONIS-APO(a)-LRx | 58 healthy volunteers | 1/2 | %change in fasting Lp(a) | −92% |