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Therapeutic strategies for atherosclerosis and atherothrombosis: Past, present and future
27 October 2016
Accepted after minor revision: 10 June 2016
11 November 2017 (online)
Even two centuries after they were first described, atherosclerosis and atherothrombosis remain among the leading causes of death worldwide. Over the last decades it has become clear that atherosclerosis is not only a lipid-driven disease but also a multifactorial process largely driven by inflammatory mediators, an insight that has instigated additional research and drug development focussing on anti-inflammatory therapies. In this review, we will provide a brief historical overview, followed by a more general synopsis of the range of currently available state-of-the-art therapies for atherosclerosis and atherothrombosis. Finally, we will highlight some of the promising therapeutic strategies that are currently under intense investigation. We believe that the next years will witness highly interesting developments and clinical trials investigating yet more novel therapies, and at the same time looking into potential combinations of all available therapies. This prospect closes in on the ultimate goal, which is to reduce the residual risk that still persists despite present therapeutic options.
- 1 Leibowitz JO. The History of Coronary Heart Disease. Berkeley: University of California Press; 1970
- 2 Go AS. et al. Heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation 2014; 129: e28-e292.
- 3 Zarins CK. et al. Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress. Circulation research 1983; 53: 502-514.
- 4 Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arteriosclerosis, thrombosis, and vascular biology 1995; 15 (05) 551-61.
- 5 Vogel J. The Pathological Anatomy of the Human Body. London: H Baillere; 1847
- 6 Linden F. et al. Inflammatory therapeutic targets in coronary atherosclerosis-from molecular biology to clinical application. Frontiers in physiology 2014; 5: 455.
- 7 Morrison LM. Reduction of mortality rate in coronary atherosclerosis by a low cholesterol-low fat diet. Am Heart J 1951; 42: 538-545.
- 8 Pedersen TR. The Success Story of LDL Cholesterol Lowering. Circulation Res 2016; 118: 721-731.
- 9 Group HTC. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013; 34: 1279-1291.
- 10 Investigators A-H. et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. New Engl J Med 2011; 365: 2255-2267.
- 11 Taylor AJ. et al. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. Curr Med Res Opin 2006; 22: 2243-2250.
- 12 Taylor AJ. et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004; 110: 3512-3517.
- 13 Taylor AJ. et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. New Engl J Med 2009; 361: 2113-2122.
- 14 Siperstein MD, Guest MJ. Studies on the site of the feedback control of cholesterol synthesis. J Clin Invest 1960; 39: 642-652.
- 15 Hansson GK. Immune and inflammatory mechanisms in the development of atherosclerosis. Br Heart J 1993; 69 (Suppl. 01) S38-S41.
- 16 Okopien B. et al. Current and future trends in the lipid lowering therapy. Pharmacological reports : PR 2016; 68: 737-747.
- 17 Boekholdt SM, Hovingh GK, Mora S. et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol 2014; 64: 485-494.
- 18 Preiss D. et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. J Am Med Assoc 2011; 305: 2556-2564.
- 19 Cannon CP. et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. New Engl J Med 2015; 372: 2387-2397.
- 20 Chang TY, Chang C. Ezetimibe blocks internalization of the NPC1L1/cholesterol complex. Cell Metabol 2008; 7: 469-471.
- 21 Cohen J. et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nature Genet 2005; 37: 161-165.
- 22 Robinson JG. et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. New Engl J Med 2015; 372: 1489-1499.
- 23 Stone NJ, Lloyd-Jones DM. Lowering LDL cholesterol is good, but how and in whom?. New Engl J Med 2015; 372: 1564-1565.
- 24 Zhang XL. et al. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med 2015; 13: 123.
- 25 Ridker PM. et al. Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: Rationale and design of the Studies of PCSK9 Inhibition and the Reduction of vascular Events (SPIRE) Lipid Lowering and SPIRE Cardiovascular Outcomes Trials. Am Heart J 2016; 178: 135-144.
- 26 Schwartz GG. et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 2014; 168: 682-689.
- 27 Nicholls SJ. et al. Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial. J Am Med Assoc 2016 ; Epub ahead of print.
- 28 Cuchel M. et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet 2013; 381: 40-46.
- 29 Roeters van Lennep J. et al. Treating homozygous familial hypercholesterolemia in a real-world setting: Experiences with lomitapide. J Clin Lipidol 2015; 9: 607-617.
- 30 Aggarwal D. et al. JTT-130, a microsomal triglyceride transfer protein (MTP) inhibitor lowers plasma triglycerides and LDL cholesterol concentrations without increasing hepatic triglycerides in guinea pigs. BMC Cardiovasc Disord 2005; 5: 30.
- 31 Kim E. et al. A small-molecule inhibitor of enterocytic microsomal triglyceride transfer protein, SLx-4090: biochemical, pharmacodynamic, pharmacokinetic, and safety profile. J Pharmacol Exp Therap 2011; 337: 775-785.
- 32 Visser ME. et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur Heart J 2012; 33: 1142-1149.
- 33 McGowan MP. et al. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PloS one 2012; 7: e49006.
- 34 Wang A. et al. Systematic Review of Low-Density Lipoprotein Cholesterol Apheresis for the Treatment of Familial Hypercholesterolemia. J Am Heart Assoc 2016 ; Epub ahead of print.
- 35 Kingwell BA. et al. HDL-targeted therapies: progress, failures and future. Nature Rev Drug Discov 2014; 13: 445-464.
- 36 Barter PJ. et al. Effects of torcetrapib in patients at high risk for coronary events. New Engl J Med 2007; 357: 2109-2122.
- 37 Kastelein JJ. et al. Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet 2015; 385: 2153-2161.
- 38 Schwartz GG. et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. New Engl J Med 2012; 367: 2089-2099.
- 39 Lp PLASC, Thompson A, Gao P. et al. Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet 2010; 375: 1536-1544.
- 40 Investigators S, White HD, Held C. et al. Darapladib for preventing ischemic events in stable coronary heart disease. New Engl J Med 2014; 370: 1702-1711.
- 41 O’Donoghue ML. et al. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. J Am Med Assoc 2014; 312: 1006-1015.
- 42 Nicholls SJ, Kastelein JJ, Schwartz GG. et al. Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial. J Am Med Assoc 2014; 311: 252-262.
- 43 Stachon P. et al. Dual pathway therapy in acute coronary syndrome. J Thromb Thrombol 2016; 42: 254-260.
- 44 Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. Br Med J 1994; 308: 81-106.
- 45 Depta JP, Bhatt DL. New approaches to inhibiting platelets and coagulation. Annu Rev Pharmacol Toxicol 2015; 55: 373-397.
- 46 Yusuf S. et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. New Engl J Med 2001; 345: 494-502.
- 47 Schomig A. Ticagrelor--is there need for a new player in the antiplatelet-therapy field?. New Engl J Med 2009; 361: 1108-1111.
- 48 Jakubowski JA. et al. Prasugrel: a novel thienopyridine antiplatelet agent. A review of preclinical and clinical studies and the mechanistic basis for its distinct antiplatelet profile. Cardiovasc Drug Rev 2007; 25: 357-374.
- 49 Wiviott SD. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. New Engl J Med 2007; 357: 2001-2015.
- 50 Gurbel PA. et al. Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study. Circulation 2009; 120: 2577-2585.
- 51 Wallentin L. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. New Engl J Med 2009; 361: 1045-1057.
- 52 Bonaca MP. et al. Long-term use of ticagrelor in patients with prior myocardial infarction. New Engl J Med 2015; 372: 1791-1800.
- 53 Ferreiro JL. et al. Cangrelor: a review on its mechanism of action and clinical development. Expert Rev Cardiovasc Ther 2009; 7: 1195-1201.
- 54 Bhatt DL. et al. Intravenous platelet blockade with cangrelor during PCI. New Engl J Med 2009; 361: 2330-2341.
- 55 Harrington RA. et al. Platelet inhibition with cangrelor in patients undergoing PCI. New Engl J Med 2009; 361: 2318-2329.
- 56 Bhatt DL. et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. New Engl J Med 2013; 368: 1303-1313.
- 57 Becker RC. et al. Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet 2009; 373: 919-928.
- 58 Goto S. et al. Safety and exploratory efficacy of the novel thrombin receptor (PAR-1) antagonist SCH530348 for non-ST-segment elevation acute coronary syndrome. J Atheroscl Thromb 2010; 17: 156-164.
- 59 Tricoci P. et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. New Engl J Med 2012; 366: 20-33.
- 60 Morrow DA. et al. Vorapaxar in the secondary prevention of atherothrombotic events. New Engl J Med 2012; 366: 1404-1413.
- 61 Tsipis A. et al. Novel oral anticoagulants in peripheral arterial and coronary artery disease. Cardiovasc Hematol Agents Med Chem 2014; 12: 21-25.
- 62 Oldgren J. et al. New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. Eur Heart J 2013; 34: 1670-1680.
- 63 Wallentin L. et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 2003; 362: 789-797.
- 64 Ahrens I. et al. Anticoagulation during and after acute coronary syndrome. Hamostaseol 2014; 34: 72-77.
- 65 Alexander JH. et al. Apixaban with antiplatelet therapy after acute coronary syndrome. New Engl J Med 2011; 365: 699-708.
- 66 Cannon CP. et al. Intensive lipid lowering with atorvastatin in coronary disease. New Engl J Med 2005; 353: 93-96.
- 67 van der Vorst EP. et al. A disintegrin and metalloproteases: molecular scissors in angiogenesis, inflammation and atherosclerosis. Atherosclerosis 2012; 224: 302-308.
- 68 van der Vorst EP. et al. Myeloid A disintegrin and metalloproteinase domain 10 deficiency modulates atherosclerotic plaque composition by shifting the balance from inflammation toward fibrosis. Am J Pathol 2015; 185: 1145-1155.
- 69 Gaudet D. et al. Targeting APOC3 in the familial chylomicronemia syndrome. New Engl J Med 2014; 371: 2200-2206.
- 70 Nicholls SJ. et al. Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial. J Am Coll Cardiol 2011; 57: 1111-1119.
- 71 Tardif JC. et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. J Am Med Assoc 2007; 297: 1675-1682.
- 72 Nissen SE. et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. J Am Med Assoc 2003; 290: 2292-2300.
- 73 Tardif JC. et al. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial. Eur Heart J 2014; 35: 3277-3286.
- 74 Tricoci P. et al. Infusion of Reconstituted High-Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial. J Am Heart Assoc 2015; 4: e002171.
- 75 Ridker PM, Luscher TF. Anti-inflammatory therapies for cardiovascular disease. Eur Heart J 2014; 35: 1782-1791.
- 76 Strowig T. et al. Inflammasomes in health and disease. Nature 2012; 481: 278-286.
- 77 Ridker PM. et al. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J 2011; 162: 597-605.
- 78 Ridker PM. et al. Effects of interleukin-1beta inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial. Circulation 2012; 126: 2739-2748.
- 79 Scialla JJ. et al. Soluble P-selectin levels are associated with cardiovascular mortality and sudden cardiac death in male dialysis patients. Am J Nephrol 2011; 33: 224-230.
- 80 Tardif JC. et al. Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention for non-ST-segment elevation myocardial infarction: results of the SELECT-ACS trial. J Am Coll Cardiol 2013; 61: 2048-2055.
- 81 Stahli BE. et al. Effects of P-Selectin Antagonist Inclacumab in Patients Undergoing Coronary Artery Bypass Graft Surgery: SELECT-CABG Trial. J Am Coll Cardiol 2016; 67: 344-346.