Failure to Launch: Targeting Inflammation in Acute Coronary Syndromes

Abstract

The importance of inflammation and inflammatory pathways in atherosclerotic disease and acute coronary syndromes (ACS) is well established. The success of statin therapy rests not only on potently reducing levels of low-density lipoprotein cholesterol, but also on the many beneficial, pleiotropic effects statin therapy has on various inflammatory mechanisms in atherosclerotic disease, from reducing endothelial dysfunction to attenuating levels of serum C-reactive protein. Due to the growing awareness of the importance of inflammation in ACS, investigators have attempted to develop novel therapies against known markers of inflammation for several decades. Targeted pathways have ranged from inhibiting C5 cleavage with a high-affinity monoclonal antibody against C5 to inhibiting the activation of the p38 mitogen-activated protein kinase signaling cascades. In each of these instances, despite promising early preclinical and mechanistic studies and phase 2 trials suggesting a potential benefit in reducing post-MI complications or restenosis, these novel therapies have failed to show benefits during large, phase 3 clinical outcomes trials. This review discusses several examples of novel anti-inflammatory therapies that failed to show significant improvement on clinical outcomes when tested in large, randomized trials and highlights potential explanations for why targeted therapies against known markers of inflammation in ACS have failed to launch.

Keywords: ACS, acute coronary syndromes; CABG, coronary artery bypass graft; CAD, coronary artery disease; HDL-C, high-density lipoprotein cholesterol; IL, interleukin; LDL-C, low-density lipoprotein cholesterol; Lp-PLA2, lipoprotein-associated phospholipase A2; MAPK, mitogen-activated protein kinase; MI, myocardial infarction; NSTEMI, non–ST-segment myocardial infarction; PCI, percutaneous coronary intervention; PSGL, P-selectin glycoprotein ligand; STEMI, ST-segment elevation myocardial infarction; SVG, saphenous vein grafts; TBR, tissue-to-background ratio; acute coronary syndrome; anti-inflammatory; drug targets; hsCRP, high-sensitivity C-reactive protein; sPLA2, secretory phospholipase A2.

Graphical abstract

Central Illustration

Mechanisms of Anti-Inflammatory Agents in ACS ACS = acute coronary syndromes; IL = interleukin; Lp-PLA₂ = lipoprotein-associated phospholipase A₂; MAPK = mitogen-activated protein kinase; PSGL-1 = P-selectin glycoprotein ligand-1; sPLA2 = secretory phospholipase A2; TNF = tumor necrosis factor.

Figure 1

6-Month Kaplan-Meier Curves for Mortality by Randomized Treatment Assignment (COMMA, Phase 2) COMMA = COMplement inhibition in Myocardial infarction treated with Angioplasty.

Figure 2

30-Day Mortality and Composite of Death, Shock, or CHF by Treatment With Pexelizumab Versus Placebo (APEX-AMI, Phase 3) (A) 30-day mortality; (B) composite of death, shock, or CHF. APEX AMI = Assessment of Pexelizumab in Acute Myocardial Infarction; CHF = congestive heart failure; CI = confidence interval; HR = hazard ratio.

Figure 3

Kaplan-Meier Survival Curves for the Primary Composite Outcome in Patients Treated With Placebo Versus Varespladib (VISTA-16, Phase 3) VISTA-16 = Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 weeks; other abbreviations as in Figure 2.

Figure 4

Cumulative Incidence Curves for CHD Death, MI, or Urgent Coronary Revascularization for Myocardial Ischemia for Treatment With Darapladib Versus Placebo (SOLID-TIMI 52, Phase 3) CHD = coronary heart disease; MI = myocardial infarction; SOLID-TIMI 52 = Stabilization of pLaques usIng Darapladib-Thrombolysis In Myocardial Infarction 52; other abbreviations as in Figure 2.

Figure 5

Cumulative Incidence Curves for Cardiovascular Death, MI, or Severe Recurrent Ischemia Leading to Urgent Revascularization Through 12 Weeks With Losmapimod Versus Placebo (LATITUDE-TIMI 60, Phase 3) CI = confidence interval; LATITUDE-TIMI 60 = Losmapimod to Inhibit p38 MAP Kinase as a Therapeutic Target and Modify Outcomes After an Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 60; MI = myocardial infarction.

Figure 6

Potential Reasons for Surrogate Endpoint Failure (A) The surrogate endpoint is not in the causal pathway of the disease state. (B) There are several causal pathways of the disease state, but the intervention only impacts the pathway mediated by the surrogate endpoint. (C) There are several causal pathways of the disease state, but the pathway mediated by the surrogate endpoint is not impacted by the intervention. (D) The intervention acts on a pathway separate from the disease process.