|Year : 2018 | Volume
| Issue : 1 | Page : 3-5
Landmark trials in 2017s
Alok Kumar Singh
Department of Cardiology, Heritage Hospital, Varanasi, Uttar Pradesh, India
|Date of Web Publication||27-Apr-2018|
Alok Kumar Singh
Department of Cardiology, Heritage Hospital, Varanasi, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Singh AK. Landmark trials in 2017s. Heart India 2018;6:3-5
In this series, I will discuss the summary of five studies published in 2017 which will impact the future cardiology practice in significant way.
| Evolocumab and Clinical Outcomes in Patients With Cardiovascular Disease-(Fourier) Study|| |
Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. FOURIER  study was randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease, and LDL cholesterol levels of 70 mg/DL or higher who were on statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end-point was the composite of cardiovascular death. In FOURIER  trial, inhibition of PCSK9 with evolocumab on a background of statin therapy-lowered LDL cholesterol levels to a median of 30 mg/DL (0.78 mmol/L) and reduced the risk of cardiovascular events. The median duration of follow-up was 2.2 years. One very important contribution to cardiology literature by this study is that patients of atherosclerotic cardiovascular disease will benefit from lowering of LDL cholesterol levels till 30 mg/dl, well below current treatment targets.
| Inclisiran in Patients at High Cardiovascular Risk With Elevated Low-Density Lipoprotein Cholesterol-(Orion1) Study|| |
A single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in LDL cholesterol levels over the course of 84 days in healthy adults in earlier studies. In ORION  study, 501 patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end-point was the change from baseline in LDL cholesterol level at 180 days. Patients who received inclisiran had dose-dependent reductions in both PCSK9 and LDL cholesterol levels. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. Hence, investigators of ORION1 have concluded inclisiran reduced significantly both LDL and PCSK 9 levels in patients who are at high cardiovascular risk. Although this trial did not shows any cardiovascular event reduction in my opinion, this is first R.N.A-based treatment showed efficacy in cardiology.
| Effects of Anacetrapib in Patients With Atherosclerotic Vascular Disease (Randomized Evaluation of the Effects of Anacetrapib Through Lipid Modification) Study|| |
The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. Another landmark study of anacetrapib Randomized Evaluation of the Effects of Anacetrapib through Lipid modification (REVEAL) study published in 2017 has shown different result in comparison to the previous CETP inhibitors trials. Authors of this study conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg/DL a mean non-HDL cholesterol level of 92 mg/DL, and a mean HDL cholesterol level of 40 mg/DL. The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction (MI), or coronary revascularization. The dosage of anacetrapib used in this trial was 100 mg over the median follow-up period of 4.1 years; the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (10.8% vs. 11.8%). Authors of this study concluded that, among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. It is highly possible that anacetrapib succeeded where other CETP inhibitors failed because of relative safety (compared with torcetrapib), potency (compared with dalcetrapib), and a study design that included enough statistical power and considerably long duration to uncover the benefit (compared with evacetrapib). In REVEAL, HDL cholesterol was increased by 104%, and LDL cholesterol decreased by 17%. There was a 0.7 mm increase in systolic blood pressure and 0.3 mm in diastolic blood pressure in anacetrapib-treated particpants in REVEAL, similar in magnitude to what was observed with evacetrapib and dalcetrapib, but much less than for torcetrapib.
| Anti-Inflammatory Therapy With Canakinumab for Atherosclerotic Disease (The Canakinumab Anti-Inflammatory Thrombosis Outcome Study) Study|| |
In coronary artery disease (CAD) one landmark study published this year which will certainly fueled the debate of role of anti-inflammatory therapy in CAD. Experimental studies suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease, but it is not established that anti-inflammatory therapy will reduce cardiovascular events. The Canakinumab Anti-Inflammatory Thrombosis Outcome Study (CANTOS) trial was a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous MI and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50, 150, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end-point of the CANTOS trial was nonfatal MI, nonfatal stroke, or cardiovascular death. Conclusion of the study was anti-inflammatory with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. Canakinumab was associated with a higher incidence of fatal infection than was placebo. The overall positive effect was a reduction in the incidence of a recurrent cardiovascular event from 16% in the placebo-treated group to 14% in the 150-mg canakinumab group during the median 3.7-year follow-up. Important to note, this outcome was primarily the result of reduced recurrent MI with no significant change in nonfatal stroke, cardiovascular death, or all-cause mortality. There was no significant difference in all-cause mortality. The latter was because of offsetting effects of reduced cancer mortality but increased fatal infections. In CANTOS, 91% of patients were on statin therapy and the mean LDL cholesterol was relatively well-controlled at 82 mg/dL. However, it is reasonable to think that, if the LDL were much below to the achieved one in CANTOS does the still trial have yielded the same result, it seems questionable?. In my personal opinion, although CANTOS yielded some hope, t as there is no benefit in all-cause mortality so still jury is not out at present.
| Percutaneous Coronary Intervention Strategies in Patients With Acute Myocardial Infarction and Cardiogenic Shock (Culprit-Shock) Study|| |
Approximately, 7%–8% of cases of acute MI are complicated by cardiogenic shock, which is associated with early mortality of 40%–50%. Nearly 20 years ago, the SHOCK (Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) trial established that mortality was lower with emergency revascularization than with initial medical stabilization and selective delayed revascularization in patients with ST-segment elevation MI. In the SHOCK trial, percutaneous coronary intervention (PCI) of the culprit lesion only was the most common therapy for initial revascularization. Although more complete revascularization might have been expected to have an increased benefit, based on which most guidelines recommended complete revascularization in shock patients. In this multicenter trial (CULPRIT-SHOCK ), trialist randomly assigned 706 patients who had multivessel disease, acute MI, and cardiogenic shock to one of two initial revascularization strategies: Either PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, or immediate multivessel PCI. The primary end-point was a composite of death or severe renal failure leading to renal replacement therapy within 30 days after randomization. Safety end-points included bleeding and stroke. After 30 days of event, the composite primary end-point of death or renal replacement therapy had occurred in 158 of the 344 patients (45.9%) in the culprit-lesion-only PCI group and in 189 of the 341 patients (55.4%) in the multivessel PCI group. One of the key findings was that mortality was 43% for culprit-only and 51% for multivessel PCI. The time to hemodynamic stabilization, the risk of catecholamine therapy and the duration of such therapy, the levels of troponin T and creatine kinase, and the rates of bleeding and stroke were similar in both strategies.
| References|| |
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al.
Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, et al.
Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017;376:1430-40.
HPS3/TIMI55–REVEAL Collaborative Group, Bowman L, Hopewell JC, Chen F, Wallendszus K, Stevens W, et al.
Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017;377:1217-27.
Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al.
Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31.
Thiele H, Akin I, Sandri M, Fuernau G, de Waha S, Meyer-Saraei R, et al.
PCI strategies in patients with acute myocardial infarction and cardiogenic shock. N Engl J Med 2017;377:2419-32.