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 Table of Contents  
Year : 2017  |  Volume : 6  |  Issue : 4  |  Page : 157-160

Landmark trials: Key messages from the European Society of Cardiology 2017 Annual Meeting

Department of Cardiology, Medanta - The Medicity, Gurgaon, Haryana, India

Date of Web Publication27-Oct-2017

Correspondence Address:
Ravi R Kasliwal
Medanta - The Medicity, Sector 38, Gurgaon - 122 001, Haryana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCPC.JCPC_42_17

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How to cite this article:
Mahansaria K, Kasliwal RR. Landmark trials: Key messages from the European Society of Cardiology 2017 Annual Meeting. J Clin Prev Cardiol 2017;6:157-60

How to cite this URL:
Mahansaria K, Kasliwal RR. Landmark trials: Key messages from the European Society of Cardiology 2017 Annual Meeting. J Clin Prev Cardiol [serial online] 2017 [cited 2022 Jan 26];6:157-60. Available from: https://www.jcpconline.org/text.asp?2017/6/4/157/217395

  Anti-inflammatory Therapy with Canakinumab for Atherosclerotic Disease Top

Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. N Engl J Med 2017;377:1119-1131.

  Trial Summary Top

Background: Clinical and laboratory data have proven the additional effect of inflammation and inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP) and interleukin-6 (IL-6) in atherothrombosis and increased risk of cardiovascular events independent of cholesterol levels. Yet, no evidence has shown reduced cardiovascular events through reduction of inflammation in the absence of concomitant lipid lowering. Therefore, the inflammatory hypothesis of atherothrombosis has so far remained unproven. This Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) evaluated the role of IL-1 β inhibition a fully human monoclonal antibody Canakinumab in preventing recurrent vascular events in stable patients with previous myocardial infarction (MI).

Methods: A total of 10,061 patients with a history of MI and a blood level of hs-CRP ≥2 mg/lt. Despite the use of aggressive secondary prevention strategies were randomly assigned in a 1:1:1:1 ratio to receive placebo, Canakinumab 50 mg, Canakinumab 150 mg, or Canakinumab 300 mg administered subcutaneously every 3 months. The primary endpoint was nonfatal MI, nonfatal stroke, or cardiovascular death. Key secondary endpoint was hospitalization for unstable angina that led to urgent revascularization.

Results: At 48 months, the median reduction in hs-CRP from baseline was 26% points greater in 50 mg Canakinumab, 37% points greater in 150 mg Canakinumab, and 41% points greater in 300 mg Cankinumab than in placebo group (P < 0.001 for all groups). Similar results were seen with IL-6 measured up to 12 months. No reduction in low-density lipoprotein (LDL) was seen with Canakinumab compared to baseline. Incidence rate of primary end-point at median follow-up of 3.7 years was 4.5 events per 100 person-years in placebo, 4.11 events per 100 person-years in 50 mg Canakinumab (heart rate (HR) = 0.93, P = 0.30), 3.86 events per 100 person-years in 150 mg Canakinumab (HR = 0.85, P = 0.021), and 3.90 events per 100 person-years in 300 mg Canakinumab (HR = 0.86, P = 0.031) [Figure 1]. The 150 mg Canakinumab group met the criteria for the threshold of adjusted statistical significance for both the primary endpoint and the secondary endpoint of hospitalization due to unstable angina (HR = 0.83, P = 0.005). Rates of fatal infection and sepsis were significantly higher in pooled Canakinumab groups compared to placebo (incidence rate of 0.31 vs. 0.18 in placebo, P = 0.02).
Figure 1: Results of the Canakinumab Anti-inflammatory Thrombosis Outcome Study Trial

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Conclusion: The anti-inflammatory drug Canakinumab at a dose of 150 mg administered every 3 months led to a significantly lower rate of recurrent cardiovascular events compared to placebo independent of lipid lowering.

  Perspective Top

Activation of the proinflammatory cytokine IL-1 β stimulates the downstream IL-6 receptor-signaling pathway that has been implicated in the pathogenesis of atherothrombosis. Canakinumab is a human monoclonal antibody against IL-1 β and is approved for use in systemic juvenile arthritis, and its anti-inflammatory effect is now being evaluated in several conditions where autoimmunity and inflammation play a key role. In the CANTOS Trial, the 150 mg dose group reached statistical significance with regards to lower incidence of both the primary and secondary end-points. The effect of the 300 mg dose group looked similar but did not achieve statistical significance.

In general, all patients in the CANTOS Trial had well-controlled levels of LDL-cholesterol at baseline. In spite of this, rates of both the primary and secondary end-points were higher in the placebo group. The authors' claim that statin-treated patients with residual inflammatory risk (as assessed by hs-CRP levels ≥2 mg/l) have future event rates as high as, if not higher than, statin-treated patients with residual risk due to LDL cholesterol levels, is not ill-founded. Furthermore, IL-1 β inhibition therapy with Canakinumab may represent only one of potential many anti-inflammatory pathways causing atherothrombosis.

However, a better understanding of this form of therapy is needed. For one, a detail of MI (Q-wave vs. non-Q wave and spontaneous vs. procedural.) is needed to better understand the effect of canakinumab. Additional information about the fatal infections encountered is also needed (attributed to neutropenia by the authors). Safety and efficacy in select high-risk populations such as diabetics and elderly needs to be assessed further. Canakinumab has undoubtedly helped move the inflammatory hypothesis of coronary artery disease forward.

  Rivaroxaban With or Without Aspirin in Stable Cardiovascular Disease Top

Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, et al. N Engl J Med 2017; 377:1319-1330.

  Trial Summary Top

Background: Despite effective secondary prevention strategies in patients with established stable atherosclerotic disease, the risk of recurrent events remains in the range of 5%–10%/year. Rivaroxaban is a factor Xa inhibitor that is used to prevent and treat venous thromboembolism and to prevent stroke and systemic embolization in atrial fibrillation (AF). The aim of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial was to test the hypothesis that rivaroxaban in combination with aspirin or alone is more effective than aspirin alone in preventing recurrent cardiovascular events in patients with the stable atherosclerotic vascular disease.

Methods: In this double-blind randomized trial, 27,395 patients with stable atherosclerotic vascular disease across 602 centers in 33 countries were assigned to receive rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg once daily. The primary outcome was a composite of cardiovascular death, stroke, or MI. The International Society on Thrombosis and Hemostasis (ISTH) criteria for major bleeding was modified as the main safety criteria and included all bleeding that led to presentation to an acute care facility or hospitalization.

Results: The study was stopped for the superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months. The primary outcome occurred in 496 patients (5.4%) in the aspirin alone group [Figure 2]. Comparatively, the primary outcome occurred in 379 (4.1%) patients in the rivaroxaban-plus-aspirin group (HR = 0.76, P < 0.001) and 448 (4.9%) patients in rivaroxaban alone group (HR = 0.9, P = 0.12). There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (HR = 0.82, P = 0.01; threshold P for statistical significance = 0.0025). The risk of composite net clinical benefit outcome of cardiovascular death, stroke, MI, fatal bleeding, or symptomatic bleeding into a critical organ was lower with rivaroxaban-plus-aspirin group than with aspirin alone (431 patients [4.7%] vs. 534 patients [5.9%]; HR = 0.80, P < 0.001). The risk of net clinical benefit outcome was not significantly lower in the rivaroxaban alone group. Bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group compared to aspirin alone (288 patients [3.1%] vs. 170 patients [1.9%]; HR = 1.70, P < 0.001). However, there was no significant difference in intracranial or fatal bleeding between these two groups, and the increased rates of bleeding were mainly due to bleeding into the gastrointestinal tract. Major bleeding events including symptomatic bleeding into a critical organ happened more with rivaroxaban alone group than in aspirin alone group (255 patients [2.8%] vs. 170 patients [1.9%]; HR = 1.51, P < 0.001).
Figure 2: Results of the Cardiovascular Outcomes for People Using Anticoagulation Strategies Trial

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Conclusion: Among patients with the stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes but more bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events.

  Perspective Top

The potential benefit of rivaroxaban in patients with cardiovascular disease has been previously evaluated in the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome 2-Thrombolysis in MI 51 ( Atlas More Details ACS 2-TIMI 51) TRIAL. The findings of the present COMPASS trial are consistent with those of the ATLAS ACS 2-TIMI 51 trial.

Various antithrombotic regimens have been tested as alternatives to aspirin for long-term cardiovascular prevention. Vitamin K antagonists (VKAs) reduced subsequent cardiovascular events in patients with stable cardiovascular disease but showed no benefit in patients with peripheral arterial disease and led to increased rates of major bleeding events. Patients who received clopidogrel had lower rates of major cardiovascular events as compared to aspirin, but there was no significant difference in the rates of cardiovascular deaths or death from any cause. Ticagrelor plus aspirin led to reduced major adverse cardiovascular events but no significant difference in mortality when compared to aspirin alone and did not differ in rates of major adverse cardiovascular events when compared to clopidogrel alone. With this in mind, the results of the COMPASS trial bear significance with regards to prevention of recurrent cardiovascular events.

Although the rates of bleeding were higher in the rivaroxaban plus aspirin group, there was no difference in the rates of intracranial bleeding, fatal bleeding, or bleeding into a critical organ between the two groups. The authors also conclude that the definition of major bleeding used in the trial (a modification of the definition of the ISTH) might have overestimated the rates of bleeding compared to other trials as it did not take into consideration whether the bleeding was associated with a decrease in hemoglobin level ≥2 g/dl or with blood transfusion of ≥2 units of whole blood or red cells; and rather included all bleeding events that led to hospitalization or presentation to acute care. Despite this, the authors contend that the net clinical benefit balanced the lower rates of cardiovascular death, stroke, and MI against the most serious bleeding events and showed a significant benefit of combination therapy.

The limitations of the study aside, the results of the COMPASS trial are an important step forward in thrombocardiology.

  Oxygen Therapy in Suspected Acute Myocardial Infarction Top

Hofmann R, James SK, Jernberg T, Lindahl B, Erlinge D, Witt N, et al. N Engl J Med 2017; 377:1240-9.

  Trial Summary Top

Background: Supplemental oxygen therapy has been used for long in patients suspected to have MI with a rationale that it may limit the infarct and further complications. However, there have been no large studies or RCTs to support the use of supplemental oxygen in this population. In fact, reperfusion injuries due to increase in reactive oxygen species and coronary vasoconstriction is a well-known phenomenon in patients with above-normal oxygen levels is blood. Although the benefit of oxygen therapy in patients having an MI with hypoxemia is well established, its advantages in patients who do not have hypoxemia are far less certain. The aim of the determination of the role of oxygen in suspected MI trial (DETO2X-AMI) trial was to evaluate the effect of oxygen therapy on all-cause mortality at 1 year among patients with suspected MI who did not have hypoxemia at baseline.

Methods: A total of 6629 patients with suspected MI across 69 hospitals in Sweden were randomized to either receive supplemental oxygen therapy at 6 l/min for 6–12 h delivered through open face mask, or ambient air. The primary end-point was death from any cause within 365 days after randomization. Secondary endpoint included death from any cause within 30 days after randomization, rehospitalization with MI, rehospitalization with heart failure and cardiovascular death.

Results: Totally, 6243 patients (94.2%) were enrolled because of chest pain and 140 patients (2.1%) because of shortness of breath. The median duration of oxygen therapy was 11.46 h, with a median oxygen saturation of 99% in oxygen group and 97% in ambient air group. Hypoxemia developed in 1.9% of patients in oxygen group as compared to 7.7% in the other group. The final diagnosis was MI in 5010 patients (75.6%) (including 2952 patients [44.5%] with ST-elevation myocardial infarction (STEMI)), angina pectoris in 374 patients (5.6%), other cardiac disease in 511 patients (7.7%), pulmonary disease in 32 patients (0.5%), unspecified chest pain in 492 patients (7.4%), and other noncardiovascular condition in 210 patients (3.2%). The primary end point (death from any cause within 1 year) occurred in 5% of patients in the oxygen cohort as compared to 5.1% of patients assigned to the ambient air cohort (HR = 0.97; P = 0.80). Rehospitalization with MI was done in 3.8% patients in oxygen group compared to 3.3% patients from the ambient air group (HR = 1.13; P = 0.33). No significant difference between the two groups was detected at 30 days with regard to death, rehospitalization with MI or composite of these two endpoints. Data on Cardiac Trop T during hospitalization were available for 79.4% patients with confirmed MI, and it did not differ significantly between the study groups.

Conclusion: In patients with suspected MI who did not have hypoxemia, routine use of supplemental oxygen was not found to reduce 1-year all-cause mortality.

  Perspective Top

The above results are consistent with those of various meta-analyses and with those of the recently published Supplemental Oxygen in Catheterized Coronary Emergency Reperfusion trial in which oxygen was not found to have any effect on infarct size. On the other hand, the Australian Air Versus Oxygen in MI (AVOID) trial reported larger infarct size in patients with STEMI who received oxygen when compared to patients who did not and therefore oxygen was expected to increase mortality.

The DETO2X-AMI trial differed from the AVOID trial in several ways. DETO2X-AMI trial recruited 15 times as many patients as the AVOID trial. The DETO2X-AMI trial had recruited patients with suspected MI whereas the AVOID trail had patients with STEMI. DETO2X-AMI enrolled patients with an oxygen saturation of 90% or higher and administered oxygen at a rate of 6 l/min through an open mask. In contrast, the AVOID Trial enrolled patients with oxygen saturation 94% or more and delivered oxygen at a rate of 8 l/min through a closed mask.

The results of this study have provided definite support to the lack of benefit of supplemental oxygen therapy in patients with acute MI who have normal oxygen saturation.

  Apixaban versus Heparin/Vitamin K Antagonist in Anticoagulation-naive Patients with Atrial Fibrillation Scheduled for Cardioversion Top

Ezekowitz MD, Pollack CV, et al. European Society of Cardiology Congress 2017. Barcelona, Spain; August 28, 2017.

  Trial Summary Top

Background: Nonvalvular AF (NVAF) affects 1 in 4 adults aged more than 60 years. Electrical or pharmacological cardioversion or both together are standard practice for restoring sinus rhythm in selected patients with persistent AF. The goal of anticoagulation in the setting of cardioversion is to prevent stroke and systemic embolism without causing bleeding. Post hoc analyses of cardioversion in the RE-LY, ARISTOTLE, ROCKET-AF, and ENGAGE-AF trials suggest that the non-VKA oral anticoagulants (NOACs) may be a reasonable alternative to heparin and warfarin for patients with NVAF undergoing cardioversion and that event rates are very low. The major limitation of these post hoc analyses, however, is the prolonged period of anticoagulation preceding the cardioversion. The need for more immediate cardioversion frequently arises in patients presenting with newly identified AF. No studies have specifically evaluated a NOAC in a population of patients who are anticoagulation naive and who are undergoing cardioversion. The purpose of the EMANATE trial was to compare the rates of stroke and bleeding with apixaban versus warfarin with heparin in anticoagulation-naive (defined as having received <48 h of anticoagulation therapy) patients scheduled for elective cardioversion of predominately new onset NVAF.

Methods: This is a randomized, active-controlled, open-label study of approximately 1500 patients randomized 1:1 to apixaban or usual care parenteral heparin and/or oral anticoagulation with VKAs goal international normalized ratio 2.0–3.0, excluding other NOACs. Those assigned apixaban received a loading dose of 10 mg unless they were at least 80 years old, weighed <60 kg or had a serum creatinine level <1.5 mg/dl. Patients who met two of the criteria received a loading dose of 5 mg. Anticoagulants were administered for either 30 days after cardioversion or a maximum of 90 days if cardioversion was not performed. Rates of stroke, systemic embolism, death, major bleeding, and clinically relevant nonmajor bleeding were compared between the two groups.

Results: Patients treated with apixaban had fewer strokes and similar bleeding to those receiving usual care. There were no strokes in the 753 patients treated with apixaban compared to six strokes in the 747 receiving usual care (P = 0.01). There were no systemic embolic events in either group. Major bleeds occurred in three and six patients in the apixaban and usual care groups, respectively, while clinically significant nonmajor bleeding occurred in 11 and 13 patients. There were two deaths in the apixaban group and one in the heparin/warfarin group. Out of 753 patients in the apixaban group, 342 received a loading dose. In this subgroup, there were no strokes or systemic embolic events, one death, one major bleed, and four clinically relevant nonmajor bleeds. Imaging identified left atrial appendage thrombi in 61 patients; all continued anticoagulation. There were no outcome events. Among those with repeat imaging (37 ± 11 days after the initial imaging) thrombi resolved in 52% versus 56% in the apixaban and heparin/VKA groups.

Conclusion: In patients with AF undergoing cardioversion, apixaban with or without a loading dose was safe, resulting in few bleeding events and less strokes than conventional anticoagulant therapy.

  Perspective Top

The X-VeRT trial was the first prospective trial of a NOAC in the setting of cardioversion and found rivaroxaban, an oral factor Xa inhibitor, comparable to VKA in patients with NVAF undergoing cardioversion within 5 days or after 3 weeks and up to a maximum of 8 weeks of anticoagulation, once again with very low event rates (0.5% and 0.6% for efficacy and safety for rivaroxaban and 1.0% and 0.8% for usual therapy, both not significantly different). No studies have specifically evaluated a NOAC in a population of patients who are anticoagulation naive and who are undergoing cardioversion.

The authors estimated that for the study to have adequate power they would require 48,000 participants, a number far in excess of practicality. The figure of 1500 patients was considered clinically meaningful and achievable. In that respect, this study is underpowered.

All participants undergoing cardioversion in the ARISTOTLE trial had been chronically anticoagulated before cardioversion, so there was no information on the safety of apixaban in participants newly presenting with AF or in those patients naive to anticoagulation in whom early cardioversion is indicated. The EMANATE trial sheds some light on this information gap. Further research is indeed warranted to fully understand the safety of NOACs.

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Conflicts of interest

There are no conflicts of interest.


  [Figure 1], [Figure 2]


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