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Year : 2017  |  Volume : 6  |  Issue : 3  |  Page : 122-124

Key messages from the american college of cardiology 2017 meeting

Department of Non-invasive Cardiology, Max Super Speciality Hospital, Saket, New Delhi, India

Date of Web Publication4-Jul-2017

Correspondence Address:
Rahul Mehrotra
Max SuperSpeciality Hospital, 2, Press Enclave Road, East Block, Saket, New Delhi - 110 017
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JCPC.JCPC_21_17

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How to cite this article:
Mehrotra R, Bhat SH. Key messages from the american college of cardiology 2017 meeting. J Clin Prev Cardiol 2017;6:122-4

How to cite this URL:
Mehrotra R, Bhat SH. Key messages from the american college of cardiology 2017 meeting. J Clin Prev Cardiol [serial online] 2017 [cited 2023 Mar 24];6:122-4. Available from: https://www.jcpconline.org/text.asp?2017/6/3/122/209380

  Cardiovascular Efficacy And Safety Of Bococizumab In High-Risk Patients Top

Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al. For the SPIRE cardiovascular outcome investigators. N Engl J Med 2017;376:1527-39.

  Trial Summary Top

Background: This trial sought to evaluate the efficacy of bococizumab in patients at high cardiovascular (CV) risk. Bococizumab is a humanized monoclonal antibody (unlike evolocumab and alirocumab) that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol.

Methods: With different entry criteria for LDL cholesterol levels, 27,438 patients were randomly assigned to receive bococizumab (150 mg dose every 2 weeks vs. placebo) in two concurrent, multinational trials. 16,817 patients were enrolled in SPIRE-1 (low-risk group) while 10,621 patients were enrolled in SPIRE-2 (high risk) group trial. The primary end point was nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or CV death. The trials were prematurely stopped owing in part to the development of high rates of antidrug antibodies. The median follow-up was 10 months.

Results: The results were divided into two categories. In the high-risk group SPIRE-2 (patients had a baseline LDL cholesterol level of ≥100 mg/dl and the median follow-up was 12 months), major CV events occurred in 179 and 224 patients in the bococizumab group and the placebo group, respectively (hazard ratio, 0.79; 95% confidence interval (CI), 0.65–0.97; P= 0.02). In the low-risk SPIRE-1, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg/dl and the median follow-up was 7 months), major CV events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95%, CI, 0.80–1.22; P= 0.94). The absolute risk of a primary end point event was lower in SPIRE-1 than in SPIRE-2 (3.02 vs. 4.19 events per 100 person-years). In the SPIRE lipid-lowering program, antidrug antibodies developed in nearly half the patients who received bococizumab and neutralizing antibodies developed in 29%, which in some affected patients substantially attenuated LDL-cholesterol lowering over time. Injection site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P< 0.001).

Conclusions: Bococizumab was found to have significant benefit with respect to major CV events in the SPIRE-2 trial involving high-risk group (baseline LDL ≥100 mg/dl) while no benefit was seen in the low-risk arm SPIRE-1 (baseline LDL ≥70 mg/dl).

  Perspective Top

Monoclonal antibodies that inhibit PCSK(lower the levels of plasma LDL by around 60%.LDL lowering is linearly associated with overall CV risk reduction. PCSK9 inhibitors are thus promising agents for reducing cardiovascular disease risk. Patients who have received the fully human monoclonal antibodies evolocumab and alirocumab, for example, have had reductions in CV events in preliminary analyses. Bococizumab is a third inhibitor of PCSK9 that, unlike evolocumab and alirocumab, is a humanized monoclonal antibody in which approximately 3% of the murine sequence remains in the antigen-binding complementarity-determining region. Although bococizumab lowered LDL cholesterol, the effect was attenuated over time, and thus, no significant effect was seen on the primary end point in combined analysis of both trials. The patients in SPIRE-2 were at a higher risk and were treated for a longer duration (median of 12 months) as compared to SPIRE-1 (lower risk patients treated for a median of 7 months). The SPIRE-2 trial did show significant benefit in terms of CV event reduction. In both trials, however, up to 50% patients developed antidrug antibodies and up to 30% developed neutralizing antibodies, an effect due to the fact that it was not a fully human monoclonal antibody. The useful takeaway from this trial was the observations that there was no significant increase in adverse effects, including the development of cataract and diabetes. Injection site reactions were the only side effects, more common in the drug arm. This establishes the safety of this approach along with LDL cholesterol-lowering efficacy.

  Evolocumab and Clinical Outcomes in Patients With Cardiovascular Disease Top

Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. On behalf of the FOURIER Steering Committee and Investigators. N Engl J Med 2017;376:1713-22.

  Trial Summary Top

Background: Evolocumab is a monoclonal antibody which lowers LDL cholesterol by inhibiting PCSK9. It lowers LDL cholesterol by up to 60% but whether it prevents CV events is uncertain.

Methods: In this randomized double-blind placebo-controlled trial, 27,562 patients from over 1200 sites in 49 countries were included in the study. The patients who were between 40 and 85 years old and were diagnosed with clinical atherosclerotic CV disease were included in the study. All the patients were on optimal statin therapy (high-intensity statin or at least an equivalent of 20 mg atorvastatin, with or without ezetimibe) with LDL cholesterol of at least 70 mg/d or nonhigh-density lipoprotein (HDL) cholesterol of at least 100 mg/dl. The patients were randomized in 1:1 ratio to receive subcutaneous evolocumab (140 mg every 2 weeks or 420 mg monthly according to the patients' preference) or placebo subcutaneous injections. The primary efficacy end point was a composite of CV death, MI, stroke, myocardial revascularization, or hospitalization for unstable angina. The key secondary efficacy end point was a composite of CV mortality, stroke, and MI. Safety was assessed based on the data collected on adverse events and on the basis of results of the tests conducted at the central laboratory. The patients were followed up for a median duration of 2.2 years.

Results: The patients were evenly distributed among the two groups for all the baseline characteristics. The mean age was 63 years and around 25% patients were women. Around 81% patients had a history of MI, 19% had a history of nonhemorrhagic stroke, and 13% suffered from symptomatic peripheral artery disease. Around 70% patients were on high-intensity statin therapy, while 30% were on moderate-intensity statin therapy with 5% patients also taking ezetimibe at baseline. Only around 10% patients had their regimen changed during the study period. The median LDL at baseline was 92 mg/dl. At the end of 1 year (48 weeks), there was 59% least squares mean percentage reduction in LDL cholesterol in the evolocumab arm compared with placebo arm (P < 0.001), with a mean absolute reduction of 56 mg/dl. This reduction in LDL cholesterol was maintained over time. In 87% of patients, the LDL cholesterol value was at or below 70 mg/dl and in 67%, at or below 40 mg/dl in the evolocumab arm as compared to 18% and 0.5%, respectively, in the placebo arm. At 48 weeks, evolocumab also lowered other atherogenic lipid parameters (non-HDL cholesterol and apolipoprotein-B) significantly more than the placebo. Evolocumab also significantly reduced the primary efficacy end point (9.8% vs. 11.3%; hazard ratio 0.85; 95% CI, 079–0.92; P< 0.001) and the key secondary efficacy end point of CV death, MI, and stroke (5.9% vs. 7.4% in the placebo; 95% CI, 0.73–0.88; P< 0.001). Importantly, the magnitude of risk reduction tended to increase over time. There was reduction in MI, stroke, and myocardial revascularization but no observable effect on other outcomes. The beneficial effects of evolocumab were consistent across subgroups, with baseline LDL levels, intensity of statin use, and with both dose regimens. In terms of adverse effects, there was no significant difference in the evolocumab and placebo arm except for the higher occurrence of injection site reaction with evolocumab (2.1% vs. 1.6%) which were rare.

Conclusions: In this study, inhibition of PCSK9 with evolocumab in patients with clinical atherosclerotic disease with statin therapy resulted in median LDL cholesterol reduction to 30 mg/dl and also translated in reduced CV events.

  Perspective Top

The benefits of LDL reduction for CV risk reduction are well known. It has been proven consistently the extent of CV risk reduction with LDL lowering is linear but is seen after the sometime of LDL reduction. Statin therapy has thus become the standard of care for CV risk reduction for primary as well as secondary prevention. Elegant trials have consistently helped give us newer targets up to which LDL cholesterol could be safely lowered for maximal benefit. The current recommendations of targets of 70 mg/dl or less are based on the results of the Pravastatin or Atorvastatin Evaluation and Infection Therapy, Thrombolysis in Myocardial Infarction 22, and Treating to New Targets studies where LDL cholesterol was lowered to 70 mg/dl with the use of more intensive statin therapy. The use of ezetimibe in addition to statin in the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial study further lowered this target to 54 mg/dl from 70 mg/dl with further improvements in CV outcomes. The use of evolocumab, a PCSK9 inhibitor given subcutaneously, reduced the LDL cholesterol to a median of 30 mg/dl in the background of mostly intensive statin therapy, resulted in 15% reduction the risk of the composite end point of CV death, MI, stroke, myocardial revascularization, or unstable angina. Further, it resulted in a 20% reduction in the risk of the more serious, key secondary end point a composite of CV death, MI, or stroke. This achievement occurred in all subgroups, irrespective of the use of ezetimibe or intensity of statin therapy in the background, and was sustained, after a median follow-up of 26 months. The most remarkable part is that there was no increase in any kind of adverse event (including the mush debated, diabetes, and neurocognitive effects) except for an increased incidence of injection site reaction – which did not translate in increased discontinuation of the study drug. There was no evidence of formation of neutralizing antibodies, unlike what was seen with bococizumab (a humanized antibody).

The results of this dedicated CV outcomes trial have come as a shot in the arm for the “Lower is better” concept of LDL cholesterol lowering for further improvements in CV outcomes. Further, the use of fortnightly or monthly injections is going to be a paradigm shift in terms of treatment strategies. A longer duration study perhaps would have been much more informative as most statin trials have been of 4–5 years' duration.

  Fractional Flow Reserve-Guided Multivessel Angioplasty in Myocardial Infarction Top

Smits PC, Wahab MA, Neuman FJ, Boxma de-klerk BM, Lunde K, Schotborgh CE, et al. For the compare-acute investigators. N Engl J Med 2017;376:1234-44.

  Trial Summary Top

Background: The benefits of primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI) are proven beyond doubt. However, the use of PCI in noninfarct-related arteries in the setting of STEMI in multivessel disease has been a subject of debate.

Methods: In this study, 885 patients from 18 to 85 years of age, from centers in Europe and Asia, with STEMI, presenting within 12 h of symptom onset, where primary PCI was indicated and were having multivessel disease, were included in the study. The patients were divided into two groups – 295 patients underwent complete revascularization of noninfarct-related coronary arteries guided by fractional flow reserve (FFR) while in 590 patients, noninfarct-related coronary arteries were not addressed. The primary end point was a composite of death from any cause, nonfatal MI, revascularization, and cerebrovascular events at 12 months.

Results: The primary outcome occurred in 23 patients in the complete-revascularization group and in 121 patients in the infarct-artery-only group that did not receive complete revascularization, a finding that translates to 8 and 21 events per 100 patients, respectively (hazard ratio, 0.35; 95% CI, 0.22–0.55; P< 0.001). Death occurred in four patients in the complete-revascularization group and in ten patients in the infarct-artery-only group (1.4% vs. 1.7%) (hazard ratio, 0.80; 95% CI, 0.25–2.56), MI in 7 and 28 patients (2.4% vs. 4.7%) (hazard ratio, 0.50; 95% CI, 0.22–1.13), revascularization in 18 and 103 patients (6.1% vs. 17.5%) (hazard ratio, 0.32; 95% CI, 0.20–0.54), and cerebrovascular events in 0 and 4 patients (0 vs. 0.7%). An FFR-related serious adverse event occurred in two patients (both in the group receiving infarct-related treatment only).

Conclusions: In patients with STEMI and multivessel disease who underwent primary PCI of an infarct-related artery, the addition of FFR-guided complete revascularization of noninfarct-related arteries in the acute setting resulted in a risk of a composite CV outcome that was lower than the risk among those who were treated for the infarct-related artery only. This finding was mainly supported by a reduction in subsequent revascularizations.

  Perspective Top

Percutaneous coronary intervention with stent implantation is the treatment of choice for the patients of STEMI. The standard approach has been to address only the infarct-related artery and leave the other lesions alone. Given that almost 50% patients have severely stenotic lesions in non-infarct-related arteries, merited an answer to the question whether these lesions should be addressed in the acute setting itself. There had been nonrandomized trials and trials based on visual assessment of lesion severity, but this issue had not been addressed using FFR as the basis of selecting functionally significant lesions. This randomized trial has demonstrated that addressing all the functionally significant lesions at the time of primary PCI results in a lower rate the composite end point of death from any cause, nonfatal MI, myocardial revascularization, and cerebrovascular events. The result mainly being driven by reduced need of subsequent myocardial revascularizations. Importantly, it showed that visual assessment of lesion severity is not accurate, and FFR should be used to assess functional significance of stenotic lesions. Almost 50% of the lesions in noninfarct-related arteries that were considered significant were not found to be significant when FFR was performed on these lesions. This approach is likely to reduce the number of unnecessary revascularizations performed without the use of FFR and also result in less cost, predischarge stress test, and readmissions for revascularizations.

This study may, however, have some element of bias as the design was open label, and the physicians may have resorted to readmission and revascularization in patients in the infarct-related artery revascularization only arm as they were aware of the angiographic results of these patients having multivessel disease. Besides, the study was not powered to detect less frequently occurring events such as death, stroke, and reinfarction.

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