Research Article | Volume 20 Issue 1 (Jan-Dec, 2015) | Pages 1 - 5
Top Cardiovascular Research in 2017
1
Author affiliations: Instituto do Coração, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil Address for correspondence: Luis H. W. Gowdak, Instituto do Coração, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Eneas de Carvalho Aguiar, 44, São Paulo, SP 05403-000 Brazil
Under a Creative Commons license
Open Access
Received
Jan. 1, 2017
Revised
May 5, 2017
Accepted
July 8, 2017
Published
Dec. 31, 2017
Abstract

The 2017 annual meeting of the European Society of Cardiology took place in Barcelona, Spain, and, despite the terrible events that transpired less than 2 weeks before the congress in La Rambla, one of the most famous points in the city connecting Plaça de Catalunya in the center with the Christopher Columbus Monument at Port Vell, it did not prevent almost 32 000 people from gathering in the Fira Gran Via to renew their commitment to foster science for the benefit of those afflicted by, or at risk of, cardiovascular disease. As usual, the Congress was the place for breakthrough clinical trials to be presented, some of which are highlighted in this paper.

CARDIOVASCULAR ATHEROSCLEROTIC DISEASE

Atherosclerosis is a complex, multifactorial pathogenic process affecting millions worldwide with clinical manifestations related to the main arterial territories involved (ie, the brain, the heart, and/or the inferior limbs). This year, the science presented at the ESC offered exciting news on how we can decrease cardiovascular risk further by effectively targeting inflammation and by using a strategy of dual anti-thrombotic therapy. Moreover, the always controversial/debatable issue on how low LDL-C levels can go and remain safe was addressed. Taken together, these data may indeed affect future guidelines on cardiovascular prevention.

FROM BENCH TO BEDSIDE: A TALE OF SUCCESS FROM CANTOS

As much as our understanding of atherosclerosis being an inflammatory disease has deepened, it has yet to be proven whether targeting the inflammation cascade directly would affect both the inflammatory mediators and, more importantly, the clinical outcomes. The CANTOS trial, tested the hypothesis that canakinumab, a human IL-1B-targeted monoclonal antibody that lowers systemic inflammation by reducing the plasma levels of IL-6, could reduce cardiovascular events in patients with stable coronary artery disease and a residual inflammatory risk, defined as an hsCRP level of at least 2 mg/dL.

 

CANTOS was a large trial that included 10 061 patients who were randomized to placebo or 1 of 3 different doses of canakinumab (300 mg, 150 mg, or 50 mg) given subcutaneously once every 3 months. The primary end point was a composite of the first occurrence of a nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The study population was comprised mainly of middle-aged men with a median LDL-C level of 82 mg/dL and an hsCRP level of 4.1 mg/dL. Patients were on optimal medical therapy, which included the use of lipid-lowering agents (93%) and an oral antithrombotic drug (95%). The results of the trial showed that canakinumab, at a median follow-up of 3.7 years, led to a significant 15% risk reduction in the primary end point in the group receiving 150 mg of canakinumab, with no discernible effect on LDL-C or HDL-C levels. Other findings of the trial included a significantly higher incidence of fatal infections and sepsis with canakinumab than with a placebo and a reduction in platelet counts with no corresponding increase in the risk of bleeding. On the other hand, cancer mortality was significantly lower among treated patients (0.45/100 person-years) compared with placebo (0.64/100 person-years).

 

 

In an era in which patients are already on medical therapy that has been proven to lower overall cardiovascular risk, the findings of the CANTOS trial are welcome, showing that, by understanding the underlying mechanisms of the disease better, new opportunities for better therapeutic strategies may arise. Nevertheless, the price of a single 150 mg dose of canakinumab, which is estimated to be around $16 000, may be prohibitive for its widespread use, considering the target population of the drug.

DUAL ANTITHROMBOTIC THERAPY IN PATIENTS WITH ATHEROSCLEROSIS: ARE WE HEADED IN A NEW DIRECTION?

One of the main pillars in the treatment of all forms of atherosclerotic disease (cerebrovascular, coronary, and/or peripheral) is the use of an antithrombotic agent, such as aspirin. In patients after an acute coronary event or who are undergoing a PCI, the current guidelines recommend dual antiplatelet therapy for different periods of time afterward. A more complex scenario arises in patients who have another preexisting prothrombotic condition, such as atrial fibrillation, which must also be specifically managed. In the latter, effective anticoagulation should be offered to lower the risk of a cardioembolic event. The role of NOACs (rivaroxaban and dabigatran) were put to the test in two trials (ie, COMPASS and RE-DUAL PCI), which were presented in Barcelona, and new light was shed on how safely and effectively we can manage antithrombotic strategies in different clinical, but some- times challenging, scenarios.

 

Based on the positive results of the ATLAS ACS 2-TIMI 51 trial in patients with an acute coronary syndrome. investigators from McMaster University in Hamilton, Canada, tested, in the COMPASS trial, the hypothesis that low doses of rivaroxaban, a selective direct factor Xa inhibitor, alone or in combination with aspirin, could further reduce the incidence of cardiovascular events (cardiovascular death, stroke, or myocardial infarction) relative to aspirin alone in patients with stable coronary artery disease or peripheral artery disease. In this international, multicenter trial, 27 395 high risk patients were included and randomized to receive rivaroxaban 2.5 mg twice Page 620101200 mana derivaroxaban 5 mg twice. a day, or aspirin 100 mg daily. The included mostly men with a mean age of 68 years; 91% had coronary artery disease and 27% peripheral artery disease. After a mean follow-up of only 23 months, the trial had to be stopped prematurely due to a significant efficacy favoring the combination of rivaroxaban + aspirin. The dual antithrombotic therapy significantly reduced the composite rate of cardiovascular death, stroke, and myocardial infarction by 24%. As expected, both rivaroxaban treatment arms resulted in more major bleeds than aspirin alone. In the combination arm, major bleeding was increased by 70%, although there was no increase in fatal bleeding or intracranial hemorrhage. In conclusion, the COMPASS trial showed that, in high-risk patients with coronary and/or peripheral artery disease, a dual antithrombotic strategy of low dose rivaroxaban + aspirin reduces cardiovascular events, at the expense of an increase in nonfatal major bleeding. 

 

In patients with atrial fibrillation undergoing a PCI, triple antithrombotic therapy (warfarin + DAPT) is considered the usual care, although this strategy carries a higher risk of bleeding complications. NOACs have consistently shown efficacy and good tolerability in patients with atrial fibrillation compared with warfarin. In the RE-DUAL PCI trial, investigators assessed the efficacy and safety of dual therapy with dabigatran a P2Y12 inhibitor (ticagrelor or clopidogrel) vs triple therapy (warfarin + DAPT) in 2 725 patients with atrial fibrillation who had undergone a PCI. The results of the trial revealed that the dual therapy (dabigatran 110 mg + a P2Y12 inhibitor) cut the incidence of major or clinically relevant nonmajor bleeding at 14 months by almost 50%; the dual therapy with dabigatran 150 mg yielded a significant 5.5% absolute risk reduction in bleeding complications. Regarding the rates of thrombotic events, dual therapy was non-inferior to triple therapy for the incidence of death, thromboembolic events, or unplanned revascularization (13.7% vs 13.4%, respectively). These data could provide another treatment strategy for patients with atrial fibrillation who need a PCI. Maybe now we have an answer for the old riddle: "What is not enough for one, just right for two, and too much for three?"

DIMINISHING LDL-C VALUES: HOW LOW CAN WE GO?

It is irrefutable that lower LDL-C levels are associated with a lower incidence of cardiovascular events across different populations at risk for cardiovascular disease. As strategies, beyond statins, that are more effective at lowering LDL-C hit the market, a growing concern is that maybe we have just gone too far. In the FOURIER trial, evolocumab, a PCSK-9 inhibitor, demonstrated a 59% reduction in LDL-C, which was accompanied by significant reductions in cardiovascular outcomes. In a prespecified subanalysis of FOURIER, the safety and efficacy of achieving progressively lower LDL-C levels were assessed in 25 982 patients with stable cardiovascular disease., The overall results of the trial showed a significant and progressive relationship between lower LDL-C levels and a reduction in cardiovascular outcomes (cardiovascular death, myocardial infarction, unstable. angina, coronary revascularization, or stroke). No safety flags were raised in any patient subgroup, including liver or muscle toxicity, neurocognitive decline, cancer, or new cases of diabetes mellitus. Of note, one-third of patients achieved an LDL-C level between 20 mg/dL and 50 mg/dL, and 10% achieved an LDL-C level <20 mg/dL. Once again, future guidelines will have to deal with the new information provided by FOURIER, considering that extremely low levels of LDL-C are usually only achieved by a combination of lipid-lowering strategies. 

 

Finally, inclisiran, the "new kid on the block" for lowering lipid levels, targets the PCSK-9 messenger RNA, which produces dose-dependent reductions in LDL-C. The ORION-1 trial, enrolled 501 patients on statin therapy with or at a high risk of atherosclerotic cardiovascular disease with LDL-C levels 70 mg/dL or 100 mg/dL, respectively. The comparison of different regimens of inclisiran with placebo revealed that the best regimen was inclisiran 300 mg given subcutaneously at days 1 and 90, with a maintenance dose of 300 mg at day 270, and then every 6 months. With this regimen, a 46% time-averaged reduction in LDL-C levels over 12 months could be achieved. The safety profile was good with only 5% of the patients presenting injection-site reactions. Clinical outcomes were not assessed in ORION-1 and they are eagerly awaited.

CONCLUSION

Cardiovascular research is unstoppable. Clinical investigators, along with basic scientists, work in tandem to bring new discoveries from the laboratory, which may open the door for new therapies in the clinical arena. The 2017 ESC congress was packed with science at the highest level, so physicians and health care providers alike, on their way back home after the meeting, had a lot on their minds. We learned about the first trial designed to look at inflammation as a potential therapeutic target in atherosclerotic cardiovascular disease, which successfully affected clinical outcomes, although its high cost may hamper a more far-reaching use. Different antithrombotic strategies were also presented, with many safe and effective options to deal with high-risk patients, and the "the lower, the better" theory behind LDL-C seems to remain unchallenged. New evidence is paving the way to a change in clinical practice. 

 

As we left Barcelona, our minds had already turned to Munich 2018 with great expectations for what will be in store for us during the next ESC meeting.

 


Adiós, Barcelona. Hallo, München.

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