The Take Home: ESC Congress
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The European Society of Cardiology Congress was held Aug. 26 to 29 in Barcelona, Spain, and online, having an in-person component for the first time since 2019.
The meeting featured cutting-edge science important to the cardiology community, and Healio spoke to a number of experts to get their perspectives on it. Offering their insights were Gregg C. Fonarow, MD, FACC, FAHA, FHFSA, from David Geffen School of Medicine at UCLA; Robert A. Harrington, MD, FAHA, from Stanford University; Cardiology Today Editorial Board Member Dipti Itchhaporia, MD, FACC, FESC, from Hoag Memorial Hospital and the University of California, Irvine; Cardiology Today Editorial Board Member Steven E. Nissen, MD, MACC, from Cleveland Clinic; Florian Rader, MD, from Smidt Heart Institute at Cedars-Sinai; and Heba Wassif, MD, MPH, from Cleveland Clinic.
Editor’s Note: All coverage from the ESC Congress can be found here .
DELIVER
Rader: This large, randomized trial of 6,263 patients showed that dapagliflozin (Farxiga, AstraZeneca) reduces worsening HF events in patients with HF with preserved ejection fraction, and it did so safely.
The primary outcome of worsening HF, defined as an unplanned HF hospitalization or urgent HF visit, or CV death, occurred in 16.4% of participants in the dapagliflozin group and 19.5% of participants in the placebo group, for an HR of 0.82 (95% CI, 0.73-0.92; P < .001). CV death was not affected; however, this may have been due to the relatively short (2.3 years) follow-up period of this trial. This is now the second large trial demonstrating that SGLT2 inhibitors can positively impact patient outcomes and also symptoms, based on the Kansas City Cardiomyopathy Questionnaire score.
SGLT2 inhibitors should be considered in symptomatic patients with HFpEF, especially in those in whom other reversible causes of HF, such as uncontrolled hypertension, cannot be improved.
Now that two studies were able to show a clinically meaningful benefit of SGLT2 inhibitors in patients with HFpEF, further research on their mechanisms is needed. While a diuretic effect may play a role, a more complete understanding of this medication class in HF may help identify those patients who benefit most. The fact that the subgroup analysis suggested that both patients with a greater BMI and higher BP seemed to benefit most is intriguing.
SECURE
Nissen: This trial is a puzzle. The whole concept of the polypill is that you get much better adherence, better LDL and better BP reduction. In the SECURE trial of 2,499 older adults with prior MI, both the conventional treatment arm and the polypill arm had almost identical LDL, systolic BP and diastolic BP. So why was there a difference in outcomes? I don’t think it makes a good deal of sense. I am puzzled by it, as I am sure many people will be.
At 36 months, the primary composite outcome of CV death, nonfatal MI, nonfatal ischemic stroke or urgent revascularization occurred in 9.5% of patients assigned the polypill-based strategy and in 12.7% assigned usual care (HR = 0.76; 95% CI, 0.6-0.96; P = .02).
The reasons for the difference in outcomes were not really addressed in the manuscript. The authors talked about pleiotropic effects, which is what everybody says when they get a result they cannot explain. And I cannot explain the results. I cannot tell you that the results answer the question about the polypill in the absence of additional understanding of what is going on. The authors are going to have to do a lot of explaining.
I have been a skeptic about the polypill. I believe that good medicine is about individualizing care. Not everybody needs the same amount of BP reduction. I do not think it is a strategy for a sophisticated clinician in a higher-income country. It might be reasonable in low- or middle-income countries, but I still think it is a great puzzle. This trial takes us a little bit forward, but it leaves as many questions as it answers.
CTT analysis of statins and muscle-related symptoms
Fonarow: Statin therapy has been demonstrated to be highly effective in preventing and treating atherosclerotic CVD, with reductions in acute coronary events, stroke, the need for hospitalization and premature CV death.
Despite these proven benefits, concerns regarding potential side effects, particularly skeletal muscle pain and weakness, have resulted in eligible patients not initiating or continuing on statin therapy.
In individual clinical trials where patients are randomly assigned to either statin medication or matching placebo in a double-blind fashion, the rates of muscle pain and weakness with statin therapy is generally low and comparable to placebo. In clinical practice, where patients know they are receiving statin therapy, high rates of muscle pain and weakness are reported.
In this new, very large analysis of 23 trials of statin therapy involving over 150,000 men and women, there was very little excess in muscle pain, and when it occurred, more than 90% of the time it was not due to statin therapy. The small excess in muscle pain detected was usually mild and did not differ by which statin or which dose.
The key findings are that the benefits of statins outweigh the potential risks and that for most patients experiencing muscle pain or weakness they perceive to be caused by the statin, those symptoms are not actually due to the statin.
These findings should be very reassuring to patients concerned with or experiencing skeletal muscle-related symptoms, as the probability that the symptoms are actually caused by the statin is low and less than one in 10.
DANCAVAS
Itchhaporia: The question being asked in this trial — whether doing a screening program for CVD can decrease the risk for CV mortality — is an important question.
The DANCAVAS trial enrolled more than 46,600 men aged 65 to 74 years who were randomly assigned to undergo screening for subclinical CVD or no screening. After a median follow-up of 5.6 years, an invitation for screening did not significantly reduce the primary outcome of death from any cause, which occurred in 12.6% of men in the invited group and 13.1% in the control group (HR = 0.95; 95% CI, 0.9-1; P = .06).
I think all-cause mortality was very ambitious as a primary outcome. When you look at the results, a few things come up. One is that the prespecified subgroup analysis did show that the 65- to 69-year-olds benefited the most in terms of all-cause mortality, rather than the older population. Several questions arise: Did the investigators choose the right population to target this outcome? The trial enrolled only men; we don’t have data on women. But this study is being done. Also, were these all the appropriate screening tests?
The general thinking from other trials has been that some sort of CV screening program is helpful to decrease CV risk. This study did not show this, but it does not mean that a CV screening may not work. We need more data. The take-home is that there was a signal for the younger patients aged 65 to 69 years, so, to me, there is an opportunity to continue to ask these questions and consider different ways to look at this issue further. I don’t think we stop here.
AXIOMATIC-SSP
Wassif: Milvexian is a first-in-class agent, as it’s anti-factor XIa. Antiplatelets have been the mainstay in management of ischemic stroke; the Warfarin-Aspirin Recurrent Stroke Study (Mohr JP, et al. N Engl J Med. 2001;doi:10.1056/NEJMoa011258) showed no difference between aspirin and warfarin. In addition, there is the concern of hemorrhagic transformation in setting of acute ischemic stroke. The role of direct factor X inhibitors (dabigatran [Pradaxa, Boehringer Ingelheim]) and Xa inhibitors (apixaban [Eliquis, Bristol Myers Squibb/Pfizer] and others) has not been well established and remains class IIb. Support for the use of short-term combination aspirin and clopidogrel for secondary prevention in patients with ischemic stroke comes from post hoc analyses of clinical trials and randomized controlled trials studying surrogate endpoints for stroke (Kleindorfer DO, et al. Stroke. 2021;doi:10.1161/STR.0000000000000375). In other words, this drug fills a gap as a novel anticoagulant target in ischemic stroke.
AXIOMATIC-SSP was a carefully designed study of 2,295 patients with acute ischemic stroke or transient ischemic attack assessing the efficacy and safety of a variety of doses of milvexian (Bristol Myers Squibb/Janssen). The main objective was to determine the dose-response relationship of milvexian in participants with acute ischemic stroke or TIA who were treated with aspirin and clopidogrel. The main secondary objective was to assess the rate of major bleeding in this population compared with placebo. The background of dual antiplatelet therapy is the current practice. It appears that the investigators chose that design to address two pathways; however, I would have been also interested in a direct comparison to standard of care.
For twice-daily milvexian 25 mg, 50 mg and 100 mg, there was an approximately 30% relative risk reduction for symptomatic ischemic stroke compared with placebo; however, no dose response was observed:
- 25 mg twice daily (RR = 0.69; 95% CI, 0.36-1.3);
- 50 mg twice daily (RR = 0.72; 95% CI, 0.39-1.33); and
- 100 mg twice daily (RR = 0.65; 95% CI, 0.33-1.25).
The risk reduction was lesser for patients assigned to milvexian 25 mg once daily compared with placebo (RR = 0.83; 95% CI, 0.46-1.49) and there was an increased risk for stroke within the 200 mg twice-daily group (RR = 1.4; 95% CI, 0.87-2.25). There was no increase in fatal bleeding or covert brain infarction associated with milvexian compared with placebo.
As a clinician, I would wonder which patients for whom would I pursue this strategy of care and who would benefit beyond the standard of care. In addition, there are many key exclusion criteria that one has to keep in mind.
The fact that one of the doses (therapeutic dose of 25 mg twice daily) appeared to have the best RR ratio, with no bleeding, though not statistically significant, remains promising. The current data are insufficient for practice, but are enough to provide dosing data for phase 3. It would be interesting to have long-term data for efficacy and safety as information beyond 90 days.
INVICTUS
Harrington: The main takeaway from INVICTUS is that this is exactly why we need the evidence from randomized clinical trials. The investigators designed this trial with the hypothesis that rivaroxaban (Xarelto, Janssen/Bayer) would be noninferior to the vitamin K antagonists in patients with rheumatic heart disease-associated atrial fibrillation, and then people could switch to the easier-to-monitor approach of rivaroxaban. In fact, the exact opposite proved true.
It’s an ongoing lesson that your intuition is great to establish hypotheses, but your hypotheses really need to be tested. I would have predicted that rivaroxaban would be noninferior. This was a surprise.
This was a well-done trial by very good investigators. This is a very important question for many parts of the world.
Among 4,565 patients with rheumatic heart disease-associated AF followed for a mean duration of 3 years, a primary efficacy endpoint event — which included stroke, systemic embolism, MI or death from vascular or unknown causes — occurred in 560 patients assigned rivaroxaban and 446 assigned vitamin K antagonist therapy (proportional HR = 1.25; 95% CI, 1.1-1.41; P < .001).
The vitamin K antagonists are not going away. If you have a patient with rheumatic heart disease and AF — which is more common outside the U.S., but there are pockets where we do see rheumatic heart disease with AF — and they are candidates for anticoagulation, these data would tell you that we should anticoagulate them with vitamin K antagonists, and there is a benefit to be gained over the direct oral anticoagulants.
And rheumatic heart disease is too common in many parts of the world. The American Heart Association is involved around the world with the reduction of rheumatic heart disease, so this study is relevant to the association’s global work.
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