The Take Home: ESC Congress
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The European Society of Cardiology Congress was, for the first time, held virtually. From Aug. 29 to Sept. 1, the digital experience drew virtual attendees from around the world, to watch and hear the latest on topics ranging from the benefits of SGLT2 inhibition in patients without diabetes to the first randomized trial on the question of whether to stop ACE inhibitors and angiotensin receptor blockers in patients with COVID-19.
Cardiology Today and Healio interviewed a number of experts for their takes on the latest science, including John D. Day, MD, FACC, FHRS, from Intermountain Heart Institute; Mark Drazner, MD, MSc, from University of Texas Southwestern Medical Center; Athena Poppas, MD, FACC, from Lifespan Cardiovascular Institute and Warren Alpert Medical School, Brown University; Janani Rangaswami, MD, FACP, FCRS, FAHA, from Einstein Medical Center and Thomas Jefferson University in Philadelphia; Grant Reed, MD, MSc, FACC, from Cleveland Clinic; Paul M. Ridker, MD, MPH, from Brigham and Women’s Hospital and Harvard Medical School; and B. Hadley Wilson, MD, FACC, from Atrium Health’s Sanger Heart & Vascular Institute and UNC School of Medicine.
Editor’s Note: All Healio coverage from the ESC Congress can be found here .
LoDoCo2
Ridker: LoDoCo2 is a blockbuster. It is a clear confirmation of the inflammation hypothesis of atherosclerosis, and with an inexpensive and widely available drug.
In 5,522 patients with chronic coronary disease, at a median of 28.6 months of follow-up, the primary endpoint of CV death, spontaneous MI, ischemic stroke and ischemia-driven coronary revascularization occurred in 6.8% of patients assigned colchicine 0.5 mg per day with no loading dose vs. 9.6% of those assigned placebo (incidence, 2.5 per 100 person-years vs. 3.6 per 100 person-years; HR = 0.69; 95% CI, 0.57-0.83).
With two positive colchicine trials as well as CANTOS, guidelines need to change, and physicians must start recognizing residual inflammatory risk as a unique and different entity than residual cholesterol risk. Physicians, however, must also be made aware that colchicine is contraindicated in patients with chronic kidney disease (CKD). That group is at very high risk and we need an alternative anti-inflammatory strategy for those with renal dysfunction.
EMPEROR-Reduced
Drazner: EMPEROR-Reduced is now the second study showing meaningful clinical benefits of an SGLT2 inhibitor in patients with HFrEF, even in the absence of diabetes. The reduction in HF hospitalizations and favorable impact on renal function are impressive.
Among 3,730 patients with HF and an EF of 40% or less, treatment with empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) in addition to recommended therapy reduced the primary composite endpoint of CV death or HF hospitalization by 25% (P < .001), reduced total HF hospitalizations by 30% (P < .001) and reduced renal events by 50% (P < .001) compared with placebo. Further, the benefits of empagliflozin in EMPEROR-Reduced seemed present even in those on state-of-the-art guideline-directed medical therapy, including sacubitril/valsartan (Entresto, Novartis).
As new therapies emerge, practitioners need to assess the evidence supporting their use and determine if that evidence base warrants adoption into routine clinical practice. Personally, I am always more convinced when the putative benefits of a therapy in one trial are confirmed by a second trial. In essence, you are repeating the experiment and duplicating the results. Now, we have two trials demonstrating important clinical benefits of SGLT2 inhibitors in patients with HFrEF, even in the absence of diabetes. These data support the concept that SGLT2 inhibitors join angiotensin receptor-neprilysin inhibitors, beta-blockers and mineralocorticoid receptor antagonists as foundational therapies for patients with HFrEF unless there is intolerance or a contraindication.
It would be of interest to test the benefit of SGLT2 inhibitors in large trials of hospitalized patients with decompensated HF, rather than those with chronic HF. That population is at high risk and in desperate need of beneficial pharmacological therapies. Also, it would be of interest to test SGLT2 inhibitors in patients with even more advanced HF than those in EMPEROR-Reduced.
DAPA-CKD
Rangaswami: The DAPA-CKD trial shows the clear benefits with the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca): a reduction with respect to reducing the progression of chronic kidney disease, reaching end-stage kidney disease and reduction in kidney and CV deaths.
During a median follow-up of 2.4 years in 4,304 patients, the primary composite endpoint of worsening renal function — defined as at least a 50% sustained decline in estimated glomerular filtration rate (eGFR) or onset of end-stage renal disease — or death due to renal disease or CVD was reduced by 39% with dapagliflozin 10 mg compared with placebo (HR = 0.61; 95% CI, 0.51-0.72).
This is importantly an incremental benefit in a population with very high use of current standard-of-care therapies to slow down kidney disease progression, ie, 97% use of ACE inhibitors/angiotensin receptor blockers. We now have a therapy available that slows down CKD progression after 2 decades of lack of newer effective therapies outside the use of ACE inhibitors/angiotensin receptor blockers, BP control and, in patients with diabetes, achieving targets for glycemic control.
This class of agents changes the landscape of what constitutes standard of care in patients with CKD regardless of underlying diabetes status. In addition to the kidney benefits shown, there is a very relevant benefit of reduction of HF burden, which is a dominant phenotype of CVD in CKD. It is also important to note that patients with lower eGFR all the way down to 25 cc/min were enrolled in DAPA-CKD, and the drug was continued to the point patients reached the need for dialysis. The adverse event profile is overall reassuring, with no significant differences between treatment and placebo arms that would raise concerns for safety. Notably, there were no patients with diabetic ketoacidosis, which is one of the feared complications.
We are now approaching a place where there are high-quality data showing benefits for reduction in adverse CV and kidney events with the SGLT2 inhibitors, as well as other drug classes in this space. However, there remains a major implementation gap with ensuring that high-risk patients appropriately get access to these therapies, and several barriers exist in clinical practice that fuel this trend. It is extremely important to ensure we translate the science into practice as soon as possible and all efforts to implement multidisciplinary cardiorenal metabolic care models to achieve these goals are imperative at this time.
In addition to the SGLT2 inhibitors, other newer agents with cardiorenal benefits such as the GLP-1 receptor agonists as well as newer nonsteroidal mineralocorticoid receptor antagonists such as finerenone (Bayer) are also of big impact in the cardiorenal metabolic space. There are exciting prospects for implementing personalized medicine using combinations of these agents to achieve best outcomes in patients with high cardiorenal risk.
BRACE CORONA
Wilson: BRACE CORONA is an important trial because ACE inhibitors and angiotensin receptor blockers are very prevalent and effective agents for CV treatment. We know that they save lives in patients with HF and are also one of our mainstays for antihypertensive therapy, among other uses. There were early concerns and observations since the start of the COVID-19 pandemic that people on ACE inhibitors and angiotensin receptor blockers might be more susceptible to SARS-CoV-2 and to worse outcomes. There are millions of people on ACE inhibitors and angiotensin receptor blockers; to think about having to stop them is a very serious concern.
The BRACE CORONA trial demonstrates that continuing ACE inhibitors and angiotensin receptor blockers does not worsen outcomes in patients with mild or moderate COVID-19. Among 659 patients with mild to moderate COVID-19, at 30 days, the primary outcome of mean number of days alive and out of hospital was 21.9 days for patients who suspended ACE inhibitors and angiotensin receptor blockers vs. 22.9 days for those who continued their medications (mean difference, –1.1 days; 95% CI, –2.33 to 0.17). The mean ratio for days alive and out of hospital between the suspended and continued groups was 0.95 (95% CI, 0.9-1.01; P = .09).
It is very reaffirming that we now have a randomized trial that corroborates the fact that we may continue our patients safely on these essential medications.
EXPLORER-HCM
Poppas: Patients with symptomatic obstructive hypertrophic cardiomyopathy are particularly challenging to manage. The population is relatively small, but their symptoms can be difficult and variable, and none of the available medications work predictably well. What is exciting about mavacamten (MyoKardia), a first-in-class cardiac myosin inhibitor, is that it reduces the actin-myosin cross-bridge formation to target the underlying pathophysiology of hypertrophic cardiomyopathy. This therapy works in a completely different manner than the other medications; it works directly on the sarcomeres.
The trial’s primary endpoint of a 1.5 mL/kg/min or greater increase in peak oxygen consumption (VO2) and at least one NYHA class reduction, or a 3 mL/kg/min or greater peak VO2 increase without worsening of NYHA class was met in 36.6% of patients assigned mavacamten vs. 17.2% assigned placebo (difference, 19.4%; 95% CI, 8.7-30.1; P = .0005).
The EXPLORER-HCM study design was very important. Combining NYHA class with an objective measure of VO2 max was powerful, and it is striking that there was a 19% difference in the primary endpoint of this trial. The reduction in N-terminal pro-B-type natriuretic peptide was also impressive. One caveat is that four patients in the mavacamten group had left ventricular EF reduction to less than 50% at 30 weeks. When the medication was discontinued, LVEF recovered. Careful monitoring and postmarketing surveillance will be crucial to ascertain if this observation is a true side effect.
It will be interesting to see how we can apply this to the nonobstructive hypertrophic cardiomyopathy subtype. Will we see the same effects if patients do not have a significant level of obstructive either at rest or with exertion? Overall, I think these findings will and should change practice in patients with symptomatic, obstructive hypertrophic cardiomyopathy.
EAST-AFNET 4
Day: It has been nearly 20 years since we have had a good study comparing rate control vs. rhythm control for atrial fibrillation. Also, in the last 20 years, catheter ablation has emerged as an important component to a subset of patients opting for normal sinus rhythm (rhythm control strategy), so it was important to redo these studies.
The rate vs. rhythm control studies 20 years ago were highly flawed in that anticoagulation was primarily given to the rate-control patients rather than the rhythm-control patients. Also, maintaining normal sinus rhythm (rhythm control) with only antiarrhythmics may expose patients to increased risks compared with catheter ablation, where normal rhythm can usually be maintained without the constant exposure to the toxicities of antiarrhythmics.
In the EAST-AFNET 4 trial of 2,789 patients with AF diagnosed less than 1 year before enrollment, the composite of CV death, stroke or hospitalization with worsening HF or ACS occurred in fewer patients assigned patients assigned early rhythm control (3.9 per 100 person-years) compared with those assigned usual care (5 per 100 person-years; HR = 0.79; 96% CI, 0.66-0.94). The early rhythm control and usual care groups had a similar number of nights spent in the hospital per year (5.8 days vs. 5.1 days; P = .23).
The key finding of this study is that now with appropriate use of anticoagulation — now based on clearly defined stroke risk factors independent of a rate vs. rhythm control strategy — and a rhythm control treatment strategy, which includes the use of catheter ablation, that a rhythm control strategy decreases the composite endpoint of CV death, strokes, worsening HF or MI.
Another key finding is that the researchers targeted patients with recently diagnosed AF. Our research, as well as research from others, suggests that the sooner you can treat AF, thereby avoiding the degenerative changes that occur to the heart with AF, the better the patient’s long-term freedom from AF.
Since the rate vs. rhythm control studies of 20 years ago, medical guidelines have generally recommended more involved AF treatment only for those patients with AF symptoms. In other words, if patients did not have any AF symptoms, they were often told to just live with their hearts constantly beating out of rhythm. The results of this study show that AF is definitely not benign, that anticoagulation based on stroke risk factors in all patients is important in preventing AF complications and that more patients could benefit from having their hearts staying in normal rhythm.
More research is still needed comparing antiarrhythmics vs. catheter ablation for a rhythm control strategy. The problem is that, given antiarrhythmics often do not allow patients to maintain normal sinus rhythm long term, there is a high crossover rate to catheter ablation. Thus, it is hard to compare antiarrhythmics to ablation since so many of the patients randomly assigned to antiarrhythmics end up getting an ablation before the study is over. We especially need a study that can accurately account for this high crossover rate.
Also, we need better research comparing ablation as first-line therapy compared with an antiarrhythmic.
POPULAR TAVI
Reed: POPULAR TAVI was an open-label, randomized controlled trial designed to answer a common and important question: Do patients really need dual antiplatelet therapy after transcatheter aortic valve replacement, or is aspirin alone enough for most patients?
In POPULAR TAVI, 690 patients were randomly assigned to aspirin alone or aspirin plus clopidogrel for 3 months after TAVR. The study’s findings are provocative and challenge common practice of DAPT prescription after TAVR. They show that for patients without another reason for DAPT or anticoagulation, aspirin alone is associated with fewer bleeding events than DAPT. The difference was rather dramatic, as aspirin was associated with a nearly threefold reduction in Valve Academic Research Consortium (VARC) major bleeding at 12 months compared with DAPT (2.4% vs 7.5%).
Among patients who received aspirin and clopidogrel, 26.6% experienced the primary outcome of all bleeding at 1 year compared with 15.1% of the aspirin-alone group (RR = 0.57; 95% CI, 0.42-0.77). Similarly, nonprocedural bleeding occurred in 24.9% of patients assigned to aspirin plus clopidogrel vs. 15.1% of patients assigned to aspirin alone (RR = 0.61; 95% CI, 0.44-0.83). Interestingly, in the study there did not seem to be a significant cost of using aspirin alone, as there was no difference in ischemic events including stroke, MI, or valve thrombosis, and aortic valve function was no different in the aspirin alone or DAPT groups out to 12 months.
I do feel that POPULAR TAVI will make a meaningful clinical impact. This study answers an important clinical question and is very relevant to clinical practice. I expect the results will persuade most clinicians to adopt an aspirin-only strategy after TAVR, as now there are data to support this.
The main limitation of POPULAR TAVI is that it is an open-label trial. However, bleeding is an objective clinical endpoint, so I do not view this to be a major issue.
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