Mandrola's Top 10 Cardiology Stories of 2023

Obesity Treatments

Hyperbole is almost impossible when describing the potential benefits of the glucagon-like peptide-1 (GLP-1) receptor agonists. Obesity is that big of a problem.

The biggest breakthrough of the year for this drug class came in the SELECT trial. Semaglutide reduced cardiovascular outcomes in patients with established cardiovascular disease and obesity but without diabetes. SELECT turned semaglutide into a cardiac drug.

Two meta-analyses suggested that the dual GLP-1a and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide is the more potent weight-reducing agent, but the sure-to-come cardiovascular indication will probably make semaglutide more popular, at least initially. I'd bet on a class effect regarding cardiac protection.

The placebo-controlled STEP-HFpEF trial of semaglutide in patients with obesity and heart failure with preserved ejection fraction (HFpEF) was unblinded and too small to conclude much about outcomes but at least hinted at safety in HFpEF.

Downsides include gastrointestinal intolerance and costs. And the just-published results of the SURMOUNT-4 withdrawal trial underscores the challenge of weight regain when the drugs are stopped.

This drug class may be the biggest story in medicine of the past 10 years.

The Sobering Results of the RCT Duplicate Project

I have often argued that one of the greatest innovations of modern medicine has been the randomized controlled trial (RCT). The power of an RCT is that randomization, not a clinician, chooses treatment. This balances both known and unknown baseline characteristics, reduces bias, and allows clinicians to make causal inferences. The problem is that RCTs are resource intensive and not applicable to many important questions.

Real-world evidence, such as that in healthcare databases, is plentiful. But none of it is randomized, which makes causal inference much more difficult.

The goal of the RCT Duplicate initiative is to learn to what extent real-world evidence could be used to provide RCT-level causal inference. If feasible, the ability to reliably emulate an RCT from real-world evidence would represent a Nobel prize–level advance in medical science.

The Journal of the American Medical Association published the results of an attempt to emulate 32 RCTs from insurance claims data. The group of experts from Harvard Medical School, led by Shirley Wang, PhD, ScM, first chose trials on their feasibility to be emulated. This required the database and the trials to include similar metrics, such as treatments, comparators, and outcomes. They then quantified the degree of agreement in the trial emulation vs the actual RCT.

The results were mixed. The positive was that some of the trials could be emulated closely with nonrandomized data. For instance, three of the DOAC vs vitamin K antagonist (VKA) trials (RE-LY, ROCKET AF, ARISTOTLE) were closely emulated using real-world evidence. But many trials did not emulate. For instance, the EINSTEIN-PE trial of rivaroxaban vs VKA yielded a nonsignificant hazard ratio of 1.12 while the real-world-evidence trial emulation found a highly significant HR of 0.67 (95% CI, 0.55-0.80). Results went in the opposite direction with PARADIGM-HF, an RCT of sacubitril/valsartan vs enalapril in patients with heart failure and a reduced ejection fraction. The RCT reported a hazard ratio of 0.80 (95% CI, 0.73-0.87) but the trial emulation attempt found no significant difference, with an HR of 1.02 (95% CI, 0.97-1.14).

The authors were honest in their conclusions. They wrote that real-world evidence can reach similar conclusions as RCTs, but this may be difficult to achieve.

I highlight this paper and initiative because of its sobering conclusions regarding causal inference from nonrandomized data. That is, in this best-case scenario (experts in trial emulation using selected trials), real-world evidence did not consistently and reliably emulate an RCT.

Changing Ideas About Atrial Fibrillation

We learned this year that not all atrial fibrillation (AF) is the same.

For an older patient with stroke risk factors and 3 hours of AF on a cardiac device, pre-2023 thinking would have us leaning toward anticoagulation. The results of the ARTESIA and NOAH-AFNET 6 trials strongly question that idea.

NOAH-AFNET randomly assigned about 2500 older patients with short-duration device-detected AF (median duration, 2.8 hours) to edoxaban vs placebo. The trial was stopped early at 21 months for perceived futility and excess bleeding in the edoxaban arm. Edoxaban reduced the primary endpoint of stroke, systemic embolism, and cardiovascular death by 19% (HR, 0.81; 95% CI, 0.60-1.08; P = .15) but increased bleeding by 31% (HR, 1.31; 95% CI, 1.02-1.67; P = .03).

ARTESIA randomly assigned about 4000 older patients with short-duration AF (median duration, 1.5 hours) to apixaban vs aspirin. More patients and longer follow-up of 3.5 years translated to more events. Apixaban reduced the primary endpoint of stroke or systemic embolism by 37% (HR, 0.63; 95% CI, 0.45- 0.88; P = .007). This was countered by an 80% increase in major bleeding (HR, 1.80; 95% CI, 1.26- 2.57; P = .001).

The results of both trials were consistent: Direct-acting oral anticoagulants reduce thrombotic events but increase bleeding rates. The biggest discovery — and reason for debate about net benefit — was the low stroke rates (< 1% per patient-year) in both trials. What clinicians need, and is probably forthcoming, is an analysis correlating duration of AF and net benefit. Right now, anticoagulation decisions with device-detected short-duration AF require high doses of judgement and patient preference.

The Failure of Extracorporeal Life Support

Extracorporeal membrane oxygenation (ECMO) may be the highest-level supportive care we can offer. It is, basically, a heart-lung machine. Two trials published this year provided clarity on whether it is useful.

In January, Dutch investigators published results of the INCEPTION trial, in which extracorporeal cardiopulmonary resuscitation (CPR) or conventional CPR (standard advanced cardiac life support) were compared. The trial enrolled 160 patients who had out-of-hospital cardiac arrest, due to a ventricular arrythmia, and initial bystander CPR without return of spontaneous circulation within 15 minutes. They found no significant improvement in the primary endpoint of survival with a favorable neurologic outcome. (odds ratio, 1.4; 95% CI, 0.5-3.5; P = .52).

In the ECLS-SHOCK trial, a German team studied the use of extracorporeal life support (ECLS) in the treatment of acute infarct–related cardiogenic shock. Slightly more than 400 patients were randomly assigned to ECLS plus medical therapy vs medical therapy alone. The primary outcome of all-cause death occurred in 48% and 49% of the ECLS and control group, respectively (RR, 0.98; 95% CI, 0.80-1.19; P = .81). Bleeding complications occurred 2.4-fold more often in the ECLS group, and peripheral vascular complications were nearly threefold more common in the ECLS group.

These trials show that this invasive procedure has little to no role in these two dire conditions. This story also highlights the need for RCTs, even in our sickest patients.

ORBITA-2 Changes the Conversation of Stable CAD

It took decades, but (I think) most of cardiology agrees that percutaneous coronary intervention (PCI) in stable coronary artery disease should be done to relieve symptoms, not extend life or prevent future myocardial infarction (MI).

In patients with stable disease, guidelines and consensus favor medical treatment first and PCI for recurrent symptoms and medication intolerance. The problem with that plan is that ORBITA-1 had shown no significant symptom relief from PCI when added to maximal medical management.

ORBITA-2 upends that paradigm. The design and idea differed from the first ORBITA trial. In ORBITA-2, the Imperial College London team aimed to study PCI alone as an antianginal therapy. About 300 patients with stable coronary artery disease were recruited and stabilized on meds. Then 2 weeks before the actual PCI or placebo-PCI, the antianginal drugs were stopped. This allowed the authors to observe the effect of PCI alone rather than as an add-on to meds.

The authors used the same careful blinding of the PCI and PCI-placebo procedure. They recorded symptom relief via a novel daily symptom score from a smartphone app. ORBITA-2 results were clearly positive. The primary endpoint of mean angina symptom score was significantly lower in the PCI group. Secondary endpoints, such as mean treadmill exercise time and Canadian Cardiovascular Society (CCS) angina class, also favored the PCI arm.

The results of ORBITA-2 provocatively suggest that restricting PCI to patients who do not respond well to medications may be selecting a group least likely to improve.

ORBITA-2 therefore heralds a new approach wherein PCI could be offered as first-line therapy in lieu of medications. This, of course, would require a careful discussion of the nuances of either approaches. Some patients will prefer PCI, while others may wish to avoid metal cages in their arteries.

FDA Approves Renal Denervation

Late this year, the US Food and Drug Administration approved two renal-denervation devices for the treatment of patients with hypertension. One device uses ultrasound and the other uses radiofrequency energy.

For the ultrasound device, the reduction in daytime ambulatory systolic blood pressure at 2 months was 6 mm Hg compared with sham control. At 6 months, it was only 3 mm Hg.

The radiofrequency device was studied in populations on and off antihypertensive medications. In the off-medicine group, the reduction in 24-hour systolic blood pressure was 4 mm Hg at 3 months compared with sham control. But in the on-medicine studies, there were no significant changes in systolic blood pressure at 6 months. This led an advisory panel to vote 7-6 against its efficacy. Yet FDA still granted approval in November.

Payers have yet to sort out coverage criteria and reimbursement for this procedure. Hypertension is an important health problem. Medication and lifestyle adherence is often challenging. The idea of a relatively simple procedure to treat a lifelong problem is compelling.

I have three worries about putting these catheters into the hands of doctors: One is that the blood pressure reductions are modest, equivalent to, or less than those with a generic medicine. Second, the durability of the blood pressure reductions is questionable because the sham-controlled data go out to only 6 months. The final worry is cost efficacy. A reimbursable procedure plus the likely direct-to-patient marketing could make renal denervation one of the lowest-value procedures in all of cardiology.

Longer-Term Data on TAVR in Low-Surgical-Risk Patients

Clinical trialists reported longer-term data on transcatheter aortic valve replacement (TAVR) vs surgical aortic valve replacement (SAVR) in patients with aortic stenosis at low surgical risk.

In 5-year follow-up of the PARTNER 3 trial of balloon-expandable TAVR or SAVR, the short-term advantage of TAVR had decreased. A primary outcome event occurred in 22.8% vs 27.2% of patients treated with TAVR and SAVR, respectively. That -4.3% absolute risk difference no longer met statistical significance. The rate of death was 10% in the TAVR group vs 8.2% for SAVR. The secondary hierarchical endpoint revealed no significant differences in outcomes. Hemodynamic performance of the valves was similar, though there was more aortic regurgitation in the TAVR arm.

The Evolut Low Risk authors reported 4-year results of self-expandable TAVR vs SAVR. The primary endpoint of death or disabling stroke occurred in 10.7% of patients in the TAVR arm vs 14.1% of the SAVR arm, which met statistical significance (HR, 0.74; 95% CI, 0.54-1.00; P = .05). TAVR patients also had sustained improvement in hemodynamics vs SAVR. New permanent pacemaker rates remained higher in the TAVR arm.

The most curious difference between the two studies was that in the self-expandable trial, outcomes increasingly favored TAVR over time; whereas in the balloon-expandable trials, TAVR gradually lost its early advantage over SAVR.

Both trials will continue to follow patients, which is great news because a number of surgeons have told me that, historically, 7-10 years is when signals of failure often show in bioprosthetic valves. It's hard not to be impressed with the technological innovation in the aortic valve space.

Tricuspid Valve Interventions: Hype or Real?

Tricuspid valve regurgitation (TR) is common but rarely occurs as a primary problem. Even when it is believed to be a primary lesion, surgical therapy is quite risky. Percutaneous tricuspid transcatheter edge-to-edge repair (TEER), similar to that done for mitral regurgitation, offers a potential solution.

The TRILUMINATE trial tested TEER vs medical therapy in patients with symptomatic severe TR. The trial delivered a positive result for TEER, but even modest critical appraisal revealed serious flaws in the interpretation of the results.

The authors chose a three-component hierarchical primary endpoint of all-cause death or tricuspid surgery, hospitalization for heart failure, or an improvement in quality of life as measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ). Note the two objective and one subjective endpoints.

The results favored TEER, with a win ratio of 1.48 (95% CI, 1.06-2.13; P = .02). Positive results occurred solely due to the quality-of-life improvements. There were no significant differences in death, need for tricuspid valve surgery, or even hospitalizations for heart failure. The problem was that TRILUMINATE did not include a placebo (sham) procedure. It's highly likely, therefore, that a placebo effect drove the positive results.

I find this the most disappointing trial of the year, because if PCI of severe coronary stenoses could be subjected to placebo controls, surely tricuspid regurgitation could as well.

The Roller Coaster of Factor XI inhibitors

The year began with excitement over the potential of factor XI inhibitors. Both oral and injectable agents had shown promise in prevention of venous thrombosis. Factor XI inhibition also had biologic plausibility; perhaps it was to be the Goldilocks anticoagulant.

Three dose-finding phase 2b trials of asundexian — PACIFIC-Stroke, PACIFIC-AMI, and PACIFIC-AF — all reported encouraging safety. While phase 2 studies are not designed to detect clinical signals, none of these trials even hinted at efficacy.

Later in the year, we learned that the AZALEA-TIMI 71 trial of the injectable abelacimab vs rivaroxaban in patients with AF was stopped early because of an "overwhelming reduction in bleeding" in the abelacimab arm.

The shocker came in November when the makers of asundexian, Bayer, announced termination of the OCEANIC-AF trial because of inferior efficacy of asundexian vs apixaban. This surprised our field because the trial had been ongoing for such a short time.

OCEANIC news was quite bad for the drug class, but there is still hope. Perhaps the asundexian dose was too low? Plus, there are other factor XI compounds to test. We shall see.

Gene Therapy

This is tangential to clinical cardiology, but The New England Journal of Medicine published a remarkable report of gene therapy to treat patients with sickle cell disease.

Investigators used the Nobel prize–winning CRISPR-Cas9 editing technology to alter cells from affected patients. They then ablated the bone marrow and transfused the genetically altered cells. The authors are careful not to call this a cure, but the response was remarkably positive. FDA has actually approved the approach.

As a clinician, that report reads a bit like a science-fiction thriller. I mention this remarkable science not because we will be referring patients for gene editing next year, but because we may be on the cusp of a completely new way to treat human disease.

Thanks for your support this year. I am happy to learn what I have missed in this list. Please tell me in the comments.

John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. 

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