Alex Nowbar’s journal review—11 September 2020

Alex Nowbar reviews the latest research from the top medical journals


The new normal in heart failure 

Zannad et al did a meta-analysis of two large randomised trials of SGLT2 inhibitors for heart failure with reduced ejection fractionEMPEROR-Reduced and DAPA-HF. These trials are basically gold. They found these drugs reduced the risk of death with a hazard ratio of 0.87 (and all the other key heart failure endpoints including hospitalisation for heart failure). Both drugs have already drifted into practice for heart failure for people with and without diabetes, but this is the final confirmation that will make these drugs as mandatory as ACE-inhibitors for heart failure. The hurdle to overcome will be getting people onto these drugs, hurdles like patient preference to take as few tablets as possible, doctor preference to prescribe as few tablets as possible, and lack of awareness about the prognostic benefit of these drugs. 

A winner for hypertrophic cardiomyopathy

The two prongs of hypertrophic cardiomyopathy management are risk reduction (ventricular tachycardia, stroke, and sudden death) and symptom reduction (chest pain, breathlessness, and limited exercise tolerance). For the former, there are implantable cardioverter defibrillators and anticoagulation. For the latter, there are myomectomy, septal ablation, β blockers, calcium channel blockers, and, now, oral cardiac myosin inhibitor mavacamten. The EXPLORER-HCM trial was a double-blind, randomised, controlled trial of this first-in-class drug in 251 symptomatic patients with left ventricular outflow tract obstruction (because there is also non-obstructive hypertrophic cardiomyopathy). The trial was positive for its primary endpoint—based on improved exercise capacity measured by peak oxygen consumption and improved symptoms measured by NYHA classification. And it seemed to be safe. Aside from the positive results, the way the trial was run was impressive—collecting several detailed endpoints on patients at 68 cardiovascular centres across 13 countries.


Low dose colchicine is back

Low dose colchicine (500 μg once a day) for reducing myocardial infarctions was highlighted recently in a large randomised trial from Australian researchers in patients with “chronic coronary syndrome.” Colchicine had slightly faded into the background as something of vague interest for the heart, but no one was fully convinced and who wants all those gastrointestinal side effects anyway? In this double-blind trial, patients were randomised after they had tolerated colchicine in the open label, run-in phase. There was a reduction in the primary endpoint (a combination of cardiovascular death, infarction, ischaemic stroke, and ischaemia-driven coronary revascularisation) with colchicine compared with placebo. Unsettlingly, death from any cause and death from non-cardiac causes were more frequent in the colchicine group, so I am not sure anyone will be in a rush to prescribe this.

Are we barking up the wrong tree by looking for a gold bullet for the inflammatory process in cardiovascular disease? And, a more existential question, what is the value of chronic coronary disease, this new entity that has found its way onto the cardiology scene? In this trial it was defined as any coronary disease on invasive angiography or calcium above 400 Agatson units on CT and clinical stability for six months. It would have been helpful to work out if this diagnostic label had net benefit for patients and healthcare systems before rolling it out.

A nanoparticle vaccine against SARS-CoV-2

I cannot claim to have any sort of grasp on the vaccine race as a whole, but here we have the spike nanoparticle vaccine. Nanoparticle vaccines are supposed to overcome the limitations of live attenuated, inactivated, and subunit vaccines. Nanoparticles can be heavily engineered to have the right properties for the purpose. This vaccine talks the talk, but does it walk the walk? First, safety: yes, there were no safety concerns in over 100 healthy adults who received the vaccine. This is reasonable enough to proceed, but an official vaccine would be given to people who aren’t necessarily young and healthy, so there’s still a question mark there. Second, immunogenicity (does the vaccine maketh the immune response?): yes, the vaccine induced plenty of neutralising antibodies. Third, efficacy (does the vaccine stop people getting infected?): unknown as yet, but an efficacy trial is the planned next step.

Early rhythm control of atrial fibrillation

EAST-AFNET 4 was an open-label, randomised trial comparing early rhythm control with “usual care” in 2789 patients diagnosed with atrial fibrillation 12 or fewer months previously. This is based on the idea that rhythm control might be more effective if delivered sooner after the atrial fibrillation diagnosis rather than later. The primary endpoint (which was positive) was a composite of death from cardiovascular causes, stroke, or hospitalisation with worsening of heart failure or acute coronary syndrome. “Usual care” was “limited rhythm control to the management of atrial fibrillation-related symptoms.” And early rhythm control not only included antiarrhythmics and ablation, but patients sending electrocardiograms to their site team twice a week. Recurrence of atrial fibrillation would trigger escalation of rhythm control therapy. More people in the early rhythm control group had serious adverse events relating to rhythm control (4.9% of them compared with 1.4% in the usual care arm). That being said, fewer strokes and cardiovascular deaths probably trump the serious adverse events from early rhythm control. Symptoms, left ventricular function, and nights spent in hospital were no different at two years. Costs weren’t assessed.

It’s hard to know how to apply these results in practice. If treatment pathways are adapted to increase access to early rhythm control and patients are asked to send in ECGs, would that deliver the benefits seen in this trial? Strategy trials (rather than specific intervention trials) always raise this question. We don’t know which aspect of the treatment strategy delivered the benefit. Was it drugs and ablation or was it in the increase in clinical contact? Could something in between simple rate control and aggressive rhythm control deliver prognostic benefit with fewer adverse events at a lower cost? We don’t know but that’s probably close to what usual care already is at many centres.

Alex Nowbar is a clinical research fellow at Imperial College London

Competing interests: None declared.