2021's best Cardiology news
M3 India Newsdesk Jan 06, 2022
2021 was a tough year battling COVID-19, however, studies in the field of cardiology took off well and there have been some significant developments so far. Here listed are ten major trials in the field of cardiology that were done in 2021.
1. Inhibitors of the sodium-glucose cotransporter 2 have had a less impressive year
In 2020, the class of SGLT2 inhibitors dominated. Dapagliflozin demonstrated efficacy in improving renal outcomes in patients with chronic kidney disease (CKD). Empagliflozin joined dapagliflozin in demonstrating efficacy in patients with heart failure with reduced ejection fraction (HFrEF) and the combined SGLT21/2 inhibitor sotagliflozin demonstrated efficacy in patients with diabetes, heart failure, and CKD.
However, the 2021 outcomes were less remarkable. Although the EMPEROR-Preserved study compared empagliflozin to placebo in patients with heart failure with preserved ejection fraction (HFpEF), the topline result was "positive," it was far from a victory.
The 21% decrease in the composite main outcome of heart failure hospitalisations and cardiovascular (CV) mortality was due to fewer heart failure hospitalisations. CV death was not statistically different. And hospitalisations for heart failure accounted for less than 20% of all hospitalisations. The issue could have been with the HFpEF categorisation.
Unlike HFrEF, which has a single underlying cause, HFpEF is fundamentally a disease of ageing, deconditioning, and metabolism. Patients with HFpEF may have numerous concurrent morbidity and mortality reasons. The reason medications have had little impact on HFpEF is that these patients experience a plethora of complications.
2. Obesity's good and bad
Obesity rates among young individuals in the United States are alarmingly high, according to a study paper published in November. In light of the pandemic, fighting obesity has become even more critical, since the risk of severe COVID-19 is directly proportional to body mass index.
Many randomised controlled studies this year indicated that the GLP-1 analogue semaglutide resulted in considerable and long-lasting weight reduction. Weight reduction of 15 kg was seen in STEP I Trial, a randomised, controlled study of obese adults without diabetes. The finest aspect of this tale is that new medications are being developed to help individuals with obesity. Tirezepatide (a GLP-1 and GLP-2 counterpart), as well as cagrilintide (an amylin analogue), showed encouraging results in early tests.
The fact that a weekly injection may produce and sustain weight reduction compared to that achieved by major abdominal surgery is a significant development in the treatment of obesity.
3. The surgical closure of the left atrial appendage succeeds
The LAAOS III study evaluated the stroke-preventive effects of an add-on surgical closure of the left atrial appendage (LAA) in patients undergoing cardiac surgery who had a history of atrial fibrillation (AF). Over 2000 patients were randomised to either further heart surgery or to receive just their assigned cardiac surgery.
Both groups got normal therapy, which included anticoagulation by oral administration. Surgical closure of the LAA resulted in a statistically significant absolute risk decrease of 2.2 per cent for stroke or systemic embolism. There was no increase in bleeding and the additional pump time was about six minutes.
LAAOS III is the year's most significant trial. Clinically meaningful and statistically robust improvements were seen. When our patients with atrial fibrillation have cardiac surgery, the surgeon should seal their appendage using the LAAOS III procedures, which mostly included excision and primary closure.
4. Not so much with percutaneous left atrial appendage closure
In 2021, percutaneous closure of the appendage with foreign entities inserted into the left atrium remained doubtful. A paper detailed risk factors for device-related thrombosis, the procedure's Achilles heel. Two observational studies showed that women and people with chronic kidney disease had a considerably greater incidence of in-hospital complications.
PRAGUE-17's long-term results do not convince much. Although the topline outcome of the LAA closure (Watchman [Boston Scientific] or Amulet [Amplatzer]) versus direct-acting oral anticoagulant study convinced investigators of continuing noninferiority, no decrease in stroke occurrences were seen. The minor benefit of the device arm in terms of decreased bleeding rates was offset by serious procedural complications, including two fatalities.
Keep in mind that appendage closure is a prophylactic treatment that provides only probable future advantages. The distinction between concurrent surgical and percutaneous closure is that whereas LAAOS III reported no upfront adverse events, real-world data on percutaneous closure clearly demonstrate that patients undergoing this surgery face significant upfront procedural risks.
5. Angiotensin receptor neprilysin inhibitor, too, has a hard time
Sacubitril/valsartan was approved by the FDA in February for the treatment of individuals with HFpEF. The PARAGON-HF study compared sacubitril/valsartan to valsartan alone in individuals with HFpEF. The 13% decrease in the composite endpoint of heart failure hospitalisation and CV death achieved statistical significance with the ARNI medication.
After extensive discussion at the FDA over subgroups, the approval was granted with ambiguous language:
"The benefits are most obvious in patients with a left ventricular (LV) ejection fraction (LVEF) less than normal... but because LVEF is a variable metric, clinical judgement should be used when determining who to treat."
Two studies evaluating sacubitril/valsartan also failed to reach statistical significance this year. Sacubitril/valsartan did not substantially lower a composite endpoint of CV mortality or heart failure in the PARADISE-MI study, which included almost 5600 patients with LV dysfunction and symptoms of heart failure after myocardial infarction (MI).
In the LIFE study, sacubitril/valsartan (versus valsartan alone) had no meaningful effect on either the main endpoint of N-terminal pro-brain natriuretic peptide ratio or the secondary objective of days alive and free of heart failure episodes in 335 patients with advanced heart failure. As previously stated, the pivotal PARADIGM-HF study compared the ARNI medication against low-dose enalapril.
6. Stable coronary artery disease appears to be very stable
Prior to 2021, trial data established unequivocally that supplementing effective medical treatment with revascularisation (or adopting an early interventional strategy) did not lower the likelihood of MI or mortality in people with stable coronary artery disease (CAD). Nonetheless, it is not convincing that this research has changed the ordinary clinician's or patient's thinking. When it comes to angina and localised lesions, pathos takes precedence over logos.
CLARIFY, an observational research may help allay our collective worries. This was a global prospective registry of over 30,000 individuals with stable coronary artery disease. At baseline, about 7000 people experienced angina.
Consider this- over 40% of patients with baseline angina resolved without revascularisation during the first year, and the majority of patients with baseline angina resolved within five years. Only 5% of individuals with resolved angina required revascularisation.
Professor Gabriel Steg, the senior author of CLARIFY, put it succinctly:
"It is perfectly reasonable to conduct a trial of watchful waiting with medical treatment in patients with angina and stable coronary artery disease because the risk of events is low, the chance of remission is very high, and if remission occurs, they have an excellent outcome."
7. The ultimate test for AF screening
The rationale for AF screening is that AF is often asymptomatic. It raises the likelihood of stroke, and anticoagulants may help minimise the risk of stroke. However, the journey from asymptomatic AF detection to improved clinical outcomes is fraught with obstacles- misdiagnosis, overdiagnosis, downstream cascades, and bleeding from oral anticoagulants, to name a few. Two randomised studies released this year indicated that AF monitoring would not significantly improve clinical outcomes.
STROKESTOP randomly allocated all persons aged 75 to 76 years in two counties in Sweden to receive either AF screening or normal care. Two-daily single-lead electrocardiography was used for screening. Over a nearly seven-year follow-up period, the screened group maintained a statistically significant decrease in the primary outcome of ischemic or hemorrhagic stroke, systemic embolism, bleeding necessitating hospitalisation, and all-cause mortality. The issue was that the impact size was tiny (0.23% absolute risk reduction), and the findings were weak (.045 P-value).
In the LOOP research, elderly persons were randomly allocated to receive an implanted loop recorder or standard care. The continuous recorder identified much more AF and resulted in roughly threefold increased anticoagulant usage. Nonetheless, screening did not result in a statistically meaningful decrease in the main outcome of stroke or systemic embolism during a 5-year period.
A caveat- With the proliferation of consumer-oriented rhythm monitoring devices, the majority of AF screening will likely occur regardless of whether a physician prescribes it. These gadgets will convert individuals into patients. This is beneficial for the healthcare system, but the results to yet indicate that the individual-turned-patient receives a little net benefit.
8. FFR Is a failure
In 2021, two attempts to use fractional flow reserve to enhance percutaneous coronary intervention (PCI) results failed. The FLOWER-MI study randomised patients with ST-segment elevation MI and multivessel disease who had previously had successful PCI to receive full revascularisation guided by FFR or angiography. The FFR group had a 32% higher risk of all-cause mortality, MI, and hospitalisation for urgent revascularisation as a composite main outcome.
The FAME 3 study randomly allocated patients with three-vessel coronary artery disease (CAD) to either coronary artery bypass grafting (CABG) or FFR-guided percutaneous coronary intervention (PCI). Because previous studies comparing CABG to PCI in three-vessel disease did not include FFR, the hope was that FFR would bring PCI on a level with surgery. That was not to be the case. At one year, the PCI arm had substantially more serious adverse cardiac or cerebrovascular events (17.8 per cent versus 12.4 per cent for CABG; P =.002).
FAME-3's failure is remarkable only if one adheres to a clogged-pipe model of cardiac disease. A neutral Martian who was only aware of the paucity of evidence showing revascularisation improves outcomes in stable patients over medical care would wonder why anybody believed identifying the functional importance of a localised blockage would be necessary.
9. CABG versus PCI- Meta-analysis
Typically, a medical trial generates average event rates in a treatment arm versus a control arm. Because we conduct the experiment just once, we must examine the event rates and determine if the outcomes were attributable to chance or to actual differences.
The current practice is to assume that there is no prior knowledge and that there are no differences between the two arms (the null hypothesis), and then to assess how weird the results are in light of these assumptions (the P-value). However, physicians are not interested in this information. We want to know the likelihood that the active arm is advantageous in light of the available data and previous information- as if it were a stress test.
This year, the TIMI research group at Harvard used both frequentist and Bayesian methodologies to examine a significant study. This was a meta-analysis of studies comparing PCI versus CABG for left main coronary artery disease. They first reported fatality rates in a conventional manner: 11.2 per cent in the PCI arm against 10.2 per cent in the CABG arm. The hazard ratio was 1.10, and the 95 per cent confidence intervals (CIs) varied between 0.91 and 1.32. The P-value of.33 indicated that this would not be shocking results if there was no difference between the two treatments (It makes no difference, correct?).
However, they subsequently presented the Bayesian analysis, which found that the likelihood of CABG having any mortality advantage over PCI was 85.7 per cent, and the probability of CABG having an absolute benefit of 1% or higher was 49 per cent. (Yes, it seems probable that there is a difference in favour of CABG.)
This is a significant tale because Bayesian interpretations of trials make greater clinical sense. Professor Jay Brophy of McGill University released a Bayesian interpretation of the EXCEL trial in 2020, and now that Harvard researchers have adopted it as well, this acts as a catalyst for standardising Bayesian evidence interpretation.
10. Therapeutic hypothermia in cardiac arrest
We frequently embrace treatments in medicine not because of evidence, but because of what John Hampton referred to as therapeutic fashion. A procedure that makes logical and "has always been done" may readily become ingrained in the standard of care, even if the evidence to support it is lacking.
Therapeutic hypothermia is one such technique for cardiac arrest survivors. Cooling makes sense and has been incorporated into recommendations for over two decades. However, the data came from tiny, skewed research conducted in 2002. In 2013, a bigger experiment found that chilling had little effect, yet the practice remained unchanged.
The worldwide TTM2 study, published in the New England Journal of Medicine in 2021, randomly allocated 1900 patients to cooling or normothermia and showed no difference in mortality or neurologic outcomes, as well as a 45 per cent greater risk of adverse events in the cooling arm.
The moral of this narrative extends beyond the care of cardiac arrest survivors. Yes, it is reassuring to learn that chilling does not aid these people. However, the most important lesson for our profession is about the dangers of hubris and the randomised controlled trial's ability to influence medical practice.
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Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.
The author is a practising super specialist from New Delhi.
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