COMMENTARY

Dec 4, 2020 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

December 04, 2020

Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast.

In This Week’s Podcast

For the week ending December 4, 2020, John Mandrola, MD comments on the following news and features stories.

COVID Vaccine

On Wednesday morning, the United Kingdom (UK) announced that they have approved the mRNA vaccine from Pfizer and plan to begin shots soon. That is huge news. The US Food and Drug Administration meets soon to review both the Pfizer and Moderna vaccines and approval seems highly likely. Vaccine development for this virus has been a sheer triumph for biomedical research.

Also, over the last two weeks, the Oxford team issued a press release on the Astra-Zeneca vaccine. This vaccine uses a modified adenovirus vector, and it does not require storage at freezing temps. The results were positive but a bit more peculiar. Unlike the two mRNA vaccines, which came from single large RCTs, the AZ vaccine data comes from two separate studies, one in Brazil and one in the UK.

The two trials differed in methods: they did not use a standardized dosing regimen, and used different control injections. The other peculiar issue is that efficacy of the vaccine looked better in a smaller group of patients who accidently received half the dose in the first shot. We will have to wait for more data and regulatory review of this vaccine but it simply doesn’t look as good as the mRNA varieties.

AHA 2020: Tocilizumab After Out of Hospital Cardiac Arrest (OHCA)

Comatose patients who have just been resuscitated after an OHCA surely have high levels of inflammation. High inflammation could worsen brain recovery and negatively impact cardiac function. A group from Denmark studied the use of tocilizumab in comatose patients after cardiac arrest. They found a “very dramatic effect” of the drug on the primary endpoint.

But here’s the problem: the primary endpoint was levels of C-reactive protein (CRP). Yes, CRP was 84% lower in the treatment arm. Cardiac enzymes were also lower with active treatment. The lead author said in the news story that this trial demonstrated the feasibility to reduce systemic inflammation after OHCA.

But I am not sure this late-breaking trial of 80 patients tells us anything useful. Yes, it is a positive study, but there is only one important outcome for patients in a coma after OHCA—meaningful neurologic recovery. Does showing that a drug reduces a non-specific marker of inflammation give us enough info to spend further dollars and time on a larger trial?

Tocilizumab is a costly drug with risks of secondary infection. Evidence for its use ought to include studies powered to assess clinical outcomes not nonspecific biomarkers.

AHA 2020: FIDELIO-DKD

There is another potential new drug coming to diabetes, renal, and cardiology clinics. Finerenone is a mineralocorticoid receptor antagonist, but unlike spironolactone and eplerenone, finerenone is a nonsteroidal blocker of aldosterone and this is a huge advantage.

FIDELO-CKD, which was presented at Kidney Week and published in the New England Journal of Medicine, enrolled about 5700 patients with chronic kidnet disease (CKD) and type 2 diabetes (T2D) to finerenone vs placebo. Nearly all patients were on RAS inhibitors. In the main trial, finerenone resulted in an 18% relative risk reduction in the composite of kidney failure, a decrease of 40% in the estimated glomerular filtration rate (eGFR) from baseline, or death from renal causes vs placebo. This was statistically significant.

A secondary outcome was a composite of cardiovascular (CV) events. In the composite of CV death, myocardial infarction (MI), stroke, and heart failure hospitalization (HFH), finerenone resulted in a 14% relative risk reduction vs placebo. Hyperkalemia was more common in the finerenone group--2.3% vs 0.9%--but 2.3% is less than seen in trials of spironolactone.

At AHA, we heard more details about the CV outcomes. Circulation published this FIDELO-CKD substudy that looked at the rate of CV events according to having a history of heart disease at baseline—was the drug more effective in patients with known heart disease? The main finding was that finerenone reduced CV events by 15% in patients with known heart disease and by 14% in those without heart disease. The P for interaction was nonsignificant.

The authors also reported renal outcomes based on presence or absence of heart disease. In patients with heart disease, finerenone reduced renal outcomes by 30%, which was significant, but in patients without heart disease, finerenone did not result in a significant reduction of renal events.

I am not sure this was a prespecified analysis, but it is surely plausible that patients with CKD, diabetes, and heart disease benefit more from the drug than those without heart disease. The incidence of hyperkalemia was elevated to a similar degree in patients with and without a history of CKD.

AHA 2020: Type 2 MI

Gosh there is so much confusion about myocardial infarction (MI). This study was published in letter form in Circulation Outcomes and presented at AHA 2020, and is from a group at Harvard Medical School, who studied the work-ups of patients admitted with type 2 MI at their center. The main question was how often these patients are evaluated by a cardiologist during the hospital admission and whether or not this changes testing and treatments.

As set out in the Fourth Universal definition, type 1 MI (or a traditional heart attack) is defined by atherosclerotic plaque rupture; this can be ST-elevation MI (STEMI) or non-STEMI but is essentially an acute coronary syndrome (ACS). Type 2 MI is everything else—it can be myocardial ischemia due to a mismatch in supply and demand (spasm, dissection, tachycardia, anemia); it can be due to acute myocardial injury caused by things like myocarditis, Takosubo, ablation, cardioverter-defibrillator shocks, acidosis, pulmonary embolism, even strenuous exercise, or it could be due to chronic myocardial injury due to heart failure, chemotherapy, infiltrative diseases, and CKD.

But the key concept is that patients with type 1 MI should be admitted and treated by cardiology–often with early intervention, especially in the setting of STEMI. But patients with type 2 MI, which are the majority of patients, should be managed by treating the underlying condition.

The authors did chart reviews on 359 patients with type 2 MI; 57% were seen by a cardiologist; 43% were not. Patients seen by cardiology had more risk factors, and more abnormalities on echo.

Patients seen by a cardiologist had nearly 5 times more stress testing, 4 times more echo, and more coronary angiography. Patients seen by cardiology more often received statins, beta blockers, and clopidogrel but there was no difference in the use of RAS inhibitors. Only a little more than a third of patients had outpatient cardiology follow-up and those seen by cardiology were more likely to have cardiology follow-up. There was no difference in all-cause mortality in the cardiology vs the non-cardiology group.

The authors cited a paper from 1998 that found an association of cardiology care and lower in-hospital mortality from MI, and then conclude, “Our analysis raises the possibility of gaps in care for patients with type 2 MI.” The authors rightly cited the huge limitations of an uncontrolled chart review survey, but this conclusion boggles my mind. You can’t cite a flawed paper from 1998. In that era, most MIs were type 1 and of course, those cared for by cardiologists did better. Now, with higher sensitivity troponin assays, most MIs are found not to be due to plaque rupture and are therefore type 2 MIs. Since the therapy for these patients means treating the underlying disorder, which is often not cardiac, I would argue that many patients would do best without cardiologists. Cardiologists often have a narrow focus—the heart, or more specifically, the coronary arteries—but what most patients with type 2 MI need is a doctor who sees the whole scenario. That is often not the cardiologist. Patients with type 2 MI need a clinician to think—what is the underlying cause? And treat that. It is often not the heart.

AHA 2020: Coronary CTA

The RAPID-CTCA trial, performed in Scotland, was a pragmatic RCT that studied about 1700 patients who presented with chest pain but had higher risk, defined by elevated troponin levels, ischemic ECG changes, or known coronary artery disease (CAD). The primary endpoint (PEP), all cause death or MI, occurred in 5.8% in the group that underwent coronary CT angiography (CTA) and 6.1% of control arm. No significant difference.

CTA was associated with longer hospital stays and greater costs but no difference in coronary revascularizations. The authors concluded that findings do not support the routine use of early coronary CTA in intermediate or high-risk patients with acute chest pain. One interesting side note was that 52% of patients with high-risk features (ECG, troponin, or known CAD) did not have obstructive disease.

AHA 2020: More Good News on SGLT2 Inhibitor Drugs.

Sotagliflozin is the newest kid on the block. The twist with this drug is that it blocks sodium-glucose-cotransporter (SGLT) 2 channels in the kidney and also the SGLT1 channel in the gut. At AHA, we learned the results of two RCTs of sotagliflozin. NEJM published both.

SOLOIST-WHF randomized about 1200 patients with T2D who were recently hospitalized for heart failure. The PEP was CV death and heart failure (HF). The trial ended early because of loss of funding from the sponsor

The drug was started during the hospital stay in about half the patients and within 2 days in the other half. The rate of the PEPs was significantly lower in the sotagliflozin arm: 51 per 100 patient-years vs 76 in the placebo arm. As with other SGLT2 inhibitors, the PEP was driven by lower rates of recurrent HF. CV death and all-cause death trended lower but did not reach significance. The key feature of SOLOIST was the efficacy of early initiation of SGLT inhibition.

In the SCORED trial, more than 10,000 patients with T2D, CKD (eGFR 25-60), and risk factors for CV disease were randomized to sotagliflozin or placebo. The PEPs were CV deaths and HF. These were changed during the trial owing to loss of funding. The drug reduced the PEP with a hazard ratio of 0.74 and confidence interval ranging from 0.63 to 0.88. Once again, the composite was driven by lower rates of HF, not so much CV death.

In both trials, rates of diarrhea were higher with the drug. In SCORED, diabetic ketoacidosis (DKA) occurred in 30 patients on sotagliflozin and 14 on placebo. The FDA rejected sotagliflozin earlier this year for use in patients with type 1 diabetes due to DKA concerns.

The loss of funding led to internal validity concerns, which the authors laid out in the manuscript: Change in endpoint to total events rather than first event, lack of independent adjudication of events, and about a third of HF hospital admissions were not confirmed to be primary events. This led to the overestimation of the number of events.

In SCORED, sotagliflozin reduced HbA1c substantially across all levels of CKD, even in those with eGFR less than 30. For patients with heart failure with preserved ejection fraction (HFpEF), there may be a signal of benefit.

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