COMMENTARY

Jun 19, 2020 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

June 19, 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 Jun 19, 2020, John Mandrola, MD comments on the following news and features stories.

Brief COVID Update

In the United States, the rate of growth of cases is 1.10x, about flat from last week (2.2 million). US deaths last week were 115,000 and this week they are 120,000, for a steady rate of rise of 1.04x.

The increases in cases in the West and South continue. The spike in cases coincides with both the relaxing of restrictions and the beginning of the protests. Internationally, Brazil, Mexico, and now India look worrisome.

Big News in COVID

The RECOVERY trial is an RCT from University of Oxford researchers. It began in March and includes about 11,500 patients with COVID from 175 National Health Service hospitals in England. On June 8th recruitment in the dexamethasone arm was halted by the DSM board because of efficacy.

Overall dexamethasone reduced the 28-day mortality rate by 17%. The effect was greatest in sicker patients: 35% reduction in ventilated patients; 20% in patients on oxygen; and no benefit in patients who did not require ventilatory support. This corresponded to an absolute 12% reduction in death in patients on the ventilators, or an NNT of 8.

This data comes from a press release; the authors say a paper is forthcoming in a week or so. While we surely need to study the paper when it comes out, this information is practice-changing and this press release is different from many pharma press releases:

  • The authors have published the trial protocol.

  • The authors are respected researchers who have no financial conficts of interest as dexamethasone costs nearly nothing.

  • Given the well-described inflammatory response to COVID, especially later in the course, the inflammation-suppressing mechanism of action of dexamethasone’s activity is highly plausible.

  • Mortality is a bias-free endpoint.

  • The p-values suggest the chance of type 1 error is very low.

  • The downsides of this drug are minimal. Remember, we hand out dose packs of steroids often, say, for flares of gout, thus, we should hardly worry about giving it to a patient super sick with later stage COVID.

A caveat and serious question to my ICU colleagues: why do we see such dramatic results in this case but previous studies of corticosteroids in ICU setting have been inconclusive?

Finally, a super-interesting and cautionary Tweet from the new-to-Twitter Dr. Sanjay Kaul from Cedars Sinai: “Anyone remember VEST 1: vesnarinone reduced mortality in CHF by 62%, p=0.002 in a trial conducted by TIMI. VEST 2 failed to replicate and showed a 21% increase in mortality. I hope there are other ongoing RCTs to confirm this stunning result.”

Coronary Artery Calcium Scoring

A French study presented at the American Diabetes Association (ADA) meeting suggested that CAC scoring may be beneficial in patients with diabetes and high cardiac risk. Almost everything about this study is misguided. I discuss the problems not to attack the authors but rather to frame what we know about heart disease in light of the recent ISCHEMIA trial findings.

The researcher’s aim was to test various criteria to select asymptomatic patients with diabetes to be screened for silent myocardial ischemia (SMI). Why would you look for silent ischemia?

Last week I discussed the ISCHEMIA trial. This large study included only patients with ischemia; 41% were diabetics. It showed—unequivocally—that revascularization did not reduce hard outcomes in patients treated with optimal medical therapy. From ISCHEMIA, COURAGE, and BARI2D, we know that the indiscriminate search for ischemia is often misguided. Namely, if revascularization of focal stenoses in stable patients does not reduce MI or death, why look for them?

Another issue with the study: the authors look at about 400 patients with type 2 diabetes (T2D) and multiple cardiac risk factors and want to know if CAC screening helps in the search for silent ischemia. They found CAC > 100AU in about 43%. Of these, about 40 had silent ischemia, and 11 of these patients ended up with revascularization. We don’t know how many of the revascularization procedures were bypass for left main, but it’s likely most were PCI (percutaneous coronary intervention), which we know does not reduce outcomes. And since these patients were asymptomatic, they could not have had angina relief. That is 11/40 patients with nonbeneficial procedures.

The authors then tested the performance of CAC vs other criteria (such as nuclear perfusion imaging, or the presence of severe peripheral vascular disease or nephropathy) in discriminating silent ischemia. They concluded that the algorithm with CAC was the most “cost effective,” and recommend screening only high-risk diabetics who have peripheral artery disease, severe nephropathy, or a high CAC score (> 100AU). This sort of conclusion boggles my mind. How does CAC change anything? If you have a high-risk patient with diabetes you are going to maximally medically manage, whether they have no calcium or lots of calcium. CAC simply tempts you to reduce medical therapy when it’s low and perform unnecessary angiography and PCI when it’s high.

VERTIS-CV

The virtual ADA meeting featured another large cardiovascular (CV) RCT called VERTIS. Patients with T2D with ASCVD were randomized to two doses of the SGLT2 inhibitor called ertugliflozin, which I have not seen used much, but was FDA approved in 2017.

VERTIS is a suite of trials and this was the mandated CV outcomes trial. Previous trials have shown that ertugliflozin has typical SGLT2 inhibitor effects, including modest reductions of A1c, weight loss, and reductions in blood pressure. VERTIS began enrolling around 2013-2014 before the results of EMPA-REG, CANVAS, and DECLARE were posted.

This was a global RCT of about 8200 patients with approximately 2700 patients in placebo vs 2700 on ertugliflozin 5mg and 2700 on ertugliflozin 15mg daily. The primary endpoint was composite of MACE—CV death, MI, stroke and follow-up was 3.5 years.

The results were nearly identical to placebo; 11.9% had events on drug vs 11.9% on placebo. The individual components of the MACE did not come close to differing. A secondary endpoint of CV death or heart failure hospitalization (HFH) showed 12% relative risk reduction that did not meet significance.

The statistical plan had this as the first in hierarchical testing and since it did not meet significance, other secondary endpoints cannot be called significantly different. HFH was reduced by 30% in relative terms and 1.1% in absolute terms. While this p value was nominally significant, it cannot be considered “definitive” due to the way the statistical plan was made.

I am an outside observer here but what I see is a drug that has class effects—weight loss, BP reduction, and favorable effects on the A1c but does not reduce CV outcomes. We have empagliflozin and canagliflozin that do reduce CV outcomes. Canagliflozin in the CREDENCE trial clearly improved renal outcomes, and dapagliflozin which was hugely beneficial in heart failure, so why do we need another SGLT2 inhibitor?

However, what do people do when their chosen drug underperforms relative to its competitors? They do a meta-analysis of the trials of this class and say the nonsignificance findings were in line with other drugs? I am highly suspicious that this is an attempt to detract from the disappointing findings. I looked at the Forest plots of the trials in the meta-analysis. While you can say the confidence intervals overlap with each other, all the other trials are solidly to the left of the null favoring active drug. Data from VERTIS hovers over the null line.

Vericiguat

A brief note on another failure in heart failure with preserved ejection fraction (HFpEF). In an RCT presented at the Heart Failure Association meeting, vericiguat, a novel oral soluble guanylate cyclase stimulator, did not improve patient reported quality of life (QOL) or walking time on a six-minute walk test.

The trial of almost 800 patients with HFpEF was not powered to assess outcomes but the lack of improvement in patient reported outcomes was disappointing, as a previous phase 2 trial called SOCRATES-PRESERVED did show a modest benefit in QOL. Even more disappointing was that symptomatic hypotension was more common on vericiguat.

While this drug did not seem to help in HFpEF—no drug really has, the chemistry and outcomes of this drug are notable and a big trial called the VICTORIA trial, presented at the virtual American College of Cardiology meeting in March, found that vericiguat improved outcomes in patients with heart failure with reduced ejection fraction (HFrEF).

I wondered why this may be. Here is what I learned. Soluble guanylate cyclase is deficient in systolic dysfunction. The drug directly stimulates soluble guanylate cyclase and it sensitizes it to endogenous nitric oxide. These novel chemical actions may improve contractile function; may improve diastolic function; and have anti-fibrotic actions.

VICTORIA was a multicenter RCT in 5000 pts with HFrEF. The primary endpoint was composite of CV death or HFH. Over 2.5-year follow-up the primary endpoint was reduced by 10%. The difference was mostly driven by fewer HFH. CV death was modestly lower; the authors wrote in the discussion that it was “possibly” lower. All-cause mortality did not differ. While serious adverse events were similar, low BP and syncope trended higher in the vericiguat arm.

This seems like a darn modest effect. More than one-third of 5000 patients have an event and the p-value is 0.02. The primary endpoint was driven by a softer HFH endpoint, no difference in all-cause mortality, and more hypotension.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....