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In This Week’s Podcast
For the week ending November 13, 2020, John Mandrola, MD comments on the following news and features stories.
As of Friday morning, there are 52.5 million COVID-19 cases worldwide, 1.3 million have died. The United States has 10.7 million total cases and 247,000 deaths. Thus, it is still bad. In the United States, it is worse. As of yesterday, the moving 7-day average was still going higher. Hospitalizations are increasing and the number of deaths has nudged up—though still not at the rates seen in the spring or summer.
Before I get to the vaccine news – let me quote just one sentence from the medical conservative tenets published in the American Journal of Medicine: “The medical conservative sees benefits from the confluence of interests between profit motives of industry and progress in research; we do not oppose industry-physician collaboration.”
Very early Monday, well before the markets opened, Pfizer released a short press release of their phase 3 vaccine trial. It was hugely good news. “The Vaccine was 90% effective in preventing COVID-19 in participants without evidence of prior SARS-CoV-2 infection in the first interim efficacy analysis.”
Recall the first data safety monitoring board look at the data was going to be after only 32 of 164 cases. But by the time all was said and done, and perhaps due to the increasing cases in North America, the first look included 94 cases. The goal was to have an efficacy greater than 50% and even if the next 70 cases don’t perform as well, the 90% efficacy this far along makes it highly likely that the vaccine is effective. (It could also get better in its efficacy).
The study had enrolled nearly 44,000 people, with 42% from diverse backgrounds. About 39,000 have received their second dose. The press release said no serious side effects, but there was no data to support this. Preclinical studies have found that immune symptoms like fever, and aches, are common. Problematic from a logistical standpoint is that the vaccine has to be stored to very cold temps and this will make distribution difficult.
Two other pieces of good news: Dr. Fauci announced this week that they were very close to a similar look at the Moderna vaccine trial’s first interim result, and that he expected similar efficacy. And researchers in Moscow announced that the Russia Sputnik V vaccine also had 92% efficacy, but this was based only on 20 cases after 16,000 volunteers. (The Sputnik trial protocol has not been made public.) There are at least 10 vaccine candidates in late-stage trials.
Reasons for caution:
We don’t know how the vaccine performs in reducing serious cases of COVID.
We don’t know how the vaccine performs in the most vulnerable.
Since the vaccine creates an immune reaction, it is likely participants knew their treatment assignment and could have acted accordingly.
Without a lot more published trial data, we don’t know if the vaccine could increase the intensity of infection.
Safety is hugely unknown – the Pfizer trial is expected to be completed in 2 weeks. That will give us short-term safety data on about 22,000 people. That sounds like a lot but this vaccine could be given to millions if not billions of people.
It would not take many cases of a severe but rare reaction to change public perception.
On the matter of safety and low-occurring events of a highly efficacious vaccine, I highly recommend Lisa Rosenbaum’s New England Journal of Medicine piece on trolleyology regarding the Dengue vaccine and its backlash in the Philippines.
Thrombolysis for Later Presentation Stroke
The Lancet has published an individual patient meta-analysis of four randomized trials that studied alteplase use in patients with unknown time of onset of symptoms. The meta-analysis included the WAKE-UP, EXTEND, THAWS, and ECASS-4 trials and each used either MRI or CT imaging to determine eligibility. The four trials provided individual patient data for 843 patients, about half in alteplase and the other in placebo. Remember, three of the trials did not show statistically significant results in the primary endpoint; the one that did, WAKE-UP, was stopped prematurely, had a three times higher rate of death and a five times greater rate of intracerebral hemorrhage (ICH).
As is customary in these trials, the primary outcome was favorable functional outcome (modified Rankin score [mRS] of 0–1, indicating no disability) at 90 days. This was achieved by 47% of patients who received alteplase, vs 39% of those in the control groups, giving an adjusted odds ratio of 1.49 (P = .011). In a secondary outcome, looking at mRS of 0-2, alteplase still looked better with an odds ratio of 1.50.
The problem of course is that these benefits in mRS, which is a highly subjective judgment with inter-observer variability, have to be balanced against two highly objective super bad outcomes. Death at 90 days occurred in 6% of alteplase vs 3% placebo. Symptomatic ICH occurred in 3% of alteplase vs 0.5% of placebo.
This was a well-done study but interpretation is a matter of opinion. Alteplase helps a few more people get to an mRS of 0-1 (8% absolute risk reduction, number needed to treat 12.5) and kills a few more people (absolute risk increase 3%, number needed to harm 33.3). Almost 40% of people in the control arm achieved an mRS of 0-1 and almost 60% achieved an mRS of 0-2. So if you injected saline, six out of ten people eligible for alteplase would remain independent; they’d be 2-fold less likely to die and 3.5-fold less likely to have a catastrophic ICH.
If it were me, give me an injection of saline.
JAMA has published two papers on exchange of money from industry to doctors. Theheart.org | Medscape Cardiology has news coverage and commentary from the amazing communicator, Dr. F. Perry Wilson, from Yale.
The first paper looked at trends in industry payments from the Centers for Medicare and Medicaid Services (CMS) open database. Open payments began in 2013 and the idea was to increase transparency of what docs make from industry. It included about 800,000 docs. In 2014, 52% received at least one payment; in 2018 that had declined a bit to about 45%. Over the 4 years, 90.1% of physicians who accepted payments received less than $10 000 – the median amount is small at $215. Those receiving more than $50,000 accounted for 3.4% of physicians receiving payments but 82% of the total value. For these high-earning docs, annual payment values increased or remained stable over time.
F Perry Wilson had this comment: “Pharma spent about $9 billion paying US physicians. Almost 50% of that went to physicians who received more than $500,000 a year from industry. Industry is not an equal opportunity lender.”
Does it matter? Of course, it does
The second study – also in JAMA, from the group at Yale led by Jeptha Curtis and Joe Ross, looked at the correlation between industry payment to ICD—defibrillator—implanters and the devices they put in. This was another huge study of nearly 150,000 ICD implants by 4435 docs using devices from 4 device makers. They also used open payments database and combined it with National Cardiovascular Data Registry data. Some key findings – 94% of ICD implanting docs received industry money; median payment was $1211; and “Patients were substantially more likely to receive devices made by the manufacturer that provided the largest payment to the physician who performed implantation than they were from each other individual manufacturer.”
The problem with industry payments to doctors –even when modest monies are exchanged—goes back to Stark’s Tripartite of conflict of interest. A nice paper from Daniel Goldberg from University of Colorado describes this.
The first issue is the antecedent act. Such acts may consist of a meal, a sponsored talk, and attendance at a continuing professional education event that is organized, sponsored, or branded by the commercial entity, or a visit from a sales rep. These antecedent acts give rise to the second stage, which is ‘states of mind.’ The antecedent acts tend to build a favorable state of mind. Humans are social and gifts promote social adhesion by facilitating reciprocity. Once there are favorable states of mind, there is a behavior of partiality. If you go to a course sponsored by industry you get the designation of being a Complex Higher-risk-Indicated Procedure operator. Alas, doing said complex procedures also includes using expensive tools like Impella.
We have many examples in electrophysiology. Fellows’ courses sponsored by industry are there to create antecedent acts and then favorable states of mind, so as to induce behaviors of impartiality. EP docs feel pressure to do all the latest procedures which involve using industry products.
I am not against working with industry—its a must in cardiology. Industry will likely get us out of the pandemic. Industry is not evil; they have one purpose—to make money—and it would be wise of us to consider this in our assessment of the evidence.
American Heart Association Meeting Notes
There will be number of worthy studies on the atrial fibrillation (AF) front. I am looking forward to the mSToPS study, a 3-year clinical outcomes (emphasis mine) study. It is a nationwide randomized, pragmatic clinical trial of AF screening Back in 2018, the mSToPS researchers reported in JAMA that an ECG monitoring patch in older patients led to higher rates of AF diagnosis, more initiation of anticoagulant therapy, and increased healthcare utilization.
This is interesting because it says it will report on outcomes at AHA. Recall that most screening studies, including a number you will hear about at AHA, include AF incidence. Screening must do more than pick up disease and send people into the profit-driven healthcare system. Screening must reduce the chance of dying or suffering. These are the only outcomes that matter.
On the AF ablation front, my friend Jason Andrade, from University of British Columbia in Vancouver, will present results of multi-center EARLY AF trial, which is an RCT of cryoballoon (CB) ablation vs medications for initial rhythm control in patients with yet untreated AF. The primary endpoint is first determined recurrence of any atrial tachyarrhythmia.
Osama Wasni from Cleveland Clinic presented very positive results of a similar trial, STOP-AF, at European Society of Cardiology meeting. This study found CB to be far superior in reducing AF. Thus, it is likely that the Canadian EARLY AF trial will also show reductions in AF. Both trials are at least partially sponsored by Medtronic—a company whose non-nefarious interest is in selling more cryoballoons.
As I wrote in my preview, early AF ablation worries me because AF can abate on its own, and although the risks of the an ablation procedure are small in absolute terms, the asymmetry of having an atrial-esophageal fistula or stroke is substantial.
Another highlight of AHA will be hearing about the new mineralocorticoid antagonist (MRA) drug finerenone, a novel nonsteroidal MRA. At the recent kidney week meeting, finerenone resulted in lower risks for chronic kidney disease progression and cardiovascular (CV) events in the FIDELIO-DKD trial. This RCT enrolled more than 5700 patients with chronic kidney disease and type 2 diabetes. The primary endpoint was a renal composite, but the secondary outcomes were CV death, myocardial infarction, stroke, and hospital admissions for heart failure. CV outcomes trended positive for the drug, and at AHA we will hear the data. The optimistic aspect of this drug is that it seems to have lower rates of hyperkalemia and of course its nonsteroidal nature means no more anti-androgen side effects
Finally, we will hear results of two trials of another SGLT2 inhibitor drug, sotagliflozin. Both trials will enroll patients with diabetes and both are CV outcomes trials. Thinking from a Bayesian perspective, it would be hard to bet against any SGLT2i class in high -risk patients.
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Cite this: Nov 13, 2020 This Week in Cardiology Podcast - Medscape - Nov 13, 2020.