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In This Week’s Podcast
For the week ending January 29, 2021, John Mandrola, MD comments on the following news and features stories.
My review of the Johns Hopkins site today reveals entirely good news. Cases in the United States, especially California, are in steep decline. Vaccines are being rolled out—albeit with difficulty. A new single-shot Johnson & Johnson vaccine is potentially on the horizon. But COVID numbers in our hospital are not budging; in fact, we have gone up a slight amount.
Atrial Fibrillation and COVID-19
The Northwell group in New York has published a study looking at the effect of atrial fibrillation (AF) in patients admitted with COVID-19. About 9500 patients from 13 hospitals had COVID-19 over a 2-month period in the spring. They found that AF occurred in nearly 1700 or about 1 in 5 patients. These patients formed one group. The control group included patients without AF. Obviously these groups will differ in characteristics, so the authors used propensity matching to attempt to match patients with AF and those without AF. Characteristics they used to match patients were smoking, age, body mass index, etc. The key finding was that having AF increased the risk of dying: 54.3% vs 37.2%, relative risk about 1.5.
This is an observational, non-randomized, likely biased study with results that I believe. Why? The authors nicely explain that AF serves as a risk factor for death in many other conditions that afflict patients who are sick enough to be in the hospital. Things like sepsis, MI, heart failure. And the association is probably both causal and non-causal. Namely, AF surely serves as a marker for more advanced cardiac disease (that’s the correlative part), and AF complicates therapy (that’s the causal part).
This study highlights the all-important notion that (except in rare cases) AF occurs as a downstream effect of stuff that puts stress on the atria. In the case of pneumonias, AF occurs because of the hypoxia and illness. In the case of obesity, obstructive sleep apnea, and hypertension, AF occurs because of electrical and structural atrial disease. When you see AF, always look upstream. Something is causing it to happen. Treat that cause and AF likely improves.
COVID and Thrombosis
Circulation recently published a cardiac pathology series from Italian and American authors of 40 patients who died from COVID-19. Their goal was to determine the pathologic mechanisms of cardiac injury. They categorized the hearts according to presence or absence of acute myocyte necrosis and then strived to determine the underlying mechanisms of cardiac injury.
Fourteen (35%) hearts had evidence of myocyte necrosis, predominantly of the left ventricle. Cardiac thrombi were present in 11/14 (78.6%) cases with necrosis; 2/14 (14.2%) had epicardial coronary artery thrombi while 9/14 (64.3%) had microthrombi in myocardial capillaries, arterioles, and small muscular arteries.
In her coverage, journalist Debra Beck interviewed the senior author who emphasized not only what they saw, but what they didn’t see: “What we saw in the majority of patients with myocardial injury were these small areas of infarct and microthrombi in small vessels. What we didn't see was any evidence of myocarditis and/or huge infarcts in, like, the LAD (left anterior descending) artery. What we're seeing here is not clinically detectable.... There is no test that will tell you there are microthrombi and no imaging tests that will show these focal areas of necrosis, but that doesn't mean it's not there."
The authors compared the components of the micro-emboli with both COVID-positive and COVID-negative patients who had macro-emboli within the myocardium due to epicardial obstruction, and compared the micro-emboli with clots aspirated during PCI for STEMI in non-COVID patients. The autopsy-obtained microthrombi had significantly more fibrin and terminal complement C5b-9 immunostaining. (Higher fibrin and more complement suggest that micro-emboli in COVID-19 is likely based in immune reactions.)
Caution is warranted. Everyone believes COVID-19 is especially strong in its ability to cause thrombosis—this study supports that. But I am not so sure about the COVID-thrombosis connection. We don’t have good controls.
For instance, it is easy to believe the thrombosis rate is significantly higher in COVID-19 because clot rates in COVID are higher than in previous flu outbreaks or in past studies of patients with serious medical diseases. But in 2021, we are a lot better at detecting venous thromboemboli. What if next year we used the same intensity to look for thrombosis in patients with RSV or influenza? Also, we know COVID-19 more often affects older sicker people—people who already have a predilection to have altered hemostasis. Thus, is it the virus or the host? Finally, pathology cannot at all determine therapy, anticoagulation, for example. We will soon learn the results of three RCTs looking at anticoagulation in patients with COVID-19. The press releases suggest mixed results.
Last week, the FDA approved the novel drug vericiguat for the treatment of patients with heart failure with reduced ejection fraction (HFrEF). The hard-to-pronounce drug stimulates guanylate cyclase which ultimately sensitizes cells to endogenous nitric oxide. That may be important because in HF, endothelial dysfunction and reactive oxygen species reduce nitric oxide bioavailability, and that results in relative deficiency of soluble guanylate cyclase and reduced cyclic GMP generation. The selectivity of vericiguat for cyclic GMP is not seen with other vasodilatory drugs like nitrates or phosphodiesterase inhibitors.
Little of this biochemistry matters to the clinician and patient. We care about outcomes. The placebo-controlled VICTORIA trial was published in the New England Journal of Medicine in May 2020. The trial enrolled about 5000 patients with HFrEF, mean age 67 years, mostly male, with a mean EF of 28%.
The primary endpoint (PEP) was cardiovascular (CV) death and/or first hospital admission for HF (HFH).
The results were modest.
Over just 11 months a PEP occurred in 35.5% in the vericiguat arm and 38.5% in the placebo arm. That is a hazard ratio of 0.90 – a 10% relative risk reduction.
Confidence interval (CI) went from 0.82 to 0.98. Note the lower bound or best case of only 0.82. CI are hard to define exactly, but here, we can be 95% certain that the true mean difference in the two arms is not better than an 18% reduction.
The p-value calculated at 0.02.
CV death was 16.4% in vericiguat vs 17.5% in placebo arm; the total difference in this trial of more than 5000 patients was 27 fewer CV deaths. HFH were 27.4% with vericiguat vs 29.6% in the placebo arm. Neither of the components of the PEP alone reached statistical significance. Overall death also did not reach statistical significance.
Compare these results with some major trial results of other guideline-directed medical therapies for HFrEF.
Carvedilol: 65% reduction in DEATH (stopped early for efficacy).
Sacubitril/Valsartan (PARDADIGM): 20% reduction in CV death or HFH (stooped for efficacy). Significant reductions in CV death.
Spironolactone (RALES trial): 30% reduction in death (stopped early for efficacy).
Dapagliflozin (DAPA-HF): 26% reduction in CVD and HFH, including a significant reduction in CV Death.
Relative to beta blockers, RAS inhibition, mineralocorticoid receptor antagonists, and SGLT2 inhibitors, this drug has modest effects. By the US Food and Drug Administration approving the drug, the stimulus to do another trial to confirm or refute the borderline findings is unlikely.
Postural Orthostatic Tachycardia Syndrome
Postural orthostatic tachycardia syndrome (POTS) is about as complex and difficult a condition to treat as there is in cardiology.
The Journal of the American College of Cardiology published a clinical trial of lower body compression for POTS from Dr Satish Raj’s group in Calgary. The lead author was Kate Bourne. They enrolled 30 patients, 28 of them women, mean age 32 years, who underwent 10-minute head-up tilt with each of 4 compression conditions—none, lower leg only, abdomen and thigh compression, and full abdomen and leg compression.
These were carefully selected patients who had a physician diagnosis of POTS, defined as a ≥30 beats/min increase in heart rate within 10 minutes of upright posture, in association with orthostatic symptoms, in the absence of orthostatic hypotension, and in the absence of medications that could increase the heart rate at the time of diagnosis.
The results were clear: the compression garment reduced heart rate and improved symptoms during head-up tilt in a dose-dependent manner. Figure 4 in their paper elegantly shows the graded response of leg, abdomen, and full compression relative to the control group of no compression. Patients who had the greatest heart rate response at baseline (eg the patient’s with the most “severe” POTS) had the greatest heart rate reduction with compression.
The authors concluded that this compression garment when used in the highest dose or most compression reduced HR and improved symptoms during a HUT.
Bourne and colleagues were selective in their experiment. They made sure patients had truly abnormal responses to head-up tilt. POTS in the wild may not be that simple.
Two luminaries in the field of electrophysiology, Drs. Bendit and Sutton wrote the editorial accompanying this experiment. They note that POTS has become a much broader condition that may include symptoms that are unrelated to posture, such as chronic fatigue, migraine, GI disturbances and even brain fog. Head-up tilt testing, they write, may only address a small part of POTS. In that editorial, they link to two worthy papers; one a review by Brian Olshansky and others; the other a position statement from the Canadian CV Society, authored by Satish Raj.
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Cite this: Jan 29, 2021 This Week in Cardiology Podcast - Medscape - Jan 29, 2021.