A Man Coughed Up This Perfectly Shaped Blood Clot, Stunning His Doctors


If someone showed you the above picture without context, you’d probably think it was an intact blood vessel. Readers, it is not. It is a perfect cast of the branching air passages in the right lung of a man dying of heart failure, formed from coagulated blood that had been accumulating therein.

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The man’s doctors were absolutely gobsmacked by the thing, which they published in the New England Journal of Medicine.

First, let’s get one thing clear. It’s not actually part of his lung, as some news headlines are claiming. It’s not possible to cough up a lung (although you can cough so hard a lung herniates through your ribs. That’s not fun, so try to avoid it).

In fact, bronchial tree clots – called casts – aren’t uncommon at all. Several blood clot casts have been reported in the last few years – coughed up by a 57-year-old-woman with lupus in 2010, a 25-year-old pregnant woman in 2005, and an 80-year-old man in 2015.

And if you head on over to medical image-sharing social network Figure 1 and search for ‘bronchial cast’, you’ll see a variety of casts, formed from coagulated blood, or from mucus that accumulates in the lungs in certain medical conditions.

What makes this particular cast so intriguing is not that it happened at all, but that it’s absolutely enormous – and the patient coughed it up in one piece, without it breaking.

“We were astonished,” the man’s doctor, Georg Wieselthaler, told The Atlantic. “It’s a curiosity you can’t imagine – I mean, this is very, very, very rare.”

The patient, an anonymous 36-year-old man, coughed up the cast while being treated for acute end-stage heart failure in the ICU, after a long history of heart failure.

His doctors connected his heart to a device to help it pump blood around his body. But because these devices can also cause blood clots, they had to give him a continuous infusion of an anticoagulant called Heparin to try and prevent this from happening.

Except coagulation is a necessary part of the body’s self-repair system, working to keep blood vessels from developing tiny tears that will result in internal bleeding – or, if they occur in the blood vessels that transport blood around the lungs, from leaking into the air passages and accumulating there.

Sadly, this is what happened with the patient. Over the course of the week after his doctors implemented the Impella device and the Heparin treatment, he started to cough up smaller blood clots, culminating in an extreme fit of coughing during which he brought up a giant mass.

When the doctors unfolded it, they saw a cast so perfect they were able to clearly identify it as the man’s right bronchial tree.

They think what held it together could have been a protein called fibrinogen, which is vital to the clotting process. Although the patient was on anticoagulants, his infection caused an elevated level of fibrinogen in his blood – this could have held the clot together while he coughed it up.

Sadly, although he felt better after the clot was out of his lungs, and coughed up no further clots, the condition of his heart was too severe. He died just over a week later from complications of heart failure.

4 Research-Backed Supplements to Boost Your Hair, Skin, and Nails


fish oilCollagen. Biotin. Shark cartilage. Frankincense. Even… placenta? Every day, patients in my dermatology practice ask about supplements claiming to restore or improve the skin, hair, or nails. But do they, really?

Unlike medicines, which are regulated by the Food & Drug Administration, over-the-counter supplements are subject to little oversight. There is no guarantee that their claims or ingredients are backed by science (or that the ingredients on the label are actually even in the tablet) – making the supplement aisle the wild west of every pharmacy. While no vitamin or supplement should ever be taken without consulting a physician first, there are a few that are backed by scientific research showing that they may have a positive effect on our strands, skin, or nails. Here are some of them.

For skin cancer prevention: Vitamin B3, also called nicotinamide, has been shown to lower the risk of nonmelanoma skin cancers (such as basal cell carcinoma or squamous cell carcinoma) and precancerous growths (called actinic keratoses). In a 2015 New England Journal of Medicine study of more than 600 patients with a history of skin cancer, 500mg of B3 taken twice daily led to a 23% drop in new cancerous growths over 1 year. Sun protection remains the most important way to lower skin cancer risk – but those stats aren’t too shabby, for a vitamin.

For brittle nails: Biotin (also called vitamin H or B7) was shown to increase nail plate thickness by 25% in patients with brittle nails, while reducing splitting and improving nail smoothness, according to studies from the Journal of the American Academy of Dermatology (JAAD) and Cutis. The optimal dose isn’t known, but dermatologists have suggested 2.5mg daily for those with delicate nails. Just be sure to let your doctor know if you take biotin, and consider holding off on the vitamin prior to any bloodwork: In 2017, the FDA issued a warning that it can interfere with certain lab tests, including some measuring cardiovascular and thyroid levels.

For thinning hair: As a dermatologist, I never used to recommend dietary supplements for patients with sparse or shedding hair, unless there was a specific nutritional or medical issue to correct. Now I sometimes do for patients with male or female pattern hair loss – the gradual thinning many of us are prone to later in life. Small, randomized, double-blind, placebo-controlled studies of men and women with thinning hair, published in the Journal of Cosmetic Dermatology and Dermatology Research and Practice, showed a significant increase in hair density with reduced shedding over 3 to 6 months on a marine supplement called Viviscal. And the plant-based Nutrafol led to an increased number of hairs, with increased thickness, volume and growth rate in women over 3 to 6 months, according to a May 2018 study from the Journal of Drugs in Dermatology. This supplement contains ingredients said to reduce inflammation, antioxidants to help guard against cell-damage, and saw palmetto, which may inhibit hormonal factors that can contribute to hair thinning.

For psoriasis: Fish oil supplements may help to alleviate rashes in those suffering from psoriasis – a chronic condition of scaly, pink skin that often affects the elbows, knees, scalp, and other areas. A 2014 meta-analysis published in JAAD showed a moderate benefit in psoriasis – reduced area of rash, and improved thickness and redness of psoriasis – after supplementing with omega-3 polyunsaturated fatty acids from fish oils (eicosapentanoic acid, EPA, and docosahexanoic acid, DHA). The study authors suggested doses of 0.45 to 13.5 grams of EPA and up to 9 grams of DHA daily – and explained that the supplements are expected to be most helpful when used along with established psoriasis medications.

For whatever ails you: If there’s a supplement you believe in, it might just work – due to the powerful placebo effect. Decades of research have shown that the expectation of results is sometimes enough to actually see results. That’s one reason I don’t discourage vitamins that have a decent safety profile, if a patient truly believes in them.

But before starting any supplement, be sure to talk to your doctor to find out if it’s right for you and whether it’s safe to take with other medicines.

Lp(a) Levels May Modulate CV Benefits of Evolocumab: FOURIER


Patients treated with the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab (Repatha, Amgen) may experience a greater reduction in cardiovascular events if they have higher baseline levels of lipoprotein(a) [Lp(a)], US investigators have shown.

The results are from a preplanned analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, published in March 2017 in the New England Journal of Medicine.

As reported by theheart.org | Medscape Cardiology at that time, main FOURIER results showed that evolocumab was associated with a 15% reduced risk for a composite of myocardial infarction (MI), stroke, cardiovascular disease (CVD), coronary revascularization, and unstable angina hospitalization at 22 months compared with placebo (P < .001).

Moreover, treatment was associated with a 20% reduction in a composite of CVD, MI, and stroke vs placebo (P < .001), which occurred in tandem with large reductions in low-density lipoprotein (LDL) cholesterol levels.

The current analysis, presented here at the European Atherosclerosis Society (EAS) 2018 meeting, shows evolocumab also achieves significant reductions in Lp(a) levels of more than 25%.

The researchers found that the greatest effect of the drug compared with placebo on the risk for cardiovascular death, MI, and stroke was in patients with higher baseline Lp(a) levels, at 24% vs 15% in those with lower levels, at a twofold increase in the absolute risk reduction.

Study presenter Michelle L. O’Donoghue, MD, Brigham and Women’s Hospital, Boston, Massachusetts, told theheart.org | Medscape Cardiology that whether or not the benefits offered by Lp(a) reduction are “above and beyond” the LDL reduction is an area of ongoing study.

“But I think it’s worthwhile that we were able to see that baseline Lp(a) concentration appears to help identify individuals who derive greater benefit from treatment with evolocumab,” she added.

“So if those individuals have a larger magnitude of benefit and a smaller number needed to treat, then that’s perfect, as we’re trying to think about different high-risk features that might help to identify individuals who get the greatest benefit from the drug in a cost-effective manner.”

For O’Donoghue, one of the key aspects of their results is that they suggest that evolocumab affects both Lp(a) and LDL separately to lower the risk for cardiovascular outcomes. This was underlined by data showing that the greatest benefit was seen in individuals who achieved both their Lp(a) and LDL cholesterol target.

“With a drug like evolocumab, you’ve got multiple effects, and it becomes almost like a pleiotropic effect, because you’ve got LDL lowering, which is obviously very compelling, in addition to the effects on Lp(a),” she said.

“I think there’s a lot of work to be done to figure out whether or not the Lp(a) reduction on its own offers as much, or greater, or less benefit than LDL reduction on its own,” she added. “It’s interesting to see, though, that those who achieved the dual targets of lower levels of both are those who do best.”

Evolocumab and Lp(a)

The FOURIER trial involved 27,564 patients with stable atherosclerotic CVD and LDL cholesterol levels of 1.8 mmol/L (70 mg/dL) or higher who were receiving statin therapy and were randomly assigned to evolocumab, 140-mg injections every other week or 420-mg injections monthly, or to placebo.

After a mean follow-up of 2.2 years, evolocumab treatment was associated with a 59% relative reduction (P < .00001), or a 56-mg/dL absolute reduction, in LDL levels down to a median of 30 mg/dL, alongside the observed clinical benefits.

Previous Mendelian randomization data suggested that Lp(a) plays a causal role in the risk for coronary heart disease (CHD), and PCSK9 inhibitors have been shown to significantly reduce Lp(a) levels, so the team examined the impact of evolocumab on Lp(a) in FOURIER.

As part of the trial, Lp(a) levels were measured at baseline and weeks 12 and 58, with results available for 25,096 participants. The median Lp(a) level was 37 nmol/L (interquartile range [IQR], 13 – 165 nmol/L).

Individuals in the highest quartile of Lp(a) levels were, compared with those in the lower quartiles, significantly less likely to be male, to have ischemic stroke and diabetes mellitus, and to currently use tobacco (P < .001 for trend).

In contrast, individuals in the highest quartile were significantly more likely to have had a MI, to have peripheral artery disease, and to have higher baseline LDL cholesterol levels than those in the lower quartiles (P < .001 for trend).

As expected, higher baseline Lp(a) levels were associated in the placebo group with a significantly higher risk for CHD death or MI, cardiovascular death, MI or stroke, and MI and coronary death individually on multivariate analyses taking into account a range of potential confounding factors.

For example, the adjusted hazard ratio of CHD death or MI in participants with an Lp(a) in quartile 4 vs those in quartile 1 was 1.26 (95% CI, 1.02 – 1.56).

Among 11,864 participants given evolocumab, treatment was associated with a mean absolute change in Lp(a) levels at week 48 of –11 nmol/L (IQR, –31 nmol/L to –1 nmol/L), or a median percentage change of –26.9% (IQR, –46.7% to –6.2%).

The correlation between percentage change in Lp(a) and change in LDL cholesterol at 48 weeks in treated patients was r = 0.37 (P < .001), while that for absolute change was r = 0.21.

When the team divided the patients into those whose baseline Lp(a) level was above the median and those whose level was at or below the median, they found a difference in the impact of evolocumab on cardiovascular outcomes vs placebo.

Specifically, patients with a baseline Lp(a) level above the median had a hazard ratio of cardiovascular death, MI, or stroke with evolocumab vs placebo of 0.76 (95% CI, 0.66 – 0.86), or an absolute risk reduction of 2.8% and a number needed to treat of 36.

This compares with a hazard ratio for evolocumab vs placebo among patients with a baseline Lp(a) level at or below the median of 0.85 (95% CI, 0.73 – 0.97), or an absolute risk reduction of 1.28% and a number needed to treat of 79.

Next, the team looked at Lp(a) and LDL cholesterol together in terms of the impact of evolocumab treatment on the risk for combined cardiovascular events after week 12.

The risk was lower in patients who achieved a reduction of Lp(a) and LDL cholesterol to at or below the median at baseline (6.57%) than in those who achieved that milestone only with Lp(a) (7.88%), those who got there only with LDL cholesterol (8.45%), and those who achieved that for neither measure (9.43%) (P < .001 overall).

Concluding her presentation, O’Donoghue said their findings show that evolocumab significantly reduces Lp(a) levels and that “patients starting with higher Lp(a) levels appear to derive greater absolute benefit.”

Moreover, individuals “who achieve lower levels of both LDL cholesterol and Lp(a) have the lowest subsequent risk of CV events.”

Speaking after the session in an interview, she said that this latter finding is particularly interesting when one thinks of the individuals who have a reduction in Lp(a) levels “but a rise in LDL cholesterol levels at the same time.”

“What are those genetic predictors that help to identify those individuals? It’s not completely clear,” she said.

Completely Different Story

Commenting on the findings, Alberico L. Catapano, MD, PhD, professor of pharmacology at the University of Milan, Italy, and past president of the EAS, told theheart.org | Medscape Cardiology that “it’s a completely different story” between Lp(a) and LDL cholesterol.

He explained that with LDL cholesterol, the greater the reduction in plasma levels, the greater the benefit, while with Lp(a), “there’s always been a struggle” to demonstrate a similar relationship.

“Lp(a) is related to cardiovascular disease, but the strongest relationship is with calcification of the aortic wall, or aortic stenosis,” he said.

However, Catapano noted that the “exact mechanism is still not completely clear,” unlike the situation with LDL.

“Of course, we’ll never know everything for sure but we have robust evidence with LDL,” he said. “With Lp(a), it’s not clear whether it’s coagulation, whether it’s atherosclerosis and the buildup of cholesterol, or both together.”

“Having said that,” he added, “there is clearly a relationship that is not linear but sort-of hyperbolic, so that above a certain level, the correlation gets stronger and the risk becomes higher.”

Catapano pointed out, however, that the median Lp(a) levels seen in the FOURIER trial were lower than those seen in the general population and lower than the 50 mg/dL that has been linked to a substantially increased cardiovascular risk, “so you would not expect a huge benefit” with Lp(a) reduction in this population.

“The second point is they saw a benefit that was larger in absolute terms according to the levels of Lp(a), [which] is entirely in line with what we know,” he said. “We know that Lp(a) contributes to the risk and we know that we have a higher risk if we have higher Lp(a), and that reducing LDL cholesterol for sure reduces the risk.”

“Whether the contribution of Lp(a) to that reduction of risk is important, we do not know; it would be almost impossible to disentangle from the data,” he said. “That’s my personal view.”

However, Catapano believes, these answers may be provided  with the results of ongoing studies into antisense nucleotides, which target Lp(a) specifically.

FOURIER was funded by Amgen. O’ Donoghue reports receiving research grant support from GlaxoSmithKline, Eisai, Merck & Co, Janssen, Amgen, The Medicines Company, and AstraZeneca. Catapano reports being a consultant for and receiving honoraria from Pfizer, Sanofi, Genzyme, Merck, Akcea, and Amgen; receiving honoraria from Kowa, Mediolanum, Farmaceuti, Menarini, Bayer, Eli Lilly, Recordati, and Genzyme; and receiving research grants from Pfizer, Merck, Sanofi, Menarini, Regeneron, Mediolanum, and Farmaceutici.

 

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New Standard of Care in Advanced Renal Cell Carcinoma?


Combination immunotherapy could be a new standard of care for some patients with advanced renal cell carcinoma (RCC), suggest the results of a large randomized phase 3 trial

In the trial, both overall survival and objective response rates were significantly higher with nivolumab (Opdivo, Bristol-Myers Squibb) plus ipilimumab (Yervoy, Bristol-Myers Squibb) as compared to sunitinib (Sutent, Pfizer) in patients with intermediate- and poor-risk advanced RCC.

The 18-month overall survival rate was 75% with nivolumab plus ipilimumab vs 60% with sunitinib; the objective response rate was 42% vs 27%.

The findings were initially presented at the European Society of Medical Oncology 2017 Congress and were reported by Medscape Medical News at that time. They have now been published online in the New England Journal of Medicine.

“The study showed improvement in response and overall survival compared to sunitinib for patients with intermediate or poor features, comprising about 80% of patients with metastatic RCC,” said lead author Robert Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York City.

“In this group, nivolumab plus ipilimumab should be a new treatment option — pending regulatory approval — and a new standard of care,” he told Medscape Medical News. “The benefit was seen in the entire kidney cancer population as well, but in the small subset of patients with favorable-risk disease, the sunitinib group had higher response rates. So sunitinib will be regarded by most as the option of choice for favorable-risk patients.”

The combination of nivolumab plus ipilimumab has already been investigated in several tumor types, and response rates tend to be better than those of either agent used alone. The combination has been approved for the treatment of advanced melanoma.

The combination has also demonstrated antitumor activity in untreated and previously treated patients with advanced RCC, the authors note.

Significant Improvement in Survival and Response

The cohort included 1082 patients with previously untreated clear-cell advanced RCC who were randomly assigned to receive treatment with nivolumab plus ipilimumab (n = 547) or with sunitinib (n = 535). In the intent-to-treat population, 423 patients had intermediate-risk disease, and 416 patients had poor-risk disease.

The coprimary end points were overall survival, objective response rate, and progression-free survival in the group at intermediate or poor risk.

In the intermediate- and poor-risk group, the 12-month overall survival rate was significantly better in the nivolumab plus ipilimumab arm compared with that in the sunitinib arm: 80% vs 72% (hazard ratio for death, 0.63; 99.8% confidence interval, 0.44 – 0.89; P < .001).

The median overall survival was not reached with nivolumab plus ipilimumab. It was 26.0 months with sunitinib.

A complete response was observed in 40 patients (9%) in the nivolumab plus ipilimumab arm and in 5 patients (1%) in the sunitinib arm. Among the intermediate- and poor-risk patients, 81% in the nivolumab plus ipilimumab arm demonstrated a duration of response of at least 1 year; 70% of patients in the sunitinib arm demonstrated a duration of response of at least 1 year. The median duration of response not reached in the nivolumab plus ipilimumab arm; it was 18.2 months in the sunitinib arm.

For progression-free survival, the median was 11.6 months with nivolumab plus ipilimumab and 8.4 months with sunitinib, but the difference between groups did not meet the prespecified threshold (P = .009) for statistical significance (hazard ratio for disease progression or death, 0.82; P = .03).

The authors assessed outcomes for the entire intent-to-treat population (patients with favorable, intermediate, or poor risk). The 12-month overall survival rate was 83% for immunotherapy vs 77% with sunitinib; the 18-month overall survival rate was 78% vs 68%.

The median overall survival was not reached for the nivolumab plus ipilimumab arm; it was 32.9 months for the sunitinib arm. The rate of independently assessed objective response was 39% with nivolumab plus ipilimumab and 32% with sunitinib (P = .02; not significant per the prespecified 0.001 threshold).

Median progression-free survival rates were similar for both groups: 12.4 with nivolumab plus ipilimumab and 12.3 months with sunitinib (hazard ratio for disease progression or death, 0.98; P = .85).

Favorable Risk Favors Sunitinib

The subgroup of patients who were considered to be at favorable risk did worse with immunotherapy than with sunitinib. An exploratory analysis found that in this small subgroup (n = 249), response rates were higher and progression-free survival was longer with sunitinib than with the combination of nivolumab and ipilimumab.

The 12-month overall survival rate was 94% with nivolumab plus ipilimumab and 96% with sunitinib. The 18-month overall survival rates were 88% and 93%, respectively (the hazard ratio for death favored sunitinib: 1.45; 99.8% CI, 0.51 – 4.12; P = .27). The objective response rate was 29% with nivolumab plus ipilimumab vs 52% with sunitinib (P < .001). The median progression-free survival was 15.3 months vs 25.1 months (hazard ratio for disease progression or death, 2.18; 99.1% CI, 1.29 – 3.68; P < .001), favoring sunitinib.

The rate of complete response, however, was 11% with nivolumab plus ipilimumab and 6% with sunitinib.

“It is important to evaluate and better understand the underlying tumor biology of each of these groups to better define what is driving response to nivolumab plus ipilimumab and to sunitinib,” said Motzer. “We have not compared the combination to nivolumab alone, although cross-study comparisons favor the nivolumab/ipilimumab combination in producing tumor responses.”

Patients who received the immunotherapy combination had fewer grade 3-4 adverse events than those who received sunitinib (46% vs 63%), but there were more discontinuations (22% with immunotherapy vs 12% with sunitinib) and more treatment-related deaths (8 patients vs 4 patients). Overall, treatment-related adverse events of any grade occurred in 93% of patients in the immunotherapy group vs 97% of those treated with sunitinib.

Curative Treatments Needed

In an accompanying editorial, Brendan Curti, MD, from the Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, writes that it is “notable that tumors with a greater number of mutations appear more likely to have a response to checkpoint immunotherapy.”

This may account for the better response with immunotherapy seen in some patients but not others. There may be a “higher tumor mutational load and a broad, though ineffective, extant adaptive immune response in patients with intermediate- and poor-risk renal-cell carcinoma as compared with patients with favorable-risk disease,” says Curti.

But importantly, the combination of ipilimumab and nivolumab is a step in the right direction when it comes to improving treatment in RCC. He notes that for the past quarter century, treatment has evolved from “infrequently effective cytokine-based immunotherapy to active but rarely curative TKI [tyrosine kinase inhibitor] treatment, and now to more effective immunotherapy that in some clinical settings is superior to TKIs.”

However, with current therapies, there is still only a small probability of complete response or cure. “The goal of future immunotherapy development should be not just transient response or tumor control, but rather cure in a higher proportion of patients,” Curti emphasizes.

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Oral Edoxaban May Be an Alternative to Dalteparin for Cancer-Related VTE


Hello. I am David Kerr, professor of cancer medicine from the University of Oxford, in England. I want to talk about a study published in the February 15 edition of the New England Journal of Medicine.[1] This was a beautifully well-designed and conducted randomized trial that compared edoxaban, a novel oral anticoagulant, with dalteparin in patients with cancer who had a venous thromboembolism (VTE).

The trials group calls itself the Hokusai Group. For those of you who don’t know Hokusai, he was an important Japanese painter who created many woodblock prints and was a member of the school of ukiyo-e, painters of passing, or everyday, life. There is something about the ephemerality of their art that has always attracted me. Among the more famous paintings are different views of Mount Fuji. My apologies if I am being a smarty pants, a clever clogs. But some of these paintings, particularly The Great Wave, are absolutely beautiful.

This trials group randomly assigned just over 1000 patients to receive oral edoxaban (after 5 days of low-molecular-weight heparin) or subcutaneous dalteparin. It was a noninferiority trial; treatment was given for a minimum of 6 months and a maximum of 12 months after the initial venothrombotic or embolic event. The composite endpoint, which is being used more and more in these trials of novel oral anticoagulants, was the recurrence rates of VTE and major bleeding incidents. The trial showed that edoxaban is not inferior to subcutaneous dalteparin.

Within the composite endpoint, there were fewer further thromboembolic events in the edoxaban arm but more bleeding events in the edoxaban arm. They evened each other out in terms of the noninferiority.

This was quite a useful study. It is an important first step in being able to show that we can substitute useful oral treatment for daily subcutaneous dalteparin. Patients don’t like dalteparin. We’ve all had patients who self-administer dalteparin during chemotherapy, and they are covered in bruises; they are sore. It’s a nuisance and it’s necessary, but if we find that we can substitute edoxaban, which is given orally and is well tolerated, then this is quite an important landmark study.

The major bleeds were predominantly in the upper gastrointestinal (GI) area. Quite a number of the patients who had GI bleeding had previously undergone GI surgery of some sort. Interpret that as you will.

This is an important study—well designed, well conducted, well reported—that tells us that we have a possible alternative to discuss with patients, offering them edoxaban instead of subcutaneous dalteparin.

Thank you for listening. Thank you for allowing me to segue into stories about Hokusai and the painters of ukiyo-e. Think about the passing life, the ephemerality. W.H. Auden called life the gallop to the grave; there’s some truth in that.

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Steroids and Saline in the ICU: One Critical Care Physician’s Perspective


New studies inform ongoing controversies about steroids for patients with septic shock and about crystalloid solutions for fluid resuscitation in the intensive care unit.

On March 1, 2018, three studies that generated much discussion in the critical care community were published in the New England Journal of Medicine. Two of these studies focused on use of corticosteroids in treating patients with septic shock; in the third study, researchers examined whether crystalloid choice in intensive care unit (ICU) patients influenced outcomes. Are these trials practice-changing?

Should steroids be given to septic shock patients?

The controversy regarding corticosteroids for treating patients with septic shock has been ongoing for nearly 2 decades. These two new trials add to the debate but probably won’t end it, because they generated partially conflicting results. In one trial, APROCCHSS, 90-day mortality was significantly lower in patients who were treated with both the glucocorticoid hydrocortisone (50 mg every 6 hours for 1 week) and the mineralocorticoid fludrocortisone than in placebo recipients (43% vs. 49%; NEJM JW Gen Med Mar 1 2018 and N Engl J Med 2018; 378:797). In contrast, the other trial (ADRENAL) was a comparison of hydrocortisone alone versus placebo, and mortality was virtually the same in both groups – about 28% (NEJM JW Gen Med Apr 15 2018 and N Engl J Med 2018; 378:809). Key differences between the trials were use of a mineralocorticoid and higher overall mortality (suggesting a sicker patient population) in APROCCHSS. Notably, in both studies, the mean duration of septic shock was shorter in the steroid groups; in ADRENAL, this translated into less time in the ICU. Corticosteroid side effects were minimal in both trials.

Multiple trials now have shown that steroids shorten the duration of septic shock. If this effect shortens the length of ICU stay, as it did in ADRENAL, steroid use might result in cost savings and less arduous hospitalizations for some patients and families. In other words, even if the mortality benefit is marginal, these secondary effects might be worthwhile, given the low cost and apparent absence of harm from relatively brief courses of moderate-dose steroids.

After talking to several colleagues in Seattle and across the country, my sense is that these studies will reinforce previous practice preferences, whatever they might have been. Those who previously were steroid skeptics will not necessarily change their practice, whereas clinicians who had low thresholds for giving steroids will continue to do so and will note that APROCCHSS supports their practice. Like many of my peers, I will continue using glucocorticoids for patients with refractory septic shock who are on escalating doses of vasopressors or who require multiple vasopressors. In my discussions, reactions to adding fludrocortisone were mixed. My take is that fludrocortisone is inexpensive and low risk, so I probably will add it when I start glucocorticoids.

Is a balanced crystalloid better than normal saline for ICU patients?

The third trial (SMART) was conducted because of concern about potential adverse renal effects of the high chloride content of normal saline. Investigators compared normal saline with “balanced” crystalloid solutions (either lactated Ringer’s solution or Plasma-Lyte A) in more than 15,000 patients in ICUs at Vanderbilt University. The primary outcome was major adverse kidney events — a composite outcome that included death, renal-replacement therapy, or doubling of creatinine at discharge. Patients in the normal saline group had more primary outcome events than those in the balanced solution group (15% vs. 14%); this small difference was statistically significant for the composite outcome, but no significant difference was found for any individual component (NEJM JW Gen Med Apr 15 2018 and N Engl J Med 2018; 378:819).

In my discussions with other intensivists, most told me that their practices already were changing to preferential use of lactated Ringer’s instead of normal saline, except in unique patient populations (e.g., those with traumatic brain injury). So, although debate continues on how to interpret the results of SMART, and experts express caution about using a single-center trial to drive practice, the results reinforce the practice of reaching for lactated Ringer’s first, for most critically ill patients who require fluid resuscitation.

Birth Defects in 7% of Zika Pregnancies in French Territories


Stats in line with U.S. numbers, but not Brazil’s

Neurological and ocular birth defects possibly associated with Zika virus infection were present in 7% of fetuses and infants of pregnant women who had symptomatic, confirmed infection in France’s territories in the Americas, researchers for the prospective ZIKA-DFA-FE study reported.

Birth defects occurred more often in fetuses and infants whose mothers had been infected early in pregnancy, reported Bruno Hoen, MD, PhD, of the University Medical Center of Guadeloupe in Pointe-a-Pitre, France, and colleagues, in the New England Journal of Medicine.

“Zika virus infection during pregnancy has been identified only recently to cause severe birth defects, including microcephaly, other brain defects, and the congenital Zika syndrome,” Hoen told MedPage Today. “However, the magnitude of this risk was not clearly defined, with discrepancies between observational data from Brazil and the U.S. Zika pregnancy registry.”

In Brazil, birth defects from Zika virus were estimated to be higher than 40% according to a prospective observational study. In the United States, percentages have ranged from 5% to 10%.

In French territories of the Americas — French Guiana, Guadeloupe, and Martinique — the Zika virus epidemic began in early 2016. ZIKA-DFA-FE used several recruitment methods to enroll women whose pregnancies overlapped with the epidemic period. In each territory, pregnant women with suspected infection went to a prenatal diagnosis center for Zika infection testing and were asked to join the study.

Only pregnant women with clinical symptoms consistent with acute Zika virus infection and laboratory confirmation of recent infection with a positive result on a molecular testing of blood or urine samples were included. The researchers considered the date of the first Zika virus-related symptom onset as the date of infection.

Of 555 fetuses and infants in the 546 pregnancies included in the ZIKA-DFA-FE study, 28 were not carried to term or were stillborn, and 527 were born alive. Neurologic and ocular defects possibly associated with Zika virus infection were present in 39 fetuses and infants (7.0%; 95% CI 5.0%-9.5%). Microcephaly was detected in 32 fetuses and infants (5.8%), of whom 9 (1.6%) had severe microcephaly, and congenital Zika syndrome was identified in 17 (3.1%).

“Whichever endpoint was considered — neurologic and ocular defects, microcephaly, or Zika congenital syndrome — abnormalities were more common when Zika infection occurred during the first trimester than when it occurred during the second or third trimester of pregnancy,” Hoen said. For example, neurologic and ocular defects were 12.7% when Zika virus infection occurred in the first trimester, 3.6% when it occurred in the second trimester, and 5.3% when it occurred in the third trimester.

These findings are remarkably similar to ones in the U.S. Zika Pregnancy and Infant Registry, wrote Margaret Honein, PhD, MPH, of the Centers for Disease Control and Prevention in Atlanta in an accompanying editorial. In the U.S., approximately 5% of pregnancies with possible Zika virus infection and 10% of the subset of pregnancies with laboratory-confirmed Zika virus infection resulted in a Zika virus-associated birth defect, she noted; the risk estimate was 15% when the confirmed infection occurred in the first trimester.

“Although there is growing clarity about the magnitude of the risk of serious birth defects associated with Zika virus infection detected during the newborn period, the full range of disabilities, including the possible effect on neurodevelopment, remains unknown,” she noted.

And while studies of pregnant women with symptomatic Zika virus infections are important, they don’t provide information about the estimated 80% of pregnant women with Zika virus infections who have no reported symptoms, she added: “Population level increases in Zika virus-associated birth defects are unlikely to be recognized without ongoing timely and comprehensive surveillance of birth defects that captures all affected fetuses and infants regardless of whether maternal Zika virus exposure or infection was identified.”

The difference between these rates and those observed in Brazil is not attributable to the percentage of infants and fetuses with microcephaly, but to the percentage with wider neurologic birth defects, Hoen and colleagues noted. The clinical implications of Brazil findings are not yet known and may be determined through longer-term follow-up.

“The Zika virus should definitely be added to the list of infectious agents that can cause severe birth defects, as are rubella virus, cytomegalovirus, and others,” Hoen said.

To protect fetal health in the future, Zika virus serology should be included in initial pregnancy work-ups for women in endemic areas, and fetal ultrasound monitoring should be enhanced when Zika virus infection has been diagnosed, he added.

Genetic Mutation May Underlie AV Malformations


Arteriovenous malformations of the brain may arise due to a genetic mutation, acquired later in life, that activates a cellular signaling pathway in endothelial cells — the same one that drives tumor formation, a study showed.

Often the root of hemorrhagic stroke in young adults and children, these abnormal connections between arteries and veins in the brain vasculature were sampled via temporal lobectomy, after which exome DNA sequencing detected somatic activating KRAS mutations in 45 out of 72 tissue samples.

Researchers led by Sergey Nikolaev, PhD, of University of Geneva Medical School, reported in the New England Journal of Medicine that expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased extracellular signal-regulated kinase (ERK) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior. Inhibition of MAPK (mitogen-activated protein kinase)-ERK signaling reversed these processes.

“We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells,” Nikolaev’s group wrote, suggesting that active KRAS “dysregulates angiogenesis and vascular remodeling in endothelial cells.”

“How might alterations in RAS signaling in endothelial cells induce arteriovenous malformations? The mutations that we have identified are known to drive strong and constitutive MAPK-ERK signaling and are important drivers of tumorigenesis. Arteriovenous malformations of the brain are not associated with cancer, which suggests a context-dependent role for KRAS mutations in the endothelium. The finding that somatic activating KRAS mutations in endometriosis do not cause cancer is consistent with this interpretation.”

Even if not all arteriovenous malformation samples showed activating KRASmutations, they still had more MAPK-ERK signaling in endothelial cells. This led the investigators to conclude that activation of this pathway may be a defining feature of these malformations.

“In the absence of available direct pharmacologic inhibitors of KRAS, small-molecule MEK inhibitors, which are used in clinical practice for treating cancers, represent candidates for testing in clinical trials to treat arteriovenous malformations of the brain,” the authors suggested.

 Nikolaev and colleagues conducted their study using tissue and blood samples from 72 patients with arteriovenous malformations, a group comprising patients from Canada’s Toronto Western Hospital and an independent validation group from Finland.

Participants were eligible if they had unifocal arteriovenous malformations with a defined nidus and arteriovenous shunting found on digital subtraction angiography. Additionally, they couldn’t have a family history of arteriovenous malformations or documented history of genetic vascular disease.

“The causal mutations here are acquired in life and only present in the diseased tissue,” emphasized Sekar Kathiresan, MD, of Massachusetts General Hospital, who was not involved with the study, explaining that these KRAS mutations therefore “cannot be tested for from a blood sample.”

Indeed, the study authors found no KRAS mutations in patients’ blood.

“I would not recommend genetic testing for patients based on this finding alone,” said Shyam Prabhakaran, MD, of Northwestern Memorial Hospital in Chicago, who also was not involved with the study. He added that there is no prognostic or treatment implication yet, anyway.

 It will be necessary to replicate the present data given that they come from such a limited sample, Prabhakaran said. “Further studies could consider whether this mutation or dysregulation of the RAS-MAPK pathway is associated with arteriovenous malformation growth or rupture.”

Nevertheless, the findings by Nikolaev’s group are “truly novel,” according Kathiresan. “Now, one can basically think of this disease like a cancer of blood vessel lining cells. The finding suggests a treatment hypothesis as well — inhibiting the KRAS pathway may prevent growth of these malformations.”

“This finding builds on an emerging theme of acquired mutations as a cause of common diseases,” he continued. His own research group recently found that acquired mutations in blood stem cells increase the risk of heart attack.

MRI May Still be OK for Legacy Cardiac Devices


MRI scanning may be safe even for patients with legacy pacemakers or implantable cardioverter-defibrillators (ICDs) not known to be MRI-ready, as long as a safety protocol is followed, a prospective study suggested.

The most important event to watch out for was device reset to a backup mode immediately after scanning, according to Saman Nazarian, MD, PhD, of University of Pennsylvania Perelman School of Medicine, and colleagues. This happened in nine out of 2,103 scans (0.4%), where eight of those resets were transient.

The one case where a reset couldn’t be fixed by device reprogramming was when a patient had a legacy pacemaker with less than 1 month of battery life left; the device had to be replaced, the authors reported online in the New England Journal of Medicine.

“If power-on reset occurs, the device reverts to an inhibited pacing mode. Therefore, in pacing-dependent patients, the device may transiently cease pacing because of electromagnetic interference, and electrocardiographic monitoring and pulse oximetry are warranted so that the scanning can be stopped if inhibition of pacing occurs,” they said.

A prespecified safety protocol dictated that pacing be switched to asynchronous mode for pacing-dependent patients; pacing placed in demand mode for others; and tachyarrhythmia functions disabled.

When it came to changes in device parameters, 1% of patients had P-wave amplitude fall by at least 50% after going into the MRI.

No adverse events observed in the 63% of patients that had a follow-up at 1 year. By then, device interrogations showed that the most common changes (by ≥50%) were:

  • Decreases in P-wave amplitude (4%)
  • Increases in P-wave amplitude (4%)
  • Increases in atrial capture threshold (4%)
  • Increases in right ventricular capture threshold (4%)
  • Increases in left ventricular capture threshold (3%)

“No change in device parameters that occurred either immediately after the MRI or at long-term follow-up in any patient was large enough to result in lead or system revision or device reprogramming,” Nazarian’s group emphasized.

Their study population was a group of 1,509 patients who underwent 1.5-Tesla MRI scans deemed clinically necessary despite having a pacemaker (58%) or ICD (42%) not meeting FDA criteria for being MRI-conditional. Clinicians performed device interrogation at baseline and immediately after the MRI.

“In our smaller study that was reported previously, we noted an association between thoracic imaging and changes in long-term right ventricular sensing and capture threshold. However, the current larger study, in which the follow-up period was longer, does not suggest any association between the region of imaging and detrimental changes in device parameters,” according to Nazarian’s group.

“The primary detrimental associations were a larger reduction in right atrial and right ventricular lead sensing immediately after the MRI with ICD systems than with pacemakers, as well as a larger reduction in long-term right ventricular lead sensing with longer lead length than with shorter lead length.”

Besides being a single-center study, the analysis included patients with a wide variety of cardiac devices, so the number of each pacemaker or ICD included was small. Furthermore, a 20% rate of patients lost to follow-up was a major study limitation.

Even so, they maintained, the present findings complement those of the older, similar MagnaSafe Registry.

Clinical Trialists, You Can’t Always Get What You Want


Investigators have lost control of their trials’ messages

The following is a lightly edited version of a talk I presented (without slides!) at the CVCT Forum workshop in Washington, D.C., earlier this month. The topic was the changing role of media in communicating the results of clinical trials.

When it comes to the role of media in communicating the results of clinical trials, I have some bad news for this audience. In the past, it may have been possible to “control” the message from a clinical trial. This is now no longer possible. You have lost control of media, and you cannot control the message.

 The New England Journal of Medicine‘sJohn Jarcho pointed out a few weeks ago that many trials published 20 to 30 years ago would not pass muster today. But many of those imperfect trials delivered results that profoundly and permanently altered the field of cardiology. The same can not be said of today’s trials.

In the beginning — and by the beginning I mean when I was new to the business — a big cardiology trial was easy to understand. As journalists, we were told, and dutifully reported, what the trials meant and how they should be interpreted. Some of the first really important trials I reported in the late 1980s and early 1990s were GISSI, V-HeFT, ISIS-2, CONSENSUS, 4S, and GUSTO. It is difficult to convey now the excitement and interest that these trials generated at the time.

The messages from these trials could not have been more clear, and these were important messages. The thrombolytic trials were especially dramatic. The media took it upon ourselves to help our readers marvel at the remarkable developments in the field of cardiology, which had, for the first time, achieved something quite astonishing and praiseworthy. For the first time, it had come up with new treatments for cardiovascular disease, the leading cause of death and disability in the developed world.

Often there was a commercial angle, but we were too polite to talk about that — unless of course that was part of the story, like the “miracle” of Genentech’s tPA, approved in 1987.

There was broad harmony among the trial investigators, the medical societies, industry, regulators, and other interested parties about the importance of these trials and what they meant. It was easy to “control” the message. Over time, the machinery to convey this message became increasingly efficient, peaking in the early 1990s with the GUSTO trial and the statin trials. If memory serves, GUSTO, now nearly 25 years ago, was the first trial with a simultaneous publication, considered an astonishing feat at that time. It was presented at a symposium that lasted several hours. The key point is that the GUSTO team, and their Genentech partners, had complete control of the process and the message. They achieved total victory. One of the biggest controversies in cardiology ever was, essentially, resolved in the course of a few hours.

The trials got even bigger — and so, we thought at first, even better and more important — but in truth they were bigger because they were only trying to show an incremental advantage. The easy work, it turns out, had been done. The low hanging fruit had been picked. I remember listening — and failing to comprehend — as Richard Peto talked about the difference between placebo-controlled trials and active-controlled trials. It was a long time before I was able to understand his message.

Let’s jump ahead now to the COURAGE trial. Somehow it now seems appropriate that this came out in 2007, at the same time as a far larger economic and political turmoil was starting to wreak havoc. Was COURAGE representative of something even larger? There had, of course, been many long and hard-fought battles in cardiology before. In GUSTO, it had been the thrombolytic wars between the tPA and streptokinase forces, and this had been a truly bitter division. But back then the different sides spoke the same language. When it came to COURAGE, it became clear, the common culture had split and divided. The two sides seemed to exist in alternate, mutually-exclusive worlds.

The war over COURAGE was fought on multiple battlefronts, nowhere more intensely or publicly than in the media, including the mainstream media, the specialized medical media, and, for the first time, the online medical media, such as TheHeart.org, where I was the editor at the time.

Something completely unprecedented happened early on. Martin Leon, the single most influential interventional cardiologist in the known universe, was busted for sharing the main result and criticizing the trial at a satellite symposium prior to the embargo lift. Leon had been a reviewer for the NEJM paper and was subsequently sanctioned by both the American College of Cardiology, where the results were presented, and by NEJM. My point here is that neither the trial investigators nor the trial critics were able to control the message.

In recent years, this loss of control — by either investigators or critics — has continued to accelerate. For important and potentially controversial trials, it is no longer possible to control or even predict the way results are communicated to either the profession or the general public. The investigators may have an intended message, but this can now be changed or even hijacked by outsiders, even non-expert outsiders like myself, using both traditional and social media. (A corollary is that unoriginal or unimportant trials may be completely ignored or, alternately, subject to manipulation by interested parties.)

Let me briefly mention a few studies from the last few years. The PARADIGM trial was almost immediately subject to intense criticism from skeptics on the CardioExchange website. In the space of 24 to 48 hours, the terms and scope of the debate about PARADIGM were established. This swiftly dominated the broader reception of the trial both in the general media and even, to a remarkable degree, the academic discussion of the trial.

I’ve written a lot about SPRINT in the last few years. I just want to make one point here now. The SPRINT investigators forgot it was a new century. They thought they could pull off a GUSTO-type shock and awe campaign and steamroll everyone with their predetermined message. Let’s just say it didn’t work and, in fact, their efforts backfired on them.

More recently the reception of ORBITA shows how this trend continues to accelerate, in this case in dizzying fashion. For good reason, most physicians and academics are skeptical or even afraid of Twitter. But in this case if you weren’t on Twitter, you missed out on an amazing event: the immediate, overwhelming, and, in general, really high-quality discussion about the trial. This discussion included a large number of prominent general and interventional cardiologists and clinical trialists engaged in furious debate. They almost immediately identified the topics that will undoubtedly be the main source of discussion about this trial for a long time.

Many of you in this room probably don’t feel comfortable with social media in general and Twitter in particular, but you will almost certainly have to recognize its impact. If you want to have any say in the reception of an important or controversial trial, you may need to change your tune. The role of social media is evolving and much about it is unclear and unknown, but it is certain that social media has changed the way clinical trials are received.