Team players

One of my good friends is in the hospital right now recovering from extensive abdominal surgery. She's doing beautifully, but, as expected after a 10 hour operation, the road back to health is slow and painful. Each morning, her 'surgical team' breezes through, asks her how she is feeling, then flitters out without really hearing the answer. Imagine their surprise when they announced that it was time to stop the IV pain meds, and she announced "I'M NOT READY!"

The surgical team scuttled out the door and discontinued the IV drip for pain.

One day later the 'psychiatry team' shows up. Team members are one unhappy-looking med student and one psychiatry resident. They ask permission to be there, permission to talk in front of me the visitor, but choose not a we're-all-just-human-here sort of opener such as "Geez, what a journey you've been on, how are you holding up?" Rather med student leads off with "Are you feeling a little anxious?" Hell yes, major surgery, slow discouraging recovery, still got chemo treatments left to go, what on earth do you expect... says my friend.

"Well," says Dr. Psych Resident, taking charge, "your team asked our team to come in and find out why you're anxious." I kid you not, and he said it with a straight face. He continues, "They wondered what the problem was."

The problem? That one team needs another team to find out why a post-operative patient in pain reacts strongly to a surgeon who won't listen to what she says.

Denosumab

Current choices in therapy for osteoporosis are something short of satisfactory. Estrogen works well but many women are reluctant or unwilling to take it for long due to its association with increased risk for breast cancer when used over a period of years. The bisphosphonates-- Boniva, Actonel, Reclast, and Fosamax-- are a good, non-hormonal choice if you don't mind taking a pill on an empty stomach 1/2 hr. before eating in the a.m. then sitting bolt upright 'til breakfast so the drug won't cause acid reflux and heartburn. Evista works but may give you blood clots or hot flashes, and Forteo is a dandy boost for way low bone density if you're o.k. with a daily shot.

Thank heavens, a new choice is moving through phase 3 studies on its way to the old gal market (guys can get osteoporosis too, but their major problem now is that no one thinks to check them for it). This medication, denosumab, is a selective inhibitor of receptor activator of nuclear factor-B ligand (RANKL). No surprise that a ligand know as RANKL is the cause of our skeletal woes joining the ranks of other things that rankle in our golden years--thinning hair, receding gums, falling arches, and teen-aged boys.

Here's the scoop. RANKL is a protein made by osteoblasts or those cells in charge of making new bone cells. RANKL hooks up with RANK to activate the RANKL-RANK pathway which then activates osteoclasts or the cells that break down bone. This whole bone thing is a regular Ecclesiastesian cycle, all this building up and breaking down at the right time and right place. When your season turns to menopause, however, the balance shifts, and suddenly you're breaking down via osteoclasts more than you're building up via osteoblasts.

Enter denosumab, a human monoclonal antibody that grabs the RANKL before it can grab the RANK. In doing so, the drug acts like osteoprotegerin(OPG) which was the normal RANKL inhibitor back in the day when you didn't need to worry about the state of your bone density. Apparently, both estrogen and Evista increase levels of OPG whereas denosumab has a biological activity equivalent to it.

So what do you have to do to be on denosumab? Get up early, stand up straight, endure hot flashes, worry about your breasts? No, none of that. Denosumab is administered as a shot twice a year, a shot under the skin no less, not like one of those stingy tetanus jabs into your deltoid muscle. Here's what lead investigator Steven Cummings, MD had to say about that: "it's a whole lot easier . . . to give what is essentially [like a] flu shot."

Panic attacks and menopausal women

The first time I had a panic attack, I assumed that my heart rhythm was abnormal, and that was why I felt like I would lose consciousness as I drove to Boulder. By the second panic attack, my educated guess was that a tumor was pressing on my trachea, and that was why I could not draw a deep breath and might have a seizure at the wheel. Needless to say, driving after my snowy day collision with a moving van became a bit of an ordeal. As a result of my experience, I know that panic attacks are not about an anxious fear that you might die but rather a strong bodily feeling that you will die.

I was interested, therefore, to read a study in last year's Archives of General Psychiatry about cardiovascular outcomes in postmenopausal women who suffer from panic attacks. Panic attacks are common among women in this age group (although mine occurred over a decade ago). Researchers collected data from nearly 3400 women who participated in the Women's Health Initiative Observational Study.* The women self-reported whether or not they'd experienced panic attacks over a 6-month period, then they were followed for the occurence of coronary heart disease (CHD), stroke, or death in the next 5 years.

A 6-month history of full-blown, real deal, I-can't-get-a-deep-breath or I'm-going-to-die sort of panic attacks was significantly correlated with both outcomes in a scary sort of way. The women demonstrated a 4.2 fold increased risk for CHD, a 3.08 increased risk for the combined outcome of CHD or stroke, and (yikes!) a 1.75 times increased risk that those subjects who ducked heart attack or stroke would die of any other thing.

No surprise, panic attacks are awful, and they simply are not good for you.
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*Participants in the WHIOS were those women who either were not eligible for the hormone portions of the WHI but agreed to provide investigators with other information about their lifestyles and health outcomes. This particular sub-study was the Myocardial Ischemia and Migrained Study.

Zetia and cancer

So first we find out that maybe Zetia (ezitimibe) isn't all it's cracked up to be. In an earlier study of patients with familial hypercholesterolemia--as in big-time LDL-cholesterol elevations of 300 and beyond-- the addition of Zetia to Zocor, a combination also known as Vytorin, did not slow down progression of arterial disease as measured in the carotid artery. Worst case scenario, we thought, was that Zetia wasn't really much use, and perhaps, we theorized, these high LDL patients do not represent our typical everyday high cholesterol patients so why compare outcomes in the one to clinical courses in the other?

Until now. Just out this week in the New England Journal of Medicine are the results of the SEAS trial(1), as in Simvastatin and Ezetimibe in Aortic Stenosis. This study compares the use of Vytorin to placebo in old folks with narrowing of their aortic valves. Mattered not in these elderly valves whether the owners used Vytorin with respect to progression of the stenosis or cardiac disease in general. What mattered, however, mattered a lot in fact, is that the seniors randomized to active treatment were significantly more likely to get cancer and borderline more likely to die of it.

In this same issue of the NEJM, another group looked at cancer data from two other Zetia studies. After studying the combined data from these larger, ongoing trials, they concluded:

There was no overall excess of cancer (313 active-treatment vs. 326 control) and no significant excess at any particular site. Among patients assigned to ezetimibe, there were more, albeit not significantly more, deaths from cancer (97, vs. 72 in the control group; P=0.07)... The available results from these three trials do not provide credible evidence of any adverse effect of ezetimibe on rates of cancer.

Oh gad, now what to do? An accompanying editorial theorizes that Zetia might not only interfere with the absorption of cholesterol but also other molecules that affect the growth of cancer cells. And the doctors conclude: "Physicians and patients are unfortunately left for now with uncertainty about the efficacy and safety of the drug."

I think I'm done with Zetia.
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(1) Rossebø AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med 2008;359. DOI: 10.1056/NEJMoa0804602.