News on Niaspan, Cholesterol Drugs and Biomarkers

The Times alerted me, this evening:

Lowering bad cholesterol levels reduces heart attack risks, and researchers have long hoped that raising good cholesterol would help, too. Surprising results from a large government study announced on Thursday suggest that this hope may be misplaced….

Common wisdom has been that such patients should take a statin drug like Lipitor or Zocor to lower bad cholesterol and, in many cases, the vitamin niacin to raise their good cholesterol. But in the trial, niacin provided no benefit over simple statin therapy.

It wasn’t clear to me which was the study, but Bloomberg News explains:

Niaspan failed to prevent heart attacks and may have boosted stroke risk in a U.S.-funded study that calls into question the benefit of raising good cholesterol to combat the leading cause of death.

The National Institutes of Health said today it stopped a 3,414-person study early after the addition of Niaspan to simvastatin, a standard therapy for high cholesterol, was linked to strokes in 1.6 percent of patients, compared with 0.7 percent in the control group. The combination failed to reduce heart attacks, heart-related hospitalizations and the need for procedures to reduce chest pain and restore strong blood flow.

So Niacin, what’s supposed to lower triglycerides and raise HDL – the “good” cholesterol – turns out to be a bust, at least when it’s given in the form of Abbot’s Niaspan.

As to how well cholesterol levels reflect a person’s real risk for heart and other vascular disease, I’ve been skeptical for years.

blueberries with oatmeal (at breakfast this morning, with a bit of grapefruit juice nearby, photo taken by sheer coincidence)

Still, I have faith in oatmeal, with skim milk and fruit, for breakfast.


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Informed Consent on Paper, but Not in Reality

Over the long weekend I caught up on some reading. One article* stands out. It’s on informed consent, and the stunning disconnect between physicians’ and patients’ understanding of a procedure’s value.

The study, published in the Sept 7 Annals of Internal Medicine, used survey methods to evaluate 153 cardiology patients’ understanding of the potential benefit of percutaneous coronary intervention (PCI, or angioplasty). The investigators, at Baystate Medical Center in Massachusetts, compared patients’ responses to those of cardiologists who obtained consent and who performed the procedure. As outlined in the article’s introduction, PCI reduces heart attacks in patients with acute coronary syndrome – a more unstable situation than is chronic stable angina, in which case PCI relieves pain and improves quality of life but has no benefit in terms of recurrent myocardial infarction (MI) or survival.

The main result was that, after discussing the procedure with a cardiologist and signing the form, 88% of the patients, who almost all had chronic stable angina, believed that PCI would reduce their personal risk for having a heart attack. Only 17% of the cardiologists, who completed surveys about these particular patients and the potential benefit of PCI for patients facing similar scenarios, indicated that PCI would reduce the likelihood of MI.

This striking difference in patients’ and doctors’ perceptions is all the more significant because 96% of the patients “felt that they knew why they might undergo PCI, and more than half stated that they were actively involved in the decision-making.”

What we have, here, is a study of informed consent, set up in a way that the doctors knew the study was ongoing – because they and their patients were participating, all in one division of one hospital – and, presumably, spent if anything more time and not less than usual talking with patients and answering questions about the procedure. (Note: this particular point is an assumption on my part, supported by the reported fact that 83% of the patients reported that their questions had been answered.)

The central finding is a failure of communication between doctors and patients about the potential benefit of the procedure: 88% of the patients, who’d signed consent, thought that PCI would prevent heart attacks and only 17% of the cardiologists at the same medical center thought the same. This matters, first, because over a million people in the U.S. undergo angioplasty each year and, more broadly, because it represents an everyday outgrowth of the  phenomenon of therapeutic misconception – when patients think a procedure has a greater potential benefit than it does.

The concept of therapeutic misconception, as was initially defined narrowly in the context of clinical trials, applies to all areas of medicine. In cancer treatment it’s a big deal but, in my experience, under-addressed. A common misconception among breast cancer patients, for example, concerns the benefit of adjuvant chemotherapy, which generally reduces the odds of recurrence by about a third. So if you have a stage II tumor with good molecular features and the odds of recurrence are somewhere around 15%, that comes down to around 10% with the treatment, which does bear significant side effects and risks. Another fairly common misunderstanding in oncology is in the area of Phase I clinical trials, in which the drugs are tested for toxic effects in humans, and to see how much people can withstand, and not for therapeutic effect.

This topic is worthy of lots more discussion than I can afford here. I do recommend reading the full article, including the methods about how the survey was done, and the editorial* in the Annals, which accompanied the paper, which like so many other provocative and significant reports in the medical literature, didn’t get much attention in the lay press.

One point the editorial considers is that, perhaps, the PCI consent form used by the study authors and said to be at a 12th grade reading level, should instead be provided at an 8th grade level, as some institutions recommend and require. I’m not so sure about this, because I think a lot of medical ideas and decisions simply cannot be communicated at a lower level without loss of content, i.e. nuanced information.

I’m eager for readers’ views on this – how often is it that doctors effectively convey why a procedure should be done or a treatment be given, and what might be done to improve the process?


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Lots of Excitement about Anacetrapib, a Cholesterol-Lowering Drug

I’m a bit puzzled by all the excitement about Merck’s new drug, Anacetrapib (MK-0859), that’s said to lower risk for cardiovascular disease by lowering bad cholesterol. Earlier this week at the annual meeting of the American Heart Association, researchers presented promising findings on the drug, including results from the phase III DEFINE (Determining the EFficacy and Tolerability of CETP INhibition with AnacEtrapib) trial. The list of disclosures for that abstract is long and fairly shocking. On Wednesday, the results were published on-line in the NEJM.*

The new drug interests me, as an oncologist, because it’s an enzyme inhibitor – in some ways like many new and in-the-pipeline cancer treatments. Anacetrapib raises high-density lipoprotein (HDL, a.k.a. “good cholesterol”) and lowers low-density lipoprotein (LDL, a.k.a. “bad cholesterol”) by interfering with a cholesterol enzyme transfer protein (CETP). The experimental medication is a pill that, based on earlier safety studies, is taken at 100 mg by mouth, once daily. So it’s convenient enough.

In some respects, the results of this randomized, placebo-controlled large trial are knock-your-socks-off impressive: patients on the drug had, an average, a more-than doubling of their serum HDL levels, from 41 to 101 mg per deciliter.** At the same time, the HDL shift was just 40 to 46 for patients assigned to the placebo (control). Conversely, LDL levels went down dramatically in patients taking Anacetrapib, from 81 to 45 mg per deciliter on average, and the corresponding drop seen among the control patients was only 82 to 77. These numbers are really terrific, and the results highly significant from a statistical perspective. The study lasted for 76 weeks, i.e. well over a year, and the drug was very-well tolerated according to all published reports.

What’s wrong here? Well, it’s that we don’t know for sure how this new drug affects heart disease and other vascular conditions. In this study, the plasma cholesterol levels were monitored as surrogate markers for risk of atherosclerotic events, but these laboratory parameters are not the same thing as direct measures of disease. It is uncertain if this drug has any impact on mortality, or even on heart attacks, strokes or other clinical endpoints.

In my opinion, we need a lot more information about this new drug before we prescribe it to thousands or millions of people who have hyperlipidemia. Fortunately, as pointed out by Dr. Harlan Krumholz, writing for Forbes, Merck is “doing the right thing” by testing the drug in additional studies now, with clinical endpoints in mind. Still, his enthusiasm for what amount to very favorable blood testing seems extreme in light of the previous experience to which he refers with Pfizer’s torcetrapib, a drug of the same class that turned out to have significant side effects, and Merck’s previous marketing of Zetia.

According to the New York Times, John Boris, an analyst at Citigroup, wrote in a note to investors on Wednesday that the drug could potentially have sales of more than $1 billion a year. Dr. Steven Nissen, a sometimes cautious leader in the field, found the results encouraging, according to widely-cited comments such as those appearing in the Dow Jones Newswires.

In a few years, we’ll see what Merck finds out with the ongoing trials, and if the drug really helps reduce heart attacks and deaths in people with hyperlipidemia.

Meanwhile, since my cholesterol’s crept up, just a bit above 200, I’ve started eating oatmeal and quinoa more often. I take only skim milk in my cereal at breakfast, cut out most cheese and pizza, and enjoy ice cream but occasionally. I don’t wish to ingest any experimental enzyme inhibitors that aren’t essential in the life-saving sense.

The NIH offers tips for therapeutic lifestyle changes that can help reduce hyperlipidemia in many patients.

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**cholesterol units: milligrams per deciliter

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About Those Skipped Heart Test Results

Harlem Hospital Center stands just three miles or so north of my home. I know the place from the outside glancing in, as you might upon exiting from the subway station just paces from its open doors. The structure seems like one chamber of its neighborhood’s heart; within a few long blocks’ radii you’ll find rhythms generated in the Abyssinian Baptist Church; readings at the Schomburg Center and artery-clogging cuisine at the West 135th Street IHOP.

So I was saddened to hear about the missed heart studies. Or should I say unmissed? No one noticed when nearly 4,000 cardiac tests went unchecked at the Harlem center, a public hospital managed by the city’s Health and Hospitals Corporation. The skipped beats began sometime in 2007.

According to the Times report, that’s when hospital administrators, hurting perhaps for doctors sufficiently skilled in reading echocardiograms, OK’d a process by which technicians scanning the images would alert the responsible physicians if they noticed abnormalities. Otherwise they stored the results – pictures of the heart’s contractions, wall thickness and size, valves and some large vessels – for review, later.

Usually when a person gets an echocardiogram there’s a reason. Mine, for example, was done before I received a chemotherapy drug, adriamycin that can affect the heart’s function and, another time, before I had a major operation – basically to make sure my heart was strong enough to handle the stress of surgery. Years earlier, I’d had an echo (as doctors sometimes call these tests) to evaluate shortness of breath I experienced while pregnant. I like echocardiograms, as cardiac imaging methods go, although I must admit I find the blobby representations cryptic if not frankly rorschachian. These tests rely on ultrasound, the same technology we routinely use to examine unborn fetuses by projecting and canvassing sound waves. There’s no radioisotope or x-rays. Not even a magnet’s involved.

Echocardiogram reveals 4 heart chambers - adapted from Wikimedia Commons

What generally happens is that after the procedure a doctor, usually a cardiologist, inspects the images and provides a written assessment. Ideally, the test report reflects the reason for doing the procedure. So if a teenage soccer player has an echo to evaluate an episode of fainting on the field, the physician-reviewer would focus on structural heart abnormalities associated with sudden death in some young athletes. Sometimes the studies reveal enlargement of the heart; this can occur in alcoholics, in people with chronic forms of severe anemia like sickle cell disease, and in other conditions. For patients with atrial fibrillation – a disorder in which the heart flutters irregularly – doctors might look to see if there’s clot inside the heart’s walls that might, unmitigated, migrate through the arteries to the brain. Echocardiogram can assess the heart’s condition after a heart attack or in congestive heart failure. They can visualize holes in the heart chamber walls of infants, lapsed valves and more.

The Times story indicates that doctors didn’t review images for over half of the echocardiograms performed at Harlem Hospital since 2007. The medical center, staffed by doctors from Columbia University, had six attending cardiologists and six fellows in 1999, according to the paper. Now the hospital has only three full-time cardiologists and lacks a fellowship program. The hospital runs approximately 2,500 echocardiograms each year. Among those 4,000 patients whose tests went unread, some 200 have died since the time of the procedure. Hospital officials say it’s unlikely that any deaths are attributable to the lapse.

Since the story emerged last week, a squad of doctors has been scrambling to review the images. Heads rolled at Harlem Hospital: the clinical director was fired and the medical director has been demoted. An investigation, led by Dr. John N. Morley of the State Health Department, is underway. The press, or at least my local newspaper, is all over the matter.

So what’s to be learned from this oversight? My take’s two, so far:

1. It appears that at least some physicians working at Harlem Hospital felt it was understaffed and that they were too overworked to meet their clinical responsibilities, and that the administration did not adequately address their concerns. And while Health and Hospitals Corporation has indicated this problem is unique to that particular department – the echo lab – at one hospital, I’m not convinced.

Having worked for years in hospitals where cardiologists, gastroenterologists, hematologists and even pathologists spend much of their time putting out fires, so to speak, it’s scarily easy for me to envision how non-urgent tests could pile up without review. When hospitals operate with money as a bottom line, the difficult work doctors do doesn’t get easier. So we might blame individual physicians for not signing those reports. But I’d take the system to task, and not just at one Harlem hospital.

2. No one’s mentioned the patients’ role in all of this, which seems strange to me. These days, we expect that most patients will enter into discussions with their physicians about what tests they need done. Maybe at a medical center like Harlem Hospital, which serves a relatively poor population, the expectations differ regarding patients’ involvement in medical decisions. But if that is the case, those separate standards reflect another problem – of poor communication between physicians and their patients – equally demanding of our attention.

Lastly, as I’ve said previously here and elsewhere, we waste a lot of medical resources by ordering procedures without thinking. If a person undergoes a medical test there should be a reason for it, sufficient that either the doctor or the patient cares enough to find out the results.

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