A 2013 front page New York Times article by Gina Kolata on PCSK9 inhibitors was inaccurate. Here is Kolata’ lede:
She was a 32-year-old aerobics instructor from a Dallas suburb — healthy, college educated, with two young children. Nothing out of the ordinary, except one thing.
Her cholesterol was astoundingly low. Her low-density lipoprotein, or LDL, the form that promotes heart disease, was 14, a level unheard-of in healthy adults, whose normal level is over 100.
The reason was a rare gene mutation she had inherited from both her mother and her father. Only one other person, a young, healthy Zimbabwean woman whose LDL cholesterol was 15, has ever been found with the same double dose of the mutation.
Here is an excerpt from the FDA clinical review of Sanofi/Regeneron’s PCSK9 inhibitor alirocumab:
We are aware of three cases of individuals homozygous (or compound heterozygous) for loss-of-function PCSK9 alleles with very low LDL-C concentrations that have been reported in the literature:
1. a 21-year-old African woman with an LDL-C of 15 mg/dL; no further information about this patient was provided, except that she was identified for genotyping at a postnatal clinic,
2. a 32-year-old African American woman with an LDL-C of 14 mg/dL; she is an apparently healthy, normotensive, fertile, college-educated individual with normal liver and renal function tests, and
3. a 49-year-old French white man who was found to have extremely low LDL-C (7 mg/dL) on admission for rapid-onset of an insulin-requiring diabetes mellitus of unknown etiology; LDL-C not during acute illness was reported to be 16 mg/dL. This patient was shown to have moderate liver steatosis on abdominal ultrasound with normal hepatic enzymes and liver function tests. He had no reported history of diarrhea, eye, or neurological abnormalities related to any vitamin deficiency. His mother was deceased at age 66 from dementia, whereas his father was healthy at age 79. His grandparents died at the ages of 79, 87, 91, and 94 years.
At this time there are too few cases to provide conclusive data about loss-of-function PCSK9 polymorphisms and the risk of human disease, although given the association of statins with diabetes risk, the development of diabetes in the 49-year-old man discussed above is of interest. (See Dr. Roberts’ safety review for further discussion of alirocumab and glycemic parameters).
The third case is the one missed by Kolata. It was published in Arteriosclerosis, Thrombosis, and Vascular Biology, an American Heart Association journal, in 2009, and could have been found with a PubMed search. The case is interesting in that it conflicts with one of the oft-repeated but inaccurate narratives with respect to PCSK9 inhibitors, the idea that all known persons with extremely low LDL due to having two PCSK9 loss-of-function mutations are completely healthy. I agree with the FDA reviewer that there are too few such cases to provide conclusive data about loss-of-function PCSK9 polymorphisms that result in extremely low LDL levels and the risk of disease. (The issue of whether alirocumab increases blood glucose and the risk of developing diabetes is also discussed extensively in the review, with the reviewer concluding that the evidence is inconclusive at this point.)
Two PCSK9 inhibitors, evolocumab and alirocumab, are under consideration at the FDA and will be the subject of advisory committee meetings on June 9 and 10. Evolocumab and alirocumab are monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme that plays a role in regulating levels of LDL cholesterol by binding to LDL receptors and promoting their degradation; the resulting reduction in LDL receptors reduces the liver’s ability to remove circulating LDL. PCSK9 inhibitors prevent PCSK9 from degrading LDL receptors; the increased LDL receptor density results in increased clearance of LDL from the bloodstream. The expectation is that lower LDL levels in patients who receive PCSK9 inhibitors will result in a reduction in cardiovascular events and this strategy is currently being tested in large outcomes trials, which will be completed in a few years. Until those trials are completed, the safety and efficacy of these drugs will not be known.
One of the unknowns with PCSK9 inhibitors is their effect (if any) on blood glucose levels and the development of new-onset diabetes. Statins are known to increase the risk of new-onset diabetes by about 9% overall, with increased risk from intensive vs. moderate intensity statin therapy. One reason to wonder whether PCSK9 inhibitors might have a similar effect is that both statins and PCSK9 inhibitors, though having different mechanisms of action, both involve the removal of LDL through upregulation of LDL receptors. The reason statins increase blood glucose is unknown, but recently it has been suggested that that the LDL receptor might be involved, with greater LDL receptor activity correlating with a higher risk of diabetes. A recent study showed that patients with familial hypercholesterolemia (FH) in the Dutch FH registry have a lower prevalence of type 2 diabetes as compared to their unaffected relatives. FH is a genetic disease in which the LDL receptor function is reduced, leading to higher serum levels of LDL cholesterol. In addition, the study found a dose-response relationship, with more severe FH mutations linked to lower risk of diabetes as compared to less severe mutations. In other words, the study showed an association between less functional LDL receptors and a lower prevalence of type 2 diabetes. In an editorial, David Preiss and Naveed Sattar note that the study suggests that “the expression and function of LDL receptors may be important for glucose homeostasis” and that the advent of PCSK9 inhibitors provides an opportunity to further examine a possible link between LDL receptor expression and glycemia and diabetes risk.
I’ve looked at some of the published data on PCSK9 inhibitors and blood glucose and diabetes risk. With respect to alirocumab, I abstracted a subset of the data in an abstract presented at the March 2015 American College of Cardiology conference.
As you can see, the data show small numerical increases in new-onset diabetes and worsening of preexisting diabetes, as well as larger increases in fasting glucose and hemoglobin A1c over the course of a year in patients on alirocumab as compared to patients on placebo (all patients were also on a statin). With respect to evolocumab, I found the following data:
1. A 52-week placebo-controlled trial of evolocumab in patients with hyperlipidemia published in the New England Journal of Medicine in 2014 found the mean change from baseline for fasting glucose at week 52 was 1.3 mg per deciliter for evolocumab and 0.4 mg per deciliter for placebo. The mean change from baseline for HbA1c at week 52 was 0.02% for evolocumab and 0.00% for placebo (table 3 and supplementary table S3).
1. The Osler trials recently published in the New England Journal of Medicine showed that 1.1% of the patients who received evolocumab developed diabetes, as compared to 0.7% of the patients in the standard of care group.
What do all these small differences add up to? It’s not possible to say yet, but I assume someone will do a meta-analysis at some point, and there may be some discussion of this issue in the FDA review of these agents, which will be posted prior to advisory committee meetings.
I should note that even if PCSK9 inhibitors do increase blood glucose and the risk of developing diabetes, they would still be very worthwhile for patients who are at significant risk of heart attack and stroke, if they are shown to be effective and have acceptable safety.
The long-awaited IMPROVE-IT trial was presented last month at the American Heart Association Scientific Sessions. Here are the presentation slides:
IMPROVE-IT was a trial that tested the ability of ezetimibe (Zetia) to lower the risk of heart attacks and strokes when added to simvastatin. See Larry Husten’s background post here, and if you type “ezetimibe” in the search box on this blog or on the Gooznews blog, you will find some previous posts of mine relating to ezetimibe. I admit I was a bit surprised that the trial was positive. I was expecting it to be negative, based on the negative results of the ENHANCE trial. Still, the benefit was small, a 6.4% reduction in risk of the primary endpoint (composed of cardiovascular death, heart attack, unstable angina requiring hospitalization, coronary revascularization, and stroke). In the high-risk trial participants — all patients who had been hospitalized for acute coronary syndrome within the 10 days before randomization — this translated to a 2% absolute benefit over 7 years. Of note, there was no reduction in all-cause or cardiovascular mortality.
I only want to make a few comments now, but I intend to write more when the trial is published. First, a 6.4% reduction is risk is a very small benefit, and many people would only consider that reduction in risk meaningful in a high risk population. Second, it is regrettable that we had to wait 12 years after the drug’s approval to find out whether it improves outcomes.
Addendum, May 5, 2015: Unfortunately, the GoozNews blog is no longer up on the web. I asked Merrill Goozner what happened and he said he decided to stop paying the annual fee for the website. So the posts I wrote on ezetimibe for GoozNews are no longer up.
Welcome Jesse Ballenger to the blogosphere. Jesse is a historian who specializes in the history of medicine and is the author of Self, Senility and Alzheimer’s Disease in Modern America. Gary Schwitzer alerted me to Jesse’s post on Gina Kolata’s recent Sunday New York Times piece, How Do You Live Knowing You Might Have an Alzheimer’s Gene?, as well as to the existence of his blog, To Conquer Confusion: A Historian’s Perspective on the Science and Experience of Alzheimer’s Disease and Dementia. Jesse has both praise and criticism for Kolata’s story, and his post brings needed perspective on the history of research on Alzheimer’s as well as on the choice on Kolata’s part to present only the very optimistic views of certain Alzheimer’s researchers who “say that within a decade there could be a drug that staves off brain destruction and death.” I agree with him that “Kolata should have raised questions about this claim, and talked to experts not directly involved in the research who are far less optimistic about its potential to so quickly lead to effective treatments.” So please go read his post.
Kolata describes an American family in which many members are afflicted with early-onset Alzheimer’s caused by an autosomal dominant mutation. Because the mutation is dominant, each affected family member has a 50% chance of passing the mutation on to each of his or her chidren. The story is tragic and brought to my mind the emotions I experienced in 2001, when my daughter was diagnosed with heterozygous familial hypercholesterolemia (heFH) at age 8. This is a genetic disease that causes very high LDL-cholesterol from birth and if untreated leads to early heart disease in a high percentage of patients. At the time, I was only vaguely aware that there was a history of heart disease in my husband’s family and that his mother had had a heart attack. At the urging of my daughter’s cardiologist, we asked my husband’s mother for more details and learned that her father had died of a heart attack at 35 and her brother, her only sibling, died of a heart attack at 40. My mother-in-law suffered her first heart attack at age 58. My husband inherited the mutation but has only a mild case, and my mother-in-law had never been told anything other than that she had high cholesterol, so my daughter’s diagnosis was the first occasion anyone in the family realized that the family history of early heart attacks was caused by a mutation. Fortunately, unlike the case of Alzheimer’s disease, the risk associated with heFH can now be greatly reduced if patients are treated from an early age with a statin. Homozygous FH patients, who have two copies of an FH mutation, are not so lucky and usually must undergo LDL apheresis on a regular basis.
Back to Kolata’s article: I want to expand a little on a comment I wrote on Jesse’s post. My comment related to Kolata’s comparison between the development of statins and the development of drugs to prevent Alzheimer’s. As described in Kolata’s article, certain drugs in development are being tested in persons who are carriers of an Alzheimer’s mutation but have not yet developed symptoms of the disease. The patients will receive one of several drugs or a placebo, and will be monitored for the development of certain biomarkers and, importantly, for the development of memory problems. Kolata states that “Statins, the drugs that are broadly prescribed to block the body’s cholesterol synthesis, were first found effective in studies of people who inherited a rare gene that led to severe and early heart disease.”
The disease Kolata is presumably referring to is FH, but whether her statement is accurate depends on how one defines “effective.” Early in the development of statins, after they had been tested in animals, they were given to a few patients with homozygous FH and heterozygous FH, as described in this 1992 article in the Journal of Lipid Research. However, at that time the drugs were only being tested for their ability to lower LDL and for safety. LDL-lowering is a surrogate endpoint. If by “effective” one means the prevention of heart attacks and other cardiovascular events, the statement is inaccurate. When statins came on the market in the late 1980s, FH patients were excluded from the clinical trials that were conducted to show than statins not only lowered LDL but also prevented heart attacks, strokes and death. It was considered unethical to give an FH patient a placebo. To this day, no randomized controlled trial of statins with clinical endpoints has been done in FH patients and it is unlikely that one will ever be done.
Direct evidence of the effectiveness of statins in heFH includes two observational studies, one of patients in a British registry and one of patients in a Dutch registry. In addition, the ASAP trial compared a high dose statin with a moderate dose statin in heFH patients, but the endpoint was carotid intima media thickness, “IMT” (i.e., thickness of the carotid artery measured by ultrasound). There was also a trial of statin vs. placebo in teenage FH patients using IMT as an endpoint. In addition, many trials of statins have shown a benefit in non-FH patients with elevated LDL and it is reasonable to assume that this benefit would carry over to FH patients.
Thus, the comparison between the trials of investigational Alzheimer’s drugs in mutation carriers and the testing of statins in FH patients is not particularly apt. The Alzheimer’s trials in patients with hereditary Alzheimer’s will be measuring the development of clinical symptoms of Alzheimer’s (i.e., memory loss, confusion, etc.). The tests of statins in FH patients looked only at the effect of the drug on a surrogate endpoint (i.e., LDL-lowering) and no trials with clinical endpoints (i.e., heart attacks and other cardiovascular events and death) were done in FH patients.
Endo A. The discovery and development of HMG-CoA reductase inhibitors. J. Lipid Res. 1992 33:(11) 1569-82.
Neil A, Cooper J, Betteridge J, et al. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J 2008; 29: 2625-2633.
In January, I blogged about an open letter by Harlan Krumholz and Rodney Hayward to the panel that is currently engaged in writing new guidelines for cholesterol management. As discussed in my post, their letter challenges the committee to replace the current “treat to target” paradigm with a “tailored treatment” approach. This has been one of my more popular posts of all time, and people often find my blog by Googling “Krumholz Hayward open letter” and the like. It also has been discussed on CardioExchange. So I knew their paper had created a bit of a buzz in the cardiology community. Well, it appears that some in that community are not happy that someone is challenging the current paradigm. Dr. Krumholz reports on CardioExchange that he was approached by an influential person and asked to stop speaking out on the new approach he is advocating:
I had an experience the other week that reminded me that speaking your mind has its challenges. I was approached by someone with influence who asked me to cease my discussions on a particular topic. The reason was oblique – and I was told that people are viewing me negatively because my views are strong and wondering if there are conflicts of interest that are influencing me. In essence, I was told that people are whispering about me – though no names were given.
Now this topic was part of a scientific debate that has strong implications for guidelines and performance measures – and, well, patients. It is a situation where I am questioning conventional wisdom – and the long held beliefs by many individuals. I am trying to do so respectfully – and through the use of evidence – but still it is questioning dogma.
This conversation prompted me to write a message to my younger colleagues urging them to stand up for what they believe – and be willing to speak truth to power. I quote my friend Victor Montori, who eloquently advised a junior colleague about how to manage a concern about whether to express an opinion that was likely to be viewed negatively by her superiors. That person had been told to hold opinions tight until he had more grey hair. Victor starts by saying: ‘I have struggled with this issue for years. Turns out that this is a common struggle for those who find themselves unable to stay silent in the face of waste, error, low integrity, or abuse.’
The message Dr. Krumholz wrote is in the form of an editorial in Circulation: Cardiovascular Quality and Outcomes, entitled “A Note to My Younger Colleagues … Be Brave.” The editorial is open access, so I urge you to go read it in its entirety, but I’m going to quote this paragraph, which seems key:
If you take the path toward clarity, I guarantee that you will occasionally find people who will disparage you. They may seek to undermine you, find ways to marginalize you, and try to incriminate you. They may come from directions that surprise you. Powerful ideas often attract attacks that focus more on individuals than ideas. If you raise inconvenient truths or voice uncomfortable opinions, particularly if they threaten someone’s comfortable status quo, then you will discover much about the character of those with whom you disagree. But always take the high road, engage in dialogue about ideas and evidence, and be motivated by the opportunity to best serve patients and the public. You will not regret it.
Although I am not a physician, I certainly recognize and have experienced the issues Dr. Krumholz is describing in my own life. Speaking uncomfortable truths often isn’t considered nice and doesn’t win popularity contests, but it is necessary for progress to be made. So I will keep covering this controversy, and I invite you to read Dr. Krumholz’s editorial and then let me know your thoughts.
Addendum: Here are comments by Ben Goldacre on Dr. Krumholz’s editorial.
Hayward and Krumholz: Open Letter to the Adult Treatment Panel IV of the National Institutes of Health
Rodney Hayward and Harlan Krumholz have published an open letter to the committee that is currently engaged in writing updated guidelines for cardiovascular risk reduction. Their letter challenges the committee to replace the current “treat to target” paradigm with a “tailored treatment” approach, as discussed below.
The primary focus of the current set of guidelines, ATP III , was a strategy of treating patients to target LDL-cholesterol levels, known as the “treat to target” paradigm. Moreover, the “cutpoints,” or triggers, for initiating therapy are also based on LDL levels, with higher risk patients having lower cutpoints. However, as Hayward, Krumholz and colleagues have previously argued (see here, here and here), the treat to target paradigm was not based on the results of clinical trials, since no major randomized controlled trial has tested the benefits of treating patients to LDL targets. Rather, the trials have used fixed doses of lipid-lowering drugs.
Hayward and Krumholz argue that LDL levels are not particularly useful in assessing the 2 factors that help determine the benefit of a treatment for an individual patient: (1) risk of morbidity and mortality in the absence of treatment (baseline risk) and (2) the degree to which the treatment reduces that risk. For calculating baseline risk, LDL is only one of several factors that are considered, including age, gender, smoking, blood pressure, HDL, and family history of premature cardiovascular disease and in most cases contributes little to the estimate of cardiovascular risk. For the second factor, clinical trials of statins demonstrate that the relative benefits of statins are not substantially related to pretreatment LDL levels. Thus, a high risk person may have low LDL levels and a low risk person may have high LDL levels and the high risk person will derive more absolute benefit more from treatment even though his or her LDL is low (illustrated in this table).
Hayward and Krumholz also argue that treating to LDL targets can lead to treatments that have not been shown to be safe. The treat to target approach can mean initiating treatment in patients at a relatively young age, leading to potentially many years of statin treatment. The long-term safety of this approach is not yet known. In addition, the perceived need to reach an LDL target often leads to the addition of nonstatin drugs such as niacin and ezetimibe when the maximum dose of a statin is reached and the patient’s LDL is still above goal. The benefit and safety of adding these drugs on top of statin therapy has not yet been demonstrated.
The “tailored treatment” approach Hayward and Krumholz advocate bases intensity of statin treatment on a person’s 5- or 10-year cardiovascular risk. In a previous paper, Hayward et al. tested a tailored treatment model of primary prevention using 5-year coronary artery disease (CAD) risk and compared it with the treat to target approach. In their model, a person with 5% to 15% risk would be prescribed 40 mg simvastatin and a person with greater than 15% risk would be prescribed 40 mg atorvastatin. Using this simulated model, the tailored treatment approach was found to prevent more CAD events while treating fewer persons with high-dose statins as compared to the treat to target approach.
For the reasons stated above, the tailored treatment approach does appear to me to be superior to the treat to target approach. At the same time, I note that the decision to take a statin is a personal decision. For primary prevention, the absolute benefit for most people of taking a statin over a 5 or 10 year period is small. Each person should calculate their baseline risk (there are online risk calculators for this), look at how much their risk can be lowered with a statin, and ask themselves if the benefit seems worth it to them in terms of cost, inconvenience and possible side effects (including a small increase in risk of developing diabetes).
In addition, I note that neither approach is designed to apply to patients with heterozygous familial hypercholesterolemia (FH). Due to the very high risk of premature coronary heart disease in FH patients (approximately 85% of male FH patients and 50% of female FH patients will suffer a coronary event by age 65 if untreated), the treatment paradigm for FH patients is that all are treated with statins starting in childhood or early adulthood (not everyone agrees that it is necessary to start treatment in childhood but that’s a topic for another day). In other words, FH patients are treated based on their lifetime risk, not their 5- or 10-year risk.
Hayward RA, Krumholz HM. Three reasons to abandon low-density lipoprotein targets: an open letter to the Adult Treatment Panel IV of the National Institutes of Health. Circ Cardiovasc Qual Outcomes. 2012:5;2-5.
Hayward RA, Hofer TP, Vijan S. Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med. 2006;145:520-530.
Krumholz HM, Hayward RA. Shifting views on lipid lowering therapy. BMJ. 2010;341:c3531.
Hayward RA, Krumholz HM, Zulman DM, Timbie JW, Vijan S. Optimizing statin treatment for primary prevention of coronary artery disease. Ann Intern Med. 2010;152:69-77.
Rind DM. Intensity of lipid lowering therapy in secondary prevention of coronary heart disease. In: Freeman MW, Sokol HN, eds. UpToDate. 19.3 ed.
A review article in a medical journal is an attempt to summarize the current state of research on a particular topic. A review article does not present original research but rather collects and interprets the research that has been done, describes gaps in the research and controversies that exist, and how to apply the research in clinical practice. A review article can be a good starting point to get a grasp of a topic. However, because the authors are generally experts on the topic they are discussing, they often have a point of view that may not be obvious to someone not expert in the field.
But what if the agenda for the article were out in the open? What if, say, a drug company sponsored a review article on its own drug and paid a medical journal to publish it? That appears to have happened with this review article on fibrates in a journal called Reviews in Cardiovascular Medicine, published by MedReviews, LLC. The acknowledgment discloses the following:
Abbott Laboratories, Inc., provided funding to MedReviews, LLC. No funding was provided to authors. Abbott Laboratories, Inc. had the opportunity to review and comment on the publication content; however, all decisions regarding content were made by the authors.
So, while it is unclear who produced the initial draft of the article, Abbott Laboratories reviewed and commented on the article before publication and paid the publisher for publishing the article. Abbott just happens to sell two fibrates, TriCor and Trilipix.
Never having heard of this journal, I looked at the journal’s website and confirmed that it is a peer-reviewed journal and is indexed in PubMed and Medline. It’s editorial board includes some well-known academic physicians. The website also discloses that MedReviews has formed a partnership with the California Chapter of the American College of Cardiology.
I’m having a hard time understanding why anyone would want to spend their time reading a medical journal that publishes review articles that have such a high level of involvement from a commercial enterprise with a vested interest in the topic. I’m also having a hard time understanding why the California Chapter of the ACC and the members of the editorial board would want to be associated with this journal.
H/T Harlan Krumholz.
Addendum January 7, 2012: Howard Brody has weighed in on the Hooked: Ethics, Medicine, and Pharma blog.
Addendum January 10, 2012: Also see this post on Pharmalot blog.
Addendum August 16, 2012: See this followup post by Kevin Lomangino on the Health News Watchdog blog.
I have a guest post up at Merrill Goozner’s blog explaining why Merck’s application for a new indication for its drugs Vytorin (simvastatin/ezetimibe) and Zetia (ezetimibe) should not be approved. The proposed indication is for the reduction of major cardiovascular events in patients with chronic kidney disease and is based on the results of the SHARP trial. However, because SHARP compared the combination of simvastatin and ezetimibe with placebo — there was no simvastatin arm — we have no way of knowing if ezetimibe contributed anything to the result. The FDA requires that combination drugs have additive effects over either drug alone. Merck has not shown that ezetimibe contributed anything to the effect in SHARP, so the new indication should not be approved.
Addendum January 25, 2012: Merck issued a press release today stating that the FDA did not approve the new indication. “Because SHARP studied the combination of simvastatin and ezetimibe compared with placebo, it was not designed to assess the independent contributions of each drug to the observed effect; for this reason, the FDA did not approve a new indication for VYTORIN or for ZETIA® (ezetimibe) and the study’s efficacy results have not been incorporated into the label for ZETIA.” The SHARP results were incorporated into the Vytorin label (see pages 27-28).
Addendum, May 5, 2015: Unfortunately, the GoozNews blog is no longer up on the web.
I have a guest post up on Gary Schwitzer’s blog critiquing Sanjay Gupta’s promotion of calcium scans and overhyping of extreme diets.
Like my last post, this post is inspired by Harriet Hall’s recent review of The Mayo Clinic Book of Home Remedies on the Science-Based Medicine blog. For elevated cholesterol, the book recommends trying “natural products,” including garlic.
In 2007, the results of a randomized controlled trial of garlic on cholesterol concentrations on adults with moderate hypercholesterolemia were reported in Archives of Internal Medicine. The trial evaluated raw garlic and two commonly used garlic supplements. None of the forms of garlic, including raw garlic, when given at an approximate dose of a 4 gram clove per day, 6 days a week for 6 months, had statistically or clinically significant effects on LDL-C or other plasma lipid concentrations.
In addition, a meta-analysis was published in 2008 that did not find beneficial effects of garlic on total cholesterol, LDL, triglycerides, or apoB.
Based on the above, it seems like a waste of time and effort for anyone to try to lower their cholesterol with garlic.
Gardner, et al., Effect of raw garlic vs commercial garlic supplements on plasma lipid concentrations in adults with moderate hypercholesterolemia: a randomized clinical trial. Arch Intern Med. 2007;167(4):346-353.
Khoo, et al., Garlic supplementation and serum cholesterol: a meta-analysis. Journal of Clinical Pharmacy and Therapeutics. Volume 34, Issue 2, pages 133–145, April 2009.