Archief Roodbont

These results suggest that daytime blood pressure, adjusted for nighttime blood pressure, predicts fatal combined with nonfatal cardiovascular events, except in treated patients, in whom antihypertensive drugs might reduce blood pressure during the day, but not at night. One reason for this could be that antihypertensive treatment acts as a major confounder, the researchers suggest. Patients with more severe hypertension or a history of cardiovascular complications are more likely to be treated and at higher risk than other patients, and they take their medications during daytime, and that activity that lowers blood pressure wears off at night. This mechanism leads to a reduced daytime blood pressure, increased nighttime blood pressure, and a decreased night-to-day blood pressure ratio.

Participants with systolic night-to-day ratio value of ≥ 1 or more were older, at higher risk of death, and died at an older age than those whose night-to-day ratio was normal (≥ 0.80 to < 0.90). The researchers suggest that higher nighttime than daytime blood pressure might be a marker rather than a cause of a poor outcome.
Conclusion

Dr. Boggia and his colleagues say that the findings of this study support the conclusions that:

* Ambulatory blood pressure should be recorded during the whole day;

* Clinical decisions should be based on diagnostic thresholds for the 24-hour blood pressure rather than the dipping pattern; and

* Antihypertensive drugs should be administered so that the blood pressure is lowered over 24 hours, so that a normal night-to-day blood pressure ratio is preserved.

However, the researchers point out that there is no evidence supporting the efficacy of chronotherapy in terms of blood-pressure control or outcome. Furthermore, the classification of patients according to the night-to-day blood pressure ratio greatly depends on arbitrary criteria, is poorly reproducible, and has a different prognostic meaning according to the disease outcome under study, the prevailing 24-hour blood pressure level, and treatment status. They recommend that "in future publications any categorical representation of the night-to-day ratio be supported by continuous analyses adjusted for the 24-hour blood pressure and be stratified for treatment status."
Comment

In an invited commentary on the study,[11] Stéphane Laurent, MD, PhD (Hôpital Européen Georges Pompidou and Université Paris-Descartes, Paris, France) agrees with Dr. Boggia and colleagues that the main finding, that daytime blood pressure independently predicts the composite of fatal and nonfatal outcomes, might not apply to patients with treated hypertension. Although the investigators did not include cohorts of patients with hypertension and selected general populations instead, Prof. Laurent notes, 22% of the overall study population were being treated for hypertension at baseline and analysis of a significant interaction with antihypertensive treatment status at enrollment was possible.

The contrasting findings in untreated participants and treated patients suggest a need for an additional meta-analysis of individual data for ambulatory blood pressure that includes a substantial number of patients on treatment for hypertension, Prof. Laurent suggests. "Although the findings of Boggia and colleagues are in favor of recording the ambulatory pressure for the whole day, the question arises as to whether 24-hour blood pressure values from patients taking antihypertensive therapy should be interpreted differently from those of untreated participants," he proposes. He believes that the results of the study may have importa

The Epidemiology of Hypertension: Latest Data and Statistics

Posted 11/16/2007

Linda Brookes, MSc
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Abstract

Hypertension may be a largely asymptomatic condition -- but the consequences are far from insignificant. New data report that hypertension is the largest cause of the absenteeism that, in addition to "presenteeism," costs US businesses as much as $30 billion per year -- with clear implications for what businesses should be doing to address this problem. Another report documents hypertension as the single greatest cause of long-term healthcare in Europe. A third report finds that hypertension, in all its forms, is on the increase again in young people and adolescents (after years of decline), concomitant with the "epidemic" of obesity, while another US study, after discussion of the guideline definition of adolescent hypertension, reports that hypertension is underdiagnosed in this population. Finally in this month's Highlights, a new study carefully dissects the relative contributions of daytime vs nighttime blood pressure readings for predicting future events.
Section 1 of 5
Next Page: New Report Documents Economic Impact of Hypertension in the United States

Summary and Comment
Landmark Human Stem Cell Breakthrough

A feat once deemed impossible has been accomplished — the deprogramming of a fully differentiated human cell into an embryonic stem cell.

Two laboratories report a breakthrough that may one day allow full exploration of the potential benefits of human embryonic stem cell (ESC) therapy and that will eliminate the ethical objections.

In June 2007, Japanese and American teams reported that they had tricked fully differentiated mouse cells into becoming undifferentiated pluripotent cells with all the characteristics of mouse ESCs (Journal Watch Jun 21 2007). Now, just 5 months later, the Japanese team and another American team report the same feat with human cells. Both teams introduced four genes into differentiated cells using retroviral vectors. A small number of cells emerged that had all the biochemical markers of ESCs and that could differentiate into all three germ layers in vitro.

Comment: It now is possible to make embryonic stem cells containing the genome of a patient who might need them, without creating (and then destroying) a human embryo — the primary ethical concern about ESC therapy. There is a risk of turning cells cancerous when retroviral vectors are used and when (as was true with the Japanese group) an oncogene is part of the "cocktail" for creating ESCs. Therefore, more work is needed to optimize this technique before it can be used for regenerative therapy. Nevertheless, a feat once deemed impossible has been accomplished — the deprogramming of a fully differentiated human cell into an ESC. Almost surely, this work will be regarded as a turning point in the history of human stem cell therapy.

— Anthony L. Komaroff, MD

Published in Journal Watch General Medicine November 29, 2007

Citation(s):

Takahashi K et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007 Nov 20; [e-pub ahead of print]. (http://images.cell.com/images/edimages/cell/ieps/3661.pdf)

Yu J et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 2007 Nov 20; [e-pub ahead of print]. (http://dx.doi.org/10.1126/science.1151526)

Plos biology vol 5 issue11
nov 2007 27-11-2007

Gek of heilig is vaak geen groot verschil

Taken together, these results indicate that Fabp7 is responsible for differences in the animals' PPI responses and that the gene plays a vital role in brain development. Given the link between in utero malnutrition and increased risk for schizophrenia, the researchers reason that dysregulation of Fabp7 and lipid metabolism during development may cause long-term changes in gene expression, explaining an excess of Fabp7 in the schizophrenic cortex. Whether Fabp7 operates alone or with other genes on Chromosome 10 must be explored in future studies. And while no methods to prevent schizophrenia exist, the researchers recommend designing cohort studies to find out whether supplementing the diets of pregnant mothers in high-risk families with DHA proves beneficial.

De meest gebruikte coumarine antistollingsmiddelen zijn warfarine (Coumadin, Marevan®), acenocoumarol (Sintrom) and fenprocoumon (Marcoumar). Warfarine is het meest gebruikte coumarine in de wereld, voornamelijk in de Engels sprekende landen en in Scandinavië, terwijl acenocoumarol en fenprocoumon vooral in de andere landen in West-Europa worden gebruikt. Het werkingsmechanisme is hetzelfde voor de drie producten maar ze hebben verschillende farmacokinetiek. Fenprocoumon werkt het langste met een halfwaardetijd van ongeveer 140 uur; warfarine heeft een halfwaardetijd van 40 uur en acenocoumarol is de kortstwerkende met een halfwaardetijd van ongeveer 11 uur. Alle drie worden vlot opgenomen door de darmen, wat nauwelijks beïnvloed wordt door de aanwezigheid van voedsel, met maximale concentraties in het bloed na ongeveer 90 minuten. Ze worden verwerkt in de lever en uitgescheiden door de nieren.
De coumarines werken door het verstoren van het vitamine K gebruik, en daardoor wordt het effect op de stolling beïnvloed door het vitamine K gehalte van het voedsel. Belangrijke interacties bestaan ook met andere medicijnen, waarvan sommige het effect van de coumarines nog versterken, terwijl andere het effect juist verminderen. Ook het lichaamsmetabolisme en de aanwezigheid van andere aandoeningen hebben een effect op de werking van de coumarines.

medscape family 23-11=07


November 16, 2007 — A new analysis of data from the Three-City cohort study in France shows reduced risks for dementia and Alzheimer's disease (AD) with increased consumption of fish, omega-3 oils, and fruits and vegetables, particularly for those who do not carry the apolipoprotein E ε4 (ApoE ε4) allele that is associated with increased risk for AD.

Consumption of omega-6 oils, however, if not compensated for by omega-3 oils, was associated with an increased risk for dementia in the ApoE ε4 noncarriers, the study authors note. Their report appears in the November 13 issue of Neurology.

"Given that most people do not carry the ApoE ε4 gene, these results could have considerable implications in terms of public health," said study author Pascale Barberger-Gateau, PhD, of the Institut National de la Santé et de la Recherche Médicale (INSERM), the French National Institute for Health and Medical Research, in Bordeaux, France, in a statement from the American Academy of Neurology. "However, more research is needed to identify the optimal quantity and combination of nutrients which could be protective before implementing nutritional recommendations."

Factors related to adherence to statin therapy.
Medscape family med 21-11-2007


Abstract

Background: Retrospective database analyses have revealed that 50% of patients receiving statins discontinue therapy after one year of treatment. Typically, these data do not focus on patient-specific reasons for discontinuation.
Objective: To examine the reasons that patients discontinue statins and compare the patient and clinical factors of those who do and do not discontinue therapy.
Methods: All patients with a new statin prescription between January 1, 2004, and March 31, 2004, were identified through pharmacy claims. Patients who had discontinued and continued statin therapy were identified. Medical records were reviewed to determine whether there were documented reasons for statin discontinuation. Subsequently, telephone surveys addressing statin knowledge, relationships, communication with healthcare providers, and general health status were conducted.
Results: At one year, 47.5% (n = 671) of patients had obtained fewer than 80% of the refills of their prescribed statin. We reviewed 435 medical records and conducted 255 patient surveys. A total of 29.9% of discontinuers had reasons documented in the medical record. Compared with continuers, fewer discontinuers had follow-up and/or laboratory visits with a provider within 6 months after the start of statin therapy. The surveys indicated that more continuers than discontinuers trusted their providers (p < 0.05) and felt that providers had adequate knowledge to answer their questions (p < 0.001). In contrast, more discontinuers felt the statin was of limited benefit/unsure of the benefit (p < 0.001) and believed that their providers were not interested in their input on their medical condition (p < 0.01).
Conclusions: Utilizing pharmacy claims records alone to determine statin nonadherence may not only overestimate the percentage of patients who are nonadherent, but also prevent healthcare providers from understanding the reasons that patients discontinue or continue statin therapy. Statin adherence is complex and affected by several factors. Interventions to improve adherence should focus on patient communications, education, and follow-up.

November 14, 2007 — New research suggests that atrial fibrillation, systolic hypertension, and angina are associated with a greater rate of cognitive decline and may represent modifiable risk factors for secondary prevention in Alzheimer's disease.

The study found that individuals with systolic hypertension at the time of diagnosis of Alzheimer's disease had a rate of cognitive decline that was twice as rapid as their counterparts without the condition. Similarly, study subjects with Alzheimer's disease with angina and atrial fibrillation also experienced a more rapid decline in cognitive function compared with individuals without these vascular risk factors.

"The good news is that vascular factors can be modified, so these results may suggest strategies for slowing the progression of Alzheimer's," study author Michelle Mielke, PhD, of The Johns Hopkins University School of Medicine in Baltimore, Maryland, said in a statement from the American Academy of Neurology.

The study is published in the November 6 issue of Neurology.

What is most applicable to physicians is that there was an approximate 30% reduction in triglyceride levels among those treated with the omega-3 fatty acids," said Bays. "When we look at the LDL-cholesterol levels, there was no significant difference in the change in LDL cholesterol in this trial. There was a small median increase, which wasn't significant. The reason this is important is because we can now say that many patients who have persistent elevations in their triglyceride levels, even after they've been on stable statin therapy, can benefit from dietary supplementation. Adding the omega-3 fatty acid can lower triglycerides and lower non-HDL cholesterol, all without adversely affecting LDL levels."

Herpes zoster
From Wikipedia, the free encyclopedia


Herpes zoster, colloquially known as shingles, is the reactivation of varicella zoster virus, or VZV. The virus, one of the Herpesviridae group, leads to a group of painful blisters over the area of a dermatome.

After an attack of chicken pox, the varicella-zoster virus retreats to nerve cells within the ganglion or the spinal cord, where it lies dormant for several months up to several decades.[1] Aging, stress, or disease cause the virus to reactivate and reproduce, at which point it is called "herpes zoster". The herpes zoster travels along the path of a nerve to the skin's surface, where it causes shingles.[2] [3]

Treatment is generally with antiviral drugs such as aciclovir (Zovirax), or prodrugs such as famciclovir (Famvir), or valaciclovir (Valtrex). The antiviral drugs are most effective if the treatment begins within 72 hours of appearance of definitive symptoms.[4][5]

Summary and Comment
What Is the Incidence of Shingles?

Data on incidence rates of shingles might help patients who are undecided about vaccination.

Although the recently licensed shingles vaccine is recommended for older people (age, ≥60), some patients ask, "How likely am I to get shingles?" before deciding whether to be vaccinated. To address that question, Mayo Clinic researchers analyzed a comprehensive database covering all Olmsted County, Minnesota, residents and reviewed the records of adults in whom shingles were diagnosed.

From 1996 to 2001, 1669 cases of shingles were diagnosed. Half the patients were 60 or older; only about 8% were immunosuppressed. The overall incidence rate (adjusted to reflect the age and sex distribution of the U.S. population) was 3.6 per 1000 person-years, but the rate increased with age: For example, it was about 2 per 1000 person-years among adults younger than 50, and increased to 5, 7, 10, and 12 cases per 1000 person-years among adults in their 50s, 60s, 70s, and 80s, respectively. About 18% of patients reported pain for at least 1 month, 4% experienced ocular complications, and 3% had neurologic complications. The rate of recurrent shingles within 3 years was 1.4%.

Comment: Assuming that these data reasonably represent the U.S. population, they enable us to provide estimates for patients. For example, patients in their 70s could be told that their risk for shingles is roughly 1% during the next year (or 10% during the next 10 years). Such information — combined with the 50% efficacy reported for the vaccine — might be useful for patients who are undecided about vaccination.

— Allan S. Brett, MD

Published in Journal Watch General Medicine November 15, 2007

Citation(s):

Yawn BP et al. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Mayo Clin Proc 2007 Nov; 82:1341.

Medline abstract (Free)

uit Wikipedia

In medicine and pharmacology, pravastatin (Pravachol® or Selektine®) is a member of the drug class of statins, used for lowering cholesterol and preventing cardiovascular disease.

Pravastatin was identified originally in a bacterium called Nocardia autotrophica by researchers of the Sankyo Pharma Inc. It is presently being marketed outside Japan by the pharmaceutical company Bristol-Myers Squibb.

The U.S. Food and Drug Administration approved a generic version of Pravastatin for sale in the United States for the first time on April 24, 2006. Generic Pravastatin Sodium Tablets (10mg, 20mg and 40mg) are manufactured by TEVA Pharmaceuticals in Kfar Sava, Israel. FDA Press Release

In 2005, Pravachol was the 22nd highest-selling brand-name drug in the United States. FDA Press Release

[edit] External links

* Pravachol information from the National Institute of Health
* Package insert for Pravachol

[hide]
v • d • e

pravastatin is hydrofiel en simvastatine is lipofiel. Juist andersom als ik dacht. Wel is het zo dat de lipofiele de brainbarrier kunnen paseren. Zie volgende stukje over pravastatine.
Je moet wel 40 mg nemen om zelfde lowering effect te hebben als met 20 mg simvastatin



November 8, 2007 (Orlando) — Results of a randomized trial show that simvastatin, but not pravastatin, appears to interfere with sleep quality and increase sleep problems, as assessed by patients.

"Simvastatin users exhibited significantly worse subjective sleep, relative to either placebo or pravastatin, despite comparable sleep ratings at baseline," lead author Beatrice Golomb, MD, from the University of California at San Diego School of Medicine, told attendees here at the American Heart Association 2007 Scientific Sessions.

Their findings are "important but also timely," she said, since more patients are being switched to simvastatin as it goes off patent," Dr. Golomb said. However, she cautioned that their study defines neither the precise nature of the sleep problems nor the mechanisms that may be involved.

Not everyone will have sleep problems with simvastatin, but if they do occur, she said, "then it might be prudent to consider a change of medication to a different statin."

To Sleep, Perchance to Dream

Since statins were first released, case reports and case series have cited instances of sleep disturbance and insomnia on statins, Dr. Golomb said. More recently, nightmares have been reported as adverse effects on statins, and a number of clinical trials and studies of statins have cited insomnia as an adverse effect.

A number of clinical trials have directly evaluated the impact of statins on sleep, she noted; some of these were placebo controlled and randomized, with either a crossover or parallel design, although they had quite small sample sizes and short durations of follow-up. Many of the studies compared placebo with lipophilic statins such as lovastatin or simvastatin with the hydrophilic statin pravastatin because lipophilic statins can cross the blood-brain barrier.

Most of those studies found no effect on sleep, except one, which showed simvastatin adversely affected sleep relative to pravastatin, although neither was significantly different than placebo.

For this study, Dr. Golomb and colleagues used an adapted version of the tool used in that study, the Leeds Sleep Scale, measuring sleep quality, because it had been able to distinguish between the 2 drugs in that prior study and because, Dr. Golomb said, "it looks at the sleep outcome that is most relevant to patients, which is how does your sleep feel to you."

Noncardiac Effects of Statins

The current study, called the University of California, San Diego (UCSD) Statin Study, was a double-blind, randomized, placebo-controlled trial evaluating noncardiac effects of statins. A total of 1016 men older than 20 years and postmenopausal women were enrolled if they had low-density lipoprotein (LDL)-cholesterol levels between 115 and 190 mg/dL, no known cardiovascular disease or diabetes, and fasting blood glucose of below 140 mg/dL. At the time the study began, statin therapy was considered optional for these subjects.

They were randomized to receive 40 mg of pravastatin, 20 mg of simvastatin (considered pharmacologically equivalent), or placebo, and followed up for 6 months. Sleep was a prespecified secondary endpoint of this trial.

Sleep was assessed by the adapted Leeds Sleep Scale, rating sleep quality on a scale of 0 to 30, and a sleep-problems scale, where patients rated their general experience of sleep problems without defining the nature of the problems, on a scale of 0 to 10 at baseline, and then rated them from "much better" to "much worse" on a 5-point scale.

At baseline, the 3 randomized groups were equivalent in terms of their sleep quality and sleep problems. On follow-up, however, "the simvastatin group reported significant worsening relative both to the placebo group and the pravastatin group in both the sleep-quality outcome and the sleep-problem outcome," Dr. Golomb said. Pravastatin did not differ significantly from placebo on either of these measures.

Their study is limited to some degree by including only 1 lipophilic and 1 hydrophilic statin, the relatively low doses used at the time the study was begun, and the lack of assessment of a dose response. It's also not clear if these effects would be different in the groups that were excluded from the study, she noted.

The mechanism of this difference is also unclear, she said. It may relate to the lipophilicity of simvastatin vs hydrophilicity of pravastatin, the difference in cholesterol lowering, which was greater with simvastatin, or some other unknown factors.

What is clear is the importance of sleep to good health, function (including memory and cognition), mood, well-being and safety, Dr. Golomb concluded, "so the importance in terms of potential ramifications to health of sleep problems is quite large."

Modest Increase in Risk

Asked to comment on these findings for Medscape Neurology and Neurosurgery, Roger Blumenthal, MD, from Johns Hopkins University Medical Center in Baltimore, Maryland, called the current study "one of the more persuasive ones so far that there is a modest increased risk with simvastatin vs pravastatin, and it's good for physicians to be aware of this."

In their practice, they have not seen a big difference in sleep disturbances, he said, "at least what's been reported to us, but nowadays there's a much bigger push for managed care to want us to switch people to generic simvastatin, and Vytorin, which is simvastatin and ezetimibe in combination, is slowly but surely growing in frequency." The "flipside," he added, is that pravastatin is not as potent as simvastatin or atorvastatin, which tend to be metabolized in a similar way.

"So it's a provocative study but still relatively small," Dr. Blumenthal said. "In my mind, the absolute differences are modest, but it's important, I think, that physicians need to be aware that drugs in the same class may differ and have side effects.

"Probably the first step if someone complains of sleep disturbances with cholesterol-lowering medicine is to take it earlier in the day, and if that doesn't work, then to switch to a different statin," he added.

Dr. Golomb's group, he concluded, "is one of few groups throughout the world that has tried to look at side effects of statins over the long term. We await future studies that can clarify why 10 out of 100 people in my experience just don't tolerate statins for one side effect or another."

The study was funded by the National Heart, Lung, and Blood Institute. Coauthor Joel Dimsdale has disclosed an unrelated grant from Sepracor. All other authors have disclosed no relevant financial relationships.

American Heart Association Scientific Sessions 2007: Abstract 3725. Presented November 7, 2007.

Potential Benefit of Good BP Control

Asked for comment on this work by Medscape Neurology & Neurosurgery, session moderator John M. Flack, MD, from Wayne State University, in Detroit, Michigan, said he thinks there is significant potential for this kind of approach to treating hypertension.

"There are potential safety issues — for example, in pregnant women, where angiotensin II is needed for the development of the fetus," Dr. Flack said. "On the other hand, in appropriately selected populations, this really overcomes 1 significant barrier, and that is the daily compliance required to receive the full effect of antihypertensive treatment.

"I think that once the right doses are found and the immune response and its link to blood pressure is better understood, that this is a very promising branch point in our ability to treat hypertension, a chronic condition, over the long term," he said.

The study was funded by Cytos Biotechnology AG, Schlieren, Switzerland, developer of this vaccine. Dr. Nussberger reports he received funding from Cytos for performing biochemical analyses for this study.

American Heart Association Scientific Sessions 2007: Abstract 2519. Presented November 6, 2007.

Summary and Comment

Combination ACE-Inhibitor and Angiotensin-Receptor Blocker Therapy: A Review of Safety Data

Proceed with caution when combining drugs that target the renin-angiotensin system.

Citation(s):

Phillips CO et al. Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction: A quantitative review of data from randomized clinical trials. Arch Intern Med 2007 Oct 8; 167:1930.

Original article (Subscription may be required)

Medline abstract (Free)

Noncardiac Effects of Statins

The current study, called the University of California, San Diego (UCSD) Statin Study, was a double-blind, randomized, placebo-controlled trial evaluating noncardiac effects of statins. A total of 1016 men older than 20 years and postmenopausal women were enrolled if they had low-density lipoprotein (LDL)-cholesterol levels between 115 and 190 mg/dL, no known cardiovascular disease or diabetes, and fasting blood glucose of below 140 mg/dL. At the time the study began, statin therapy was considered optional for these subjects.

They were randomized to receive 40 mg of pravastatin, 20 mg of simvastatin (considered pharmacologically equivalent), or placebo, and followed up for 6 months. Sleep was a prespecified secondary endpoint of this trial.

Sleep was assessed by the adapted Leeds Sleep Scale, rating sleep quality on a scale of 0 to 30, and a sleep-problems scale, where patients rated their general experience of sleep problems without defining the nature of the problems, on a scale of 0 to 10 at baseline, and then rated them from "much better" to "much worse" on a 5-point scale.

At baseline, the 3 randomized groups were equivalent in terms of their sleep quality and sleep problems. On follow-up, however, "the simvastatin group reported significant worsening relative both to the placebo group and the pravastatin group in both the sleep-quality outcome and the sleep-problem outcome," Dr. Golomb said. Pravastatin did not differ significantly from placebo on either of these measures.

Their study is limited to some degree by including only 1 lipophilic and 1 hydrophilic statin, the relatively low doses used at the time the study was begun, and the lack of assessment of a dose response. It's also not clear if these effects would be different in the groups that were excluded from the study, she noted.

The mechanism of this difference is also unclear, she said. It may relate to the lipophilicity of simvastatin vs hydrophilicity of pravastatin, the difference in cholesterol lowering, which was greater with simvastatin, or some other unknown factors.

What is clear is the importance of sleep to good health, function (including memory and cognition), mood, well-being and safety, Dr. Golomb concluded, "so the importance in terms of potential ramifications to health of sleep problems is quite large."

Medscape contributor Linda Brookes, MSc, spoke with Dr. Harris about the COMBOS study.

Medscape: What is non-HDL-C and why is it important in the context of the COMBOS study?

Dr. Harris: Triglycerides are primarily carried by very-low-density lipoproteins (VLDL). People with elevated triglycerides typically have an associated increase in VLDL remnant particles. Because VLDL remnants appear to have atherogenic potential similar to that of LDL, The VLDL-C level can be added to the low-density lipoprotein cholesterol (LDL-C) value to produce a new index of risk and secondary target of therapy: non-HDL-C. The non-HDL fraction in people with high triglycerides (ie, a large number of VLDL remnant particles) is greatly enriched with VLDL-C relative to LDL-C compared with patients with a normal triglyceride level. The sum of LDL-C and VLDL-C, the non-HDL-C value, is really important in predicting risk because these people with elevations in non-HDL-C are at high risk even if their LDL-C is not terribly high. We are focusing more and more on non-HDL-C as a risk factor. It is a very good marker of risk, particularly in people with high triglycerides, and even more in women, because high triglyceride (or high non-HDL-C) levels in a woman attribute more risk for heart disease than the same level does for a man.

Medscape: Is it as easy to measure non-HDL-C as LDL-C?

Dr. Harris: It is very simple. Just subtract HDL-C from the total cholesterol value. Both measurements are routine in the laboratory.

Medscape: Is non-HDL-C as good as or even better than LDL-C at predicting cardiovascular disease?

Dr. Harris: There is growing consensus that non-HDL-C is better. People have just now started looking at it, but it makes sense, because it includes LDL-C and adds additional cholesterol from particles that we know can cause heart disease, such as intermediate-density lipoprotein (IDL, the other name for VLDL remnants) and VLDL, and puts them all into one number. So as people look more carefully, they are finding that the non-HDL-C predicts as well as, if not better than, LDL-C.

Medscape: Is non-HDL-C still as reliable a predictor in people with triglyceride levels as high as 500 mg/dL?

Dr. Harris: Non-HDL-C is not as useful when triglyceride levels are ≥ 1000 mg/dL, because people with levels this high have other problems that are not heart disease-related but are related to the risk for pancreatitis. However, there are not many people with triglycerides > 500 mg/dL, let alone > 1000 mg/dL. But yes, in patients with triglycerides up to 500 mg/dL, the non-HDL-C is quite useful.

Medscape: The patient population in the COMBOS study had LDL-C levels within 10% of goal but triglyceride levels between 200 and 499 mg/dL. Are these patients that physicians encounter often?

Dr. Harris: Yes; there are many more patients like this than patients with triglycerides > 500 mg/dL.

Medscape: Presumably they would have had dietary counseling at the start of their original statin treatment.

Dr. Harris: Yes, and that would not change.

Medscape: So these patients start on a statin and get the LDL-C level down, but they are left with a residual atherogenic component. Would there be any other option than omega-3 ethyl esters (Lovaza)?

Dr. Harris: Another drug that targets LDL-C, such as ezetimibe, would not make much of a difference in the level of non-HDL-C. It might drop it another 10 or 20 points, but in people with triglycerides in the 200-500 mg/dL range, much of the non-HDL-C is from the VLDL, particularly remnant VLDL, not the LDL which ezetimibe affects. Patients with triglycerides in this elevated range and taking statins typically have LDL well under control, so adding another LDL-targeting drug (like ezetimibe) will not be helpful.

Omega-3 ethyl esters (Lovaza, formerly Omacor), was first submitted to the FDA because there was good evidence that it could lower triglycerides significantly in people with triglycerides > 500 mg/dL. That was the study that we did in our laboratory over 10 years ago.^[3] We found that Lovaza 4 × 1 g capsules per day over 4 months lowered mean triglyceride concentrations about 45% in people whose triglycerides averaged around 800 mg/dL. These data were strong enough for the FDA to approve the indication for treating that patient population, and Lovaza (Omacor) was approved in the United States in 2005. At the time of the approval for the treatment of very high triglycerides, the FDA also issued an Approvable Letter citing the requirements for Lovaza to be approved for the treatment of elevated non-HDL-C and triglycerides (200-499 mg/dL) in adult patients concurrently taking a statin at or near LDL-C treatment goal, as an adjunct to diet. The COMBOS study was carried out to address this patient population. It sought to show that Lovaza would not reverse the effect of the statin and that a good overall lowering in non-HDL-C could be achieved. LDL-C and VLDL-C fell by 9.0% in the Lovaza/simvastatin group, and fell by 2.2% in the simvastatin/placebo group, a net difference of about 7%; and, as expected, Lovaza produced a significant fall of 29.5% in triglycerides in these patients whose LDL-C was already well controlled with simvastatin (40 mg).

Medscape: The NCEP/ATP III goal for non-HDL-C is 30 mg/dL higher than the LDL-C goal. What would the LDL-C goal have been in these patients?

Dr. Harris: In some of the patients it would have been 100 mg/dL and in others 130 mg/dL, depending on the other CHD risk factors present (eg, hypertension, smoking, personal CHD history).

Medscape: The results of the study appear to show a slight increase in LDL-C. How can this be explained?

Dr. Harris: Modest increases in plasma levels of LDL-C are seen with Lovaza monotherapy in people with high triglycerides (≥ 500 mg/dL), and the FDA wanted to be sure that this did not occur in patients on statins. Ideally LDL-C levels would decrease or at least not change when Lovaza was added. Because the study was so large, however, the clinically insignificant change in LDL-C (an increase of 0.7%) was statistically significant when compared with the 2.8% drop in LDL-C observed in the placebo group. When the results of the study were submitted to the FDA in June, the FDA issued an Approval Letter permitting the addition of select study data within the clinical studies section of the label for Lovaza, but it did not approve the additional indication. So it is a confusing situation, to be able to talk about the COMBOS data (because they are in the package insert), but not to have Lovaza indicated in this population, What is not confusing, however, is the effect of Lovaza on non-HDL-C, which fell by 9% in the Lovaza/statin group compared with 2% in the simvastatin/placebo group, for a net decrease of about 7%.

Looking at the bottom line in the study, the Lovaza group started with median LDL-C 91 mg/dL at baseline and finished the study at 88 mg/dL. This looks like a decrease, but because the median percent changes were reported it looks like an increase. This is a puzzling message. The median percent change is the percent change that was in the middle of the group. In other words, for each individual in the study, a percent change in LDL-C was calculated from baseline to end of treatment. Those percent changes were ranked from the greatest to the least. The value in the middle happened to be a person who had a 0.7% increase. So that is recorded as the median percent change, even though the median LDL value actually decreased. If you look at the placebo group, the median LDL-C went from 88 mg/dL to 85 mg/dL, the same decrease as was seen in the Lovaza group; but it is a -2.8% median percent change in the placebo group, when compared with the median 0.7% increase in the Lovaza group, that together produced the final reported net increase 3.5% in LDL-C. It is only an increase because LDL-C in the placebo group decreased, not because LDL-C in the Lovaza group increased. Because the sample size was so large (254 patients), this small difference was statistically significant, and thus the authors had to conclude that the addition of Lovaza caused a significant increase in LDL-C. Another problem was that the P value for the difference between groups was .052, which does not actually meet the < .05 criterion for declaring statistical significance. Hence, strictly speaking, there was no statistically significant increase in LDL-C in this study. This would have been even more evident had the study not been so large. If the study had enrolled perhaps 20 less people, that P value would have probably been clearly in the nonsignificant zone. It would not have reached statistical significance and the investigators could have concluded that they did not get a significant change in LDL-C. Here is an example where statistical significance and clinical significance diverge.

Medscape: So it was a statistical accident?

Dr. Harris: Yes, in a way. The study enrolled a lot of people so that it could show a significant non-HDL-C effect; but you do not want to have so many people that you can detect a tiny difference in LDL, and they actually did. So it was a rare example, I think, of a study being too large. I also think it is very important to point out that a percent increase in LDL-C may be meaningless and driven more by the denominator than the numerator. For example, a 5-mg/dL increase in a person whose LDL is 100 mg/dL is a 5% increase, but the same increase in another person with LDL-C 50 mg/dL is a 10% increase. It is still just a 5-mg/dL change, but the percent increase can be huge, depending on the starting level. As the denominator gets smaller, the percent increase becomes huge. The LDLs were relatively low in this study (because of the simvastatin) and that contributed to this outcome. However, that is the way the FDA wanted to see the data, I believe.

Medscape: The patients in the COMBOS study were not particularly high-risk and they had already lowered their LDL-C.

Dr. Harris: Their LDL-C levels were at target at baseline, and after Lovaza they were all still at the same target. A typical target for these patients is 100 mg/dL, so on average, they were below target.

Medscape: Some of the patients switched to simvastatin from a different statin at the start of the study. Would that have had any effect on LDL-C levels?

Dr. Harris: Not likely. Because most patients under "real life" clinical care only imperfectly comply with their statin prescription, it's likely that the subjects' LDL-C was under better control in the study than before it. This is because not only was the simvastatin (40 mg) provided at no cost, but patients also are more compliant with medications when they are in a clinical trial than when they are not. So although their LDL-C levels were probably improved compared with pre-study, I seriously doubt that this would have altered the study's outcome.

Medscape: Has Lovaza been studied with other statins besides simvastatin?

Dr. Harris: Yes; in a small study from Australia^[4] some years ago it was shown to be effective in combination with atorvastatin. Actually, a study similar to COMBOS is being carried out right now with atorvastatin and Lovaza. Two hundred patients with high to very high triglycerides and non-HDL-C above NCEP/ATP III goals were randomized -- after a 4-week diet-only lead-in period -- to atorvastatin 10 mg/day plus either Lovaza 4 g per day or placebo for 8 weeks. After the initial 8-week treatment period, the dose of open-label atorvastatin is titrated to 20 mg per day for an additional 4 weeks, and at week 12, a second titration of atorvastatin to 40 mg is maintained for an additional 4 weeks. The primary outcome measure, again, is change in non-HDL-C, with changes in other lipids and biomarkers as secondary outcome measures. That study will close in about a couple of weeks and then the data have to be analyzed. The results are expected within a year.

Medscape: Would you expect the outcome to be the same with an equivalent dose of another statin plus Lovaza?

Dr. Harris: Yes. As alluded to earlier, there have been other studies with a variety of statins plus Lovaza, and the outcome was much the same in terms of the effects on non-HDL-C. In one study^[5] the addition of Lovaza lowered LDL-C even further, which was surprising. The patients were on various dosages of different statins. In another study,^[4] when they were on atorvastatin adding a different patient population, there was no change in LDL-C. I do not think there will be a change in LDL-C in the Lovaza/atorvastatin study either.

Medscape: Are there any other lipid results in COMBOS that were of particular interest?

Dr. Harris: The apolipoprotein B (apo B) is a different way of looking at non-HDL-C because the particles that constitute non-HDL-C (LDL, IDL, and VLDL) all contain 1 apo B molecule per particle, so changes in apo B follow those in non-HDL-C. A statistically significant decrease was seen in apoB, and there was also a significant rise in HDL-C. This is a really nice pattern of add-on therapy for an agent like Lovaza that has no side effects and no drug interactions.

Medscape: Do statins and omega-3s have any additive effects?

Dr. Harris: I think they do. If you have a new patient who has high LDL-C and high triglycerides whom you put on a statin and Lovaza from the start, you are going to get a combined effect, because the statin is going to have some triglyceride-lowering effect, with Lovaza having a larger effect on top of that. What is suggested from the COMBOS study is that even though the triglycerides come down with statins (not measured directly in this study), the addition of 4 g of Lovaza will lower them further.

Medscape: The incidence and nature of adverse effects were reported to be similar in both groups in the trial. Fasting blood glucose was significantly increased with Lovaza/simvastatin compared with placebo/simvastatin (P < .002); was this clinically significant?

Dr. Harris: I do not think so. Compared with the net benefit of the fall in non-HDL-C and the rise in HDL-C, a 5-mg/dL change in glucose, which was about what it was, is irrelevant, especially when no change in fructosamine was observed.

Medscape: So would there be any reason not to prescribe Lovaza as an add-on therapy in a similar type of patient to those of the COMBOS study population?

Dr. Harris: There are reasons why you might not. There are convenience issues; some people find that taking 4 capsules a day is inconvenient. Some people get a "fishy burp" after taking the capsules, but this can be avoided by taking the capsules at bedtime. The alternatives are fibrates or niacin, both of which have more drug-drug interactions and more potential side effects than Lovaza. Lovaza has no medically significant side effects, and there are other data suggesting that omega-3 fatty acids may reduce risk for arrhythmias and potentially even lower risk for Alzheimer's disease and depression. There are therefore significant "pleiotropic effects" of Lovaza that you would expect to benefit from in addition to triglyceride lowering.

Supported by an independent educational grant from Reliant Pharmaceuticals

Table. COMBOS: Lipid and Lipoprotein Median Values (adapted from Table II: Davidson MH, et al. Clin Ther. 2007;29:1354-1367)

References

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Published at www.nejm.org November 5, 2007 (10.1056/NEJMe0707221)

Frederick A. Masoudi, M.D., M.S.P.H.

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Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) represent one of the most important pharmacologic advances in the prevention of cardiovascular disease in decades. Since the publication of the Scandinavian Simvastatin Survival Study in 1994,¹ several trials have demonstrated important benefits of statins in patients with established coronary disease. These findings have resulted in strong recommendations for the use of statins in clinical-practice guidelines.² Statins are one of the few classes of drugs that are embedded in clinical-performance measures for coronary artery disease, which indicates that clinicians should be considered remiss if they do not prescribe these agents for all their eligible patients.³

In the context of the strong evidence base and recommendations supporting the use of statins for secondary prevention of cardiovascular disease, in this issue of the Journal Kjekshus et al.⁴ report on a study assessing the efficacy of 10 mg of rosuvastatin daily in patients with heart failure and left ventricular systolic dysfunction attributed to coronary artery disease. The study, called the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA), was a randomized, placebo-controlled trial involving patients who were at least 60 years of age (mean, 73 years) who were receiving high rates of evidence-based therapy for left ventricular systolic dysfunction, including angiotensin-converting–enzyme inhibitors or angiotensin-receptor blockers and beta-blockers. As compared with placebo, treatment with rosuvastatin resulted in no significant difference in the primary composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, even though the drug was associated with substantial reductions in levels of low-density lipoprotein (LDL) cholesterol and high-sensitivity C-reactive protein. Patients in the rosuvastatin group had significantly fewer hospitalizations for cardiovascular causes, including heart failure; rates of adverse drug events did not differ between the two study groups. Rosuvastatin therapy had no effect on the health status of patients, as assessed on the basis of New York Heart Association class and the McMaster Overall Treatment Evaluation questionnaire, which were designated as tertiary outcomes.

Results aside, one might ask whether a study of a statin for secondary prevention in this population was warranted. Although the numbers of patients with systolic heart failure who have been enrolled in previous secondary-prevention trials have been inadequate to generate robust evidence, observational studies have suggested benefits of statin therapy on morbidity and mortality in this population.⁵ Statins also have a favorable effect on surrogate end points (e.g., endothelial function), which in theory would be beneficial for patients with heart failure.

Given these facts, it might be tempting to assume that patients with ischemic left ventricular systolic dysfunction would accrue benefits from statins similar to those identified in previous trials. However, there are several reasons to resist this temptation. First, the limitations of assumptions based on observational data⁶ and surrogates⁷ are well documented. Furthermore, the need to understand specifically the balance of risks and benefits of drug therapy in patients with heart failure is magnified by particular characteristics of this population. Although patients with ischemic left ventricular systolic dysfunction have high rates of adverse outcomes, their risk of ischemic cardiovascular events — outcomes that statins seem most likely to prevent — may occur less frequently than in other patients with coronary disease. Moreover, heart failure disproportionately affects older persons, who often have a substantial risk of coexisting illnesses, a factor that raises questions about the applicability of evidence from clinical trials involving younger patients with a single, dominant clinical problem.⁸ Finally, typical regimens for this population involve multiple drugs, both because of the burden of coexisting illnesses and the number of drugs used to treat heart failure.⁹ The addition of a new drug to an already complex regimen increases not only the cost but also the risk of adverse drug interactions. When coupled with a theoretical concern about possible adverse drug effects from statins specific to patients with heart failure,¹⁰ such factors amplify the need to understand the safety and efficacy of this therapy.

How, then, can the clinical findings of the CORONA study be reconciled with the existing randomized trials of statins in patients with established coronary artery disease? First, statins as a class may not be efficacious in patients with ischemic left ventricular systolic dysfunction who are already receiving evidence-based therapy for heart failure. An attenuated effect of statins could reflect the distribution of the causes of outcomes in this population. For example, among patients in the CORONA study, rates of nonfatal myocardial infarction were about one quarter of the rates reported in patients in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) study,¹¹ a statin trial that enrolled patients whose mean age was about 75 years and who had a mean follow-up of about 38 months (as compared with 32.8 months in the CORONA study). It is also important to point out that the confidence intervals around the primary end point in the CORONA study are consistent with as much as a 17% relative reduction in risk or an absolute risk reduction of approximately 2%. An absolute benefit of this magnitude would be clinically significant and is similar to that identified in PROSPER. Second, it is possible that even though rosuvastatin lowered levels of LDL cholesterol and high-sensitivity C-reactive protein, the drug does not share the same benefits regarding important health outcomes with other statins. Although several statins have proven clinical efficacy, supporting the assumption of a class effect, experience with cerivastatin has shown that such assumptions can lead us astray. It is reassuring that in the CORONA study, patients in the rosuvastatin group had fewer hospitalizations for cardiovascular causes and no greater risk of adverse events than did those in the placebo group. Finally, statins may have less incremental benefit in a population of older patients who are at higher risk for competing events, which could reduce the likelihood of ascertaining a benefit for specific cardiovascular outcomes. Although only a minority of deaths in the CORONA study were designated as having noncardiovascular causes, deaths that did not have a clear cause were presumed to be cardiovascular in nature, potentially limiting the quantification of the magnitude of competing risks.

Future trials may shed light on some of these unresolved questions. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) (ClinicalTrials.gov number, NCT00239681 [ClinicalTrials.gov] ) trial¹² should provide additional perspective on the general effect of rosuvastatin on important health outcomes in patients without established cardiovascular disease. The results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca Heart Failure Study (GISSI-HF) (ClinicalTrials.gov number, NCT00336336 [ClinicalTrials.gov] ),¹³ a randomized trial in which patients with heart failure are receiving either rosuvastatin or placebo, will complement the findings of the CORONA study. The GISSI-HF study is also enrolling patients with nonischemic cardiomyopathies and those with preserved left ventricular systolic function, both important subgroups of the population with heart failure who were not evaluated in the CORONA study.

The results of the CORONA study highlight issues that are central to the conduct of trials involving patients with heart failure. When important questions are raised about the benefits and risks of a therapy that is well established in other populations, it may still be essential to establish treatment effects in the population with heart failure. Admittedly, enrolling subjects in trials that challenge well-established treatment paradigms may be difficult despite equipoise on an intellectual level. Second, trials simply must focus more attention on including patients who are representative of those seen in clinical practice. In enrolling older patients, the CORONA study made important strides, although the proportion of women who were enrolled (less than 25%) was no higher than that in previous heart failure trials. Finally, because health status (including symptom burden and quality of life) provides a patient-centered understanding of the effect of any treatment, it should be included as an outcome in all studies of heart failure. Ideally, health status outcomes would not be consigned to tertiary status and would be assessed with valid, reliable, and clinically sensitive instruments designed specifically for use in populations with heart failure.¹⁴ Trials enrolling more representative populations and assessing a broader range of outcomes are instrumental to informed decision making.¹⁵

Meanwhile, enough uncertainty exists about the mechanisms underlying the primary results of the CORONA study that clinicians should continue to prescribe statins for patients with ischemic heart failure and left ventricular systolic dysfunction. Until further evidence accumulates, we cannot tell to what extent the CORONA study reflects the limitations of the use of statins for patients with heart failure, the problems associated with a particular drug, or the intrinsic challenges of treating older patients with complex coexisting illnesses.

Dr. Masoudi reports receiving consulting fees from Amgen, UnitedHealthcare, and Takeda and grant support from Amgen. No other potential conflict of interest relevant to this article was reported.

Source Information

From the Department of Medicine, Division of Cardiology, Denver Health Medical Center, Denver, and the Department of Medicine, Division of Cardiology, University of Colorado at Denver and Health Sciences Center, Aurora, CO.

This article (10.1056/NEJMe0707221) was published at www.nejm.org on November 5, 2007. It will appear in the November 29 issue of the Journal.

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