Effects of n-3 fatty acids on major cardiovascular events in statin users

These statistics seem to show that omega-3 are better at secondary prevention than statins.

Effects of n-3 fatty acids on major cardiovascular events in statin users and non-users with a history of myocardial infarction

1. Simone R.B.M. Eussen1,2,
2. Johanna M. Geleijnse3,
3. Erik J. Giltay4,
4. Cathy J.M. Rompelberg2,
5. Olaf H. Klungel1 and
6. Daan Kromhout3,*

Abstract

Aims Recent secondary prevention trials have failed to demonstrate a beneficial effect of n-3 fatty acids on cardiovascular outcomes, which may be due to the growing use of statins since the mid-1990s. The aim of the present study was to assess whether statins modify the effects of n-3 fatty acids on major adverse cardiovascular events in patients with a history of myocardial infarction (MI).

                    

Methods and results Patients who participated in the Alpha Omega Trial were divided into consistent statin users (n = 3740) and consistent statin non-users (n = 413). In these two groups of patients, the effects of an additional daily amount of 400 mg eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA), 2 g α-linolenic acid (ALA), or both on major cardiovascular events were evaluated. Multivariable Cox's proportional hazard models were used to calculate adjusted hazard rate ratios (HR_adj). Among the statin users 495 (13%) and among the statin non-users 62 (15%) developed a major cardiovascular event. In statin users, an additional amount of n-3 fatty acids did not reduce cardiovascular events [HR_adj 1.02; 95% confidence interval (CI): 0.80, 1.31; P = 0.88]. In statin non-users, however, only 9% of those who received EPA–DHA plus ALA experienced an event compared with 18% in the placebo group (HR_adj 0.46; 95% CI: 0.21, 1.01; P= 0.051).

Conclusion In patients with a history of MI who are not treated with statins, low-dose supplementation with n-3 fatty acids may reduce major cardiovascular events. This study suggests that statin treatment modifies the effects of n-3 fatty acids on the incidence of major cardiovascular events.

                    

ClinicalTrials.gov number: NCT00127452.

Key words

• n-3 fatty acids
• Eicosapentaenoic acid
• Docosahexaenoic acid
• α-linolenic acid
• Cardiovascular diseases
• Statins
• Lipids

• Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2012.

Noncardiac Benefits of Statins Found Lacking

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By Kristina Fiore, Staff Writer, MedPage TodayPublished: May 21, 2010
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

 

 

Claims of unintended benefits of statins appear to be largely unsubstantiated and known risks -- including liver and renal problems and myopathy -- confirmed, British researchers concluded based on findings from a large prospective open cohort study.

The study involving more than two million people, "largely confirmed other studies that reported no clear association between statins and risk of cancers," Julia Hippisley-Cox, MD, and Carol Coupland, MD, of the University of Nottingham in England reported online in BMJ.

The sole exception was esophageal cancer, the risk for which appeared to decrease with statin use. Men and women on simvastatin, for instance, had a 31% reduced risk of the disease (95% CI 0.50 to 0.94), and men on atorvastatin had a 27% reduced risk (95% CI 0.55 to 0.96).

On the other hand, they found that statins were associated with an increased risk of moderate or serious liver dysfunction, acute renal failure, moderate or serious myopathy, and cataracts.

Cox and Coupland also calculated numbers needed to treat to see a benefit for cardiovascular disease, and to harm for other outcomes.

They found that for women at high risk of heart disease, the number needed to treat to prevent one case over five years was 37. For men, it was 33.

With regard to esophageal cancer, the number needed to treat to prevent one cancer case was substantially higher -- at 1,266 among women and 1,082 among men.

For adverse outcomes among women, the number needed to harm for an additional case of acute renal failure over five years was 434, 259 for myopathy, 136 for liver dysfunction, and 33 for cataract.

Those numbers were similar among men, except for myopathy, which was significantly lower at 91.
Statins are among the most widely prescribed medicines, and researchers say their use is likely to continue to increase. For example, in February, the FDA approved rosuvastatin (Crestor) for primary prevention of cardiovascular disease. (See FDA Okays Statin for Primary Prevention)
Other studies have investigated potential benefits of statins in a variety of conditions, including multiple sclerosis and colorectal cancer.

Still, the literature remains unclear as to the full range of risks and benefits of the drugs, Cox and Coupland wrote.

To quantify unintended effects of statins, the researchers conducted a prospective open cohort study involving 368 general practices in England and Wales that participate in the QResearch database.
A total of 2,004,692 patients ages 30 to 84 were involved in the cohort, and about 11% were new users of statins -- 70.7% were prescribed simvastatin, 22.3% atorvastatin, 3.6% pravastatin, 1.9% rosuvastatin, and 1.4% fluvastatin.

The primary outcome was the first recorded occurrence of any malady -- including cardiovascular disease, liver dysfunction, renal failure, venous thromboembolism, Parkinson's disease, dementia, rheumatoid arthritis, cataract, osteoporotic fracture, gastric cancer, esophageal cancer, colon cancer, lung cancer, melanoma, renal cancer, breast cancer, or prostate cancer.

Besides the lack of relationship with all but esophageal cancer, the researchers found no association between statins and risk for Parkinson's disease, rheumatoid arthritis, venous thromboembolism, dementia, or osteoporotic fracture.

Risks for liver and kidney problems,  myopathy, and cataracts were generally similar across statin types, except for liver dysfunction, in which risk was highest for fluvastatin. In women, risk of liver dysfunction was increased 2.53-fold with that statin (95% CI 1.84 to 3.47) and in men it was 1.97-fold higher (95% CI 1.43 to 2.72).

There was generally a dose-response effect for both renal failure and liver dysfunction.

The good news, the researchers found, was that after stopping statin therapy, the risk of developing cataracts returned to normal within a year, and the risk of acute renal failure and liver dysfunction did so within one to three years.

The researchers said that further study is needed in order to confirm the associations and to understand which patients are at the highest risk of adverse effects so that they can be monitored safely.

Overall, they said, the findings "would tend to support a policy of using lower doses of statins in people at high risk of the adverse event."

In an accompanying editorial, Alawi A. Alsheikh-Ali, MD, of Sheikh Khalifa Medical City in Abu Dhabi in the United Arab Emirates, and Richard H. Karas, MD, of Tufts University in Boston, said the findings are "reassuring" in that they didn't find an association between statins and a host of diseases.

"Statin use is not associated with cancer, severe muscle toxicity is rare, and liver abnormalities seem to be reversible, which is consistent with analyses of trial data," they wrote.

Still, they cautioned that physicians "should not overstate the benefits of statins."

"It would be wise to interpret the present observations in the context of the confirmed cardioprotective effects of statins," they wrote, "and remind ourselves and our patients that these drugs, although considered safe, are, like any intervention in medicine, not entirely free of adverse events."

Primary source: BMJ
Source reference:Cox JH, Coupland C "Unintended effects of statins in men and women in England and Wales: Population based cohort study using the QResearch database" BMJ 2010; DOI: 10.1136/bmj.c2197.
Additional source: BMJ
Source reference:Alsheikh-Ali AA, Karas RH "Balancing the intended and unintended effects of statins" BMJ 2010; DOI: 10.1136/bmj.c2197.
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Read the full article here.

Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid?

J Eval Clin Pract. 2012 Feb;18(1):159-68. doi: 10.1111/j.1365-2753.2011.01767.x. Epub 2011 Sep 25.

Is the use of cholesterol in mortality risk algorithms in clinical guidelines valid? Ten years prospective data from the Norwegian HUNT 2 study.

Petursson H, Sigurdsson JA, Bengtsson C, Nilsen TI, Getz L.

Source

Research Unit of General Practice, Department of Public Health and General Practice, Norwegian University of Science and Technology (NTNU), Trondheim, Norway. halfdanpe@gmail.com

Abstract

RATIONALE, AIMS AND OBJECTIVES:

Many clinical guidelines for cardiovascular disease (CVD) prevention contain risk estimation charts/calculators. These have shown a tendency to overestimate risk, which indicates that there might be theoretical flaws in the algorithms. Total cholesterol is a frequently used variable in the risk estimates. Some studies indicate that the predictive properties of cholesterol might not be as straightforward as widely assumed. Our aim was to document the strength and validity of total cholesterol as a risk factor for mortality in a well-defined, general Norwegian population without known CVD at baseline.

METHODS:

We assessed the association of total serum cholesterol with total mortality, as well as mortality from CVD and ischaemic heart disease (IHD), using Cox proportional hazard models. The study population comprises 52 087 Norwegians, aged 20-74, who participated in the Nord-Trøndelag Health Study (HUNT 2, 1995-1997) and were followed-up on cause-specific mortality for 10 years (510 297 person-years in total).

RESULTS:

Among women, cholesterol had an inverse association with all-cause mortality [hazard ratio (HR): 0.94; 95% confidence interval (CI): 0.89-0.99 per 1.0 mmol L(-1) increase] as well as CVD mortality (HR: 0.97; 95% CI: 0.88-1.07). The association with IHD mortality (HR: 1.07; 95% CI: 0.92-1.24) was not linear but seemed to follow a 'U-shaped' curve, with the highest mortality <5.0 and ≥7.0 mmol L(-1) . Among men, the association of cholesterol with mortality from CVD (HR: 1.06; 95% CI: 0.98-1.15) and in total (HR: 0.98; 95% CI: 0.93-1.03) followed a 'U-shaped' pattern.

CONCLUSION:

Our study provides an updated epidemiological indication of possible errors in the CVD risk algorithms of many clinical guidelines. If our findings are generalizable, clinical and public health recommendations regarding the 'dangers' of cholesterol should be revised. This is especially true for women, for whom moderately elevated cholesterol (by current standards) may prove to be not only harmless but even beneficial.
© 2011 Blackwell Publishing Ltd.

Comment in

• J Eval Clin Pract. 2012 Feb;18(1):169; author reply 170-1.

PMID:

21951982

[PubMed - in process]

PMCID:

PMC3303886

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Read the article here.

Slicing The Salami (and calling it steak).

Not about heart disease, cholesterol or statins but excellent excoriation of the ?study? published in Archives of Internal Medicine. Thanks blackdog!
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Slicing The Salami (and calling it steak).

I am taking a brief respite from the 'Loss of Innocence' saga, to excoriate about the publicity for the study about the intake of meats causing Cancer. Much was made of this in the print and broadcast media with precious little criticism or adverse comment from, well anyone. But in truth it was like most of these proselytising studies, that attempt to steer us from the path of our demise by feeding us the results from 'scientific' research that is not really scientific at all.

The study, published in the Archives of Internal Medicine is an observational study, which means it is not presenting any evidence, merely drawing conclusions from data provided by food frequency questionnaire's filled in by the cohort every four years! I can't even remember what I had for dinner last Tuesday, except to know it would have had meat in it, probably lots of it. These epidemiological type studies are really the starting point of a hypothesis to test it's credibility. They are not the end point, merely the beginning of a journey that should encompass all of the checks and balances that science should pursue to ensure that any statement made about anything should at least be founded in proven fact. So, is it likely that the cohort from whom the data was drawn, reported the facts of their diet without telling a few little lies? I really think not, but that's a side issue really.

Let us then look a little deeper. Firstly we see that all meat, processed or otherwise so long as it's red, is alarmingly 'lumped' together, although they

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 So eating preserved meats does have a mechanism that could be causative of some cancers, because it does actually exist, but frankly you would have to eat really large amounts, on a regular basis. And, the bun surrounding the 'unprocessed' burger meat (sic) is likely to be more harmful. And what country is renowned for it's consumption of burgers and barbecued meats? Might that be the country of origin of the cohort of this study, the USA? Always remember, long suffering reader, that observation (and correlation) does not prove causation.
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Read the full article by BLACKDOG here.

 

And I learned a new word - excoriate: to denounce vehemently; censure severely.

Vitamin D deficiency was associated with several cardiovascular-related diseases, including hypertension, coronary artery disease, cardiomyopathy, and diabetes

From the American Journal of Cardiology on 3 Feb 2012.Vitamin D and CVD - AJC Feb 2012.pdf

Vitamin D Deficiency and Supplementation and Relation to Cardiovascular Health

It is very interesting in that, whilst it was an observational study, it looked not only at serum Vitamin D levels, but also at the relationship of D3 supplementation to CVD. It suggests a strong association between supplementation and reduced CVD, particularly among those who were deficient at the baseline.

See abstract and discussion below:

"Recent evidence supports an association between vitamin D deficiency and hypertension, peripheral vascular disease, diabetes mellitus, metabolic syndrome, coronary artery disease, and heart failure. The effect of vitamin D supplementation, however, has not been well studied. We examined the associations between vitamin D deficiency, vitamin D supplementation, and patient outcomes in a large cohort. Serum vitamin D measurements for 5 years and 8 months from a large academic institution were matched to patient demographic, physiologic, and disease variables. The vitamin D levels were analyzed as a continuous variable and as normal (≥30 ng/ml) or deficient (<30 ng/ml). Descriptive statistics, univariate analysis, multivariate analysis, survival analysis, and Cox proportional hazard modeling were performed. Of 10,899 patients, the mean age was 58 ± 15 years, 71% were women (n = 7,758), and the average body mass index was 30 ± 8 kg/m². The mean serum vitamin D level was 24.1 ± 13.6 ng/ml. Of the 10,899 patients, 3,294 (29.7%) were in the normal vitamin D range and 7,665 (70.3%) were deficient. Vitamin D deficiency was associated with several cardiovascular-related diseases, including hypertension, coronary artery disease, cardiomyopathy, and diabetes (all p <0.05). Vitamin D deficiency was a strong independent predictor of all-cause death (odds ratios 2.64, 95% confidence interval 1.901 to 3.662, p <0.0001) after adjusting for multiple clinical variables. Vitamin D supplementation conferred substantial survival benefit (odds ratio for death 0.39, 95% confidence interval 0.277 to 0.534, p <0.0001). In conclusion, vitamin D deficiency was associated with a significant risk of cardiovascular disease and reduced survival. Vitamin D supplementation was significantly associated with better survival, specifically in patients with documented deficiency."

Discussion

Vitamin D has important physiologic functions beyond bone and calcium metabolism. Because vitamin D receptors are involved in the expression of nearly 3,000 human genes, a deficiency could potentially affect numerous disease processes.  Cardiovascular, oncologic, and immunologic disorders have been associated with vitamin D deficiency. Our study showed an association between vitamin D deficiency and many cardiovascular disease states, including hypertension, coronary artery disease, cardiomyopathy, and cardiovascular risk factors, such as hypertension, diabetes mellitus, and hyperlipidemia.

Numerous studies and meta-analyses have suggested that vitamin D deficiency has a negative association with survival; however, the effect of vitamin D supplementation on overall mortality has not been studied. Our findings are consistent with these previous studies, suggesting poorer patient outcomes for patients with vitamin D deficiency. In addition, our data further extend these findings by demonstrating better survival with vitamin D supplementation. The benefits of vitamin D supplementation on survival were significant for those patients with a documented deficiency. This benefit was independent of the concomitant use of other cardioprotective drugs such as aspirin or statins.

These findings could have clinical implications for the usual recommended daily allowance for vitamin D. The regular intake of the recommended 400 IU/day might be adequate to avoid deficiency in many people, and supplementation of _1,000 IU/day might be required to achieve optimal levels.

When included in survival and hazard models with several disease states, vitamin D deficiency is a strong independent predictor of all-cause death. Several studies have reported on the association between obesity and low vitamin D levels, which we also observed in our study cohort. Because the prevalence of obesity is increasing in the United States, as well as in many other developed and emerging nations, vitamin D deficiency could be increasingly common in the future. In addition, our study showed an association between vitamin D deficiency and unfavorable serum lipid values.

Because vitamin D deficiency is widespread, strategies directed at population-based supplementation programs could prove beneficial. To date, however, prospective studies evaluating vitamin D supplementation are few and have not consistently shown benefit. It is possible that the lack of benefit in these studies resulted from suboptimal levels of vitamin D supplementation or other unknown factors. Many previous studies of vitamin D supplementation have used doses of 400 to 800 IU, which might not be adequate to ensure optimal serum levels, with more appropriate daily supplement doses suggested as 1,000 to 2,000 IU. Nevertheless, the growing body of observational data demonstrating relatively high rates of low vitamin D serum levels warrant additional welldesigned studies to investigate the relation between vitamin D and cardiovascular health.

Additional investigation with long-term prospective studies of various vitamin D dosage levels in both healthy and diseased populations are indicated to firmly establish the role of vitamin D supplementation on overall outcomes and mortality. Our study suggests a significant association of vitamin D supplement use and improved survival in deficient subjects, supporting the potential benefit of this intervention. Recent guidelines for the evaluation and treatment of vitamin D deficiency have been published that can help the clinician with patient treatment.

 This was a retrospective, observational study with a selected population, introducing possible selection bias. The study population was derived from patients who had had their vitamin D levels measured at a hospital laboratory and who were patients in a cardiovascular practice and included in its electronic medical records. Extrapolation to other populations might not be appropriate. Also, isolated vitamin D measurement might not reflect long-term levels. We made an arbitrary decision to use the lowest vitamin D measurement for analysis because this value was thought to most likely represent the subjects’ baseline nonsupplemented level. We were unable to accurately associate the timing of vitamin D measurement and supplement initiation. The dose and duration of vitamin D supplementation were not analyzed, and patient compliance was not measured. Inclusion of vitamin D in multivitamin supplements was not considered.

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See Am J Cardiol 2012;109:359–363