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Showing posts with label LDL-C. Show all posts
Showing posts with label LDL-C. Show all posts

Friday, May 26, 2017

The Elderly on Primary-Prevention Statins: No Survival Gains in ALLHAT - Medscape

The Elderly on Primary-Prevention Statins: No Survival Gains in ALLHAT

CHICAGO, IL — Statins for primary prevention do not lower the risk of death, whether cardiovascular or from any cause, when given to people aged 65 years or older with CV risk factors, suggests a secondary analysis of a major trial that caused a stir 15 years ago[1].
The ALLHAT-LLT trial had randomized >10,000 people aged >55 with dyslipidemia and hypertension but no clinical heart disease to receive open-label pravastatin 40 mg/day or usual care. In its 2002 publication[2], the trial famously saw no significant mortality reduction for the statin after 6 years, nor an improvement in fatal or nonfatal coronary heart disease events.

The results were similar in the new post hoc analysis of the trial focusing on the 2867 participants aged 65 years and older, as a whole and by the two age groups 65 to 74 years and >75 years, according to a report published May 22, 2017 in JAMA Internal Medicine with lead author Dr Benjamin H Han (New York University Langone School of Medicine, NY).
Although no significant outcomes differences were seen between the two randomized groups in any of the age categories, there was a trend (P=0.07) for increased all-cause mortality on the statin in the oldest age group.

As Han pointed out for heartwire from Medscape, the overall trial had well-recognized limitations. For example, the statin was given on an open-label basis. Also, it has been long noted that the ALLHAT-LLT usual-care group could receive statins at the physicians' discretion, which could potentially blur any differences in treatment outcomes.

Calls for Caution

"I would be very cautious in drawing any real conclusions from this study, as the study was not specifically designed to study statins in older adults, so all of the analyses are underpowered. None of their major conclusions were statistically significant," according to Dr Ann Marie Navar (Duke Clinical Research Institute, Durham, NC), who isn't connected with the ALLHAT-LLT report.
"Most statin trials have shown no difference in mortality, but [they showed] that statins do reduce the risk of coronary heart disease, a trend also seen in this secondary analysis," Navar told heartwire by email.


"The trend toward increasing mortality is certainly provocative but really needs to be explored in a trial specifically designed to test this issue."
The post hoc analysis included 1467 participants who had been randomized to pravastatin; their mean age was 71.3, and 48% were women. Their mean LDL-C level was 147.7 mg/dL at baseline and 109.1 mg/dL after 6 years.
The 1400 participants in the usual-care group had a mean age of 71.2 years, and 51% were female. Their mean LDL-C level was 147.6 mg/dL at baseline and 128.8 mg/dL after 6 years.
For all patients over the age of 65 who took pravastatin, the hazard ratio for all-cause mortality was 1.18 (95% CI 0.97–1.42, P=0.09) compared with the usual-care group. It was 1.08 (95% CI 0.85–1.37, P=0.55) for the 65–74 group and 1.34 (95% CI 0.98-1.84 P=0.07) for those aged 75 and older. Nor were there significant HRs for the secondary CHD end points.

In multivariate analysis, the corresponding HRs were 1.15 (95% CI 0.94–1.39) for 65 and older, 1.05 (95% CI 0.82–1.33) for those 65 to 74, and 1.36 (95% CI, 0.98-1.89) for 75 and older. The prospectively defined covariates included age, sex, race/ethnicity, primary-prevention aspirin use, smoking history, type 2 diabetes, body mass index, and systolic and diastolic blood pressures.

The Issues
"We are seeing a lot more older adults being put on statins for primary prevention, but the problem is, the evidence for doing so is limited," Han said.

"As geriatricians, we emphasize that treatment recommendations really need to be individualized with patients and need to also take into account not just what their cardiovascular risk is, but what their life expectancy is, what other competing risks they may have, and what their functional status and everyday activities are," Han observed.
Moreover, "for older adults, taking another medicine every day for the rest of your life isn't a small thing, especially if you have other chronic conditions, and right now we don't have any evidence that there's any benefit to doing so if you do not have any history of cardiovascular disease."

An editor's note accompanying the ALLHAT-LLC report points out the potential risks of extending statins to groups that may be unlikely to benefit clinically[3]. For example, statin therapy may be associated with myopathy, myalgias, muscle weakness, and arthropathies, notes Dr Gregory Curfman (Harvard Medical School, Boston, MA).

"These disorders may be particularly problematic in older people and may contribute to physical deconditioning and frailty. Statins have also been associated with cognitive dysfunction, which may further contribute to reduced functional status, risk of falls, and disability," he writes.
"The combination of these multiple risks and the ALLHAT-LLT data showing that statin therapy in older adults may be associated with an increased mortality rate should be considered before prescribing or continuing statins for patients in this age category."

Is There a "Point of No Return"?

"It takes decades for the plaque to build up in the arteries that eventually causes strokes and heart attacks. Data from thousands of adults studied in clinical trials show us that statins, when started early, can interrupt or slow down that process," according to Navar.

But, "we don't know if there is a 'point of no return' where it's too late to start a statin, and ALLHAT was not designed to answer that question. We need a large randomized trial to really know how effective statins are when started in older adults without cardiovascular disease," she said.
"There is a lot of negative press about statins, and I really worry about the effect of studies like these on the public's perception. This study was a secondary analysis of a trial that was not designed to study the effect of statins in older adults," Navar observed.

"Data from thousands of adults in multiple randomized trials have shown that statins prevent heart disease and do not kill people. I hope that the media, in the never-ending search for clickbait, doesn't overemphasize the statistically nonsignificant mortality trend and lead people who are known to benefit to discontinue their statins."

The study was funded by the National Heart Lung & Blood Institute. Study medications were contributed by Pfizer, AstraZeneca, and Bristol-Myers Squibb, and financial support was provided by Pfizer. The study authors and Curfman report no relevant financial relationships. Navar reported research support from the National Institutes of Health, Amgen, and Sanofi & Regeneron Pharmaceuticals and serving as a consultant for Amgen and Sanofi.

Read the full article here.

Monday, July 21, 2014

Do statins prevent or promote cancer? - Current Oncology

Do statins prevent or promote cancer?

Mark R. Goldstein MD FACP, Medical Director, Fountain Medical Court, 9410 Fountain Medical Court, Suite
The Editor, Current Oncology December 24, 2007
 
In their commentary, Drs. Takahashi and Nishibori discuss putative antitumour effects of statins. However, prospective data suggest that statins actually increase cancer in certain segments of the population. Additionally, new findings regarding the immunomodulatory effects of statins may explain the mechanism by which that increase occurs.

Statins increase the number of regulatory T cells (Tregs) in vivo by inducing the transcription factor forkhead box P3. Although that increase may be beneficial in stabilizing atherosclerotic plaque by reducing the effector T-cell response within the atheroma, it might impair both the innate and adaptive host antitumour immune responses. Not surprisingly, the number of Tregs present in many solid tumours correlate inversely with patient survival.

Indeed, analysis of large randomized statin trials demonstrate a highly significant (p = 0.009) inverse association between achieved low-density lipoprotein cholesterol levels and cancer. Close inspection of statin trials reveal the specific populations at risk for the development of incident cancer with statin treatment. These include the elderly and people with a history of breast or prostate cancer,. Furthermore, statin-treated individuals undergoing immunotherapy for cancer may be at increased risk for worsening cancer.

The elderly are relatively immunosuppressed and are more likely to harbour occult cancers. In the prosper (Prospective Study of Pravastatin in the Elderly at Risk) trial, a 3.2-year prospective study of pravastatin for cardiovascular disease prevention in the elderly (mean age at trial entry: 75 years) at high risk for cardiovascular disease, cancer incidence was significantly increased in subjects randomized to pravastatin. In fact, the increase in cancer mortality equalled in magnitude the decrease in cardiovascular disease mortality in the statin-treated patients, leaving all-cause mortality unchanged. Likewise, post hoc analysis of the lipid study, a 6-year prospective trial of pravastatin in individuals with cardiovascular disease, revealed a significant increase in cancer incidence in the elderly subjects (age: 65–75 years) randomized to pravastatin. In a secondary analysis of the tnt (Treating to New Targets) study, elderly subjects randomized to high-dose atorvastatin (80 mg daily) versus low-dose atorvastatin (10 mg daily) demonstrated a trend toward increased death, largely from an increase in cancer mortality. Therefore, the increase in incident cancer in the elderly might be dose-related. It is highly plausible that the elderly are particularly sensitive to a statin-induced increase in Tregs, further impairing their immune response to cancer.

An alarming increase in breast cancer incidence, some of which were recurrences, was seen in women randomized to pravastatin in the care trial Thereafter, cancer was an exclusion criterion in randomized statin trials. In clinical practice, however, it is not infrequent to find an association between recurrence of breast cancer and concurrent statin therapy. Long-term follow-up (10 years after trial completion) of woscops (West of Scotland Coronary Prevention Study), a 5-year prospective trial of pravastatin in hypercholesterolemic men, revealed an increase in prostate cancer in the men who were randomized to pravastatin therapy. That finding indicates that cancers may become evident a decade or more after treatment with statins. Treg increases have been associated with both breast and prostate cancers,, and therefore, it is highly plausible that the increase in cancers seen with statin therapy is related to a statin-induced increase in Tregs.

Statin therapy has been associated with tumour progression leading to radical cystectomy in patients treated for bladder cancer with bacille Calmette–Guérin immunotherapy. That association may be likewise due to a statin-induced increase in Tregs, resulting in impaired host antitumour immunity.
Statin trials have typically randomized subjects free of prevalent cancers and have been about 5 years in duration. Long-term follow-up data are limited, particularly for the development of cancer. Statins are now promoted for widespread use in adults of all ages and at high doses, potentially for decades. Importantly, they are used in individuals with other significant comorbidities such as cancer. Unfortunately, the post-market surveillance of drugs has been poor. Because cancer is highly prevalent in the population, particularly in the elderly, a statin-induced increase in cancer incidence will likely go unrecognized.

Long-term prospective data are needed on the feasibility of statin therapy in the very elderly, the immuno-suppressed, and those with prevalent cancer. Furthermore, long-term outcome data are needed in young individuals treated with statins for prolonged time periods. Perhaps a constant increase in Tregs over years, even in the young, will weaken host antitumour immune surveillance and increase the risk for various cancers.

In conclusion, we feel that there is ample evidence that statins may promote cancer in certain segments of the population. Currently, the indications for statin therapy are based on lipoprotein levels, prevalent cardiovascular disease, other vascular risk factors, and family history. Maybe it is time for a new paradigm that also includes age extremes, prevalent cancer, a past history of cancer, and overall immunocompetence.

REFERENCES

1. Takahashi HK, Nishibori M. The antitumour activities of statins. Curr Oncol. 2007;14:246–7. [PMC free article] [PubMed]
2. Mausner–Fainberg K, Luboshits G, Mor A, et al. The effect of hmg-coa reductase inhibitors on naturally occurring cd4+cd25+ T cells. Atherosclerosis. 2007 [Epub ahead of print] [PubMed]
3. Goronzy JJ, Weyand CM. Immunosuppression in atherosclerosis: mobilizing the opposition within. Circulation. 2006;114:1901–4. [PubMed]
4. Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS. cd4+cd25+Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci U S A. 2007;104:19446–51. [PMC free article] [PubMed]
5. Curiel TJ. Tregs and rethinking cancer immunotherapy. J Clin Invest. 2007;117:1167–74. [PMC free article] [PubMed]
6. Yakirevich E, Resnick MB. Regulatory T lymphocytes: pivotal components of the host antitumor response. J Clin Oncol. 2007;25:2506–8. [PubMed]
7. Alsheikh–Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol. 2007;50:409–18. [PubMed]
8. Shepherd J, Blauw GJ, Murphy MB, et al. on behalf of the prosper (Prospective Study of Pravastatin in the Elderly at Risk) study group. Pravastatin in elderly individuals at risk of vascular disease (prosper): a randomised controlled trial. Lancet. 2002;360:1623–30. [PubMed]
9. Hunt D, Young P, Simes J, et al. Benefits of pravastatin on cardiovascular events and mortality in older patients with coronary heart disease are equal to or exceed those seen in younger patients: results from the lipid trial. Ann Intern Med. 2001;134:931–40. [PubMed]
10. Wenger NK, Lewis SJ, Herrington DM, Bittner V, Welty FK. on behalf of the Treating to New Targets Study Steering Committee and Investigators. Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med. 2007;147:1–9. [PubMed]
11. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996;335:1001–9. [PubMed]
12. Ford I, Murray H, Packard CJ, Shepherd J, Macfarlane PW, Cobbe SM. on behalf of the West of Scotland Coronary Prevention Study Group. Long-term follow-up of the West of Scotland Coronary Prevention Study. N Engl J Med. 2007;357:1477–86. [PubMed]
13. Hoffmann P, Roumeguère T, Schulman C, van Velthoven R. Use of statins and outcome of bcg treatment for bladder cancer. N Engl J Med. 2006;355:2705–7. [PubMed]
14. Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol. 2007;211:144–56. [PMC free article] [PubMed]
15. Winer EP, Harris JR, Smith BL, D’Alessandro HA, Brachtel EF. Case records of the Massachusetts General Hospital. Case 32-2007. A 62-year-old woman with a second breast cancer. N Engl J Med. 2007;357:1640–8. [PubMed]
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Read the complete article here.

Monday, March 31, 2014

Patients Managed to Target LDL Particle Number Experience Fewer Cardiovascular Events

Patients Managed to Target LDL Particle Number Experience Fewer Cardiovascular Events Than Patients Managed to Target LDL Cholesterol, According to Study

Data demonstrates that the NMR LipoProfile® test provides clinically reliable information to help reduce cardiovascular events, especially in patients with diabetes and those on statin therapy

 
WASHINGTON, March 31, 2014 /PRNewswire/ -- LipoScience, Inc. (NASDAQ: LPDX), a diagnostic company pioneering a new field of personalized nuclear magnetic resonance (NMR) diagnostics to advance the quality of patient care in cardiovascular, metabolic and other diseases, today announced data showing that patients managed to a target LDL particle (LDL-P) number, as measured by LipoScience's NMR LipoProfile test, achieved a 22 to 25 percent greater reduction in the risk of cardiovascular (CV) events over a three-year period compared to patients who attained LDL cholesterol (LDL-C) targets.
 
These data, presented in a poster session at the 63rd American College of Cardiology (ACC) Scientific Sessions in Washington, D.C., are derived from a real-world sample of commercially insured patients who were at a high risk of CV events, including patients with Coronary Heart Disease and Diabetes Mellitus. The investigators found that patients who achieved target LDL-P levels (<1000 aggressive="" concentrations="" dl="" ldl-c="" lipid-lowering="" mg="" more="" nmol="" p="" reaching="" received="" target="" than="" those="" treatment="">
 
Those treatment differences were associated with better outcomes (as measured by the reduction in CV event rates) over one to three years of follow-up. The study was sponsored by LipoScience and jointly designed by LipoScience and HealthCore, with clinical input from Terry A. Jacobson, MD, Professor of Medicine at Emory University, Atlanta, and Peter P. Toth, MD, PhD, Director of Preventive Cardiology at CGH Medical Center in Sterling, Ill.
 
"These new data add to the growing body of evidence suggesting that NMR measurement of LDL particle number, when used in conjunction with other lipid measurements, is a valuable cardiovascular risk management tool," commented Dr. Jacobson, the lead author of the study. "Due to the wide variance in the cholesterol content of LDL particles among individuals, measurements of LDL cholesterol and LDL particle number frequently disagree, especially in patients with insulin resistance and those treated with lipid-lowering therapies. When a disagreement between LDL-P and LDL-C is present, quantification of LDL particle number is a more clinically reliable measure of LDL and of treatment outcomes than measurement of LDL cholesterol."
 
Dr. Jacobson and colleagues analyzed data from more than 4,000  high-risk patients (over 2,000 with LDL-P < 1000 nmol/L and over 2,000 with LDL-C < 100 mg/dL) selected from the HealthCore Integrated Research DatabaseSM who were followed for as long as three years. Those who achieved LDL-P target <1000 100="" 22="" 25="" a="" above="" achieved="" as="" at="" baseline="" below="" but="" compared="" concentrations="" cv="" dl.="" event="" follow-up.="" group="" higher-potency="" in="" ldl-c="" ldl-p="" levels="" likely="" lower="" measured="" medications="" mg="" more="" nmol="" not="" noted="" of="" one="" over="" p="" patients="" percent="" receive="" risk="" statin="" target="" than="" the="" three="" to="" was="" were="" who="" whose="" years="">
Dr. Jacobson's poster, "Comparison of cardiovascular events between patients achieving low-density lipoprotein particle targets and patients achieving low-density lipoprotein cholesterol targets," will be presented Monday, March 31 from 9:30 a.m. to 12:30 p.m. in Hall C of the Washington Convention Center. The poster number is 150.
 
"The HealthCore data add an important, real-world, analysis to the ongoing discussion of how best to optimize individual patient management. These findings are consistent with the recommendations of various expert panels and organizations such as the National Lipid Association, the American Association for Clinical Chemistry, and the American Association of Clinical Endocrinologists, each of which advocates the use of LDL-P as a target of therapy in managing at-risk patients," stated William C. Cromwell, MD, Chief Medical Officer of LipoScience.  "We hope the findings encourage greater adoption by clinicians to manage their patients to an LDL-P target to reduce CVD events."
The ACC Scientific Session also includes the following poster presentations that support the clinical utility of NMR-based lipoprotein particle measurement:
  • Poster #143: May HT, et al. Utility of high-density lipoprotein cholesterol, particle concentration, and size in predicting future major adverse cardiovascular events among patients undergoing angiography: The Intermountain Heart Collaborative Study.
    • Saturday, March 29, 9:30am to 12:30pm, Hall C
  • Poster #146: Muhlestein JB, et al. GlycA and GlycB, novel NMR biomarkers of inflammation, strongly predict future cardiovascular events, but not the presence of coronary artery disease (CAD), among patients undergoing coronary angiography: The Intermountain Heart Collaborative Study.
    • Sunday, March 30, 9:30am to 12:30pm, Hall C
  • Poster #128: Koren MJ, et al. Effects of alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, on lipoprotein particle concentrations determined by nuclear magnetic resonance: Substudy of a randomized double-blind phase II clinical trial.
    • Sunday, March 30, 9:30am to 12:30pm, Hall C
  • Poster #134: Xu R, et al. Effects of evolocumab on lipoprotein particles and subclasses in hypercholesterolemic and heterozygous familial hypercholesterolemia subjects on statin therapy
    • Sunday, March 30, 9:30am to 12:30pm, Hall C
  • Poster #141 Alexander V, An antisense inhibitor of apolipoprotein C-III significantly decreases apolipoprotein C-III, triglycerides, Very-Low-Density Lipoprotein cholesterol and particle number, and increases High-Density Lipoprotein cholesterol and particle number in hypertriglyceridemic patients on a fibrate.
    • Monday, March 31, 9:30am to 12:30pm, Hall C
 
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Read the complete article here.

Thursday, March 20, 2014

Ezetimibe Prescribing Fails to Keep Up With Evidence - JAMA

Ezetimibe Prescribing Fails to Keep Up With Evidence     
Mike Mitka, MSJ 
             
JAMA. Published online March 19, 2014. doi:10.1001/jama.2014.2896
          
 
Although physicians like to think they practice evidence-based medicine, that appears to not be the case with prescribing the cardiovascular drug ezetimibe. And some critics say that use of surrogate markers to guide practice rather than clinical outcomes such as occurrence of myocardial infarction, stroke, or death has likely played a role.
 
Ezetimibe is an intestinal cholesterol absorption inhibitor found to reduce low-density lipoprotein cholesterol (LDL-C) levels by about 20% when given alone. It also further reduces LDL-C levels when added to statin therapy, which blocks cholesterol synthesis in the liver by inhibiting HMG-CoA reductase.
 
The Food and Drug Administration approved ezetimibe in 2002 for use in the United States primarily because it lowered LDL-C levels, a surrogate marker for prevention of cardiovascular disease. Whether ezetimibe improved clinically meaningful outcomes remained a question.
 
That question was somewhat answered in January 2008, with the announcement that the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, sponsored and conducted by industry, found that the addition of ezetimibe failed to reduce atherosclerosis progression compared with simvastatin alone, despite lowering LDL-C levels. Atherosclerosis progression was determined by a change in the intima-media thickness of the walls of the carotid and femoral arteries—yet another surrogate end point (Kastelein JJP et al. N Engl J Med. 2008;358[14]:1431-1443).
Place holder to copy figure label and caption
US and Canadian physicians continue to prescribe ezetimibe even after a study found giving the drug with a statin failed to reduce atherosclerosis progression compared with the statin alone.
 
 
The ENHANCE result prompted some leaders in the cardiology community to question ezetimibe’s place in cardiovascular disease treatment. Harlan Krumholz, MD, professor of medicine and epidemiology and public health at Yale University in New Haven, Connecticut, said the study should change practice. “Although not definitive, [ENHANCE] increases our uncertainty about the clinical value of this novel drug. Without some evidence of improved outcomes associated with its use, ezetimibe should be relegated to a last option for patients who need medication for hypercholesterolemia, and even in these cases, it is reasonable for clinicians and their patients to wait for further information before considering it,” he wrote in NEJM Journal Watch (http://tinyurl.com/pk9xr29).
 
So did the ENHANCE results change practice? In the United States, the answer is “somewhat,” while in Canada, the answer appears to be “no.”
 
In a study published in the American Heart Journal, researchers looked at ezetimibe prescription trends before and after ENHANCE, using data collected from CompuScript in Canada and IMS Health in the United States from January 1, 2002, to December 31, 2009. The researchers found the monthly number of ezetimibe prescriptions per 100 000 population rose from 6 to 1082 in the United States from November 2002 to January 2008 and then declined to 572 per 100 000 population by December 2009, a decrease of 47.1%. In Canada, however, use continuously increased from 2 to 495 per 100 000 from June 2003 (when the drug was approved in Canada) to December 2009 (Lu L et al. Am Heart J. doi:10.1016/j.ahj.2014.01.014 [published online February 27, 2014]).
 
Coauthor Cynthia A. Jackevicius, PharmD, MSc, a professor of pharmacy practice and administration at Western University of Health Sciences in Pomona, California, and an adjunct scientist, Institute for Clinical Evaluative Sciences, in Toronto, said her team was initially surprised by the Canadian results.
 
“Previous findings showed ezetimibe use in Canada experienced a more conservative uptake, so we expected to see a decrease in use in response to the ENHANCE study,” Jackevicius said. “So we looked for different factors, and one is the Canadian lipid guidelines, which specifically said ezetimibe could be added to statins, and that didn’t change after ENHANCE came out.”
A study of ezetimibe use in Saskatchewan, the only Canadian province that lists the drug for open formulary access, even though guidelines say it’s a second-line agent for lowering cholesterol, reflects Jackevicius’s team’s findings. Using data from provincial health administrative databases, the Saskatchewan researchers found that ezetimibe prescriptions were 2.5% of cholesterol-lowering dispensations in 2004 and 8.8% of such dispensations in 2011 (Alsabbagh WM et al. Can J Cardiol. 2014;30[2]:237-243). The authors concluded that allowing unrestricted use of ezetimibe in Saskatchewan may have led to a large number of inappropriate prescriptions, at odds with Canadian clinical guidelines.
 
And although ezetimibe use declined in the United States, its use per 100 000 population is still greater than Canada’s, generating US expenditures of more than $2.2 billion in 2009.
 
Krumholz, one of the coauthors on the study with Jackevicius, remains perplexed as to the continuing popularity of ezetimibe. “The drug continues to defy gravity, and that’s probably a result of really strong marketing and the singular focus on cholesterol numbers,” he said.
 
Krumholz said heart health campaigns urging patients to “know your numbers” and treatment goals based on cholesterol measurements, such as getting asymptomatic individuals’ LDL-C levels below 130 mg/dL, have worked in ezetimibe’s favor at the expense of evidence-based medicine. “Is this the drug that lowers your LDL-C and helps you? We don’t know that,” he said. “The comfort of hitting a target offers little benefit if you don’t know that it is really protecting you.”
 
Although ENHANCE has not derailed ezetimibe prescribing, the newest cholesterol management guidelines just might. The guidelines, issued late last year by the American College of Cardiology and the American Heart Association, abandon the idea of reaching a target level for LDL-C, instead recommending the use of statins to reduce LDL-C levels only for certain types of patients.
Will this change in the guidelines affect ezetimibe prescribing? “It will be interesting to see what the guidelines will do,” Krumholz said.
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Read the complete article here.

Monday, January 13, 2014

Does Wheat Cause Coronary Heart Disease?

Does Wheat Cause Coronary Heart Disease?

Introduction

Coronary heart disease (CHD) is the leading cause of deaths worldwide - killing 7 millions people every year. In the following text, we will see that wheat consumption is probably a risk factor for CHD.

Conventional Wisdom on Wheat

Most health organizations currently view wheat as a safe food except for people having celiac disease - affecting up to 1% of the population - and people having non-celiac gluten sensitivity. Also whole wheat - as part of whole-grains - is considered to be one of the healthiest food. In fact a diet rich in whole-grains is considered to be protective against CHD.

Why? Because observational studies consistently find that whole-grain consumption is associated with a decreased risk of CHD. Do these results contradict wheat consumption causing CHD?

Are Whole-Grains Protective Against CHD?

According to this study:
Whole-grain intake consistently has been associated with improved cardiovascular disease outcomes, but also with healthy lifestyles, in large observational studies. Intervention studies that assess the effects of whole-grains on biomarkers for CHD have mixed results.
Indeed many studies show that whole-grain consumption is associated with a decreased risk of CHD. But these studies are observational and can only show correlation but not causation.

In fact there is an health-conscious population bias in these studies: for example people consuming the most whole-grains also exercise more and smoke less:
Whole-grain intake and lifestyles
Data from Majken K Jensen et al., Intakes of whole grains, bran, and germ and the risk of coronary heart disease in men, 2004

Of course researchers adjust the data with these risk factors. But it is very difficult, maybe impossible, to adjust for all risk factors. For example the two previously cited studies did not adjust for important risk factors like socioeconomic status or social support.

A classic example of an occurrence of this bias can be found in hormone replacement therapy (HRT): observational studies had found that HRT was decreasing the risk of heart disease risk while a controlled study finally found that HRT was indeed slightly increasing the risk of heart disease.

A proof that this health-conscious bias could explain the seemingly protective effect of whole-grains can be found in randomized controlled studies: many of them fail to find any beneficial effect of whole-grains compared to refined grains.

So according to these randomized controlled studies whole-grains are neutral toward CHD risks. How then can we say that wheat causes CHD?

Are All Grains Created Equal?

Many randomized controlled studies compared wheat with other grains. These trials are usually quite short. So instead of looking at the number of heart attacks, short-term studies focus on risk predictors of CHD like weight gain or markers of inflammations. Apolipoprotein B (ApoB) level is another risk factor. It represents the number of LDL particles - often called “bad cholesterol”. It is now considered to be a better predictor than LDL-C - the amount of cholesterol contained in LDL particles. The lower the level of ApoB the lower is the risk of CHD.

Here are some results of these studies:
  • a study concluded that a bread diet may promote fat synthesis/accumulation compared with a rice diet
  • wheat increased BMI compared to flaxseed in a 12 months study
  • wheat increased ApoB level by 5.4% compared to flaxseed in a 3 weeks study
  • wheat increased ApoB level by 7.5% compared to flaxseed in a 3 months study
  • wheat increased ApoB level by 0.05 g/L compared to flaxseed in a 12 months study
  • oat decreased ApoB level by 13.7% while wheat had no significant effect in a 21 days study
  • wheat increased the number of LDL particles by 14% while oat decreased them by 5% in a 12 weeks study
  • ApoA to ApoB ratio (a risk predictor similar in efficiency to ApoB alone - here the higher the better) was increased by 4.7% for oat bran and 3.9% for rice bran compared to wheat bran in a 4 weeks study
These studies show that some grains like oat improve the risk factors of CHD compared to wheat. In addition, these studies often show an absolute improvement of the CHD risk profile in groups eating oat and an absolute deterioration in groups eating wheat. Although we cannot say for sure, it would suggest that oat is protective against CHD - which is confirmed by other studies - while wheat increase the risk of CHD.

That could help explaining why people eating more whole-grains are healthier in observational studies since it looks like that they eat more grains like rice and oat and less typically wheat-made food like white bread, pasta and doughnuts:
Whole-grain intake and different grain intakeData from Andersson A. et al., Intakes of whole grains, bran, and germ and the risk of coronary heart disease in men, 2007

Now let’s have a look at studies linking wheat and CHD.

Observational Studies on Wheat

Some observational studies linked wheat and waist circumference gains - waist circumference being a strong predictor of CHD:
  • a study showed a correlation between consumption of white bread and waist circumference gains
  • a study concluded that: ”reducing white bread, but not whole-grain bread consumption, within a Mediterranean-style food pattern setting is associated with lower gains in weight and abdominal fat
  • a Chinese study found that ”vegetable-rich food pattern was associated with higher risk of obesity” but as noted by obesity researcher Stephan Guyenet the association between obesity is in fact stronger with wheat flour than with vegetables
A more pertinent result is found in the data of a large observational study in China. Researchers analysed these data and found a 0.67 correlation between wheat flour intake and CHD. They also found a 0.58 correlation between wheat intake and BMI.
CHD mortality and wheat intake
From Denise Minger
But this is just a single unadjusted correlation and does not prove much. However blogger Denise Minger thoroughly analysed the data of this study and found that the association held strongly after multivariate analysis with any other variable available like latitude, BMI, smoking habits, fish consumption, etc.

Since it is an observational study it cannot prove anything but it is yet another evidence suggesting that wheat consumption causes CHD. Let’s now have a look at randomized controlled trials.

Randomized Controlled Trials on Wheat

In addition to the previous randomized controlled trials comparing wheat with other grains there are two additional studies suggesting that wheat consumption causes CHD.

The first one is a study involving rabbits. While studies involving animals are not always relevant to humans - especially studies with herbivore animals like rabbit - the results of this study are quite interesting.

The researchers fed rabbits an atherogenesis diet (i.e. promoting formation of fatty masses in arterial walls) with a supplement of cottonseed oil, hydrogenated cottonseed oil, wheat germ or sucrose. And as they concludes:
Severity of atherosclerosis after 5 months was greatest on the wheat germ-supplemented diet, whereas there were no differences among the other three groups.
The second study is the Diet And Reinfarction Trial (DART). In this 2-year randomized controlled trial, people who already had recovered from an heart attack were split into groups receiving various advices. The main result of this study was that the group advised to eat fatty fish had a reduction in mortality from CHD.

One other advice - the fibre advice - was:
to eat at least six slices of wholemeal bread per day, or an equivalent amount of cereal fibre from a mixture of wholemeal bread, high-fibre breakfast cereals and wheat bran
Seeing this advice we can guess that most of cereal fibres intake by this group was from wheat although we cannot be sure.

This advice resulted on a 22% death increase:
Total mortality in the fibre advice groupFrom Stephan Guyenet
However this result bordered on statistical significance: the 95% confidence interval being 0.99–1.65.
For people not familiar with statistics, a result is usually defined as statistically significant when there is less than 5% chance that the result is due to luck alone. Here there is a 95% probability that the relative risk is between 0.99 (1% decreased chance of dying) and 1.67 (67% increased chance of dying).

Since the probability that the fibre advice resulted in a protective or neutral effect was a little too high, this result has been quite overlooked. Had the study last a little longer, it would have raised way more suspicion toward whole-grains.

In fact, researchers found this effect to be statistically significant in a follow-up study. After adjusting for pre-existing conditions and medication use, we can see in the table 4 of this study an hazard ratio of 1.35 (95% CI 1.02, 1.80) for the 2-year period of the randomized controlled trial.

These results are quite telling: according to these researchers, a 2 year randomized controlled trial showed that advising people recovering from an heart attack to eat at least six slices of wholemeal bread per day resulted in a statistically significant 35% percent chance increase of CHD compared to people not receiving this advice.

Wheat, Vitamin D Deficiency And Heart Disease

Many studies found that vitamin D deficiency is associated with CHD.
However vitamin D deficiency does not seem to cause heart disease. For example several studies found that vitamin D supplementation did not prevent heart disease.
As this study concludes:
A lower vitamin D status was possibly associated with higher risk of cardiovascular disease. As a whole, trials showed no statistically significant effect of vitamin D supplementation on cardiometabolic outcomes.
Wheat consumption causing CHD could help explaining these results. A study found that wheat consumption depletes vitamin D reserves. That could explain why vitamin D deficiency is associated with heart disease and why it does not seem to cause it: both vitamin D deficiency and heart disease could be consequences of wheat consumption.

Of course this is not the only explanation. For example the DART study shows that fish consumption prevents CHD and fish is a food rich in vitamin D.

Not the Perfect Culprit

To be clear, if it seems likely that wheat consumption is a risk factor of CHD it is not the only one nor the primary one. There are many other factors like smoking, hypertension, lack of exercice or stress. Even among dietary factors wheat is probably not the main one. For example the DART study shows that the protective effect of fish intake is stronger than the adverse effect of wheat.

In addition, deleterious wheat effects might not affect everybody. One study showed that the ApoB level variation following wheat and oat bran intake was different depending on the genotype of the individuals. In another study whole-wheat intake worsened the lipid profile only in people having a specific genotype compared to refined wheat.

How the wheat is cooked may have a role too. Studies show that sourdough bread improve mineral bioavailability (such as magnesium, iron, and zinc) compared to yeast bread or uncooked whole-wheat. Also content in proteins with potential adverse consequences like gluten or wheat germ agglutinin differs depending of the food type.

Conclusion

There are strong evidences that wheat consumption is a risk factor for CHD. People at risk of CHD should avoid wheat as should those trying to lose weight. In all cases, stopping wheat consumption for a month for example to see how one feel without wheat is always a good idea since there is currently no available method to diagnose non-celiac wheat sensitivities and that even for celiac disease the average delay in diagnostic is 11 years in the US.

More studies looking at the links between wheat and CHD are urgently needed since CHD is the leading cause of deaths while wheat is the second most widely consumed food and whole-wheat is often advised to lower risk of CHD. Studies considering grains as a whole are bound to give inconsistent results since different grains seem to have opposite effects in the case of CHD. So as much as possible future studies should treat grains separately and consider things like type of wheat products and genetic variability.

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Read the complete article here or here.

Friday, November 1, 2013

BMJ exposes ways we have been misled over the ‘benefits’ of statins - Briffa

BMJ articles exposes the ways we have been misled over the ‘benefits’ of statins

The ‘Cochrane Collaboration’ is an international collective of researchers whose self-proclaimed role is to provide accurate and robust assessments of health interventions. The group specialises in ‘meta-analyses’: the grouping together of several similar studies on interventions including drug therapies.
In 2011, Cochrane researchers assessed the evidence relating to statin use in individuals at low risk of cardiovascular disease (defined as a less than 20 per cent risk over 10 years), and concluded that there was limited evidence of overall benefit [1]. I appeared on Channel 4 news to discuss this publication and the issues surrounding it, and you can see the discussion here.

Earlier this year, the same Cochrane group updated their data and concluded that overall risk of death and cardiovascular events (e.g. heart attack or stroke) were reduced by statins in low risk individuals, without increasing the risk of adverse events (including muscle, liver and kidney damage) [2]. It seems the Cochrane reviewers had had quite some change of heart. A paper published in the BMJ on 22 October questions the evidence on which this U-turn appears to have been made [3].

The authors of the BMJ piece note that although the 2013 meta-analysis included four additional trials, these trials did not substantially change the findings. The change in advice was actually based on another meta-analysis, published in 2012, conducted by a group known as the Cholesterol Treatment Trialists’ (CTT) collaboration [4].

Among other things, the CTT authors concluded that, in low risk individuals, for each 1.0 mmol/l (39 mg/dl) reduction in LDL-cholesterol, statins reduce overall risk of death and heart attack by about 9 per cent and 20 per cent respectively. The conclusion was that statins have significant benefits in low risk individuals that greatly exceeded known risks of treatment.

However, the CTT authors took the odd step of calculating the benefits of statins according to a theoretical reduction in LDL-cholesterol levels. A much more realistic appraisal would be simply to calculate if, compared to placebo, statins actually reduce the risk of health outcomes.
The BMJ authors use the data from the CTT meta-analysis and found that risk of death was not reduced by statins at all. So, the CTT authors had used had extrapolated the data in a way that showed a benefit that actually does not exist in reality.

And what of the claim that statins reduce the risk of cardiovascular events such as heart attack or stroke? The data shows that about 150 low-risk individuals would need to be treated for five years to prevent one such event (i.e. only about one in 750 individuals will benefit per year).

They also draw our attention to the impact of statin treatment on ‘serious adverse events’. This outcome can be improved by statins as a result of, say, a reduced number of heart attacks, but worsened through side effects such as muscle or liver damage. The BMJ authors note that the CTT review did not consider serious adverse events (a major omission). Without knowing more about this, though, we simply cannot make a judgement regarding the overall effect of statins, and whether the net effect is beneficial or not. Interestingly, of three major trials that were included in the CTT review that assessed overall serious adverse effects, none found overall benefits from statin treatment.
So, while the CTT authors seem to have over-hyped the benefits of statins, they seem at the same time to have been quite keen to steer clear of talk of their very real risks and the absence of evidence foroverall benefit.

The BMJ authors draw our attention to the fact that every single trial included in the CTT was industry funded. Such trials are well known to report results more favourably and perhaps downplay risks than independently funded research. The BMJ authors cite specific ways in which the adverse effects of drugs seen in clinical trials can be ‘minimised’. These include:
  • The exclusion of individuals from trials with known health issues likely to be exacerbated by statins or signal susceptibility to statin side effects (such as liver, kidney and muscle disease).
  • The use of a ‘run-in’ period before the study starts which detects and then excludes individuals who do not tolerate statins.
  • The possibility that individuals ‘drop out’ from the study because of side effects, meaning that the incidence of some side effects can be ‘lost’ from the data.
  • Failure of the study investigators to assess and monitor adverse events such as muscle damage and changes in brain function.
  • Failure to properly ascertain or report adverse events.
It is noted that the Cochrane authors admit the reporting of adverse effects in studies is generally poor, but also state that it’s unlikely statins have major life-threatening hazards. The authors of the BMJ piece are not convinced, though, writing: “[The] large discrepancies between the frequency of adverse events reported in commercially funded randomised controlled trials included in the CTT meta-analysesand non-commercially funded studies show that determination of harms cannot be left to industry alone.”

The BMJ piece is accompanied by an editorial from the journal’s editor, Fiona Godlee [5]. Her comment on this issue starts:
None of this does much to bolster confidence in the published literature.
Godlee goes on to write:
Nor am I reassured by discussions at two recent meetings co-hosted by the European Federation of Pharmaceutical Industry Associations (EFPIA). Drug company AbbVie is suing the European Medicines Agency to stop summary reports of its clinical trials becoming publicly available. AbbVie’s lawyer made clear that the company considers even the data on adverse events to be commercially confidential. Despite industry’s claims to be in favour of greater transparency, EFPIA and its American counterpart PhRMA are supporting Abbvie. The BMJ and BMA have joined forces to intervene on behalf of the EMA.
If I were to summarise, I’d say that, at best, there seems to be a degree of complacency regarding the veracity of statin data on the part of both the CTT and the Cochrane researchers. There is a sense that they are happy to present the ‘positive’ findings in the best possible light, and at the same time seem relaxed about the clear gaps we have in our knowledge about potential harms. The fact that statins appear to have no overall benefit in those at low risk of cardiovascular disease should not go unacknowledged, either.

Worse still, we have evidence that drug trials can be designed, conducted and reported in ways that obscure the truth. And sometimes, even when we have data that can help us make informed decisions about the appropriateness of a treatment, some drug companies will fight tooth and nail to prevent that data seeing the light of day.

This sort of subterfuge may be good for sales and share price, but it is almost certainly bad for our collective health. On this point, the BMJ authors state than instead of doctors following guidelines and prescribing statins for individuals at low risk of cardiovascular disease, they should explain the magnitude of benefits and uncertainties regarding harm. In addition, they might also discuss the fact that the vast majority of cardiovascular disease risk is linked with lifestyle factors such as smoking, diet and physical activity. Fiona Godlee backs this approach, but states that the benefits of lifestyle change are: “something that the dominance of industry sponsored clinical trials too often obscures.”
Personally, I am delighted that the misdeeds of drug companies and some researchers can now be exposed in this way, and in a high-profile medical journal at that. In the past, I think there was much more opportunity for the industry and its hired hands to mislead us. Greater transparency means that the industry as a whole is getting more of what I believe it deserves: our contempt.
References:
1. Taylor F, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2011;1:CD004816.
Medline

2. Taylor F, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev2013;1:CD004816.
3. Abramson JD, et al. Should people at low risk of cardiovascular disease take a statin?
BMJ 2013;347:f6123

4. Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. The Lancet 2012;380(9841):581–90.
5. Godlee F. Statins for all over 50? No BMJ 2013;347:f6412.
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Read the complete article here.

Monday, October 7, 2013

Increased blood levels of Lp-PLA2 have been linked to increased risk for...

Lp-PLA2 (Lipoprotein-Associated Phospholipase A2)
  
Clinical Use
  • Assess risk of coronary heart disease and cardiovascular disease
  • Assess risk of stroke
Clinical Background
Traditional markers of lipidemia identify only about half of the individuals at risk of cardiovascular disease (CVD).1 Atherosclerosis is now recognized as an inflammatory disease, and inflammatory markers, most notably high-sensitivity C-reactive protein (hs-CRP), have been shown to identify additional individuals who are at risk. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is another marker of vascular inflammation, and because it is not associated with systemic inflammation it is more vascular-specific than is CRP.2 It is produced by macrophages and other inflammatory cells and is found in atherosclerotic lesions.
Increased blood levels of Lp-PLA2 have been linked to increased risk for: 1) cerebral thrombosis,3 2)
first4 and recurrent5 coronary events, 3) adverse prognosis after acute coronary syndrome,6 and 4) CVD associated with metabolic syndrome7 or type 2 diabetes mellitus.8 Evidence from more than 25 prospective studies has shown an approximate doubling of risk for coronary artery disease (CAD), CVD, and stroke when comparing Lp-PLA2 values in the top quintile versus the bottom quintile.2 The predictive value typically remains after adjustment for LDL-cholesterol and other established CVD risk factors.2
Thus, a consensus panel has recommended testing Lp-PLA2 as an adjunct to traditional risk factor assessment in individuals with moderate or high risk of CVD as defined by Framingham risk scores.9 According to the recommendation, an elevated Lp-PLA2 (ie, >200 ng/mL) suggests an individual’s risk is actually higher than that determined using Framingham risk scores, and more intensive therapy would be appropriate.9 For example, an individual with a moderate Framingham risk score and an elevated Lp-PLA2 may be reclassified as being at high risk, and the LDL-cholesterol goal would then be reduced from <130 dl.="" dl="" mg="" sup="" to="">9
The individual would also receive recommendations for more intensive life-style changes. Similarly, in individuals with an elevated Lp-PLA2 and high Framingham risk score, the LDL-cholesterol goal would be reduced from <100 dl.="" dl="" mg="" sup="" to="">9 Note that others have recommended a Lp-PLA2 cut point of 235 ng/mL, which coincides with the 50th percentile of the U.S. population, rather than the 200 ng/mL recommended by the consensus panel.10
The consensus panel further recommends use of Lp-PLA2 to refine risk for stroke.9
Screening with both Lp-PLA2 and hs-CRP may provide a better risk assessment for CVD and stroke than using either test alone. Elevated levels of Lp-PLA2 and hs-CRP were independent and complementary in identifying increased risk for future coronary events among healthy middle-aged men4 and patients with CVD.11
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Read the complete article here.
 
Also listen to The Tuesday Talk Show where Dr William Blanchet discusses Lp-PLA2 here.

Tuesday, September 3, 2013

So is niacin a dead drug? Dayspring

Commentary on Niacin’s Effect on Lp(a) in AIM HIGH


Here are my thoughts as a clinical lipidologist (By: Thomas Dayspring, MD, FACP, FNLA, NCMP)

We must get apoB (LDL-P) to goal in all at-risk patients. Lifestyle therapies and statins are the mainstay of therapy. However residual risk is high if apoB (LDL) remains elevated despite at-goal LDL-C, non-HDL-C), any level of HDL-C or if Lp(a) mass is elevated.

So I would have no hesitancy in adding niacin to high and very high risk patients who have not achieved apoB (LDL-P) goals with whatever therapies they are using or using niacin as a monotherapy in those intolerant of other apoB lowering meds.

Data from HPS THRIVE 2 (discussed in a recent commentary) suggested statin plus ezetimibe was better at event reduction than statin plus niacin [9]. In view of that and the very significant side effects reported in HPS THRIVE 2 [bleeding (GI, intracranial, other) in the niacin group: 326 (2.5%) to 238 (1.9%) and infection 1031(8%) to 853 (6.6%)] [3] makes niacin a tertiary or quaternary add-on drug (some may prefer the bile acid sequestrant colesevelam as an apoB lowering medication).
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Read the complete article here.