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STATINS FOR
THE GENERAL POPULATION


THERE IS WELL ESTABLISHED EVIDENCE
THAT THE 'STATINS' CAN PREVENT AND ALSO REDUCE ALREADY FORMED CHOLESTEROL PLAQUES IN THE CORONARY ARTERIES AND OTHER ARTERIES AS WELL


THERE IS A GROWING BODY OF  EVIDENCE
THAT THE 'STATINS'
 MAY HAVE A PROTECTIVE EFFECT AGAINST CANCER


 CHECK THIS HEART UPDATE - APRIL 2005
STATIN GUIDELINES (2004) DECLARED BY THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE OF THE NATIONAL INSTITUTE OF HEALTH

 

HOW TO PREVENT HEART ATTACKS AND STROKES IN LYMPHOMA PATIENTS

AN EDITORIAL COMMENTARY
by Mortimer J. Lacher, M.D.

IT IS TIME TO CONSIDER INSTITUTING 'STATIN' THERAPY FOR ALL LYMPHOMA PATIENTS WITH 'NORMAL' LEVELS OF CHOLESTEROL AS WELL AS THOSE WITH AN ELEVATED CHOLESTEROL

 

WITH SPECIAL CONSIDERATION FOR PATIENTS TREATED WITH RADIATION THERAPY TO CHEST AND NECK AREAS
 


IN PATIENTS TREATED FOR HODGKIN'S DISEASE WITH RADIATION THERAPY TO THE CHEST AND NECK AREAS THERE IS AN INCREASED INCIDENCE OF ATHEROSCLEROSIS IN CORONARY ARTERIES AND OTHER MAJOR BLOOD VESSELS AS WELL AS DAMAGE TO THE HEART VALVES.  THIS HAS BECOME AN ESPECIALLY IMPORTANT DEVASTATING LATE COMPLICATION IN PATIENTS SUCCESSFULLY TREATED FOR HODGKIN'S DISEASE...
BUT NOW IT APPEARS THAT SOMETHING MIGHT BE DONE ABOUT IT.

SEE THE DATA BELOW and CHECK OUT THE 2005 UPDATE...

AND THE LYMPHOMA FOUNDATION SEPTEMBER 2005 NEWSLETTER FOR COMMENTARY CONCERNING POSSIBLE SOLUTIONS TO THE LATE OCCURRING UNWANTED SIDE-EFFECTS OF RADIATION THERAPY.

THERE IS INCREASINGLY CLEAR SCIENTIFIC EVIDENCE THAT THE 'STATINS' CAN PREVENT AND CAN ALSO REDUCE ALREADY FORMED CHOLESTEROL PLAQUES IN THE CORONARY ARTERIES AND OTHER ARTERIES AS WELL

Excerpts from an Editorial in JAMA
High-Intensity Statin Treatment for Coronary Heart Disease
Journal of the American Medical Association (JAMA.March 3, 2004;291:1132-1134) Frank M. Sacks, MD, of the Harvard School of Public Health 
( NOTE that all the emphasis markings are mine)

"All told, nearly 70 000 patients have participated in large placebo-controlled clinical trials of statins of at least 3 years in duration.

The study populations have been diverse, including those without clinical evidence of coronary artery disease and those with various presentations of coronary artery disease prior to statin treatment.

Risk reduction has been similar (range, 20%-30%) across most of these trials in mortality and in virtually every atherosclerotic cardiovascular event that has been evaluated. All of the statins that have been studied in these trials, namely pravastatin (40-mg dose), simvastatin (20- to 40-mg dose),
lovastatin (40-mg dose), fluvastatin (80-mg dose), and atorvastatin (10-mg dose),*** have produced risk reduction in serious coronary vascular end points.

Although there is some variation between the trials in the results of the population subgroups, considering the results across all trials, it now seems true that statins produce similar relative risk reduction across a wide variety of patient types and clinical presentations. Therefore, health benefit (i.e., absolute risk reduction), is principally dependent on the underlying level of risk. This is explicitly recognized by national guidelines for lipid treatment."

Excerpts from an Editorial in NEJM
INTENSIVE STATIN THERAPY - A SEA CHANGE IN CARDIOVASCULAR PREVENTION

 New England Journal of Medicine (Volume 350:1562-1564: April 8, 2004) Dr. Eric J. Topol of the Cleveland Clinic Lerner College of Medicine and the Department of Cardiovascular Medicine, Cleveland Clinic Foundation
 (NOTE that all the emphasis markings are mine):

"In the management of atherosclerotic vascular disease, statin drugs have already surpassed all other classes of medicines in reducing the incidence of the major adverse outcomes of death, heart attack, and stroke. A decade ago, their effectiveness was first demonstrated by the results of the Scandinavian Simvastatin Survival Study (4S), a trial that provided definitive evidence of the benefit of simvastatin, as compared with placebo, in improving survival. By 1996, statins were dubbed "miracle drugs," and their underuse was duly noted. Prominent scientists in the field even speculated that heart attacks might be "gone with the century."

Dr. Topol continued: "In 2002, the Heart Protection Study not only confirmed the benefit of statins but raised new questions. This study, the largest trial of a statin, showed that an overall 25 percent reduction in the incidence of coronary events was associated with a reduction of 40 mg per deciliter (1.03 mmol per liter) in the LDL cholesterol level.  Equally important, patients with a "normal" base-line LDL cholesterol level — that is, below 100 mg per deciliter (2.59 mmol per liter) — according to the currently accepted National Cholesterol Education Program guidelines for therapy, received just as much benefit as those with high LDL cholesterol levels."

"Taken together, the REVERSAL and PROVE-IT trials herald a shake-up in the field. Previously, it was considered optimal to lower the LDL cholesterol level to less than 100 mg per deciliter. That axiom has now come under serious question, because we know that atherosclerotic progression and clinical outcomes will be ameliorated by much more aggressive use of statins. Indeed, the 80-mg dose of atorvastatin is the most intensive LDL-lowering regimen for which data on clinical outcomes are available."

It is clear that
we are at a very important turning point but only if the number of persons receiving statin therapy is increased as Dr. Topol noted "Even today, only a fraction of the patients who should be treated with a statin are actually receiving such therapy."

 But, now with the new recognition of the value of the statins the number of patients treated with statins should increase and as Dr. Topol concluded:

"There will soon be a sea change in the prevention and management of atherosclerotic vascular disease. The proportional reduction in major clinical outcomes that results from aggressive statin therapy is of the same order of magnitude as that seen when statins were compared with placebo in controlled trials. Intensive therapy with statins, monitored by means of measurements of LDL cholesterol or biologic markers of inflammation, is likely to result in even greater steps toward actualizing the full benefit of this remarkable class of medicines. "

*** Commercial trade names associated with the generic names of the statins:
pravastatin  - PRAVACHOL
simvastatin  - ZOCOR
lovastatin  - MEVACOR
fluvastatin  - LESCOL
atorvastatin  - LIPITOR

The remarkable effect of the statins highlighted by the Editorials noted in part (above) were written in response to two extensive studies published in March-April 2004 comparing high and low dose statins

Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis  Nissen SE, Tuzcu EM, Schoenhagen P, et al. in JAMA March 3, 2004;291:1071-1080

Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes
Cannon, C.P., Braunwald, E., McCabe, B.S., et al in  NEJM  April 8, 2004;350:1495-1504
 

THIS RESEARCH RESULTED IN A MAJOR MODIFICATION AND PUBLICATION OF NEW STATIN DOSE GUIDELINES (2004) TO ACHIEVE GREATER REDUCTION IN CHOLESTEROL LEVELS

The value of more intensive statin therapy has just been approved by a new set of national recommendations by an Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults and a CLINICAL ADVISORY on how to use the STATINS was issued jointly by the American College of Cardiology (ACC) the American Heart Association (AHA) and the National Heart, Lung, Blood Institute (NHLBI) of the National Institutes of Health and published in the medical journal of the American Heart Association Circulation. 2004;110:227-239.

It is recommended that the administered dose of the statins should be high enough to achieve the following results::

  • High-risk people: The general goal of cholesterol-lowering treatment remains the same.  However, in order to reduce LDL cholesterol levels to under 100 mg/dL, the panel makes an LDL goal of less than 70 mg/dL a therapeutic option for people at very high risk of heart attack or death.  Patients are considered at very high risk if they already have cardiovascular disease plus diabetes, persistent cigarette smoking, poorly controlled hypertension, or multiple risk factors of the metabolic syndrome (high triglycerides, low levels of “good” HDL cholesterol, obesity), and immediately after a heart attack.

  • Moderately high risk: Moderately high-risk people are those who have multiple risk factors and are estimated to have a 10 to 20 percent chance of heart attack or cardiac death within 10 years.  The new guidelines reinforce the need for treatment if LDL cholesterol levels are 130 mg/dL or higher, and add an optional consideration of drug therapy if levels are between 100-129 mg/dL.
  • In general, if drug therapy is used in people at high or moderately high risk, it should be aimed towards achieving a 30 to 40 percent reduction in LDL cholesterol.
  • Lower or Moderate risk: Recommendations for treatment in people at lower or moderate risk are unchanged.
  • Older peopleEvidence from the new studies bolstered the idea that it is never too late to benefit from intervention to lower cholesterol levels.

As of this date... there are no special statin recommendations for patients treated with radiation therapy who are subject to the late occurring side effect of artery and heart valve damage from the radiation... but it is hoped that the Oncology groups in conjunction with the cardiologists will pay attention to this issue and eventually make official special recommendations for this unique group of individuals.

Each person should review the need to receive a statin medication with their physician... with the understanding that the importance of adding statin medication after treatment with radiation therapy or after certain particular types of chemotherapy probably will not be scientifically determined with absolute certainty for at least 10-15 or more years in the future… and will only be determined only after long-term monitoring and follow-up study. 

FOR ADDITIONAL INFORMATION... CONTACT
 
THE LYMPHOMA FOUNDATION

 
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STATINS FOR A UNIQUE GROUP OF PATIENTS
 
AND
THE GENERAL POPULATION

Unfortunately, although statin therapy...  as early as 1994... had been shown to be of great value in reducing  mortality from cardiovascular disease (see references below)... no particular studies using 'statins' have been conducted in patients who received or are about to receive radiation therapy or other forms of cardiovascular toxins.

However, prudent advice would be to recommend the institution of 'statin' therapy in these patients as they (especially those who received upper body radiation therapy) are uniquely vulnerable to disability and early death from cardiovascular (heart and blood vessel) disease. Although this unique group of lymphoma patients constitutes an extremely small portion of the general population they should be carefully monitored for cardiovascular changes induced by their cancer therapy and they should be added to the groups generally considered to be at higher risk for cardiovascular disease who should receive statin treatment.

THE IMPORTANCE OF STATIN TREATMENT in the GENERAL POPULATION is EMPHASIZED BY THE DECISION BY THE BRITISH... as reported by Lizette Alvarez in The New York Times on May 15, 2004: "Britain will become the first country in the world to sell a cholesterol reducing drug, called a statin, without a prescription"

"Starting in July, a low dosage of the drug Zocor will be sold over the counter to people at moderate risk of heart disease, a number that could reach 5 million to 10 million. That group includes all men older than 55, as well as men over 45 and women over 55 who smoke, are overweight, have a family history of heart disease or come from the Indian subcontinent, all groups that are at higher risk than 'the general population'.

  ...The decision to broaden the availability of statins is expected to curb the rate of coronary disease in Britain, which kills 100,000 people in England alone

  ...Dr. John LaRosa, a nationally recognized expert on statins, said Britain's decision was a significant step in the prevention of heart disease despite the concerns, which he called reasonable. Preventive efforts by doctors and governments to help stymie heart disease have not been nearly as successful as they could be, he said.

"There is a significant percentage of people who should be getting treated with statins who are not getting treated for one reason or another," said Dr. LaRosa, president of the State University of New York Downstate Medical Center. "You can make an argument that something is better than nothing."

The drugs, with few exceptions, have been proven safe and beneficial to the "overwhelming majority of the patients who take them," he said. On balance, he added, “They are much safer than aspirin.’’

LIZETTE ALVAREZ in The New York Times May 15, 2004

The success of achieving long survival times in patients treated for Hodgkin's disease and other lymphomas has to be tempered with the fact that many young patients will not achieve a true old age status because of the development of various late developing complications secondary to their radiation treatment and/or chemotherapy treatment that is destined to cut their life short unless various successful interventions can be achieved.

Therefore, the institution of 'statin' therapy may prove to be a means to prevent one serious late occurring side-effect of radiation treatment that reduces life expectancy. Certainly if statin therapy is good for the general population it should not cause any harm in the lymphoma population.  On a strict scientific basis this remains to be exactly determined.

To settle this issue Oncologists, in general, and Radiation Oncologists in particular should institute clinical studies in conjunction with cardiology specialists even if this proves to be a relatively complex study... because the statin dose needed to get the best results... and the exact time to start the statin therapy once radiation treatment is completed...  must also be determined. 

At this time, however, the ability to obtain even a low statin dose 'over the counter' at a reasonable price may prove to be a good start to a potentially wonderful  outcome.
 

REFERENCES

2004
Cannon, C.P., Braunwald, E., McCabe, B.S., et al Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes NEJM 2004;350:1495-1504

Topol, E. J. (2004). Intensive Statin Therapy -- A Sea Change in Cardiovascular Prevention. N Engl J Med 350: 1562-1564 Editorial in response to Cannon, et al in NEJM 2004 (reference above)

Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis. JAMA 2004;291:1071-1080

Sacks, F.M. High-Intensity Statin Treatment for Coronary Heart Disease JAMA. 2004;291:1132-1134.  Editorial in response to Nissen, et al in JAMA 2004
(reference above)

LaRosa JC.New and emerging data from clinical trials of statins. Curr Atheroscler Rep 2004;6:12-19

Alavarez L. (May15, 2004) Britain to Start Direct Sale of an Anti-Cholesterol Drug.
The New York Times
  Page A10 International Section

2003
Bonetti PO, Lerman LO, Napoli C, Lerman A. Statin effects beyond lipid lowering -- are they clinically relevant? Eur Heart J 2003;24:225-248
2002
Taylor AJ, Kent SM, Flaherty PJ, et al. ARBITER: Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol: a randomized trial comparing the effects of atorvastatin and pravastatin on carotid intima medial thickness. Circulation. 2002;106:2055-2060

2001
Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001;357:577-581.

 Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345:1583-1592
1998
The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-1357

Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS: Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615-1622
1996
Sacks RM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-1009
1995
Pitt B, Mancini GB, Ellis SG, et al. Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC I): reduction in atherosclerosis progression and clinical events: PLAC I investigation. J Am Coll Cardiol. 1995;26:1133-1139
1994
Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4 444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389


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THERE IS A GROWING BODY OF EVIDENCE
THAT THE 'STATINS'
 MAY HAVE A PROTECTIVE EFFECT AGAINST CANCER

STATINS MAY REDUCE THE RISK OF DEVELOPING BREAST CANCER

The Association Between 3-hydroxy-3-methylglutaryl conenzyme A Inhibitor Use and Breast Carcinoma Risk Among Postmenopausal Women A Case Control Study.  Denise M. Boudreau, Ph.D., Jacqueline S. Gardner, Ph.D., Kathleen E. Malone, Ph.D., et al Center for Health Studies, Group Health Cooperative, Seattle, Washington School of Pharmacy, University of Washington, Seattle, Washington, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, Department of Epidemiology, School of Public Health and Community Medicine, University of Washington, Seattle, Washington CANCER Volume 100, Issue 11, Pages 2308-2316 Published Online: 1 June 2004

 “CONCLUSIONS: The results of the current study provided some degree of assurance to the increasing numbers of women using statins that such use is not associated with an increased risk of breast cancer Although the data gave some support to a reduced risk of breast carcinoma among long-term users of statins, further research is needed to confirm this association.”

STATINS MAY REDUCE THE RISK OF COLON CANCER

A STUDY PRESENTED AT THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY (ASCO) MEETING IN JUNE 2004 PROVIDED A COMPELLING RATIONALE FOR MORE RESEARCH REGARDING THE STATINS ABILITY TO REDUCE THE RISK OF DEVELOPING COLORECTAL CANCER

HMG CoA reductase inhibitors and the risk of colorectal cancer. J. N. Poynter, G. Rennert, J. D. Bonner, H. S. Rennert, J. K. Greenson, S. B. Gruber; University of Michigan, Ann Arbor, MI; CHS National Cancer Control Center, Haifa, Israel
BACKROUND: 3-hydroxy-2-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) are effective lipid-lowering agents that also inhibit the growth of colon cancer cell lines and were noted to be associated with a reduced risk of colorectal cancer (CRC) in a randomized clinical trial of patients with myocardial infarction.
METHOD: The association between HMG CoA reductase inhibitors and colorectal cancer in a population-based case-control study of incident CRC was investigated.  The Molecular Epidemiology of Colorectal Cancer Study (MECC) is a study of 1608 colorectal cancer cases diagnosed in northern Israel between 1998 and 2002, and 1734 population-based controls matched for age, gender, and ethnicity

CONCLUSION: HMG CoA reductase inhibitors (statins) are associated with a 51% reduction in the risk of colorectal cancer, and the protective effect is specific to this class of lipid-lowering agents. The significant protective effect of HMG CoA reductase inhibitors in CRC indicates that these drugs deserve further investigation in chemoprevention and therapeutic clinical trials.

STATINS MAY REDUCE THE RISK OF A WIDE SPECTRUM OF CANCERS

The Risk of Cancer in Users of Statins  Matthijs R. Graaf, Annette B. Beiderbeck, Antoine C.G. Egberts, Dick J. Richel, Henk-Jan Guchelaar From the Academic Medical Center, Departments of Clinical Pharmacy and Oncology, Amsterdam; Department of Pharmaco-epidemiology & Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht; and Department of Clinical Pharmacy and Toxicology, Leiden University Medical Centre, Leiden, the Netherlands  Journal of Clinical Oncology, Vol 22, No 12 (June 15), 2004: pp. 2388-2394

“RESULTS: In the study base, 3,129 patients were identified and matched  to 16,976 controls. Statin use was associated with a risk reduction of cancer of 20% (adjusted odds ratio [OR], 0.80; 95% CI, 0.66 to 0.96). Our data suggest that statins are protective when used longer than 4 years (adjusted OR, 0.64; 95% CI, 0.44 to 0.93) or when more than 1,350 defined daily doses are taken (adjusted OR, 0.60; 95% CI, 0.40 to 0.91).

“CONCLUSION: This observational study suggests that statins may have a protective effect against cancer.

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