Tuesday, September 18, 2012

SIMPOSIUM PENOLONG PEGAWAI FARMASI KEBANGSAAN

1. PENGENALAN
1.1 Simposium Penolong Pegawai Farmasi Kebangsaan adalah sesuatu yang di idamkan lama oleh Persatuan Penolong Pegawai Farmasi. Profesion ini telah menjalani penjenamaan semula melalui penukaran gelaran jawatan serta skim iaitu dari Pembantu Farmasi kepada Penolong Pegawai Farmasi.
Ia juga secara tidak langsung memberi pengiktirafan kepada lebih 6,000 Penolong Pegawai Farmasi yang berkhidmat di Kementerian Kesihatan Malaysia, Hospital Universiti, Hospital Swasta dan lain-lain Institusi seperti Pusat Perubatan Badan berkanun dan swasta.

1.2 Pendidikan dan latihan juga telah melalui beberapa peningkatan dan naik taraf dari Sijil Pembantu Farmasi kepada Diploma Pembantu Farmasi dan seterusnya kepada Diploma Farmasi 3 tahun.
Namun selepas melalui beberapa proses peningkatan gelaran jawatan dan naik taraf pendidikan, status profesion, peranan dalam tugas harian serta kepada perkhidmatan Farmasi secara amnya tidak mengalami sebarang perubahan besar sebaliknya semakin berkurang jika dibandingkan dengan peranan besar dahulu semasa taraf sijil.

1.3 Justeru itu Persatuan merasakan Profesion ini sangat memerlukan satu platform untuk membincangkan aspek peranan, halatuju dan peluang dalam memperluaskan skop perkhidmatan kepada semua Penolong Pegawai Farmasi supaya mereka lebih bersemangat, berbangga dan mendapat lebih motivasi dalam kerja seharian. Ia juga secara tidak langsung akan meningkatkan produktiviti Jabatan amnya.

2.  APAKAH DIA SIMPOSIUM ?

Mengikut maklumat dari internet: www.answer.com :
 "A symposium is an educational conference where people get together to discuss thoughts and exchange ideas, rather than to be lectured at".

 Maklumat dari www.dictionary.reference.com : 
"1. A symposium is a meeting or conference for the discussion of some subject,especially a meeting at which several speakers talk on or discuss a topic before an audience".
2. A collection of opinions expressed or articles contributed by several persons on a given subject or topic.

Maksudnya, simposium adalah satu majlis di mana sebilangan orang berkumpul, membincang, bertukar pendapat  kearah satu topik yang sama dan mempunyai pembentang.

3. TUJUAN SIMPOSIUM

3.1  Untuk membincangkan kearah satu topik yang sama iaitu halatuju baru profesion sejak naiktaraf gelaran jawatan Pembantu Farmasi kepada Penolong Pegawai Farmasi pada 1 Jun 2009 dan juga naik taraf sistem pembelajaran dan kelulusan naik taraf anugerah sijil Pembantu Farmasi kepada Diploma Farmasi.
                 
3.2  Memartabatkan Profesion Penolong Pegawai Farmasi Malaysia baik dikalangan Institusi kerajaan ataupun swasta.

3.3  Memulihkan kedudukan status Penolong Pegawai Farmasi dikalangan paramedik yang amat rendah dari segi perkembangan profesion dalam pendidikan, latihan, moral, imej dan peranan kepada jabatan dan negara.

3.4  Melahirkan Penolong Pegawai Farmasi yang cemerlang serta berpeluang untuk menjalankan kajian, berkeupayaan untuk membentang kertas kerja hasil kajian dan berinovasi serta berdaya saing supaya berupaya memberi perkhidmatan yang efektif dan berkualiti


4.        OBJEKTIF

4.1  Mewujudkan budaya kerja yang berpengetahuan tinggi dan sentiasa mengikuti arus perkembangan semasa dalam bidang penjagaan farmaseutikal.

4.2  Berusaha menjadikan Penolong Pegawai Farmasi sebagai anggota yang berkeyakinan tinggi, positif dan berkemampuan menjalankan tugas dengan penuh komited serta kualiti sejajar dengan Misi dan Visi Kementerian Kesihatan Malaysia.

4.3  Bersama menjana transformasi perkhidmatan farmaseutikal dalam bidang teknikal dan berpotensi secara kreatif untuk mencipta inovasi perkhidmatan atau produk untuk perkembangan perkhidmatan Farmasi.

4.4  Menaikkan imej dan moral profesion serta motivasi dalam tugas seharian selaras dengan penukaran gelaran jawatan dan naik taraf Diploma Farmasi.

4.5 Mendedahkan semua peserta dengan kepentingan kerja berpasukan, mengutamakan kehendak pelanggan dan memahami prinsip-prinsip pelaksanaan tugas dan tatacara jabatan dan kementerian demi memperkasakan Perkhidmatan Farmasi.
5.  KEADAAN SEMASA PPF

5.1  Para Penolong Pegawai Farmasi kurang diberi peluang dalam penjagaan farmaseutikal secara menyeluruh kepada pelanggan. Kebanyakan tugas-tugas expanded dan extended role lebih melibatkan Pegawai Farmasi sahaja.

5.2   Tugas-tugas kepakaran yang dilakukan dahulu telah ditarik dan diberikan kepada PRP di hospital-hospital atas alasan Akta. Pendispensan Methadone terpaksa melalui proses yang sukar walaupun tugas mendispen dadah merbahaya masih dilakukan di Klinik-klinik kesihatan sejak 50 tahun lalu tanpa memikirkan hal-hal Akta kerana tiada Pegawai Farmasi berkhidmat di pendalaman.

5.3  Penolong Pegawai Farmasi Kanan Gred U36, U38 dan U40 masih kelihatan tidak mendapat pengiktirafan sebagaimana yang di nikmati oleh paramedik lain di beberapa negeri.

5.4  Ketua Profesion PPF sendiri tidak mempunyai bilik walaupun beliau melakukan tugas-tugas pengurusan dan pentadbiran 100% di Bhg Perkhidmatan Farmasi KKM, Petaling Jaya.
Seorang Penyelia Jururawat di Hospital-hospital seluruh Malaysia, Pen.Pegawai Perubatan U32 diberikan bilik oleh Ketua Jabatan mereka. Kenapa PPF menerima nasib sedemikian???

5.5.  Senarai tugas terlalu bertindih di antara PPF dan Peg.Farmasi yang menyukarkan sebarang tuntutan oleh pihak Kesatuan untuk kebajikan PPF.

5.6  Stress dikalangan PPF amatlah tinggi dan perlu perhatian serta kajian segera untuk mengurangkan kes ini berlanjutan. (bukti melalui kajian oleh kaunselor HKL pada 2005- pembentangan di Mesyuarat Saintifik 2006 di Melaka)

5.7   Kurang peluang pendidikan lanjutan dan sekatan oleh Lembaga Farmasi keatas PPF yang ingin melanjut pelajaran dengan CGPA 3.5 keatas dengan syarat ketat keputusan SPM dengan sekurang-kurangnya 5B tanpa mengambil kira langsung keatas pengalaman dan Diploma Farmasi 3 tahun.

6.  RUMUSAN

Melihatkan status PPF terkini, ia memberi satu justifikasi supaya satu usaha dilakukan untuk mengkaji kesemua hal ehwal PPF dalam aspek pendidikan, senarai tugas, peranan, pengiktirafan, penghormatan, motivasi di tempat kerja dan berusaha mengujudkan keseronokan bekerja serta juga menekankan budaya Kerja Berpasukan secara serius dan ikhlas.

Sekian, semuga PPF lebih cemerlang, dihormati dan kompiten di masa hadapan.

"BERKHIDMAT UNTUK NEGARA"

Ganesan G.Narayanan
Yang DiPertua
Persatuan Penolong Pegawai Farmasi Malaysia




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Saturday, September 8, 2012

Supplement Use in the Prevention and Treatment of Cardiovascular Disease in the Aging Population


From American Journal of Lifestyle Medicine

Ruth A. Reilly, PhD, RD, LD; Colette Janson-Sand, PhD, RD, LD

Abstract and Introduction

Abstract

As the elderly population grows, so does the incidence of cardiovascular disease and the use of medications. Because of the side effects and cost of prescribed medicine, many aging individuals are seeking out alternative treatment options. Complementary and alternative medicine is gaining popularity, with about a third of people older than 60 years currently using one or more of these therapies. Many individuals are using herbs and nutritional supplements to prevent and treat a variety of cardiovascular diseases and their symptoms. Herbs and nutritional supplements are considered food by the Food and Drug Administration and are exempt from mandatory testing for their safety or efficacy. Also, many individuals consider these products as natural and do not recognize the negative impact that these alternative treatments may have on the efficacy of prescribed medications and overall health. To date, research has reported conflicting evidence as to the beneficial effects of these products; health care providers should exercise caution in recommending their use to avoid drug interactions and side effects.

Introduction

Aging increases the risk for many chronic diseases, including cardiovascular disease (CVD). CVD is the leading cause of death and disability in the industrialized world with nearly 82% of Americans older than 65 years dying from this disease.[1,2] Prevention and treatment of CVD includes lifestyle changes and pharmaceutical interventions. People aged 65 years and older are the largest consumers of both prescription and overthe- counter drugs.[3] Medications, although effective, may cause many unwanted side effects. As a result, many elderly individuals are seeking out complementary and alternative medicine (CAM) to augment or substitute for the medications prescribed by their health care provider. The use of CAM has been growing in popularity in recent years and currently more than 15 million people in the United States use herbal or high-dose vitamins for the prevention and treatment of various diseases.[4] Herbal supplement use is high among individuals who are being treated with prescription medications, particularly the elderly.[5] A recent survey reported that approximately 32% of individuals using CAM are older than 60 years.[6] Many people do not realize that herbs and vitamins are considered food and, unlike prescription medications, are not tested for safety or efficacy. Instead, people regard herbs and nutritional supplements as natural substances and therefore consider them safe. Because CAM may interfere with the absorption and metabolism of prescribed medications, the use of CAM can lead to many health risks. The objective of this article is to identify widely used herbs and nutrient supplements and review their efficacy, potential side effects, and risks for the aging population.

The B Vitamins: Folate, B6, B12, and Niacin

Vitamin B6 performs a wide variety of functions in the body and is involved in more than 100 enzyme reactions, most related to protein metabolism.[7] In the late 1960s, a Boston doctor hypothesized that elevated levels of homocysteine could lead to atherosclerosis.[8]Folate, B6, and BB12 were shown to have the ability to enhance homocysteine conversion to methionine, an amino acid used in building proteins, and consequently decrease homocysteine levels in the blood.[9] Several well-designed research studies showed that B vitamins could lower homocysteine levels but did not show any reductions in CVD.[10–12] A systematic review further confirmed that these supplements do not reduce the risk of developing or dying from CVD.[13] Furthermore, the Norwegian Vitamin Trials (NORVIT) reported that the combination of these 3 B vitamins can have harmful effects in those individuals who have already experienced a myocardial infarction or have coronary stents.[14] Niacin, in the form of nicotinic acid, has long been used as a pharmacologic agent to reduce triglycerides and low-density lipoprotein (LDL) levels and to increase high-density lipoprotein (HDL) in the treatment of atherosclerotic CVD.[9] The European Consensus Panel on HDL considered nicotinic acid to be the most potent agent for increasing HDL as well as being very effective in reducing LDL and lipoprotein (a).[15] When combined with statin therapy, nicotinic acid has been shown to have an even greater lipid-reducing effect.[16,17] However, in 2011, a large, National Institutes of Health clinical trial was stopped 18 months early because there was no sign that high-dose niacin coupled with statins reduced cardiovascular problems in people versus using statins alone. Although niacin raised levels of HDL, this did not translate into fewer fatal and nonfatal heart problems.[18,19] Pharmacologic dosages of niacin can cause flushing of the skin, hyperuricemia, abnormal liver function, and hyperglycemia and therefore should be monitored by a physician.[20]

Coenzyme Q10

Coenzyme Q10, commonly referred to as CoQ10, is also known as ubiquinone. It is a vitamin-like substance produced in the mitochondria of cells; as a component of the electron transport chain, CoQ10 generates ~95% of the human body's energy in the form of adenosine triphosphate (ATP).[21] CoQ10 has demonstrated antioxidant properties and therefore has been studied for its effect on cardiovascular health. A recent study showed that CoQ10 plasma concentrations are an independent predictor of mortality in chronic heart failure, with CoQ10 deficiency being a factor in the long-term prognosis of chronic heart failure.[22] CoQ10 and cholesterol share the same biosynthetic pathway, and the production of mevalonate, an intermediate in this pathway, is inhibited by certain beta blockers[23] and statins.[24] Indeed, statins can reduce serum levels of coenzyme Q10 by up to 40%.[25] Therefore, some research studies recommend supplementing statin use with coenzyme Q10as a routine adjunct. In view of the fact that CoQ10 can lower blood pressure and therefore may not be suitable for certain individuals, people should not begin taking this supplement without first consulting with their physician to insure that there are no contraindications to its use.

Fish Oil Supplements

Most epidemiological studies have found a correlation between fish consumption and a lower risk of coronary artery disease. Fish is a rich source of the essential omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Fish oil supplements have gained popularity in recent years for the prevention and treatment of many diseases, including CVD, largely because of their anti-inflammatory effects.[26] Fish oil supplements reduce serum triglycerides levels by reducing the hepatic production of very low density lipoproteins (VLDL) and accelerating VLDL clearance.[27]However, the role of omega-3 fatty acids in reducing mortality, heart failure, myocardial infarctions, and arrhythmias has not been established.[26] In a recent metaanalysis, 14 randomized, double-blind placebo-controlled trials indicated that fish oil supplements are ineffective in treating individuals with diagnosed CVD.[28] The US Food and Drug Administration has approved only one dietary omega-3 fatty acid supplement: Lovaza (GlaxoSmith Kline). A 1-g capsule contains 375 mg of DHA and 465 mg EPA.[26] Relative safety has been shown in both primary and secondary prevention of heart disease, but caution should be exercised in individuals taking antiplatelet or anticoagulant drugs, vitamin E, or aspirin.[29 (p351)]

Garlic

Garlic (Allium sativan) has been used for more than 5000 years as a medicine and in cooking. Garlic's proposed cardiovascular effects include controlling blood cholesterol and blood pressure, reducing platelet aggregation, improving circulation, and improving the elasticity of blood vessels.[30 (pp172-187)] Epidemiological evidence has shown that garlic consumption may delay the progression of CVD, but more comprehensive studies need to be conducted to confirm this positive effect.[31] In a recent clinical trial, 192 adults with high LDL were randomly assigned into 3 treatment groups and 1 placebo group. The treatment groups were given raw, powdered, or aged garlic supplements for 6 months. There were no significant effects on LDL concentrations in all groups.[32] A recent metaanalysis examined the effect of garlic on blood pressure and reported that 10 of the 25 studies reviewed showed garlic reduced both systolic and diastolic blood pressure in hypertensive individuals when compared with the placebo group.[33] The active component in garlic, ajoene, has been shown to have antiplatelet effects and it is therefore recommended that individuals on anticoagulant or antiplatelet therapies should avoid garlic supplements. It is also advised that individuals planning surgery should discontinue its use 10 days before surgery.[34] Garlic is well tolerated by most individuals with its greatest side effect being undesirable body odor. It is important to note that an average clove of raw garlic contains ~3 g and most of the research on the therapeutic effects of garlic has used ~2 to 5 g of raw garlic, easily consumed in a normal diet.[35 (p293)]

Grape Seed Extract

Grapes (Vitis vinifera) have been used for centuries for eating, and for making juice, wine, and medicines. Grape seed extract, sold commercially in 50- or 100- mg tablets, comes from the seeds of the red grapes and the active ingredient is a subclass of flavonoids called proanthocyanidins.[36,37] Proanthyocyanidins are powerful antioxidants and also improve vascular elasticity.[30] It has been suggested that grape seed extract could be important in the prevention of atherosclerosis and cancer and in wound healing and also in the treatment of hyperlipidemia. In a recent meta-analysis, Feringa et al[38] evaluated the effects of grape seed extract in both animal and human studies. Although animal studies have suggested cardiovascular benefits from grape seed extract, human studies report conflicting results. Grape seed extract administered to humans lowered systolic blood pressure and heart rate but had no significant effect on diastolic blood pressure, C-reactive protein, or lipid levels.[38] There are few reported side effects from grape seed extract except for allergic reactions.[39]

Green Tea

Tea comes from the Camillia sinensis plant and is consumed in various parts of the world as black, oolong, or green tea.[40] Green tea was first exported from India to Japan in the 17th century and is now produced around the world[41] and available as loose tea (caffeinated or decaffeinated) or as a supplement.[30] Green tea has been used to treat a variety of conditions because of its polyphenol (antioxidant) content. Catechins account for 80% to 90% of the polyphenols found in green tea and are thought to confer most of its health benefits.[42] A recent systematic meta-analysis reported on the effect of green tea on lipid concentrations (LDL, HDL, and triglycerides) in humans. Subjects who consumed green tea (doses 145–3000 mg/d) for 3 to 24 weeks had a 5.46 mg/dL reduction in total cholesterol and a 5.30 mg/dL reduction in LDL when compared with controls, with no significant change in HDL.[30,43] Another review of the literature evaluated the health benefits of green tea in the prevention and treatment of metabolic syndrome, hypertension, cancer, and CVD in humans and animals. There is some evidence that green tea may lower blood pressure and thus reduce the risk of stroke and coronary artery disease, but human studies are still limited and more research is needed to confirm these benefits.[40] Side effects of green tea include allergic reactions (rare), gastrointestinal complaints, irregular heartbeat, and sleeplessness.[39] Consumption of green tea has been shown to reduce the effect of warfarin and so should be used with caution by individuals taking anticoagulants. Green tea extract may interfere with iron absorption and caffeinated green tea or supplements should not be used by individuals taking medications that have negative interactions with caffeine such as amphetamines, clozapine, theophylline, and so on.[30]

Hawthorn

Hawthorn is an herb (Crataegus oxyacantha L. and Crataegus monogyna) that is used to treat angina, congestive heart failure (CHF), and cardiac arrhythmias. A review of 14 studies on the effect of hawthorn use in the treatment of congestive heart failure found beneficial effects of this herb as an adjuvant to standard therapy for patients with CHF.[44,45] Exercise tolerance and oxygen consumption improved in patients with CHF who were consuming the hawthorn extract as compared with the placebo. However, the effect of hawthorn on morbidity and mortality has not been studied.[44]Hawthorn's use in the treatment of hypertension and hyperlipidemia has demonstrated positive outcomes in animals, but its use with humans is speculative.[46] In spite of these positive effects from the use of hawthorn, its efficacy and safety have not been elucidated. Hawthorn should be used with caution by patients taking digitalis as it may result in toxicity.[47] Hawthorn can also increase bleeding time and should not be used by patients taking antiplatelet or anticoagulant drugs.[29] The efficacy of hawthorn use in the treatment of patients with CHF is still unclear and caution should be used with patients currently using digoxin and vasodilating drugs (ie, theophylline). Health care providers should use caution and carefully monitor patients who are using this herb. Reported side effects were mild and included nausea, dizziness, increased heart rate, and gastrointestinal complaints.[45]

Policosanol

Policosanol is a mixture of longchain aliphatic alcohols obtained from sugar cane, beeswax, and wheat germ.[48] Policosanol has been marketed for the treatment of a variety of cardiovascular and circulatory disorders such as hypercholesterolemia, atherosclerosis, and intermittent claudication.[49] The appeal of this drug—its promise to lower cholesterol without significant side effects—has made it one of the fastest growing overthe- counter supplements in the United States.[50] Early studies were done by one research facility in Cuba. These studies claimed that 1 to 20 mg/d of policosanol could produce significant reductions in both total cholesterol and LDL cholesterol. These studies also showed that policosanols were potent antioxidants, beneficial to endothelial cell function, and inhibitors of platelet aggregation and thrombosis.[48] Several randomized, double-blind crossover studies in which participants received low to high doses of policosanol derived from sugar cane and either used alone or with statins, were not able to show significant reduction in LDL or total cholesterol levels.[51–54]Although side effects are mild, such as indigestion, skin rash, headache, insomnia, and weight loss, policosanol may increase the effect of medications that interfere with blood clotting or antiplatelet drugs, such as aspirin, warfarin (Coumadin), heparin, clopidogrel (Plavix), ticlopidine (Ticlid), or pentoxifylline (Trental), or supplements such as garlic, ginkgo, or high-dose vitamin E. Policosanol may also increase the efficacy and side effects of levodopa, a medication used for Parkinson's disease.[29,55]

Red Yeast Rice

Red yeast rice is produced by fermenting red rice with the yeastMonascus purpureus. It was marketed for a number of years under the name Cholestin because it contained the drug lovastatin, known to reduce cholesterol levels and cause small to modest increases in HDL levels.[56] A 1999 US district court ruled Cholestin could be sold without a prescription, but in 2000, the 10th US circuit court reversed the ruling.[57,58] As a result, Cholestin was reformulated to contain policosanol instead of lovastatin although red yeast rice formulations containing lovastatin are still available in other countries online.[59]
For most of the over-the-counter red yeast rice products, there is no indication of statin level: different strains of the Monascus fungus can produce different amounts of statin. There are also some accounts of products being spiked with high doses of lovastatin.[60,61] The safety of red yeast rice products has not been established, and some of the supplements samples have been found to contain high levels of a toxin, citrinin.[62] Statin drugs can cause muscle and liver damage. Rhabdomyolysis, associated with statins, can result in kidney damage and possibly lead to renal failure.[63,64] Therefore, anyone taking statins should be monitored by a physician. People choose red yeast rice over pharmaceuticals because they find it to be a more "natural" form of the drug and because it is much less expensive. Red yeast rice can interact with some 188 different medications, of which 40 have major serious effects. Examples of these include all statins, a large number of antibiotics, antifungal and antiviral agents, as well as niacin supplements.[65]

Vitamin E

Vitamin E is a fat-soluble vitamin whose active form, Ī±-tocopherol, functions as an antioxidant. The oxidation process contributes to the development of atherogenesis.[66,67] Oxidized LDL causes endothelial cells to produce inflammatory markers, and has a role in foam cell formation, destruction of endothelial cells, inhibition of the motility of tissue macrophages, and inhibition of nitric oxide–induced vasodilation.[68] Vitamin E has been shown to decrease oxidative stress in vitro and prevent atherosclerotic plaque formation in mouse models.[69] However, reviews of research studies in humans have concluded that vitamin E is of no benefit in the prevention of CVD. In fact, vitamin E supplementation might be linked to an increase in mortality, heart failure, and stroke.[67,70] It has also been shown to decrease HDL, which has a protective effect on the cardiovascular system.[71] The American Heart Association does not support the use of vitamin E supplements to prevent CVD but does recommend the consumption of foods abundant in vitamin E and other antioxidants.[72] This dietary practice has been associated with a lower risk of heart disease in middle-aged and older men and women.[73,74] Doses exceeding 400 IU per day should be avoided when taking anticoagulants and antiplatelet medications.[75]

Conclusion

Since CAM has gained popularity in recent years, health care professionals should be alert to the fact that their patients, especially their older patients, may be taking herbs and other supplements to treat and prevent a variety of illnesses. The combination of many of these substances, especially with traditional medications, can result in serious side effects. Therefore, asking patients whether they are using any herbals or supplements, and educating patients as to the risks their use may present, should be part of every medical assessment.

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Continuation With Statin Therapy and the Risk of Primary Cancer: A Population-Based Study CM


Abstract

Introduction. Studies have suggested that statins may inhibit tumor cell growth and possibly revent carcinogenesis. The objective of this study was to investigate the association between persistent statin use and the risk of primary cancer in adults.
Methods. This retrospective study was conducted by using the computerized data sets of a large health maintenance organization (HMO) in Israel. The study population was 202,648 enrollees aged 21 or older who purchased at least 1 pack of statin medication from 1998 to 2006. The follow-up period was from the date of first statin dispensation (index date) to the date of first cancer diagnosis, death, leaving the HMO, or September 1, 2007, whichever occurred first. Persistence was measured by calculating the mean proportion of follow-up days covered (PDC) with statins by dividing the quantity of statin dispensed by the total follow-up time.
Results. During the study period, 8,662 incident cancers were reported. In a multivariable model, the highest cancer risk was calculated among nonpersistent statin users. A strong negative association between persistence with statin therapy and cancer risk was calculated for hematopoietic malignancies, where atients covered with statins in 86% or more of the follow-up time had a 31% (95% confidence interval, 0.55-0.88) lower risk than patients in the lowest ersistence level (≤12%).
Conclusion. Our study demonstrated that persistent use of statins is associated with a lower overall cancer risk and particularly the risk of incident hematopoietic malignancies. In light of widespread statin consumption and increases in cancer incidence, the association between statins and cancer incidence may be relevant for cancer prevention.

Introduction

Cancer is the second most common cause of death in the United States, exceeded only by heart diseases.[1] Annual deaths from cancer are projected to continue rising and are estimated to be 17 million worldwide in 2030.[2] Cancer is the leading cause of death in Israel (approximately 25% of all-cause mortality) and is a major cause of morbidity in the population.[3]
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) effectively reduce cholesterol levels and decrease the incidence of cardiovascular and cerebrovascular events.[4] Large randomized controlled trials (RCTs) that examined the safety and effectiveness of statins in reventing cardiovascular diseases indicated that statins were not associated with increased cancer risk.[5] However, these RCTs were limited to short-term follow-up, the duration of which was insufficient to adequately evaluate carcinogenesis risk.[6]
After statins were introduced into clinical practice, they were shown to have effects other than lipid lowering, referred to as pleiotropic effects.[7] More than 15 years ago, cholesterol decrement was first shown to inhibit tumor cell growth, metastasis of tumor cells, and induction of apoptosis.[7] Inhibition of HMG-CoA reductase by statin in effect prevents the synthesis of mevalonic acid, a precursor of nonsteroidal isoprenoids, lipid attachment molecules for small G roteins, such as Ras, Rho, and Rac. Thus, statins may inhibit the synthesis of isoprenoids and thereby suppress the activation of small G proteins.[7]
Statins have been associated with a significantly lower risk of breast,[8] colorectal,[9] and lymph cancers[10-12] in several observational studies.[10,13] Most previous observational studies have been limited by a small number of cases, short follow-up period, unverified self-reports on use and consistency of statins therapy, and no assessment of statins efficacy.
Our previous study[14] demonstrated a strong negative association between ersistent use of statins and all-cause mortality reduction among patients with and without a history of coronary heart disease (CHD). The observed reduced mortality in statin users cannot be explained by lower incidence of CHD death alone. The objective of this study was to investigate the association between ersistent use of statins and the risk of overall and site-specific cancer in adults, to assess dose-response relationship, and to examine the effects of varying types of statins. We focused on breast and genitourinary, colorectal, lung and bronchus, prostate, leukemia, hematopoietic, and lymphoma malignancies.

METHODS

We conducted this study among members of Maccabi Healthcare Services (MHS), established in 1941. MHS has become Israel’s second-largest health maintenance organization, with a membership of 2 million countrywide. All data for this analysis were obtained from MHS automated databases.
The cohort of statin users has been described previously.[14,15] Briefly, the study was conducted with a follow-up spanning the period between the date of first dispensed statin to the date of cancer diagnosis, death, leaving MHS, or September 1, 2007, whichever occurred first. New users of statins were identified among all MHS enrollees aged 21 or older on January 1, 1998, who had at least 1 dispensed prescription of statin medications from January 1, 1998, to September 1, 2006; the date of first dispensation was classified as the index date. We included only patients who had no record of purchasing statin medication before the index date to allow for evaluation of new users. A total of 227,131 new users of statin medications were eligible for analysis. We excluded all patients who were diagnosed with cancer before the index date (n = 12,499). To avoid incidence-prevalence bias, we excluded cases diagnosed with cancer within 1 year from index date, and we excluded all patients with a minimal exposure period of statins under 1 year, the period required for statin medication to have any effect on the development of cancer (n = 11,984). After applying the inclusion and exclusion criteria, 202,648 (89%) patients were eligible for analysis.
Data on cancer occurrence during the study follow-up period were obtained from the Israel National Cancer Register (ICR). Established in 1960, the ICR collects information on diagnosed cancer cases from all medical institutions in the country with a completeness of above 93.5% for solid tumors and approximately 90% for nonsolid tumors.[3] We classified all cancer cases according to the 3rd edition of the International Classification of Diseases for Oncology (ICD-O). All cases are based on histological reports, hospital discharge forms, oncology reports, and death certificates. Approximately 92% of registered cases had a valid histology or cytology report. The study population and the ICR were cross-linked by the members’ unique identifying number, given to all newborns or immigrants to Israel; name; sex; and date of birth.
Following previous categorization of statin therapy,[16] we categorized initial statin therapy into 3 efficacy levels that were created on the basis of expected amounts of low-density lipoprotein cholesterol (LDL-C) reduction from baseline: low efficacy (daily dose of simvastatin, 10 mg or less; pravastatin, 10 mg; fluvastatin, 40 mg or less; lovastatin, 20 mg or less; or cerivastatin, 0.2 mg), moderate efficacy (daily dose of simvastatin, 20 mg; pravastatin, 20 mg or 40 mg; fluvastatin, 80 mg; lovastatin, 40 mg; atorvastatin, 10 mg; rosuvastatin, 10 mg or less; or cerivastatin, 0.3 or 0.4 mg), or high efficacy (daily dose of simvastatin, 40 mg or 80 mg; pravastatin, 80 mg; lovastatin, 80 mg; atorvastatin, 20 mg or more; rosuvastatin, 20 mg or more; or cerivastatin, 0.8 mg).
Continuation with statin therapy was individually assessed by calculating the mean proportion of follow-up days covered (PDC) with statins by dividing the quantity of statin packs dispensed by the total follow-up days. PDC was categorized into quintiles (≤12%, 13%–39%, 40%–66, 67%–85%, and ≥86%).
Demographic variables at index date included baseline values of age, sex, marital status, place of residency, years of stay in Israel (for new immigrants) and religiosity (categorized into ultra-orthodox Jewish, other Jewish, and non-Jewish). These categories were determined on the basis of self-reported data obtained by MHS for marketing purposes. Socioeconomic level was categorized into quartiles and determined according to the poverty index of the member’s census enumeration area (small areas defined by the Israeli Bureau of Statistics for the 1995 national census data collection). The poverty index, ranging from 0 (lowest) to 20 (highest), is based on several parameters including household income, educational qualifications, crowding, material conditions, and car ownership.[17] History of other comorbid conditions at index date, such as diabetes mellitus, cardiovascular disease, hypertension, or obesity, was identified on the basis of outpatient diagnoses. Information on health service use, such as data on hospitalizations in general hospitals or visits to outpatient clinics during the year before the index date, was collected from ersonal medical files.
Chi-square test for categorical variables and Kruskal-Wallis test for continuous variables were performed to determine significant differences in baseline characteristics among quintiles of PDC. To address the effect of statin type, we conducted sensitivity analyses of simvastatin users (n = 159,197). Cox’s proportional hazards[18] model with years of follow-up as the time scale was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) and to identify variables significantly associated with cancer incidence. The full multivariable model included the following baseline values: age at baseline (in 1-year intervals), sex, marital status, socioeconomic level by quartile, resence of chronic comorbidity, use of health services, and efficacy of the initial statins therapy. To estimate the effects of smoking status we performed subanalysis for participants with smoking status in the models. Assumptions of roportional hazards were performed, and the ratio of hazards was the same across time. Data were analyzed with SPSS version 15 (SPSS Inc, Chicago, Illinois). The study was approved by the Assuta Health Systems Institutional Review Board.

RESULTS

During the follow-up period (952,202 person years [PY], a mean of 4.70 PY per atient), 9,256 patients (4.6%) died and 2,787 (1.4%) left MHS. The mean age of the total population was 57.3 years (Table 1 ). In general, patients in the highest PDC quintile were more likely to be older, men, or new immigrants, to belong to a higher socioeconomic level, and to have chronic diseases. Of the initial statin medications purchased by the 202,648 study participants, 159,197 (78.6%) were simvastatin.
A total of 8,662 incident cancer cases were reported during the follow-up eriod ( Table 2 ). The incidence density rate of overall cancer was 9.10 per 1,000 PY (9.66 per 1,000 PY among men and 8.54 per 1,000 PY among women). Only 0.1% of cancers occurred within the first year of follow-up, whereas a total of 78.7% of cancers occurred after 3 years of follow-up. The most frequent types of diagnosed tumors in women were breast cancer (1,368 cases) and in men, prostate cancer (1,311 cases). Colorectal cancer was the most frequent type of malignancy among both sexes (1,247 cases). Among nonsolid cancers, the most frequent lymphomas were non-Hodgkin lymphoma (approximately 90%), and most leukemia cases were lymphocytic leukemia (40%) and myeloid leukemia (26.5%).

Figure.

Enlarge
Proportional Effects of Persistence With Statin Therapy on Reduction of Risk for Overall Cancer Per 10% of Followup Days Covered With Statins. Squares indicate adjusted hazard ratios for all covariates listed in Table 2. Horizontal lines indicate 95% confidence intervals. The 3 statin efficacy levels were created on the basis of expected amounts of low-density lipoprotein reduction from baseline. [A tabular description of this figure is also available.]
After adjusting for potential confounders and statin efficacy, an inverse association between persistence with statin therapy and cancer risk was observed for all-site and site-specific cancers ( Table 2 ). In a multivariable model, the highest cancer risk was calculated among nonpersistent statin users (lowest PDC quintile). However, we found no indication for a dose-response association between persistence with statin therapy and colorectal, breast, prostate, and lung cancers. Similar results were obtained when analyses were limited to atients with 3 or more years of follow-up and 5 or more years of follow-up and in subanalysis including only participants with known smoking status (data not shown). The sensitivity analysis included all study participants with smoking status (n = 63,863) with a total of 2,999 incident cancer cases. Of the 63,863 atients, 51,057 (79.9%) were never smokers, 4,166 (6.5%) were past smokers, and 8,640 (13.5%) were current smokers.
In the multivariable model, increased PDC quintile was associated with a significant risk reduction of all-site cancers with P = .001 for linear trend with an HR of 0.80 (0.76–0.86) for 5th PDC quintile compared with nonpersistent statin users (data not shown). The fully adjusted HR for hematopoietic cancers was 0.69 (95% CI, 0.55–0.88) for the highest PDC quintile; for lymphoma the HR was 0.69 (95% CI, 0.51–0.94, P = .002 for linear trend), and for leukemia the HR was 0.58 (95% CI, 0.37–0.91) ( Table 2 ).
When PDC with statins was analyzed as a continuous variable, an increase of 10% in PDC level was associated with an adjusted HR of 0.98 (95% CI, 0.97–0.99; = .02). In stratified analyses, substantially lower risk of cancer was calculated for patients aged 50 or older and for patients treated with high-efficacy statins (Figure).
Adjusted HR for all-site cancers and hematopoietic malignancies were stratified by sex ( Table 3 ). Although the negative association between continuation with statin therapy and leukemia risk between the sexes was similar, significant differences were observed between men and women in relation to the risk of lymphoma. In men, increased PDC with statins was associated with lower risk of lymphoma, reaching approximately 40% lower incidence among adherent patients.

DISCUSSION

The results of our cohort study indicate that patients with longer continuation of statin therapy had a lower risk of cancer compared with nonpersistent users. Our results are similar to those of several smaller studies, including a nested case-control study[19]that demonstrated a lower cancer risk among statin users compared with bile acid–binding resin users and a cohort study of 12,251 statin users and 334,754 nonusers.[20]
In a site-specific analysis, we found that persistent use of statins was associated with a significant decrement in the long-term risk of leukemia and lymphoma (mostly non-Hodgkin lymphoma). Early meta-analysis[21] of 14 studies (6 RCTs, 7 case-control studies, and 1 cohort study) published between 1996 and 2006 indicated an insignificant inverse association between statin use and the risk of hematologic malignancies. However, a more recent study from the Cancer revention Study II Nutrition Cohort[22] found that compared with nonusers, atients who used statins for more than 5 years had a significant 25% reduction for non-Hodgkin lymphoma. Also, an inverse association was reported among statin users for lymphoma in EPILYMPH,[12] a multicenter case-control study. Moreover, in vivo and in vitro reports have provided evidence that statins inhibit the growth and promote the self-destruction of leukemia cells.[23,24]
When our analyses were stratified by sex, the significant negative association between continuation with statins and lymphoma risk was limited to men only. The reduction of hematopoietic cancer risk by sex also has been reported in other studies of prescription medications,[12,25] but few studies have addressed statins. An inverse relationship between risk of non-Hodgkin lymphoma and statins was reported in a study that compared 601 histologically confirmed incident cases of non-Hodgkin lymphoma and 717 population-based controls among Connecticut women.[26] However, the association was limited only to women with short to moderate therapy periods. The potentially differential sex-specific effect of statins on non-Hodgkin lymphoma risks warrants further research.
Our study had several methodologic strengths, including its historical rospective design, a large and unselected study population, systematic data collection, and a long follow-up period. The threat of methodologic biases was further reduced by an individual evaluation of statin persistence based on dispensing information, which is the most feasible method of estimating medication use in large populations.[27] The use of the ICR cancer reports also reduced the threat of outcome misclassification bias. To minimize the potential effect of indication bias, only new users of statins who had at least 1 dispensed prescription of statins during the study period were eligible for analysis. Finally, the exposure start date is equal to the day of study initiation to avoid immortal time bias.[28]
However, some potential limitations should be discussed. Statin users are frequently under continuous surveillance of various specialists, and more screening tests could have led to surveillance bias. However, such bias is usually associated with earlier cancer detection and higher observed cancer risk and thus cannot explain the negative association between PDC with statins and cancer risk observed in our cohort. A healthy user bias is another potential bias. Persistent users may be more likely to have more aspects of a healthy lifestyle such as diet, exercise, and avoidance of risky behaviors.[29] To avoid this bias, our study models were adjusted for visits to primary physicians during the year before the index date. Moreover, our study indicated that ersistent use of statins is associated with reduced risk of hematopoietic neoplasms, for which screening tests are not available as they are for breast, colorectal, and prostate cancers.
Data on some variables that can be associated with statins and cancer, such as physical activity, diet, and family history of cancer, were missing in our analysis. However, none of these is an established risk factor for hematologic neoplasms. Smoking, a well-established risk factor for several types of cancer, is an additional confounder for which data were incomplete. Statins are more likely to be prescribed for cigarette smokers because of their higher risk of atherosclerotic cardiovascular disease. However, results from subanalyses for atients with valid smoking status were similar to overall analysis. The results of sensitivity analyses by follow-up duration suggest that the threat of methodologic biases such as misclassification of exposure were unlikely.
Our study showed that overall cancer risk decreased with increasing level of statin efficacy, but we found no significant differences between lipophilic and hydrophilic statins. Several studies[9,30] have also failed to demonstrate differences in cancer risk between statin types except for 2 cohort studies of lipophilic statin users, who had a reduced risk of breast cancer[8] and rostate cancer[31] incidence compared with nonusers.
In light of widespread statin consumption and the indications for long-term or lifelong use, the association between statin use and lower cancer risk may contribute to improved public health. For example, the incidence of leukemia in Israel is 32 per 100,000 for Jewish men aged 60 to 69 years.[3] Using the calculated HR of 0.56 to calculate the absolute reduction in risk, we determined that statin therapy could prevent 14 cases per 100,000 Jewish men in this age group. The observed effect might be greater with the introduction of more efficacious statins in recent years. Additional controlled clinical trials are needed to investigate the potential anticancer benefit of statins, particularly in nonsolid tumors.

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