and 7 years since they postulated that statin benefit might be negated long-term by adverse non- CVD mortality at CVD risk below 1.3%pa.
It is almost 40 years since as a junior medical registrar I was first advised to take lipid-lowering drugs (clofibrate- just a few years before the cancer link came out),
and have since then been advised to take statins .
I have never done so (for my familial mild-moderate type 2b lipidemia), because the evidence has never justified such experimental and long-term unproven synthetics (as with modern antidiabetic and anti-osteoporotic wannabe money spinners) in search of $billions for the western Drug Corporations and their investors and lobbyists.
Lately, despite the massive statin trials, the last statin metanalysis (2003 from University Slovenia) again failed to show any reduction in non-CVD cardiovascular disease mortality;
and since CVD is the major cause of death and disability ONLY in those who already have such disease, statins remain indicated only in secondary prevention -as was shown in the last two major trials published, in 2002 ( ALLHAT-LLT and WESCOPS), now confirmed in the Japanese MEGA study (2006) of low dose statin, which (in primary prevention in a slim population) showed similar barely significant 1/3 CVD mortality benefit- significant reduction only in myocardial infarction – but no significant other cardiovascular or non-vascular benefit even after a mean of 5.3years, 41 000 patient-years.
Last month Theo Jacobson from Emory University in Atlanta GA commented that myalgia is the leading reason why patients abandon statins.
In 2000 he already questioned the marketing hype for statins that “the lower the cholesterol level is driven, the better” .
The growing scandal is the increasing marketing pressure by Big Pharma lobbyists (including some Regulator staff) to promote prescription and even over-the-counter use of statins to achieve ever-lower low-density lipoprotein levels even in the absence of any vascular disease or CVD risks- including the farcical inclusion of statin in a PolyPill (led by Ward and Law and the BMJ in UK). .
Last year Kilmer McCully himself (the father of the homocysteine hypothesis in CVD 1969) points out that the dramatic fall in CVD mortality since it’s USA peak in 1955 correlates well with voluntary and mandatory fortification with B6, B9 and B12 (let alone niacin) .
We may also note that falling premature CVD mortality coincides with
- the increasing use of metformin the past decades (which lowers all-cause morbidity and mortality, and new diabetes, by 1/3, and overweight by about 8%); for both treatment and prevention of type 2 diabetes, overweight, lipidemia and polycystic ovary syndrome.;
- and with increasing use of appropriate sex hormone replacement for aging men and women (which lowers all-cause morbidity and mortality by 1/3); .
- and with targeting of lower blood pressure levels even in the elderly hypertensives since the SHEP trial (1985).
- and with growing intake of supplementary fish oil ((which lowers all-cause morbidity and mortality by almost 1/2);
- and of other insulin sensitizer- Nitrric oxide – antioxidant -metabolic promoters (like vitamins A, B1, B3,B7, C, D, E, K, calmag, zinc, chromium and other trace elements), and the dozens of our other crucial biologicals that decline with aging and illness, (like coQ10, n-acetyl cysteine, arginine, carnitine, carnosine, ribose, chondroglucosamine, lipoic acid, taurine, bioflavinoid, thyroid, melatonin etc).
And while statins have legion adverse effect from insidious fatigue to myositis and hepatorenal impairment; dermatitis, depression; reducing steroid levels and virility; and lately producing even lung damage, (unlike the natural supplements listed that are the best drugs), they have never been shown to have the slightest benefit on non-CVD pathology, from overweight and insulin resistance – diabetes to arthritis. Manufacturers and lobbyists have studiously avoided head-on trial comparison with the natural CVD preventatives listed above which simutaneously address both the underlying metabolic cause of hypercholesterolemia (insulin resistance and atheroma) and all the other major common degenerative diseases of aging. So the direct highpressure marketing od statins to the public – without prescription – for other than severe resistant hypercholesterolemia is thus dangerous massive corporate fraud.
So there is every reason why statin use should be severely limited to only high-risk CVD cases i.e. those with dangerous homozygous familial hypercholesterolemia resistant to all other interventions.
see for references:
Mayo Clin Proc. 2008 ;83:687-700.Toward “pain-free” statin prescribing: clinical algorithm for diagnosis- management of myalgia.
Myalgia, which often manifests as pain or soreness in skeletal muscles, is among the most salient adverse events associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Clinical issues related to statin-associated myotoxicity include (1) incidence in randomized controlled trials and occurrence in postmarketing surveillance databases; (2) potential differences between statins in their associations with such adverse events; and (3) diagnostic and treatment strategies to prevent, recognize, and manage these events. Data from systematic reviews, meta-analyses, clinical and observational trials, and post-marketing surveillance indicate that statin-associated myalgia typically affects approximately 5.0% of patients, as myopathy in 0.1% and as rhabdomyolysis in 0.01%. However, studies also suggest that myalgia is among the leading reasons patients discontinue statins (particularly high-dose statin monotherapy) and that treatment with certain statins (eg, fluvastatin) is unlikely to result in such adverse events. This review presents a clinical algorithm for monitoring and managing statin-associated myotoxicity. The algorithm highlights risk factors for muscle toxicity and provides recommendations for (1) creatine kinase measurements and monitoring; (2) statin dosage reduction, discontinuation, and rechallenge; and (3) treatment alternatives, such as extended-release fluvastatin with or without ezetimibe, low-dose or alternate-day rosuvastatin, or ezetimibe with or without colesevelam. The algorithm should help to inform and enhance patient care and reduce the risk of myalgia and other potentially treatment-limiting muscle effects that might undermine patient adherence and compromise the overall cardioprotective benefits of statins.
n-3 Fatty acids (FAs) when used in doses of 3-4 g/d eicosapentaenoic acid and docosahexaenoic acid have profound effects on triacylglycerol (TG) concentrations. The mechanism for their TG reduction relates to their favorable effects on reducing hepatic production and secretion of VLDL and VLDL apolipoprotein B particles, along with favorable effects on plasma lipolytic activity through lipoprotein lipase-mediated clearance, as well as stimulation of beta-oxidation of other FAs in the liver. Their hypotriglyceridemic properties are related to both the dose of n-3 FAs used and the baseline TG concentrations of the population. In patients with TG concentrations >500 mg/dL, 4 g n-3 FAs have been shown to reduce TGs by 45%, VLDL by 42%, and non-HDL by 10.2%. A recent pooled meta-analysis with multiple doses of n-3 FAs ranging from 0.8 to 5.4 g revealed changes in TGs of -27 mg/dL (95% CI: -33, -20), in HDL of +1.6 mg/dL (95% CI: + 0.8, +2.3), and in LDL cholesterol of +6 mg/dL (95% CI: + 3, +8). The clinical uses of n-3 FAs include treatment of severe and moderate hypertriglyceridemia, use in statin-treated patients with elevated TG concentrations or non-HDL cholesterol (mixed hyperlipidemia), and use in the secondary and primary prevention of cardiovascular disease. Existing large-scale clinical trials such as the GISSI-Prevenzione Study and JELIS with low doses of n-3 FAs (1-2 g) show clinical benefit in reducing coronary heart disease without substantial changes in concentrations of TGs or other lipids. Future clinical trials need to determine whether the TG-lowering doses of n-3 FAs (3-4 g/d) result in additional risk reduction.
Since the publication of the second set of guidelines by the National Cholesterol Education Program, a solid body of data from landmark clinical studies has demonstrated that reduction in low-density lipoprotein (LDL) cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (“statin”) therapy sharply diminishes the risk for coronary artery disease. These trials include the Scandinavian Simvastatin Survival Study, the West of Scotland Coronary Prevention Study, the Air Force/Texas Coronary Atherosclerosis Prevention Study, the Cholesterol and Recurrent Events investigation, and the Long-Term Intervention with Pravastatin in Ischaemic Disease trial. Coronary event rates and, in some cases, all-cause mortality decreased significantly after about 5 years of statin therapy in patients at risk for and those who had coronary artery disease at baseline. In contrast, recent subgroup analyses of these pivotal studies have in the aggregate challenged the premise that lower LDL cholesterol levels necessarily lead to further declines in risk for coronary artery disease, particularly among the patients most likely to be seen by the clinician: those with moderately elevated or normal cholesterol profiles. Indeed, when LDL cholesterol levels are in this range, further lowering with statin therapy elicits diminishing returns in terms of coronary event rates. These findings are readily accommodated by the curvilinear, or log-linear, model between serum cholesterol level and risk for coronary artery disease, which is predicated on data from large epidemiologic studies. In light of the current climate involving competing health care costs, the pursuit of progressively diminishing returns in terms of reductions in coronary artery disease risk through more aggressive lowering of LDL cholesterol levels appears to be unwarranted. Until data are published from ongoing randomized, clinical trials that can more effectively resolve the clinical utility of aggressive lipid-lowering strategies to improve coronary event rates, a prudent, evidence-based strategy seems warranted.
In mid-20th century United States, deaths from vascular disease reached a peak incidence in 1955, but little was known about the underlying causes of this epidemic of disease. The significance of homocysteine in human disease was unknown until 1962, when cases of homocystinuria were first associated with vascular disease. Analysis of an archival case of homocystinuria from 1933 and a case of cobalamin C disease from 1968 led to the conclusion that homocysteine causes vascular disease by a direct effect of the amino acid on arterial cells and tissues. The homocysteine theory of arteriosclerosis attributes one of the underlying causes of vascular disease to elevation of blood homocysteine concentrations as the result of dietary, genetic, metabolic, hormonal, or toxic factors. Dietary deficiency of vitamin B-6 and folic acid and absorptive deficiency of vitamin B-12, which result from traditional food processing or abnormal absorption of B vitamins, are important factors in causing elevations in blood homocysteine. Numerous clinical and epidemiologic studies have established elevated blood homocysteine as a potent independent risk factor for vascular disease in the general population. Dietary improvement, providing abundant vitamin B-6, folic acid, and cobalamin, may prevent vascular disease by lowering blood homocysteine. The dramatic decline in cardiovascular mortality in the United States since 1950 may possibly be attributable in part to voluntary fortification of the food supply with vitamin B-6 and folic acid. Fortification of the US food supply with folic acid in 1998, as mandated by the US Food and Drug Administration, was associated with a further decline in mortality from vascular disease, presumably because of increased blood folate and decreased blood homocysteine in the population.
Am J Pathol. 1969;56:111-28. McCully KS. Vascular pathology of homocysteinemia: implications for pathogenesis of arteriosclerosis.
QJM. 2007 ;100:277-89. Economic analysis of treatments reducing coronary heart disease mortality in England and Wales, 2000-2010.
Fidan D, Unal B, Critchley J, Capewell S.University of Liverpool, UK.
BACKGROUND: Coronary heart disease (CHD) in the UK affects approximately 3 million people, with >100,000 deaths annually. Mortality rates have halved since the 1980s, but annual NHS treatment costs for CHD exceed 2 billion pounds. AIM: To examine the cost-effectiveness of specific CHD treatments in England and Wales. METHODS: The IMPACT CHD model was used to calculate the number of life-years gained (LYG) from specific cardiological interventions from 2000 to 2010. Cost-effectiveness ratios (costs per LYG) were generated for each specific intervention, stratified by age and sex. The robustness of the results was tested using sensitivity analyses. RESULTS: In 2000, medical and surgical treatments together prevented or postponed approximately 25,888 deaths in CHD patients aged 25-84 years, thus generating approximately 194,929 extra life-years between 2000 and 2010 (range 143,131-260,167). Aspirin and beta-blockers for secondary prevention following myocardial infarction or revascularisation, for angina and heart failure were highly cost-effective (< 1000 pounds per LYG). Other secondary prevention therapies, including cardiac rehabilitation, ACE inhibitors and statins, were reasonably cost-effective (1957 pounds, 3398 pounds and 4246 pounds per LYG, respectively), as were CABG surgery (3239 pounds-4601 pounds per LYG) and angioplasty (3845 pounds-5889 pounds per LYG). Primary angioplasty for myocardial infarction was intermediate (6054 pounds-12,057 pounds per LYG, according to age), and statins in primary prevention were much less cost-effective (27,828 pounds per LYG, reaching 69,373 pounds per LYG in men aged 35-44). Results were relatively consistent across a wide range of sensitivity analyses. DISCUSSION: The cost-effectiveness ratios for standard CHD treatments varied by over 100-fold. Large amounts of NHS funding are being spent on relatively less cost-effective interventions, such as statins for primary prevention, angioplasty and CABG surgery. This merits debate.
J Gen Intern Med. 2003 ;18:190-5. Comparison of current guidelines for primary prevention of coronary heart disease: risk assessment and lipid-lowering therapy. Broedl UC, Geiss HC, Parhofer KG.University Munich, Germany.
OBJECTIVE: In primary prevention of atherosclerotic disease, it is difficult to decide when medical treatment should be initiated. The main goal of the study was to compare different guidelines for coronary heart disease (CHD) risk assessment and initiation of lipid-lowering therapy. DESIGN: Cross-sectional evaluation. SETTING: An outpatient lipid and diabetes clinic in a university hospital. PARTICIPANTS/METHODS: Risk factor data obtained on 100 consecutive patients (58 men and 42 women) without clinical evidence of cardiovascular disease were used to compare the Framingham risk equation, the U.S. National Cholesterol Education Program (Adult Treatment Panel III) (NCEP ATP III) guidelines, the joint European Societies guidelines, the joint British guidelines, the revised Sheffield table, and the Munster Heart Study calculator (PROCAM) CHD risk assessment and lipid-lowering therapy. RESULTS: Guidelines could be applied to different subsets of the cohort, ranging from 22% (PROCAM) to 95% of the cohort (revised Sheffield table). All guidelines (except PROCAM) could be applied to a total of 62 patients. Guidelines predicted > or =20% risk for developing CHD over 10 years in 53% (NCEP ATP III), 26% (European) and 32% (British), while Framingham predicted this risk level in 34%. CHD risk was estimated to be > or =3%/year in 5% according to Sheffield, while Framingham predicted this risk in 13%. Lipid-lowering drug therapy is recommended in 52% by NCEP ATP III, while European, British, and Sheffield guidelines recommend this in 26%, 35%, and 5%, respectively. CONCLUSIONS: Guidelines for assessing CHD risk and lipid-lowering therapy differ greatly. Therefore, these algorithms must be used with caution.
Br J Clin Pharmacol. 2001:52:439-46.Statins for primary prevention: at what coronary risk is safety assured? Jackson PR, Wallis EJ, Haq IU, Ramsay LE. Univ Sheffield,
AIMS: Increasingly HMG CoA reductase inhibitors (statins) are being used for primary prevention of vascular disease in patients with a raised cholesterol but at low absolute risk of coronary heart disease (CHD). This study uses clinical trial results to explore the limits of absolute safety for statin use in such patients. METHODS: The major placebo controlled statin outcome trials were identified by automated and manual literature searches. Principal results including all cause mortality in placebo and intervention groups and baseline values of standard coronary risk factors were abstracted for each trial. For the trials identified the reduction in overall mortality with statin treatment for each study was regressed against the underlying CHD risk of the population recruited into that trial using a statistically robust method. RESULTS: The regression line describing the relationship between mortality benefit and risk suggests that statin use could be associated with an increase in mortality of 1% in 10 years. This would be sufficiently large to negate statin’s beneficial effect on CHD mortality in patients with a CHD event risk less than 13% over 10 years. CONCLUSIONS: Absolute safety of statins has not been demonstrated for patients at low risk of CHD. Patients absolute risk of CHD should be calculated before starting statin treatment for primary prevention. Extensions of such treatment to low risk patients should await further evidence of safety.
Lancet.1995 ;346:1467-71.Haq IU, Jackson PR, Yeo WW, Ramsay LE. Sheffield risk & treatment table for cholesterol lowering for primary prevention of coronary heart disease
Postgrad Med J. 2002 ;78:269-72.Comparative evaluation of the new Sheffield table and the modified joint British societies coronary risk prediction chart against a laboratory based risk score calculation. Rabindranath KS, Anderson NR, Gama R, Holland MR. New Cross Hospital, Wolverhampton, West Midlands, BACKGROUND: Management of borderline hypertension and hypercholesterolaemia is based on an individual’s coronary heart disease (CHD) risk rather than arbitrary values for blood pressure or serum cholesterol. Prediction of CHD risk involves using tables, charts, or computer programs based on the Framingham equations. The new Sheffield table and modified joint British societies coronary risk prediction (JBS) chart are widely used. The JBS chart approximates age and systolic blood pressure, and the new Sheffield table dichotomises blood pressure, and these simplifications may lead to diagnostic inaccuracy. METHODS: The diagnostic performance of the charts against an individualised laboratory based CHD risk calculation in 1102 subjects in primary care were evaluated and compared. RESULTS: The new Sheffield table and modified JBS chart performed equally well with a respective diagnostic sensitivity and specificity of 91.6% (95% confidence interval 86.7% to 95.1%) and 93.8% (91.1% to 97.9%), and 93.6% (90.4% to 96.0%) and 94.7% (92.6% to 96.1%) at 10 year CHD risk of 15%; and of 95.2% (82.8% to 99.4%) and 97.9% (96.8% to 98.7%), and 90.5% (75.6% to 97.4%) and 100% (99.7% to 100%) at 10 year CHD risk of 30%. The modified JBS chart graphic display provides graded risk, which may be an advantage over the new Sheffield table, which identifies thresholds of risk. The new Sheffield table, unlike any other method, can be used as screening tool for cholesterol measurement. CONCLUSIONS: The new Sheffield table and modified JBS chart are valid for use in primary care since their diagnostic accuracy is unaffected by approximations in age and blood pressure. It is suggested that practitioners should choose whichever risk assessment tool they are comfortable with and use it.
Circulation. 2006;114:2788-97. Risks associated with statin therapy: a systematic overview of randomized clinical trials.
Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT, Krumholz HM. Yale University New Haven, Conn, USA.
BACKGROUND: Although statins reduce the risk of cardiovascular events, concerns about adverse effects may deter physicians from prescribing these agents. We performed a systematic overview of randomized statin trials to quantify the risks of musculoskeletal, renal, and hepatic complications associated with therapy. METHODS AND RESULTS: Major statin trials were identified by electronic search of the MEDLINE database from 1966 to December 2005. We included English language reports of adults with documented hyperlipidemia; double-blind, random allocation of > or = 100 patients to statin monotherapy versus placebo; and reports of myalgia, creatine kinase elevations, rhabdomyolysis, transaminase elevations, and discontinuation due to adverse events. Among 74,102 subjects enrolled in 35 trials (follow-up range, 1 to 65 months), statin therapy (excluding cerivastatin) did not result in significant absolute increases in risks of myalgias (risk difference/1000 patients [RD], 2.7; 95% CI, -3.2 to 8.7), creatine kinase elevations (RD, 0.2; 95% CI, -0.6 to 0.9), rhabdomyolysis (RD, 0.4; 95% CI, -0.1 to 0.9), or discontinuation due to any adverse event (RD, -0.5; 95% CI, -4.3 to 3.3). The absolute risk of transaminase elevations was significantly higher with statin therapy (RD, 4.2; 95% CI, 1.5 to 6.9). CONCLUSIONS: On the basis of data available from published clinical trials, statin therapy is associated with a small excess risk of transaminase elevations, but not of myalgias, creatine kinase elevations, rhabdomyolysis, or withdrawal of therapy compared with placebo. Further study is necessary to determine whether the results from these published clinical trials are similar to what occurs in routine practice, particularly among patients who are older, have more severe comorbid conditions, or receive higher statin doses than most patients in these clinical trials.
Minn Med. 2003 ;86:41-5. Food as medicine–cost-effective health care? The example of omega-3 fatty acids. Plotnikoff GA. University of Minnesota , USA.
The United States accounts for more than 51% of the dollar 430.3 billion expended on pharmaceutical products worldwide each year. Yet, in comparison to other advanced industrial societies, the United States has relatively worse health outcomes across many measures. This disparity challenges the perceived efficacy and cost effectiveness of pharmaceutical agents in promoting the public health. Before access to prescription drugs, our society first needs access to low-cost, nontoxic, non-expert-dependent interventions to ensure basic health outcomes. Food may represent the most cost-effective means of promoting public health. This article introduces the topic of food as medicine by discussing briefly the evidence base for omega-3 fatty acid-rich foods as modulators of physiologic pathways. It provides background on the physiological role of omega-3 and omega-6 fatty acids, discusses their roles in disease and disease prevention, and looks at changes in food production in this country that have led to a decrease in omega-3 consumption. It also recommends dietary interventions to remedy omega-3 deficiency and asserts that now is the time for our state and our nation to more aggressively fund research into medicinal foods.
Minn Med. 2003 Jan;86:43-5. Vitamin D–the steroid hormone prescription for every patient. Plotnikoff GA.University of Minnesota, USA.
Physicians in the United States rarely screen for hypovitaminosis D and rarely prescribe vitamin D, even when medically indicated. This is of particular concern in Minnesota. The sun’s intensity at Minnesota’s latitudes limits vitamin D production, at best, to March through October. A variety of lifestyle situations, including long work hours, may preclude adequate sun exposure. Additionally, people of Northern European background may avoid sun exposure to reduce risk of skin cancer and premature aging. And people of Asian and African heritage may not have sufficient vitamin D production due to increased skin pigmentation. This brief article summarizes key points regarding the importance of vitamin D, including its action as a steroid hormone and its role in cancer, hypertension, and autoimmune disease as well as in perinatal and prenatal health. The potential benefit of hypovitaminosis D screening and vitamin D supplementation is discussed, as are the populations most likely to need screening and supplementation.
BACKGROUND: It is well known that statins reduce the risk of cardiovascular disease. However, the effect of statins in women for the primary prevention of cardiovascular disease has not been determined. We conducted an exploratory analysis of the effect of diet plus pravastatin therapy on the primary prevention of cardiovascular events in women with data from a large-scale primary prevention trial with pravastatin. METHODS AND RESULTS: Patients with hypercholesterolemia (5.7 to 7.0 mmol/L) and no history of coronary heart disease or stroke were randomized to diet or diet plus pravastatin 10 to 20 mg/d and followed up for > or = 5 years. We investigated the effect of diet plus pravastatin treatment on cardiovascular events in 5356 women during the 5-year follow-up. The incidence of cardiovascular events in the women was 2 to 3 times lower than that in men. The occurrence of cardiovascular events was 26% to 37% lower in the diet plus pravastatin treatment group than in the diet alone group. Although these differences did not reach statistical significance, the overall risk reductions were similar to those in men. Notably, women > or = 60 years of age treated with diet plus pravastatin had markedly higher risk reductions for coronary heart disease (45%), coronary heart disease plus cerebral infarction (50%), and stroke (64%) than did women treated with diet alone. CONCLUSIONS: Treatment with pravastatin in women with elevated cholesterol but no history of cardiovascular disease provides a benefit similar to that seen in men, and this benefit is more marked in older women. This treatment should be considered routinely for primary cardiovascular protection in women with elevated cholesterol levels.
Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study): a prospective randomised controlled trial. Nakamura H, ea MEGA Study Group. Mitsukoshi Health and Welfare Foundation, Tokyo, Japan.
BACKGROUND: Evidence-based treatment for hypercholesterolaemia in Japan has been hindered by the lack of direct evidence in this population. Our aim was to assess whether evidence for treatment with statins derived from western populations can be extrapolated to the Japanese population. METHODS: In this prospective, randomised, open-labelled, blinded study, 8214 outpatients with hypercholesterolaemia (total cholesterol 5.69-6.98 mmol/L) and no history of coronary heart disease or stroke were randomly assigned diet or diet plus 10-20 mg pravastatin daily. Included were postmenopausal women aged < or =70 years and men aged 40-70 years with mildly elevated total cholesterol (TC) level 220-270 mg/dL. FINDINGS: 3966 patients were randomly assigned to the diet group and 3866 to the diet plus pravastatin group. Mean follow-up was 5.3 years. At the end of study, 471 and 522 patients had withdrawn, died, or been lost to follow-up in the diet and diet plus pravastatin groups, respectively. Mean total cholesterol was reduced by 2.1% (from 6.27 mmol/L to 6.13 mmol/L) and 11.5% (from 6.27 mmol/L to 5.55 mmol/L) and mean LDL cholesterol by 3.2% (from 4.05 mmol/L to 3.90 mmol/L) and 18.0% (from 4.05 mmol/L to 3.31 mmol/L) in the diet and the diet plus pravastatin groups, respectively. Coronary heart disease was significantly 33% lower in the diet plus pravastatin group than in the diet alone group (66 events vs 101 events; HR 0.67, 95% CI 0.49-0.91; p=0.01). There was no difference in the incidence of malignant neoplasms or other serious adverse events between the two groups. INTERPRETATION: Treatment with a low dose of pravastatin reduces the risk of coronary heart disease in Japan by much the same amount as higher doses have shown in Europe and the USA.
Int J Clin Pharmacol Ther. 2003 Dec;41(12):567-77. Use of statins in primary and secondary prevention of coronary heart disease and ischemic stroke. Meta-analysis of randomized trials. Vrecer M, Turk S, Drinovec J, Mrhar A University of Ljubljana, Slovenia.
OBJECTIVE: To estimate the relative risk reduction of the clinical outcomes (coronary events, strokes, cardiovascular, non-cardiovascular and all-cause mortality) associated with statin therapy in primary and secondary prevention. DATA SOURCES: A literature search of the Medline and Cohrane databases for articles published from 1985 to July 2002 was performed. The data on systematic reviews and preliminary reports were also included in this study. Primary and secondary prevention trials and regression trials were eligible. DATA EXTRACTION AND STATISTICAL METHOD: Data were extracted by 2 authors according to the defined inclusion criteria. Disagreements were resolved by consensus or by a third reviewer. Testing for heterogeneity was applied and on the basis of these results a fixed effect model or a random effect model was used for calculation of relative risk values (RR) and 95% confidence intervals (95% CI). Sensitivity analysis tested the impact of the individual study–duration of study, type of statin therapy and study size. The number of patients needed to treat was calculated as an absolute measure of clinical effectiveness of statin therapy when appropriate. RESULTS: Data from 15 trials with 63,410 participants and mean duration of treatment of 3.6 years, were included in this overview. Tests for heterogeneity showed that the variability between study estimates is sufficiently small to assume that they are estimating the same underlying treatment effect. Statin therapy was associated with a 22% reduction in total cholesterol, 29% reduction in LDL cholesterol, 12% reduction in triglycerides and 6% increase in HDL cholesterol.
CONTEXT: Studies have demonstrated that statins administered to individuals with risk factors for coronary heart disease (CHD) reduce CHD events. However, many of these studies were too small to assess all-cause mortality or outcomes in important subgroups. OBJECTIVE: To determine whether pravastatin compared with usual care reduces all-cause mortality in older, moderately hypercholesterolemic, hypertensive participants with at least 1 additional CHD risk factor. DESIGN AND SETTING: Multicenter (513 primarily community-based North American clinical centers), randomized, nonblinded trial conducted from 1994 through March 2002 in a subset of participants from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). PARTICIPANTS: Ambulatory persons (n = 10 355), aged 55 years or older, with low-density lipoprotein cholesterol (LDL-C) of 120 to 189 mg/dL (100 to 129 mg/dL if known CHD) and triglycerides lower than 350 mg/dL, were randomized to pravastatin (n = 5170) or to usual care (n = 5185). Baseline mean total cholesterol was 224 mg/dL; LDL-C, 146 mg/dL; high-density lipoprotein cholesterol, 48 mg/dL; and triglycerides, 152 mg/dL. Mean age was 66 years, 49% were women, 38% black and 23% Hispanic, 14% had a history of CHD, and 35% had type 2 diabetes. INTERVENTION: Pravastatin, 40 mg/d, vs usual care. MAIN OUTCOME MEASURES: The primary outcome was all-cause mortality, with follow-up for up to 8 years. Secondary outcomes included nonfatal myocardial infarction or fatal CHD (CHD events) combined, cause-specific mortality, and cancer. RESULTS: Mean follow-up was 4.8 years. During the trial, 32% of usual care participants with and 29% without CHD started taking lipid-lowering drugs. At year 4, total cholesterol levels were reduced by 17% with pravastatin vs 8% with usual care; among the random sample who had LDL-C levels assessed, levels were reduced by 28% with pravastatin vs 11% with usual care. All-cause mortality was similar for the 2 groups (relative risk [RR], 0.99; 95% confidence interval [CI], 0.89-1.11; P =.88), with 6-year mortality rates of 14.9% for pravastatin vs 15.3% with usual care. CHD event rates were not significantly different between the groups (RR, 0.91; 95% CI, 0.79-1.04; P =.16), with 6-year CHD event rates of 9.3% for pravastatin and 10.4% for usual care. CONCLUSIONS: Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C. The results may be due to the modest differential in total cholesterol (9.6%) and LDL-C (16.7%) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention.
Shepherd J, Gaw A; West of Scotland Coronary Prevention Study Group. Royal Infirmary, Glasgow, UK.
OBJECTIVE: Treatment of hyperlipidemia to reduce the risk of ischemic heart disease was, prior to the statin era, disappointingly limited in its ability to yield the benefits expected from the strong relationship known to exist between serum cholesterol and coronary death. Three primary prevention trials, using clofibrate, cholestyramine and gemfibrozil, had achieved modest reductions in fatal and nonfatal coronary events but none was able to extend life overall or even to reduce cardiovascular mortality; and combined analyses of the three raised disquiet over potential links between cholesterol reduction, cancer and aggressive or violent behaviour. The time was therefore ripe to determine whether statins could help prevent that first and all important myocardial infarction. METHODS: The West of Scotland Coronary Prevention Study recruited 6,595 45- to 64-year-old men with no history of prior myocardial infarction and with low-density lipoprotein cholesterol in the range 4-6 mmol/l (155-232 mg/dl). Subjects who had undergone coronary revascularisation or had been hospitalised for angina pectoris in the previous 12 months were excluded, as were those with significant electrocardiographic abnormalities. Participants were randomised to receive pravastatin 40 mg/day or matching placebo and were followed for an average of 4.9 years. RESULTS: Treatment with pravastatin reduced the combined risk of fatal and nonfatal myocardial infarction by 31%. Cardiovascular death overall fell by 32% and the need for coronary revascularisation procedures was reduced by 37%. All of these endpoint benefits were statistically significant. Because there was no increase in non-cardiovascular mortality, the reduction in death from any cause also proved to be statistically significant (p = 0.051 by log rank test and p = 0.037 after adjustment for baseline risk factors). CONCLUSIONS: The West of Scotland Coronary Prevention Study is the first to show that cholesterol reduction with pravastatin helps avoid the first myocardial infarction, reduces coronary mortality and extends life. Ongoing exploration of the study database continues to unearth additional surprisingly beneficial effects of the treatment and permits authoritative decision-making on the effective use of lipid-lowering drugs.