Statinsin the Preventionand Treatment
of Cardiovascular Diseases
José Enrique Castellanos Heredia, Sailí Páez Quevedo
Hospital Clínico Quirúrgico Lucía Ïñiguez Landín.
Universidad de Ciencias Médicas de Holguín.
Calle 21, Nº 12-A % 26 y 30. Pueblo Nuevo, Holguín, Cuba.
The authors declare not having a conflict of interest.
Statins, inhibitorsof hydroxymethylglutaryl-CoA reductase, arelipid-lowering drugswith proved pleiotropiceffects, among whichthe beneficialantiatheroscleroticeffectby differentmechanisms is included. A review of multiple international clinical trials published in different databases (Hinari, PubMed, Ebsco, SciELO) was made, showing the protective effect of low doses in prevention of chronic renal disease, cerebrovascular disease, ischemic heart disease, cardiovascular surgery, arterial and venous thrombosis, hepatitis C virus, sympathetic activity, osteogenesis, arterial hypertension and oxidative stress. In turn,high doses ofstatins reduce, when administeredearly, cardiovascular complications that can arise.In conclusion,lowerdosesare beneficialin primary preventionof cardiovascular events,and high dosesare usefulin the presence ofacute vascular eventsto reduce their complications. They arewell tolerated andits adverse effects disappear with the withdrawal of the drug. Its therapeuticimplementationis cost-effective and so arehigh doses.
|Key words: Statins. Inhibitorsof hydroxymethylglutaryl-CoA reductase Primary and secondary prevention.
Rev Fed Arg Cardiol. 2013; 42(2): 96-101
The group of drugs known as statins was initially used as lipid-lowering drugs in hypercholesterolemias. They were discovered in the second half of the last century. The following are part of the group: Pravastatin, Simvastatin, Fluvastatin, Lovastatin, Pitavastatin, Atorvastatin, and Rosuvastatin. All of them have similar effects. In this century, multiple clinical trials have shown that this group drugs also have other beneficial effects in prevention, reduction of complications, and a better recovery of different clinical forms of cardiovascular disease. Statins have a strong anti-inflammatory effect at endothelial level, causing modifications in the atherogenic process by different mechanisms, which has allowed for its use to extend beyond the treatment of dyslipidemias.
MECHANISM OF ACTION AND PHARMACOLOGICAL ACTIONS
The lipid-lowering effect of statins is due to their inhibiting competitively and in a reversible manner, 3-hydroxy-3-methylglutaryl coenzyme A reductase that blocks the formation of mevalonate, initial step that limits the synthesis of cholesterol. This causes a decrease of intrahepatic cholesterol, which causes increase in the expression of LDL-C receptors and entails an increase of blood clearance of this lipoprotein.
Pharmacokinetics: They are absorbed rapidly after oral administration, reaching peak concentrations in 1 to 2 hours. Absorption is increased in proportion to the administered dose. The absolute bioavailability is approximately 12% and the inhibiting capacity of HMG-CoA reductase is close to 30%. They join in 98% to plasma proteins. They are metabolized by the cytochrome P-450 3A4 at ortho and para-hydroxylated derivatives and other products of betaoxidation. The metabolism of first step, by cytochrome P-450 3A4 differs from the different statins, as with rosuvastatin. Approximately 70% of the inhibiting activity of HMG-CoA reductase is attributed to active metabolites. Statins and their products are substrates of P-glycoprotein. They are removed by bile pathway after the hepatic and extra-hepatic metabolism. Their half life is 14 hours, but the inhibition of the enzymatic inhibitory activity persists from 20 to 30 hours.
EFFECTS OF STATINS ON SPECIFIC POPULATION GROUPS
In patients with chronic renal failure (CRF)
In patients with stages I-IV of CRF, statins showed to increase the velocity of pulse wave at carotid level, an effect that achieves a greater elasticity of the vessel . In patients without cardiovascular disease symptoms, they significantly reduce cardiovascular events . Several studies showed that in patients with CRF, statins decrease the inflammatory state by reducing the intima-media ratio of the carotid artery, the levels of biochemical markers of inflammation: C reactive protein (CRP), interleukins (IL) IL-1, IL-B1, IL-6, IL-8, tumor necrosis factor alpha (TNF-α), levels of total cholesterol, triglycerides (TG) and LDL-cholesterol; however, they did not show to reduce asymmetric dimethylarginine (ADMA), an enzyme that inhibits nitric oxide synthase. In the patients with CRF and diabetes, high doses of atorvastatin decrease the incidence of major cardiovascular events (myocardial infarction (MI), death, unstable angina and revascularization) [3-8].
In the CARE study of secondary prevention, a randomized multicenter study, in patients with “average levels of cholesterol”, a substudy in patients selected according to creatinine clearance, with glomerular filtration (GF) <75 ml/min, there was a significant reduction of cholesterol levels and major cardiovascular events, without a report of severe adverse events related to the medication of the study . In those patients that were found in the first stages of the disease, pravastatin reduced oxidative stress and improved endothelial function, with the resulting vasodilator response to reactive hyperemia at the level of brachial artery, reduction in albumin excretion and lower intima-media ratio at carotid level .
In patients with polycystic kidneys, simvastatin improved glomerular filtration and endothelium-dependent vascular function .
In patients in dialysis, with an average age >60 years old, they reduce in an accelerated manner the concentration of LDL cholesterol, although not cardiovascular events.
In the AURORA Study Group, the treatment with rosuvastatin in patients in a dialysis plan, reduced the levels of LDL cholesterol, but had no significant beneficial effects in the primary combined endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) , with some authors indicating that in the age group studied (50 to 80 years), there are already significant vascular structural alterations that interfere with its vasodilator effect; however, the combination of simvastatin with ezetimibe did show a reduction in major cardiovascular events .
Given the absolute benefit of the use of pravastatin in patients with diabetes and chronic kidney disease in stage 2 or 3, the recommendation arises of using statins in this population . Atorvastatin, even in alternate days has the same effectiveness on the cholesterol levels as a daily administration.
The use of rosuvastatin (10 mg/day), just as with simvastatin, in patients in peritoneal dialysis with hypercholesterolemia, reduced total cholesterol after 3 months of treatment, and the levels of ultrasensitive CRP , and in the follow-up at 6 months showed anti-platelet aggregation effect, improving the extrinsic fibrinolytic activity and endothelial function .
The total antioxidant state assessed by biochemical markers of oxidative stress as 8-hydroxy-2-deoxyguanosine (8-OH-2 DG) was reduced in the patients in dialysis in whom rosuvastatin 10 mg/day was indicated .
In patients with systolic heart failure
In patients with systolic heart failure and chronic renal failure in hemodialysis, statins reduce the levels of Gp 91 (enzyme that stimulates betaoxidation) and also decrease the levels of 150 prostane, a metabolite of oxidative stress .
In patients carriers of ischemic heart disease
In patients with ischemic heart disease (IHD) in the CORONA study, 2 mg/day of rosuvastatin improved the endothelial function by reducing oxidative stress and increasing the levels of adiponectin in plasma , a fact that also occurred in the dialysis patients, as mentioned previously when dealing with patients with CRF.
In patients with hypercholesterolemia and heart failure of ischemic etiology, statins improve ventricular function and in progressive ergometer test could increase the functional capacity, reduce the time and voltage of ST depression; in brief, they decreased the area of ischemia, with no report of adverse severe events .
The results of the LEAD study showed that the combination of 10 mg of ezetimibe with 10-20 mg of simvastatin may provide a better alternative, to reduce LDL cholesterol levels, than the double dose of simvastatin (40 mg/day) in diabetic patients with hypercholesterolemia and CAD with high cardiovascular risk .
In a meta-analysis of 70,388 patients, without established cardiovascular disease, but with cardiovascular risk factors, the use of statins was associated with a significant increase of survival and an evident reduction of major cardiovascular events .
In subjects with atherosclerosis, 40 mg/day of atorvastatin in a term of 12 weeks, significantly reduced arterial inflammation and several biomarkers, such as metalloproteinases (MMP-9) and ultrasensitive C reactive protein (us-CRP) .
In patients with bone metabolism alterations
Rosuvastatin (2.5 mg/day) in patients with type 2 diabetes and hypercholesterolemia may have a beneficial effect on bone metabolism, stimulating the function of osteoblasts and bone formation, regardless of cholesterol levels decrease . Statins may also offer a certain protection, when a prolonged treatment with steroids is necessary, to prevent the development of osteonecrosis.
In patients with increase of sympathetic activity
Experimental studies in animals and in humans, in hypertensive individuals and with heart failure, they showed by microneurographic techniques, that statins reduce the sympathetic activity of postganglionic fibers at muscle level with the subsequent reduction in heart rate, without modification of plasma levels of norepinephrine [22,23]. In hypertensive patients after 8 weeks of treatment, they also increased the activity of baroreceptors, when reducing sympathetic activity .
In patients with hypertension
Statins reduce pressure mildly by decreasing heart rate by inhibition of sympathetic activity, but also atorvastatin, in the ASCOT study, by reducing the thickness of the carotid artery wall, makes this get more elastic and thus reduces the pressure inside .
In patients carriers of atherosclerosis
At experimental level, statins inhibit the Rho kinase (ROCK) enzyme, thus reverting endothelial dysfunction in atherosclerosis. In humans, randomized studies with 80 mg/day of atorvastatin showed that the inhibition of this enzyme improves the vasodilator response dependent on the endothelium, unrelated to cholesterol levels or CRP [26,27]. Another study also proposes that what they inhibit is not Rho kinase, but the expression of Rac1 and at this point is where the vasodilator effect lies .
In patients with arrhythmias
High doses of atorvastatin (60 mg/day) 24 hours after acute coronary syndrome reduced the incidence of premature ventricular contractions and non-sustained ventricular tachycardia, without the appearance of adverse events . Retrospective studies showed that the prior use of statins reduce de novo atrial fibrillation in patients undergoing cardiopulmonary bypass .
In patients with atheroma plaques
In a subanalysis of the JAPAN-ACS study, in diabetic patients with acute coronary syndrome, 72 h of treatment with the usual doses of pitavastatin (4 mg/day) and atorvastatin (20 mg/day) showed, by endoscopy and 3-dimensional intravascular ultrasonography, a significant reduction of the volume of the atheromatous plaque and qualitative characteristics by reducing the lipid core of the plaque . Also, in a Japanese population in the COSMOS study, with stable chronic angina, rosuvastatin effectively reduced the volume of the plaque, even in those that had previously received other lipid-lowering drugs .
The increase of the body mass index (independent predictor of the change of volume of a plaque) mitigates the regression of coronary atherosclerosis that is reached with pravastatin .
Serial angioscopic analysis in patients with documented CAD treated with atorvastatin, showed an early loss of the lipid core of the plaque, and by IVUS, the volumetric analysis showed the subsequent regression of the plaque. These changes indicate a lower vulnerability of the plaque .
In patients with pulmonary hypertension
In animal models with pulmonary arterial hypertension (PAH), simvastatin reduced the levels of pressure in the pulmonary artery and induced regression of right ventricular hypertrophy. Eighty mg/day of simvastatin added to the conventional therapy, reduced minimally and transitorily, the right ventricular mass and also the NT-proBNP levels in individuals with PAH , a beneficial effect that could not be sustained in the follow-up at 12 months.
In patients scheduled for cardiovascular surgery
The pre-operative administration of statins was associated to a lesser post-operative risk of delirium after cardiopulmonary bypass surgery .
In diabetic patients
The cardioprotective effect of statins in this population is known, as well as these drugs decreasing morbi-mortality by cadiovascular disease. In these patients, the combination of simvastatin with fibrates is not superior to the therapy with just simvastatin in the reduction of fatal and non-fatal cardiovascular events. These results do not support the routine use of mixed therapy to reduce cardiovascular risk .
In regard to use, 20 mg per day of atorvastatin compared to 20 mg of atorvastatin administered in alternate days, have a similar effect on LDL cholesterol and high levels of ultrasensitive CRP .
In patients carriers of the hepatitis C and HIV
In vitro studies show that statins inhibit the replication of the virus of hepatitis C and have a synergic effect with recombinant interferon alpha. Eighty mg/day of fluvastatin did not increase the sustained virologic response, although they did so with the rapid virologic response .
In women with polycystic ovary syndrome
Atorvastatin (20 mg/day) is effective in reducing inflammation, biochemical hyperandrogenemia and the metabolic parameters of polycystic ovary syndrome .
In cerebrovascular disease (CBVD)
In the JUPITER study, in apparently healthy individuals, with cholesterol <130 mg/dl and CRP >2.0 mg/dl, the use of 20 mg of rosuvastatin reduced the incidence of ischemic ictus to a half in the follow-up at 5 years .
In those patients that have already suffered CBVD, statins may also reduce the recurrence of ischemic ictus . A meta-analysis, that included 25,709 patients, with high doses of atorvastatin, the relative risk of ischemic ictus was significantly reduced . In turn, in the patients that present intraparenchymal hematoma, and were previously taking statins, the rate of mortality and disability was lower . It should also be highlighted that in patients treated with high doses of atorvastatin (80 mg/day) with and without disease in the territory of the carotid arteries, in both groups the cerebral ischemic episodes were reduced .
In patients with arterial and venous thrombosis
In patients <70 years old with LDL cholesterol <3.4 mmol/L, 40 mg of simvastatin for 3 months, reduced the levels of ultrasensitive CRP, improved the rate of rechanneling of the obstructed vessel, with less time of lysis of the clot and greater susceptibility to it .
In venous thromboembolic disease, in 17,802 patients that took 20 mg/day of rosuvastatin, during an average of 1.9 years, a significant reduction was achieved in the occurrence of deep venous thrombosis .
In patients that took statins previous to acute myocardial infarction happening, when trying to reperfuse pharmacologically, these patients with a fibrinolytic agent; in a therapeutic window of less than 12 hours of the onset of the symptoms, there was a significant reduction in the size of infarction and a greater rate of success to achieve an effective rechanneling .
Beyond the beneficial effect in the reduction of LDL cholesterol and apolipoprotein B levels, atorvastatin in increasing doses of 10, 20, 40, and 80 mg/day, significantly increased insulinemia in a fasting state and the levels of glycosylated hemoglobin, consistent with symptoms of insulin resistance .
In patients with history of myocardial infarction, with a range of ages of 18-80 years old, when comparing 20 vs. 80 mg of simvastatin for a year, the reduction of major vascular events was 6%, a finding similar to other studies, with an increase of 0.9% of the rate of myopathies with the daily dose of 80 mg of simvastatin .
The intensive therapy with statins since admittance for acute coronary syndrome, has immediate effects on the monitoring of lipids. Atorvastatin (80 mg) reduced the levels of total cholesterol (6%) in the following morning, but in contrast the levels of triglycerides increased (20%) .
In a prospective, cohort study, the unwanted adverse effects were similar to all the types of statins, except for hepatic dysfunction, the risk of which was greater with fluvastatin. The dose-response effect was evident for acute renal failure and hepatic dysfunction. All the adverse effects persisted while the treatment was in place, were more marked during the first year, and are reversible when the drug is suspended .
In the Heart Protection Study (HPS), in 20,536 high risk patients from the United Kingdom, with vascular disease and/or diabetes, treated with simvastatin 40 mg/day, for 5 years, the incidence of myopathy was very low (<0.1%). The risk of hepatitis was almost undetectable, and for this reason routine monitoring of the liver function tests during the treatment with simvastatin 40 mg/day is not justified .
It is still a topic of debate whether statins (HMG-CoA reductase inhibitors) along with their pleiotropic effects are associated both to increased risk and decreased risk of suffering cancer .
In brief, the adverse effects with the use of statins are minimal, reversible when the drug is suspended, do not require any specific treatment, and do not endanger the life of the patients either.
The treatment with atorvastatin in comparison to simvastatin, in active employees of USA (18 to 64 years old) was associated to a reduction in the risk of cardiovascular events, of the indirect costs in health, with a minimal difference in total costs .
From a Canadian point of view, in the IDEAL study in 8,888 patients with prior myocardial infarction with an average follow-up of 4.8 years, atorvastatin in high doses (80 mg/day) was cost-effective in comparison to simvastatin at standard doses (20-40 mg/day) . In turn, the intensive treatment with atorvastatin (80 mg) is cost-effective in comparison to atorvastatin (10 mg) in Canadian patients with stable CAD .
In primary prevention, low doses of statins are effective before any risk factor of cardiovascular disease.
Their adverse effects are minimal and revert when suppressing the treatment.
To reduce the cardiovascular complications, high doses should be used.
The high doses of statins are well tolerated and are also cost-effective.
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Publication: June 2013