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59-425: NNH is similar to number needed to treat (NNT), where NNT usually refers to a positive therapeutic result and NNH to a detrimental effect or risk factor. Marginal metrics: are also used. The NNH is an important measure in evidence-based medicine and helps physicians decide whether it is prudent to proceed with a particular treatment which may expose the patient to harms while providing therapeutic benefits. If

118-443: A Cochrane systematic review the dose-related magnitude of atorvastatin on blood lipids was determined. Over the dose range of 10 to 80 mg/day total cholesterol was reduced by 27.0% to 37.9%, LDL cholesterol by 37.1% to 51.7% and triglycerides by 18.0% to 28.3%. Atorvastatin undergoes rapid absorption when taken orally, with an approximate time to maximum plasma concentration ( T max ) of 1–2 h. The absolute bioavailability of

177-662: A clinical endpoint is devastating enough without the drug (e.g. death , heart attack ), drugs with a low NNH may still be indicated in particular situations if the NNT is smaller than the NNH. However, there are several important problems with the NNH, involving bias and lack of reliable confidence intervals, as well as difficulties in excluding the possibility of no difference between two treatments or groups. Number needed to treat The number needed to treat ( NNT ) or number needed to treat for an additional beneficial outcome ( NNTB )

236-436: A first-line treatment. It is taken by mouth . Common side effects include joint pain, diarrhea, heartburn, nausea, and muscle pains. Serious side effects may include rhabdomyolysis , liver problems, and diabetes . Use during pregnancy may harm the fetus . Like all statins, atorvastatin works by inhibiting HMG-CoA reductase , an enzyme found in the liver that plays a role in producing cholesterol . Atorvastatin

295-449: A four-fold increase in both C max and AUC. People with Child Pugh stage B liver disease show a 16-fold increase in C max and an 11-fold increase in AUC. Geriatric people (>65   years old) exhibit altered pharmacokinetics of atorvastatin compared to young adults, with mean AUC and C max values that are 40% and 30% higher, respectively. Additionally, healthy elderly people show

354-672: A greater pharmacodynamic response to atorvastatin at any dose; therefore, this population may have lower effective doses. Several genetic polymorphisms may be linked to an increase in statin-related side effects with single nucleotide polymorphisms (SNPs) in the SLCO1B1 gene showing a 45 fold higher incidence of statin related myopathy than people without the polymorphism. There are several studies showing genetic variants and variable response to atorvastatin. The polymorphisms that showed genome wide significance in Caucasian population were

413-455: A high cardiovascular disease risk; however, there is limited clinical benefit noted for most cardiovascular outcomes. Statins with shorter half-lives are more effective when taken in the evening, so their peak effect occurs when the body’s natural cholesterol production is at its highest. A recent meta-analysis suggested that statins with longer half-lives, including atorvastatin, may also be more effective at lowering LDL cholesterol if taken in

472-461: A key aspect of the overall design. The final commercial production of atorvastatin relied on a chiral pool approach, where the stereochemistry of the first alcohol functional group was carried into the synthesis—through the choice of isoascorbic acid , an inexpensive and easily sourced plant-derived natural product. The atorvastatin calcium complex involves two atorvastatin ions, one calcium ion and three water molecules. Bruce Roth , who

531-434: A large cohort need to be conducted in different ethnicities to identify more polymorphisms that can affect atorvastatin pharmacokinetics and treatment response. The first synthesis of atorvastatin at Parke-Davis that occurred during drug discovery was racemic followed by chiral chromatographic separation of the enantiomers . An early enantioselective route to atorvastatin made use of an ester chiral auxiliary to set

590-587: A month's supply—until other manufacturers began to supply the medication in May 2012. In other countries, atorvastatin calcium is made in tablet form by generic medication makers under various brand names including Atoris, Atorlip, Atorva, Atorvastatin Teva, Atorvastatina Parke-Davis, Avas, Cardyl, Liprimar, Litorva, Mactor, Orbeos, Prevencor, Sortis, Stator, Tahor, Torid, Torvacard, Torvast, Totalip, Tulip, Xarator, and Zarator. Pfizer also makes its own generic version under

649-518: A negative effect on any individual. However, in the case where the treatment may benefit some individuals and harm others, the NNT as defined above cannot be estimated from a Randomized Controlled Trial (RCT) alone. The inverse of the absolute risk reduction only provides an upper bound, i.e., NNT ⩽ 1 / ( I u − I e ) {\displaystyle {\text{NNT}}\leqslant 1/(I_{u}-I_{e})} . The modern approach defines NNT literally, as

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708-404: A therapeutic intervention and NNH to a detrimental effect or risk factor. A combined measure, the number needed to treat for an additional beneficial or harmful outcome (NNTB/H), is also used. The NNT is an important measure in pharmacoeconomics . If a clinical endpoint is devastating enough ( e.g. death , heart attack ), drugs with a high NNT may still be indicated in particular situations. If

767-501: Is a competitive inhibitor of HMG-CoA reductase . Unlike most others, however, it is a completely synthetic compound. HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate , which is the rate-limiting step in hepatic cholesterol biosynthesis. Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein receptors ( LDL receptors ) on hepatocytes . This increases LDL uptake by

826-403: Is a similar thought process with using high-dose atorvastatin as a form of secondary thrombotic stroke recurrence prevention. The liver is the primary site of action of atorvastatin, as this is the principal site of both cholesterol synthesis and LDL clearance. It is the dosage of atorvastatin, rather than systemic medication concentration, which correlates with extent of LDL-C reduction. In

885-517: Is an epidemiological measure used in communicating the effectiveness of a health-care intervention, typically a treatment with medication . The NNT is the average number of patients who need to be treated to prevent one additional bad outcome. It is defined as the inverse of the absolute risk reduction , and computed as 1 / ( I u − I e ) {\displaystyle 1/(I_{u}-I_{e})} , where I u {\displaystyle I_{u}}

944-451: Is estimated, NNT is given as NNT = PNS − 1 {\displaystyle {\text{NNT}}={\text{PNS}}^{-1}} . However, due to the counterfactual nature of PNS, only bounds can be computed from an RCT, rather than a precise estimate. Tian and Pearl have derived tight bounds on PNS, based on multiple data sources, and Pearl showed that a combination of observational and experimental data may sometimes make

1003-496: Is evidence from systematic review and meta-analyses that statins, particularly atorvastatin, reduce both decline in kidney function (eGFR) and the severity of protein excretion in urine, with higher doses having greater effect. Data are conflicting for whether statins reduce risk of kidney failure. Statins, including atorvastatin, before heart surgery do not prevent acute kidney injury. Prior to contrast medium (CM) administration, pre-treatment with atorvastatin therapy can reduce

1062-424: Is for the treatment of dyslipidemia and the prevention of cardiovascular disease : A 2014 meta-analysis showed high-dose statin therapy was significantly superior compared to moderate or low-intensity statin therapy in reducing plaque volume in people with acute coronary syndrome . The SATURN trial, which compared the effects of high-dose atorvastatin and rosuvastatin , also confirmed these findings. There

1121-589: Is less likely to happen with other CYP3A4 inhibitors such as diltiazem , erythromycin , fluconazole , ketoconazole , clarithromycin , cyclosporine , protease inhibitors , or verapamil , and only rarely with other CYP3A4 inhibitors, such as amiodarone and aprepitant . Often, bosentan , fosphenytoin , and phenytoin , which are CYP3A4 inducers, can decrease the plasma concentrations of atorvastatin. Only rarely, though, barbiturates , carbamazepine , efavirenz , nevirapine , oxcarbazepine , rifampin , and rifamycin , which are also CYP3A4 inducers, can decrease

1180-424: Is no evidence that it reduces all-cause mortality associated with CI-AKI. Overall, the evidence concludes that statin therapy, irrespective of the dose, is still more effective than no treatment or placebo at reducing the risk of CI-AKI. Statins (predominantly simvastatin ) have been evaluated in clinical trials in combination with fibrates to manage dyslipidemia in people who also have type 2 diabetes, and

1239-603: Is primarily through cytochrome P450 3A4 hydroxylation to form active ortho- and parahydroxylated metabolites , as well as various beta-oxidation metabolites. The ortho- and parahydroxylated metabolites are responsible for 70% of systemic HMG-CoA reductase activity. The ortho-hydroxy metabolite undergoes further metabolism via glucuronidation . As a substrate for the CYP3A4 isozyme, it has shown susceptibility to inhibitors and inducers of CYP3A4 to produce increased or decreased plasma concentrations, respectively. This interaction

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1298-530: Is relatively inexpensive. Under provisions of the Patient Protection and Affordable Care Act (PPACA) in the United States, health plans may cover the costs of atorvastatin 10 mg and 20 mg for adults aged 40–75 years based on United States Preventive Services Task Force (USPSTF) recommendations. Some plans only cover other statins. Atorvastatin calcium tablets are sold under

1357-408: Is the incidence in the control (unexposed) group, and I e {\displaystyle I_{e}} is the incidence in the treated (exposed) group. This calculation implicitly assumes monotonicity, that is, no individual can be harmed by treatment. The modern approach, based on counterfactual conditionals , relaxes this assumption and yields bounds on NNT. A type of effect size ,

1416-409: Is typically a type of study that would occur only if both the control and the tested treatment carried significant risks of serious harm, or if the treatment was unethical for a healthy participant (for example, chemotherapy drugs or a new method of appendectomy - surgical removal of the appendix). Most drug trials test both the control and the treatment on both healthy and "diseased" participants. Or, if

1475-545: The HMG-CoA reductase inhibitory activity appears to have a half-life of 20–30 hours, which is thought to be due to the active metabolites. Atorvastatin is also a substrate of the intestinal P-glycoprotein efflux transporter, which pumps the medication back into the intestinal lumen during medication absorption. In hepatic insufficiency , plasma concentrations of atorvastatin are significantly affected by concurrent liver disease. People with Child-Pugh Stage A liver disease show

1534-411: The NNT depending on the situation. The treatment may be a drug in the form of a pill or injection, a surgical procedure, or many other possibilities. The following examples demonstrate how NNT is determined and what it means. In this example, it is important to understand that every participant has the condition being treated, so there are only "diseased" patients who received the treatment or did not. This

1593-453: The NNT was described in 1988 by McMaster University 's Laupacis, Sackett and Roberts. While theoretically, the ideal NNT is 1, where everyone improves with treatment and no one improves with control, in practice, NNT is always rounded up to the nearest round number and so even a NNT of 1.1 becomes a NNT of 2 . A higher NNT indicates that treatment is less effective. NNT is similar to number needed to harm (NNH), where NNT usually refers to

1652-652: The SNPs in the apoE region; rs445925, rs7412, rs429358 and rs4420638 which showed variable LDL-c response depending on the genotype when treated with atorvastatin. Another genetic variant that showed genome wide significance in Caucasians was the SNP rs10455872 in the LPA gene that lead to higher Lp(a) levels which cause an apparent lower LDL-c response to atorvastatin. These studies were in Caucasian population, more research with

1711-473: The bounds collapse to a point estimate. Mueller and Pearl provide a conceptual interpretation for this phenomenon and illustrate its impact on both individual and policy-makers decisions. Atorvastatin Atorvastatin is a statin medication used to prevent cardiovascular disease in those at high risk and to treat abnormal lipid levels . For the prevention of cardiovascular disease, statins are

1770-408: The brand name Lipitor. Pfizer also packages the medication in combination with other medications, such as atorvastatin/amlodipine . Pfizer's U.S. patent on Lipitor expired on 30 November 2011. Initially, generic atorvastatin was manufactured only by Watson Pharmaceuticals and India's Ranbaxy Laboratories . Prices for the generic version did not drop to the level of other generics—$ 10 or less for

1829-549: The combination of digoxin and atorvastatin is reasonable. In contrast to some other statins, atorvastatin does not interact with warfarin concentrations in a clinically meaningful way (similar to pitavastatin ). Vitamin D supplementation lowers atorvastatin and active metabolite concentrations, yet synergistically reduces LDL and total cholesterol concentrations. Grapefruit juice components are known inhibitors of intestinal CYP3A4. Drinking grapefruit juice with atorvastatin may cause an increase in C max and area under

Number needed to harm - Misplaced Pages Continue

1888-468: The combined use of statins and the fibrate drug class (such as gemfibrozil , fenofibrate ) may increase the risk of myopathy and rhabdomyolysis , there is insufficient evidence to firmly establish this association with atorvastatin. Co-administration of atorvastatin with one of CYP3A4 inhibitors such as itraconazole , telithromycin , and voriconazole , may increase serum concentrations of atorvastatin, which may lead to adverse reactions. This

1947-439: The curve (AUC). This finding initially gave rise to concerns of toxicity, and in 2000, it was recommended that people taking atorvastatin should not consume grapefruit juice "in an unsupervised manner." Small studies (using mostly young participants) examining the effects of grapefruit juice consumption on mainly lower doses of atorvastatin have shown that grapefruit juice increases blood levels of atorvastatin, which could increase

2006-400: The effects of grapefruit juice consumption on atorvastatin will vary according to factors such as the amount and frequency of juice consumption in addition to differences in juice components, quality and method of juice preparation between different batches or brands. A few cases of myopathy have been reported when atorvastatin is given with colchicine . As with other statins, atorvastatin

2065-399: The efficacy of statins in lowering cholesterol proving for the first time not only that a "statin reduced 'bad' LDL cholesterol but also that it led to a sharp drop in fatal heart attacks among people with heart disease." In 1996, Warner-Lambert entered into a co-marketing agreement with Pfizer to sell Lipitor, and in 2000, Pfizer acquired Warner-Lambert for $ 90.2   billion. Lipitor

2124-423: The endpoint is minor, health insurers may decline to reimburse drugs with a high NNT. NNT is significant to consider when comparing possible side effects of a medication against its benefits. For medications with a high NNT, even a small incidence of adverse effects may outweigh the benefits. Even though NNT is an important measure in a clinical trial, it is infrequently included in medical journal articles reporting

2183-457: The evening. However, the only study included in the meta-analysis of atorvastatin in people with heart disease did not specifically investigate if morning or evening dosing was more effective for reducing LDL cholesterol. The trial did confirm that, irrespective of dosing time, atorvastatin is very effective at reducing total cholesterol, LDL cholesterol and triglycerides, and increasing HDL cholesterol levels. Hence, atorvastatin should be taken at

2242-526: The hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Like other statins, atorvastatin also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol . In people with acute coronary syndrome , high-dose atorvastatin treatment may play a plaque-stabilizing role. At high doses, statins have anti-inflammatory effects, incite reduction of the necrotic plaque core, and improve endothelial function, leading to plaque stabilization and, sometimes, plaque regression. There

2301-399: The information conveyed by the NNT may be incomplete or even contradictory compared to the traditional statistics of interest in survival analysis. A comprehensive research on adjustment of the NNT for explanatory variables and accommodation to time-dependent outcomes was conducted by Bender and Blettner, Austin, and Vancak et al. There are a number of factors that can affect the meaning of

2360-481: The medication is about 14%, but the systemic availability for HMG-CoA reductase activity is approximately 30%. Atorvastatin undergoes high intestinal clearance and first-pass metabolism , which is the main cause for the low systemic availability. Administration of atorvastatin with food produces a 25% reduction in C max (rate of absorption) and a 9% reduction in AUC (extent of absorption), although food does not affect

2419-486: The name Zarator. In the US, Lipitor is marketed by Viatris after Upjohn was spun off from Pfizer. On 9 November 2012, Indian drugmaker Ranbaxy Laboratories Ltd. voluntarily recalled 10-, 20- and 40-mg doses of its generic version of atorvastatin in the United States. The lots of atorvastatin, packaged in bottles of 90 and 500 tablets, were recalled due to possible contamination with very small glass particles similar to

Number needed to harm - Misplaced Pages Continue

2478-648: The number of patients one needs to treat (on the average) before saving one. However, since "saving" is a counterfactual notion (a patient must recover if treated and not recover if not treated) the logic of counterfactuals must be invoked to estimate this quantity from experimental or observational studies. The probability of "saving" is captured by the Probability of Necessity and Sufficiency (PNS), where PNS = P ( Recovery if and only if treated ) {\displaystyle {\text{PNS}}=P({\text{Recovery if and only if treated}})} . Once PNS

2537-440: The plasma LDL-C -lowering efficacy of atorvastatin. Evening dose administration is known to reduce the C max and AUC by 30% each. However, time of administration does not affect the plasma LDL-C-lowering efficacy of atorvastatin. The mean volume of distribution of atorvastatin is approximately 381 L. It is highly protein bound (≥98%), and studies have shown it is likely secreted in human breastmilk. Atorvastatin metabolism

2596-461: The plasma concentrations of atorvastatin. Oral contraceptives increased AUC values for norethisterone and ethinylestradiol ; these increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin. Antacids can rarely decrease the plasma concentrations of statin medications, but do not affect the LDL-C -lowering efficacy . Niacin also is proved to increase

2655-430: The results of clinical trials. There are several important problems with the NNT, involving bias and lack of reliable confidence intervals, as well as difficulties in excluding the possibility of no difference between two treatments or groups. NNT may vary substantially over time, and hence convey different information as a function of the specific time-point of its calculation. Snapinn and Jiang showed examples where

2714-477: The risk of adverse effects. No studies assessing the impact of grapefruit juice consumption have included participants taking the highest dose of atorvastatin (80 mg daily), which is often prescribed for people with a history of cardiovascular disease (such as heart attack or ischaemic stroke ) or in people at high risk of cardiovascular disease. People taking atorvastatin should consult with their doctor or pharmacist before consuming grapefruit juice, as

2773-565: The risk of contrast-induced acute kidney injury (CI-AKI) in people with pre-existing chronic kidney disease (CKD) (eGFR < 60mL/min/1.73m2) who undergo interventional procedures such as cardiac catheterisation, coronary angiography (CAG) or percutaneous coronary intervention (PCI). A meta-analysis of 21 RCTs confirmed that high dose (80 mg) atorvastatin therapy is more effective than regular dose or low dose statin therapy at preventing CI-AKI. Atorvastatin therapy can also help to prevent in-hospital dialysis post CM administration, however there

2832-421: The risk of myopathy or rhabdomyolysis. Some statins may also alter the concentrations of other medications, such as warfarin or digoxin , leading to alterations in effect or a requirement for clinical monitoring. The increase in digoxin levels due to atorvastatin is a 1.2 fold elevation in the area under the curve (AUC) , resulting in a minor drug-drug interaction. The American Heart Association states that

2891-560: The risks for cognition are likely outweighed by the beneficial effects of adherence to statin therapy on cardiovascular and cerebrovascular disease. A 2012 meta-analysis found that statin therapy might reduce the risk of pancreatitis in people with normal or mildly elevated blood triglyceride levels. Statins seem to have a positive effect on erectile dysfunction . Fibrates are a class of drugs that can be used for severe or refractory mixed hyperlipidaemia in combination with statins or as monotherapy. While studies have suggested that

2950-769: The same time each day, at a time that is most convenient for the patient, so it does not compromise compliance. The following have been shown to occur in 1–10% of people taking atorvastatin in clinical trials: Atorvastatin has been associated with a small increase in fasting blood glucose levels over a 2-year period, particularly in patients with Type 2 Diabetes, however evidence is conflicting and clinical significance of this increase has not been determined. Regular blood glucose monitoring may be advised in patients with Type 2 Diabetes. There have been rare reports of reversible memory loss and confusion with all statins, including atorvastatin; however, there has not been enough evidence to associate statin use with cognitive impairment, and

3009-422: The stereochemistry of the first of the two alcohol functional groups via a diastereoselective aldol reaction . Once the compound entered pre-clinical development , process chemistry developed a cost-effective and scalable synthesis. In atorvastatin's case, a key element of the overall synthesis was ensuring stereochemical purity in the final drug substance, and hence establishing the first stereocenter became

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3068-462: The table below: ASCOT-LLA manufacturer-sponsored study addressed the benefit of atorvastatin 10 mg (a cholesterol -lowering drug) in patients with hypertension (high blood pressure) but no previous cardiovascular disease ( primary prevention ). The trial ran for 3.3 years, and during this period the relative risk of a "primary event" (heart attack) was reduced by 36% (relative risk reduction, RRR). The absolute risk reduction (ARR), however,

3127-477: The treatment's purpose is to prevent a condition that is fairly common (an anticoagulant to prevent heart attack for example), a prospective study may be used. A study which starts with all healthy participants is termed a prospective study, and is in contrast to a retrospective study, in which some participants already have the condition in question. Prospective studies produce much higher quality evidence, but are much more difficult and time-consuming to perform. In

3186-514: Was hired by Warner-Lambert as a chemist in 1982, had synthesized an "experimental compound" codenamed CI 981 – later called atorvastatin. It was first made in August 1985. Warner-Lambert management was concerned that atorvastatin was a me-too version of rival Merck & Co. 's orphan drug lovastatin (brand name Mevacor ). Mevacor, which was first marketed in 1987, was the industry's first statin and Merck's synthetic version – simvastatin –

3245-493: Was in the advanced stages of development. Nevertheless, Bruce Roth and his bosses, Roger Newton and Ronald Cresswell, in 1985, convinced company executives to move the compound into expensive clinical trials. Early results comparing atorvastatin to simvastatin demonstrated that atorvastatin appeared more potent and with fewer side effects. In 1994, the findings of a Merck-funded study were published in The Lancet concluding

3304-481: Was much smaller, because the study group did not have a very high rate of cardiovascular events over the study period: 2.67% in the control group, compared to 1.65% in the treatment group. Taking atorvastatin for 3.3 years, therefore, would lead to an ARR of only 1.02% (2.67% minus 1.65%). The number needed to treat to prevent one cardiovascular event would then be 98.04 for 3.3 years. The above calculations for NNT are valid under monotonicity, where treatment can't have

3363-566: Was on the market by 1996. By 2003, Lipitor had become the best selling pharmaceutical in the United States. From 1996 to 2012, under the trade name Lipitor, atorvastatin became the world's best-selling medication of all time, with more than $ 125   billion in sales over approximately 14.5   years. and $ 13 billion a year at its peak, Lipitor alone "provided up to a quarter of Pfizer Inc.'s annual revenue for years." Pfizer's patent on atorvastatin expired in November 2011. Atorvastatin

3422-567: Was patented in 1986, and approved for medical use in the United States in 1996. It is on the World Health Organization's List of Essential Medicines . It is available as a generic medication . In 2022, it was the most commonly prescribed medication in the United States, with more than 109   million prescriptions filled for over 27 million people. In Australia, it was one of the top 10 most prescribed medications between 2017 and 2023. The primary uses of atorvastatin

3481-545: Was tested in vitro with concurrent administration of erythromycin , a known CYP3A4 isozyme inhibitor, which resulted in increased plasma concentrations of atorvastatin. It is also an inhibitor of cytochrome 3A4. Atorvastatin is primarily eliminated via hepatic biliary excretion, with less than 2% recovered in the urine . Bile elimination follows hepatic and/or extrahepatic metabolism. There does not appear to be any entero-hepatic recirculation . Atorvastatin has an approximate elimination half-life of 14 hours. Noteworthy,

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