Rosuvastatin safety: a comprehensive, international pharmacoepidemiology programme

pharmacoepidemiology and drug safety 2006; 15: 454–461ww.interscience.wiley.com). DOI: 10.1002/pds.1260
Published online 30 May 2006 in Wiley InterScience (w
ORIGINAL REPORT

Rosuvastatin safety: a comprehensive, internationalpharmacoepidemiology programme

Saga Johansson MD, PhD1,2,a*, Eileen E. Ming ScD, MPH1,a, Mari-Ann Wallander PhD1,3,a,Luis A. Garcıa Rodrıguez MD, MSc4,a,c, Ron M. C. Herings PharmD, PhD5,b,c,Wim G. Goettsch PhD5,b,c, Antonio Gonzalez-Perez MSc4,b,Andrew T. McAfee MD, MSc6,7,b and Alexander M. Walker MD, DrPH6,b

1AstraZeneca R&D Molndal, Sweden2Section of Preventive Cardiology, Goteborg University, Sweden3Department of Public Health and Caring Science, Uppsala University, Sweden4Centro Espanol de Investigacion Farmacoepidemiologica (CEIFE), Madrid, Spain5PHARMO Institute, Utrecht, The Netherlands6i3 Drug Safety, Auburndale MA, USA7Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, USA

SUMMARY

Results from clinical trials and clinical practice have shown statins to be generally well tolerated with a low frequency ofclinically relevant side effects. Nevertheless, there are rare occasions when adverse events (AEs), sometimes serious, mayoccur. Rosuvastatin is the newest statin to be approved in the USA and many other countries. As part of the continuedassessment of the benefit-risk profile of rosuvastatin, AstraZeneca has developed a progressive, comprehensive pharma-coepidemiology programme to complement safety data obtained from randomised clinical trials and spontaneous reportingsystems, which have demonstrated that rosuvastatin has a safety profile in line with comparator statins. This programmecomprises nine studies conducted in recognised centres of excellence assessing over 50 000 patients treated withrosuvastatin. It consists of three components: patient characteristics studies (four studies), safety evaluation studies (fourstudies); and review of data generated from the Prescription-Event Monitoring (PEM) study, designed and run by anindependent third party. Patient characteristics studies are designed to describe the characteristics and drug utilisationpatterns of new users of rosuvastatin compared with new users of other statins in automated databases. Safety evaluationstudies will examine the rates of specific AEs in different cohorts of statin users and determine risk factors for these eventsusing data recorded prospectively in automated databases with case adjudication via medical record review. The independentPEM study will monitor any significant events recorded by general practitioners since starting rosuvastatin treatment. Thisarticle is an overview of the rationale and methodology of the rosuvastatin pharmacoepidemiology programme. Copyright#2006 John Wiley & Sons, Ltd.

key words—pharmacoepidemiology; rosuvastatin; statin; safety

*Correspondence to: Dr S. Johansson,MD, PhD, AstraZeneca R&DMolndal, Molndal SE-43183, Sweden.E-mail: [email protected] of AstraZeneca, manufacturers of rosuvastatin.bauthors who received funding from the company to support work onthe project.cauthors who received unrestricted research or educational supportfrom AstraZeneca.

Copyright # 2006 John Wiley & Sons, Ltd.

INTRODUCTION

Results from numerous clinical studies haveestablished that lowering low-density lipoproteincholesterol (LDL-C) by HMG-CoA reductaseinhibitors (statins) reduces total mortality andcardiovascular events in both primary and secondaryprevention.1–6 The LDL-C-lowering activity of

Received 3 February 2006Revised 27 March 2006Accepted 2 April 2006

rosuvastatin pharmacoepidemiology programme 455

rosuvastatin, the newest member of the statin class tobe approved in the USA and many other countries, isgreater than other available statins. A higherproportion of patients treated with rosuvastatin10–40mg achieve lipid goals compared withatorvastatin 10–80mg, simvastatin 10–80mg andpravastatin 10–40mg.7,8

Results from controlled clinical studies and use inclinical practice have demonstrated that the statins aregenerally well tolerated with a low frequency ofclinically significant side effects.9,10 As with anymedical treatment, adverse events (AEs), sometimesserious, may occur. Known important, but rare,adverse effects associated with statins are myopathy,rhabdomyolysis and an asymptomatic increase inhepatic transaminases.11 The most serious AEassociated with statins is rhabdomyolysis.12,13 Obser-vational and anecdotal data suggest that there arecomorbidities, concomitant medications and othercircumstances that may increase the risk of myotoxi-city, depending on the properties of the givenstatin.14 The publicity surrounding the removal ofcerivastatin from the market in 2001 due to theenhanced risk of rhabdomyolysis has likely contrib-uted to an increase in awareness of potential safetyissues with statins.15

Data contributing to the benefit-risk profile of amedicine is usually generated from at least threesources: controlled clinical trials, post-marketingsurveillance and pharmacoepidemiology studies. Eachof these sources has its own strengths and limitations.The essential safety data from clinical trials may belimited in its extrapolation to patients treated outsideof the clinical trial environment due to relatively smallnumbers of people exposed to the drug in trials,selection bias of clinical trial participants (both ingeneral and that induced by specific inclusion andexclusion criteria), study durations often shorter thanthe preferred duration of treatment, fixed follow-upvisits and very specific treatment protocols.

Spontaneous reporting systems are a standard andinvaluable method of signal detection, generatingearly warnings of drug hazards not recognisedpreviously in the total population of treated individ-uals, and are particularly effective at detectingpossible signals for rare events. These systems relyon voluntary reporting to industry or regulatory groupsof suspected adverse drug reactions observed inpractice or by dispensers and citizens but lacksaccurate numerator and denominator data. Spon-taneous reporting systems have well-recognisedlimitations, permitting only hypothesis generationand not hypothesis testing.16

Copyright # 2006 John Wiley & Sons, Ltd. P

Traditionally, AE report databases have been used forsignal generation while pharmacoepidemiological stu-dies, using large automated healthcare databases, havebeen used for signal validation and risk quantification.Pharmacoepidemiology studies complement random-ised clinical trials and spontaneous reporting systemsthrough their effective ability to study large hetero-geneous groups of people for an extended period oftime. This allows estimation of effectiveness andincidence of events (adverse or beneficial) in thegeneral population, study of delayed drug effects orevents too common for adequate detection by spon-taneous reporting systems, and observation of uncom-mon drug effects and interactions with other drugs ordisease states to be evaluated. Furthermore, such datacollected in usual clinical practice allows study ofpatients who are being treated for several disorderssimultaneously, those taking multiple prescription andnon-prescription medicines/natural remedies, and eventhose using medications off-label or due to misdiagno-sis. In addition, pharmacoepidemiology studies may bedesigned to compare the safety profile of a new drug tothose of other drugs. Thus, scientific evidence fromcontrolled clinical trials, post-marketing surveillanceand pharmacoepidemiology studies when combinedprovide the best information to assess a drug’s benefit-risk profile.The manufacturer of rosuvastatin, AstraZeneca, has

adopted an industry-leading approach to continuerigorous assessment of the safety of the drug. Thesafety profile of rosuvastatin has been evaluatedextensively and in great detail in clinical studies, andits approval was based upon the largest clinical trialdevelopment programme in its class. A summary ofthe information provided to the US Food and DrugAdministration from a multinational phase II/IIIprogramme involving 12 400 patients treated withrosuvastatin 5–40mg has been published.17 Thesedata have shown that rosuvastatin was well toleratedby a broad range of patients with dyslipidaemia, andits safety profile was similar to those of the comparatorstatins (atorvastatin 10–80mg, simvastatin 10–80mgand pravastatin 10–40mg) investigated in thisprogramme. In addition, and beyond enhancedsurveillance, a broad global pharmacoepidemiologyprogramme with various studies is currently inprogress. Data from these studies will increase theunderstanding of the risks associated with rosuvastatintherapy and enable evaluation of these risks in thecontext of the benefit of rosuvastatin to patients inactual practice.Recent guidance from regulatory authorities has

highlighted the importance and value of good

harmacoepidemiology and Drug Safety, 2006; 15: 454–461

456 s. johansson ET AL.

pharmacovigilance and pharmacoepidemiology stu-dies in the post-marketing period for a new drug.18–20

In particular, carefully designed and conductedpharmacoepidemiological studies, specifically obser-vational (non-interventional, non-experimental) studiesare important tools, and are the basis for therosuvastatin pharmacoepidemiology programme.When conducting comparative pharmacoepide-

miology studies on a recently marketed drug versusother drugs in the class timing is an essentialconsideration as there is need to balance assemblingsufficient numbers of patients exposed to the drug withcomplete data and the importance of obtaining studyresults in a timely manner for benefit-risk evaluations.In this programme the populations for the studies aredrawn from four data sources in different geographicalregions with different timelines for data availability.Over 50 000 rosuvastatin-treated patients are followedlongitudinally and the studies will be conducted andreported in a stepwise fashion using information as itbecomes accessible in the various databases. Thestudies are being conducted by independent, renownedcentres of excellence. All studies are observational,with no intervention in the patient’s usual care nor anyinteraction with any patient.The goal of the pharmacoepidemiology programme

is to provide real-life data on patient characteristicsand specific AE rates in patients taking rosuvastatincompared to those taking other statins based onpreviously existing databases and medical recordreview. This article provides an overview of theprogramme and study methodology. More detaileddescriptions of the individual studies will be reportedas the results become available.

METHODS

Programme design

The studies of the pharmacoepidemiology programmeare designed as prospective cohort studies, followingusers, and in one case non-users, of statins over time,allowing estimation of incidence rates, attributablerisks and relative risks for AEs. In this study design,physicians are unaware of the study at the time oftreatment decision-making, such that the studyinvestigator has no influence on assigning thetreatment. The pharmacoepidemiology programmefor rosuvastatin consists of nine studies, in fourcountries, grouped into three components: patientcharacteristic studies (four studies), safety evaluationstudies (four studies) and review of data generatedfrom the Prescription-Event Monitoring (PEM) study,


designed and run by the Drug Safety Research Unit(DSRU), a research charity affiliated with theUniversity of Portsmouth in the UK. All the studiesin this programme are being performed in accordancewith Good Pharmacoepidemiology Practice guide-lines21 and have been reviewed and approved by theappropriate ethics committees.

Patient characteristics studies

The purpose of these four studies is to describe thecharacteristics and drug utilisation patterns of newusers of rosuvastatin compared to new users of otherstatins, including demographics, diagnoses, comor-bidities, healthcare use, concomitant medication,statin dose, prior statin use and lipid levels (availablein three studies), in the USA, the Netherlands, UK andCanada. Each study observed all new users in the first1–2 years of rosuvastatin availability in the respectivecountries, during 2003–2005. There are data from over325 000 statin-treated patients included in thesestudies, with the vast majority (about 220 000) ofpatients in the US study (Table 1).

Safety evaluation studies

The purpose of these four studies is to examine therates of specific events across statins and determinerisk factors for these events in the USA, theNetherlands, UK and Canada. In each study, patientswho start a new statin (statin-naive or non-naive)during the observation period will be identified andfollowed for death or hospitalisation with specifiedmuscle-related, renal or hepatic events. Medicalrecords from the suspected event will be abstractedfor validation. Incidence rates for specified events foreach statin will be compared.

The patients included in these studies will be drawnfrom the same databases used in the patient character-istics studies. The four studies will be conducted assimilarly as possible, given the characteristics of eachdatabase and health system, so that their results can beconsidered alongside one another to provide a broadview. The numbers of patients followed will vary witheach study, with about 50 000 patients in both the USand Netherlands studies (Table 1). The follow-up periodwill be up to 2 years in the non-US safety evaluationstudies, and up to 18 months in the US safety evaluationstudy, and 1 year in PEM.

Prescription-Event Monitoring study (UK)

PEM is a non-interventional, observational cohortform of post-marketing surveillance.22 The goals of


Table 1. Overview of the constituent studies of the rosuvastatin pharmacoepidemiology programme

Study and database Accrual period (from–to) End of follow-up Approximate sample size

Patient characteristics studiesUSA September 2003–August 2004 NA 220 000Netherlands January 2002–June 2004 NA 22 500Canada July 2003–June 2004 NA 15 000UK April 2003–March 2005 NA 70 000

Safety evaluation studiesUSA September 2003–February 2004 February 2005 50 000Netherlands January 2003–December 2004 December 2004 50 000Canada July 2003–June 2005 June 2005 Not knownUK April 2003–December 2005 December 2005 Not known

Prescription-Event Monitoring studyAugust 2003–December 2003 August 2003* 11 500

NA, not applicable.*Median follow-up of 307 days per patient.


this PEM study are to examine the safety ofrosuvastatin as used in general medical practice inEngland and to quantify the incidence of and betterunderstand frequently and rarely reported events andpreviously unrecognised adverse drug reactions usingdata collected from questionnaires mailed to generalpractitioners. This study was designed and isconducted independently by the DSRU. Decisionsabout which medicines or safety concerns should bestudied are made independently by the DSRU. TheDSRU receives unconditional donations from phar-maceutical companies, who have no control over theconduct or the publication of the studies carried out bythe unit.

By virtue of a long-standing confidential agree-ment, the UK Prescription Pricing Authority providesthe DSRU with copies of all prescriptions formonitored drugs during the specified observationperiods. Approximately 6 months from the firstprescription of the monitored drug for each individualpatient, the DSRU sends the prescriber a ‘green form’questionnaire seeking information relating to demo-graphics, indication for treatment, duration of therapy,dosage, AEs, clinical events and reasons for discon-tinuation.22 The unique feature of this type of study isthat PEM collects event data through an open-endedquestionnaire and does not ask the physician todetermine if any particular event is due to anadverse drug reaction. Events of interest arefollowed up through a written request for furtherinformation.

Green forms for approximately 11 500 rosuvastatinusers have been returned and those indicating eventsof interest are being followed up. There have been 90


drugs from a variety of classes evaluated by the PEMmethodology and until now no statin has been studiedusing this approach.23

Databases

The databases used for the patient characteristics andsafety evaluation components of this programme arewell established and have been used in many previousindependent pharmacoepidemiology studies. Thesedatabases have data available for analysing infor-mation on comorbidities, co-prescriptions and hospi-talisations, and they allow medical chart abstraction.In addition, these sources encompass large popu-lations, and thus are expected to accrue a sufficientnumber of rosuvastatin users to observe rare events.Each database has different characteristics, requiringvariations in methods used for data collection andanalysis. Subject accrual periods depend on the launchdate and extent of use of rosuvastatin in the respectivecountries. Once subjects are accrued, results fromeach study will become available depending on theduration of follow-up, time required for patientexperiences to be recorded in the database, time toreview medical records to validate the selectedoutcomes, and time for analysis. Note that there isan inherent trade-off between assembling a sufficientnumber of patients receiving rosuvastatin withcomplete data in the databases and the importanceof obtaining results early from the pharmacoepide-miological studies for benefit-risk evaluations. It isanticipated that all the studies will be completed bylate 2006. Taken as a whole, these large sources of datawill provide insight about patient characteristics and



risk for adverse outcomes in diverse populations indifferent countries.

USA: managed care claims database

The US study is based on the comprehensiveadministrative databases of one of the largest healthinsurers in the USA, which includes data on10 million individuals per year, and includes allmedical and pharmacy claims. Patients are followedlongitudinally, for as long as they are continuouslycovered by the health insurer. Investigators canabstract inpatient records identified from thedatabase and analyse them in aggregate. Distributionof age and sex of individuals represented in thisdatabase compares favourably with estimates fromthe US Census, though with under-representation ofthose aged over 65 years.24,25

For the patient characteristics study, characteristicsof those newly prescribed rosuvastatin will becompared with those newly prescribed other statinsbetween September 2003 and August 2004. The safetyevaluation study will follow patients accrued betweenSeptember 2003 and February 2004 until February2005 to compare incidence rates of specified seriousAEs among initiators of rosuvastatin with initiators ofother statins (Table 1). The determinants of theprobability of being prescribed rosuvastatin asopposed to another statin will be assessed to createbalanced cohorts, based on demographics, clinicalfactors, comorbidities, concomitant medications andhealthcare services utilisation.

The Netherlands: PHARMO RecordLinkage System

The PHARMO Medical Record Linkage Systemcontains patient demographics, drug-dispensingrecords from community pharmacies, hospitaldischarge records, clinical laboratory data and otherclinical data on 2 million individuals per year. Dataare patient-centric with a follow-up period of at least8 years. These individuals represent all residents of45 demographically and geographically definedareas scattered throughout the Netherlands, repre-senting over 10% of all Dutch inhabitants.26

Hospitalisation records are obtained from thePRISMANT organisation, an institute that collatesall hospital discharge records in the Netherlands. Forthe patient characteristics study, rosuvastatin andother-statin use is observed in patients during marketintroduction, from January 2002 (before rosuvastatin


availability) to June 2004, using the medical recordlinkage database of more than 1 million residents ofover 25 areas in the Netherlands. The safetyevaluation study uses the expanded database of over2 million residents over 45 areas in the Netherlands,and follows patients initiating rosuvastatin, patientsinitiating other statins and a random sample of non-statin users from January 2003 until December 2004(Table 1).

Canada: Saskatchewan health databases

Saskatchewan, one of 10 provinces in Canada,provides universal healthcare coverage for itsapproximately 1 million residents (about 3.4% ofthe national population).27 Individuals not covered bySaskatchewan Health include those with federallyfunded health care, such as members of the RoyalCanadian Mounted Police and Canadian Forces.27

About 90% of the covered population is eligible forprescription drug benefits. The database includesprescription drug usage, patient demographics,medical services and diagnostic codes for outpatientvisits and hospitalisations. Each database captures thebeneficiary’s unique lifetime registration number,which allows the databases to be linked. The validityof the data for use in research has been documented forseveral outcomes.27

For the patient characteristics study, characteristicsof first time users of rosuvastatin will be compared tothose of first time users of other statins from July 2003to June 2004; the safety evaluation study will followthese users for up to 2 years in order to compareincidence rates of specified serious AEs amonginitiators of rosuvastatin with initiators of other statinsuntil June 2005 (Table 1).

UK: General Practice Research Database (GPRD)

The GPRD has been collecting patient records fromgeneral practices in the UK continuously since itsinception in 1987, and contains over 35 millionpatient-years of data accrued in the database. Itcontains computerised information currently enteredby approximately 1500 general practitioners in theUK, who record demographic information, medicaldiagnoses, consultant and hospital referrals andwritten prescriptions for over 3 million patients (5%of the UK population). This information is sentanonymously to the Medicines and Healthcareproducts Regulatory Agency that organises it for



use in research projects. The accuracy and complete-ness of data from the GPRD have been documented inprevious validation studies.28–30

For the patient characteristics study, characteristicsof first time users of rosuvastatin will be compared tothose of first time users of other statins during April2003–March 2005; the safety evaluation study willfollow these users for up to 21 months to compareincidence rates of the specified outcomes amonginitiators of rosuvastatin and initiators of other statinsuntil December 2005 (Table 1).

DISCUSSION

Proper evaluation of the benefit-risk profile of amedicine is based on information provided by atleast three sources. First, data from three phases ofclinical trial studies are used to demonstrate, forapproval and registration, that a drug is effective andreasonably safe for its recommended use. Second,once the drug is marketed post-marketing surveil-lance occurs, which relies on a collection ofspontaneous reports of adverse drug reactions togenerate signals of possible adverse drug events.Third, rigorous pharmacoepidemiology studies pro-vide robust data on benefits and risks of medicationsin clinical practice once the drug has been marketed.The rosuvastatin pharmacoepidemiology pro-gramme has been designed to form a key part ofthis evaluation. Each of these approaches comp-lements one another and so information obtainedfrom all three should be considered together, as awhole, to provide an assessment of the safety of adrug in clinical practice.

To date, all safety and tolerability data obtainedfrom phase II and phase III clinical studies withrosuvastatin have shown a profile in line with otherstatins.17 These data have been generated from areview of over 12 000 patients who had receivedrosuvastatin 5–40mg in 27 multinational clinicalstudies. This clinical development programme wasdesigned to study a representative patient populationwith dyslipidaemia who were eligible for statintherapy in clinical practice.

Post-marketing surveillance casts the largest net tocapture events, by incorporating all drugs, prescribers,dispensers and patients, and is able to detect rareeffects in ‘real-life’ usage, aiding hypothesis gener-ation. However, patterns in spontaneous reporting mayvary across countries, increase during the first fewyears after launch and subsequently decrease,31 or beaffected by publicity.32 These two latter artefacts bias


spontaneous reporting rates against the most recentmarket entrants and drugs subjected to negativepublicity; both apply to rosuvastatin.To thoroughly assess the safety of rosuvastatin,

AstraZeneca have extended the usual post-marketingevaluation of the drug by proactively implementing auniquely comprehensive, transparent and multi-pronged pharmacoepidemiology programme. Over50 000 patients treated with rosuvastatin will beincluded in this exemplary evaluation. Many patientstreated with other statins will be included to enablecomparisons across the drug class.All the pharmacoepidemiology studies included in

this programme are purely observational as they arebased on data from existing databases and medicalrecord review. The five data sources used for thesenine constituent studies are all well recognised in thefield of pharmacoepidemiology, and include suffi-ciently large populations with adequate periods ofdrug exposure in order to detect rare outcomes. Theirvalidity and use for pharmacoepidemiology researchhave been described previously.22,24–29,33 Thesestudies are being conducted in databases with differentcharacteristics, data collection methods, and healthcare systems. At the same time, an important strengthof this programme is that the studies conducted in eachcountry are sufficiently similarly designed that theycan be taken as a whole, providing comparable insightabout patient characteristics and risk for adverseoutcomes in diverse populations in different countries.The pharmacoepidemiology programme includespassive and active surveillance, and descriptive studieswhich are all key methods used in pharmacovigilance.Furthermore, they are recommended by regulatoryauthorities for pharmacovigilance planning andpractices.18–20

In conclusion, the rosuvastatin pharmacoepide-miology programme has been designed to charac-terise the users of rosuvastatin and to determine therates of specific AEs in users of each statin. This willbe achieved by accessing data from large, well-established, recognised databases in four countriesand including over 50 000 patients treated withrosuvastatin. It is anticipated that the constituentstudies from this programme will be completedduring 2006. A strength of the programme is that theindividual study results can be considered alongsideone another and not in isolation. In addition, theprogramme is designed to complement data fromrandomised clinical trials and post-marketing spon-taneous reporting systems in order that the mostaccurate benefit-risk profile of rosuvastatin inclinical practice is obtained.


KEY POINTS

� The international rosuvastatin pharmacoepide-miology programme will assess over 50 000patients treated with the drug.

� Four patient characteristics studies willexamine the characteristics and drug usepatterns of new users of rosuvastatin comparedwith other statins using automated databases.

� Four safety evaluation studies will examine therates of specific AEs in cohorts of statin usersand determine risk factors for these eventsusing automated databases.

� An independent Prescription-Event Monitoringstudy will determine significant events withrosuvastatin treatment recorded by generalpractitioners.

� All studies in the programme are conducted byrecognised centres of excellence.


ACKNOWLEDGEMENTS

We thank Dr Andrew Thomson from Prime MedicaLtd who providedmedical writing support on behalf ofAstraZeneca.

REFERENCES

1. Downs JR, Clearfield M, Weis S, et al. Primary prevention ofacute coronary events with lovastatin in men and women withaverage cholesterol levels: results of AFCAPS/TexCAPS. AirForce/Texas Coronary Atherosclerosis Prevention Study. JAMA1998; 279: 1615–1622.

2. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravas-tatin on coronary events after myocardial infarction in patientswith average cholesterol levels. Cholesterol and RecurrentEvents Trial investigators.N Engl J Med 1996; 335: 1001–1009.

3. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronaryheart disease with pravastatin in men with hypercholesterole-mia.West of Scotland Coronary Prevention Study group.N EnglJ Med 1995; 333: 1383–1389.

4. Scandinavian Simvastatin Survival Study (4S). Randomisedtrial of cholesterol lowering in 4444 patients with coronaryheart disease. Lancet 1994; 19: 1383–1389.

5. Sever PS, Dahlof B, Poulter NR, et al. ASCOT investigators.Prevention of coronary and stroke events with atorvastatin inhypertensive patients who have average or lower-than-aver-age cholesterol concentrations, in the Anglo-ScandinavianCardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet2003; 361: 1149–1158.


6. Heart Protection Study Collaboration Group. MRC/BHF HeartProtection Study of cholesterol lowering with simvastatin in20,536 high-risk individuals: a randomized placebo-controlledtrial. Lancet 2002; 360: 7–22.

7. Jones PH, Davidson MH, Stein EA, et al. STELLAR StudyGroup. Comparison of the efficacy and safety of rosuvastatinversus atorvastatin, simvastatin, and pravastatin across doses(STELLAR trial). Am J Cardiol 2003; 93: 152–160.

8. McKenney JM, Jones PH, Adamczyk MA, et al. STELLARStudy Group. Comparison of the efficacy of rosuvastatin versusatorvastatin, simvastatin, and pravastatin in achieving lipidgoals: results from the STELLAR trial. Curr Med Res Opin2003; 19: 689–698.

9. Black DM. A general assessment of the safety of HMG-CoAreductase inhibitors (statins).Curr Atheroscler Rep 2002; 4: 34–41.

10. Davidson MH. Safety profiles of the HMG-CoA reductaseinhibitors: treatment and trust. Drugs 2001; 61: 197–206.

11. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus onclinical pharmacokinetics and drug interactions. Circulation2004; 109(Suppl III): III-50–III-57.

12. Grundy SM. The issue of statin safety. Circulation 2005; 111:3016–3019.

13. Graham DJ, Staffa JA, Shatin D, et al. Incidence of hospitalizedrhabdomyolysis in patients treated with lipid-lowering drugs.JAMA 2004; 292: 2585–2590.

14. Rosenson RS. Current overview of statin-induced myopathy.Am J Med 2004; 116: 408–416.

15. Psaty BM, Furberg CD, Ray WA, et al. Potential for conflict ofinterest in the evaluation of suspected adverse drug reactions.JAMA 2004; 292: 2622–2631.

16. Strom BL. Potential for conflict of interest in the evaluation ofsuspected adverse drug reactions. JAMA 2004; 292: 2643–2646.

17. Shepherd J, Hunninghake DB, Stein EA, et al. Safety ofrosuvastatin. Am J Cardiol 2004; 94: 882–888.

18. U.S. Department of Health and Human Services Food and DrugAdministration. Guidance for industry: E2E pharmacovigilanceplanning. April 2005. Available at: URL: http://www.fda.gov/cber/gdlns/ichpvp.pdf [accessed 14 February 2006].

19. U.S. Department of Health and Human Services Food and DrugAdministration. Guidance for industry: good pharmacovigi-lance practices and pharmacoepidemiologic assessment. March2005. Available at: URL: http://www.fda.gov/cder/guidance/6359OCC.pdf [accessed 14 February 2006].

20. European Medicines Agency. Guideline on risk managementsystems for medicinal products for human use. 14 November2005. Available at: URL: http://www.emea.eu.int/pdfs/human/euleg/9626805en.pdf [accessed 14 February 2006].

21. Epstein M. Guidelines for good pharmacoepidemiology prac-tices (GPP). Pharmacoepidemiol Drug Saf 2005; 14: 589–595.

22. Shakir SAW. PEM in the UK. In Pharmacoepidemiology. MannRD, Andrews EB (eds). John Wiley and Sons Ltd: Chichester,2002; 333–344.

23. Drug Safety Research Unit. Completed studies 2005. Availableat: URL: http://www.dsru.org/completed2002.html [accessed29 July 2005].

24. Quam L, Ellis LBM, Venus P, et al. Using claims data forepidemiologic research: the concordance of claims-basedcriteria with the medical record and patient survey for identify-ing a hypertensive population. Med Care 1993; 31: 498–507.

25. Lanza LL, Dreyer NA, Schultz NJ, et al. Use of insuranceclaims in epidemiologic research: identification of peptic ulcers,GI bleeding, pancreatitis, hepatitis and renal disease. Pharma-coepidemiol Drug Saf 1995; 4: 239–248.



26. The PHARMO Institute. PHARMO database. Available at:URL: http://www.pharmo.nl [accessed 18 July 2005].

27. Downey W, Beck P, McNutt M, et al. Health databases inSaskatchewan. In Pharmacoepidemiology. Strom BL (ed.).3rd edn. John Wiley and Sons Ltd: Chichester, 2000; 325–345.

28. Jick H, Jick SS, Derby LE. Validation of information recordedon general practitioner based computerised data resource in theUnited Kingdom. BMJ 1991; 302: 766–768.

29. Jick SS, Kaye JA, Vasilakis-Scaramozza C, et al. Validity of theGeneral Practice Research Database. Pharmacotherapy 2003;23: 686–689.


30. Hollowell J. General Practice Research Database: scope andquality of data. Office for Population Censuses and Surveys.London, 1994.

31. Weber JCP. Epidemiology of adverse reactions to nonsteroidalantiinflammatory drugs. Adv Inflam Res 1984; 6: 1–7.

32. Wallenstein EJ, Fife D. Temporal patterns of NSAID spon-taneous adverse event reports: the Weber effect revisited. DrugSafety 2001; 24: 233–237.

33. Herings RMC. PHARMO: a record linkage system for post-marketing surveillance of prescription drugs in The Netherlands.PhD thesis 1993. Department of Pharmaco-Epidemiology andTherapy, Utrecht University, Utrecht, The Netherlands.


Documents

Rosuvastatin safety: a comprehensive, international pharmacoepidemiology programme