Tolerability of atorvastatin in a population aged ≥65 years: A retrospective pooled analysis of results from fifty randomized clinical trials

The American Journal of Geriatric Pharrnacotherapy J.H. Hey-Hadavi at al.

Tolerability of Atorvastatin in a Population Aged ___65Years: A Retrospective Pooled Analysis of Results from Fifty Randomized Clinical Trials Judith H. Hey-Hadavi, DDS, MD; Erik Kuntze, MD; Don Luo, PhD; Paul Silverman, PharmD; Donald Pittman, PharmD; and Barbara LePetri, MD Pfizer Human Health, Pfizer Inc., New York New York

ABSTRACT Objective: The aim of this study was to compare the safety profile of atorvastatin calcium at 4 doses with that of placebo in elderly patients (age, >65 years). Methods: A single pooled database (Pfizer Atorvastatin Clinical Program Database) of 50 published and unpublished completed clinical trials was analyzed retrospectively. Tolerability data from male and female study participants aged >65 years at the time of study enrollment were extracted from this database and grouped based on treatment: atorvastatin 10, 20, 40, or 80 m g / d , or placebo. Analyses included comparisons of treatment-related and serious adverse events (AEs) of the musculoskeletal, hepatic, and renal systems. Descriptive statistics were employed. No inferential statistical analyses were performed. Results: A total of 5924 patients were included in the pooled analysis (range of mean age, 71-74 years; white race, 5437 [91.8%]; female sex, 2506 [42.3%]; treatment with atorvastatin 10 m g / d , n = 2042; atorvastatin 20 m g / d , n = 667; atorvastatin 40 m g / d , n = 522; atorvastatin 80 m g / d , n = 1698; and placebo, n = 995). The overall AE profiles appeared similar with all atorvastatin doses and placebo. The proportions of patients experiencing at least 1 treatment-related AE were 16.1%, 10.2%, 11.3%, 15.0%, and 15.3% in the atorvastatin 10-, 20-, 40-, and 80-mg/d, and placebo groups, respectively. The rates of discontinuation due to treatment-associated AEs appeared comparable between all doses of atorvastatin and placebo (2.1% vs 1.7%). Serious AEs were rare (<1.0%) and seldom led to withdrawal. The prevalence of treatment-associated myalgia was low in all treatment groups (<1.8%). None of the patients experienced persistent creatine kinase elevations >10-fold the upper limit of normal (X ULN), and no cases of myopathy or rhabdomyolysis were reported. The rates of patients with persistent elevation (>3 X ULN) of hepatic aminotransfcrases were 0.1%, 0%, 0.2%, 0.5%, and 0.2% in the atorvastatin 10-, 20-, 40-, and 80-mg/d, and placebo groups, respectively. Although the prevalences of alanine aminotransfcrase (ALT) and aspartate aminotransfcrase (AST) elevations appeared slightly higher in the 80-mg/d group (3.2% vs <0.9% in all other groups), specific musculoskeletal and hepatic AEs were rare (<3.0%). Conclusions: This pooled analysis of 50 published and unpublished studies in elderly patients found that the overall prevalences of AEs did not appear to increase with dose and appeared comparable to that observed with placebo. Although the prevalences of ALT/AST elevations appeared slightly higher in the 80-mg/d group (3.2% vs <0.9% in all other groups), specific musculoskeletal and hepatic AEs were rare (<3.0%). The rates of discontinuation appeared comparable between all 4 doses of atorvastatin and placebo. The results of this analysis support the favorable safety profile of atorvastatin across the full dose range in patients aged >65 years. ( A m J Geriatr Pharrnacober. 2006;4: 112-122) Copyright @ 2006 Excerpta Medica, Inc. Key words: atorvastatin, safety, elderly, coronary heart disease. Accepted for publication February 6, 2006. Printed in the USA. Reproduction in whole or part is not permitied.

Iil

June 2006

Volume4 • Number2

doi:l 0. 1016/j.amjopharm.2006.06.00 I 1543 5946/06/$19.00

Copyright© 2006 ExcerptaMedica,Inc.

J.H. Hey-Hadavi et al.

INTRODUCTION O f the 70.1 million US adults with cardiovascular discase (CVD), an estimated 27 million arc elderly (age, _>65 years)} Elderly people arc at high risk for CVD, including stroke. Most new-onset ischcmic heart discase ( I H D ) events and deaths occur in elderly persons, and almost 40% of patients hospitalized for myocardial infarction arc aged _>75 years} The aging of the population will certainly rcsuk in a concomitant increase in the prcvalcnccs of coronary artery disease, congestive heart failure, and stroke. 3 Elevated cholesterol is a major risk factor for IHD. Epidcmiologic evidence has shown that at moderate levels of baseline total cholesterol (TC) (>253 m g / d L ) , the risk for I H D is increased by 2% to 3% with each 1% elevation in plasma TC. 4 Furthermore, an estimated 10% population-wide decrease in TC levels might result in an estimated 30% decrease in I H D prevalence. 5 In elderly men, elevated TC levels have been associated with an increased risk for all-cause- and IHD-rclatcd death. 6,7 Tha latest National Cholesterol Education Program (NCEP) report s stated that the results of recent trials of hydroxymcthylglutaryl cocnzymc A rcductasc inhibitors ("statins") provided a strong justification for intensive low-density lipoprotcin cholesterol (LDL-C)-lowcring therapy in older persons with or without established CVD. 9,1° Despite those recommendations, many (30%-60%) therapy-eligible elderly patients admitted to the hospital for treatment of acute coronary syndromes (ACSs) do not receive evidencebased therapies, such as 13-blockcrs or lipid-lowering therapies, during their hospitalization, n Older individuals with angiographically defined I H D and stcnosis _>70% have bccn reported to bc significantly less likely to receive lipid-lowering therapy compared with younger patients} 2 Tran ct a113 conducted a retrospective chart review of a random sample of 5131 patients hospitalized with acute myocardial infarction and coneluded that the undcrusc of all evidence-based therapies in the elderly might bc associated with a lack of awareness by some physicians of the benefits of these therapies. However, concern regarding adverse events (AEs) and drug interactions might also make physicians reluctant to prescribe statins in older patients. Recent large clinical trials in almost 20,000 patients support the overall tolcrability of atorvastatin calcium during long-term treatment} 4 17 Although previous analyses have assessed clinical tolerability data in a broad range of dyslipidcmic patients, based on a M E D L I N E search for English-language literature concerning statin treatment in the elderly (key terms: elderly, statin use,

The American Journal of Geriatric Pharmacotherapy

safety, coronary heart disease; years: i 9 6 6 - 2 0 0 5 ) , none

has been conducted solely in an older population. In this retrospective pooled analysis of data from 50 completed clinical trials, wc compared the tolcrability profiles of atorvastatin 10, 20, 40, and 80 m g / d , and placebo in individuals aged _>65 years. MATERIALS A N D M E T H O D S Study Designs Data from a single pooled database (Pfizer Atorvastatin Clinical Program Database) of 50 published and unpublished clinical atorvastatin trials that began in 1992 or thereafter and were completed by September 15, 2004, were analyzed. Data were entered into the database as the studies were completed and if at least 1 of the study arms received atorvastatin as active treatment. Tolerability data from the database have been published elsewhere} s,m O f these 50 trials, 44 assessed lipid lowering as the primary efficacy parameter in a variety of patient populations, 3 were surrogate end point trials, 2° 22 and 3 wara clinical and point trials. 2345 In 21 trials, patients were enrolled in an initial 2- to 8-week run-in period in which they received placebo Q D and followed the N C E P Step 1 diet. The run-in period allowed lipid levels to stabilize before the active-treatment phase began. Patients in the trial were randomly assigned to receive active treatment for 2 to 208 weeks (4.3 years) in the various studies. Twenty-six trials had a parallelgroup design in which patients were maintained on the same dose throughout the study. Twenty-four trials had either dose titration or treatment changes, in which patients received a fixed dose of treatment for the first 4 to 16 weeks, after which the dose was increased or treatment was changed from placebo to active treatment or from a single active treatment to combination treatment. The Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) 14 was not included in the current analysis because the parent hypertension study was not completed by September 15, 2004. The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE-IT-TIMI-22) trial 16 was also not included because we did not have access to individual patient data. The Treating to New Target (TNT) study 17 data were not available at the time of this analysis. Data from those 3 studies have been published elsewhere}< 16,17 Pooled Studies Database Pooled data from all 50 trials were maintained in a single database and divided into 5 treatment g r o u p s - atorvastatin 10, 20, 40, and 80 m g / d , and placebo.

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The American Journal of Geriatric Pharmacotherapy J.H. Hey-Hadavi et al.

For the dose-titration studies (24 studies, 2769 patients), patients were assigned to the treatment that they had received for the longest duration, thereby ensuring each patient was allocated to only T group. Patient Populations Study participants were men and women of different ethnic backgrounds with varying degrees of cardiovascular risk. Eligibility criteria in many postmarketing surveillance studies allowed enrollment of patients with established IHD, including patients at high cardiovascular risk. In all studies, except T comparing the effects of atorvastatin with those of usual care, patients were advised to avoid any lipid-lowering medications that were not prescribed by study protocol. At study entry, most patients had LDL-C levels >130 m g / d L and triglyceride levels <600 m g / d L . Tolerability Analysis At each clinic visit, AEs were recorded by the investigators based on symptoms reported by the patient, physical examination findings, and the results of any laboratory tests as indicated by the Good Clinical Practice guidelines56 AEs were recorded throughout the treatment phase and up to 30 days after trial discontinuation and converted to preferred terms and body systems using the fourth edition of the Coding Symbols for Thesaurus of Adverse Reaction TermsS For each patient, a particular AE was counted once; for the titration studies, individual AEs were attributed to the dose of longest treatment duration to avoid double counting. AEs were classified based on their relationship to the study drug (definitely not, unlikely, possibly, probably, or definitely related; or insufficient information) as determined by the investigator. AEs characterized as possibly, probably, or definitely related to the study drug were classified as treatment related. If there was insufficient information, or no relationship was designated on the case-report form, the AE was considered related to the study drug. As previously described, is serious AEs were defined according to US Food and Drug Administration criteria. In 3 trials, 14,16,17 cardiac-related serious AEs were considered as end points and were not summarized in the tolerability results. Laboratory parameters were assessed using fasting (>12 hours) blood samples drawn 6 to 18 hours after study drug administration. The assessments were performed at central laboratories in multicenter trials and local laboratories in single-center trials. The designated laboratory determined the normal ranges for each laboratory parameter. Physical examinations and electro-

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cardiography wcrc pcrformcd at lcast twicc in cach patient (baseline and at the end of the trial). Any rcports of muscular symptoms wcrc rccordcd throughout thc trcatmcnt and follow-up pcriods and assessed using standard clinical measures of functional capacity and muscular strength when considered appropriatc by thc invcstigator. An analysis was pcrformcd to quantify the number of patients with any creatine kinase (CI0 clcvation >3, >5, and >T0-fold thc uppcr limit of normal ( × ULN) and pcrsistcnt CK clcvations (dcfincd as 2 consccutivc valucs >3, >5, or >T0 × ULN). Myopathy was dcfincd as an clcvation in CK >T0 × ULN with associatcd muscular symptoms (cg, gcncralizcd myalgia, fatiguc, wcakncss)5 s,29 Thc incidcncc of clcvations >3 × U L N in thc hcpatic enzymes alaninc aminotransfcrasc (ALT) and aspartatc aminotransfcrasc (AST) wcrc asscsscd. Pcrsistcnt clcvations in ALT or AST >3 × ULN wcrc charactcrizcd as 2 consccutivc valucs >3 × ULN within a T4-day pcriod. Thcsc convcntions arc consistcnt with thc clinical advisory on thc usc and safety of statins issucd by thc Amcrican Collcgc of Cardiology; thc Amcrican Hcart Association; and thc National Hcart, Lung, and Blood Institutc ( A C C / A H A / N H L B I ) . 3° Renal AEs and tolcrability paramctcrs, including hcmaturia and albuminuria (defined as albuminuria, microalbuminuria, or protcinuria), wcrc rccordcd for thc rcnal tolcrability analysis. Frcqucncy of usc of clinically important concomitant mcdications, such as warfarin, amiodaronc, vcrapamil, and clopidogrcl, was analyzcd to idcntify potcntial drug intcractions.

Statistical Analyses Dcscriptivc statistics arc prcscntcd. No infcrcntial statistical analyscs wcrc pcrformcd. For thc rcporting of laboratory tolcrability paramctcrs, thc total numbcr of cldcrly paticnts with at lcast T mcasurcmcnt of thc givcn laboratory tcst on study trcatmcnt or during thc lag timc of 30 days was uscd as thc dcnominator, and thc number of subjects with notable laboratory abnormalitics (cg, CK >T0 × ULN or ALT/AST >3 × ULN) was uscd as thc numcrator to calculatc thc abnormality ratc. RESULTS Patient Characteristics and Treatment Exposure Within the pooled database of 50 published and unpublished completed clinical trials, a total of 5924 patients aged >65 years at the time of study enrollment were identified and included in the pooled analysis. The most commonly used atorvastatin doses were T0 and 80 m g / d (T0, 20, 40, and 80 m g / d , and placebo,

J.H. Hey-Hadavi et d.

2042, 667, 522, i698, and 995 patients, respectively). The total drug exposures were 1747, 702,617, 1275, and 429 patient-years for atorvastatin 10, 20, 40, and 80 mg/d, and placebo, respectively. Patients received treatment for various lengths of time. The proportions of patients receiving treatment for >12 weeks appeared similar (1241/2042 [60.8%] to 1166/1698 [68.7%] in the atorvastatin 10- to 80-mg groups vs 814/995 [81.8%] in the placebo group). Of patients receiving atorvastatin 10, 20, 40, and 80 mg/d, and placebo, 951 (46.6%), 131 (19.6%), 115 (22.0%), 318 (18.7%), and 71 (7.1%), respectively, received treatment for >1 year. The demographic and baseline clinical characteristics of the patients are shown in Table I. The mean age of the patients ranged from 71 to 74 years across

The American Journal of Geriatric Pharmacotherapy

groups, and 5437 (91.8%) were white; 1598 (27.0%) were >75 years of age, 2506 (42.3%) were female, 3697 (62.4%) had hypertension, 1342 (22.7%) had diabetes, and 3738 (63.1%) had known CVD. The frequency of use of clinically important concomitant medications were digoxin, 559 (9.4%); warfarin, 397 (6.7%); verapamil, 223 (3.8%); clopidogrel, 146 (2.5%); and amiodarone, 74 (1.2%). Tolerability

The AE profiles of all 4 atorvastatin doses and placebo are shown in Table II. The proportions of elderly patients experiencing at least 1 treatmentrelated AE were 329 (16.1%), 68 (10.2%), 59 (11.3%), 255 (15.0%), and 152 (15.3%) in the atorvastatin 10-,

Table I. Demographic and baseline clinical characteristics of the study patients (N = 5924). Atorvastatin Dose 10 mg/d (n 2042)

20 mg/d (n 667)

40 mg/d (n 522)

80 mg/d (n 1698)

Placebo (n 995)

Mean (BE), y

71 (0, I)

71 (0,2)

71 (0,2)

72 (0, I)

74 (0,2)

Median, y Range, y >75 y, no, (%)

70

70

72

73

65 85

65 93

65 94

431 (21,1)

71 65 81 119 (17,8)

103 (19,7)

525 (30,9)

420 (42,2)

Sex, no, (%) Male Female

1076 (52,7) 966 (47,3)

369 (55,3) 298 (44,7)

326 (62,5) 196 (37,5)

1041 (61,3) 657 (38,7)

606 (60,9) 389 (39, I)

Race,* no, (%) White Black Asian Other

1895 84 26 37

608 40 4 15

482 29 4 7

1566 47 21 64

886 29 20 60

BMI, mean (SE), kg/m 2

27,6 (0, I)

28,4 (0,2)

28, I (0,2)

27,5 (0, I)

27,0 (0,2)

Plasma lipid levels, mean (SE), mg/dL LDbC TC HDL C TC Non H D b C / H D L C ratio, mean (SE)

168 254 49 189 4,5

176 262 47 200 4,9

174 258 47 193 4,8

148 230 47 179 4,2

126 207 47 172 3,7

Medical history, no, (%) Diabetes Hypertension CVD

384 (18,8) II 88 (58,2) 1021 (50,0)

Characteristic Age

65 89

(92,8) (4, I) (I,3) (I,8)

(0,8) (0,9) (0,3) (2,0) (0,0)

BMI body mass index; LDC C low density lipopr~otein cholesterol;TC CVD cardiovasculardisease. *Percentages might not total 100% due to rounding.

(91,2) (6,0) (0,6) (2,2)

(I,3) (I,6) (0,5) (3,8) (0, I)

140 (21,0) 417 (62,5) 416 (62,4)

(92,3) (5,6) (0,8) (I ,3)

(I,7) (2,1) (0,6) (4,2) (0, I)

98 (18,8) 316 (60,5) 352 (67,4)

total cholesterol; HDbC

(92,2) (2,8) (I,2) (3,8)

(I,2) (I,4) (0,3) (2,2) (0,0)

417 (24,6) I I I I (65,4) 1205 (71,0)

high density lipoprotein cholesterol;TG

(89,0) (2,9) (2,0) (6,0)

(I,I) (I,3) (0,4) (2,8) (0,0)

303 (30,5) 665 (66,8) 744 (74,8)

triglycerides;

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J.H. Hey-Hadavi et al.

20-, 40-, and 8 0 - m g / d , and placebo groups, respectively. The rates of withdrawals due to treatmentrelated AEs were 76 (8.7%), 8 (0.4%), 11 (2.1%), 88 (1.9%), and 17 (1.7%) in the atorvastatin 10-, 20-, 40-, and 8 0 - m g / d , and placebo groups, respectively. The prevalence of death was low (_<0.6%) in each of the treatment groups. None of the deaths were considered to be treatment related. Incidences of all-cause and treatment-rdated nonfatal serious AEs appeared comparable between all 4 atorvastatin groups. The

most common treatment-related serious AEs by body system were associated with the digestive system with each of the atorvastatin doses (_<0.6% for all groups) and with the body as a whole in the placebo group (27 [2.7%]). The most common AEs were related to the digestive system (143 [7.0%], 29 [4.3%], 29 [5.6%], 127 [7.5%], and 40 [4.0%] patients receiving atorvastatin 10, 20, 40, and 80 m g / d , and placebo, respectively) (Table III). Tile use of concomitant medication was not associated with specific AEs.

Table II. Prevalence of adverse events (AEs) in elderly (age, >65 years) patients receiving atorvastatin or placebo.Values are no. (%) of patients. Atorvastatin Dose

Parameter

10 mg/d (n 2042)

20 mg/d (n 667)

40 mg/d (n 522)

Patients with _>1 AE All cause Treatment related

1229 (60,2) 329 (I 6, I)

370 (55,5) 68 (10,2)

221 (42,3) 59 (11,3)

823 (48,5) 255 (15,0)

392 (39,4) 152 (I 5,3)

Withdrawals due to AEs All cause Treatment related

II 7 (5,7) 76 (3,7)

10 (I,5) 3 (0,4)

15 (2,9) II (2, I)

55 (3,2) 33 (I,9)

30 (3,0) 17 (I,7)

Serious, nonfatal AEs All cause Treatment related

225 (I 1,0) 7 (0,3)

69 (10,3) 0

34 (6,5) 0

167 (9,8) 17 (I,0)

87 (8,7) 67 (6,7)

13 (0,6)

3 (0,4)

I (0,2)

9 (05)

2 (0,2)

Deaths

80 mg/d (n 1698)

Placebo (n 995)

Table III. Prevalence of treatment-related adverse events, by body system, in elderly (age, >65 years) patients receiving atorvastatin or placebo.Values are no. (%) of patients. Atorvastatin Dose

System

Digestive Body as a whole Musculoskeletal Skin/appendages Nervous Cardiovascular Metabolic/nutritional Urogenital Special senses

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10 mg/d 2042)

20 mg/d (n 667)

40 mg/d (n 522)

80 mg/d (n 1698)

Placebo (n 995)

143 (7,0) 105 (5,1) 55 (2,7) 39 (I,9) 36 (I,8) 25 (I,2) 25 (I,2) 15 (0,7) 12 (0,6)

29 (4,3) 13 (I,9) 16 (2,4) 9 (I,3) 8 (I,2) 3 (0,4) 4 (0,6) 2 (0,3) 2 (0,3)

29 (5,6) 10 (I,9) 16 (3, I ) 5 (I,0) 6 (I,I) 3 (0,6) 6 (I, I ) 3 (0,6) I (0,2)

127 (7,5) 81 (4,8) 16 (0,9) 15 (0,9) 27 (I,6) II (0,6) 30 (I,8) 7 (0,4) 7 (0,4)

40 (4,0) 59 (5,9) 13 (I,3) I 0 (I,0) 19 (I,9) 8 (0,8) I 0 (I,0) I I (I, I) 2 (0,2)

(n

J.H. Hey-Hadavi et al.

The American Journal of Geriatric Pharmacotherapy

atorvastatin 10- and 2 0 - m g / d and placebo groups, respectively, compared with 7 (0.5%) patients receiving atorvastatin 80 m g / d . Specific serious hepatobiliary AEs were rare in all 5 groups. Cholecystitis and cholelithiasis were reported as serious AEs in 7 (0.3%) and 6 (0.3%) patients, respectively, in the atorvastatin 1 0 - m g / d group, and 5 (0.3%) and 2 (0.1%) patients, respectively, in the atorvastatin 8 0 - m g / d group. Hepatitis B was reported in 1 (0.1%) atorvastatin 80-mg/d-treated patient, and unspecified hepatitis was reported in 3 (0.2%) atorvastatin 80-mg/d-treated patients. In all 3 patients with hepatitis, the condition was considered by the investigator to be treatment related. The onset of symptoms occurred, on average, at 4 weeks (range, 1-8 weeks) after treatment initiation. All cases of hepatitis resolved within 4 weeks after discontinuation of atorvastatin. Other, less frequent serious hepatic AEs were abnormal liver function test results (reported in 1 [0.1%] and 4 [0.2%] patients treated with atorvastatin 10 and 80 m g / d , respectively) and cholestatic jaundice (reported in 1 [0.1%] atorvastatin 80-mg/d-treated patient).

Musculoskeletal Adverse Events

The most common all-cause or treatment-related musculoskeletal AE was myalgia. The prevalence of myalgia was low (all cause, _<3.0%; treatment related, _<1.8%) in patients receiving atorvastatin (Figure). Myalgia was recorded as a serious AE in 3 (0.2%) patients treated with atorvastatin 80 m g / d and 1 (0.1%) patient receiving placebo. In the atorvastatin-treated patients, myalgia was considered by the investigators to be unrelated or probably unrelated to study medication. None of these patients had myopathy. Elevations in CK >10 × U L N were rare, and were not restricted to any specific time frame after treatment initiation. Two (0.1%) patients receiving atorvastatin 10 m g / d , 1 (0.2%) patient receiving atorvastatin 20 m g / d , and 1 (0.1%) patient receiving atorvastatin 80 m g / d experienced elevations in CK >10 × U L N (Table IV). None of these elevations were accompanied by muscular symptoms. None of the patients in the atorvastatin or placebo group experienced persistent CK elevations >10 × ULN. No cases ofmyopathy or rhabdomyolysis were observed in any of the elderly patients receiving atorvastatin or placebo.

Renal Adverse Events

Hematuria was rare (<0.6%) in all 5 study groups, and was reported as a serious AE in 1 (0.1%) patient each in the atorvastatin 8 0 - m g / d and placebo groups. In both cases, hematuria was considered by the investigators as related to treatment. Albuminuria was reported as a nonserious AE in 1 (0.2%) patient receiving atorvastatin 40 m g / d , and 1 (0.1%) patient receiv-

Hepatic Adverse Events

The prevalences of any A L T / A S T elevations >3 × U L N were 14 (0.7%), 5 (0.8%), 9 (1.7%), 50 (3.2%), and 8 (0.9%) in the atorvastatin 10-, 20-, 40-, and 80-mg/d, and placebo groups, respectively (Table IV). Persistent elevations in A L T / A S T >3 × U L N occurred in 3 (0.1%), 0%, and 2 (0.2%) patients in the

• All cause F1 Treatment related

2

0

(n = 2042)

(n = 667)

(n = 5~22)

(n = 16~98)*

(n = 995)t

Ato rvastatin Dose

Figure. Prevalence of myalgia in elderly (age, >65 years) patients receiving atorvastatin or placebo. *Three (0.2%) cases were considered serious; I (0.1%) case was considered serious.

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The American Journal of Geriatric Pharmacotherapy J.H. Hey-Hadavi et al.

Table IV. Prevalence of adverse events (AEs) related to the musculoskeletal and hepatic systems in elderly (age,_>65 years) patients receiving atorvastatin or placebo. Values are no. (%) of patients unless otherwise specified. Atorvastatin Dose AE CK No, of patients < CK >3 X ULN Persistent Any CK >5 X ULN Persistent Any C K > I 0 X ULN Persistent Any

I0 mg/d

20 mg/d

40 mg/d

80 mg/d

Placebo

1936

651

509

832

146

0 15 (0,8)

0 7 (I, I)

1(0,2) 6 (I ,2)

0 I 0 (I ,2)

0 I (0,7)

0 8 (0,4)

0 3 (0,5)

1(0,2) 3 (0,6)

0 4 (0,5)

0 0

0 2 (0,1)

0 I (0,2)

0 0

0 I (0, I)

0 0

2004

664

520

1555

865

3 (0,1) 14 (0,7)

0 5 (0,8)

I (0,2) 9 (I ,7)

7 (0,5) 50 (3,2)

2 (0,2) 8 (0,9)

ALT/AST

No. of patients~ ALT/AST>3 X ULN Persistent Any

CK creatineI
alanineaminotransferase;AST aspactateaminotransferase.

ing atorvastatin 80 m g / d . Neither case of albuminuria was considered treatment related. DISCUSSION Recently completed trials comparing the effects of the 80-mg dose of atorvastatin with those of moderate doses of other statins have supported the clinical benefit and tolerability of atorvastatin at the highest dose.16,20,21,31 37 The present analysis, based on pooled data from 50 published and unpublished completed clinical trials conducted between 1992 and 2004 and including 5924 patients aged _>65 years, found that the AE profile ofatorvastatin across all doses appeared comparable to that of placebo. These observations are consistent with results from previous analyses of the tolerability of atorvastatin in clinical trial populations, is,19 Bakker-Arkema et a119 analyzed the tolerability of atorvastatin in reducing L D L - C levels to <80 m g / d L and found that reducing L D L - C to these levels did not alter the atorvastatin safety profile. Another analysis of a pooled database of 44 clinical trials of atorvastatin found that the overall incidence of treatment-associated AEs did not increase in the 10- to 80-mg dose range and was similar to that of placebo. Is

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In this analysis, no important interactions were noted in patients receiving concomitant medications (eg, digoxin [9.4%], warfarin [6.7%], verapamil [3.8%], clopidogrel [2.5%], and amiodarone [1.2%]). These findings are consistent with previous data 32 35 and further support the safety profile of atorvastafin used concomitantly with these agents. Atorvastatin was found to have no consistent effect on the anticoagulant activity of warfarin and adjustments in warfarin should not be necessary. 32 Concomitant use of atorvastatin and verapamil or amiodarone did not show an increased rate of hepatic or muscular AEs. 33,34 Serebruany et a135 found that atorvastafin did not affect the platelet inhibition of dopidogrd. The proportions of patients experiencing at least 1 treatment-related AE appeared similar between all 4 atorvastatin groups and the placebo group. In general, atorvastatin was well tolerated across all doses, with the most common AEs related to the digestive system (<7.5% in each group). The inddences of myalgia and CK elevations >10 X U L N also appeared comparable across all 4 atorvastafin dose groups (<3.0% and <0.1%, respectively). No cases of elevation in CK >10 X U L N were accompanied by muscular symptoms. There were no reported cases of rhabdomyolysis in these 50 clinical trials.

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Some clinical trials of other statins have shown a direct relationship between the dose of statin used and the incidence of myopathy a n d / o r rhabdomyolysis.36,37 Based on the prescribing information for simvastatin, 38 the prevalences of myopathy in clinical trials of simvastatin were -0.02% with the 2 0 - m g / d dose and 0.07% with the 4 0 - m g / d dose. Those studies also found that with simvastatin, the prevalence of myopathy increased substantially, to -0.3%, when used at the 8 0 - m g / d dose. The randomized, double-blind A to Z trial 37 compared the effects of an early intensive versus a delayed conservative simvastatin strategy in 4497 patients with ACSs in 41 countries. Despite the exclusion of patients with significant risk factors for myopathy in the A to Z trial, there were 9 cases of treatment-related myopathy (CK >10 × ULN plus muscular symptoms) reported in 2265 patients treated with simvastatin 80 mg and 1 case in the placebo-plus-simvastatin group. The conditions of 3 of the 9 patients met the definition of rhabdomyolysis. Rhabdomyolysis is considered an important serious AE associated with the use of statins. In this analysis of atorvastatin data, no cases of rhabdomyolysis were found. Risk factors such as advanced age, small body frame, multisystem disease, perioperative periods, and alcohol abuse increase the risk for myopathy.3° In the current analysis, all patients were aged _>65 years, and ages ranged up to 94 years. Despite the increased risk that might be associated with advancing age, no cases of rhabdomyolysis were reported. The tolerability data reported in this pooled analysis were consistent with those from 3 other atorvastatin trials not included in our database. 14,16,17 The multicenter, randomized, double-blind ASCOT-LLA trial 14 (10,305 patients; mean [SD] age, 63.1 [8.5] years; 63.6% patients >60 years) reported that the safety profile (serious AEs and rate of abnormal liver enzyme levels) of atorvastatin 10 m g / d was comparable to that of placebo. In that study, there was 1 case of rhabdomyolysis, in a male patient randomly assigned to receive atorvastatin 10 m g / d . However, that patient had significant risk factors for myopathy, including high alcohol intake and a recent febrile illness. The randomized, double-blind, double-dummy PROVE-IT-TIMI-22 study16 compared the effects of intensive LDL-C lowering with atorvastatin 80 m g / d with those of moderate LDL-C lowering with pravastatin 40 m g / d on the rate of death or major cardiovascular events in 4162 patients with ACSs. AE data from PROVE-IT-TIMI-22 (mean [SD] age, 58.1 [11.2] years), in which no cases of myopathy or rhabdomyolysis were reported, further support the musculoskeletal safety of

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the 8 0 - m g / d dose of atorvastatin. A recent additional tolerability analysis 39 of the PROVE-IT-TIMI-22 trial showed that the aggressive lowering of LDL-G levels to as low as 40 m g / d L with atorvastatin 80 m g / d was not assodated with any increase in adverse clinical outcomes. The recently published randomized, double-blind TNT trial 17 (10,001 patients) compared the effects of atorvastatin 10 m g / d (mean [SD] age, 60.9 [8.8] years) with those ofatorvastatin 80 m g / d (mean [SD] age, 61.2 [8.8] years) on the prevalences of major cardiovascular events in patients with stable IHD. In the TNT trial, 38% of the patients studied were aged _>65 years. AEs related to treatment occurred in 289 (5.8%) patients receiving atorvastatin 10 mg versus 406 (8.1%) patients receiving atorvastatin 80 mg (P < 0.001). Rates of discontinuation due to treatment-related AEs were 5.3% and 7.2%, respectively (P < 0.001). A total of 234 (4.7%) patients in the atorvastatin 10-mg/d group reported treatmentrelated myalgia compared with 241 (4.8%) patients in the atorvastatin 80-mg/d group; this difference was not statistically significant. In the TNT study, 5 cases of rhabdomyolysis were reported (3 in the atorvastatin 10-mg/d group; 2 in the atorvastatin 8 0 - m g / d group). After review, none of these 5 cases identified by the investigators providing care for the patients were believed to be related to atorvastatin, nor did they meet the criteria of the A C C / A H A / N H L B I 3° for rhabdomyolysis (CK level >10 × ULN plus muscular symptoms plus elevated crcatininc or urinary abnormalities [cg, myoglobinuria]). Asymptomatic elevations in A L T / A S T >3 × U L N have been observed in patients receiving statin treatment. 4° Although such increases are rarely accompanied by hepatic AEs, it is recommended in the prescribing information of statins that hepatic aminotransferase levels be measured periodically in patients receiving statin therapy, and that the dose of statin be reduced, or therapy discontinued, if the elevations in A L T / A S T persist. 4° Based on the prescribing information of atorvastatin, 4° in clinical trials, the prevalences of persistent A L T / A S T elevations >3 × U L N wcrc reported as 0.2%, 0.2%, 0.6%, and 2.3% in patients receiving the 10-, 20-, 40-, and 8 0 - m g / d doses, respectively. In the current pooled analysis, a greater incidence of persistent A L T / A S T elevations >3 × ULN was observed in the 8 0 - m g / d group (0.5%) compared with those with the other 3 atorvastatin doses and placebo (_<0.2%). However, serious hepatic AEs were rare (_<0.3%), and of the 3 (0.2%) patients in the 8 0 - m g / d group in whom unspecified hepatitis developed, all cases resolved within 4 weeks after discontinuation of atorvastatin.

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We also examined the AEs hematuria and albuminuria, which can be considered predictors of increased mortality in the elderly.41 Recent guidelines from the National Kidney Foundation 42 recommended that all patients with chronic kidney disease be assessed and considered for lipid-lowering therapy. This pooled analysis did not show a dose-related increase in the prevalence of hematutia or albuminutia with atorvastatin. The prevalences of these AEs with each atorvastatin dose were low (albuminutia, <0.2%; hematuria, <0.6%) and similar to that in the placebo group (0% and 0.2%, respectively). Renal disease has not been found to influence the plasma concentration or LDL-C reduction achieved with atorvastatin. 4° Thus, dose adjustment in patients with renal dysfunction is not necessary. 4° Although there was an apparently higher prevalence of A L T / A S T elevations in the 8 0 - m g / d group (3.2% vs <0.9% in all other groups), in this analysis, the overall tolerability profiles of atorvastatin 10, 20, 40, and 80 m g / d were comparable to that of placebo. Consistent findings related to the AE profiles of atorvastatin 10 and 80 m g / d have been observed in large-scale atorvastatin trials. M,14 17 Those trials support the safety profile of atorvastatin in various risk cohorts, including patients with hypertension a n d / o r type 2 diabetes. Various reports of other statins have raised the question of whether high-dose statin therapy is associated with higher prevalences of AEs. No such evidence was found in the present pooled data analysis comparing atorvastatin 10, 20, 40, and 80 m g / d , and placebo. This tolerability analysis had several limitations. In the 24 trials with dose titration or treatment changes (2769 patients), some AEs were recorded as occurring at the dose that the patient received the longest rather than the dose at which the AE actually occurred. Inferential statistics were not used because the prcvalences were low and the study was not powered to detect statistical differences (ie, significant differences could have occurred by chance). Therefore, we chose to present the raw rates of AEs to allow health care providers to assess benefits versus risks. Because this was an analysis of pooled data from 50 clinical studies, the total exposure times of the different atorvastatin doses were disparate. However, all groups had adequate representation, with the highest exposures found in the atorvastatin 10- and 8 0 - m g / d groups (1747 and 1275 patient-years, respectively). CONCLUSIONS

This pooled analysis of 50 published and unpublished studies in elderly (age, >65 years) patients found that the overall prevalences of AEs did not appear to

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increase with dose and appeared comparable to that observed with placebo. Although the prevalences of A L T / A S T elevations appeared slightly higher in the 8 0 - m g / d group (3.2% vs <0.9% in all other groups), specific musculoskeletal and hepatic AEs were rare (<3.0%). The rates of discontinuation appeared comparable between all 4 doses of atorvastatin and placebo. The results of this analysis support the favorable safety profile of atorvastatin across the full dose range in these patients aged >65 years. REFERENCES

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A d d r e s s c o r r e s p o n d e n c e to: Judith H. Hcy-Hadavi, D D S , M D , Pfizer H u m a n Health, Pfizer Inc., 235 East 4 2 n d Street, N e w York, NY 10017. E-mail: [email protected]

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