Clinical Investigation and Reports
`
`Safety and Tolerability of Pravastatin in Long-Term
`Clinical Trials
`Prospective Pravastatin Pooling (PPP) Project
`
`Marc A. Pfeffer, MD, PhD; Anthony Keech, MD; Frank M. Sacks, MD; Stuart M. Cobbe, MD;
`Andrew Tonkin, MD; Robert P. Byington, PhD; Barry R. Davis, MD, PhD;
`Carola P. Friedman, MD; Eugene Braunwald, MD
`
`Background—Therapeutic decisions regarding pharmacological therapy should be based on safety and tolerability as well
`as efficacy data. Clinical trials designed to assess efficacy are often insufficiently powered to generate reliable safety
`data.
`Methods and Results—The West of Scotland Coronary Prevention Study (WOSCOPS), the Cholesterol and Recurrent
`Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies collectively
`accumulated ⬎112 000 person-years of exposure in double-blind randomized trials comparing placebo and pravastatin
`(40 mg once daily). During 5 years of exposure, the incidence of fatal and nonfatal cancers was similar between
`pravastatin and placebo groups. No differences in noncardiovascular serious adverse events were detected. With
`⬎243 000 blood sample analyses, the percentage of patients with any abnormal liver function test after baseline
`sampling was similar (⬎3⫻ the upper limit of normal for alanine aminotransferase: 128 [1.4%] versus 131 [1.4%]
`patients for pravastatin versus placebo, respectively). Study medication was withdrawn in 3 pravastatin and 7 placebo
`patients due to creatine phosphokinase elevations; no cases of mild or severe myopathy were reported. A Cox regression
`model considering treatment group, age, diabetes, smoking, whether primary or secondary prevention study, and
`cardiovascular serious adverse events indicates that the likelihood of discontinuing pravastatin was less than placebo.
`Conclusions—This prospective analysis indicates that during prolonged exposure, 40 mg of pravastatin is well tolerated,
`with no excess of noncardiovascular serious adverse events, including liver function abnormalities and laboratory and
`clinical evidence for myositis. These extensive safety and tolerability data provide important information for therapeutic
`decisions regarding this pharmacological agent. (Circulation. 2002;105:2341-2346.)
`
`Key Words: statins 䡲 pravastatin 䡲 safety 䡲 rhabdomyolysis 䡲 myositis
`
`Reductions in the prevalence and severity of cardiovascu-
`
`lar risk factors have been prominent contributors toward
`the decline in cardiovascular morbidity and mortality ob-
`served in the last several decades.1,2 Favorable lifestyle
`modifications such as avoidance of smoking, weight reduc-
`tion, dietary modifications, and increasing physical activity
`are based on sound epidemiological data and raise no safety
`concerns. However, a strategy that uses long-term pharma-
`cological therapy for cholesterol lowering as well as for other
`risk factors, such as hypertension, should be based on
`definitive data concerning efficacy and the safety and toler-
`ability of the therapy to derive a rational risk-benefit assess-
`
`ment. In many respects, safety and tolerability are as impor-
`tant as efficacy in defining the clinical thresholds to initiate
`long-term pharmacological therapy to modify a risk factor.
`Large scale, well-conducted, placebo-controlled, random-
`ized clinical trials have established conclusive evidence that
`the long-term use of certain 3-hydroxy-3-methylglutaryl co-
`enzyme A reductase inhibitors (statins) results in important
`reductions in the risk of experiencing major cardiovascular
`events in patients with a wide range of lipid levels, both3
`with4 – 6 and without7,8 a history of heart disease. These major
`clinical trials were designed with sufficient statistical power
`to detect the efficacy of the particular statin in reducing
`
`Received February 26, 2002; revision received March 27, 2002; accepted March 27, 2002.
`From the Brigham and Women’s Hospital, Boston, Mass (M.A.P, F.M.S, E.B.); University of Sydney, Camperdown, Australia (A.K.); University of
`Glasgow, Glasgow, UK (S.M.C.); National Heart Foundation of Australia, Victoria, Australia (A.T.); Section of Epidemiology, Wake Forest University,
`Winston-Salem, NC (R.P.B.); University of Texas Health Science Center at Houston (B.R.D.); and Bristol-Myers Squibb Company, Hillside, NJ (C.P.F.).
`This article originally appeared Online on April 22, 2002 (Circulation. 2002;105:r95–r100).
`Dr Pfeffer has received honoraria and other financial support from AstraZeneca, Aventis, Bristol-Myers Squibb, Novartis, and Pfizer. Dr Sacks receives
`research support from Bristol-Myers Squibb and consults for or has received honoraria from Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb,
`KOS, Fournier, and Sankyo.
`Correspondence to Dr Marc Pfeffer, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail
`mpfeffer@rics.bwh.harvard.edu
`© 2002 American Heart Association, Inc.
`Circulation is available at http://www.circulationaha.org
`
`DOI: 10.1161/01.CIR.0000017634.00171.24
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`
`individually,
`predefined cardiovascular events. However,
`these studies generally do not provide sufficient exposure to
`uncover relatively uncommon safety issues. Indeed, before
`these studies, the safety of earlier pharmacological strategies
`to lower cholesterol had been questioned9 when nonsignifi-
`cant increases in noncardiovascular deaths were reported with
`cholestyramine and gemfibrozil therapy in some studies.10,11
`Rodent toxicity data raised questions concerning the possible
`carcinogenesis of lipid-lowering agents.12 Because statins
`inhibit a major liver enzyme, hepatic safety has been an
`ongoing concern. Marked elevations in plasma levels of
`certain statins metabolized by C4P3A4 have been experi-
`enced with coadministration of other agents that inhibit this
`pathway.13 Indeed, reports of rhabdomyolysis with the coad-
`ministration of mibefradil and statins sharing this metabolic
`pathway led to the withdrawal of this antihypertensive agent.
`The recent worldwide withdrawal of cerivastatin as a conse-
`quence of postmarketing reports of a relatively high rate of
`fatal rhabdomyolysis has appropriately heightened concerns
`about the use of statins.14
`The investigators from the West Of Scotland Coronary
`Prevention Study (WOSCOPS), the Cholesterol And Recur-
`rent Events (CARE) study, and the Long-term Intervention
`with Pravastatin in Ischemic Disease (LIPID) study formed
`the Prospective Pravastatin Pooling (PPP) project to combine
`the cumulative experience of their 3 major long-term, large,
`placebo-controlled trials of a single dose of pravastatin.15 The
`objective was to prospectively and cooperatively pool data to
`derive more precise quantitative estimates of the efficacy of
`pravastatin in predefined subgroups,16 for less common
`events such as stroke,17 and to evaluate potential safety
`these 3 studies amassed ⬎112 000
`issues.15 Collectively,
`person-years of experience comparing pravastatin (40 mg
`once daily) with placebo in a rigorous double-blind manner.
`This report describes the tolerability and safety analyses of
`the PPP project.
`
`Methods
`The protocol for the PPP collaboration has been described previous-
`ly,15 as have the major subgroup,16 stroke analyses,17 and mortality
`data.18 The individual data sets from these 3 large double-blind trials
`were combined for statistical analysis. Previous PPP analyses were
`based on the intent-to-treat principle, including all 19 768 patients
`randomized into any of the 3 trials. This prespecified safety analysis
`includes the 19 592 patients who received at least one dose of
`blinded study medication (n⫽9809 for pravastatin; n⫽9783 for
`placebo) and excludes 176 patients (⬍1%) who were not exposed to
`study medication. The duration of exposure to study drug was
`calculated from the day of the first dose to the last day taken, without
`adjustments for temporary treatment interruptions.
`
`Safety Analysis
`Safety was evaluated by multiple analyses using the frequency of all
`reported fatal and nonfatal serious adverse events. A serious adverse
`event was defined as an adverse event that was fatal, immediately
`life-threatening, permanently disabling, a congenital anomaly, can-
`cer, an overdose, or that required overnight or prolonged hospital-
`ization. Fatal events, whether cardiovascular or noncardiovascular,
`were previously described for the PPP cohort.15 To analyze cancers,
`the incidence of primary malignancies reported during and within 30
`days after study completion was compared.
`Prestudy concerns regarding the potential of statins to induce
`abnormalities of liver function or musculoskeletal adverse events led
`
`to the incorporation of protocol-directed laboratory evaluations of
`alanine aminotransferase (ALT) and creatine phosphokinase (CPK)
`in all 3 studies. Central laboratories were used for WOSCOPS and
`CARE, but
`the LIPID study used local
`laboratory evaluations.
`During the first year, all 3 studies measured ALT at baseline and at
`the 3, 6, 9, and 12-month visits. In WOSCOPS and LIPID, liver
`function was then tested biannually and in CARE annually. From
`18 637 participants, a total of 243 506 samples were analyzed for
`ALT, representing a mean of 13 evaluations per patient. An ALT
`abnormality was defined as any postrandomization value (regardless
`of baseline) that exceeded 1.5⫻ the upper limit of normal (ULN),
`and the incidence of postbaseline abnormalities is expressed as the
`total number of subjects with at
`least one abnormality in that
`measurement on any postrandomization sample. Aspartate amino-
`transferase was also analyzed in a similar fashion to ALT; however,
`it was not routinely obtained in the LIPID study. Concomitant
`measures of CPK were performed except in LIPID, in which CPK
`measurements were obtained annually. Because normal ranges for
`CPK were not specified in the local laboratories in the LIPID study,
`these data are presented for CARE and WOSCOPS only. Prespeci-
`fied analyses were also performed to examine the severity of
`abnormalities (ⱖ1.5⬍3⫻ULN, ⱖ3⬍5⫻ULN, ⱖ5⬍7⫻ULN,
`ⱖ7⬍9⫻ULN, and ⱖ9⫻ULN). Frequency of events or incidence of
`abnormalities between the pravastatin and placebo-treated groups
`were compared.
`
`Tolerability
`The number of patients who permanently discontinued their study
`medication for any reason was ascertained. Tolerability was ex-
`pressed as a percent of exposed patients remaining on their assigned
`study medication. Patients who completed the study on blinded
`medication or who died within 7 days of a dose of study medication
`were considered tolerant of medication. Adverse events leading to
`discontinuation were classified by body systems and by cardiovas-
`cular and noncardiovascular causes. Because pravastatin use had a
`major impact in reducing the risk of experiencing a cardiovascular
`event, a separate exploratory analysis of tolerability was conducted
`in a subgroup defined as having or not having experienced a
`cardiovascular event after randomization.
`
`Statistical Analysis
`Cancer incidence and laboratory abnormality occurrence differences
`were calculated with associated probability values and 95% confi-
`dence intervals using either ␹2 or Fisher’s exact tests. The time to
`discontinuation of study medication was analyzed using a Cox
`proportional hazards model with baseline terms for treatment group
`(pravastatin or placebo), sex, primary (WOSCOPS) or secondary
`(CARE and LIPID) prevention study, history of diabetes, smoking
`status, and treatment by primary or secondary prevention study
`interaction, as well as the presence of a serious cardiovascular event
`after randomization. Hazards ratios for risk of discontinuation of
`study medication and 95% confidence intervals are presented.
`
`Results
`Demographics and baseline characteristics of the 19 592
`patients in the safety analysis of the PPP were very similar to
`those previously reported in the overall PPP cohort.16 Of the
`19 592 patients, 13 173 were enrolled in either CARE or
`LIPID (secondary prevention studies) and 6419 patients were
`enrolled in WOSCOPS (primary prevention study). The
`median age of the overall population was 59 years, with a
`maximum of 75 years at the time of study drug initiation.
`Approximately 25% of the population was ⱖ65 years at
`randomization. The overall population was 89% male and
`11% female (WOSCOPS was confined to men). The mean
`exposure to study medication was ⬎4.5 years, with a median
`of 5 years and a maximum duration of 7.1 years (Table 1).
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`TABLE 1.
`
`Total Extent of Exposure to Study Medication
`
`TABLE 2. Primary Cancer: Incidence by Body System
`
`Pfeffer et al
`
`Long-Term Safety of Pravastatin
`
`2343
`
`40 mg of
`Pravastatin
`(n⫽9809)
`
`Placebo
`(n⫽9783)
`
`Body System
`
`Total number of subjects with at
`least one primary cancer adverse
`event†
`Dermatological
`Endocrine‡/metabolic/electrolyte
`imbalance
`Gastrointestinal
`General
`Hematopoietic
`Hepatic/biliary
`Musculoskeletal/connective tissue
`Nervous system
`Renal/genitourinary
`Respiratory
`Special senses
`
`Treatment Group
`
`Pravastatin,
`n (%)
`
`Placebo,
`n (%)
`
`946 (9.6)
`
`914 (9.3)
`
`357 (3.6)
`24 (0.2)
`
`330 (3.4)
`12 (0.1)
`
`137 (1.4)
`16 (0.2)
`38 (0.4)
`10 (0.1)
`9 (⬍0.1)
`16 (0.2)
`266 (2.7)
`122 (1.2)
`4 (⬍0.1)
`
`149 (1.5)
`21 (0.2)
`52 (0.5)
`6 (⬍0.1)
`1 (⬍0.1)
`12 (0.1)
`247 (2.5)
`133 (1.4)
`3 (⬍0.1)
`
`P *
`
`0.480
`
`0.313
`0.065
`
`0.475
`0.417
`0.140
`0.454
`0.021
`0.571
`0.421
`0.489
`⬎0.999
`
`*Difference of incidence.
`†A total of 48 pravastatin and 107 placebo-treated patients had ⬎1 body
`system cancer; ‡including breast.
`
`There were no differences in the number of serious adverse
`events reported for noncardiovascular reasons (Figure 1).
`
`Hepatic Safety
`There was no difference in serious adverse events related to
`the hepatobiliary system between the pravastatin (n⫽255;
`2.6%) and the placebo-treated subjects (n⫽297; 3.0%). The
`most common reported serious adverse event related to the
`hepatobiliary system was gallbladder disorders, which was
`reported in 186 (1.9%) of pravastatin-treated and 208 (2.1%)
`of placebo patients. The incidence of any abnormality of ALT
`after baseline was similar between the pravastatin and the
`
`Figure 1. Most common serious adverse events, excluding car-
`diovascular events. GI indicates gastrointestinal.
`
`Extent of exposure to study
`medication
`Mean⫾SD, y
`Median, y
`Minimum, d
`Maximum, y
`Extent of exposure to study
`medication, n (%)
`⬍1 year
`1–⬍2 years
`2–⬍3 years
`3–⬍4 years
`4–⬍5 years
`5–⬍6 years
`ⱖ6 years
`Percentages for extent of exposure are based on the number of subjects who
`received at least one dose of study medication; 1 year⫽365.25 days.
`
`4.5⫾1.8
`5.0
`1
`7.1
`
`826 (8)
`538 (5)
`449 (5)
`710 (7)
`2465 (25)
`3322 (34)
`1473 (15)
`
`4.6⫾1.7
`5.0
`1
`7.1
`
`755 (8)
`431 (4)
`339 (3)
`579 (6)
`2527 (26)
`3488 (36)
`1690 (17)
`
`Safety
`Deaths and Cancer
`Fewer pravastatin-treated patients died. This was due to a
`reduction in cardiovascular deaths in those assigned to
`pravastatin (n⫽394)
`compared with placebo (n⫽502;
`P⬍0.001), with no difference observed in noncardiovascular
`deaths. There was no category of noncardiovascular death in
`which the proportion of deaths differed between the prava-
`statin and placebo-assigned groups. Fatal primary cancers
`occurred in 455 of the 19 592 (2.3%) patients, with no
`differences between treatment groups in these relatively
`infrequent events. Adding the incidence of nonfatal cancers
`increased the number of patients in whom at
`least one
`primary cancer was diagnosed to 9.5% of the population
`(1860 of 19 592; Table 2). There were no differences between
`the pravastatin and placebo groups for any primary cancer as
`categorized by body system, except
`in musculoskeletal/
`connective tissue, which were composites of different histo-
`logical types and anatomic sites with no pattern according to
`treatment assignment.
`The incidence of breast cancer was 0.2% (n⫽22) in the
`pravastatin-treated group and 0.1% (n⫽11) in those assigned
`to placebo (P⫽0.080). An imbalance in breast cancer had
`previously been noted in the CARE study.5 The LIPID study,
`compared with CARE, enrolled a larger number of women:
`756 were in the pravastatin-treated group and 760 were in the
`placebo-treated group. In the LIPID study, there were 10
`reports (1.3%) of breast cancer in pravastatin-treated women
`and 8 reports (1.1%) in placebo-treated women. In addition, 2
`cases of breast cancer were reported in men; both were
`assigned placebo.
`
`Serious Adverse Events
`Reports of serious adverse events related to the cardiovascu-
`lar system were less frequent in the pravastatin-treated group.
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`TABLE 3. Serum Chemistry Abnormalities
`
`Pravastatin
`40 mg
`(n⫽9185),
`n (%)
`
`Any value ⬎1.5⫻ULN
`⬎1.5⫻ULN to ⱕ3⫻ULN
`⬎3⫻ULN to ⱕ5⫻ULN
`⬎5⫻ULN to ⱕ7⫻ULN
`⬎7⫻ULN to ⱕ9⫻ULN
`⬎9⫻ULN
`ULN⫽upper limit of normal.
`
`804 (8.8)
`676 (7.4)
`84 (0.9)
`24 (0.3)
`6 (⬍0.1)
`14 (0.2)
`
`ALT Abnormalities
`
`CPK Abnormalities
`
`Placebo
`(n⫽9152),
`n (%)
`
`746 (8.2)
`615 (6.7)
`90 (1.0)
`19 (0.2)
`9 (⬍0.1)
`13 (0.1)
`
`95% CI of
`Difference
`⫺0.21, 1.42
`⫺0.11, 1.39
`⫺0.36, 0.22
`⫺0.10, 0.21
`⫺0.13, 0.06
`⫺0.11, 0.13
`
`Pravastatin
`40 mg
`(n⫽5245),
`n (%)
`
`587 (11.2)
`480 (9.2)
`84 (1.6)
`8 (0.2)
`6 (0.1)
`9 (0.2)
`
`Placebo
`(n⫽5233),
`n (%)
`
`563 (10.8)
`460 (8.8)
`79 (1.5)
`16 (0.3)
`6 (0.1)
`2 (⬍0.1)
`
`95% CI of
`Difference
`⫺0.78, 1.65
`⫺0.75, 1.48
`⫺0.40, 0.59
`⫺0.36, 0.05
`⫺0.15, 0.15
`⫺0.02, 0.28
`
`placebo groups (Table 3). Moreover, there were no differ-
`ences in severity of abnormality of ALT. Similarly, no
`differences in postbaseline abnormalities of aspartate amino-
`transferase were observed.
`The risk of exacerbating an already existing liver function
`abnormality was evaluated by a subgroup analysis of the 579
`patients who were randomized with an abnormal ALT value.
`At baseline, 317 (3.2%) of the pravastatin-treated subjects
`and 262 (2.6%) of the placebo-treated subjects had ALT
`elevations that exceeded baseline (between 1 and 3⫻ULN).
`The number of these patients who subsequently showed an
`increase that was between 1.5 and 3⫻ULN was comparable
`(127 of 317 [40.1%] versus 101 of 262 [38.5%] for prava-
`statin and placebo, respectively). Importantly, the number of
`these patients with baseline abnormalities in whom ALT was
`subsequently ⬎3⫻ULN on any postrandomization sample
`was 16 of 317 (5.0%) in the pravastatin-treated subjects
`versus 19 of 262 (7.3%) for placebo-treated subjects.
`
`Musculoskeletal Safety
`There were no cases of myopathy, which was defined as
`muscle aching or muscle weakness in conjunction with
`increases of CPK ⬎10⫻ULN, or confirmed cases of rhabdo-
`myolysis reported for either pravastatin or placebo-treated
`groups. The incidence of adverse events due to myalgia
`and/or myositis was comparable between treatment groups.
`Although women reported myalgia and myositis more fre-
`quently than men, there was no treatment effect. No differ-
`ences were observed between older versus young subjects.
`Postbaseline abnormalities of CPK occurred with similar
`frequencies in the placebo- and pravastatin-treated groups
`(Table 3).
`
`Renal Safety
`Renal failure or chronic renal failure was designated as a
`serious adverse event in 78 of 9783 (0.79%) placebo and 48
`of 9809 (0.49%) pravastatin subjects. Although more detailed
`evaluations were not conducted, there was at the least no
`suggestion of drug-induced severe renal problems.
`
`Tolerability
`Discontinuation of the blinded study medication for any
`reason was less frequent in the pravastatin than in the placebo
`group (2217 of 9809 [22.6%] versus 2728 of 9783 [27.8%]
`
`for pravastatin versus placebo, respectively; P⬍0.001; Figure
`2). An analysis of reported adverse experiences leading to
`drug discontinuation by body system did not reveal any
`increase in discontinuation rate attributed to pravastatin
`therapy for any body system. Indeed, patients taking placebo
`were more likely to discontinue due to an adverse event
`classified as related to the cardiovascular, endocrine/metabol-
`ic, and general body systems. Therefore, an additional ex-
`ploratory analysis that excluded patients who discontinued
`medication after a cardiovascular event still indicated that
`discontinuation of the blinded study medication was less
`frequent in the pravastatin than in the placebo group (2050 of
`9642 [21.3%] versus 2451 of 9506 [25.8%] for pravastatin
`versus placebo, respectively; P⬍0.001).
`The likelihood of discontinuing study medication was
`analyzed with a Cox proportional hazards model, which in
`addition to treatment group used covariates of age, enrollment
`in either the primary or secondary prevention studies, history
`of diabetes, smoking status, presence of a serious adverse
`event attributed to the cardiovascular body system, and
`treatment by primary or secondary prevention study interac-
`tion. Despite the attempts to adjust for potential confounders
`for long-term continuation on study medication, assignment
`to pravastatin remained a significant determinant of reduced
`likelihood to discontinue study medication (increased tolera-
`bility; Table 4). Individuals with a history of diabetes,
`smokers, and those in the primary prevention study were
`more likely to discontinue study medication, whereas those
`
`Figure 2. Time to discontinuation of study medication in the PPP.
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`
`Factors Affecting Discontinuation of Study Medication:
`TABLE 4.
`Results From the Multivariate Cox Regression Model
`
`Parameter
`
`Treatment group (pravastatin)
`Age
`Male sex
`Primary/secondary prevention
`History of diabetes
`Smoking status
`Presence of a serious adverse event
`in the cardiovascular body system*
`Treatment by primary/secondary
`prevention interaction
`
`*Time-dependent covariate.
`
`Hazard
`Ratio
`
`0.69
`1.00
`0.83
`1.15
`1.34
`1.25
`0.76
`
`1.40
`
`95% CI
`
`0.64, 0.74
`1.00, 1.01
`0.76, 0.91
`1.04, 1.26
`1.21, 1.49
`1.16, 1.36
`0.71, 0.81
`
`P
`
`0.001
`0.471
`0.001
`0.004
`0.001
`0.001
`0.001
`
`1.24, 1.57
`
`0.001
`
`experiencing a serious adverse cardiovascular event or who
`were men were more likely to continue their assigned
`medication. Independent of these and other factors, assign-
`ment to pravastatin was associated with a higher likelihood of
`continuing study medication (Table 4).
`
`Discussion
`The safety of a pharmaceutical agent is a relative term. Safety
`concerns for agents used long-term in the treatment of
`relatively well
`individuals as preventive therapies would
`differ from those for agents used for the treatment of
`life-threatening illnesses for shorter durations. Statins are
`generally used for long-term exposure. Indeed, even in a
`secondary prevention study such as LIPID, which enrolled
`patients with previous acute coronary syndromes who had a
`median age of 62 years, the averaged modeled life expectancy
`was ⬇15 years. Even longer durations of therapy would be
`anticipated in younger patients with less overt vascular
`disease. Acquisition of safety data are also cumulative,
`because the safety profile of a pharmaceutical agent becomes
`more precise with increasing exposure of the molecule to
`subjects. During initial drug development, animal toxicology
`is used to recognize those compounds that have already raised
`possible safety concerns before clinical evaluation. Early
`short-term clinical efficacy studies, as designed, can only be
`expected to detect adverse events that occur with relatively
`high frequency. Indeed, it is acknowledged that regulatory
`approval for clinical use “does not and cannot guarantee
`safety.”19 Large-scale, placebo-controlled trials with long
`durations provide a greater degree of comfort regarding drug
`safety and are again dependent on the duration of exposure
`and the absolute level of risk for the specific safety concern.
`As the result of major clinical trials involving thousands of
`patient years of exposure,
`the first generation of statins
`(lovastatin, pravastatin, and simvastatin) have not only
`proven their efficacy but also provided important quantitative
`safety information. Cerivastatin did not have this degree of
`exposure from long-term clinical trials and the heightened
`risk of rhabdomyolysis was only detected after marketing
`surveillance.
`
`Statins decrease intracellular cholesterol production in the
`liver by partial inhibition of this rate-limiting enzyme for
`cholesterol biosynthesis. As such, the potential for hepatic
`toxicity has been a concern since their early development, as
`has their potential to produce myopathy and rhabdomyolysis.
`Given these concerns about skeletal muscle and liver function
`abnormalities, relevant assays for safety surveillance were
`incorporated into the protocols of these large-scale trials.
`Indeed, in many respects, patients in clinical trials generally
`have much closer surveillance than those in general practice.
`Trial protocols require frequent visits and, depending on the
`study, surveillance laboratory evaluations. As a result, in the
`combined PPP experience, ⬇243 000 blood samples were
`obtained and analyzed. On the basis of this extensive expe-
`rience, we were able to quantitate that the risk of developing
`elevations in hepatic transaminase levels while taking prava-
`statin (40 mg once daily) was no greater than placebo.
`Similarly, in the Air Force/Texas Coronary Atherosclerosis
`Prevention Study, the frequency of detection of consecutive
`3⫻ULN elevations in hepatic transaminase was not signifi-
`cantly increased with lovastatin compared with placebo.20 In
`the Scandinavian Simvastatin Survival Study, the finding of
`any 3⫻ULN value of ALT during frequent surveillance was
`slightly higher in the simvastatin group compared with
`placebo. However, there was no difference in the groups with
`respect to the number of patients who had therapy discontin-
`ued because of elevated hepatic enzymes (8 of 2221 simva-
`statin patients and 5 of 2223 placebo patients).21 The recent
`report of the Heart Protection Study, which has ⬎20 000
`patients (10 269 on simvastatin and 10 267 on placebo) who
`were followed for ⬇5 years, reported ALT ⬎3⫻ULN in only
`77 (0.8%) of the patients assigned the statin and 65 (0.6%) of
`those assigned placebo.3
`Similarly, despite prestudy concerns about statin-induced
`myotoxicity, increased rates of rhabdomyolysis or creatinine
`kinase ⬎10⫻ULN were not detected in these large-scale
`clinical trials of first-generation statins (lovastatin, pravasta-
`tin, and simvastatin).22 As a result of major clinical trials with
`⬎100 000 patient-years of exposure, a reliable safety profile
`of these well-studied agents was available.
`With the administration of any pharmacological com-
`pound, safety must always be a consideration. Acquisition of
`safety data is a continuous process that should never be
`considered complete. At this time, our extensive pooled data
`had a 99% chance of detecting events that had a frequency
`⬎1 in 1000 and a 62.5% chance for events with a frequency
`of ⱖ1 in 10 000 during the period of monitoring. The
`postmarketing detection of an excessive risk of fatal rhabdo-
`myolysis associated with cerivastatin serves to reinforce the
`need for specific safety information for each molecule.
`Because this particular agent was not used in long-term
`morbidity/mortality trials, the available safety information
`was much less robust. Although differences in lipophilicity,
`drug metabolism by the hepatic cytochrome P-450 system,
`and drug interactions have been postulated to explain the
`different safety profiles of statins, there should be no substi-
`tute for quantitative safety assessments such as from con-
`trolled, exposure agent–specific safety data.
`
`5 of 6
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`PENN EX. 2053
`CFAD V. UPENN
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`2346
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`Circulation
`
`May 21, 2002
`
`The PPP experience is extensive, comprising ⬎112 000
`person years, and provides quantitative data on the safety and
`tolerability of pravastatin during a median 5-year period in
`subjects both with and without known heart disease, with
`elevated and average baseline LDL cholesterol levels. The
`risk of experiencing noncardiovascular adverse events in the
`groups randomized to 40 mg of pravastatin was no greater
`than that observed in the placebo groups. The specific
`concerns about myopathy and hepatic liver enzyme abnor-
`malities during pravastatin therapy were not confirmed.
`Although the reason for administering pharmacological ther-
`apy must be based on efficacy data, the threshold at which
`one does choose an agent must also carefully consider
`quantitative safety data. In the PPP experience, the clinical
`efficacy of 40 mg of pravastatin was associated with a safety
`and tolerability profile similar to placebo.
`
`Acknowledgment
`The PPP is funded by an investigator-initiated grant from Bristol-
`Myers Squibb to Wake Forest University.
`
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