new england
`The
`journal
` medicine
`of
`
`established in 1812
`
`april
`
`8
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`
`
`2004
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`vol. 350 no. 15
`
`Intensive versus Moderate Lipid Lowering with Statins
`after Acute Coronary Syndromes
`
`Christopher P. Cannon, M.D., Eugene Braunwald, M.D., Carolyn H. McCabe, B.S., Daniel J. Rader, M.D.,
`Jean L. Rouleau, M.D., Rene Belder, M.D., Steven V. Joyal, M.D., Karen A. Hill, B.A., Marc A. Pfeffer, M.D., Ph.D.,
`and Allan M. Skene, Ph.D., for the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis
`in Myocardial Infarction 22 Investigators*
`
`abstract
`
`background
`Lipid-lowering therapy with statins reduces the risk of cardiovascular events, but the
`optimal level of low-density lipoprotein (LDL) cholesterol is unclear.
`
`methods
`We enrolled 4162 patients who had been hospitalized for an acute coronary syndrome
`within the preceding 10 days and compared 40 mg of pravastatin daily (standard therapy)
`with 80 mg of atorvastatin daily (intensive therapy). The primary end point was a com-
`posite of death from any cause, myocardial infarction, documented unstable angina re-
`quiring rehospitalization, revascularization (performed at least 30 days after randomiza-
`tion), and stroke. The study was designed to establish the noninferiority of pravastatin
`as compared with atorvastatin with respect to the time to an end-point event. Follow-up
`lasted 18 to 36 months (mean, 24).
`
`results
`The median LDL cholesterol level achieved during treatment was 95 mg per deciliter
`(2.46 mmol per liter) in the standard-dose pravastatin group and 62 mg per deciliter
`(1.60 mmol per liter) in the high-dose atorvastatin group (P<0.001). Kaplan–Meier es-
`timates of the rates of the primary end point at two years were 26.3 percent in the prav-
`astatin group and 22.4 percent in the atorvastatin group, reflecting a 16 percent reduc-
`tion in the hazard ratio in favor of atorvastatin (P=0.005; 95 percent confidence interval,
`5 to 26 percent). The study did not meet the prespecified criterion for equivalence but
`did identify the superiority of the more intensive regimen.
`
`conclusions
`Among patients who have recently had an acute coronary syndrome, an intensive lipid-
`lowering statin regimen provides greater protection against death or major cardiovas-
`cular events than does a standard regimen. These findings indicate that such patients
`benefit from early and continued lowering of LDL cholesterol to levels substantially be-
`low current target levels.
`
`From the Thrombolysis in Myocardial In-
`farction (TIMI) Study Group, Cardiovas-
`cular Division, Department of Medicine,
`Brigham and Women’s Hospital and Har-
`vard Medical School, Boston (C.P.C., E.B.,
`C.H.M., M.A.P.); the University of Penn-
`sylvania, Philadelphia (D.J.R.); the Univer-
`sity of Montreal, Montreal (J.L.R.); Bristol-
`Myers Squibb, Princeton, N.J. (R.B., S.V.J.);
`and the Nottingham Clinical Research
`Group, Nottingham, United Kingdom
`(K.A.H., A.M.S.). Address reprint requests
`to Dr. Cannon at the TIMI Study Group,
`Cardiovascular Division, Brigham and
`Women’s Hospital, 75 Francis St., Boston,
`MA 02115, or at cpcannon@partners.org.
`
`*The investigators and research coordina-
`tors who participated in the Pravastatin
`or Atorvastatin Evaluation and Infection
`Therapy–Thrombolysis in Myocardial In-
`farction 22 (PROVE IT–TIMI 22) study
`are listed in the Appendix.
`
`This article was published at www.nejm.org
`on March 8, 2004.
`
`N Engl J Med 2004;350:1495-504.
`Copyright © 2004 Massachusetts Medical Society.
`
`n engl j med
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`350;15
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`www.nejm.org april
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`8, 2004
`
`1495
`
`The New England Journal of Medicine
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`Downloaded from nejm.org on June 4, 2016. For personal use only. No other uses without permission.
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` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
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`s
`
` new england journal
`The
`
`of
`
` medicine
`
`everal large, randomized, con-
`trolled trials have documented that cholester-
`ol-lowering therapy with 3-hydroxy-3-meth-
`ylglutaryl coenzyme A reductase inhibitors (statins)
`reduces the risk of death or cardiovascular events
`across a wide range of cholesterol levels whether or
`not patients have a history of coronary artery dis-
`1-7
`ease.
` The doses of statins used in these trials re-
`duced low-density lipoprotein (LDL) cholesterol
`levels by 25 to 35 percent, and current guidelines
`recommend a target LDL cholesterol level of less
`than 100 mg per deciliter (2.59 mmol per liter) for
`patients with established coronary artery disease or
`8,9
` It is not clear whether lowering lipid lev-
`diabetes.
`els further would increase the clinical benefit. Ac-
`cordingly, the Pravastatin or Atorvastatin Evaluation
`and Infection Therapy–Thrombolysis in Myocardial
`Infarction 22 (PROVE IT–TIMI 22) trial was de-
`signed to compare the standard degree of LDL cho-
`lesterol lowering to approximately 100 mg per deci-
`2,3
`liter with the use of 40 mg of pravastatin daily
` with
`more intensive LDL cholesterol lowering to approx-
`imately 70 mg per deciliter (1.81 mmol per liter)
`10
`with the use of 80 mg of atorvastatin daily
` as a
`mean of preventing death or major cardiovascular
`events in patients with an acute coronary syndrome.
`
`methods
`
`patient population
`Between November 15, 2000, and December 22,
`2001, 4162 patients were enrolled at 349 sites in
`eight countries (see the Appendix). The protocol
`was approved by the relevant institutional review
`boards, and written informed consent was obtained
`11
`from all patients. As described previously,
` men
`and women who were at least 18 years old were el-
`igible for inclusion if they had been hospitalized
`for an acute coronary syndrome — either acute my-
`ocardial infarction (with or without electrocardio-
`graphic evidence of ST-segment elevation) or high-
`risk unstable angina — in the preceding 10 days.
`Patients had to be in stable condition and were to
`be enrolled after a percutaneous revascularization
`procedure if one was planned. Finally, patients had
`to have a total cholesterol level of 240 mg per deci-
`liter (6.21 mmol per liter) or less, measured at the
`local hospital within the first 24 hours after the onset
`of the acute coronary syndrome or up to six months
`earlier if no sample had been obtained during the
`first 24 hours. Patients who were receiving long-
`term lipid-lowering therapy at the time of their in-
`
`dex acute coronary syndrome had to have a total
`cholesterol level of 200 mg per deciliter (5.18 mmol
`per liter ) or less at the time of screening in the local
`hospital.
`Patients were ineligible for the study if they had
`a coexisting condition that shortened expected sur-
`vival to less than two years, were receiving therapy
`with any statin at a dose of 80 mg per day at the
`time of their index event or lipid-lowering therapy
`with fibric acid derivatives or niacin that could not
`be discontinued before randomization, had received
`drugs that are strong inhibitors of cytochrome P-450
`3A4 within the month before randomization or were
`likely to require such treatment during the study
`period (because atorvastatin is metabolized by this
`pathway), had undergone percutaneous coronary
`intervention within the previous six months (other
`than for the qualifying event) or coronary-artery by-
`pass surgery within the previous two months or were
`scheduled to undergo bypass surgery in response to
`the index event, had factors that might prolong the
`QT interval, had obstructive hepatobiliary disease or
`other serious hepatic disease, had an unexplained
`elevation in the creatine kinase level that was more
`than three times the upper limit of normal and that
`was not related to myocardial infarction, or had a
`creatinine level of more than 2.0 mg per deciliter
`(176.8 µmol per liter).
`
`study protocol
`The protocol specified that patients were to receive
`standard medical and interventional treatment for
`acute coronary syndromes, including aspirin at a
`dose of 75 to 325 mg daily, with or without clopid-
`ogrel or warfarin. Patients were not permitted to be
`treated with any lipid-modifying therapy other than
`the study drug. Eligible patients were randomly as-
`signed in a 1:1 ratio to receive 40 mg of pravastatin
`or 80 mg of atorvastatin daily in a double-blind, dou-
`ble-dummy fashion. In addition, patients were also
`randomly assigned to receive with the use of a two-
`by-two factorial design a 10-day course of gatiflox-
`acin or placebo every month during the trial. The re-
`sults of the antibiotic component of the trial are not
`reported here.
`Patients were seen for follow-up visits and re-
`8
` at 30 days, at 4 months,
`ceived dietary counseling
`and every 4 months thereafter until their final visit in
`August or September 2003. Patients who discontin-
`ued the study drug during the trial were followed by
`means of telephone calls. Blood samples were ob-
`tained at randomization, at 30 days, at 4, 8, 12, and
`
`1496
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`n engl j med
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`8
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`2004
`
`The New England Journal of Medicine
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`Downloaded from nejm.org on June 4, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
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`intensive vs. moderate lipid lowering with statins
`
`16 months, and at the final visit for the measure-
`ment of lipids and other components that were part
`of the safety assessment. Measurements were made
`at the core laboratories listed in the Appendix. LDL
`cholesterol levels were monitored, and the protocol
`specified that the dose of pravastatin was to increase
`to 80 mg in a blinded fashion if the LDL cholesterol
`level exceeded 125 mg per deciliter (3.23 mmol per
`liter) on two consecutive visits and the patient had
`been taking study medication and had returned for
`the required study visits. The dose of either study
`drug could be halved in the event of abnormal liver-
`function results, elevations in creatine kinase levels,
`or myalgias.
`Patients were followed for 18 to 36 months, with
`an average follow-up of 24 months. The trial con-
`tinued until 925 events had been reported to the co-
`ordinating center, after which time all patients were
`requested to return for a final study visit. Eight pa-
`tients (0.2 percent) were lost to follow-up.
`
`end points
`The primary efficacy outcome measure was the time
`from randomization until the first occurrence of a
`component of the primary end point: death from
`any cause, myocardial infarction, documented un-
`stable angina requiring rehospitalization, revascu-
`larization with either percutaneous coronary inter-
`vention or coronary-artery bypass grafting (if these
`procedures were performed at least 30 days after
`randomization), and stroke. Myocardial infarction
`was defined by the presence of symptoms suggestive
`of ischemia or infarction, with either electrocardio-
`graphic evidence (new Q waves in two or more leads)
`or cardiac-marker evidence of infarction, according
`to the standard TIMI and American College of Car-
`12,13
` Unstable angina was de-
`diology definition.
`fined as ischemic discomfort at rest for at least 10
`minutes prompting rehospitalization, combined
`with one of the following: ST-segment or T-wave
`changes, cardiac-marker elevations that were above
`the upper limit of normal but did not meet the cri-
`teria for myocardial infarction, or a second episode
`of ischemic chest discomfort lasting more than
`10 minutes and that was distinct from the episode
`that had prompted hospitalization. Secondary end
`points were the risk of death from coronary heart
`disease, nonfatal myocardial infarction, or revascu-
`larization (if it was performed at least 30 days after
`randomization), the risk of death from coronary
`heart disease or nonfatal myocardial infarction, and
`the risk of the individual components of the primary
`end point.
`
`statistical analysis
`Although the trial was designed as a time-to-event
`study, the definition of noninferiority was arrived at
`through a consideration of two-year event rates. For
`the comparison of pravastatin with atorvastatin, we
`defined the prespecified boundary for noninferior-
`ity as an upper limit of the one-sided 95 percent con-
`fidence interval of the relative risk at two years of less
`than 1.17 (corresponding to a hazard ratio through-
`out follow-up of 1.198). Assuming a two-year event
`rate of 22 percent in the atorvastatin group and that
`the two treatments had equivalent efficacy, we de-
`termined that enrollment of 2000 patients per group
`would give the study a statistical power of 87 per-
`cent and that this power would be preserved if fol-
`low-up continued until 925 end-point events had
`14
`occurred.
` A central randomization system was
`used that involved a permuted-block design in
`which assignment was stratified according to cen-
`ter. Three interim assessments of efficacy and safety
`were carried out by the data and safety monitoring
`board. Rules for stopping the study early in the event
`that the superiority of either treatment was estab-
`lished were not prespecified.
`All efficacy analyses are based on the intention-
`to-treat principle. Estimates of the hazard ratios and
`associated 95 percent confidence intervals compar-
`ing pravastatin with atorvastatin were obtained with
`the use of the Cox proportional-hazards model, with
`randomized treatment as the covariate and stratifi-
`cation according to the receipt of gatifloxacin or
`placebo. (Using the two-by-two factorial design,
`we conducted a preliminary test for interaction and
`found none. For the primary end point, the interac-
`tion P value was 0.90 and the hazard ratios compar-
`ing pravastatin with atorvastatin were almost iden-
`tical for the gatifloxacin and placebo groups.) When
`it was determined that noninferiority was not dem-
`onstrated, the subsequent assessment of superiority
`was carried out with the use of two-sided confidence
`intervals. The investigators designed the trial and
`had free and complete access to the data. Data co-
`ordination was performed by the Nottingham Clin-
`ical Research Group (see the Appendix). Investi-
`gators at TIMI, the sponsor, and members of the
`Nottingham Clinical Research Group performed
`data analysis jointly.
`
`results
`
`The two groups of patients were well matched with
`regard to base-line characteristics, with the excep-
`tion of a history of peripheral arterial disease, which
`
`n engl j med
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`350;15
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`
`8, 2004
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`1497
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`The New England Journal of Medicine
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`Downloaded from nejm.org on June 4, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
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`
` new england journal
`The
`
` medicine
`of
`
`was more common in the pravastatin group than
`the atorvastatin group (P=0.03) (Table 1). Their av-
`erage age was 58 years, and 22 percent were women.
`Before their index event, 18 percent of patients had
`had a myocardial infarction, 11 percent had previ-
`ously undergone coronary-artery bypass surgery,
`and 18 percent had diabetes mellitus. The index
`event was high-risk unstable angina in approxi-
`mately one third of the patients, myocardial infarc-
`
`tion without electrocardiographic evidence of ST-
`segment elevation in approximately one third, and
`myocardial infarction with ST-segment elevation
`in one third. Sixty-nine percent of patients under-
`went percutaneous coronary intervention for the
`treatment of their index acute coronary syndrome
`before randomization. One quarter of the patients
`were taking statin drugs at the time of the index
`event. Concomitant medications were administered
`
`Table 1. Base-Line Characteristics of the Patients.*
`
`Characteristic
`
`40 mg of Pravastatin
`(N=2063)
`
`80 mg of Atorvastatin
`(N=2099)
`
`Age — yr
`Male sex — no. (%)
`White race — no. (%)
`Diabetes mellitus — no. (%)
`Hypertension — no. (%)
`Current smoker — no. (%)
`Prior MI — no. (%)
`Percutaneous coronary intervention — no. (%)
`Before index event
`For treatment of index event
`Coronary bypass surgery before index event — no. (%)
`Peripheral arterial disease — no. (%)
`Prior statin therapy — no. (%)
`Index event — no. (%)
`Unstable angina
`MI without ST-segment elevation
`MI with ST-segment elevation
`Lipid values
`Total cholesterol
`No. of patients
`Median — mg/dl
`Interquartile range — mg/dl
`LDL cholesterol
`No. of patients
`Median — mg/dl
`Interquartile range — mg/dl
`HDL cholesterol
`No. of patients
`Median — mg/dl
`Interquartile range — mg/dl
`Triglycerides
`No. of patients
`Median — mg/dl
`Interquartile range — mg/dl
`
`58.3±11.3
`1617 (78.4)
`1865 (90.4)
`361 (17.5)
`1014 (49.2)
`766 (37.1)
`395 (19.1)
`
`320 (15.5)
`1426 (69.1)
`221 (10.7)
`136 (6.6)
`514 (24.9)
`
`614 (29.8)
`757 (36.7)
`690 (33.4)
`
`1981
`180
`158–202
`
`1973
`106
`87–127
`
`1981
`39
`33–46
`
`1984
`154
`115–207
`
`58.1±11.2
`1634 (77.8)
`1911 (91.0)
`373 (17.8)
`1077 (51.3)
`763 (36.4)
`374 (17.8)
`
`322 (15.3)
`1442 (68.7)
`233 (11.1)
`105 (5.0)
`535 (25.5)
`
`604 (28.8)
`747 (35.6)
`748 (35.6)
`
`2014
`181
`160–205
`
`2003
`106
`89–128
`
`2014
`38
`32–46
`
`2016
`158
`119–214
`
`* Plus–minus values are means ±SD. None of the differences between groups were significant with the exception of a his-
`tory of peripheral arterial disease (P=0.03). Two patients did not have information regarding the electrocardiographic
`type of acute coronary syndrome, and one patient had missing information regarding prior statin use. MI denotes myo-
`cardial infarction, LDL low-density lipoprotein, and HDL high-density lipoprotein. To convert values for cholesterol to
`millimoles per liter, multiply by 0.02586. To convert values for triglycerides to millimoles per liter, multiply by 0.01129.
`
`1498
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`8
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`The New England Journal of Medicine
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`Downloaded from nejm.org on June 4, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
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`intensive vs. moderate lipid lowering with statins
`
`40 mg of pravastatin
`
`80 mg of atorvastatin
`
`Base line
`
`30 Days
`
`4 Mo
`8 Mo
`Time of Visit
`
`16 Mo
`
`Final
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`LDL Cholesterol (mg/dl)
`
`No. of Patients
`Pravastatin
`Atorvastatin
`
`1973
`2003
`
`1844
`1856
`
`1761
`1758
`
`1647
`1645
`
`1445
`1461
`
`1883
`1910
`
`Figure 1. Median Low-Density Lipoprotein (LDL) Cholesterol Levels
`during the Study.
`To convert values for LDL cholesterol to millimoles per liter, multiply by
`0.02586.
`
`cent in the atorvastatin group (P=0.029), with a
`two-year event rate of 19.7 percent, as compared
`with 22.3 percent in the pravastatin group. The risk
`of death, myocardial infarction, or urgent revascu-
`larization was reduced by 25 percent in the atorva-
`statin group (P<0.001).
`Among the individual components of the pri-
`mary end point, there was a consistent pattern of
`benefit favoring high-dose atorvastatin over stan-
`dard-dose pravastatin, which included a significant
`14 percent reduction in the need for revasculariza-
`tion (P=0.04), a 29 percent reduction in the risk of
`recurrent unstable angina (P=0.02), and nonsignif-
`icant reductions in the rates of death from any cause
`(28 percent, P=0.07) and of death or myocardial in-
`farction (18 percent, P=0.06) (Fig. 4). Stroke was in-
`frequent, but the rates did not differ significantly be-
`tween the groups.
`The benefit of high-dose atorvastatin was con-
`sistent across the prespecified subgroups, including
`men and women, patients with unstable angina and
`those with myocardial infarction, and those with
`and those without diabetes mellitus (Fig. 5). The
`benefit appeared to be greater among patients with
`a base-line LDL cholesterol level of at least 125 mg
`per deciliter, a prespecified subgroup, with a 34 per-
`cent reduction in the hazard ratio, as compared with
`a 7 percent reduction among patients with a base-
`line LDL cholesterol below 125 mg per deciliter
`(P for interaction=0.02).
`
`to patients during the treatment period as follows:
`aspirin to 93 percent, warfarin to 8 percent, clo-
`pidogrel or ticlodipine to 72 percent initially and
`20 percent at one year, beta-blockers to 85 per-
`cent, angiotensin-converting–enzyme inhibitors to
`69 percent, and angiotensin-receptor blockers to
`14 percent.
`At the time of randomization, a median of seven
`days after the onset of the index event, the median
`LDL cholesterol levels were 106 mg per deciliter
`(2.74 mmol per liter) before treatment in each group
`(Fig. 1). The LDL cholesterol levels achieved during
`follow-up were 95 mg per deciliter (2.46 mmol per
`liter; interquartile range, 79 to 113 mg per deciliter
`[2.04 to 2.92 mmol per liter]) in the pravastatin
`group and 62 mg per deciliter (1.60 mmol per liter;
`interquartile range, 50 to 79 mg per deciliter [1.29
`to 2.04 mmol per liter]) in the atorvastatin group
`(P<0.001). Among 2985 patients (75 percent) who
`had not previously received statin therapy, the me-
`dian LDL cholesterol levels had fallen by 22 percent
`at 30 days in the pravastatin group and by 51 per-
`cent in the atorvastatin group (P<0.001). As antici-
`pated, among the 990 patients who had previously
`received statin therapy (25 percent), LDL cholesterol
`levels were essentially unchanged from base line
`(during statin therapy) in the pravastatin group,
`whereas they fell by an additional 32 percent in the
`atorvastatin group (P<0.001). Median high-density
`lipoprotein cholesterol levels rose during follow-up
`by 8.1 percent in the pravastatin group and 6.5 per-
`cent in the atorvastatin group (P<0.001). Median
`C-reactive protein levels fell from 12.3 mg per liter
`at base line in each group to 2.1 mg per liter in the
`pravastatin group and 1.3 mg per liter in the ator-
`vastatin group (P<0.001).
`
`primary end point
`For all randomized patients, the Kaplan–Meier
`event rates of the primary end point at two years
`were 26.3 percent in the standard-dose pravastatin
`group and 22.4 percent in the high-dose atorva-
`statin group, representing a 16 percent reduction in
`the hazard ratio favoring atorvastatin (P=0.005; 95
`percent confidence interval, 5 to 26 percent) (Fig. 2);
`this difference did not meet the criteria for equiva-
`lence. The benefit of high-dose atorvastatin as com-
`pared with standard-dose pravastatin emerged as
`early as 30 days and was consistent over time (Fig.
`3). The risk of the secondary end point of death due
`to coronary heart disease, myocardial infarction, or
`revascularization was similarly reduced by 14 per-
`
`n engl j med
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`350;15
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`
`8, 2004
`
`1499
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`The New England Journal of Medicine
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`Downloaded from nejm.org on June 4, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
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`
` new england journal
`The
`
`of
`
` medicine
`
`cardiovascular events, intensive therapy with high-
`dose atorvastatin resulted in a median LDL choles-
`terol level of 62 mg per deciliter, as compared with
`a level of 95 mg per deciliter for standard-dose prav-
`astatin. Among patients who had recently been hos-
`pitalized for an acute coronary syndrome, the more
`intensive regimen resulted in a lower risk of death
`from any cause or major cardiac events than did a
`more moderate degree of lipid lowering with the use
`of a standard dose of a statin. Although prior place-
`bo-controlled studies have shown that a standard-
`1-7
`dose statin is beneficial,
` we demonstrated that
`more intensive lipid lowering significantly increased
`this clinical benefit.
`Although the exact mechanism of the benefit
`cannot be established solely on the basis of our re-
`sults, the extent of the benefit afforded by the 80-mg
`dose of atorvastatin is in keeping with what would
`be expected on the basis of the greater degree of lip-
`id lowering produced by this regimen. In the Heart
`Protection study, statin treatment resulted in an LDL
`cholesterol level that was 40 mg per deciliter (1.03
`mmol per liter) lower than the value in the placebo
`group and that was accompanied by a 25 percent re-
`duction in cardiovascular events. In our study, the
`LDL cholesterol level was 33 mg per deciliter (0.85
`mmol per liter) lower in the atorvastatin group than
`in the pravastatin group. This difference should
`translate into a 20 percent reduction in clinical
`events, which is very similar to the 16 percent re-
`duction we observed and suggests that much of the
`benefit is attributable to the difference in the degree
`of LDL cholesterol lowering. However, we cannot
`exclude the possibility that the difference in clinical
`outcomes may be due in part to non–lipid-related
`pleiotropic effects, which may differ between the
`15
` Future trials involving differ-
`two statins we used.
`ent doses of a single statin should help address this
`possibility.
`Intensive therapy with high-dose atorvastatin
`had a consistent beneficial effect on cardiac events,
`including a significant 29 percent reduction in the
`risk of recurrent unstable angina and a 14 percent
`reduction in the need for revascularization. The re-
`duction in the rate of death from any cause was of
`borderline significance (28 percent, P=0.07), sug-
`gesting that more aggressive lipid lowering is im-
`portant not only to reduce the risk of recurrent is-
`chemia, but possibly also to decrease the risk of
`fatal events.
`The reduction in clinical events with the more
`intensive lipid-lowering therapy was apparent as
`
`40 mg of pravastatin
`
`80 mg of atorvastatin
`
`0
`
`3
`
`6
`
`9
`
`12
`15
`18
`Months of Follow-up
`
`21
`
`24
`
`27
`
`30
`
`P=0.005
`
`30
`
`25
`
`20
`
`15
`
`10
`
`5 0
`
`Event (%)
`
`Death or Major Cardiovascular
`
`No. at Risk
`Pravastatin
`Atorvastatin
`
`2063
`2099
`
`1688
`1736
`
`1536
`1591
`
`1423
`1485
`
`810
`842
`
`138
`133
`
`Figure 2. Kaplan–Meier Estimates of the Incidence of the Primary End Point
`of Death from Any Cause or a Major Cardiovascular Event.
`Intensive lipid lowering with the 80-mg dose of atorvastatin, as compared
`with moderate lipid lowering with the 40-mg dose of pravastatin, reduced
`the hazard ratio for death or a major cardiovascular event by 16 percent.
`
`tolerability and safety
`The rates of discontinuation of treatment because
`of an adverse event or the patient’s preference or for
`other reasons were 21.4 percent in the pravastatin
`group and 22.8 percent in the atorvastatin group at
`one year (P=0.30) and 33.0 percent and 30.4 per-
`cent, respectively, at two years (P=0.11). During
`treatment, the dose of pravastatin was increased to
`80 mg in 8 percent of patients, and the dose was
`halved among 1.4 percent of the patients in the prav-
`astatin group and 1.9 percent of those in the atorva-
`statin group (P=0.20), owing to side effects or liver-
`function abnormalities. The percentages of patients
`who had elevations in alanine aminotransferase lev-
`els that were more than three times the upper limit
`of normal were 1.1 percent in the pravastatin group
`and 3.3 percent in the atorvastatin group (P<0.001).
`The study medication was discontinued by the in-
`vestigators because of a report of myalgias or mus-
`cle aches or elevations in creatine kinase levels in
`2.7 percent of pravastatin-treated patients, as com-
`pared with 3.3 percent of atorvastatin-treated pa-
`tients (P=0.23). There were no cases of rhabdomy-
`olysis in either group.
`
`discussion
`
`In this comparison of two statin regimens of differ-
`ent lipid-lowering intensities for the prevention of
`
`1500
`
`n engl j med
`
`350;15
`
`www.nejm.org april
`
`,
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`8
`
`2004
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 4, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
`
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`intensive vs. moderate lipid lowering with statins
`
`Censoring Time
`
`Hazard Ratio (95% CI)
`
`Risk Reduction
`
`30 Days
`
`90 Days
`
`180 Days
`
`End of follow-up
`
`17
`
`18
`
`14
`
`16
`
`
`
`1.50
`
`1.25
`Standard-Dose
`Pravastatin Better
`
`0.50
`
`1.00
`
`0.75
`High-Dose
`Atorvastatin Better
`
`Event Rates
`Atorvastatin
`Pravastatin
`percent
`1.9
`
`2.2
`
`6.3
`
`12.2
`
`22.4
`
`7.7
`
`14.1
`
`26.3
`
`Figure 3. Hazard Ratio for the the Primary End Point of Death from Any Cause or a Major Cardiovascular Event at 30, 90,
`and 180 Days and at the End of Follow-up in the High-Dose Atorvastatin Group, as Compared with the Standard-Dose
`Pravastatin Group.
`Event rates are Kaplan–Meier estimates censored at the time points indicated with the use of the average duration of fol-
`low-up (two years). CI denotes confidence interval.
`
`End Point
`
`Hazard Ratio (95% CI)
`
`Risk Reduction
`
`Death from any cause
`
`Death from CHD
`
`Death from other causes
`
`MI
`
`Death or MI
`
`Death from CHD or MI
`
`Revascularization
`
`MI, revascularization, or death
`from CHD
`
`Unstable angina requiring
`hospitalization
`
`Stroke
`
`28
`
`30
`
`27
`
`13
`
`18
`
`16
`
`14
`
`14
`
`29
`
`¡9
`
`2-Yr Event Rates
`Atorvastatin
`Pravastatin
`percent
`2.2
`
`3.2
`
`1.1
`
`1.2
`
`6.6
`
`8.3
`
`7.2
`
`16.3
`
`19.7
`
`3.8
`
`1.0
`
`1.4
`
`1.8
`
`7.4
`
`10.0
`
`8.3
`
`18.8
`
`22.3
`
`5.1
`
`1.0
`
`0.50
`
`1.00
`
`High-Dose
`Atorvastatin Better
`
`1.50
`Standard-Dose
`Pravastatin Better
`
`Figure 4. Estimates of the Hazard Ratio for the Secondary End Points and the Individual Components of the Primary End
`Point in the High-Dose Atorvastatin Group, as Compared with the Standard-Dose Pravastatin Group.
`CI denotes confidence interval, CHD coronary heart disease, and MI myocardial infarction. Revascularization was per-
`formed at least 30 days after randomization.
`
`early as 30 days after the start of therapy. This rapid
`time frame is similar to that reported with statin
`treatment in the placebo-controlled Myocardial
`Ischemia Reduction with Aggressive Cholesterol
`16
` and in prior observation-
`Lowering (MIRACL) trial
`17,18
`al studies.
` We studied patients who had been
`hospitalized for an acute coronary syndrome and
`
`enrolled them immediately after their condition had
`stabilized. Three quarters of the patients were treat-
`ed with an early invasive strategy, and the majority
`were treated with multiple medications for second-
`ary prevention, including antiplatelet therapy, beta-
`blockers, and angiotensin-converting–enzyme in-
`hibitors (and a statin as part of the trial design).
`
`n engl j med
`
`350;15
`
`www.nejm.org april
`
`8, 2004
`
`1501
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on June 4, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2004 Massachusetts Medical Society. All rights reserved.
`
`7 of 10
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`PENN EX. 2072
`CFAD V. UPENN
`IPR2015-01836
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`
` new england journal
`The
`
` medicine
`of
`
`Base-Line Characteristic
`
`No. of Patients (%)
`
`Hazard Ratio
`
`2-Yr Event Rates
`Pravastatin
`Atorvastatin
`percent
`
`Sex
`
`Male
`
`Female
`
`Age
`
`≥65 yr
`
`<65 yr
`
`Diabetes
`
`Yes
`
`No
`
`Prior smoking
`
`Yes
`
`No
`
`Prior statin therapy
`
`3251 (78)
`
`911 (22)
`
`1230 (30)
`
`2932 (70)
`
`734 (18)
`
`3428 (82)
`
`3077 (74)
`
`1085 (26)
`
`23.0
`
`20.3
`
`28.1
`
`20.1
`
`28.8
`
`21.0
`
`22.8
`
`21.3
`
`26.2
`
`27.0
`
`29.5
`
`25.0
`
`34.6
`
`24.6
`
`26.5
`
`25.9
`
`Yes
`
`No
`
`Index event
`
`1049 (25)
`
`3112 (75)
`
`Unstable angina
`
`1218 (29)
`
`MI without ST-segment elevation
`
`1504 (36)
`
`MI with ST-segment elevation
`
`1438 (35)
`
`LDL cholesterol
`
`≥125 mg/dl
`
`<125 mg/dl
`
`HDL cholesterol
`
`≥40 mg/dl
`
`<40 mg/dl
`
`1091 (27)
`
`2885 (73)
`
`1776 (44)
`
`2219 (56)
`
`27.5
`
`20.6
`
`26.5
`
`19.0
`
`22.6
`
`20.1
`
`23.5
`
`21.7
`
`23.1
`
`28.9
`
`25.5
`
`31.4
`
`24.1
`
`24.2
`
`28.2
`
`25.6
`
`26.7
`
`26.0
`
`0.50
`
`1.00
`
`1.50
`
`High-Dose
`Atorvastatin Better
`
`Standard-Dose
`Pravastatin Better
`
`Figure 5. Two-Year Event Rates and Estimates of the Hazard Ratio for the Primary End Point in the High-Dose Atorva-
`statin Group, as Compared with the Standard-Dose Pravastatin Group, According to Base-Line Characteristics.
`A test for interaction was significant only for a base-line low-density lipoprotein (LDL) value of at least 125 mg per deci-
`liter, as compared with a value of less than 125 mg per deciliter (P=0.02). LDL cholesterol was measured at base line in
`a total of 3976 patients, and high-density lipoprotein (HDL) cholesterol was measured in 3995. Two patients did not
`have information regarding the electrocardiographic type of acute coronary syndrome, and one patient had missing in-
`formation regarding prior statin use. MI denotes myocardial infarction.
`
`Nonetheless, early and continued separation of the
`event curves was observed in the more intensive
`lipid-lowering group. This early reduction in event
`rates in patients with acute coronary syndromes
`contrasts with the lag of approximately one to two
`years in prior studies of statins in patients with
`1-6
`chronic atherosclerosis.
` These data suggest that
`this population of patients with acute coronary syn-
`
`dromes, who have a c