Results from the UCSD Statin Study, a Randomized Trial
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ORIGINAL INVESTIGATION Reduction in Blood Pressure With Statins Results From the UCSD Statin Study, a Randomized Trial Beatrice A. Golomb, MD, PhD; Joel E. Dimsdale, MD; Halbert L. White, PhD; Janis B. Ritchie, BSN; Michael H. Criqui, MD, MPH Background: Some studies have suggested reductions time course of BP changes after statin initiation and the in blood pressure (BP) with statin treatment, particu- effect of stopping statins on BP were examined. larly in persons with hypertension. Randomized trial evi- dence is limited. Results: Statins modestly but significantly reduced BP relative to placebo, by 2.2 mm Hg for SBP (P= .02) and 2.4 mm Hg for DBP (PϽ .001) in ITT analysis. Blood pres- Methods: We performed a randomized, double-blind, sure reductions ranged from 2.4 to 2.8 mm Hg for both placebo-controlled trial with equal allocation to simva- SBP and DBP with both simvastatin and pravastatin, in statin, 20 mg; pravastatin sodium, 40 mg; or placebo those subjects with full follow-up, and without poten- for 6 months. Nine hundred seventy-three men and tial for influence by BP medications (ie, neither receiv- women without known cardiovascular disease or dia- ing nor meriting BP medications). betes mellitus, with low-density lipoprotein cholesterol screening levels of 115 to 190 mg/dL, had assessment of Conclusions: Reductions in SBP and DBP occurred with systolic and diastolic BP (SBP and DBP, respectively). hydrophilic and lipophilic statins and extended to nor- Blood pressure values were compared for placebo vs motensive subjects. These modest effects may contrib- statins by intention-to-treat (ITT) analysis. Additional ute to the reduced risk of stroke and cardiovascular events analyses were performed that (1) were confined to sub- reported on statins. jects with neither high baseline BP (SBP Ͼ140 mm Hg Ͼ or DBP 90 mm Hg) nor receiving BP medications, to Trial Registration: clinicaltrials.gov Identifier: exclude groups in whom BP medications or medication NCT00330980 changes may have influenced results, and (2) separately evaluated simvastatin and pravastatin (vs placebo). The Arch Intern Med. 2008;168(7):721-727 OME STUDIES HAVE SUG- were used to assess the impact of random- gested reductions in blood ized assignment to statins vs placebo on pressure (BP) with statin systolic and diastolic BP (SBP and DBP, re- treatment, particularly in pa- spectively). tients with hypertension. SMany studies reporting BP reductions have METHODS been correlational, uncontrolled, tested against other active drugs with uncertain DESIGN OVERVIEW, SETTING, impact on BP, unblinded, nonrandom- AND PARTICIPANTS ized, or without assessment of statistical 1-9 significance. Some double-blind, ran- The UCSD Statin Study was a randomized, domized studies failed to show an effect double-blind, placebo-controlled trial of 6 but had a small sample size.10,11 Two small, months’ duration. Author Affiliations: randomized, double-blind, crossover stud- Subjects were 973 men and women from Departments of Medicine ies12,13 have shown significant (PϽ .05) Southern California. A total of 1016 screenees (Drs Golomb and Criqui and benefit, but to our knowledge there are no were eligible to participate in the larger trial Ms Ritchie), Family and published articles showing reductions in by virtue of having had a low-density lipopro- Preventive Medicine tein cholesterol (LDL-C) level of 115 to 190 (Drs Golomb and Criqui), BP with statins in sizeable randomized mg/dL (inclusive) at screening; no known car- Psychiatry (Dr Dimsdale), and trials. diovascular disease or diabetes mellitus; and Economics (Dr White), The BP assessments performed in the no factors that would preclude 8 months of par- University of California, double-blind, randomized, University of ticipation in the study (to convert LDL-C to San Diego, La Jolla. California, San Diego (UCSD) Statin Study micromoles per liter, multiply by 0.0259). (REPRINTED) ARCH INTERN MED/ VOL 168 (NO. 7), APR 14, 2008 WWW.ARCHINTERNMED.COM 721 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 at rest and arm at chest height using cuff sizes appropriate to 2403 Assessed for eligibility the subject. Using calibrated aneroid sphygmomanometers, staff 1387 Excluded identified SBP and DBP as phase I and phase V of the Karot- 677 Did not meet koff sounds (unless heard to a BP of 0, wherein phase IV was inclusion criteria recorded as the DBP value).17 Although BP was not a primary 720 Declined to participate outcome in the UCSD Statin Study,14,15 it was measured at the 973 Randomized 43 Excluded from BP substudy only; did not screening visit (prior to randomization) and at each on- have BP measured treatment and posttreatment visit. All subjects whose screen- at screening ing value exceeded 140 mm Hg SBP or 90 mm Hg DBP were given a letter to bring to their physicians stipulating their el- evated BP (n=210 subjects). Because of presumptive evidence 322 Allocated to 328 Allocated to 323 Allocated to pravastatin suggesting a possible benefit of statins to BP and the relative simvastatin, 20 mg placebo sodium, 40 mg ease of analysis of this end point, we received permission from 322 Received 328 Received 323 Received simvastatin, 20 mg placebo pravastatin, 40 mg the Data Safety Monitoring Board to unblind and analyze BP first, and the process of data cleaning for BP commenced prior to the last, 8-month (off-treatment) visit of the last subject. Lack of duplicate BP measurement at each time point must be con- 2 Lost to 1 Lost to 3 Lost to follow-up follow-up follow-up sidered in the context of lack of duplicate measurement of many 10 Discontinued 18 Discontinued 12 Discontinued other variables, including lipids, that show variability: this lack early, without early, without early, without of duplicate measurement was nondifferential across treatment on-treatment on-treatment on-treatment testing testing testing groups, and variance resulting from measurement variability, although potentially eroding power (and producing bias to- ward the null), can be offset by increased sample size. Forty-three of 1016 subjects (4.2%) did not have BP mea- 310 Analyzed 309 Analyzed 308 Analyzed sured at baseline, primarily owing to subjects’ time con- straints (Figure 1). The screening visit at which baseline BP Figure 1. Flowchart of participants. was assessed comprised subjects’ first trip to the study site, and some subjects were delayed in reaching the site or abridged their visit owing to other commitments. However, randomization was Blood pressure was not an entry criterion and did not influ- blinded to and independent of presence or value of screening ence eligibility to participate. The 973 subjects for the present BP. Thus, the subgroup with BP measurements (n=973 sub- BP study are the proper randomized subset of the larger sample jects) is equivalent to a proper randomized substudy and forms in whom BP was assessed at screening. A more complete de- the sample analyzed herein. (Baseline comparability is shown scription of the purpose, eligibility criteria, and study design 14,15 across treatment arms in this group.) is presented elsewhere. The study protocol was approved Change scores in BP represented the primary BP end point, by the UCSD human subjects committee, and all subjects gave subtracting baseline BP from final on-treatment BP. This may written informed consent to participate. The recruitment pe- enhance power by enabling subjects to serve as their own riod was from April 2000 through July 2003, and all subjects controls. were seen at UCSD. RANDOMIZATION AND INTERVENTIONS STATISTICAL ANALYSES A computer-generated, blocked, randomization sequence strati- Analyses were conducted using Stata statistical software (ver- fied on sex was designed by the statistician (H.L.W.) and pro- sion 8.0; StataCorp, College Station, Texas). The primary BP vided to the study pharmacist who used the sequence to match measure for the present analysis was the change from baseline assigned treatment to sequentially numbered bottles. Sequen- (screening) BP to 6-month (final on-statin) BP. All analyses were tial subjects who met eligibility criteria and gave informed con- performed for both SBP and DBP. sent were assigned sequential study identification numbers and Baseline comparability across treatment arms was assessed received the bottle with the corresponding number. Subjects in subjects to address comparability by treatment assignment. received simvastatin, 20 mg; pravastatin sodium, 40 mg; or pla- We performed t tests to compare the mean change in SBP and cebo with equal (33%) probability. A more complete descrip- DBP across treatment arms, provided that comparability across 14,15 tion of procedures is presented elsewhere. Simvastatin, 20 treatment arms was present at baseline. If baseline disparities mg, and pravastatin sodium, 40 mg, were selected as the most across treatment arms were identified, then we performed re- lipophilic and hydrophilic statins, given at dosages approxi- gression analysis to allow adjustment for baseline disparities. mately equivalent in terms of expected LDL-C reduction (the Secondary analyses evaluated the effect on BP separately for 16 study drug was to be taken at bedtime). Neither subjects nor pravastatin and for simvastatin vs placebo. study staff were aware of subject assignment during subjects’ All subjects who received an on-treatment visit (except 3 participation. [2 who received pravastatin and 1 who received simvastatin]) had an on-treatment BP measured and were included in the in- OUTCOMES AND FOLLOW-UP tention-to-treat analysis. In those with high measured BP at base- line, an “intervention” in the form of a letter to the subjects’ Visits occurred at screening, baseline, and at 1 and 6 months physicians was given—an intervention expected to contribute during treatment. Subjects received an 8-month (2 months af- variance unrelated to treatment assignment, eroding power in ter discontinuation) follow-up visit.