Usefulness of Pravastatin in Primary Prevention of Cardiovascular Events in Women
Analysis of the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA Study)
Background— It is well known that statins reduce the risk of cardiovascular disease. However, the effect of statins in women for the primary prevention of cardiovascular disease has not been determined. We conducted an exploratory analysis of the effect of diet plus pravastatin therapy on the primary prevention of cardiovascular events in women with data from a large-scale primary prevention trial with pravastatin.
Methods and Results— Patients with hypercholesterolemia (5.7 to 7.0 mmol/L) and no history of coronary heart disease or stroke were randomized to diet or diet plus pravastatin 10 to 20 mg/d and followed up for ≥5 years. We investigated the effect of diet plus pravastatin treatment on cardiovascular events in 5356 women during the 5-year follow-up. The incidence of cardiovascular events in the women was 2 to 3 times lower than that in men. The occurrence of cardiovascular events was 26% to 37% lower in the diet plus pravastatin treatment group than in the diet alone group. Although these differences did not reach statistical significance, the overall risk reductions were similar to those in men. Notably, women ≥60 years of age treated with diet plus pravastatin had markedly higher risk reductions for coronary heart disease (45%), coronary heart disease plus cerebral infarction (50%), and stroke (64%) than did women treated with diet alone.
Conclusions— Treatment with pravastatin in women with elevated cholesterol but no history of cardiovascular disease provides a benefit similar to that seen in men, and this benefit is more marked in older women. This treatment should be considered routinely for primary cardiovascular protection in women with elevated cholesterol levels.
Received November 7, 2006; accepted November 7, 2007.
It is well known that the incidence of and mortality rates from cardiovascular disease (CVD) are lower in women than in men of the same age. However, as in men, the incidence of ischemic heart disease in women rises with age, and the incidence in women reaches the level in men a decade later.1–3 Factors possibly explaining this ≈10-year lag in disease onset between men and women include direct actions of estrogen on blood vessels4 and women’s lifestyle characteristics (related to smoking, alcohol consumption, dietary style, exercise, etc) that are favorable for the prevention of cardiovascular events.5 However, the estrogen hypothesis has been controversial, and the risk factors of diabetes mellitus or hypertension are more prevalent in women.5 Thus, there is still some argument about the reasons for the delayed onset of cardiovascular events in women.6 Indeed, the risk for cardiovascular events is lower for women than for men of corresponding age because the average life expectancy is 10 years longer for women; thus, the overall number of CVD events analyzed for all age groups does not differ between men and women.1,2 Moreover, reports have shown that the prognosis for CVD is less favorable in women than in men.7 Therefore, it is important to establish valid means for preventing the onset of CVD in women. Numerous large-scale studies designed to evaluate the usefulness of hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) in primary and secondary prevention of CVD conducted since the 1990s8–17 have enrolled primarily men. No study conducted to date has conclusively demonstrated the usefulness of statin therapy as a means of primary prevention of CVD in women. Moreover, the effectiveness of statins in women remains unknown, despite some attempts to determine it through meta- analyses.18,19
Clinical Perspective p 502
In Japan, the recently reported Management of Elevated Cholesterol in the Primary Prevention Groups of Adult Japanese (MEGA) study was designed to evaluate the usefulness of pravastatin in the primary prevention of CVD.20,21 Of the 7832 patients enrolled in this study, 68% were women; >5000 women were followed up for a mean of 5.3 years. The number of women in this study is the largest of any study of statins conducted to date. Here, we summarize the comparison of the results between women and men and report the results of a detailed investigation in women in the MEGA study.
The MEGA study design and overall findings have been reported previously.20,21 Briefly, in this prospective, randomized, open, blinded end-point study22 conducted between 1994 and 2004, men and postmenopausal women (physician diagnosis) 40 to 70 years of age with hypercholesterolemia whose total cholesterol (TC) levels ranged from 5.7 to 7.0 mmol/L with no history of coronary heart disease (CHD) and cerebrovascular disease visiting the outpatient clinic were asked to join the study; all subjects provided written informed consent. The eligibility check was done on individual patients by attending physicians on the basis of their diagnosis. Then, their eligibility was determined by laboratory testing of their serum cholesterol using a standardized procedure on 2 or 3 occasions over 12 weeks. Eligible patients were randomly assigned to the National Cholesterol Education Program (NCEP) step I23 diet alone group or to the NCEP step I diet plus pravastatin by computerized randomization by the permuted-block method and stratified according to sex, age, and medical institution. Major exclusion criteria included familial hypercholesterolemia, a history of CVD, a current diagnosis of malignancy, and secondary hyperlipidemia. The dose of pravastatin was 10 to 20 mg/d, the approved dose in Japan.
Patients were evaluated during every visit to the hospital/clinic. Each patient received a medical check, including onset of end points, by the attending physician at 1, 3, and 6 months after the start of follow-up and every 6 months thereafter. For each event, the diagnosis was made by the attending physician (including data from ECG and myocardial scintigraphy as needed) and reported in detail. ECGs were performed once a year. Information on individual patients was entered into the case report forms by their attending physicians and reported to the data center. For each event, detailed information was obtained from physicians and evaluated by the End-Point Committee under blinding according to the criteria we reported previously.20 Throughout the study period, TC, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and lipoprotein(a) levels were measured centrally at the same laboratory using methods standardized by the Centers for Disease Control and Prevention (Atlanta, Ga). Low-density lipoprotein cholesterol (LDL-C) level was estimated by the Friedewald formula.24 The primary composite end point was the first occurrence of CHD, comprising fatal and nonfatal myocardial infarction, cardiac and sudden death, coronary revascularization procedure, and angina. Secondary end points included stroke, cerebral infarction, intracranial hemorrhage, CHD plus cerebral infarction, cerebral infarction plus transient ischemic attack, all cardiovascular events, and total mortality. All events were independently verified by the End-Point Committee in the blinded manner. Patients in both groups were counseled to follow the NCEP step I diet throughout the study period. Treatment in the diet plus pravastatin group was initiated at pravastatin 10 mg/d. During follow-up, the dose of pravastatin could be adjusted by the treating physician, with uptitration to 20 mg/d if the TC level did not decrease to ≤5.69 mmol/L in compliance with the approved Japanese dose. Patients in each group exceeding a TC of 6.98 mmol/L, even after enhancement of assigned treatment, could be switched to other aggressive treatments, including statin therapy. Concomitant treatment for complications was not restricted in either group.
The follow-up period was initially scheduled for 5 years; however, on the basis of the recommendation of the Data and Safety Monitoring Committee, the study was continued an additional 5 years to increase the number of events. Thus, patients who provided written consent at 5 years to continue the study were followed up until the end of March 2004. The trial was conducted in compliance with the ethics principles of the Declaration of Helsinki and the Japanese Ministry of Health, Labor, and Welfare ordinance regarding postmarketing surveillance.
Statistical analyses were performed following the intention-to-treat principle. The analysis sets were determined by the Data Review Committee before the end of the study in a blinded manner based on prerandomization patient data to avoid the possibility of introducing bias. The effect of diet plus pravastatin on primary and secondary end points in women was examined mainly using the 5-year data to reduce the effect of the high drop-in rate for statin use in the patients randomized to diet only caused by the additional follow-up period. Baseline characteristics and lipid changes during each year of the 5-year study period were evaluated in women. Time-to-event curves for major events were estimated by the Kaplan–Meier method in women and men and in both treatment groups. The effect of diet plus pravastatin treatment for women was compared with men for the major end points of CHD, CHD plus cerebral infarction, stroke, and total mortality and was evaluated in men and women stratified by age. The classification criteria of each event were reported previously.22
The evaluation of safety, including severe adverse events and cancers that occurred after 5 years, was based on the entire study period for each patient to determine the safety of long-term treatment. The log-rank test was used for comparison between groups. Hazard ratios and their confidence intervals were estimated by Cox proportional-hazards model. Adjusted analysis also was conducted by Cox proportional-hazards model with age, hypertension, diabetes mellitus, and HDL-C level as covariates. Smoking was not used as a covariate because of the low proportion of female smokers. TC was not used for the adjusted analysis because eligible patients for this study had a narrow range of TC (5.7 to 7.0 mmol/L). The factors adjusted in this model were determined by risk factor analysis of the present data. Heterogeneity of treatment effect for major end points (CHD, CHD plus cerebral infarction, stroke, and total mortality) between men and women was examined by testing for treatment-sex interaction with the Cox proportional-hazards model, including treatment group, sex, and the interaction term. For the examination of the effects of aging, Cox modeling was adjusted for diabetes, hypertension, and HDL-C level.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Baseline Characteristics and Lipid Parameters
Of the 7832 patients enrolled in MEGA, 5356 (68.4%) were women and 2476 (31.6%) were men. Table 1 summarizes the baseline characteristics by sex.
No difference was found in any baseline characteristic between the diet group and diet plus pravastatin group in women. The mean age in women was 59.7 years, slightly higher than in men. Fewer women (17.8%) than men (27.5%) had diabetes mellitus. However, slightly more women had hypertension (42.6% of women versus 40.2% of men). Baseline TC level did not differ markedly between women (6.3 mmol/L) and men (6.2 mmol/L). However, baseline TG level was lower in women (1.3 mmol/L) than men (1.7 mmol/L), and HDL-C level was higher in women (1.5 mmol/L) than men (1.4 mmol/L) (Table 1).
In women, TC levels decreased by 1.1%, 2.5%, and 2.7% in the diet group and by 12.4%, 12.6%, and 11.8% in the diet plus pravastatin group at 1, 3, and 5 years, respectively, relative to baseline. LDL-C level decreased by 1.6%, 4.6%, and 4.9% and by 19.1%, 20.2%, and 19.1% in the 2 groups at 1, 3, and 5 years, respectively. On average, TC and LDL-C reductions after diet therapy were higher by ≈0.7% and 1.3%, respectively, in women than in men, and these 2 parameters after diet plus pravastatin therapy were lower by 0.9% and 1.1%, respectively, in women than in men.
HDL-C levels rose by 2.3% on average after diet therapy and by 4.3% on average after diet plus pravastatin therapy. TG levels decreased by 1.2% on average after diet therapy and by 7.2% on average after diet plus pravastatin therapy (Table 2).
Incidence of Outcomes
The incidence of events was compared between women and men by Kaplan–Meier methods for fatal/nonfatal CHD, myocardial infarction, stroke, CVD, and total mortality during the 5-year follow-up (Figure 1). The incidence of all major events was consistently increased during the follow-up periods in both women and men, and the difference in the incidence rate between women and men did not change throughout the study period. The incidence ratios of the major end points during the 5-year follow-up in women and men by randomized group are shown in Figure 2. In women in the diet group, the incidence of CHD and CHD plus cerebral infarction was 2.9 and 4.6 per 1000 person-years, respectively, which was one-third that in men (8.9 and 12.9 per 1000 person-years, respectively), and the incidence of stroke and all-cause death was 2.7 and 3.1 per 1000 person-years, respectively, which was about one-half that seen in men (5.0 and 4.7 per 1000 person-years, respectively). In the diet plus pravastatin group, the difference between women and men for the incidence rates of these events was similar to that in the diet group.
Efficacy and Safety of Pravastatin Treatment
The incidence of CHD in women was proportionally lower by 25% (hazard ratio [HR], 0.75; 95% CI, 0.45 to 1.25) in the diet plus pravastatin group compared with the diet group, with no significant interaction (P=0.67 for interaction) between women and men (HR, 0.65; 95% CI, 0.41 to 1.02; Figures 1 and 2⇑). Furthermore, the incidence of stroke, CHD plus cerebral infarction, cerebral infarction plus transient ischemic attack, and all cardiovascular events for women was proportionally lower by 37% (HR, 0.63; 95% CI, 0.36 to 1.10), 26% (HR, 0.74; 95% CI, 0.50 to 1.12), 23% (HR, 0.77; 95% CI, 0.41 to 1.44), and 28% (HR, 0.72; 95% CI, 0.50 to 1.02), respectively, in the diet plus pravastatin versus diet group. Total mortality in women was lower by 41% (HR, 0.59; 95% CI, 0.35 to 0.997) in the diet plus pravastatin group compared with the diet group (Table 3 and Figure 1). The risk of major events was decreased by 41%, 34%, and 19% for CHD plus cerebral infarction, stroke, and total mortality, respectively, in men; no significant interaction was found between women and men (Figure 2).
In women, risk of events such as CHD rose with age and tended to rise particularly markedly in women ≥55 years of age at enrollment (Figure 3).
In the analysis according to age, diet plus pravastatin treatment reduced the incidence of CHD, CHD plus cerebral infarction, and stroke more markedly as age increased. The magnitude of risk reduction for CHD, CHD plus cerebral infarction, and stroke was greater by ≥30% in patients ≥55 years of age. No difference was observed between age and total mortality (Figure 4).
No difference was observed in the incidence of severe adverse events in women in the diet group (8.9%; n=242) and diet plus pravastatin group (9.6%; n=252). Tissue site and total incidence rate of cancer did not differ significantly between the 2 groups (n=78, 5.55/1000 person-years; and n=74, 5.46/1000 person-years, respectively; Table 4).
Of the patients enrolled in this study, ≈70% (5356 patients) were women, more than any previous study of statins and prevention. The results of the present analysis are based on detailed analyses of the women in the MEGA study. In the women in the MEGA study, the incidence of events was lower for women than for men, and the risk for women tended to rise with age, similar to the findings in previous reports.1–3 The generally low incidence of events in women requires a large sample size to make a valid comparison, which may have contributed to the lack of studies of women to date. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS),11 Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial–Lipid Lowering Trial (ALLHAT-LLT),14 Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA),15 and Heart Protection Study (HPS)16 studied primary prevention, and Scandinavian Simvastatin Survival Study (4S),8 Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID),12 Cholesterol and Recurrent Events (CARE),10 HPS,16 and Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)13 studied secondary prevention and conducted only subgroup analyses in women. Some studies demonstrated a 4% to 46% reduction in risk for relapse of CHD after treatment with statins in secondary prevention, but the reduction was statistically significant only in CARE. Among the primary prevention studies, the risk of developing CHD while on statins was significantly reduced by 24% in HPS and by 45% in AFCAPS/TexCAPS (P=NS), whereas in ALLHAT-LLT and ASCOT-LLA, no risk reduction associated with statin therapy was observed. In HPS, a significant reduction in the incidence of CHD was observed, but in AFCAPS/TexCAPS and ASCOT-LLA, there were not enough events to allow valid evaluation of the efficacy of statins in women. Moreover, ALLHAT-LLT was difficult to evaluate because a risk reduction was not observed in the main analysis.
In the present study, the incidence of cardiovascular events was lower in women than in men. Among background variables possibly associated with the risk for cardiovascular events, the percentage of smokers was lower in women. This may have contributed to the lower incidence of cardiovascular events in women than in men. Furthermore, the percentage of diabetic patients was much lower in women than in men. Body mass index and TG level were slightly lower in women. Thus, the lower percentage of women with risk factors is probably associated with the difference in the incidence of events between men and women. The influence of alcohol was not clear in the present study because alcohol intake was not measured. Thus, even with a low incidence of cardiovascular events, there was a 25% reduction in the risk of CHD with diet plus pravastatin therapy versus diet alone in the MEGA study. It is likely that the small number of events in MEGA did not allow detection of a statistical difference because the number of events experienced in present study was very low. In the comparison of risk reduction by diet plus pravastatin between men and women, the observed risk reduction for women compared with men was 25% versus 35% for CHD, 26% versus 41% for CHD plus cerebral infarction, 37% versus 34% for stroke, and 41% versus 19% for total mortality. Thus, although the incidence of CVD is 3 times lower in women than in men, women had a very similar risk reduction for overall CVD events compared with men. A significant interaction was not found between men and women for the major cardiovascular events, and these findings indicate that the best overall estimation of the effect of diet plus pravastatin treatment is based on the total population.
An epidemiological study showed that the incidence of CHD in women begins to rise sharply starting from 55 to 60 years of age, ie, at the onset of menopause.1 We observed that the incidence of CHD events rose with age in the present study (Figure 3). Because of reports that the pattern of the age-related increase of CHD in women tends to lag ≈10 years behind that in men,1,2,18 we evaluated the effect of pravastatin in relation to age and found that diet plus pravastatin treatment was more effective with increasing age in women and that the incidence of cardiovascular events was halved in older patients by diet plus pravastatin treatment in the present study. A similar observation has been reported with low-dose aspirin therapy25; no overall risk reduction for CVD events was seen in the total population, but there was a significant risk reduction in the patients ≥65 years of age (no data were reported for women 60 to 64 years). Although the exact distribution of age among women in past studies is not clear from the published reports, with the exception of PROSPER in which the mean age of women was 75 years,13 the mean age of women was ≈60 years in most previous studies and did not differ markedly from that in the present study, suggesting that these studies included relatively young patients in whom risk for cardiovascular events was low, probably leading to lack of evident difference in the magnitude of risk reduction between statin-treated and control groups. In the 2-year Canadian Coronary Atherosclerosis Intervention Trial (CCAIT) study with lovastatin,26 LDL-C level was decreased by ≈30% in both men and women, whereas progression of coronary artery stenosis was suppressed more significantly in women than in men. The estimated number needed to treat to prevent 1 event was the same in men and women in the meta-analysis of the secondary prevention trials,19 so there is no evidence for the view that the failure of statins to decrease the risk of CHD in women is associated with the mechanism of onset of CHD. The lack of evident reduction in CHD in women by statin therapy in past studies seems more likely attributable to the lack of statistical power because of the inclusion of a high percentage of relatively young patients whose risk for CHD events was very low.
In the present study, the effectiveness of pravastatin in younger women was not demonstrated because of an insufficient number of younger women enrolled to detect a difference. As recommended in the NCEP guidelines,27 coexisting risk factors should be taken into consideration when younger women are treated. In view of reports that the age-related incidence of hyperlipidemia and CHD rises in women ≈10 years later than in men, it is likely that the risk for cardiovascular events rises after menopause. It is an interesting question whether the onset of CHD events could be reduced further if cholesterol-lowering therapy were started at an earlier stage of hypercholesterolemia.
Similar to CHD, the risks for onset of stroke, CHD plus cerebral infarction, and all CVD were reduced in women in the pravastatin group by 37%, 26%, and 28%, respectively. The finding that pravastatin reduced the incidence of stroke is valuable. Calculated from absolute risk reduction in the present study, the number needed to treat to prevent 1 CHD event is 176 for women ≥55 years of age and 106 for women ≥60 years of age. For the combination of CHD plus cerebral infarction, the number needed to treat to prevent 1 event is 109 for women ≥55 years of age and 61 for women ≥60 years of age. This suggests that pravastatin may be expected to exert a particularly high efficacy in older women.
A significant reduction in total mortality was seen in the diet plus pravastatin group. Surprisingly, death from atherosclerotic causes was not reduced in women, and the reduction in total mortality was due primarily to a reduction in death from nonatherosclerotic diseases (primarily cancer). However, because the incidence of cancer was not different between the 2 treatment groups, the exact reason for this reduction in total mortality in the pravastatin plus diet group is unknown.
Severe adverse events (including cancers) did not significantly differ between the diet plus pravastatin and diet groups in women; notably, no increase in the incidence of cancers specific to women (ie, breast cancer, gynecologic genital cancer) was seen. Among previous studies, the CARE study reported that the incidence of breast cancer was significantly higher in a pravastatin group compared with a control group.10 However, considering that only 576 women were enrolled in the CARE study and that the present study included 10 times as many women and revealed a lower incidence of breast cancer in the diet plus pravastatin therapy group than in the diet alone group, it seems unlikely that taking pravastatin elevates the risk of developing breast cancer in women. These findings do not contradict the results of a meta-analysis of cancers that was recently reported.28
A limitation to consider when the results from this analysis are interpreted is that the proportional-hazards model for men regarding stroke did not appear to satisfy the proportional-hazards assumption (Figure 1C). The reason is that the occurrence of intracranial hemorrhage in men was higher in the diet plus pravastatin group than in the diet group during the first 12 months of follow-up (6 versus 1 event). However, judging from the Kaplan–Meier curves, this likely does not affect the overall conclusions. Another limitation is that the analyses in the subgroups of women according to age are exploratory because of the small numbers of events and multiple statistical testing. Thus, we need to interpret the results for these analyses with caution.
The fact that the data are from Japanese people whose risk for CVD is low compared with other countries1 is also a limitation for this analysis. The incidence of CHD is quite low for Japanese people, and the incidence of stroke differs markedly between Japanese and Western people. Although the reason for this is not entirely clear, it has been speculated that the Japanese lifestyle plays an important role because a higher incidence of CHD was observed in the Honolulu Heart Program in Japanese who migrated to Hawaii or California than in Japanese living in Japan.29 The lack of an evidently significant difference for CHD in women in the present study also seems to be attributable to the low incidence of CHD among Japanese people. However because a risk reduction with statins was observed regardless of risk factors in different populations in a large meta-analysis,30 the results of the present study may be applicable to non-Japanese populations. Because the present study was an open-label study, we took great care to avoid bias in the conduct of this study. To that end, adjudication of end points was done by the End Points Committee, which was blinded to treatment. Furthermore, detailed information about the end points for each group was collected by a contract research organization that was independent of the sponsor. In addition, physicians could at their discretion prescribe statin therapy, either the study drug or another statin, even to patients in the diet only group to limit dropouts. Because the study subjects were followed up as outpatients and are insured by a single-payer national health insurance system, it seems unlikely that treatment differed much between patients other than the allocation to study group. Yet, because we cannot rule out unpredictable bias, it is desirable to carry out a double-blind study of the effect of statins in preventing ischemic heart disease with a target set for women, especially the middle-aged and elderly population.
We thank all the study participants, physicians, comedical staff, and coworkers.
Sources of Funding
The MEGA study publication committee controlled the writing of this manuscript, and all analyses were conducted in the MEGA study data center. Research funds were provided by the Japanese Ministry of Health, Labor, and Welfare for the first 2 years of the study; thereafter, the study was funded by Sankyo Pharmaceutical (now Daiichi-Sankyo Co, Ltd) Tokyo.
The following authors have received consultant fees, travel fees, lecture fees, and/or research grants from the following companies: Dr Mizuno, Daiichi Sankyo, Pfizer, Novartis, Mitsubishi Tanabe, Pfizer, Kowa, Banyu, Astellas, AstraZeneca; Dr Nakaya, Daiichi Sankyo, Banyu, Novartis, Pfizer, Kowa, AstraZeneca; Dr Ohashi, Daiichi Sankyo, Banyu, Astellas, Pfizer, Kowa; Dr Tajima, Daiichi Sankyo, Banyu, Novartis, Astellas; Dr Kushiro, Daiichi Sankyo; Dr Teramoto, Daiichi Sankyo, Banyu, Novartis, Astellas, Pfizer, Kowa, AstraZeneca, Shionogi; Dr Uchiyama, Daiichi Sankyo, Pfizer, Novartis, Mitsubishi Tanabe, Pfizer, Kowa, Banyu, Astellas, AstraZeneca; and Dr Nakamura, Daiichi Sankyo, Banyu, Astellas.
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The beneficial effect of statin treatment in reducing the risk of cardiovascular disease is well known from the findings of many large-scale randomized clinical trials. However, there has been some debate about the use of statins in women because of their lower cardiovascular risk compared with men. Notably, a similar reduction in cardiovascular end points was demonstrated with statin use in women and men in the present analysis of the Management of Elevated Cholesterol in the Primary Prevention Groups of Adult Japanese (MEGA) study. Specifically, pravastatin reduced coronary heart disease by 25% and 35%, coronary heart disease and cerebral infarction by 26% and 41%, stroke by 37% and 34%, and total mortality by 41% and 19% in women and men, respectively. Moreover, the beneficial primary prevention effect was more marked in older women. Thus, these findings indicate that it is appropriate and beneficial to consider statin treatment in women with elevated lipids but without a history of cardiovascular disease to reduce their future risk, especially in older women. Long-term use of statin therapy was shown to be safe in the MEGA study, without any increase in serious adverse problems, including female specific cancer.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00211705.