The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease.

Data from laboratory studies, observational research, and/or secondary prevention trials suggest that vitamin D and marine omega-3 fatty acids may reduce risk for cancer or cardiovascular disease (CVD), but primary prevention trials with adequate dosing in general populations (i.e., unselected for disease risk) are lacking. The ongoing VITamin D and OmegA-3 TriaL (VITAL) is a large randomized, double-blind, placebo-controlled, 2 x 2 factorial trial of vitamin D (in the form of vitamin D(3) [cholecalciferol], 2000 IU/day) and marine omega-3 fatty acid (Omacor fish oil, eicosapentaenoic acid [EPA]+docosahexaenoic acid [DHA], 1g/day) supplements in the primary prevention of cancer and CVD among a multi-ethnic population of 20,000 U.S. men aged ≥ 50 and women aged ≥ 55. The mean treatment period will be 5 years. Baseline blood samples will be collected in at least 16,000 participants, with follow-up blood collection in about 6000 participants. Yearly follow-up questionnaires will assess treatment compliance (plasma biomarker measures will also assess compliance in a random sample of participants), use of non-study drugs or supplements, occurrence of endpoints, and cancer and vascular risk factors. Self-reported endpoints will be confirmed by medical record review by physicians blinded to treatment assignment, and deaths will be ascertained through national registries and other sources. Ancillary studies will investigate whether these agents affect risk for diabetes and glucose intolerance; hypertension; cognitive decline; depression; osteoporosis and fracture; physical disability and falls; asthma and other respiratory diseases; infections; and rheumatoid arthritis, systemic lupus erythematosus, thyroid diseases, and other autoimmune disorders.

A randomized trial of rosuvastatin in the prevention of venous thromboembolism.

BACKGROUND: Controversy persists regarding the extent of shared pathways between arterial and venous thrombosis and whether treatments of known efficacy for one disease process have consistent benefits for the other. Observational studies have yielded variable estimates of the effect of statin therapy on the risk of venous thromboembolism, and evidence from randomized trials is lacking. METHODS: We randomly assigned 17,802 apparently healthy men and women with both low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to receive rosuvastatin, 20 mg per day, or placebo. We followed participants for the first occurrence of pulmonary embolism or deep-vein thrombosis and performed analyses of the data on an intention-to-treat basis. RESULTS: During a median follow-up period of 1.9 years (maximum, 5.0), symptomatic venous thromboembolism occurred in 94 participants: 34 in the rosuvastatin group and 60 in the placebo group. The rates of venous thromboembolism were 0.18 and 0.32 event per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio with rosuvastatin, 0.57; 95% confidence interval [CI], 0.37 to 0.86; P=0.007); the corresponding rates for unprovoked venous thromboembolism (i.e., occurring in the absence of a known malignant condition, trauma, hospitalization, or surgery) were 0.10 and 0.17 (hazard ratio, 0.61; 95% CI, 0.35 to 1.09; P=0.09) and for provoked venous thromboembolism (i.e., occurring in patients with cancer or during or shortly after trauma, hospitalization, or surgery), 0.08 and 0.16 (hazard ratio, 0.52; 95% CI, 0.28 to 0.96; P=0.03). The rates of pulmonary embolism were 0.09 in the rosuvastatin group and 0.12 in the placebo group (hazard ratio, 0.77; 95% CI, 0.41 to 1.45; P=0.42), whereas the rates of deep-vein thrombosis only were 0.09 and 0.20, respectively (hazard ratio, 0.45; 95% CI, 0.25 to 0.79; P=0.004). Consistent effects were observed in all the subgroups examined. No significant differences were seen between treatment groups in the rates of bleeding episodes. CONCLUSIONS: In this trial of apparently healthy persons, rosuvastatin significantly reduced the occurrence of symptomatic venous thromboembolism. (ClinicalTrials.gov number, NCT00239681.)

Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial.

BACKGROUND: Statins lower high-sensitivity C-reactive protein (hsCRP) and cholesterol concentrations, and hypothesis generating analyses suggest that clinical outcomes improve in patients given statins who achieve hsCRP concentrations less than 2 mg/L in addition to LDL cholesterol less than 1.8 mmol/L (<70 mg/dL). However, the benefit of lowering both LDL cholesterol and hsCRP after the start of statin therapy is controversial. We prospectively tested this hypothesis. METHODS: In an analysis of 15 548 initially healthy men and women participating in the JUPITER trial (87% of full cohort), we prospectively assessed the effects of rosuvastatin 20 mg versus placebo on rates of non-fatal myocardial infarction, non-fatal stroke, admission for unstable angina, arterial revascularisation, or cardiovascular death (prespecified endpoints) during a maximum follow-up of 5 years (median 1.9 years), according to on-treatment concentrations of LDL cholesterol (>/=1.8 mmol/L or <1.8 mmol/L) and hsCRP (>/=2 mg/L or <2 mg/L). We included all events occurring after randomisation. This trial is registered with ClinicalTrials.gov, number NCT00239681. FINDINGS: Compared with placebo, participants allocated to rosuvastatin who achieved LDL cholesterol less than 1.8 mmol/L had a 55% reduction in vascular events (event rate 1.11 vs 0.51 per 100 person-years; hazard ratio [HR] 0.45, 95% CI 0.34-0.60, p<0.0001), and those achieving hsCRP less than 2 mg/L a 62% reduction (event rate 0.42 per 100 person-years; HR 0.38, 95% CI 0.26-0.56, p<0.0001). Although LDL cholesterol and hsCRP reductions were only weakly correlated in individual patients (r values <0.15), we recorded a 65% reduction in vascular events in participants allocated to rosuvastatin who achieved both LDL cholesterol less than 1.8 mmol/L and hsCRP less than 2 mg/L (event rate 0.38 per 100 person-years; adjusted HR 0.35, 95% CI 0.23-0.54), versus a 33% reduction in those who achieved one or neither target (event rate 0.74 per 100 person-years; HR 0.67, 95% CI 0.52-0.87) (p across treatment groups <0.0001). In participants who achieved LDL cholesterol less than 1.8 mmol/L and hsCRP less than 1 mg/L, we noted a 79% reduction (event rate 0.24 per 100 person-years; HR 0.21, 95% CI 0.09-0.52). Achieved hsCRP concentrations were predictive of event rates irrespective of the lipid endpoint used, including the apolipoprotein B to apolipoprotein AI ratio. INTERPRETATION: For people choosing to start pharmacological prophylaxis, reduction in both LDL cholesterol and hsCRP are indicators of successful treatment with rosuvastatin.

Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.

BACKGROUND: Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment. METHODS: We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes. RESULTS: The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes. CONCLUSIONS: In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.)

Combination therapy versus monotherapy as initial treatment for stage 2 hypertension: a prespecified subgroup analysis of a community-based, randomized, open-label trial.

BACKGROUND: Current guidelines suggest consideration of initial combination therapy for patients with stage 2 hypertension, but rates of hypertension treatment and control in clinical practice vary according to age, race, sex, and body mass index (BMI). OBJECTIVE: This was a prespecified subgroup analysis of one of the primary efficacy end points-mean change in systolic blood pressure (SBP) at 6 weeks -in a previously published community-based, randomized, open-label trial comparing valsartan monotherapy with valsartan/hydrochlorothiazide (HCTZ) combination therapy as initial treatment for high-risk patients with stage 2 hypertension. METHODS: Eligible participants with stage 2 hypertension (SBP >or=160 mm Hg and/or diastolic blood pressure [DBP] >or=100 mm Hg) were treated with valsartan 160 mg/d or valsartan/HCTZ 160/12.5 mg/d for 2 weeks, followed by forced titration to valsartan 320 mg/d or valsartan/HCTZ 320/12.5 mg/d for an additional 4 weeks. In addition to the primary blood pressure end point (change in SBP at 6 weeks), secondary blood pressure end points at 6 weeks included changes in DBP and the proportion of patients achieving a blood pressure control threshold of <140/90 mm Hg (<130/80 mm Hg for patients with diabetes), as recommended by the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7). The subgroups of interest were women, blacks, Hispanics, the elderly (age >or=65 years), patients with diabetes, smokers, and lean, overweight, and obese subjects (BMI <25, 25-<30, and =30 kg/m(2), respectively). RESULTS: The randomized trial included 1668 patients (756 [45.3%] female, 392 [23.5%] black, 109 [6.5%] Hispanic, 220 [13.2%] elderly, 970 of 1641 [59.1%] obese, 166 [10.0%] with diabetes, 467 [28.0%] smokers) with stage 2 hypertension. Among those allocated to combination therapy compared with monotherapy, the mean (SD) change in SBP at 6 weeks was -27.4 (18.5) and -19.3 (17.7) mm Hg in women, -21.4 (17.6) and -12.6 (18.5) mm Hg in black subjects, -21.7 (17.6) and -16.3 (16.5) mm Hg in Hispanic subjects, -25.5 (20.2) and -16.9 (17.9) mm Hg in the elderly, and -23.6 (18.1) and -15.9 (16.2) mm Hg in obese subjects. With the exception of the results for Hispanics, all comparisons of combination therapy and monotherapy were statistically significant (Por=65 years (43.9% vs 24.5%; P=0.004), overweight subjects (49.0% vs 31.2%; P<0.001), and obese subjects (41.4% vs 26.0%; P<0.001). In the entire study cohort, patients assigned to combination therapy had a significantly higher incidence of dizziness compared with those assigned to monotherapy (8.5% vs 4.7%; P=0.002); however, there was no statistically significant difference in the frequency of adverse events between treatment groups in the prespecified subgroups. CONCLUSIONS: Across various subgroups of patients with stage 2 hypertension, combination therapy was consistently associated with a significantly greater reduction in SBP than monotherapy. With the exception of a significantly greater increase in dizziness compared with monotherapy, combination therapy was well tolerated.

Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial.

CONTEXT: Recent randomized trials among patients with preexisting cardiovascular disease (CVD) have failed to support benefits of B-vitamin supplementation on cardiovascular risk. Observational data suggest benefits may be greater among women, yet women have been underrepresented in published randomized trials. OBJECTIVE: To test whether a combination of folic acid, vitamin B6, and vitamin B12 lowers risk of CVD among high-risk women with and without CVD. DESIGN, SETTING, AND PARTICIPANTS: Within an ongoing randomized trial of antioxidant vitamins, 5442 women who were US health professionals aged 42 years or older, with either a history of CVD or 3 or more coronary risk factors, were enrolled in a randomized, double-blind, placebo-controlled trial to receive a combination pill containing folic acid, vitamin B6, and vitamin B12 or a matching placebo, and were treated for 7.3 years from April 1998 through July 2005. INTERVENTION: Daily intake of a combination pill of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12. MAIN OUTCOME MEASURES: A composite outcome of myocardial infarction, stroke, coronary revascularization, or CVD mortality. RESULTS: Compared with placebo, a total of 796 women experienced a confirmed CVD event (406 in the active group and 390 in the placebo group). Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point (226.9/10,000 person-years vs 219.2/10,000 person-years for the active vs placebo group; relative risk [RR], 1.03; 95% confidence interval [CI], 0.90-1.19; P = .65), as well as for the secondary outcomes including myocardial infarction (34.5/10,000 person-years vs 39.5/10,000 person-years; RR, 0.87; 95% CI, 0.63-1.22; P = .42), stroke (41.9/10,000 person-years vs 36.8/10,000 person-years; RR, 1.14; 95% CI, 0.82-1.57; P = .44), and CVD mortality (50.3/10,000 person-years vs 49.6/10,000 person-years; RR, 1.01; 95% CI, 0.76-1.35; P = .93). In a blood substudy, geometric mean plasma homocysteine level was decreased by 18.5% (95% CI, 12.5%-24.1%; P < .001) in the active group (n = 150) over that observed in the placebo group (n = 150), for a difference of 2.27 micromol/L (95% CI, 1.54-2.96 micromol/L). CONCLUSION: After 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6, and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000541.

A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: results from the Women's Antioxidant Cardiovascular Study.

BACKGROUND: Randomized trials have largely failed to support an effect of antioxidant vitamins on the risk of cardiovascular disease (CVD). Few trials have examined interactions among antioxidants, and, to our knowledge, no previous trial has examined the individual effect of ascorbic acid (vitamin C) on CVD. METHODS: The Women's Antioxidant Cardiovascular Study tested the effects of ascorbic acid (500 mg/d), vitamin E (600 IU every other day), and beta carotene (50 mg every other day) on the combined outcome of myocardial infarction, stroke, coronary revascularization, or CVD death among 8171 female health professionals at increased risk in a 2 x 2 x 2 factorial design. Participants were 40 years or older with a history of CVD or 3 or more CVD risk factors and were followed up for a mean duration of 9.4 years, from 1995-1996 to 2005. RESULTS: A total of 1450 women experienced 1 or more CVD outcomes. There was no overall effect of ascorbic acid (relative risk [RR], 1.02; 95% CI, 0.92-1.13 [P = .71]), vitamin E (RR, 0.94; 95% CI, 0.85-1.04 [P = .23]), or beta carotene (RR, 1.02; 95% CI, 0.92-1.13 [P = .71]) on the primary combined end point or on the individual secondary outcomes of myocardial infarction, stroke, coronary revascularization, or CVD death. A marginally significant reduction in the primary outcome with active vitamin E was observed among the prespecified subgroup of women with prior CVD (RR, 0.89; 95% CI, 0.79-1.00 [P = .04]; P value for interaction, .07). There were no significant interactions between agents for the primary end point, but those randomized to both active ascorbic acid and vitamin E experienced fewer strokes (P value for interaction, .03). CONCLUSION: There were no overall effects of ascorbic acid, vitamin E, or beta carotene on cardiovascular events among women at high risk for CVD.

Valsartan, blood pressure reduction, and C-reactive protein: primary report of the Val-MARC trial.

Increased levels of high-sensitivity C-reactive protein (hsCRP) are associated with incident hypertension as well as cardiovascular events, and angiotensin II is a potent proinflammatory mediator. However, whether angiotensin receptor blockade lowers hsCRP is uncertain. We performed a randomized trial in which 1668 patients with stage 2 hypertension were treated with 160 mg valsartan or 160/12.5 mg valsartan/hydrochlorothiazide (HCTZ) once daily for 2 weeks with forced titration to 320 mg valsartan or 320/12.5 mg valsartan/HCTZ for an additional 4 weeks. After 6 weeks, systolic blood pressure (-25 versus -18 mm Hg; P<0.001) and diastolic blood pressure (-14 versus -9 mm Hg; P<0.001) were reduced to a greater degree among those allocated to valsartan/HCTZ than to valsartan monotherapy. The median change in hsCRP was -0.12 mg/L among those allocated to valsartan compared with +0.05 mg/L among those allocated to valsartan/HCTZ, a 13.3% difference (P<0.001); this difference between valsartan and valsartan/HCTZ was present in all subgroups evaluated despite the fact that blood pressure reduction was greater in the combined therapy group. No relationship was observed between hsCRP reduction and blood pressure; in all analyses, the proportion of variation in change in hsCRP with valsartan monotherapy explained by change in blood pressure was <2%. Thus, in this prospective trial, valsartan reduced hsCRP levels in a manner independent of degree of blood pressure reduction. These data raise the hypothesis that angiotensin receptor blockade may have anti-inflammatory effects in addition to blood pressure-lowering effects.

The Women's Antioxidant Cardiovascular Study: design and baseline characteristics of participants.

BACKGROUND: The evidence for a potential benefit of antioxidant vitamins and folic acid in cardiovascular disease (CVD) prevention is derived from laboratory, clinical, and observational epidemiological studies but remains inconclusive. Large-scale randomized trials with clinical end points are necessary to minimize confounding and provide unbiased estimates of the balance of benefits and risks, yet data from such trials are scarce, especially among women. METHODS: The Women's Antioxidant Cardiovascular Study (WACS) is a randomized, double-blind, placebo-controlled trial testing whether antioxidant vitamins and a folic acid/vitamin B(6)/vitamin B(12) combination prevent future cardiovascular events among women with preexisting CVD or >or=3 CVD risk factors. This paper describes the design of the trial and baseline characteristics of participants, evaluates the success of randomization, and addresses the generalizability of future findings. RESULTS: In a factorial design, 8171 U.S. female health professionals aged >or=40 years were randomized to vitamin E, vitamin C, beta-carotene, or placebos. Of these women, 5442 were also subsequently randomized to folic acid/vitamin B(6)/vitamin B(12) or placebo. The randomization was successful, as evidenced by similar distributions of baseline demographic, health, and behavioral characteristics across treatment groups. The clinical profile of participants was similar to that observed in another large trial of women with CVD. CONCLUSIONS: The similar distribution of known potential confounders across treatment groups provides reassurance that unmeasured or unknown potential confounders are also equally distributed. Although a definitive conclusion regarding generalizability requires additional trials in diverse populations, there is little biological basis for supposing that the benefit-risk balance differs in other high-risk women.