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Reduction of Cardiovascular Events With Icosapent Ethyl (Vascepa) -Intervention Trial - REDUCE-IT / 20% to 28% improved CVD outcomes "highly impressive" !
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"breakthrough trial" at this AHA conference. "TG seem to be a causal risk factor, not quite as potent as LDL, you need to reduce TG a lot to get the same benefits you get from reducing LDL a lot". This study was in people with CVD risk including some had diabetes, and high TG; treated with icosapent ethyl - (Vascepa) - (2 g twice daily with food).
https://www.acc.org/latest-in-cardiology/clinical-trials/2018/11/08/22/48/reduce-it
Contribution To Literature:
The REDUCE-IT trial showed that use of icosapent ethyl 2 g twice daily was superior to placebo in reducing TGs, CV events, and CV death among patients with high TGs and either known CV disease or those at high risk for developing it, and who were already on statin therapy with relatively well-controlled LDL levels.
Description:
The goal of the trial was to assess the safety and benefit of icosapent ethyl compared with placebo in reducing cardiovascular (CV) events among patients with high triglycerides (TGs).
Study Design
Eligible patients were randomized in a 1:1 fashion to either icosapent ethyl (2 g twice daily with food) (n = 4,089) or matching placebo (n = 4,090). Randomization was stratified by primary vs. secondary prevention, use of ezetimibe, and geographic region.
• Total number of enrollees: 19,212
• Duration of follow-up: 4.9 years
• Mean patient age: 64.0 years
• Percentage female: 28%
Inclusion criteria:
• Age >45 years with established CV disease or age >50 years with diabetes and ≥1 additional risk factor
• Fasting TG level from 150-499 mg/dl
• Low-density lipoprotein (LDL) cholesterol level from 41 and 100 mg/dl
• Stable dose of statin for ≥4 weeks
Exclusion criteria:
• Severe heart failure
• Active severe liver disease
• Glycated hemoglobin level >10.0%
• Planned coronary intervention or surgery
• History of acute or chronic pancreatitis
• Known hypersensitivity to fish, shellfish, or ingredients of icosapent ethyl or placebo
Other salient features/characteristics:
• Secondary prevention cohort: 70.7%
• Ezetimibe use: 6.4%
• Moderate- or high-intensity statin: 94%
• Diabetes: 59%
• Median TG levels at baseline: 216 mg/dl, LDL: 75 mg/dl, high-density lipoprotein: 40 mg/dl, high-sensitivity C-reactive protein: 2.2
Principal Findings:
The primary CV outcome of CV death, nonfatal myocardial infarction (MI), stroke, coronary revascularization, or unstable angina, for icosapent ethyl vs. placebo, was 17.2% vs. 22.0%, hazard ratio 0.75, 95% confidence interval 0.68-0.83; p < 0.0001
Secondary outcomes, for icosapent ethyl vs. placebo:
• Change in TG levels at 1 year: -39.0 mg/dl vs. 4.5 mg/dl
• Change in LDL at 1 year: 2 mg/dl vs. 7 mg/dl
• CV death or MI: 9.6% vs.12.4%, p < 0.001
• All MI: 6.1% vs. 8.7%, p < 0.001
• Revascularization: 5.3% vs. 7.8%, p < 0.001
• All-cause mortality: 6.7% vs. 7.6%, p = not significant
• Atrial fibrillation/flutter: 5.3% vs. 3.9%
• Serious adverse bleeding events: 2.7% vs. 2.1%, p = 0.06
Interpretation:
The results of this trial indicate that the use of icosapent ethyl 2 g twice daily was superior to placebo in reducing TGs, CV events, and CV death among patients with high TGs and either known CV disease or those at high risk for developing it, and who were already on statin therapy with relatively well-controlled LDL levels. Rates of revascularization and MI were lower, while atrial fibrillation/flutter and bleeding were higher with icosapent ethyl.
These are very interesting findings, and come on the heels of several negative trials with n-3 fatty acid supplementation. One aspect of this medication is that it has a higher dose of purified eicosapentaenoic acid (EPA) (4 g/day) than what was tested in other clinical trials. Other trials with moderate to high doses of EPA are ongoing. This is one of the first non-LDL targeted trials to show a CV benefit, and will likely be featured in future guidelines.
References:
Bhatt DL, Steg G, Miller M, et al., on behalf of the REDUCE-IT Investigators. Cardiovascular Risk Reduction With Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med 2018;Nov 10:[Epub ahead of print].
Editorial: Kastelein JJ, Stroes ES. FISHing for the Miracle of Eicosapentaenoic Acid. N Engl J Med 2018;Nov 16:[Epub ahead of print].
Presented by Dr. Deepak Bhatt at the American Heart Association Annual Scientific Sessions (AHA 2018), Chicago, IL, November 10, 2018.
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Vitamin D and Omega-3 Trial - VITAL
Nov 10, 2018
Video of study author interview:
https://www.acc.org/latest-in-cardiology/clinical-trials/2018/11/08/22/42/vital
Presented by Dr. JoAnn E. Manson at the American Heart Association Annual Scientific Sessions (AHA 2018), Chicago, IL, November 10, 2018.
also this additional interview: https://www.youtube.com/watch?v=tjzju6fElZM -
You have to listen to interview study author to understand study outcomes - says for fish eaters (1.5 servings of fish per week there was no benefit regarding MACE & MI, but for those eating less fish there was a MACE (19%) & MI (40%) benefit. But she recommends eating fish for benefits - BUT "to be interpreted with caution" additional data needed, its a signal, says Steve Nissen MD listen to both interviews, need confirmation of findings. In 3rd interview Kim Eagle MD says these supplements are not helpful. He also discusses methotrexate study at AGHA, it did not improve key inflammation markers. Jules
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Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial - REDUCE-IT
https://www.youtube.com/watch?v=erhAaxhOqgw
Drs. Peter Block and Kim Eagle discuss vitamin D and omega-3 fatty acid supplements in primary prevention (VITAL); low dose methotrexate for atherosclerotic event prevention (CIRT); in this high risk group fish oil high dose was beneficial - CV risk reduction with icosapent ethyl (Vascepa) for hypertriglyceridemia (4 grams of this fish oil substance) - 25% BENEFIT (REDUCE-IT). Visit http://www.acc.org/AHA2018 for full meeting coverage.
Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial ("high dose, highly purified EPA", study author Deepak Bhatt MD says) - REDUCE-IT
average TG were 260 mg/dl
Study Design
Eligible patients were randomized in a 1:1 fashion to either icosapent ethyl (2 g twice daily with food) (n = 4,089) or matching placebo (n = 4,090). Randomization was stratified by primary vs. secondary prevention, use of ezetimibe, and geographic region.
• Total number of enrollees: 19,212
• Duration of follow-up: 4.9 years
• Mean patient age: 64.0 years
• Percentage female: 28%
Inclusion criteria:
• Age >45 years with established CV disease or age >50 years with diabetes and ≥1 additional risk factor
• Fasting TG level from 150-499 mg/dl
• Low-density lipoprotein (LDL) cholesterol level from 41 and 100 mg/dl
• Stable dose of statin for ≥4 weeks
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VITAL: The VITamin D and OmegA-3 TriaL (VITAL): Principal Results for Vitamin D and Omega-3 Fatty Acid Supplementation in the Primary Prevention of Cardiovascular Disease and Cancer
Contribution To Literature:
The VITAL trial showed that supplementation with either n-3 fatty acid at a dose of 1 g/day or vitamin D3 at a dose of 2000 IU/day was not effective for primary prevention of CV or cancer events among healthy middle-aged men and women over 5 years of follow-up.
Description:
The goal of the trial was to assess the cardiovascular (CV) and cancer benefits of n-3 (also called omega-3) fatty acid and vitamin D3 supplementation compared with placebo among healthy participants.
Study Design
In a 2 x 2 factorial design, healthy participants were randomized in a 1:1 fashion to either vitamin D3 (at a dose of 2000 IU per day) (n = 12,927) or placebo (n = 12,944), or n-3 fatty acids (1 g per day as a fish-oil capsule containing 840 mg of n-3 fatty acids, including 460 mg of eicosapentaenoic acid [EPA] and 380 mg of docosahexaenoic acid [DHA]) (n = 12,933) or matching placebo (n = 12,938).
• Total number of enrollees: 25,871
• Duration of follow-up: 5.3 years
• Mean patient age: 67.1 years
• Percentage female: 51%
Inclusion criteria:
• Men >50 years or women >55 years
• No known cardiovascular disease or cancer
Exclusion criteria:
• Renal failure or dialysis
• Cirrhosis
• History of hypercalcemia
Other salient features/characteristics:
• African American: 20%
• Mean body mass index: 28 kg/m2
• Diabetes: 13.7%
Principal Findings:
The primary CV outcome of CV death, nonfatal myocardial infarction (MI), or stroke, for vitamin D3 vs. placebo, was 3.1% vs. 3.2%, hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.85-1.1.
• CV death: 1.1% vs. 1.1%, for vitamin D3 vs. placebo, respectively
• Stroke: 1.1% vs. 1.1%
• MI: 1.1% vs. 1.5%, HR 0.72, 95% CI 0.59-0.90
• Primary cancer outcome, invasive cancer: 6.1% vs. 6.4%, HR 0.96, 95% CI 0.88-1.06
The primary CV outcome of CV death, nonfatal MI, or stroke, for n-3 fatty acid vs. placebo, was 3.0% vs. 3.2%, HR 0.92, 95% CI 0.80-1.06, p = 0.24.
• CV death: 1.2% vs. 1.1%, for n-3 fatty acid vs. placebo, respectively
• Stroke: 1.1% vs. 1.1%
• MI: 1.3% vs. 1.3%
• Primary cancer outcome, invasive cancer: 6.3% vs. 6.2%, HR 1.03, 95% CI 0.93-1.13, p = 0.56
Secondary outcomes for vitamin D3 vs. placebo:
• All-cause mortality: 3.8% vs. 3.8%
Secondary outcomes for n-3 fatty acid vs. placebo:
• Total coronary heart disease: 0.3% vs. 0.4%
• All-cause mortality: 3.8% vs. 3.7%
Interpretation:
The results of this trial indicate that supplementation with either n-3 fatty acid at a dose of 1 g/day or vitamin D3 at a dose of 2000 IU/day was not effective for primary prevention of CV or cancer events among healthy middle-aged men and women over 5 years of follow-up. This is one of the largest trials on this topic. The finding of a lower MI risk with n-3 fatty acid is hypothesis generating and deserves further study. The authors also noted some interaction with baseline fish consumption, with greater CV benefit observed among participants who had low fish intake at baseline.
References:
Manson JE, Cook NR, Lee IM, et al., on behalf of the VITAL Research Group. Vitamin D Supplements and Prevention of Cancer and Cardiovascular Disease. N Engl J Med 2018;Nov 10:[Epub ahead of print].
Manson JE, Cook NR, Lee IM, et al., on behalf of the VITAL Research Group. Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N Engl J Med 2018;Nov 10:[Epub ahead of print].
Editorial: Keaney JF Jr, Rosen CJ. VITAL Signs for Dietary Supplementation to Prevent Cancer and Heart Disease. N Engl J Med 2018;Nov 10:[Epub ahead of print].
Presented by Dr. JoAnn E. Manson at the American Heart Association Annual Scientific Sessions (AHA 2018), Chicago, IL, November 10, 2018.
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