This randomized controlled trial tested the effects of eicosapentaenoic acid (EPA) supplementation on major coronary events in 18,645 Japanese patients taking statins. Patients received either EPA capsules totaling 1,800 mg daily or a placebo in addition to statin treatment for an average of 4.6 years. The primary endpoint was major coronary events including sudden cardiac death and heart attacks. The EPA group had a 19% lower relative risk of major coronary events compared to the control group. Specifically, EPA reduced non-fatal coronary events such as unstable angina. EPA supplementation showed benefits for both primary and secondary prevention of major coronary events in hypercholesterolemic patients taking statins.
The document summarizes the Japan EPA Lipid Intervention Study (JELIS), a large clinical trial examining whether EPA (eicosapentaenoic acid) can improve cardiovascular outcomes when added to HMG-CoA reductase inhibitor treatment in patients with hypercholesterolemia. JELIS involves over 18,000 Japanese participants randomized to receive EPA plus statin or statin alone. The primary endpoint is major coronary events over 5 years. Baseline characteristics showed patients had moderately elevated cholesterol. Results are expected in 2005 to determine if EPA provides additional cardiovascular benefit beyond statin therapy alone.
1. Recurrent myocardial infarction (MI) after primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) occurs in about 21% of patients and is associated with worse clinical outcomes.
2. Recurrent MI significantly increases the risks of subsequent cardiac mortality, noncardiac mortality, stroke, and bleeding.
3. Early recurrent MIs within 1 day of the initial PPCI are associated with higher unadjusted cardiac mortality compared to later recurrent MIs, but after adjustment, recurrent MIs occurring more than 1 year after PPCI carry the highest risk of cardiac death.
This expert consensus document from the World Heart Federation provides recommendations for antiplatelet therapy in East Asian patients with acute coronary syndrome or undergoing percutaneous coronary intervention. While current guidelines are based primarily on large Western clinical trials, few East Asian patients were included. Additionally, East Asians have differing risk profiles and responses to antiplatelet drugs compared to white patients. This consensus aims to determine the most appropriate antiplatelet strategies for East Asians based on available evidence.
Impact of statins and beta-blocker therapy on mortality after coronary artery...Paul Schoenhagen
Abstract
Background: We conducted a retrospective cohort study of patients after first-time isolated coronary artery bypass graft surgery (CABG) and assessed the impact of a discharge regimen including beta-blockers and statin therapy and their relationship to long-term all cause mortality and major adverse cardiovascular events (MACE).
Methods: We identified patients age >18 years, undergoing first time isolated CABG from 1993 to 2005. Patients were identified using the Cardiovascular Information Registry (CVIR). We collected follow-up information at 30, 60, 90 days and yearly follow-up. The registry is approved for use in research by the institutional review broad.
Results: We identified 5,205 patients who underwent single isolated CABG between January 1993 and December 2005. The mean age was 64.5±9.7 years and over 70% were male. There was a significant difference in the low density lipoproteins (LDL) concentration between those with or without statin medications (134±41.9 mg/dL) (no statin) vs. 126±44.8 mg/dL (with statin), P=0.001. A discharge regimen with statin therapy was associated with and overall reduction in 30 day, 1 year and long-term mortality. In addition, overall the triple ischemic endpoint of death, myocardial infarction (MI) and stroke was also significantly lower in the statin vs. no-statin group. In addition, statin and beta-blockers exerted synergistic effect on overall mortality outcomes short-term and in the long-term. We note that the predictors of overall death include no therapy with statin therapy and age [hazard ratios (HR) 1.1, 95% CI: 1.04-1.078, P<0.001] and presence of renal failure (HR 2.0, P=0.005). The estimated 11-year Kaplan Meier curves for mortality between the two groups starts to diverge immediately post discharge after single isolated CABG and continue to diverge through out the follow-up period.
Conclusions: A post-discharge regimen of statins independently reduces overall and 1 year mortality. These results confirm those of earlier studies within a contemporary surgical population and support the current clinical guidelines.
- Several large clinical trials have validated the use of beta-blockers in heart failure patients. Trials such as CIBIS II, MERIT-HF, and COPERNICUS showed reductions in mortality of 34-35% with bisoprolol, metoprolol, and carvedilol respectively compared to placebo in heart failure patients.
- The SENIORS trial also showed reductions in mortality and hospitalization with nebivolol compared to placebo in older heart failure patients (average age 76 years). A sub-analysis of the MERIT-HF trial found even larger mortality reductions of 37% in patients over 65 years of age with reduced ejection fraction.
- Therefore, beta-
This patient is a 37-year-old man with type 2 diabetes, hypertension, dyslipidemia, and a family history of coronary artery disease. Examination found elevated blood pressure and LDL, as well as signs of sympathetic overactivity.
Given the patient's sympathetic overactivity, diabetes, hypertension, and family history of CAD, treatment with a beta-blocker and high-intensity statin is recommended. Metoprolol is preferred as it has a short half-life, is excreted through the liver, and does not accumulate in renal impairment. Intensifying the statin dose is also needed given the patient's multiple risk factors to achieve a target LDL lower than 100 mg/dL.
Effects of aspirin for primary prevention in persons with Diabetes mellitusShadab Ahmad
This study evaluated the effects of low-dose aspirin (100 mg daily) for primary prevention of vascular events in 15,480 adults with diabetes but no known cardiovascular disease. It found that aspirin led to a 12% lower risk of serious vascular events but also a 29% higher risk of major bleeding. The number of vascular events prevented was similar to the number of major bleeding events caused. Therefore, the benefits of aspirin did not clearly outweigh the risks for primary prevention among adults with diabetes but no known cardiovascular disease.
Reducing Perioperative Cardiac Risk: Do Beta blockers Help?Terry Shaneyfelt
Review of the effect of beta blockers on perioperative cardiac events including updated recommendations by the ACC/AHA (August 2014. Watch my YouTube video (http://youtu.be/WPLXDm9Nzoc) describing these slides.
The document summarizes the Japan EPA Lipid Intervention Study (JELIS), a large clinical trial examining whether EPA (eicosapentaenoic acid) can improve cardiovascular outcomes when added to HMG-CoA reductase inhibitor treatment in patients with hypercholesterolemia. JELIS involves over 18,000 Japanese participants randomized to receive EPA plus statin or statin alone. The primary endpoint is major coronary events over 5 years. Baseline characteristics showed patients had moderately elevated cholesterol. Results are expected in 2005 to determine if EPA provides additional cardiovascular benefit beyond statin therapy alone.
1. Recurrent myocardial infarction (MI) after primary percutaneous coronary intervention (PPCI) for ST-segment elevation myocardial infarction (STEMI) occurs in about 21% of patients and is associated with worse clinical outcomes.
2. Recurrent MI significantly increases the risks of subsequent cardiac mortality, noncardiac mortality, stroke, and bleeding.
3. Early recurrent MIs within 1 day of the initial PPCI are associated with higher unadjusted cardiac mortality compared to later recurrent MIs, but after adjustment, recurrent MIs occurring more than 1 year after PPCI carry the highest risk of cardiac death.
This expert consensus document from the World Heart Federation provides recommendations for antiplatelet therapy in East Asian patients with acute coronary syndrome or undergoing percutaneous coronary intervention. While current guidelines are based primarily on large Western clinical trials, few East Asian patients were included. Additionally, East Asians have differing risk profiles and responses to antiplatelet drugs compared to white patients. This consensus aims to determine the most appropriate antiplatelet strategies for East Asians based on available evidence.
Impact of statins and beta-blocker therapy on mortality after coronary artery...Paul Schoenhagen
Abstract
Background: We conducted a retrospective cohort study of patients after first-time isolated coronary artery bypass graft surgery (CABG) and assessed the impact of a discharge regimen including beta-blockers and statin therapy and their relationship to long-term all cause mortality and major adverse cardiovascular events (MACE).
Methods: We identified patients age >18 years, undergoing first time isolated CABG from 1993 to 2005. Patients were identified using the Cardiovascular Information Registry (CVIR). We collected follow-up information at 30, 60, 90 days and yearly follow-up. The registry is approved for use in research by the institutional review broad.
Results: We identified 5,205 patients who underwent single isolated CABG between January 1993 and December 2005. The mean age was 64.5±9.7 years and over 70% were male. There was a significant difference in the low density lipoproteins (LDL) concentration between those with or without statin medications (134±41.9 mg/dL) (no statin) vs. 126±44.8 mg/dL (with statin), P=0.001. A discharge regimen with statin therapy was associated with and overall reduction in 30 day, 1 year and long-term mortality. In addition, overall the triple ischemic endpoint of death, myocardial infarction (MI) and stroke was also significantly lower in the statin vs. no-statin group. In addition, statin and beta-blockers exerted synergistic effect on overall mortality outcomes short-term and in the long-term. We note that the predictors of overall death include no therapy with statin therapy and age [hazard ratios (HR) 1.1, 95% CI: 1.04-1.078, P<0.001] and presence of renal failure (HR 2.0, P=0.005). The estimated 11-year Kaplan Meier curves for mortality between the two groups starts to diverge immediately post discharge after single isolated CABG and continue to diverge through out the follow-up period.
Conclusions: A post-discharge regimen of statins independently reduces overall and 1 year mortality. These results confirm those of earlier studies within a contemporary surgical population and support the current clinical guidelines.
- Several large clinical trials have validated the use of beta-blockers in heart failure patients. Trials such as CIBIS II, MERIT-HF, and COPERNICUS showed reductions in mortality of 34-35% with bisoprolol, metoprolol, and carvedilol respectively compared to placebo in heart failure patients.
- The SENIORS trial also showed reductions in mortality and hospitalization with nebivolol compared to placebo in older heart failure patients (average age 76 years). A sub-analysis of the MERIT-HF trial found even larger mortality reductions of 37% in patients over 65 years of age with reduced ejection fraction.
- Therefore, beta-
This patient is a 37-year-old man with type 2 diabetes, hypertension, dyslipidemia, and a family history of coronary artery disease. Examination found elevated blood pressure and LDL, as well as signs of sympathetic overactivity.
Given the patient's sympathetic overactivity, diabetes, hypertension, and family history of CAD, treatment with a beta-blocker and high-intensity statin is recommended. Metoprolol is preferred as it has a short half-life, is excreted through the liver, and does not accumulate in renal impairment. Intensifying the statin dose is also needed given the patient's multiple risk factors to achieve a target LDL lower than 100 mg/dL.
Effects of aspirin for primary prevention in persons with Diabetes mellitusShadab Ahmad
This study evaluated the effects of low-dose aspirin (100 mg daily) for primary prevention of vascular events in 15,480 adults with diabetes but no known cardiovascular disease. It found that aspirin led to a 12% lower risk of serious vascular events but also a 29% higher risk of major bleeding. The number of vascular events prevented was similar to the number of major bleeding events caused. Therefore, the benefits of aspirin did not clearly outweigh the risks for primary prevention among adults with diabetes but no known cardiovascular disease.
Reducing Perioperative Cardiac Risk: Do Beta blockers Help?Terry Shaneyfelt
Review of the effect of beta blockers on perioperative cardiac events including updated recommendations by the ACC/AHA (August 2014. Watch my YouTube video (http://youtu.be/WPLXDm9Nzoc) describing these slides.
Aim: of the study was to conduct a comparative analysis of inflammatory markers in patients with coronary heart disease of stable and unstable flow. Methods: 78 patients aged 36 to 75 years were enrolled in this study (mean age 58.2±12.6 years). Laboratory and instrumental data were obtained and assessed. IL-6, TNF-α in blood plasma was carried out by the method of enzyme immunoassay on a solid-phase analyzer «Humareader Single». Statistical processing of the obtained results was carried out using vibrational statistics methods recommended for biomedical research on the IBM PC AT Pentium IV. Results: In patients with unstable angina (UA), the frequency of elevated levels of CRP, TNF-α, and leukocytes was statistically significantly higher than in the group with stable ischemic heart disease (P<0.05). The mean levels of these markers were statistically significantly higher in patients with UA compared with patients with stable form of coronary heart disease (CHD, P<0.05): CRP (4.3 ± 2.4 and 2.9 ± 2.3 mg / L, p <0.05, respectively), TNF-α (10.5 ± 2.5 and 7.7 ± 3.4 pg / ml, p <0.05) and leukocytes (9.2 ± 2.5 6.9 ± 2.3x109 / l, p <0.05). The level of interleukin-6 in patients with UA was higher in comparison with patients with stable angina (SA, 3.4 ± 1.7 and 2.9 ± 0.5 pg/ml), but the difference was statistically not significant (p> 0.05 ). There were no significant differences in the level of fibrinogen and ESR between patients with UA and SA. Conclusion: It was noted that the signs of inflammation are detected both in patients with unstable forms and in patients with stable form of CHD, but the degree of inflammation in patients with UA (level of TNF-α, CRP and leukocytes) is higher than in patients with stable ischemic heart disease.
The study analyzed data from 10 phase 3 trials of alirocumab (ALI) that included nearly 5,000 patients. The trials grouped patients by ALI dose, control treatment, and use of background statin therapy. Treatment with ALI significantly reduced LDL-C levels in patients both with and without hypertension. The safety of ALI was comparable to controls in both subgroups. Across all trials, ALI was found to be an effective therapy for reducing LDL-C in patients with hypertension that was also well tolerated.
This document describes a research study that will compare the clinical outcomes of 20mg and 40mg doses of rosuvastatin in patients with ST elevation acute myocardial infarction (STEMI) who have undergone percutaneous coronary intervention (PCI) over 2 months. The study will enroll 66 patients who will be randomly assigned to receive either 20mg or 40mg of rosuvastatin. The primary outcome will be major adverse cardiovascular events over the 2 month period. Secondary outcomes include cardiac biomarker levels, new onset diabetes, and safety/tolerability. The study aims to determine if the higher 40mg dose provides improved clinical benefits compared to the 20mg dose.
Lipid management in peripheral artrerial disease .slidesashwani mehta
Peripheral arterial disease (PAD) is a manifestation of atherosclerosis associated with high mortality. Lipid-lowering therapy, especially statin drugs, has proven effective in treating PAD patients by reducing cardiovascular risk. Guidelines recommend a target LDL-C level below 100 mg/dL for all PAD patients, and below 70 mg/dL for high-risk patients. Statins provide benefits beyond lipid lowering, including reducing inflammation and improving walking ability in PAD. More intensive statin therapy targeting lower LDL-C levels is associated with better long-term outcomes for PAD patients.
Rivaroxaban has shown benefits beyond antiplatelet therapy alone in reducing cardiovascular events. The COMPASS trial found that in patients with chronic coronary artery disease or peripheral artery disease, rivaroxaban plus aspirin reduced the composite of cardiovascular death, stroke, and myocardial infarction by 24% compared to aspirin alone. It also reduced mortality by 18% and ischemic stroke by 42%. Patients with multiple risk factors such as diabetes, chronic kidney disease, or heart failure derived the greatest benefits. However, use of anticoagulants remains lower than guidelines recommend due to overestimation of bleeding risks and underestimation of thrombotic risk.
Extract from 2010 ECC Guidelines: ClopidogrelAlan Batt
Clopidogrel is an oral drug that irreversibly inhibits platelet aggregation through a different mechanism than aspirin. Several studies since 2005 have shown that clopidogrel reduces combined rates of cardiovascular mortality, nonfatal heart attack, and stroke when used in addition to aspirin and anticoagulants for patients with non-ST-elevation or ST-elevation acute coronary syndrome. Clopidogrel increases the risk of major bleeding, especially for patients undergoing coronary artery bypass grafting within 5-7 days. The guidelines recommend a clopidogrel loading dose for moderate and high risk ACS patients but the ideal dose for patients over age 75 is still unclear.
Achieving Blood Pressure Goal: From Clinical Trial into Real-World DataSuharti Wairagya
Hypertension remains a major global health issue, with over 7 million deaths annually associated with it. Less than 50% of hypertensive patients receive therapy, and approximately 70% of treated patients do not reach blood pressure goals. Most guidelines recommend initiating treatment with two drugs when blood pressure is more than 20/10 mmHg above goal or for those at high cardiovascular risk. Clinical trials have shown that the amlodipine/valsartan combination effectively lowers blood pressure and helps more patients achieve goals compared to monotherapy. Real-world Indonesian studies found that amlodipine/valsartan combination therapy was effective at controlling blood pressure in the majority of uncontrolled hypertensive patients switched from monotherapy.
Aspirin as Prevention Therapy for Cardiovascular Events in patients with Diab...Stefania Dumitrescu
The Role of Aspirin in the primary prevention of cardiovascular disease in patients with diabetes, especially T2DM - current knowledge and recommendations -
Copeptin as a Novel Biomarker in the Diagnosis of Acute Myocardial Infarction...Premier Publishers
To evaluate the diagnostic value of Copeptin as a novel biomarker in early diagnosis of Acute Myocardial Infarction. 56 patients with acute Myocardial Infarction (STEMI) and 25 healthy controls who were admitted to the Cardiology and Clinical Pathology Departments, national heart institute (NHI) from October 2015 to April 2016. The kit used a double-antibody sandwich enzyme-linked immune-sorbent assay (ELISA) to assay the level of Human Copeptin in samples. As regard copeptin, the median range of copeptin level was 242.5pg/ml in patient group and 75pg/ml in control group. The comparative study between the two groups shows a significant difference (p < 0.05) Conclusion: Copeptin is a reliable diagnostic tool in patients with AMI (STEMI) with sensitivity 85.7%, specificity 86.7%, PPV 96% and NPV 61.9%.
This study examined blood levels of homocysteine, vitamin B12, and folic acid in patients with metabolic syndrome compared to controls. The study found that patients with metabolic syndrome had significantly higher levels of homocysteine (2.6 times higher) and significantly lower levels of vitamin B12 (only 53% of controls) and folic acid (only 61% of controls). Lower levels of these vitamins were also associated with higher weight, BMI, blood sugar, and lipid levels. The study concludes that Indian patients with metabolic syndrome have a strong association with abnormal levels of these metabolites, suggesting they may play a greater role in Asians with metabolic syndrome than other populations.
Treatment strategies in patients with statin intoleranceVishwanath Hesarur
Statins are among the most prescribed drugs in the world and are first-line therapy in the management of hyperlipidemia.
Their beneficial effects on cardiovascular morbidity and mortality have been demonstrated both in primary and in secondary prevention.
They are generally safe, but in some patients, statin therapy is stopped because of intolerance to the drug that may result in muscle aches and weakness, gastrointestinal symptoms, liver enzyme abnormalities, or other nonspecific discomforts.
The rate of reported statin-related events is about 5% to 10% in randomized, placebo controlled clinical trials.
This study examined the association between blood cell count parameters and the development of new onset atrial fibrillation (AF) after acute myocardial infarction (AMI). The study found that patients who developed AF after AMI had significantly higher hemoglobin, hematocrit, and erythrocyte count levels compared to controls without AF. Logistic regression analysis revealed an independent association between higher hemoglobin, hematocrit, and erythrocyte count and increased odds of developing AF after AMI. However, the pathophysiological mechanisms for these associations require further investigation.
The document discusses exercise in the primary and secondary prevention of cardiovascular disease. It covers several key points:
1) Many studies have shown that higher levels of physical fitness are associated with lower risks of premature cardiovascular death. Regular exercise can help prevent cardiovascular disease.
2) Even relatively small amounts of daily exercise, such as 15 minutes, have been shown to significantly reduce mortality risks. More exercise provides greater benefits.
3) Exercise can help manage diabetes and obesity, two major risk factors for cardiovascular disease. It improves glucose control and cardiovascular risk profiles.
4) Cardiac rehabilitation programs that include regular exercise have been shown to significantly reduce mortality and hospitalization rates for cardiovascular patients.
Hypertension is often difficult to treat effectively despite available drugs. Combination drug therapy is usually needed to control blood pressure, as monotherapy is only effective in 40-60% of patients. Using two drugs with different mechanisms of action can more effectively lower blood pressure than monotherapy alone. Common effective combinations include a diuretic paired with a renin-angiotensin system inhibitor, calcium channel blocker, or beta blocker. This helps control blood pressure through multiple pathways and limits side effects.
Among 19,114 healthy elderly patients without cardiovascular disease who were randomized to low-dose aspirin or placebo, aspirin did not reduce the primary composite outcome of death, dementia or persistent physical disability compared to placebo after a median follow-up of 4.7 years. Aspirin was associated with a higher risk of major hemorrhage. Similar recent trials found no benefit of aspirin for primary prevention in diabetic patients or those at moderate cardiovascular risk without increasing bleeding risk. Guidelines do not recommend routine aspirin use for primary prevention in adults over 70 years old due to lack of benefit and risk of bleeding.
Goal attainments and their discrepancies for low density lipoprotein choleste...Paul Schoenhagen
Purpose: Low density lipoprotein cholesterol (LDL-C) is primary treatment target for patients with dislipidemia. The apolipoprotein B (apo B), an emerging biomarker for cardiovascular risk prediction, appears to be superior to the LDL-C. However, little is known about goal attainments and their discrepancies for LDL-C and apo B in Chinese patients with known CAD or DM.
The document discusses several studies on the use of aspirin for primary prevention of cardiovascular events. The Antithrombotic Trialists Collaboration meta-analysis found a 12% reduction in serious vascular events but a 50% increase in bleeding risks. Subsequent trials had conflicting results, with some showing no benefit for certain groups. The newer ASCEND, ARRIVE, and ASPREE trials all found aspirin reduced nonfatal heart attacks but increased bleeding risks, with no clear benefit overall when weighing risks and benefits. Primary prevention with aspirin is unlikely to reduce total mortality and may increase bleeding risks according to these studies.
Relative risk of cardiovascular morbidity is increased in Chronic Kidney Disease (CKD). According to current KDIGO guideline
cardiovascular risk can be estimated from Glomerular Filtration Rate (GFR) and proteinuria.
This document summarizes a sub-analysis of the Japan EPA Lipid Intervention Study (JELIS) that compared the risk of coronary artery disease (CAD) between patients with impaired glucose metabolism (IGM) and normoglycemic (NG) patients, and assessed the effect of eicosapentaenoic acid (EPA) on CAD incidence in IGM patients. The analysis found that IGM patients had a significantly higher risk of CAD compared to NG patients. Treatment with EPA resulted in a 22% decrease in CAD incidence in IGM patients and an 18% decrease in NG patients, although the decrease was only statistically significant for IGM patients.
1) A study examined the effects of EPA supplementation on coronary artery disease (CAD) risk in patients with multiple risk factors enrolled in the Japan EPA Lipid Intervention Study.
2) The risk of CAD increased with the number of risk factors present, including high cholesterol, obesity, abnormal triglycerides/HDL levels, diabetes, and hypertension.
3) EPA supplementation reduced CAD risk across all risk factor levels but had an especially large effect in patients with high triglycerides and low HDL cholesterol, reducing their CAD risk by 53%.
Aim: of the study was to conduct a comparative analysis of inflammatory markers in patients with coronary heart disease of stable and unstable flow. Methods: 78 patients aged 36 to 75 years were enrolled in this study (mean age 58.2±12.6 years). Laboratory and instrumental data were obtained and assessed. IL-6, TNF-α in blood plasma was carried out by the method of enzyme immunoassay on a solid-phase analyzer «Humareader Single». Statistical processing of the obtained results was carried out using vibrational statistics methods recommended for biomedical research on the IBM PC AT Pentium IV. Results: In patients with unstable angina (UA), the frequency of elevated levels of CRP, TNF-α, and leukocytes was statistically significantly higher than in the group with stable ischemic heart disease (P<0.05). The mean levels of these markers were statistically significantly higher in patients with UA compared with patients with stable form of coronary heart disease (CHD, P<0.05): CRP (4.3 ± 2.4 and 2.9 ± 2.3 mg / L, p <0.05, respectively), TNF-α (10.5 ± 2.5 and 7.7 ± 3.4 pg / ml, p <0.05) and leukocytes (9.2 ± 2.5 6.9 ± 2.3x109 / l, p <0.05). The level of interleukin-6 in patients with UA was higher in comparison with patients with stable angina (SA, 3.4 ± 1.7 and 2.9 ± 0.5 pg/ml), but the difference was statistically not significant (p> 0.05 ). There were no significant differences in the level of fibrinogen and ESR between patients with UA and SA. Conclusion: It was noted that the signs of inflammation are detected both in patients with unstable forms and in patients with stable form of CHD, but the degree of inflammation in patients with UA (level of TNF-α, CRP and leukocytes) is higher than in patients with stable ischemic heart disease.
The study analyzed data from 10 phase 3 trials of alirocumab (ALI) that included nearly 5,000 patients. The trials grouped patients by ALI dose, control treatment, and use of background statin therapy. Treatment with ALI significantly reduced LDL-C levels in patients both with and without hypertension. The safety of ALI was comparable to controls in both subgroups. Across all trials, ALI was found to be an effective therapy for reducing LDL-C in patients with hypertension that was also well tolerated.
This document describes a research study that will compare the clinical outcomes of 20mg and 40mg doses of rosuvastatin in patients with ST elevation acute myocardial infarction (STEMI) who have undergone percutaneous coronary intervention (PCI) over 2 months. The study will enroll 66 patients who will be randomly assigned to receive either 20mg or 40mg of rosuvastatin. The primary outcome will be major adverse cardiovascular events over the 2 month period. Secondary outcomes include cardiac biomarker levels, new onset diabetes, and safety/tolerability. The study aims to determine if the higher 40mg dose provides improved clinical benefits compared to the 20mg dose.
Lipid management in peripheral artrerial disease .slidesashwani mehta
Peripheral arterial disease (PAD) is a manifestation of atherosclerosis associated with high mortality. Lipid-lowering therapy, especially statin drugs, has proven effective in treating PAD patients by reducing cardiovascular risk. Guidelines recommend a target LDL-C level below 100 mg/dL for all PAD patients, and below 70 mg/dL for high-risk patients. Statins provide benefits beyond lipid lowering, including reducing inflammation and improving walking ability in PAD. More intensive statin therapy targeting lower LDL-C levels is associated with better long-term outcomes for PAD patients.
Rivaroxaban has shown benefits beyond antiplatelet therapy alone in reducing cardiovascular events. The COMPASS trial found that in patients with chronic coronary artery disease or peripheral artery disease, rivaroxaban plus aspirin reduced the composite of cardiovascular death, stroke, and myocardial infarction by 24% compared to aspirin alone. It also reduced mortality by 18% and ischemic stroke by 42%. Patients with multiple risk factors such as diabetes, chronic kidney disease, or heart failure derived the greatest benefits. However, use of anticoagulants remains lower than guidelines recommend due to overestimation of bleeding risks and underestimation of thrombotic risk.
Extract from 2010 ECC Guidelines: ClopidogrelAlan Batt
Clopidogrel is an oral drug that irreversibly inhibits platelet aggregation through a different mechanism than aspirin. Several studies since 2005 have shown that clopidogrel reduces combined rates of cardiovascular mortality, nonfatal heart attack, and stroke when used in addition to aspirin and anticoagulants for patients with non-ST-elevation or ST-elevation acute coronary syndrome. Clopidogrel increases the risk of major bleeding, especially for patients undergoing coronary artery bypass grafting within 5-7 days. The guidelines recommend a clopidogrel loading dose for moderate and high risk ACS patients but the ideal dose for patients over age 75 is still unclear.
Achieving Blood Pressure Goal: From Clinical Trial into Real-World DataSuharti Wairagya
Hypertension remains a major global health issue, with over 7 million deaths annually associated with it. Less than 50% of hypertensive patients receive therapy, and approximately 70% of treated patients do not reach blood pressure goals. Most guidelines recommend initiating treatment with two drugs when blood pressure is more than 20/10 mmHg above goal or for those at high cardiovascular risk. Clinical trials have shown that the amlodipine/valsartan combination effectively lowers blood pressure and helps more patients achieve goals compared to monotherapy. Real-world Indonesian studies found that amlodipine/valsartan combination therapy was effective at controlling blood pressure in the majority of uncontrolled hypertensive patients switched from monotherapy.
Aspirin as Prevention Therapy for Cardiovascular Events in patients with Diab...Stefania Dumitrescu
The Role of Aspirin in the primary prevention of cardiovascular disease in patients with diabetes, especially T2DM - current knowledge and recommendations -
Copeptin as a Novel Biomarker in the Diagnosis of Acute Myocardial Infarction...Premier Publishers
To evaluate the diagnostic value of Copeptin as a novel biomarker in early diagnosis of Acute Myocardial Infarction. 56 patients with acute Myocardial Infarction (STEMI) and 25 healthy controls who were admitted to the Cardiology and Clinical Pathology Departments, national heart institute (NHI) from October 2015 to April 2016. The kit used a double-antibody sandwich enzyme-linked immune-sorbent assay (ELISA) to assay the level of Human Copeptin in samples. As regard copeptin, the median range of copeptin level was 242.5pg/ml in patient group and 75pg/ml in control group. The comparative study between the two groups shows a significant difference (p < 0.05) Conclusion: Copeptin is a reliable diagnostic tool in patients with AMI (STEMI) with sensitivity 85.7%, specificity 86.7%, PPV 96% and NPV 61.9%.
This study examined blood levels of homocysteine, vitamin B12, and folic acid in patients with metabolic syndrome compared to controls. The study found that patients with metabolic syndrome had significantly higher levels of homocysteine (2.6 times higher) and significantly lower levels of vitamin B12 (only 53% of controls) and folic acid (only 61% of controls). Lower levels of these vitamins were also associated with higher weight, BMI, blood sugar, and lipid levels. The study concludes that Indian patients with metabolic syndrome have a strong association with abnormal levels of these metabolites, suggesting they may play a greater role in Asians with metabolic syndrome than other populations.
Treatment strategies in patients with statin intoleranceVishwanath Hesarur
Statins are among the most prescribed drugs in the world and are first-line therapy in the management of hyperlipidemia.
Their beneficial effects on cardiovascular morbidity and mortality have been demonstrated both in primary and in secondary prevention.
They are generally safe, but in some patients, statin therapy is stopped because of intolerance to the drug that may result in muscle aches and weakness, gastrointestinal symptoms, liver enzyme abnormalities, or other nonspecific discomforts.
The rate of reported statin-related events is about 5% to 10% in randomized, placebo controlled clinical trials.
This study examined the association between blood cell count parameters and the development of new onset atrial fibrillation (AF) after acute myocardial infarction (AMI). The study found that patients who developed AF after AMI had significantly higher hemoglobin, hematocrit, and erythrocyte count levels compared to controls without AF. Logistic regression analysis revealed an independent association between higher hemoglobin, hematocrit, and erythrocyte count and increased odds of developing AF after AMI. However, the pathophysiological mechanisms for these associations require further investigation.
The document discusses exercise in the primary and secondary prevention of cardiovascular disease. It covers several key points:
1) Many studies have shown that higher levels of physical fitness are associated with lower risks of premature cardiovascular death. Regular exercise can help prevent cardiovascular disease.
2) Even relatively small amounts of daily exercise, such as 15 minutes, have been shown to significantly reduce mortality risks. More exercise provides greater benefits.
3) Exercise can help manage diabetes and obesity, two major risk factors for cardiovascular disease. It improves glucose control and cardiovascular risk profiles.
4) Cardiac rehabilitation programs that include regular exercise have been shown to significantly reduce mortality and hospitalization rates for cardiovascular patients.
Hypertension is often difficult to treat effectively despite available drugs. Combination drug therapy is usually needed to control blood pressure, as monotherapy is only effective in 40-60% of patients. Using two drugs with different mechanisms of action can more effectively lower blood pressure than monotherapy alone. Common effective combinations include a diuretic paired with a renin-angiotensin system inhibitor, calcium channel blocker, or beta blocker. This helps control blood pressure through multiple pathways and limits side effects.
Among 19,114 healthy elderly patients without cardiovascular disease who were randomized to low-dose aspirin or placebo, aspirin did not reduce the primary composite outcome of death, dementia or persistent physical disability compared to placebo after a median follow-up of 4.7 years. Aspirin was associated with a higher risk of major hemorrhage. Similar recent trials found no benefit of aspirin for primary prevention in diabetic patients or those at moderate cardiovascular risk without increasing bleeding risk. Guidelines do not recommend routine aspirin use for primary prevention in adults over 70 years old due to lack of benefit and risk of bleeding.
Goal attainments and their discrepancies for low density lipoprotein choleste...Paul Schoenhagen
Purpose: Low density lipoprotein cholesterol (LDL-C) is primary treatment target for patients with dislipidemia. The apolipoprotein B (apo B), an emerging biomarker for cardiovascular risk prediction, appears to be superior to the LDL-C. However, little is known about goal attainments and their discrepancies for LDL-C and apo B in Chinese patients with known CAD or DM.
The document discusses several studies on the use of aspirin for primary prevention of cardiovascular events. The Antithrombotic Trialists Collaboration meta-analysis found a 12% reduction in serious vascular events but a 50% increase in bleeding risks. Subsequent trials had conflicting results, with some showing no benefit for certain groups. The newer ASCEND, ARRIVE, and ASPREE trials all found aspirin reduced nonfatal heart attacks but increased bleeding risks, with no clear benefit overall when weighing risks and benefits. Primary prevention with aspirin is unlikely to reduce total mortality and may increase bleeding risks according to these studies.
Relative risk of cardiovascular morbidity is increased in Chronic Kidney Disease (CKD). According to current KDIGO guideline
cardiovascular risk can be estimated from Glomerular Filtration Rate (GFR) and proteinuria.
This document summarizes a sub-analysis of the Japan EPA Lipid Intervention Study (JELIS) that compared the risk of coronary artery disease (CAD) between patients with impaired glucose metabolism (IGM) and normoglycemic (NG) patients, and assessed the effect of eicosapentaenoic acid (EPA) on CAD incidence in IGM patients. The analysis found that IGM patients had a significantly higher risk of CAD compared to NG patients. Treatment with EPA resulted in a 22% decrease in CAD incidence in IGM patients and an 18% decrease in NG patients, although the decrease was only statistically significant for IGM patients.
1) A study examined the effects of EPA supplementation on coronary artery disease (CAD) risk in patients with multiple risk factors enrolled in the Japan EPA Lipid Intervention Study.
2) The risk of CAD increased with the number of risk factors present, including high cholesterol, obesity, abnormal triglycerides/HDL levels, diabetes, and hypertension.
3) EPA supplementation reduced CAD risk across all risk factor levels but had an especially large effect in patients with high triglycerides and low HDL cholesterol, reducing their CAD risk by 53%.
This review article discusses the biologic plausibility of eicosapentaenoic acid (EPA) as an anti-atherosclerotic agent. It summarizes that EPA has beneficial effects on multiple processes in the development and progression of atherosclerosis, from endothelial dysfunction to plaque rupture and thrombosis. Specifically, EPA improves endothelial function, reduces oxidative stress and inflammation, decreases foam cell formation, inhibits plaque progression, reduces platelet aggregation and thrombus formation. The article argues that EPA's effects on these various atherogenic processes provide biologic rationale for its potential clinical benefits in preventing cardiovascular events when used as an adjunct to statin therapy. An ongoing clinical trial called REDUCE-IT aims to evaluate whether EPA reduces cardiovascular risk more
The document discusses the role of low molecular weight heparin (LMWH) in the management of acute coronary syndrome (ACS). It provides an overview of ACS globally and in India. It then covers the diagnosis of ACS and current treatment guidelines, which involve the use of antiplatelet and anticoagulant therapies. Specifically, it discusses the pharmacological properties and clinical evidence for the use of LMWH, such as enoxaparin, in ACS. Studies show LMWH provides benefits over unfractionated heparin (UFH) in reducing risks during coronary interventions and improving outcomes in ACS patients.
Estudio clínico randomizado para prevenir fibrilación auricular post operator...Cirugias
This randomized controlled trial tested whether supplementation with n-3 polyunsaturated fatty acids, vitamin C, and vitamin E could reduce the incidence of postoperative atrial fibrillation in patients undergoing cardiac surgery. The study found that postoperative atrial fibrillation occurred in 10 of 103 supplemented patients (9.7%) compared to 32 of 100 placebo patients (32%), a significant reduction. Supplemented patients also had lower levels of biomarkers for oxidative stress and inflammation after surgery. The results suggest that this antioxidant regimen can favorably impact postoperative atrial fibrillation by increasing antioxidant defenses and decreasing oxidative stress.
This study examined the association between the ratio of serum eicosapentaenoic acid (EPA) to arachidonic acid (AA) and risk of cardiovascular disease in a Japanese population. Over 5 years of follow up, 127 participants experienced cardiovascular events. The risk of cardiovascular disease was higher among those with a lower EPA/AA ratio and higher levels of high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation. A lower EPA/AA ratio was associated with a 52% increased risk of cardiovascular disease per 0.20 decrease in those with hs-CRP over 1.0 mg/L. The results suggest that a lower EPA/AA ratio may be linked to greater risk of
Mangement of chronic heart failure 93432-rephrasedIrfan iftekhar
Cardiac resynchronization therapy significantly reduces morbidity and mortality in patients with heart failure. A randomized controlled trial found that cardiac resynchronization reduced the primary endpoint of death from any cause by 36% compared to medical therapy alone. Mortality was lower in the cardiac resynchronization group, demonstrating improved outcomes. While cardiac resynchronization is an effective treatment, its cost-effectiveness remains uncertain due to the therapy's expense. Further research is still needed to determine its overall value.
Icosapent ethyl (IPE), a highly purified ethyl ester of eicosapentaenoic acid (EPA), was evaluated for its effect on coronary atherosclerotic plaque progression in patients with elevated triglycerides on statin therapy. In a randomized controlled trial of 80 patients, IPE 4g/day resulted in significant regression of low attenuation plaque volume compared to placebo after 18 months. IPE also reduced total, non-calcified, fibrofatty and fibrous plaque volumes but not calcified plaque volume. No significant differences in lipid levels were observed between groups.
Does Type of Dialysis Affect BNP in Fluid Overload Patients?Premier Publishers
This study investigated how type of dialysis affects brain natriuretic peptide (BNP) levels in fluid overload patients. The study compared 24 hemodialysis patients and 35 peritoneal dialysis patients. It found that BNP, left ventricular mass, and left ventricular mass index levels were significantly higher in hemodialysis patients, possibly due to hemodynamic changes during hemodialysis. BNP levels correlated with left ventricular mass index in both hemodialysis and peritoneal dialysis patients. Predialysis BNP levels in hemodialysis patients were significantly higher than postdialysis levels. The type of dialysis had a significant effect on BNP levels regardless of whether patients had hypertension.
Hypertension is a major cause of cardiovascular disease and mortality worldwide. In India, about 33% of urban and 25% of rural populations have hypertension, though only a fraction are aware of and successfully controlling their condition. Azilsartan is a new angiotensin II receptor blocker that has been shown to more effectively lower blood pressure than other ARBs. As the eighth approved drug in its class, Azilsartan may help improve blood pressure control for Indian patients with hypertension when it becomes available.
The document describes a study that evaluated the effects of administering a mixture of 11 amino acids to patients with chronic heart failure over 3 months. The study found that amino acid supplementation significantly improved exercise tolerance as measured by increased peak VO2 and VO2 at anaerobic threshold on cardiopulmonary stress tests, as well as increased 6-minute walk test distances. However, it did not significantly change patients' quality of life scores. The study suggests amino acid supplementation may improve some measures of functional capacity in patients with chronic heart failure.
Syntax Score and its Relation to Lipoprotein a –Lp (a) and Extended Lipid Par...Premier Publishers
Syntax score is a semi-quantitative visual grading system for complex coronary artery disease based on angiography findings. We investigated whether the severity of coronary artery disease (Syntax score) correlates with Lipoprotein (a) {Lp (a)} value and lipid ratios.75 non-diabetic adult patients, having age below 55 years, who presented with Acute Coronary Syndrome (ACS) were included. Coronary angiography and Syntax Score calculation was done. Various lipid ratios and Lp(a) were correlated with syntax score. Out of 75 patients ,61 (81.33%) were males and 14 (18.67%) females, having mean age of 44.37years. Majority (49.34%) having age between 41-50 years. Those 49 (65.4%) had acute myocardial infarction,21 (28%) had unstable angina and 5(6.6%) had Non-ST-elevation myocardial infarction (NSTEMI).44(58.67%) patients had one, 18(24%) had two and 13 (17.33%) had three vessels disease.58 (77.33%) had syntax score ≤22 and 17 (26.67%) had ≥ 23. Statistically significant difference (p < 0.05) was found in mean values of Total cholesterol (TC), TC/HDL ratio, LDL, LDL/HDL and Non-HDL cholesterol in patients having syntax score> 23. Mean values of other parameters like LVEF (Left ventricular ejection fraction), ApoA-1, Apo B, Apo B/Apo A, Lp(a)/HDL did not differ in two groups. Lp(a) lipoprotein levels did not show any association with the syntax score and extent of coronary artery disease. This study of western Indian young non-diabetic patients having acute coronary syndrome found association of syntax score with high non-HDL, TC, TC/HDL, LDL, LDL/HDL values. It was not correlating with LP (a) levels.
The document discusses the use of aspirin for the primary prevention of cardiovascular disease in patients with diabetes. While aspirin is proven to be effective for secondary prevention, its benefits for primary prevention in patients without a history of vascular disease are unclear based on previous studies which have been underpowered. The document describes two recent clinical trials, POPADAD and JPAD, which also did not provide definitive evidence due to low event rates. It encourages participation in the ongoing ASCEND trial, which aims to recruit 10,000 patients, in order to help resolve the uncertainty around aspirin's role in primary prevention for patients with diabetes.
Emerging MRA-Based Treatments for End-Stage Renal Disease (ESRD) Patients on ...wackysavior4064
- Chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients have high rates of cardiovascular disease mortality due to increased risk factors like hypertension, inflammation, and fibrosis.
- Recent studies have explored using mineralocorticoid receptor antagonists (MRAs) like spironolactone or eplerenone to treat CKD and ESRD patients given their cardiovascular benefits, but concerns about hyperkalemia have limited their use.
- Ongoing and planned clinical trials are investigating the effectiveness and safety of MRAs in reducing cardiovascular events for CKD and ESRD patients, including how new potassium-binding drugs may help address hyperkalemia risks.
Percutaneous Coronary Intervention [PCI] has been a revolutionary advance in cardiology, and many lives have been saved as a result of the widespread application of primary PCI. However, elective PCI has not yet been proven to save lives or reduce the risk of myocardial infarction. Despite this lack of
evidence, elective PCI has been misused and in some cases, abused for nonmedical reasons. The considerable cost of elective PCI can be reduced, and the resources could potentially be utilized for better public health outcomes. The following.article intends to highlight the lack of evidence supporting the use of elective PCI, which is a problem not only in North America and Europe but also throughout the world.
Better regulation of the elective PCI procedure could reduce health care expenditures and divert resources to cardiovascular disease prevention.
This study compared the effects of levosimendan, dobutamine, and vasodilator therapy on ongoing myocardial injury in patients with acute decompensated heart failure. The study found that while all treatments were associated with decreases in cardiac troponin I levels and improvements in hemodynamic and functional indicators, levosimendan treatment showed the most pronounced improvements, especially in left ventricular ejection fraction and systolic pulmonary artery pressure. However, none of the treatments significantly reduced cardiac troponin I levels compared to each other. The study demonstrated beneficial effects of short-term use of levosimendan, dobutamine, and nitroglycerin on ongoing myocardial injury in acute decompensated heart failure.
TEST BANK For Community Health Nursing A Canadian Perspective, 5th Edition by...Donc Test
TEST BANK For Community Health Nursing A Canadian Perspective, 5th Edition by Stamler, Verified Chapters 1 - 33, Complete Newest Version Community Health Nursing A Canadian Perspective, 5th Edition by Stamler, Verified Chapters 1 - 33, Complete Newest Version Community Health Nursing A Canadian Perspective, 5th Edition by Stamler Community Health Nursing A Canadian Perspective, 5th Edition TEST BANK by Stamler Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Pdf Chapters Download Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Pdf Download Stuvia Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Study Guide Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Ebook Download Stuvia Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Questions and Answers Quizlet Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Studocu Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Quizlet Test Bank For Community Health Nursing A Canadian Perspective, 5th Edition Stuvia Community Health Nursing A Canadian Perspective, 5th Edition Pdf Chapters Download Community Health Nursing A Canadian Perspective, 5th Edition Pdf Download Course Hero Community Health Nursing A Canadian Perspective, 5th Edition Answers Quizlet Community Health Nursing A Canadian Perspective, 5th Edition Ebook Download Course hero Community Health Nursing A Canadian Perspective, 5th Edition Questions and Answers Community Health Nursing A Canadian Perspective, 5th Edition Studocu Community Health Nursing A Canadian Perspective, 5th Edition Quizlet Community Health Nursing A Canadian Perspective, 5th Edition Stuvia Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Pdf Chapters Download Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Pdf Download Stuvia Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Study Guide Questions and Answers Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Ebook Download Stuvia Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Questions Quizlet Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Studocu Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Quizlet Community Health Nursing A Canadian Perspective, 5th Edition Test Bank Stuvia
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
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Histololgy of Female Reproductive System.pptxAyeshaZaid1
Dive into an in-depth exploration of the histological structure of female reproductive system with this comprehensive lecture. Presented by Dr. Ayesha Irfan, Assistant Professor of Anatomy, this presentation covers the Gross anatomy and functional histology of the female reproductive organs. Ideal for students, educators, and anyone interested in medical science, this lecture provides clear explanations, detailed diagrams, and valuable insights into female reproductive system. Enhance your knowledge and understanding of this essential aspect of human biology.
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Ear and its clinical correlations By Dr. Rabia Inam Gandapore.pptx
Abcc3
1. Articles
1090 www.thelancet.com Vol 369 March 31, 2007
Effects of eicosapentaenoic acid on major coronary events in
hypercholesterolaemic patients (JELIS): a randomised open-
label, blinded endpoint analysis
MitsuhiroYokoyama, Hideki Origasa, Masunori Matsuzaki, Yuji Matsuzawa, Yasushi Saito, Yuichi Ishikawa, Shinichi Oikawa, Jun Sasaki,
Hitoshi Hishida, Hiroshige Itakura,Toru Kita, Akira Kitabatake, Noriaki Nakaya,Toshiie Sakata, Kazuyuki Shimada, Kunio Shirato, for the
Japan EPA lipid intervention study (JELIS) Investigators
Summary
Background Epidemiological and clinical evidence suggests that an increased intake of long-chain n-3 fatty acids
protects against mortality from coronary artery disease. We aimed to test the hypothesis that long-term use of
eicosapentaenoic acid (EPA) is effective for prevention of major coronary events in hypercholesterolaemic patients in
Japan who consume a large amount of fish.
Methods 18645 patients with a total cholesterol of 6·5 mmol/L or greater were recruited from local physicians
throughout Japan between 1996 and 1999. Patients were randomly assigned to receive either 1800 mg of EPA daily
with statin (EPA group; n=9326) or statin only (controls; n=9319) with a 5-year follow-up. The primary endpoint was
any major coronary event, including sudden cardiac death, fatal and non-fatal myocardial infarction, and other non-
fatal events including unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting. Analysis was
by intention-to-treat. The study was registered at clinicaltrials.gov, number NCT00231738.
Findings At mean follow-up of 4·6 years, we detected the primary endpoint in 262 (2·8%) patients in the EPA group
and 324 (3·5%) in controls—a 19% relative reduction in major coronary events (p=0·011). Post-treatment LDL
cholesterol concentrations decreased 25%, from 4·7 mmol/L in both groups. Serum LDL cholesterol was not a
significant factor in a reduction of risk for major coronary events. Unstable angina and non-fatal coronary events were
also significantly reduced in the EPA group. Sudden cardiac death and coronary death did not differ between groups.
In patients with a history of coronary artery disease who were given EPA treatment, major coronary events were
reduced by 19% (secondary prevention subgroup: 158 [8·7%] in the EPA group vs 197 [10·7%] in the control group;
p=0·048). In patients with no history of coronary artery disease, EPA treatment reduced major coronary events by
18%, but this finding was not significant (104 [1·4%] in the EPA group vs 127 [1·7%] in the control group; p=0·132).
Interpretation EPA is a promising treatment for prevention of major coronary events, and especially non-fatal coronary
events, in Japanese hypercholesterolaemic patients.
Introduction
Epidemiological and clinical evidence suggests a
significant inverse association between long-term
intake of long-chain n-3 polyunsaturated fatty acids,
especially eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA), and mortality associated
with coronary artery disease.1–7
Thus, the consumption
of fish or fish-oil could protect against major events
associated with coronary artery disease, especially fatal
myocardial infarction and sudden cardiac death. Two
large-scale secondary prevention trials, the Diet and
Reinfarction Trial and the Gruppo Italiano per lo Studio
della Sopravivenza nell’ Infarto Miocardico-Prevenzione
Trial, reported that increased consumption of fish or
fish-oil supplements reduced coronary death in
postinfarction patients.8,9
No randomised trials have
examined the effects of n-3 polyunsaturated fatty acids
on major coronary events in a high-risk, primary
prevention population.
EPA ethyl ester, which is purified from n-3 poly-
unsaturated fatty acids present in fish oil, is approved
by Japan’s Ministry of Health, Labour, and Welfare as a
treatment for hyperlipidaemia and peripheral artery
disease. The biological functions of EPA include
reduction of platelet aggregation,10,11
vasodilation,12,13
antiproliferation,14
plaque-stabilisation,15
and reduction
in lipid action.16,17
Therefore the preventive effects of
EPA on major cardiovascular events are of both clinical
interest and therapeutic importance.
Primary and secondary prevention trials have proved
that cholesterol-lowering treatment with inhibitors of
3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)
reductase—statins—reduces the risk of all-cause
mortality and major cardiovascular events in patients
with a wide range of cholesterol concentrations, whether
or not they have had coronary artery disease.18–21
Thus,
statins are now established as the first-line treatment
for hyperlipidaemia.22
Preliminary data for treatment
with a combination of n-3 polyunsaturated fatty acids
and statins have shown beneficial effects on the lipid
profiles of patients with a mixed type of hyper-
lipidaemia;23–25
however, no major long-term inter-
Lancet 2007; 369: 1090–98
See Comment page 1062
Kobe University, Kobe, Japan
(MYokoyama MD); Division of
Clinical Epidemiology and
Biostatistics,Toyama
University,Toyama, Japan
(H Origasa PhD);Yamaguchi
University,Yamaguchi, Japan
(M Matsuzaki MD); Sumitomo
Hospital, Osaka, Japan
(Y Matsuzawa MD); Chiba
University, Chiba, Japan
(Y Saito MD); Kobe University,
Kobe, Japan (Y Ishikawa MD);
Nippon Medical School,Tokyo,
Japan (S Oikawa MD);
International University of
Health andWelfare Graduate
School of Public Health
Medicine, Fukuoka, Japan
(J Sasaki MD); Fujita Health
University School of Medicine,
Aichi, Japan (H Hishida MD);
Ibaraki Christian University,
Ibaraki, Japan (H Itakura MD);
Kyoto University, Kyoto, Japan
(T Kita MD); Showa Hospital,
Hyogo, Japan
(A Kitabatake MD); Nakaya
Clinic,Tokyo, Japan
(N Nakaya MD); Nakamura
Gakuen University, Fukuoka,
Japan (T Sakata MD); Jichi
Medical School,Tochigi, Japan
(K Shimada MD); and Saito
Hospital, Miyagi, Japan
(K Shirato MD)
Correspondence to:
Dr MitsuhiroYokoyama,
Cardiovascular Medicine
Division, Department of Internal
Medicine, Kobe University
Graduate School of Medicine,
7-5-2, Kusunoki-cho, Chuo-ku,
Kobe, 650-0017 Japan
yokoyama@med.kobe-u.ac.jp
2. Articles
www.thelancet.com Vol 369 March 31, 2007 1091
ventional trial has yet investigated whether the addition
of EPA to conventional statin treatment would yield an
incremental clinical benefit. The Japan EPA Lipid
Intervention Study (JELIS) tests the hypothesis that
long-term use of EPA is effective in reduction of major
coronary events in Japanese hypercholesterolaemic
patients given statins.
Methods
Study design and patients
We did a prospective, randomised open-label, blinded
endpoint evaluation (PROBE).26
Our study design, and
inclusion and exclusion criteria are described in detail
elsewhere.27
We recruited 19466 hypercholesterolaemic
patients through local physicians from all regions of
Japan between November, 1996, and November, 1999.
Figure 1 shows the trial profile. The participants
consisted of 5859 men (aged 40–75 years) and
12786 postmenopausal women (aged up to 75 years),
with or without coronary artery disease, which was
defined as previous myocardial infarction, coronary
interventions, or confirmed angina pectoris. Informed
written consent was obtained from all eligible patients
before random assignment to either the EPA treatment
or control groups.
Eligibility criteria were total cholesterol concentration of
6·5 mmol/L or greater, which corresponded to a LDL
cholesterol of 4·4 mmol/L or greater. Exclusion criteria
were: acute myocardial infarction within the past 6 months,
unstable angina pectoris, a history or complication of
serious heart disease (such as severe arrhythmia, heart
failure, cardiomyopathy, valvular disease, or congenital
disease), cardiovascular reconstruction within the past
6 months, cerebrovascular disorders within the past
6 months, complications of serious hepatic or renal
disease, malignant disease, uncontrollable diabetes,
hyperlipidaemia due to other disorders, hyperlipidaemia
caused by drugs such as steroid hormones, haemorrhage
(including haemophilia, capillary fragility, gastrointestinal
ulcer, urinary tract haemorrhage, haemoptysis, and
vitreous haemorrhage), haemorrhagic diathesis, hyper-
sensitivity to the study drug formulation, patients’ intention
to undergo surgery, and judgment by the physician in
charge that a patient was inappropriate for the study.
The primary endpoint was any major coronary event,
including sudden cardiac death, fatal and non-fatal
myocardial infarction, and other non-fatal events
including unstable angina pectoris, angioplasty,
stenting, or coronary artery bypass grafting. Secondary
endpoints (all-cause mortality, mortality and morbidity
of coronary artery disease, stroke, peripheral artery
disease, and cancer) are not reported here.
Procedures
We used the statistical coordination centre at the Toyama
Medical and Pharmaceutical University to manage
patient registration (including confirmation of eligibility
criteria), operation of the randomisation scheme, and
data management. We used permuted-block random-
isation with a block size of four. Blocks were assigned
according to the number of participants enrolled at each
centre. Patients were divided into two subgroups: one
with coronary artery disease (secondary prevention;
n=3664) and one without (primary prevention; n=14981),
and stratified accordingly. Patients were randomly
assigned to receive EPA with statin (EPA group) or statin
alone (controls). All patients first underwent 4–8 weeks
of washout from antihyperlipidaemic drugs. Patients also
received appropriate dietary advice.
All patients received 10 mg of pravastatin or 5 mg of
simvastatin once daily as first-line treatment. These
statins were available in Japan at the initiation of this
study, and these doses were recommended by the
Ministry of Health, Labour, and Welfare. For serious
hypercholesterolaemia (defined as uncontrolled), this
daily dose was increased to 20 mg pravastatin or 10 mg
simvastatin. No treatment with other antihyperlipidaemic
drugs was allowed during the study. EPA was given at a
dose of 600 mg, three times a day after meals (to a total of
1800 mg per day). We used capsules that contained
300 mg of highly purified (>98%) EPA ethyl ester
(Mochida Pharmaceuticals, Tokyo, Japan).
Local physicians monitored compliance with dietary
advice and medication, and noted adverse events at
every clinic visit. Clinical endpoints and severe adverse
events reported by local physicians were checked by
members of a regional organising committee in a
blinded fashion. Then, an endpoints adjudication
committee (see webappendix), consisting of three
expert cardiologists and one expert neurologist,
confirmed them once a year without knowledge of the
19466 patients
9319 analysed by intention-
to-treat
791 discontinued observation
9326 analysed by intention-
to-treat
883 discontinued observation
98 lost to follow-up
273 withdrew consent
420 other reasons
99 lost to follow-up
361 withdrew consent
423 other reasons
821 did not meet inclusion
criteria
805 refused to give consent
16 other reasons
18645 randomly assigned
9319 controls 9326 EPA treatment
Figure 1:Trial profile
See Online for webappendix
3. Articles
1092 www.thelancet.com Vol 369 March 31, 2007
treatment allocation. The study was approved by an
external data and safety monitoring board, by
institutional review boards at all hospitals, and by
regional organising committees. The data and safety
monitoring board also monitored the rate of endpoints
twice during the study, in March, 2002, and March,
2004. The study was followed up until November, 2004,
because both interim analyses did not reach the
stopping boundary.
We sampled blood to measure serum lipid at 6 and
12 months, and then every year until the final follow-up
visits. Plasma total fatty acid concentrations for all
patients who gave informed consent were measured
with capillary gas chromatography every year at a central
laboratory.
Statistical analysis
We used a two-sided test at the 5% significance level to
estimate that the number of enrolled patients would
give the study a statistical power of 80% for detection of
a relative reduction of 25% in the primary endpoint rate,
when the EPA group was compared with controls. The
event rate of the primary endpoint in the control group
was assumed to be 0·58% per year for primary
prevention and 2·13% per year for secondary prevention;
the proportion of primary and secondary prevention
strata was assumed to be 4:1. The accrual period was
assumed to be 3 years with a follow-up of 5 years for all
patients. All analyses were based on the intention-to-
treat principle. Time-to-event data were analysed with
the Kaplan–Meier method and the log-rank test. The
hazard ratio and its 95% confidence interval were
computed with the Cox proportional hazard model. We
did subgroup analyses with a model that included an
interaction term corresponding to the test for
heterogeneity in effects. Changes in lipid values were
compared by repeated measures of ANOVA. Data were
analysed with SAS statistical software (version 8.12).
Role of the funding source
The sponsor had no role in the study design, data
collection, data analysis, data interpretation, or writing of
the report. The JELIS steering committee had full access
to all the data in the study and had final responsibility for
the decision to submit for publication.
Results
Patients were monitored for an average of 4·6 years
(SD 1·1). Table 1 shows baseline characteristics of the
treatment groups. The mean age of all patients was
61 years and 12 786 patients (69%) were women. Mean
concentrations of total cholesterol and triglyceride were
7∙1 mmol/L and 1∙7 mmol/L; and mean LDL and HDL
cholesterol concentrations were 4∙7 mmol/L and
1∙5 mmol/L, respectively. The webtable shows baseline
characteristics for primary and secondary prevention
subgroups. Of 3664 patients with documented coronary
artery disease, 1050 had a history of myocardial
infarction, 2903 of angina pectoris, and 895 angioplasty,
stenting, or coronary artery bypass grafting.
Average doses were pravastatin 10·0 mg daily (SD
9·1) and simvastatin 5·6 mg daily (1·8). 16449 (90%)
patients took 10 mg pravastatin or 5 mg simvastatin.
The 5-year follow-up rate was 16971 (91%). Similar
proportions of participants remained compliant in each
treatment group. Study drug regimens were maintained
until trial termination by 6151 (73%) of controls and in
the treatment group 5883 (71%) of patients continued
to take EPA and 6136 (74%) continued to take statin.
586 patients (262 assigned to EPA and 324 controls)
reached the composite primary endpoint. Figure 2
shows Kaplan–Meier curves for the primary endpoint.
The 5-year cumulative rate of major coronary events
See Online for webtable
Controls (n=9319) EPA treatment
(n=9326)
Age (years) 61 (9) 61 (8)
Male 2908 (31%) 2951 (32%)
BMI (kg/m2
) 24 (3) 24 (3)
Cardiovascular history
Myocardial infarction 502 (5%) 548 (6%)
Angina 1484 (16%) 1419 (15%)
CABG or PTCA 433 (5%) 462 (5%)
Risk factors
Smoking 1700 (18%) 1830 (20%)
Diabetes 1524 (16%) 1516 (16%)
Hypertension 3282 (35%) 3329 (36%)
Serum lipid values
Total cholesterol (mmol/L) 7·11 (0·68) 7·11 (0·67)
LDL-cholesterol (mmol/L) 4·70 (0·75) 4·69 (0·76)
HDL-cholesterol (mmol/L) 1·51 (0·44) 1·52 (0·46)
Triglyceride (mmol/L)* 1·74 (1·25–2·49) 1·73(1·23–2·48)
Blood pressure
Systolic (mm Hg) 135 (21) 135 (21)
Diastolic(mm Hg) 79 (13) 79 (13)
HMG CoA RI
Pravastatin 5553 (60%) 5523 (60%)
Simvastatin 3417 (37%) 3272 (36%)
Other statin 128 (1%) 110 (1%)
Medication use
Antiplatelet agent 1342 (14%) 1258 (13%)
Calcium antagonist 2837 (30%) 2796 (30%)
β blocker 791 (8%) 794 (9%)
Other antihypertensive
agents
2424 (26%) 2366 (25%)
Nitrate 926 (10%) 863 (9%)
Hypoglycaemic agents 1126 (12%) 1081 (12%)
Data are number of patients (%) or mean (SD), unless otherwise indicated.
CABG=coronary-artery bypass grafting. PTCA=percutaneous transluminal
coronary angioplasty. LDL=low-density lipoprotein. HDL=high-density
lipoprotein. IQR=interquartile range. HMG CoA RI=3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitor. BMI=body-mass index, which is weight in kg
divided by the square of height in metres. *Median (IQR).
Table 1: Baseline characteristics
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www.thelancet.com Vol 369 March 31, 2007 1093
was 2·8% in the EPA group and 3·5% in controls,
resulting in a significant relative risk reduction of 19%
in the EPA group (p=0·011). Figure 3 shows that EPA
treatment was associated with a significant reduction of
24% in the frequency of unstable angina. The occurrence
of coronary death or myocardial infarction was not
significantly lower (22%) in the EPA group than in
controls. The frequency of fatal or non-fatal myocardial
infarction was not significantly reduced (23%) in the
EPA group; however, that of non-fatal coronary events
(including non-fatal myocardial infarction, unstable
angina, and events of angioplasty, stenting, or coronary
artery bypass grafting) was significantly lower (19%) in
the EPA group than in controls.
Table 2 sets out major coronary events in the two
treatment groups for comparison with specific
background characteristics of all populations. For
example, we grouped patients according to their LDL
cholesterol at baseline. The relative reduction in major
coronary events risk in the EPA group was of a similar
magnitude in patients with different ranges of LDL
cholesterol values, suggesting that LDL cholesterol is
not an important factor in reduction of risk for major
coronary events.
In the primary prevention subgroup, EPA treatment
was associated with a non-significant 18% reduction in
major coronary events. Figure 3 shows the non-
significant reductions of 18%, 21%, and 20% in coronary
death or non-fatal myocardial infarction, fatal or non-
fatal myocardial infarction, and non-fatal coronary
events, respectively. In the secondary prevention
subgroup, allocation to the EPA treatment was
associated with a significant 19% reduction in major
coronary events. EPA treatment was also associated
with a significant 28% reduction in the incidence of
unstable angina. This treatment also produced non-
significant reductions of 25%, 25%, and 18% in coronary
death or myocardial infarction, fatal or non-fatal
myocardial infarction, and non-fatal coronary events,
respectively.
In the other analyses, stroke occurred in 162 (1·7%)
controls and 166 (1·8%) patients given EPA. Figure 3
shows that the frequency of ischaemic and haemorrhagic
strokes did not differ between the two treatment groups,
and neither did all-cause mortality.
Figure 4 summarises the change in lipid values after
treatment. Total and LDL cholesterol at the last clinic
visit decreased significantly by 19% and 25% from
baseline in both groups, respectively. Triglyceride
decreased significantly by 9% from baseline in the EPA
group and by 4% in controls (p<0·0001 between
groups). Both treatments produced only small changes
in HDL cholesterol. The fatty acid concentrations at
baseline were the average values for all patients who
gave informed consent in the control group (n=8076)
and the EPA group (n=8321). Plasma EPA at baseline
was 2·9% of total molecules of fatty acids (mol %). To
assess the effect of EPA treatment, plasma fatty acid
values were compared for all patients who were still
compliant after 5 years of observation (controls: n=4854,
EPA group: n=4970). Plasma EPA concentration and
the ratio of EPA to arachidonic acid at baseline were
93 mg/L and 0·60 in controls, and 97 mg/L and 0·63 in
the EPA group, respectively. Plasma EPA concentration
and the ratio of EPA to arachidonic acid at year 5 were
93 mg/L and 0·59 in controls. On the other hand,
plasma EPA concentration at year 5 was 169 mg/L in
the EPA group, which was a 70% increase from baseline.
The ratio of EPA to arachidonic acid increased two-fold
from 0·63 to 1·23 in the EPA group. Similar results
were reported previously.11,28
Table 3 shows that a quarter of patients in the EPA
group had adverse experiences related to treatment,
compared with about a fifth of controls. Rates of
9319
9326
1450
1442
7958
7924
8192
8153
Hazard ratio: 0·81 (0·69–0·95)
p=0·011
Hazard ratio: 0·81 (0·657–0·998)
p=0·048
8433
8389
8671
8658
8931
8929 6482
6508
6649
6678
6823
6841
7020
7103
7210
7204
7503
7478 1514
1504
1592
1566
1658
1638
1727
1719
1841
1823
Control group
Majorcoronaryevents(%)
Years Years Years
Numbers at risk
Control
EPA
A B C
Treatment group
Hazard ratio: 0·82 (0·63–1·06)
p=0·132
0 1 2 3 4 50
0
0·5
1·0
1·5
2·0
0
4·0
8·0
12.0
0
1
2
3
4
1 2 3 4 50 1 2 3 4 5
Figure 2: Kaplan-Meier estimates of incidence of coronary events in the total study population (panel A), the primary prevention arm (panel B) and the secondary prevention arm (panel C)
5. Articles
1094 www.thelancet.com Vol 369 March 31, 2007
discontinuation because of treatment-related adverse
events were 1087 (11·7%) in the EPA group and
673 (7·2%) in the control group. Most adverse effects
attributable to EPA allocation were regarded as mild.
The following factors were more common in the EPA
group than in controls: abnormal laboratory data;
gastrointestinal disturbances such as nausea, diarrhoea,
or epigastric discomfort; skin abnormalities such as
eruption, itching, exanthema, or eczema; and
haemorrhages such as cerebral and fundal bleedings,
epistaxis, and subcutaneous bleeding. The frequency of
new cancers did not differ.
1·02 (0·91–1·13)0·785166162Stroke
0·97 (0·85–1·10)0·632115123Ischaemic
1·12 (0·91–1·39)0·2724939Haemorrhagic
0·63 (0·24–1·37)0·25225Other type or not determined
1·09 (0·92–1·28)0·333286265All-cause death
Other analyses
Items of account
Items of account
Items of account
0·82 (0·66–1·02)0·080145178Non-fatal coronary events
Combined endpoint
0·72 (0·55–0·95)0·01988123Unstable angina
0·64 (0·21–1·94)0·42158Fatal MI
0·87 (0·46–1·64)0·6671821Coronary death
0·75 (0·47–1·19)0·2233142Fatal MI or nonfatal MI
Combined endpoint
1·00 (0·32–3·11)0·99566Fatal MI
0·87 (0·62–1·21)0·4006474CABG or PTCA
0·85 (0·60–1·19)0·3385970Unstable angina
0·80 (0·52–1·24)0·3213645Non-fatal MI
1·25 (0·34–4·67)0·73654Sudden cardiac death
0·86 (0·71–1·05)
0·76 (0·62–0·95)
0·75 (0·54–1·04)
0·79 (0·36–1·74)
1·06 (0·55–2·07)
0·81 (0·69–0·95)
0·135191222CABG or PTCA
0·014147193Unstable angina
0·0866283Non-fatal MI
0·5571114Fatal MI
0·8541817Sudden cardiac death
0·011262324Major coronary events
All patients
EPA
58
148
38
13
197
119
10
51
55
127
297
31
93
113
Control
0·75 (0·51–1·12)
0·87 (0·69–1·10)
0·70 (0·42–1·14)
1·02 (0·47–2·19)
0·81 (0·66–1·00)
0·80 (0·61–1·05)
1·10 (0·47–2·60)
0·79 (0·52–1·19)
0·82 (0·55–1·22)
0·82 (0·63–1·06)
0·81 (0·68–0·96)
0·94 (0·57–1·56)
0·77 (0·56–1·05)
0·78 (0·59–1·03)
Hazard ratio (95 %CI)
0·15643Coronary death or MI
0·32245Coronary death or MI
0·132104Major coronary events
Primary prevention of CAD
0·015240Non-fatal coronary events
0·81229Coronary death
0·09171Fatal MI or nonfatal MI
0·08388Coronary death or MI
0·243127CABG or PTCA
0·15026Non-fatal MI
0·96713Sudden cardiac death
0·048158Major coronary events
Secondary prevention of CAD
0·10295Non-fatal coronary events
0·82211Coronary death
0·25340Fatal MI or nonfatal MI
p value
Combined endpoint
Number (%) of patientsEvent
(1·8)
(1·2)
(0·5)
(<0·1)
(3·1)
(8·0)
(4·8)
(0·3)
(1·0)
(1·7)
(0·1)
(0·9)
(0·8)
(0·5)
(0·1)
(2·1)
(1·6)
(0·7)
(0·1)
(0·2)
(2·8)
(2·4)
(7·0)
(1·4)
(0·7)
(8·7)
(1·3)
(0·1)
(0·5)
(0·6)
(1·4)
(2·6)
(0·3)
(0·8)
(0·9)
(1·7)
(1·3)
(0·4)
(0·1)
(2·8)
(9·7)
(6·7)
(0·4)
(1·1)
(2·3)
(0·1)
(1·0)
(0·9)
(0·6)
(0·1)
(2·4)
(2·1)
(0·9)
(0·2)
(0·2)
(3·5)
(3·2)
(8·0)
(2·1)
(0·7)
(10·7)
(1·6)
(0·1)
(0·7)
(0·7)
(1·7)
(3·2)
(0·3)
(1·0)
(1·2)
1 20
Favours controlFavours EPA
Figure 3: Estimated hazard ratios of clinical endpoints stratified by prevention stratum
MI=myocardial infarction. CABG=coronary-artery bypass grafting. PTCA=percutaneous transluminal coronary angioplasty. CAD=coronary-artery disease.
6. Articles
www.thelancet.com Vol 369 March 31, 2007 1095
Discussion
Our results show that EPA treatment reduced the
frequency of major coronary events. The composite
frequency of the primary endpoint in all patients for the
EPA group was 19% lower than in controls. The risks of
unstable angina and non-fatal coronary events were
also substantially reduced, by 24% and 19%, respectively.
The beneficial effects of EPA seemed much the same in
both the secondary prevention and the primary
prevention subgroups, although they were significant
only in the EPA group because of greater numbers of
events.
We showed that the reduced risk associated with EPA
treatment was confined to non-fatal coronary events.
However, the reduced risk did not apply to coronary
death or sudden cardiac death in any of our study
populations or secondary prevention subgroup studies.
This finding differs from the results of previous
interventional and observational studies.29
Most
observational studies report that fish intake only once
or twice a week or a small intake of fish about 30–60 g
per day is associated with a 30–60% reduction in the
risk of fatal coronary events or sudden cardiac deaths,
but not of non-fatal coronary events.1,3–5,7
Secondary
prevention trials for coronary heart disease report that a
modest intake of fatty fish (200–400 g/week) or
supplemental intake of EPA plus DHA (1 g/d) reduces
coronary mortality by about 20–30% in patients who
have already had a myocardial infarction.8,9
Experimental
and epidemiological studies suggest that fish oil at low
doses might prevent sudden cardiac death by an
antiarrhythmic effect.30
Our findings accord with a cohort study by the Japan
Public Health Centre, which used a food-frequency
questionnaire.31
Iso and co-workers31
reported that,
compared with a small intake of fish (once a week or
about 20 g per day), a high intake (eight times per week,
or about 180 g per day) was associated with a substantially
reduced risk of coronary heart disease, especially non-
fatal cardiac events, in middle-aged Japanese men and
women. This finding suggests that two protective
mechanisms of EPA or n-3 polyunsaturated fatty acids
affect the risk of coronary events: reduction of mortality
from coronary artery disease and sudden cardiac death
with a low intake of n-3 polyunsaturated fatty acid, and
reduction of all coronary events with a high intake of
n-3 polyunsaturated fatty acids. Our patients could
possibly all have had intakes of fish that were above the
threshold for prevention of fatal coronary events or
sudden cardiac death.4
One potential explanation for
the strong inverse association with non-fatal coronary
events in our study population, but not in other study
populations of non-Japanese patients, is that EPA might
affect risk only at very high levels of fish intake, such as
those common in Japan.
n-3 polyunsaturated fatty acids have antiarrhythmic
effects and other beneficial effects,32,33
such as reduced
Control (n=9319) EPA (n=9326) Hazard ratio (95%CI) Interaction p
Age (years)
<61 117/4380 (2·7) 87/4275 (2·0) 0·76 (0·57–1·00) 0·57
≥61 207/4939 (4·2) 175/5051 (3·5) 0·84 (0·68–1·02)
Sex
Female 126/6411 (2·0) 109/6375 (1·7) 0·87 (0·68–1·13) 0·43
Male 198/2908 (6·8) 153/2951 (5·2) 0·76 (0·62–0·94)
BMI
<24 136/4404 (3·1) 109/4386 (2·5) 0·80 (0·62–1·03) 0·88
≥24 148/4021 (3·7) 123/4078 (3·0) 0·82 (0·65–1·05)
Previous CAD
Absent 127/7478 (1·7) 104/7503 (1·4) 0·82 (0·63–1·06) 0·95
Present 197/1841 (10·7) 158/1823 (8·7) 0·81 (0·66–1·00)
Smoking
Non-smoker 216/7619 (2·8) 170/7496 (2·3) 0·80 (0·66–0·98) 0·89
Smoker 108/1700 (6·4) 92/1830 (5·0) 0·78 (0·59–1·04)
Diabetes
Absent 221/7795 (2·8) 175/7810 (2·2) 0·79 (0·65–0·96) 0·62
Present 103/1524 (6·8) 87/1516 (5·7) 0·86 (0·65–1·15)
Hypertension
Absent 167/6037 (2·8) 139/5997 (2·3) 0·85 (0·68–1·06) 0·57
Present 157/3282 (4·8) 123/3329 (3·7) 0·77 (0·61–0·97)
Total cholesterol (mmol/L)
<7·0 167/4700 (3·6) 145/4751 (3·1) 0·86 (0·69–1·08) 0·46
≥7·0 156/4608 (3·4) 117/4550 (2·6) 0·76 (0·60–0·97)
Triglyceride (mmol/L)
<1·7 130/4555 (2·9) 105/4635 (2·3) 0·79 (0·61–1·02) 0·75
≥1·7 188/4648 (4·0) 153/4563 (3·4) 0·84 (0·68–1·04)
HDL-cholesterol (mmol/L)
<1·5 206/4316 (4·8) 154/4149 (3·7) 0·78 (0·64–0·96) 0·26
≥1·5 91/4285 (2·1) 91/4491 (2·0) 0·96 (0·72–1·28)
LDL-cholesterol (mmol/L)
<4·7 129/4160 (3·1) 108/4251 (2·5) 0·82 (0·64–1·06) 0·83
≥4·7 156/4157 (3·8) 131/4097 (3·2) 0·86 (0·68–1·08)
Data are number of patients (%) or hazard ratio (95% CI). p values are for the test of heterogeneity. CAD=coronary
artery disease. BMI=body-mass index, which is weight in kg divided by the square of height in metres. LDL=low-density
lipoprotein. HDL=high-density lipoprotein.There is a deficit of clinical data in some patients with the events.
Table 2: Subgroup analysis
–40
–30
–20
–10
0
10
TC LDL-C HDL-C Triglyceride
All patients
Patients with
≥1·7 mmol/L
at registration
Changerates(%)
Control
EPA
Triglyceride
Figure 4: Percentage changes from baseline in serum lipid profile
TC=total cholesterol. LDL C=low-density lipoprotein cholesterol. HDL C=high-density lipoprotein cholesterol.
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1096 www.thelancet.com Vol 369 March 31, 2007
platelet aggregation,10,11
vasodilation,12,13
antiprolifer-
ation,14
plaque-stabilisation,15
and a reduction in lipid
action.16,17
One clinical study examined the morphology of
endoatherectomised carotid specimens and showed that
fish-oil supplementation increased the stability of
atherosclerotic plaque.15,34
Atherosclerotic plaque is
vulnerable to rupture because it has a thin fibrous cap
that covers a large lipid core, and an increased number of
inflammatory cells such as macrophages. n-3 poly-
unsaturated fatty acids reduce the expression of adhesion
molecules on endothelial cells35
and macrophages.36
Dietaryfishoilreducestheproductionofchemoattractants,
including leukotriene B4,37
platelet-derived growth
factor,38
and monocyte chemoattractant protein-1.39
These
mechanisms reduce the passage of monocytes and
macrophages into the plaque. Thus, EPA and DHA
reducethenumbersofmacrophagesintheatherosclerotic
plaque. Thrombus formation in the ruptured plaque
leads to acute cardiovascular events.
Our study has some specific characteristics. First, we
usedhighlypurifiedEPAratherthann-3polyunsaturated
fatty acids or fish oils. This trial is a pharmacological
intervention rather than a food-based or nutrient trial.
Nutritional data are difficult to extrapolate to
pharmacological intervention because fish oil contains
many fatty acids other than EPA and DHA. Although
both EPA and DHA are biologically active, we do not
know whether they have differential effects on
cardiovascular protection. Second, our population was
exclusively Japanese. In Japan, death from coronary
artery disease is rare and the average dietary intake of
fish is about five times higher than that in other
countries.28
We did not use a food-frequency question-
naire to measure fish intake; instead, at baseline, we
measured plasma fatty acid concentrations that indicate
fish consumption and EPA intake. Plasma EPA was
2·9 mol% at baseline in our study population, which is
similar to reports by Iso and co-workers40
that serum
EPA composition was 4·1 mol% in rural Japanese and
2·4 mol% in urban Japanese; these values are much
higher than those recorded in the USA, which are about
0·3 mol%.
Our trial has several limitations. First, we used an open
interventional design, with blinded clinical endpoint
assessment (PROBE design) to keep bias to a minimum.23
The PROBE design has the advantages of low costs and
similarity to standard clinical practice, which should
make the results easily applicable in routine medical
care; however, we cannot exclude the possibility of bias in
some of the physician-initiated endpoints, such as
coronary revascularisation and hospital treatment for
unstable angina.
Second, we prescribed either pravastatin or
simvastatin for all participants as the first-line
treatment, in part because these were the two statins
available in the Japanese market at the start of this
study. We used the low doses of statins that are
recommended by Japan’s Ministry of Health, Labour,
and Welfare. Such low doses have been reported to
control serum lipid concentrations and major coronary
events in Japanese patients.41,42
We did not use a true
placebo group.
Third, this trial was substantially underpowered for
analysis of subgroups. Death associated with coronary
artery disease in the Japanese population is about
22–26 per 100 000 person-years, which is very low in
comparison with that in the USA and northern
Europe.28
This difference is thought to be partly due to
differences in dietary habits, including fish con-
sumption. About two-thirds of patients in our study
were women, who have an incidence of coronary events
that is 2·3 times lower than that for men.41
This low
ratio of men to women and the Japanese study
population could have contributed to the overall low
rate of coronary events, including coronary death,
which failed to detect a significant effect on primary
prevention outcomes.
Studies show that use of high-dose statin treatment
can produce an extra reduction in cardiac events,
by achievement of the maximum lowering of LDL
cholesterol.43
Similar benefits could arguably be obtained
if the dose of statin was increased without the addition
of EPA; however, we noted that EPA did not affect LDL
cholesterol concentrations and that this 19% reduction
in major coronary events in the EPA group was not
related to serum LDL cholesterol. This finding suggests
that EPA exerts its effects via mechanisms that are
independent of a reduction in LDL cholesterol.
Control (n=9319) EPA (n=9326) p value
Total number of adverse experiences (%) 2004 (21·7%) 2334 (25·3%) <0·0001
Newly diagnosed cancer
Total 218 (2·4%) 242 (2·6%) 0·26
Stomach 37 (0·4%) 53 (0·6%) 0·09
Lung 37 (0·4%) 32 (0·3%) 0·54
Colorectal 29 (0·3%) 26 (0·3%) 0·68
Breast 21 (0·2%) 16 (0·2%) 0·41
Common adverse experiences
Pain (joint pain, lumbar pain, muscle pain) 180 (2·0%) 144 (1·6%) 0·04
Gastrointestinal disturbance (nausea,
diarrhoea, epigastric discomfort)
155 (1·7%) 352 (3·8%) <0·0001
Skin abnormality (eruption, itching,
exanthema, eczema)
65 (0·7%) 160 (1·7%) <0·0001
Haemorrhage (cerebral, fundal, epistaxis,
subcutaneous)
60 (0·6%) 105 (1·1%) 0·0006
Abnormal laboratory data
Total 322 (3·5%) 378 (4·1%) 0·03
CPK increased 116 (1·2%) 126 (1·4%) 0·52
GOT increased 38 (0·4%) 59 (0·6%) 0·03
Sugar blood level increased 27 (0·3%) 38 (0·4%) 0·17
CPK=creatine phosphokinase. GOT=glutamic oxaloacetic transaminase.
Table 3: Adverse experiences
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www.thelancet.com Vol 369 March 31, 2007 1097
We adopted the most widely used therapeutic dose of
EPA (1800 mg per day), which is approved by Japan’s
Ministry of Health, Labour, and Welfare. We noted no
significant difference in all-cause mortality between the
treatment and control groups. There was no difference
in the rate of cancer and stroke, including cerebral
bleeding, subarachnoidal bleeding, or both. We do not
know whether lower or higher doses of EPA would
produce different effects from those noted at the dose
used in our study.
The beneficial effects of EPA could have stemmed
from many biological effects that lead to the attenuation
of thrombosis, inflammation, and arrhythmia in
addition to a reduction of triglycerides. Overall, this
study shows that EPA, at a dose of 1800 mg per day, is a
very promising regimen for prevention of major
coronary events, especially since EPA seems to act
through several biological mechanisms. Because our
population was exclusively Japanese, we cannot
generalise our results to other populations. We need to
investigate whether EPA is effective for prevention
of major coronary events in hypercholesterolaemic
patients without or with coronary artery disease in other
countries.
Contributors
Investigators on the steering committee of the study designed,
conducted, analysed, and interpreted the present study. A statistical
coordination centre collected, managed, and analysed the data. All
authors have participated in the data analysis and reporting stage of
this manuscript. The principal investigator prepared the first draft,
and all members of the JELIS Steering Committee contributed to
writing, and have seen and approved the final version.
Conflict of interest statement
The committee members and investigators received no remuneration
for conducting this study. M Yokoyama received travel costs from
Mochida Pharmaceutical Co Ltd, Tokyo, Japan, to participate in the
scientific meeting. Other authors have no conflicts of interest.
Acknowledgments
This study was supported by grants from Mochida Pharmaceutical Co
Ltd, Tokyo, Japan. The results were presented in part at the late-
breaking clinical trials of the American Heart Association Annual
Meeting, Dallas, TX, USA, Nov, 13–16, 2005. We thank all trial
participants and the large numbers of doctors, nurses, and hospital
staff who made long-term commitments to the study.
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