Major Atherosclerotic Events Research Articles

Simvastatin plus ezetimibe reduced major atherosclerotic events in patients with chronic kidney disease

Source Citation Baigent C, Landray MJ, Reith C, et al; SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of...

The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial

SummaryBackgroundLowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients.MethodsThis randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and 6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecified outcome was first major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00125593, and ISRCTN54137607.Findings4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin plus ezetimibe yielded an average LDL cholesterol difference of 0·85 mmol/L (SE 0·02; with about two-thirds compliance) during a median follow-up of 4·9 years and produced a 17% proportional reduction in major atherosclerotic events (526 [11·3%] simvastatin plus ezetimibe vs 619 [13·4%] placebo; rate ratio [RR] 0·83, 95% CI 0·74–0·94; log-rank p=0·0021). Non-significantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction or died from coronary heart disease (213 [4·6%] vs 230 [5·0%]; RR 0·92, 95% CI 0·76–1·11; p=0·37) and there were significant reductions in non-haemorrhagic stroke (131 [2·8%] vs 174 [3·8%]; RR 0·75, 95% CI 0·60–0·94; p=0·01) and arterial revascularisation procedures (284 [6·1%] vs 352 [7·6%]; RR 0·79, 95% CI 0·68–0·93; p=0·0036). After weighting for subgroup-specific reductions in LDL cholesterol, there was no good evidence that the proportional effects on major atherosclerotic events differed from the summary rate ratio in any subgroup examined, and, in particular, they were similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per year of treatment with this combination (9 [0·2%] vs 5 [0·1%]). There was no evidence of excess risks of hepatitis (21 [0·5%] vs 18 [0·4%]), gallstones (106 [2·3%] vs 106 [2·3%]), or cancer (438 [9·4%] vs 439 [9·5%], p=0·89) and there was no significant excess of death from any non-vascular cause (668 [14·4%] vs 612 [13·2%], p=0·13).InterpretationReduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.FundingMerck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British Heart Foundation; UK Medical Research Council.

High blood hemoglobin concentration as risk factor of major atherosclerotic cardiovascular events in 114,159 healthy men and women in the Apolipoprotein MOrtality RISk study (AMORIS)

Background. Few studies have tested differences in relationships between hemoglobin (Hb) and long-term risk of major cardiovascular diseases according to age and gender in healthy subjects as opposed to anemia.Aims. Such relationships were examined and risk-tested in relation to Hb values in the Apolipoprotein MOrtality RISk (AMORIS) Study.Methods. Using data from AMORIS and the Swedish hospital discharge and mortality registers, a prospective cohort study of 114,159 subjects with mean follow-up of 11.8 years, the association between Hb and risk of acute myocardial infarction (AMI), ischemic stroke (IS), and congestive heart failure (CHF) by Cox regression analysis according to age and gender was studied.Results. Elevated Hb levels were associated to acute myocardial infarction (AMI) (HR 1.10 (1.06–1.13) per SD change), mostly confined to men and younger subjects but with greater sex similarity trends for CHF. Slightly increased risks were seen for the lowest Hb levels in the elderly and in females. IS risk was positively and more linearly associated to Hb.Interpretation. In AMORIS the highest AMI and CHF risks were found in the upper region of the distribution, but different shapes of relationships according to age and gender were found. IS associated positively with Hb. Key words:

Role of statins in preventing adverse cardiovascular outcomes in patients with chronic kidney disease.

Cardiovascular disease accounts for the majority of deaths in chronic kidney disease (CKD). Dyslipidemia is a well established cardiovascular risk factor. We summarize key aspects of available evidence relating to beneficial effects of statins in nondialysis-dependent CKD, dialysis-dependent CKD and renal transplant recipients. Previous trials and their meta-analyses suggested that statins reduce lipid levels, the risk of cardiovascular disease and all-cause mortality in nondialysis-dependent CKD. The Study of Heart and Renal Protection (SHARP) study that enrolled both dialysis-dependent and nondialysis-dependent CKD patients showed a 17% decrease in major atherosclerotic events with statins or ezetimibe. Similar cardiovascular benefits are observed in renal transplant recipients. However, such positive effects were not found in two recent clinical trials that enrolled hemodialysis patients alone. This lack of benefit might be attributed to differences in the cause of cardiovascular death seen in dialysis patients and smaller sample size. The overall benefits-harms tradeoff may benefit from meta-analysis and individual patient data meta-analysis in hemodialysis patients including the SHARP data. Nondialysis-dependent CKD patients and renal transplant recipients benefit from statins. Statins have also been found to be beneficial in one of the three large trials in hemodialysis patients, a matter which may be further explored.

Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among 9,438 patients with chronic kidney disease

Lowering low-density lipoprotein (LDL) cholesterol with statin therapy has been shown to reduce the incidence of atherosclerotic events in many types of patient, but it remains uncertain whether it is of net benefit among people with chronic kidney disease (CKD). Patients with advanced CKD (blood creatinine ≥ 1.7 mg/dL [≥ 150 μmol/L] in men or ≥ 1.5 mg/dL [ ≥ 130 μmol/L] in women) with no known history of myocardial infarction or coronary revascularization were randomized in a ratio of 4:4:1 to ezetimibe 10 mg plus simvastatin 20 mg daily versus matching placebo versus simvastatin 20 mg daily (with the latter arm rerandomized at 1 year to ezetimibe 10 mg plus simvastatin 20 mg daily vs placebo). The key outcome will be major atherosclerotic events, defined as the combination of myocardial infarction, coronary death, ischemic stroke, or any revascularization procedure. A total of 9,438 CKD patients were randomized, of whom 3,056 were on dialysis. Mean age was 61 years, two thirds were male, one fifth had diabetes mellitus, and one sixth had vascular disease. Compared with either placebo or simvastatin alone, allocation to ezetimibe plus simvastatin was not associated with any excess of myopathy, hepatic toxicity, or biliary complications during the first year of follow-up. Compared with placebo, allocation to ezetimibe 10 mg plus simvastatin 20 mg daily yielded average LDL cholesterol differences of 43 mg/dL (1.10 mmol/L) at 1 year and 33 mg/dL (0.85 mmol/L) at 2.5 years. Follow-up is scheduled to continue until August 2010, when all patients will have been followed for at least 4 years. SHARP should provide evidence about the efficacy and safety of lowering LDL cholesterol with the combination of ezetimibe and simvastatin among a wide range of patients with CKD.

Influence of fibrinogen on cardiovascular disease.

Results from prevalence, case-control, angiographic and echocardiographic investigations incriminate elevated fibrinogen levels as a strong independent risk factor for the occurrence of initial and recurrent cardiovascular events. Average fibrinogen levels are higher in women and persons with other risk factors including hypertension, diabetes, cigarette smoking, obesity, elevated haematocrit value and dyslipidaemia. Fibrinogen tends to cluster with most of these major atherogenic cardiovascular risk factors and further enhances their risk. Prospective data indicate a relationship between fibrinogen and the subsequent development of all the major atherosclerotic cardiovascular events including coronary heart disease, stroke and peripheral artery disease. Fibrinogen adds to the multivariate risk of cardiovascular events, especially in the high risk subset of the population. In the Framingham Heart Study, a comparison of risk gradients, exemplified by their regression coefficients, was similar for all outcomes (coronary heart disease, stroke, peripheral artery disease and cardiovascular disease) in men, whereas, in women, the risk gradient for fibrinogen appeared weakest for stroke. Fibrinogen exerts an independent influence on the frequency of cardiovascular disease in general, and coronary heart disease in particular. For example, in both men and women, each standard deviation increase in fibrinogen level (about 0.56 g/L) within the range of usual values is associated with about a 20% age- and risk factor-adjusted increase in the incidence of an initial cardiovascular event. Fibrinogen should be added to the list of major atherogenic cardiovascular risk factors; in addition, there is a need for intervention trials designed to test the efficacy of lowering fibrinogen in individuals at high risk for cardiovascular disease.

Childpsychiatric and neurological findings in hyperactive patients

To quantify the relation between smoking cessation after a first cardiovascular (CV) event and risk of recurrent CV events and mortality.Data were available from 4,673 patients aged 61 ± 8.7 years, with a recent (≤1 year) first manifestation of arterial disease participating in the SMART-cohort. Cox models were used to quantify the relation between smoking status and risk of recurrent major atherosclerotic cardiovascular events (MACE including stroke, MI and vascular mortality) and mortality. In addition, survival according to smoking status was plotted, taking competing risk of non-vascular mortality into account.A third of the smokers stopped after their first CV event. During a median of 7.4 (3.7–10.8) years of follow-up, 794 patients died and 692 MACE occurred. Compared to patients who continued to smoke, patients who quit had a lower risk of recurrent MACE (adjusted HR 0.66, 95% CI 0.49–0.88) and all-cause mortality (adjusted HR 0.63, 95% CI 0.48–0.82). Patients who reported smoking cessation on average lived 5 life years longer and recurrent MACE occurred 10 years later. In patients with a first CV event >70 years, cessation of smoking had improved survival which on average was comparable to former or never smokers.Irrespective of age at first CV event, cessation of smoking after a first CV event is related to a substantial lower risk of recurrent vascular events and all-cause mortality. Since smoking cessation is more effective in reducing CV risk than any pharmaceutical treatment of major risk factors, it should be a key objective for patients with vascular disease.

Predisposition to Atherosclerosis in the Head, Heart, and Legs

Findings from a 16-year follow-up study of 5,209 Framingham adults indicate that blood pressure, serum cholesterol, cigarette smoking, electrocardiographic evidence of left ventricular hypertrophy, and glucose intolerance are precursors common to all three major atherosclerotic events—atherosclerotic brain infarction (ABI), coronary heart disease (CHD), and intermittent claudication (IC). The dominant factor predisposing to ABI is high blood pressure. None is clearly dominant for CHD. Glucose intolerance is only weakly related to this disease while cigarette smoking is related weakly (if at all) to angina pectoris. All five factors play an important role in IC. In general, relationships appear to be as strong for women as men. When all five variables are considered jointly, they have a closer relationship with ABI and IC than with CHD, and equally strong relationships in every age group between 45 and 74 years of age.