A critical evaluation of the NICE guidelines for post-myocardial infarction prophylaxis. National Institute for Clinical Excellence

The UK National Institute for Clinical Excellence (NICE) has recently published guidelines on prophylaxis for patients who have experienced a myocardial infarction (MI). Based on a previously commissioned extensive review of the literature, the recommendations are antiplatelet therapy, beta-blockers and angiotensin converting enzyme inhibitors (ACEIs) for all patients; statins for those with hypercholesterolaemia; spironolactone for those with moderate-to-severe heart failure (HF); and insulin for those with diabetes. While there may be concerns about some of the details (eg., the possible adverse interaction between aspirin and ACEIs), comments on the use of statins for those with HF, the lack of advice on the choice of lipid-lowering therapy for those intolerent of statins, the dangers of spironolactone therapy and the practicality of intensive insulin treatment, the guidelines are firmly based on sound evidence of efficacy and cost effectiveness. The NICE guidelines should therefore stimulate the provision of resources to address the gap between current practice and these recommendations.     

Prescribing behaviour according to Dutch and European guidelines on the management of hypercholesterolaemia (1992-1999)

BACKGROUND: The success of the full implementation of a new guideline may depend on the observed discrepancy between daily medical practice developed before the release of the guideline and new treatment recommendations issued by the guideline. AIM: To assess whether the initiation of statin treatment for primary prevention of cardiovascular disease in an elderly population was in agreement with guidelines. METHODS: Data were obtained from the Rotterdam Study, a prospective population-based cohort study consisting of 7983 subjects aged>or=55 years. In the period 1992-1999, all patients starting statins for primary prevention were selected. Treatment eligibility was established according to Dutch guidelines based on considerations of cost effectiveness (1998) and European guidelines based on clinical effectiveness (1998 and 2003). RESULTS: Only 5.7% [95% confidence interval (CI) 3.1, 8.3] of the 299 subjects starting statins for primary prevention met the eligibility criteria of the Dutch guidelines. Most patients (92.0%, 95% CI 88.9, 95.1) met the criteria of the 2003 European guidelines. Patients who did not meet any eligibility criteria were female and had one or less cardiovascular risk factor, except for two patients with total cholesterol levels<5 mmol l-1 prior to start of statin therapy. CONCLUSIONS: The use of statins was in agreement with the most recent European guidelines in over 90% of elderly patients who started statins for primary prevention, but in only 6% of these patients according to the Dutch guidelines. As long as existing guidelines are as discrepant as they are now, variation in agreement between physicians' prescribing and guideline recommendations is unavoidable.     

Impact of the additive effect of angiotensin-converting enzyme inhibitors and /or statins with antiplatelet medication on mortality after acute ischaemic stroke

There has been recent interest in combining antiplatelets, angiotensin-converting enzyme inhibitors (ACEIs) and statins in primary and secondary ischaemic stroke prevention. This observational study was performed to evaluate the impact of adding ACEIs and/or statins to antiplatelets on post-stroke in-hospital mortality. Ischaemic stroke patients attending a hospital in Malaysia over an 18-month period were evaluated. Patients were categorized according to their vital status at discharge. Data included demographic information, risk factors, clinical characteristics and previous medications with particular attention on antiplatelets, ACEIs and statins. In-hospital mortality was compared among patients who were not taking antiplatelets, ACEIs or statins before stroke onset versus those who were taking antiplatelets alone or in combination with either ACEIs, statins or both. Data analysis was performed using SPSS version 15. Overall, 637 patients met the study inclusion criteria. After controlling for the effects of confounders, adding ACEIs or statins to antiplatelets significantly decreased the incidence of death after stroke attack by 68% (p = 0.036) and 81% (p = 0.010), respectively, compared to patients on antiplatelets alone or none of these medications. Additionally, the addition of both ACEIs and statins to antiplatelet medication resulted in the highest reduction (by 94%) of the occurrence of death after stroke attack (p < 0.001). Our results suggest that adding ACEIs and/or statins to antiplatelets for patients at risk of developing stroke, either as a primary or as a secondary preventive regimen, was associated with a significant reduction in the incidence of mortality after ischaemic stroke than antiplatelets alone. These results might help reduce the rate of ischaemic stroke morbidity and mortality by enhancing the application of specific therapeutic and management strategies for patients at a high risk of acute stroke.     

Atorvastatin and statins in the treatment of heart failure

Heart failure (HF) affects approximately five million people in the US and survival at 5 years is only 50% despite advances in medical and device therapy. Statins are of novel therapy for these patients, which may be beneficial in both ischemic and non-ischemic HF. In addition to lipid-lowering and anti-atherosclerotic effects, statins demonstrate many non-lipid or pleiotropic effects that could be beneficial in HF. They may inhibit or reverse myocardial remodeling, inhibit inflammation in HF, improve endothelial function and restore autonomic nervous system balance. Numerous observational studies of HF cohorts have linked statin therapy with significantly improved survival. Small prospective clinical studies of atorvastatin and simvastatin in systolic HF are promising, documenting improved ventricular systolic function and decreased inflammatory biomarkers with statin therapy. Definitive recommendations regarding statin therapy in all HF must await the completion of large scale outcome trials of statins in non-ischemic HF.     

Blood pressure guidelines - where are we now?

In June 2006, the National Institute for Health and Clinical Excellence (NICE) updated its recommendations on the management of patients with hypertension (published in 2004), in light of "significant new data" relating to drug treatment.1,2 The update, published in collaboration with the British Hypertension Society (BHS), recommended first-line use of a calcium-channel blocker or a thiazide-type diuretic in patients aged over 55 years or an ACE inhibitor in those aged under 55 years, and advised that beta-blockers should no longer be used for routine initial therapy.1 Recently published data from England suggest that primary care prescribing has changed in line with this new guideline.3 However, interpretation of the evidence that underpins some of the key recommendations is open to debate, particularly as there are differences from some other major guidelines in the recommendations for first-line therapy. Here we consider the updated NICE guideline, the rationale for its treatment recommendations, and the subsequent change in clinical practice. In particular, we focus on the initial drug management of adults without conditions such as diabetes mellitus or coronary heart disease that would in themselves be a key determinant of management.     

Atorvastatin and statins in the treatment of heart failure

Heart failure (HF) affects approximately five million people in the US and survival at 5 years is only 50% despite advances in medical and device therapy. Statins are of novel therapy for these patients, which may be beneficial in both ischemic and non-ischemic HF. In addition to lipid-lowering and anti-atherosclerotic effects, statins demonstrate many non-lipid or pleiotropic effects that could be beneficial in HF. They may inhibit or reverse myocardial remodeling, inhibit inflammation in HF, improve endothelial function and restore autonomic nervous system balance. Numerous observational studies of HF cohorts have linked statin therapy with significantly improved survival. Small prospective clinical studies of atorvastatin and simvastatin in systolic HF are promising, documenting improved ventricular systolic function and decreased inflammatory biomarkers with statin therapy. Definitive recommendations regarding statin therapy in all HF must await the completion of large scale outcome trials of statins in non-ischemic HF.     

Present and future pharmacotherapy for heart failure

The pharmacotherapy currently recommended by the American College of Cardiology and the American Heart Association for heart failure (HF) is a diuretic, an angiotensin-converting enzyme inhibitor (ACEI), a β-adrenoceptor antagonist and (usually) digitalis. This current treatment of HF may be improved by optimising the dose of ACEI used, as increasing the dose of lisinopril increases its benefits in HF. Selective angiotensin receptor-1 (AT₁) antagonists are effective alternatives for those who cannot tolerate ACEIs. AT₁ antagonists may also be used in combination with ACEIs, as some studies have shown cumulative benefits for the combination. In addition to being used in Stage IV HF patients, in whom it has a marked benefit, spironolactone should be studied in less severe HF and in the presence of β-blockers. The use of carvedilol, extended-release metoprolol and bisoprolol should be extended to severe HF patients as these agents have been shown to decrease mortality in this group. The ancillary properties of carvedilol, particularly antagonism at prejunctional β-adrenoceptors, may give it additional benefits to selective β₁-adrenoceptor antagonists. Celiprolol and bucindolol are not the β-blockers of choice in HF, as they do not decrease mortality. Although digitalis does not reduce mortality, it remains the only option for a long-term positive inotropic effect, as the long-term use of the phosphodiesterase inhibitors is associated with increased mortality. The calcium sensitising drug levosimendan may be useful in the hospital treatment of decompensated HF to increase cardiac output and improve dyspnoea and fatigue. The antiarrhythmic drug amiodarone should probably be used in patients at high risk of arrhythmic or sudden death, although this treatment may soon be superseded by the more expensive implanted cardioverter defibrillators, which are probably more effective and have fewer side effects. The natriuretic peptide nesiritide has recently been introduced for the hospital treatment of decompensated HF. Novel drugs that may be beneficial in the treatment of HF include the vasopeptidase inhibitors and the selective endothelin-A receptor antagonists but these require much more investigation. However, disappointing results have been obtained in a large clinical trial of the tumour necrosis factor α antagonist etanercept, where no likelihood of a difference between placebo and etanercept was observed. Small clinical trials with recombinant growth hormone to thicken ventricles in dilated cardiomyopathy have given variable results.     

Present and future pharmacotherapy for heart failure

The pharmacotherapy currently recommended by the American College of Cardiology and the American Heart Association for heart failure (HF) is a diuretic, an angiotensin-converting enzyme inhibitor (ACEI), a beta-adrenoceptor antagonist and (usually) digitalis. This current treatment of HF may be improved by optimising the dose of ACEI used, as increasing the dose of lisinopril increases its benefits in HF. Selective angiotensin receptor-1 (AT(1)) antagonists are effective alternatives for those who cannot tolerate ACEIs. AT(1) antagonists may also be used in combination with ACEIs, as some studies have shown cumulative benefits for the combination. In addition to being used in Stage IV HF patients, in whom it has a marked benefit, spironolactone should be studied in less severe HF and in the presence of beta-blockers. The use of carvedilol, extended-release metoprolol and bisoprolol should be extended to severe HF patients as these agents have been shown to decrease mortality in this group. The ancillary properties of carvedilol, particularly antagonism at prejunctional beta -adrenoceptors, may give it additional benefits to selective beta(1)-adrenoceptor antagonists. Celiprolol and bucindolol are not the beta-blockers of choice in HF, as they do not decrease mortality. Although digitalis does not reduce mortality, it remains the only option for a long-term positive inotropic effect, as the long-term use of the phosphodiesterase inhibitors is associated with increased mortality. The calcium sensitising drug levosimendan may be useful in the hospital treatment of decompensated HF to increase cardiac output and improve dyspnoea and fatigue. The antiarrhythmic drug amiodarone should probably be used in patients at high risk of arrhythmic or sudden death, although this treatment may soon be superseded by the more expensive implanted cardioverter defibrillators, which are probably more effective and have fewer side effects. The natriuretic peptide nesiritide has recently been introduced for the hospital treatment of decompensated HF. Novel drugs that may be beneficial in the treatment of HF include the vasopeptidase inhibitors and the selective endothelin-A receptor antagonists but these require much more investigation. However, disappointing results have been obtained in a large clinical trial of the tumour necrosis factor alpha antagonist etanercept, where no likelihood of a difference between placebo and etanercept was observed. Small clinical trials with recombinant growth hormone to thicken ventricles in dilated cardiomyopathy have given variable results.     

Renin–angiotensin system inhibitor and statins combination therapeutics – what have we learnt?

Hypercholesterolemia and hypertension are the most common risk factors for cardiovascular disease (CVD). Updated guidelines emphasize target reduction of overall cardiovascular risks. Hypercholesterolemia and hypertension have a synergistic deleterious effect on insulin resistance and endothelial dysfunction. Unregulated renin–angiotensin system (RAS) is important in the pathogenesis of atherosclerosis. Statins are the most important in patients with hypercholesterolemia to prevent CVD by lowering low-density lipoprotein-cholesterol, improving endothelial dysfunction, and other anti-atherosclerotic effects. Unfortunately, statin therapy dose-dependently causes insulin resistance and increases the risk of type 2 diabetes mellitus. RAS inhibitors improve both endothelial dysfunction and insulin resistance in addition to blood pressure lowering. Further, cross-talk between hypercholesterolemia and RAS exists at multiple steps of insulin resistance and endothelial dysfunction. In this regard, combined therapy with statins and RAS inhibitors demonstrates additive/synergistic beneficial effects on endothelial dysfunction and insulin resistance in addition to lowering both cholesterol levels and blood pressure and it did reduce cardiovascular events when compared with either monotherapy in patients. This is mediated by both distinct and interrelated mechanisms. Therefore, combined therapy with statins and RAS inhibitors may be important in developing optimal management strategies in patients with hypertension, hypercholesterolemia, diabetes, metabolic syndrome or obesity to prevent or treat CVD.     

Using group-based trajectory modeling to characterize the association of past ACEIs/ARBs adherence with subsequent statin adherence patterns among new statin users

BackgroundDespite well-documented benefits, statin adherence remains suboptimal. Studies have suggested that previous adherence to other chronic medications is a strong predictor of future adherence to newly initiated statins. Group-based trajectory modeling (GBTM) has been applied as a method to longitudinally depict the dynamic nature of adherence.ObjectivesThis study aimed to examine the association between patients’ adherence patterns to newly initiated statins and previous adherence trajectories of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) using GBTM.MethodsThis retrospective cohort study was conducted among continuously enrolled statin initiators using claims data. Patients were included if they had ACEI/ARB use within 1 year before statin initiation (preindex period). Monthly adherence to ACEIs/ARBs was calculated during the preindex period and monthly adherence to statins was assessed 1 year after statin initiation using proportion of days covered (PDC). The monthly PDCs were modeled as a longitudinal response in a logistic GBTM to provide distinct patterns of adherence for ACEIs/ARBs and statins, separately. A multinomial logistic regression was conducted to determine an association between ACEI/ARB adherence trajectories and future statin trajectories, controlling for patient characteristics.ResultsA total of 1078 patients were categorized into 4 distinct statin adherence trajectories: adherent (40.8%), gradual decline (37.4%), gaps in adherence (13.9%), and rapid decline (7.9%). Patients were further categorized into 4 groups on the basis of their distinct past ACEIs/ARBs trajectories: adherent (43%), gaps in adherence (29%), delayed nonadherence (15.2%), and gradual decline (12.8%). In the multinomial logistic regression, patients in the gaps in adherence or gradual decline groups were more likely to follow similar trajectories for future statin use than the adherent trajectory.ConclusionPrevious adherence trajectories of ACEIs/ARBs may predict future adherence patterns for newly initiated statins. Knowledge of past medication-taking behavior could provide valuable information for developing tailored interventions to improve adherence.     

螺内酯联合福辛普利对2型糖尿病肾病蛋白尿的影响

目的:探讨螺内酯联合福辛普利治疗2型糖尿病肾病的安全性及其对蛋白尿的影响。方法:60位2型糖尿病肾病患者随机平均分为对照组和治疗组,对照组予福辛普利10mg?d-1治疗,治疗组额外予螺内酯20mg?d-1治疗,实验持续12周,定期测量患者血压、生化指标及24h尿蛋白定量。结果 :与对照组比较,治疗组24h尿蛋白下降更显著(P<0.01),患者没有明显导致肾小球滤过率(GFR)下降、血钾上升及低血压。结论:一定剂量的螺内酯能加强血管紧张素转化酶抑制剂(ACEIs)对糖尿病肾病进程延缓作用。     

The safety and effectiveness of statins as treatment for HIV-dyslipidemia: the evidence so far and the future challenges

Introduction: Statin therapy is widely used across the globe for the treatment and prevention of cardiovascular disease (CVD). It is well established that statin therapy is associated with significant decrease in low-density lipoprotein cholesterol (LDL-C) and plasma cholesterol levels. HIV-dyslipidemia is a common problem with extensive use of combination antiretroviral therapy (CART), and is associated with an increase in incidence of cardiovascular disease (CVD), resulting in hospital admission and surgery throughout the western healthcare systems. Areas covered: This review describes the effectiveness and safety of statins in the treatment of HIV-dyslipidemia. Medline was searched for different statins as treatment for HIV-dyslipidemia. Expert opinion: Dyslipidemia in patients with HIV is different from the normal population, due to the fact that HIV treatment may not only cause dyslipidemia, but may also interact with lipid lowering medication. Statin-unresponsive HIV-dyslipidemia can be treated with the addition of ezetimibe, fenofibrate, fish oil and niacin. Current guidelines recommend the use of pravastatin and atorvastatin as first-line therapy, whereas European guidelines include rosuvastatin. There is an urgent need to confirm whether the use of statins in HIV-dyslipidemia is associated with an increase in the incidence of diabetes; this is significant because HIV patients are known to be insulin-resistant. HIV is also associated with Non-alcoholic Fatty Liver Disease (NAFLD), a condition known to be associated with insulin resistance. Further clinical trials are urgently needed to assess the impact of statins on CVD in HIV patients, and future challenges for researchers in this area are enormous.     

Effect of certain angiotensin-converting enzyme inhibitors on mortality in heart failure: A multiple-propensity analysis

BackgroundHeart failure is a major and growing public health problem in United States. There is a substantial evidence about efficacy of angiotensin-converting enzyme inhibitors (ACEIs) in heart failure (HF); however, there is no conclusive evidence on the relative effectiveness of individual ACEIs.ObjectiveTo evaluate the effect of individual ACEIs on mortality using multiple-propensity score analysis in a large real-world population.MethodsThe study was a retrospective analysis of a national cohort of patients with HF identified from the Department of Veterans Affairs. A multiple-propensity score analysis was used to balance 47 baseline patient characteristics between different nontissue ACEIs. The effect of different ACEIs on time to death was assessed using a propensity score-weighted, multivariable Cox proportional hazard model.ResultsThe study included 139,994 patients with 69.50% (97,293) on lisinopril, 21.79% (30,503) on fosinopril, 8.41% (11,775) on captopril, and 0.30% (423) on enalapril. Propensity scores balanced nearly all differences between different ACEI groups. Fosinopril (hazard ratio [HR] = 0.739, 95% confidence interval [CI]: 0.686-0.797) and lisinopril (HR = 0.818, 95% CI: 0.766-0.874) were significantly associated with reduced mortality as compared with captopril. Similar mortality was observed with enalapril (HR = 0.944, 95% CI: 0.675-1.320) as compared with captopril.ConclusionsIn patients with HF, fosinopril and lisinopril were associated with lower mortality as compared with captopril. However, the results of this observational study should be interpreted with caution, and need to be replicated and confirmed in studies for which HF severity data are available.     

The safety and effectiveness of statins as treatment for HIV-dyslipidemia: the evidence so far and the future challenges

Introduction: Statin therapy is widely used across the globe for the treatment and prevention of cardiovascular disease (CVD). It is well established that statin therapy is associated with significant decrease in low-density lipoprotein cholesterol (LDL-C) and plasma cholesterol levels. HIV-dyslipidemia is a common problem with extensive use of combination antiretroviral therapy (CART), and is associated with an increase in incidence of cardiovascular disease (CVD), resulting in hospital admission and surgery throughout the western healthcare systems.

Areas covered: This review describes the effectiveness and safety of statins in the treatment of HIV-dyslipidemia. Medline was searched for different statins as treatment for HIV-dyslipidemia.

Expert opinion: Dyslipidemia in patients with HIV is different from the normal population, due to the fact that HIV treatment may not only cause dyslipidemia, but may also interact with lipid lowering medication. Statin-unresponsive HIV-dyslipidemia can be treated with the addition of ezetimibe, fenofibrate, fish oil and niacin. Current guidelines recommend the use of pravastatin and atorvastatin as first-line therapy, whereas European guidelines include rosuvastatin. There is an urgent need to confirm whether the use of statins in HIV-dyslipidemia is associated with an increase in the incidence of diabetes; this is significant because HIV patients are known to be insulin-resistant. HIV is also associated with Non-alcoholic Fatty Liver Disease (NAFLD), a condition known to be associated with insulin resistance. Further clinical trials are urgently needed to assess the impact of statins on CVD in HIV patients, and future challenges for researchers in this area are enormous.     

Achieving LDL-C Target Levels: The Role of Statins

Summary

Epidemiological and clinical studies have clearly established the link between elevated low-density lipoprotein cholesterol (LDL-C) and coronary heart disease (CHD). Consequently, treatment guidelines have been developed that identify LDL-C as a causative factor for CHD and as a target for lipid-lowering therapy. The 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are considered the drugs of choice for lowering LDL-C in patients with hypercholesterolaemia. However, despite the proven efficacy of statins in reducing LDL-C, many patients do not achieve recommended LDL-C target levels. Surveys suggest that patients do not receive the appropriate drugs in adequate dosage to reach LDL-C target values. Success in achieving targets is lowest in patients at the highest risk, i.e. those with established CHD. The introduction of more potent HMG-CoA reductase inhibitors, or the use of higher doses of older statins, should allow more patients to achieve LDL-C target levels.     

Statins: balancing benefits, efficacy and safety

Coronary heart disease (CHD) is the leading cause of death in the US. The risk of CHD is substantially increased in people with elevated levels of low-density lipoprotein cholesterol (LDL-C). The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most effective drug class for lowering LDL-C. Long-term prospective studies have shown that statin therapy significantly reduces the risk of CHD morbidity and mortality in patients without or with evidence of established CHD (primary and secondary prevention, respectively). In 1988, treatment guidelines were first issued by the National Cholesterol Education Program Adult Treatment Panel I (NCEP-ATP I), then revised in 1993 (ATP II), to provide recommendations for the prevention and management of high cholesterol in adults. Despite these guidelines, recent national surveys have shown that effective therapies are being under-utilised and they often fail to achieve LDL-C goals established by NCEP-ATP II. The reasons appear to be multifactorial but include issues related to efficacy, safety, the potential for adverse drug reactions, failure to prescribe appropriate medication or dose and noncompliance with therapy. In the first major update of NCEP guidelines in almost a decade, the current ATP III recommendations have placed an increased number of Americans in the high-risk category, inviting even more aggressive therapy and escalating the challenge of reaching NCEP goals. New statins that may have even greater efficacy and less potential for drug interactions may help address some concerns associated with the failure to achieve treatment goals.     

Statins: balancing benefits,efficacy and safety

Coronary heart disease (CHD) is the leading cause of death in the US. The risk of CHD is substantially increased in people with elevated levels of low-density lipoprotein cholesterol (LDL-C). The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are the most effective drug class for lowering LDL-C. Long-term prospective studies have shown that statin therapy significantly reduces the risk of CHD morbidity and mortality in patients without or with evidence of established CHD (primary and secondary prevention, respectively). In 1988, treatment guidelines were first issued by the National Cholesterol Education Program Adult Treatment Panel I (NCEP-ATP I), then revised in 1993 (ATP II), to provide recommendations for the prevention and management of high cholesterol in adults. Despite these guidelines, recent national surveys have shown that effective therapies are being under-utilised and they often fail to achieve LDL-C goals established by NCEP-ATP II. The reasons appear to be multifactorial but include issues related to efficacy, safety, the potential for adverse drug reactions, failure to prescribe appropriate medication or dose and noncompliance with therapy. In the first major update of NCEP guidelines in almost a decade, the current ATP III recommendations have placed an increased number of Americans in the high-risk category, inviting even more aggressive therapy and escalating the challenge of reaching NCEP goals. New statins that may have even greater efficacy and less potential for drug interactions may help address some concerns associated with the failure to achieve treatment goals.