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Your Treatment Plan

Feedback from the larger clinical community informed revisions. This synopsis focuses on guidance relating to cardiovascular disease and risk management in nonpregnant adults with diabetes. Recommendations address diagnosis and treatment of cardiovascular risk factors hypertension and dyslipidemia , aspirin use, screening for and treatment of coronary heart disease, and lifestyle interventions. Recommendations for the treatment of confirmed hypertension in people with diabetes. Diabetes Care. Reprinted with permission of the American Diabetes Association. Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes.

Reprinted with permission from the American Diabetes Association. Management of hyperglycemia in type 2 diabetes, a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. All text, graphics, trademarks, and other intellectual property incorporated into the slide sets remain the sole and exclusive property of the ACP.

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Unauthorized use of the In the Clinic slide sets will constitute copyright infringement. Bangladesh Institute of Family Medicine and Research. This is an excellent review of ADA guideline. I like to add here that once statin is started, it should be continued lifelong. Statin discontinuation may lead to higher cardiovascular event risks [1].

My practice shows that after 3 months of discontinuation of statin for any reason, in maximum cases, LDL-C jumps much higher compared to baseline e. Other non-statins; cholesterol absorption inhibitor or PCSK9 inhibitors may be used if statin is not tolerated but in the real world statin intolerant population is not so more that is traditionally though. References: 1. Curr Pharm Des ; The recommendations of the American Diabetes Association for cardiovascular disease and risk management proposes the use of aspirin in a situation described as the primary prevention of cardiovascular disease level of recommendation C.

This is a confusion between primary and secondary prevention as defined by the World Health Organization WHO [1] : this is a frequent misclassification of prevention types observed in medical literature. According to the WHO definitions, the use of chemoprohylactic agents in the presence of risk factors is virtually in fact a secondary prevention-type intervention, and the use of a clinically apparent cardiovascular disease a tertiary prevention. These recommendations are based on relatively ancient studies, and the cited meta-analysis concludes that the net benefit of this prevention is still doubtful.

More recent publications have either not detected any benefit or the authors have declared themselves unable to conclude, due to the possibility of selective reporting bia s[2,3]. Biochemical models also have suggested that these patients might have reduced sensitivity to the effect of cyclooxygenase-1 inhibitor, due to persistent thromboxane-induced activation[4]. Introducing a limitation to indications to diabetic patients over 50 years with at least one additional cardiovascular risk factor is unlikely to modify the result, since a large majority of type 2 diabetic patients respond to this definition[5].

Furthermore, if the considered risk factor is a reversible one such as smoking, the use of a prescription drug as an alternative to smoking cessation is likely to be counterproductive. In conclusion, we propose to limit the use of aspirin to diabetic patients in tertiary prevention, ie with clinically apparent cardiovascular complications. Gordon RS Jr.

Gordon R et al. An operational classification of disease prevention. Public Health Rep. Aspirin for primary prevention of cardiovascular disease in patients with diabetes: A meta-analysis. Diabetes Res Clin Pract. Kunutsor S. Seidu K. Khuntiet al. Thromb Haemost. Prevalence of hypertension and obesity in patients with type 2 diabetes mellitus in observational studies: a systematic literature review. Diabetes Metab Syndr Obes. TO THE EDITOR: Chamberlain and colleagues May 1 issue in their Review of the American Diabetes Association Standards of Medical Care in Diabetes, maintained that the increased risk of diabetes mellitus associated with statins HMG-CoA reductase inhibitors use is small; therefore, the cardiovascular event rate reduction with statin use offsets the risk of diabetes, even in patients at high risk of developing diabetes with the use of statins.

The data from morbidity and mortality outcomes relating to diabetes mellitus complications shows benefits of diabetic treatments can be offset by increasing numbers of people diagnosed with diabetes, because although hyperglycemia can be controlled, other diabetes complications frequently cannot be treated which results in an increase in mortality and morbidity and disease burden on individual patients and a financial burden on patients and health care industry alike.

Fortunately, statin-induced diabetes may not be permanent.

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In some cases it can be reversed if use of the causative medication is discontinued, the does is decreased, or the patient is switch to a different statin, such pravastatin which is the least diabetogenic statin and if intolerance is associated with all statins, even at the lowest dose, non-statin drugs and certain healthy diet plans, exercise or alternative therapies may be advisable. Ann Intern Med. Preventive Services Task Force [Internet]. Diabetes Secondary to Treatment with Statins. Curr Diab.

Drugs and hyperglycemia: A practical guide. Am J Cardiovasc Drugs. The imperative to prevent diabetes complications: a broadening spectrum and an increasing burden despite improved outcomes. Med J Aust. Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. I peruse with interest the guidelines. However, despite the tenacity, clarity, and thoroughness of the authors, I offer a few comments to understand the guidelines in perspective and better implementation. Though not emphasized adequately, masked hypertension is not uncommon in diabetics, and particularly after year of age, it must be ruled out preferably with hour ambulatory BP monitoring rather than home BP measurements, as they are proven to be less reliable than ambulatory BP monitoring.

The isolated nocturnal hypertension and lack of nocturnal dip are another valuable features worth exploring, as Hypertension is much bigger killer than glycemia. The use of new agents to control glycemia with added cardiovascular benefits: empagliflozin is mentioned first by name, while other drugs like empagliflozin is equally good.

Now its proven to be a class effect. A completely ignored issue: Subclinical magnesium deficiency is very common in diabetics, particularly with concomitant hypertension as the soil is largely depleted of magnesium , serum magnesium is a poor marker of magnesium deficiency, the use of magnesium in patients with concomitant hypertension must be encouraged.

Best practice guidelines

Rosanoff A, Plesset MR. Magnes Res ; Published at www. Results provided by:. Sign In Set Up Account. You will be directed to acponline. Open Athens Shibboleth Log In. Subscribe to Annals of Internal Medicine. Advanced Search. Clinical Guidelines 1 May Chamberlain, MD. This article was published at Annals. Abstract Description: The American Diabetes Association ADA annually updates its Standards of Medical Care in Diabetes to provide clinicians, patients, researchers, payers, and other interested parties with evidence-based recommendations for the diagnosis and management of patients with diabetes.

Recommendations: This synopsis focuses on guidance relating to cardiovascular disease and risk management in nonpregnant adults with diabetes. Atherosclerotic cardiovascular disease ASCVD , defined as coronary heart disease, cerebrovascular disease, or peripheral artery disease, is the leading cause of morbidity and mortality in persons with diabetes and is the largest contributor to the direct and indirect costs of diabetes.

The American Diabetes Association ADA Standards of Medical Care recommend that cardiovascular risk factors be assessed at least annually in all patients with diabetes. This synopsis focuses on the ADA guidance relating to cardiovascular disease and risk management in nonpregnant adults with diabetes. To develop the standards, the ADA Professional Practice Committee, which comprises physicians, adult and pediatric endocrinologists, diabetes educators, registered dietitians, epidemiologists, and public health experts, searched MEDLINE through November and reviewed studies particularly high-quality trials that included persons with diabetes for potential incorporation into recommendations.

The committee also solicited feedback from the larger clinical community. The recommendations were rated as A, B, C, or E. Those with an A rating are based on large, well-designed, multicenter clinical trials or high-quality meta-analyses. Recommendations with lower-quality evidence may be equally important and are based on well-conducted cohort studies B rating or uncontrolled studies C rating.

Those with an E rating are consensus recommendations for cases where there is no evidence from clinical trials, clinical trials may be impractical, or there is conflicting evidence. The ADA funds development of the standards from its general revenues, with no industry support or involvement. Blood pressure should be measured at every routine clinical visit. Grade B recommendation. All hypertensive patients with diabetes should monitor their blood pressure at home.

Print this page. Your email has been sent. Please ensure that your email address is correct. If you can read this, please don't fill out these form fields. The CV effects of long-established oral glucose-lowering drugs have not been evaluated in large RCTs, as with more recent drugs. CV risk reduction with a sulfonylurea is more effective than modest lifestyle interventions alone, but is less effective than metformin. IT —a large, randomized, but unblinded comparison of pioglitazone vs. The composite endpoint and the individual components of the composite endpoint were similar in the two groups.

This led to an increase in trials to assess CV outcomes with these therapies, , most of which were designed to confirm non-inferiority of the experimental therapy vs. After a median follow-up of 6. Four of these trials confirmed statistical non-inferiority vs.

Patient characteristics of cardiovascular safety studies with glucose-lowering agents a. Modified after. After a follow-up of 3. After 2. Moreover, semaglutide led to a non-significant numerical reduction of non-fatal MI. Semaglutide also reduced the secondary endpoint of new or worsening nephropathy. Non-inferiority for CV safety of oral semaglutide was confirmed with an HR of 0. Moreover, semaglutide significantly reduced the risk for CV death [15 0.

During a median follow-up of 5. Although the mechanisms through which some of these GLP-RAs reduced CV outcomes have not been established, their long half-lives may be contributing to their CV benefits. In addition, GLP1-RAs improve several CV parameters, including a small reduction in SBP and weight loss, and have direct vascular and cardiac effects that may contribute to the results. These findings were consistent in all subgroups. However, canagliflozin led to an unexplained increased incidence in lower limb fractures and amputations albeit low numbers , a finding that was not replicated in a recent large cohort study.

In the two primary efficacy analyses, dapaglifozin did not significantly reduce MACE, but resulted in a lower rate of the combined endpoint of CV death or HF hospitalization 4. This was driven by a lower rate of HF hospitalizations HR 0. The benefit of dapagliflozin with respect to CV death or HF hospitalization was similar in the subgroup with CVD, as well as those with multiple risk factors only. A meta-analysis of the three trials suggested consistent benefits on reducing the composite of HF hospitalization or CV death, as well as on the progression of kidney disease, regardless of existing atherosclerotic CVD or a history of HF, while the reduction in MACE was only apparent in patients with established CVD.

The CV benefits of SGLT2 inhibitors are mostly unrelated to the extent of glucose lowering and occur too early to be the result of weight reduction. The rapid separation of placebo and active arms in the four studies in terms of reduction in HF hospitalizations indicates that the beneficial effects achieved in these trials are more likely the result of a reduction in HF-associated events. They could involve effects on haemodynamic parameters, such as reduced plasma volume, direct effects on cardiac metabolism and function, or other CV effects. The recommendation for empagliflozin is supported by a recent meta-analysis which found high heterogeneity between CVOTs in mortality reduction.

Although the trial-based evidence for metformin monotherapy from UKPDS is not as strong as with the novel drugs tested in recent CVOTs, it is supported by extensive observations from everyday clinical practice. In the recent CVOTs, a majority of patients received metformin before and concurrently with the newer drug under test. However, because metformin was similarly present in the active and placebo groups, it is unlikely to explain the beneficial effects of the newer drugs under test.

Recommendations for coronary revascularization. In CCS, beta-blockers are effective at reducing both exercise-induced angina and asymptomatic ischaemic episodes, while improving exercise capacity. Nitrates preferably short-acting and calcium channel blockers are indicated for relief of angina symptoms, and are frequently used when beta-blockers are contraindicated or not tolerated, or in addition to beta-blockers if patients remain symptomatic, but offer no prognostic benefit.

Ranolazine is a selective inhibitor of the late sodium current, effective in the treatment of chronic angina. These drugs should be considered as second line treatment. In secondary prevention, low-dose 75— mg aspirin, alone or in combination see section 7. Clopidogrel provides an alternative for aspirin-intolerant patients, and is combined with low-dose aspirin as dual antiplatelet therapy DAPT clopidogrel 75 mg o. Patients with DM tended to have a greater reduction in ischaemic events with prasugrel than clopidogrel, without an increase in major bleeding. Ticagrelor was associated with an increase in major bleeding, which was similar in the two groups HR 2.

The net clinical benefit favoured the combination HR 0. Recommendations for the management of patients with diabetes and acute or chronic coronary syndromes. Recommendations on glucose targets are outlined in section 6. Recommendations on glucose-lowering drugs for DM are outlined in section 7.

The anatomical pattern of CAD in patients with DM influences prognosis and the response to revascularization. Angiographic studies have shown that patients with DM are more likely to have left main CAD and multivessel CAD, and that coronary pathology is more frequently diffuse and involves the small vessels.

Paralleling the observation in non-DM, the negative impact of incomplete revascularization has also been documented in patients with DM. In non-ST-segment elevation ACS, a meta-analysis of nine RCTs including patients suggested a similar benefit at 12 months in terms of death, non-fatal MI, or hospitalization for an ACS from an early invasive strategy compared with a conservative strategy in patients with and without DM.

DM should be considered as a distinct disease entity that is critical for the selection of myocardial revascularization strategies in multivessel disease. Three RCTs have compared the two revascularization modalities in patients with DM, mostly in the setting of stable multivessel CAD using mainly first-generation drug-eluting stents DES , but one of them was prematurely terminated and underpowered. The incidences of death While patients on insulin had higher event rates, no significant interaction for the primary endpoint was observed between insulin status and treatment effect.

CABG The best surgical coronary revascularization strategy and graft selection in patients with DM is still subject to debate. The superior graft patency of the internal mammary artery, and its impact on survival when grafted to the left anterior descending LAD coronary artery, would make the use of bilateral internal mammary arteries the most logical and beneficial strategy. The appropriate revascularization modality in patients with DM and multivessel disease should be discussed by the Heart Team, taking into consideration individual cardiac and extracardiac characteristics, as well as preferences of the well-informed patient.

Overall, current evidence indicates that in stable patients with coronary anatomy suitable for both procedures and low predicted surgical mortality, CABG is superior to PCI in reducing the composite risk of death, MI, or stroke, as well as death. As a general rule, adjunctive pharmacotherapy in the setting of myocardial revascularization does not differ between DM and non-DM see section 7.

There are insufficient data to support the practice of stopping metformin 24—48 h before angiography or PCI, as the risk of lactic acidosis is negligible. In patients with CKD, metformin should be stopped before the procedure. Renal function should be carefully monitored after PCI in all patients with baseline renal impairment or on metformin.

Recommendations for the type of revascularization in patients with diabetes with stable coronary artery disease, suitable coronary anatomy for both procedures, and low predicted surgical mortality. The pathophysiological mechanisms underlying the development of CAD and the worse prognosis in patients with DM need to be further elucidated. The effects of secondary preventive measures in patients with CAD and DM are mainly based on subgroup analyses of trials enrolling patients with and without DM.

Optimal glycaemic control for the outcomes of ACS and stable CAD, as well as after coronary revascularization, remain to be established. Following revascularization, the rate of adverse events remains higher in patients with vs. Guideline-based medical and device therapies are equally effective in patients with and without DM; as renal dysfunction and hyperkalaemia are more prevalent in patients with DM, dose adjustments of some HF drugs e. RAAS blockers are advised. DM is an important risk factor for HF. Heart failure phenotypes LV diastolic dysfunction is frequent in both pre-DM and overt DM, and severity correlates with insulin resistance and the degree of glucose dysregulation.

Treatment effects are consistent with and without DM, with the exception of aliskiren, which is not recommended in patients with DM due to the risk of serious adverse events. However, the treatment effect was less pronounced in patients with baseline DM. Ivabradine improves the treatment of HFrEF in sinus rhythm, particularly with regard to the reduction of HF hospitalization and the improvement of LV function. Despite a lack of evidence for the efficacy of either thiazide or loop diuretics in the reduction of CV outcomes in patients with HF, diuretics prevent and treat symptoms and signs of fluid congestion in patients with HF.

Metformin is safe at all stages of HF with preserved or stable moderately reduced renal function i. Data on the effects of sulfonylureas on HF are inconsistent. Thiazolidinediones are not recommended in patients with DM and symptomatic HF. Saxagliptin significantly increased the risk of HF hospitalization and is not recommended in patients with DM with HF.

Alogliptin was associated with a non-significant trend towards HF hospitalization. See also section 7. Studies are needed to better understand the bidirectional relationship between DM and HF, including the pathophysiology of diabetic cardiomyopathy. Considering the divergent evidence for an association between DPP4 inhibitors and HF risk, research is needed to further clarify this association.

Atrial fibrillation AF is common in patients with DM, and increases mortality and morbidity. AF should always be confirmed by ECG. A recent study reported that DM is an independent risk factor for AF, especially in young patients. DM increases the risk of stroke in paroxysmal or permanent AF. Palpitations, premature ventricular beats, and non-sustained ventricular tachycardia VT are common in patients with DM. Diagnostic workup and treatment of ventricular arrhythmias does not differ between DM and non-DM patients. The risk of cardiac events is usually dictated by underlying heart disease rather than ectopic beats.

In highly symptomatic patients with premature ventricular beats or non-sustained VT, beta-blockers, calcium antagonists, class Ic drugs flecainide or propafenone , or catheter ablation in cases of an absence of structural heart disease can be used to suppress arrhythmias. The diagnosis and treatment of sustained VT, or resuscitated ventricular fibrillation, is similar for patients with or without DM. Most patients with sustained VT or aborted cardiac arrest without a diagnosed trigger need an ICD to prevent sudden death. Epidemiological studies have shown that patients with DM or pre-DM are at increased risk of sudden cardiac death.

The causes underlying increased vulnerability to electrical instability in patients with DM are unclear and are likely to involve several factors. Simultaneous glucose and ambulatory ECG monitoring has shown that bradycardia, and atrial and ventricular ectopic beats, are more common during nocturnal hypoglycaemia in patients with DM. Nephropathy, autonomic neuropathy, prolonged QTc interval, hypoglycaemia, and comorbidities related to DM are thought to increase the risk of sudden cardiac death.

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On the basis of the available evidence, it seems that glucose intolerance, even in pre-DM, is associated with the progressive development of a variety of abnormalities that adversely affect survival and predispose to sudden arrhythmic death. Apart from the measurement of LVEF, identification of independent predictors in patients with DM has not progressed to a point where it is possible to devise risk stratification for prevention. The role of novel wearable gadgets is not well established in the home-based diagnosis of AF and should be tested in well-designed clinical trials.

The roles of several non-invasive risk markers of sudden cardiac death—such as heart rate variability, QTc interval, albuminuria, hypoglycaemia, etc. The management of, and indications for, different treatment strategies are similar in patients with LEAD with or without DM, although the options for revascularization may be poorer because of diffuse and distal lesions.

Several studies have shown a decreased risk of abdominal aortic aneurysm in patients with DM, the reasons for which are unexplained. According to the ESC Guidelines on the diagnosis and treatment of PADs, this term includes conditions affecting all arteries, except for the aorta, and the coronary and the intracranial arteries. All of these factors increase the risk of limb infection.

Clinically, patients with DM often have atypical forms of pain on exertion that do not meet the typical criteria for intermittent claudication. Assessment of the risk of amputation: the Wound, Ischaemia, and foot Infection classification Screening and early diagnosis are of major importance in patients with DM. Clinical evaluation includes medical history, symptom assessment, and examination for neuropathy on a yearly basis. Screening for lower extremity artery disease in patients with diabetes. Patients should be assessed every year for symptoms and pulses should be checked.

The significant reduction in major adverse limb events in this COMPASS substudy raises the possibility of a novel therapeutic regimen in high-risk vascular patients to ameliorate the complications of LEAD. In patients with CLTI, strict glycaemic control is associated with improved limb outcomes. With respect to the revascularization modality of choice, we refer the reader to dedicated Guidelines.

In brief, carotid artery disease must be rapidly ruled out in all patients presenting with transient ischaemic attack or stroke. In patients with DM without a history of cerebrovascular disease, there is no evidence that carotid screening improves outcomes and systematic screening is not recommended. Asymptomatic carotid disease is frequently treated conservatively, and the patient is followed-up with duplex ultrasound. RCTs comparing carotid endarterectomy with carotid artery stenting in the peri-procedural period have shown an excess of minor strokes with carotid artery stenting, and more episodes of myocardial ischaemia and cranial nerve palsies with endarterectomy.

Post-operatively, both treatments offer similar protection from recurrent stroke and have similar rates of repeat interventions. Although restenosis rates were low at 2 years after carotid stenting 6. Recommendations for the diagnosis and management of peripheral arterial disease in patients with diabetes. See Table The regularity and mode of vascular screening in patients with DM have not been adequately assessed. Specific trials are needed to help clinicians to choose different pharmacological strategies according to the presence of PAD.

CKD is associated with a high prevalence of CVD and should be considered in the highest risk group for risk factor management. Screening for kidney disease in patients with DM requires serum creatinine measurement to enable the calculation of eGFR and urine tests of albumin excretion. CKD developing in the context of DM is a major health issue, which is associated with the highest risk of CVD 23 and should therefore be managed accordingly.

Medical management of angina: treatment of associated conditions and the role of antiplatelet drugs

Chronic kidney disease classification by estimated glomerular filtration rate and albuminuria Improving glycaemia may reduce the risk of progression of nephropathy, but is more complex in diabetic kidney disease because a fall in eGFR restricts the use of several oral glucose-lowering drugs. Accumulation of renally excreted sulfonylureas may increase the likelihood of hypoglycaemia. Data on composite kidney endpoints from recent CVOTs suggest that some of the newer oral antihyperglycaemic drugs have beneficial renal effects.

These trials did not include patients with advanced CKD and nephroprotection was not the adjudicated primary outcome. In response to these preliminary findings, several studies have been initiated to investigate renal outcomes [DAPA-CKD clinicaltrialts. The trial was stopped prematurely by the safety committee after an interim analysis demonstrated superiority. A total of patients were followed for 2.

Secondary outcomes, including the composite of CV death or hospitalization for HF; the composite of CV death, MI, or stroke; and the analysis of hospitalization for HF alone, all demonstrated significant benefits with canagliflozin. Recommendations for the prevention and management of chronic kidney disease in patients with diabetes.

Group-based structured education programmes improve disease knowledge, glycaemic control, disease management, and empowerment in patients with DM. Supporting patients in achieving and sustaining lifestyle changes on an individualized basis, using defined therapeutic goals, continues to be a challenge. Patient-centred care is an approach that facilitates shared control and decision-making between patient and provider.

It emphasizes a focus on the whole person and their experiences of illness within social contexts, rather than a single disease or organ system, and it develops a therapeutic alliance between patient and provider. Different approaches on how to integrate patient-centred care in clinical practice exist. The effects of education and self-management strategies have been evaluated on both DM outcomes and CVD risk factors. A systematic review including patients with DM found that group-based, structured education programmes resulted in clinically relevant improvements in glycaemic control, DM knowledge, triglyceride levels, BP, medication reduction, and self-management for 12—14 months.

Benefits for 2—4 years, including decreased DM-related retinopathy, were apparent when group classes were provided on an annual basis. Outcomes favoured reductions in HbA1c for group-based structured education programmes compared with controls.

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Empowerment strategies including individual consultations, phone calls, web-based sessions, and the use of a booklet were evaluated across 11 studies. Outcomes included HbA1c levels, self-efficacy, levels of DM knowledge, and quality of life. In addition, some of the studies assessed secondary outcomes in the form of CVD risk factors. Improvements with individual empowerment strategies were shown in self-efficacy, levels of DM knowledge, and quality of life. However, no statistically significant improvement was found for HbA1c levels.

Patients with pre-DM benefit from structured empowerment interventions and lifestyle education to reduce progression to DM, — and beneficial effects on CVD risk factors, such as BP and total cholesterol, have been reported. In patients with DM after an ACS, four RCTs included in a systematic review evaluated the effectiveness of structured self-management interventions plus an intensified comprehensive cardiac rehabilitation programme. The review concluded that there is currently no evidence to support the effectiveness of combined interventions in promoting self-management behaviour with regard to clinical, psychological, or behavioural outcomes.

Further research is required to determine the effects of group- and individual-based structured patient education programmes on CVD risk factors. The effects of patient-centred interventions on micro- and macrovascular complications are unknown. More research is needed to develop robust combined self-management interventions, including cost-effectiveness evaluations of joint DM and CVD interventions; future studies should compare different modes delivering individual empowerment strategies.

In patients with CVD and concomitant DM, barriers to cardiac rehabilitation should be explored, and future prospective studies should investigate the benefit of cardiac rehabilitation programmes. Possible differences between men and women with regards to optimal delivery of patient-centred care, structured education, and self-management programmes should be explored. The disclosure forms of all experts involved in the development of these Guidelines are available on the ESC website www.

The content of these ESC Guidelines has been published for personal and educational use only. No commercial use is authorized. No part of the Guidelines may be translated or reproduced in any form without written permission from the ESC. Permission can be obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal and the party authorized to handle such permissions on behalf of the ESC journals.

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  5. Disclaimer: The Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge, and the evidence available at the time of their publication. Gale United Kingdom , Diederick E. Touyz United Kingdom. Sign In. Advanced Search.