ESC Guidelines on Diabetes, Pre-diabetes, and Cardiovascular Diseases Developed in Collaboration With the EASD

The Task Force on Diabetes, Pre-Diabetes, and Cardiovascular Diseases of the European Society of Cardiology (ESC) and Developed in Collaboration With the European Association for the Study of Diabetes (EASD)

Lars Rydén (ESC Chairperson) (Sweden); Peter J. Grant (EASD Chairperson) (UK); Stefan D. Anker (Germany); Christian Berne (Sweden); Francesco Cosentino (Italy); Nicolas Danchin (France); Christi Deaton (UK); Javier Escaned (Spain); Hans-Peter Hammes (Germany); Heikki Huikuri (Finland); Michel Marre (France); Nikolaus Marx (Germany); Linda Mellbin (Sweden); Jan Ostergren (Sweden); Carlo Patrono (Italy); Petar Seferovic (Serbia); Miguel Sousa Uva (Portugal); Marja-Riita Taskinen (Finland); Michal Tendera (Poland); Jaakko Tuomilehto (Finland); Paul Valensi (France); Jose Luis Zamorano (Spain); Jose Luis Zamorano (Chairperson) (Spain); Stephan Achenbach (Germany); Helmut Baumgartner (Germany); Jeroen J. Bax (Netherlands); Héctor Bueno (Spain); Veronica Dean (France); Christi Deaton (UK); Çetin Erol (Turkey); Robert Fagard (Belgium); Roberto Ferrari (Italy); David Hasdai (Israel); ArnoW. Hoes (Netherlands); Paulus Kirchhof (Germany UK); Juhani Knuuti (Finland); Philippe Kolh (Belgium); Patrizio Lancellotti (Belgium); Ales Linhart (Czech Republic); Petros Nihoyannopoulos (UK); Massimo F. Piepoli (Italy); Piotr Ponikowski (Poland); Per Anton Sirnes (Norway); Juan Luis Tamargo (Spain); Michal Tendera (Poland); Adam Torbicki (Poland); William Wijns (Belgium); Stephan Windecker (Switzerland); Guy De Backer (Review Coordinator) (Belgium); Per Anton Sirnes (CPG Review Coordinator) (Norway); Eduardo Alegria Ezquerra (Spain); Angelo Avogaro (Italy); Lina Badimon (Spain); Elena Baranova (Russia); Helmut Baumgartner (Germany); John Betteridge (UK); Antonio Ceriello (Spain); Robert Fagard (Belgium); Christian Funck-Brentano (France); Dietrich C. Gulba (Germany); David Hasdai (Israel); Arno W. Hoes (Netherlands); John K. Kjekshus (Norway); Juhani Knuuti (Finland); Philippe Kolh (Belgium); Eli Lev (Israel); Christian Mueller (Switzerland); Ludwig Neyses (Luxembourg); Peter M. Nilsson (Sweden); Joep Perk (Sweden); Piotr Ponikowski (Poland); Zeljko Reiner (Croatia); Naveed Sattar (UK); Volker Schächinger (Germany); André Scheen (Belgium);

Disclosures

Eur Heart J. 2013;34(39):3035-3087. 

In This Article

9. Arrhythmias: Atrial Fibrillation and Sudden Cardiac Death

9.1 Diabetes Mellitus and Atrial Fibrillation

Individuals with atrial fibrillation (AF) are at substantially increased risk of stroke and have twice the mortality rate from CVD as those in sinus rhythm.[429,430] Diabetes mellitus is frequent in patients with AF. Community studies demonstrate the presence of DM in 13% of patients with AF.[431] DM and AF share common antecedents, such as hypertension, atherosclerosis and obesity: however, the independent role of DM as a risk factor for AF has not been established.

The Manitoba Follow-up Study estimated the age-specific incidence of AF in 3983 men.[432] DM was significantly associated with AF with a relative risk of 1.82 in univariate analysis. However, in the multivariable model, the association with DM was insignificant, suggesting that the increased risk may relate to ischaemic heart disease, hypertension or heart failure. In the Framingham Heart Study,[433] DM was significantly associated with AF in both genders, even after adjustment for age and other risk factors (OR 1.4 for men and 1.6 for women). When developing a risk score for AF, the Framingham Heart study did not include DM as a significant predictor of AF.[434] In another recent study, Nicholas et al. reported that DM was an independent predictor of AF in women only.[435]

A recent multi-centre study enrolling 11 140 DM patients confirmed that AF is relatively common in T2DM and demonstrated that when T2DM and AF co-exist, there is a substantially higher risk of all-cause mortality, cardiovascular death, stroke and heart failure.[436] These findings suggest that AF identifies DM patients who are likely to obtain greater benefits from aggressive management of all cardiovascular risk factors. Because AF is asymptomatic—or only mildly symptomatic—in a substantial proportion of patients (about 30%), screening for AF can be recommended in selected patient groups with T2DM with any suspicion of paroxysmal or permanent AF by pulse palpation, routine 12-lead ECG, or Holter recordings.

Diabetes and Risk of Stroke in Atrial Fibrillation: Two recent systematic reviews have addressed the evidence base for stroke risk factors in AF and concluded that prior stroke/TIA/thrombo-embolism, age, hypertension, DM and structural heart disease are important risk factors.[437,438]

Diabetes and Stroke Risk Stratification Schemes: The simplest scheme is the CHADS2 [cardiac failure, hypertension, age, DM, stroke (doubled)] risk index. The 2010 ESC Guidelines for the management of AF, updated 2012, proposed a new scheme. The use of 'low', 'moderate' and 'high' risk has been re-emphasized, recognizing that risk is a continuum.[439,440] The new scheme is expressed as an acronym CHA2DS2-VASc [cardiac failure, hypertension, age ≥75 (doubled), DM, stroke (doubled)-vascular disease, age 65–74 and sex category (female)]. It is based on a points system in which two points are assigned for history of stroke or TIA, or age ≥75 years and one point for the other variables. Heart failure is defined either as clinical heart failure or LV systolic dysfunction (EF <40%) and vascular disease as a history of MI, complex aortic plaque, or PAD.

Antithrombotic Therapy in Diabetes Patients: A meta-analysis of 16 RCTs in 9874 patients was performed to characterize the efficacy of anticoagulant and antiplatelet agents for the prevention of stroke in AF.[441] Oral anticoagulation was effective for primary and secondary prevention of stroke in studies comprising 2900 patients, with an overall 62% reduction of relative risk (95% CI 48–72). The absolute risk reduction was 2.7% per year for primary prevention and 8.4% per year for secondary prevention. Major extracranial bleeds were increased by anticoagulant therapy by 0.3% per year. Aspirin reduced risk of stroke by only 22% (95% CI 2–38), with an absolute risk reduction of 1.5% per year for primary prevention and 2.5% per year for secondary prevention. In five trials comparing anticoagulant therapy with antiplatelet agents in 2837 patients, warfarin was more effective than aspirin, with an RRR of 36% (95% CI 14–52). These responses were observed in both permanent and paroxysmal AF.

Supported by the results of several trials and the 2010 and in 2012 updated ESC Guidelines for management of AF,[439,440] oral anticoagulation with vitamin K antagonists (VKAs)—or one of the new oral anticoagulants (NOAC; for further details see below)—are recommended in patients with AF. The choice of antithrombotic therapy should be based upon the absolute risk of stroke/thromboembolism and bleeding and the net clinical benefit for a given patient. Aspirin alone is not recommended for the prevention of thromboembolic disease in patients with DM and AF but, in patients unable or unwilling to use either VKAs or NOAC, the combination of aspirin and clopidogrel should be considered.[442] VKA or NOAC should be used if there are one or more stroke risk factors, provided there are no contra-indications following careful assessment of the risk–benefit ratio and an appreciation of the patient's values and preferences.[439,440] It can be concluded that VKA or NOAC should be used in all AF patients with DM unless contra-indicated, and if accepted by the patient. With the use of VKA, an international normalized ratio (INR) of 2.0–3.0 is the optimal range for prevention of stroke and systemic embolism in patients with DM. A lower target INR (1.8–2.5) has been proposed for the elderly but this is not based on evidence.

In the ACTIVE W warfarin was superior to clopidogrel plus aspirin (RRR 0.40; 95% CI 18–56), with no difference in rates of bleeding.[442] The aspirin arm ACTIVE A aspirin found that major vascular events were reduced in patients receiving aspirin plus clopidogrel, compared with aspirin monotherapy (RR 0.89; 95% CI 0.81–0.98; P = 0.01).[443] Thus, aspirin-plus-clopidogrel therapy may be considered as an interim measure if a VKA is unsuitable, but not as an alternative in patients at high bleeding risk. Combinations of VKA with antiplatelet therapy do not offer added beneficial effects on ischaemic stroke or vascular events and lead to more bleeding events,[439] and such combinations should be avoided.

Two new classes of anticoagulants have been developed: oral direct thrombin inhibitors (e.g. dabigatran etexilate) and oral factor Xa inhibitors (e.g. rivaroxaban, apixaban, edoxiban, betrixiban). In the Randomized Evaluation of the Long-term anticoagulant therapy with dabigatran etexilate (RE-LY) study,[444] dabigatran 110 mg b.i.d. was non-inferior to VKA for stroke prevention and systemic embolism with lower rates of major bleedings. Dabigatran 150 mg b.i.d. was associated with lower rates of stroke and systemic embolism with similar rates of major haemorrhages, compared with VKA therapy. The Apixaban VERsus acetylsalicylic acid to pRevent strOkES (AVERROES) study was stopped early, due to clear evidence of a reduction in stroke and systemic embolism with apixaban 5 mg b.i.d., compared with aspirin 81–324 mg once daily.[445] A recent study, Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE), comparing warfarin with apixaban in patients with AF with a median CHADS2 score of 2.1, showed that apixaban 5 mg b.i.d. was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding and resulted in lower mortality.[446] Twenty-four per cent of the patients had DM. The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET) trial, comparing warfarin with rivaroxaban, showed the non-inferiority of rivaroxaban to warfarin in preventing stroke, systemic embolism or major bleeding among the AF patients with a relatively high CHADS2 score (median 3.5).[447] These new drugs have the potential to be used as an alternative to warfarin, especially in patients intolerant to—or unsuitable for—VKAs. In analyses of pre-specified subgroups in the ROCKET trial, patients with DM had a level of protection similar to the overall study populations.

An assessment of bleeding risk should carried out before starting anticoagulation. Using a real-world cohort of 3978 European patients with AF from the Euro Heart Survey, a new simple bleeding score known as 'Hypertension, Abnormal renal/liver function (1 point each), Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65), Drugs/alcohol concomitantly (1 point each)' (HAS-BLED) was developed,[448] which includes hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly (>65 years), drugs/alcohol, as risk factors of bleeding. A score ≥3 indicates high risk and some caution and regular review of the patients is needed following the initiation of antithrombotic therapy.

9.2 Sudden Cardiac Death

Clinical Studies of Sudden Cardiac Death in Diabetes Mellitus: Sudden cardiac death accounts for approximately 50% of all cardiovascular deaths. The majority are caused by ventricular tachyarrhythmia, often triggered by an ACS, which may occur without known cardiac disease or in association with structural heart disease.[449,450] The published epidemiological studies in general population samples have shown that people with DM are at higher risk of sudden cardiac death. In the Framingham study, DM was associated with an increased risk of sudden cardiac death in all ages (almost four-fold) and was consistently greater in women than in men.[451] The Nurses' Health Study,[452] which included 121 701 women aged 30–55 years, followed for 22 years, reported that sudden cardiac death occurred as the first sign of heart disease in 69% of cases. DM was a strong risk factor, associated with three-fold increased risk of sudden death, while hypertension was associated with a 2.5-fold and obesity with a 1.6-fold increased risk. DM increases the RR for sudden cardiac death in different ethnic groups.[453–455] A recent report from the ARIC investigators demonstrated that the magnitude of the relative increase in risk associated with DM was similar for sudden cardiac death and non-sudden cardiac death. In this study, DM attenuated the gender difference in absolute risk of sudden cardiac death.[456]

DM increases the cardiovascular mortality in patients with heart failure and in survivors of MI. In an analysis of the CHARM programme, DM was an independent predictor of mortality—including sudden cardiac death–in patients with heart failure independent of EF.[457] In a series of 3276 post-infarction patients from Germany and Finland, the incidence of sudden cardiac death was higher in T2DM with an HR of 3.8 (95% CI 2.4–5.8; P < 0.001).[458] The incidence of sudden cardiac death in post-infarction patients with DM and a LVEF >35% was equal to that of non-DM patients with an EF ≤35%. The incidence of sudden cardiac death was substantially increased among DM patients with an EF <35%, supporting the concept that a prophylactic implantable cardioverter defibrillator should be used in all symptomatic (NYHA Class II–IV) DM patients with an LVEF <35% unless contra-indicated. T2DM patients with congestive heart failure or post MI should have their LVEF measured, to identify candidates for prophylactic implantable cardioverter defibrillator therapy. Similarly, secondary prophylaxis with implantable cardioverter defibrillator therapy is indicated in DM patients resuscitated from ventricular fibrillation or sustained ventricular tachycardia, as recommended in the Guidelines.[459] All post-infarction patients with heart failure should also be treated with beta-blocking drugs, which are well established as reducing sudden cardiac death.[449,450]

Pathophysiology of Sudden Cardiac Death in Diabetes Mellitus: The causes underlying the increased vulnerability of the electrical substrate in DM are unclear and are likely to be consequent on several concomitant factors: (i) acute coronary occlusion and the presence and extent of CAD; (ii) myocardial fibrosis resulting in impaired LV filling (diastolic dysfunction) and systolic heart failure; (iii) microvascular disease and DM nephropathy; (iv) DM autonomic neuropathy; (v) abnormalities in electrical propagation in the myocardium reflected in ECG re-polarization and de-polarization abnormalities and (vi) obstructive sleep apnoea.[459–466] Experimentally induced hypoglycaemia can also cause changes in cardiac electrophysiological properties. 'Dead in bed' syndrome is a term used to describe the unexpected death of young individuals with T1DM while sleeping, suggesting that hypoglycaemia may contribute to sudden cardiac death in DM.[467]

Jouven et al.,[455] studied the RR of sudden cardiac death in groups of patients with different degrees of dysglycaemia and showed that higher values of glycaemia led to higher risk. Following adjustment for age, smoking habits, systolic blood pressure, heart disease and glucose-lowering treatment, even patients with borderline DM, defined as non-fasting glycaemia between 7.7 and 11.1 mmol/L (140 and 200 mg/dL), had an increased risk of sudden cardiac death (OR 1.24 compared with patients with normoglycaemia). The presence of microvascular disease, defined as retinopathy or proteinuria and female gender, increased risk in all groups. This study emphasizes that glucose intolerance seems to be a continuous variable directly related to the risk of sudden cardiac death, rather than supporting the previous view of risk being related to a specific threshold of glucose intolerance. This fits with the present concept that cardiovascular risk increases below present thresholds for DM already at glucose levels that have been considered fairly normal.

The Framingham investigators[468] demonstrated, in a large community-based population that, after adjusting for co-variates, indices of reduced heart rate variability were influenced by plasma glucose. Hyperglycaemia—even mild—may be associated with lower heart rate variability.[469] Similar findings were reported by the ARIC study,[470] which showed that even patients with pre-diabetes have abnormalities of autonomic cardiac function and heart rate variability. These studies further confirm that glucose levels should be considered as a continuous variable influencing autonomic control of the heart. Unfortunately these studies were not designed to answer the question of whether reduced heart rate variability in DM is an independent predictor of sudden cardiac death. A recent study showed that measurement of autonomic markers, such as heart rate turbulence and deceleration capacity from 24-h Holter recordings, predicts the occurrence of cardiac death and sudden cardiac death among T2DM patients with recent MI.[471]

Cardiovascular autonomic neuropathy was significantly associated with subsequent mortality in people with DM in a meta-analysis of 15 studies.[472] The Rochester DM neuropathy study was designed to define the risk factors for sudden cardiac death and the role of DM autonomic neuropathy in a population of 462 DM patients followed for 15 years.[473] These data suggested that kidney dysfunction and atherosclerotic heart disease are the most important determinants of the risk of sudden cardiac death, whereas neither autonomic neuropathy nor QTc were independent predictors. This study did not include heart rate variability or other risk variables among the parameters introduced in multivariable analysis. In contrast, the results of the MONICA/KORA study reported that QTc was an independent predictor of sudden death, associated with a three-fold increase in patients with DM and a two-fold increase in those without.[474] Measurements of heart rate variability and QTc may become valuable as predictors of sudden cardiac death in DM patients but evidence to support this as a general recommendation is still lacking.

On the basis of available evidence, it seems that all levels of glucose intolerance are associated with progressive development of a variety of abnormalities that adversely affect survival and predispose to sudden cardiac death. The identification of independent predictors of sudden cardiac death in DM has not progressed to a stage where it is possible to devise a risk stratification scheme for prevention.

Conclusions: Sudden cardiac death is a major cause of mortality in DM patients. While there are some risk factors for sudden cardiac death that may be specifically related to DM, such as microvascular disease and autonomic neuropathy, the focus should be on primary prevention of DM, atherosclerosis and CAD and secondary prevention of the cardiovascular consequences of these common conditions.

9.3 Gaps in Knowledge

  • Information is lacking on the long-term impact of glycaemic control on the QTc interval.

  • What is the role of hypoglycaemia and other predictors in sudden cardiac death?

9.4 Recommendations for the Management of Arrhythmias in Patients With Diabetes Mellitus

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