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

7. Management of Stable and Unstable Coronary Artery Disease in Patients With Diabetes

7.1. Optimal Medical Treatment for Patients With Chronic Coronary Artery Disease and Diabetes

DM is associated with a poorer prognosis in patients with acute and stable CAD.[294–296] This is apparent in patients with newly detected DM and IGT,[297] and although the absolute risk is higher in men, the proportionate increase in risk is higher in women, in whom loss of cardioprotection occurs with DM.[298] All patients with CAD, without previously known glucose perturbations, should, for the purpose of risk stratification and adapted management, have their glycaemic state evaluated. Elevated levels of HbA1c and FPG may establish the diagnosis of DM,[299] but a normal value does not exclude glucose abnormalities. Accordingly, and as detailed in Section 3.3, the appropriate screening method is an oral glucose tolerance test (OGTT),[3,38] which should not be performed earlier than 4–5 days after an acute coronary event (ACS) (i.e. acute MI or unstable angina) to minimize false positive results.[300,301]

In-hospital and long-term mortality after MI has declined, but the outcome is still poor amongst patients with DM. The reasons are partially unexplained but a higher prevalence of complications, in combination with lack of appropriate evidence-based treatment, contributes.[302,303]

Since very few pharmacological trials have been directed towards patients with DM, information on treatment efficacy is frequently based on subgroup analyses from existing trials. A disadvantage is the risk of looking at groups of patients with DM considered suitable for the trial but in which the DM phenotypes are not well defined. Moreover, patients with CVD often have a metabolic syndrome or undetected DM. With these limitations, available information favours a proportionately similar efficacy of cardiovascular risk management in DM and non-DM patients. Considering the higher risk for cardiovascular events, the absolute benefit is considerably higher in DM, and the NNT to avoid one cardiovascular event is lower in this population.[213]

7.1.1 Beta-adrenergic Blockers. As outlined in current European guidelines on patients with CAD, beta-blockers are advocated for the whole spectrum of CAD, with different levels of recommendations and different levels of evidence.[304–308] Beta-blockers relieve symptoms of myocardial ischaemia (angina pectoris) in patients with stable CAD and they may provide prognostic benefits, as suggested from retrospective analysis of placebo-controlled trials.[305] Beta-blockers are particularly effective in improving prognosis in post-MI patients with DM by reducing the likelihood of reinfarction, sudden death and ventricular arrhythmias.[309,310] Beta-blockers may have negative metabolic effects—for example, by increasing IR and masking hypoglycaemic symptoms—and there seems to be a difference between non-vasodilating, beta 1-antagonists (e.g. metoprolol and atenolol) and beta-blockers with vasodilating properties (e.g. the ß/α-adrenoblockers carvedilol and labetalol, and ß1-blockers with modulation synthesis of NO, nebivolol), with the latter advocated as having a better glucometabolic profile.[311] Overall the positive effects of beta-blockade on prognosis outweigh the negative glucometabolic effects.

7.1.2 Blockers of the Renin-angiotensin-aldosterone System. Treatment with ACE-I or ARB should be started during hospitalization for ACS and continued thereafter in patients with DM and left ventricular ejection fraction (LVEF) <40%, hypertension, or chronic kidney disease,[304,306,307] and considered in all patients with ST-elevation MI (STEMI). Patients with DM and stable CAD are also recommended an ACE-I.[305] The Heart Outcomes Prevention Evaluation (HOPE) study showed a 25% reduction in MI, stroke, or cardiovascular death for patients with known vascular disease or DM randomized to placebo or ramipril. This finding was consistent in the pre-specified subgroup of patients with DM.[312] A proportionately similar trend to benefit was observed in the subgroup of patients with DM in the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) trial, recruiting a population at lower cardiovascular risk.[313] The ONTARGET trial compared the ACE-I ramipril and the ARB telmisartan in a high-risk population similar to that in HOPE. In this head-to-head comparison, telmisartan was found to be equivalent to ramipril as regards the primary outcome—a composite of death from cardiovascular causes, MI, stroke or hospitalization for heart failure—while a combination of the two drugs caused adverse events without any increase in benefit.[210]

7.1.3 Lipid-lowering Drugs. The beneficial effect of statins in patients with CAD and DM is firmly established. Details on lipid-lowering therapy are outlined in Section 6.4.

7.1.4 Nitrates and Calcium Channel Blockers. There is no evidence for a prognostic impact of nitrates but they may be used for symptomatic relief.[304,306,307] Calcium channel blockers are efficacious in relieving ischaemic symptoms, and verapamil and diltiazem may prevent re-infarction and death.[304–307] These drugs may be appropriate for long-term use in patients without heart failure, as an alternative to beta-blockers or when beta-blockers may be a less attractive choice, e.g. due to obstructive airways disease. The combination of these drugs and beta-blockers should be avoided, considering the risk for bradycardia, atrio-ventricular conduction disturbances or compromised LV function. An alternative is the use of a dihydropyridine calcium channel blocker, such as amlodipine, felodipine or nicardipine.

7.1.5 Ivabradine. The specific, heart-rate lowering, anti-anginal drug ivabradine inhibits the If current—the primary modulator of spontaneous diastolic depolarization in the sinus node. Ivabradine is indicated in the treatment of chronic stable angina in CAD patients with a contra-indication or intolerance to beta-blockers, or in combination with beta-blockers if the patient remains symptomatic or has a heart rate >70 bpm, especially if there is also left ventricular (LV) dysfunction. It can be used in selected patients with non-ST elevation ACS in the event of beta-blocker intolerance, or insufficient heart rate reduction despite maximal tolerated beta-blocker dose.[305,306] High heart rate is associated with a worse outcome in patients with DM,[314] and ivabradine is effective in preventing angina in these patients without any safety concerns or adverse effects on glucose metabolism.[315]

7.1.6 Antiplatelet and Antithrombotic Drugs (See also Sections 6.5 and 7.2). In secondary prevention, antiplatelet therapy in the form of low-dose aspirin (75–160 mg) or clopidogrel (separately or in combination) reduces the risk of stroke, MI or vascular death, although the benefits are somewhat less in DM.[316] In patients with ACS without ST-segment elevation, glycoprotein IIb/IIIa receptor inhibitors seemed to be especially effective in patients with DM but this was not confirmed in the recent Early-ACS trial.[317]

Other antiplatelet drugs, such as thienopyridines (ticlopidine, clopidogrel, prasugrel and ticagrelor) reduce the risk of cardiovascular events when added to aspirin in patients with ACS.[284,304,307] The incidence of cardiovascular death, MI or stroke decreased from 11.4 to 9.3% (RR 0.80; 95% CI 0.72–0.90) an effect that was sustained in patients with DM.[282] In the Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study—recruiting patients with recent ischaemic stroke, recent MI or established PAD—those with DM and vascular disease were provided better protection from serious cardiovascular events by clopidogrel than by aspirin. The annual event rate in patients with DM was 15.6% in those randomized to clopidogrel and 17.7% in those who received aspirin, i.e. an absolute risk reduction of 2.1% (P = 0.042), which corresponds to an RRR of 13% (RR 0.87; 95% CI 0.77–0.88) and with fewer bleeding complications. Due to the elevated event rates in patients with DM, the absolute benefit of clopidogrel is amplified in this clinical setting.[285] In a subgroup analysis of the TRITON trial, patients with DM tended to have a greater reduction in ischaemic events, without an observed increase in major bleeding, with prasugrel than with clopidogrel.[280] It is important to acknowledge that many trials do not separately report outcomes for patients with DM and recommendations are based on available evidence from trials including patients with and without DM.[318]

7.1.7 Glucose Control in Acute Coronary Syndromes. Elevated plasma glucose (PG) during an ACS is associated with a more serious prognosis in patients with DM than without.[319–323] Hyperglycaemia may relate to previously undetected glucose perturbations, but also to stress-induced catecholamine release increasing FFA concentrations, decreased insulin production and increasing IR and glycogenolysis,[301] with a negative impact on myocardial metabolism and function (for details see Section 4). Two strategies have been tested in an attempt to improve the prognosis in patients with an ACS.

Metabolic modulation by means of glucose-insulin-potassium (GIK), regardless of the presence of DM or PG, is based on the assumption that an increase in intracellular potassium stabilizes the cardiomyocyte and facilitates glucose transportation into the cells.[324] Other potential benefits are decreased beta oxidation of FFAs, improved use of glucose for energy production and improved endothelial function and fibrinolysis.[301] RCTs failed to show mortality or morbidity benefits, as reviewed by Kloner and Nesto.[324] This lack of effect may be due to increased PG or negative effects of the fluid load induced by the GIK-infusion. The Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care (IMMEDIATE) trial, randomizing patients after a median time of 90 minutes of suspected ACS to out-of-hospital emergency medical service administration of GIK or placebo, demonstrated a reduction of the composite outcome of cardiac arrest or in-hospital mortality with GIK treatment, but did not impact the pre-specified primary endpoint, i.e. progression of ACS to MI within 24 h.[325]

Glycaemic control has been tested in the RCTs 'Diabetes and Insulin–Glucose Infusion in Acute Myocardial Infarction' (DIGAMI)[326,327] 1 and 2 and 'Hyperglycaemia: Intensive Insulin Infusion in Infarction' (HI-5).[328] The first DIGAMI trial randomized 620 patients with DM and acute MI to a ≥24-h insulin–glucose infusion, followed by multi-dose insulin, or to routine glucose-lowering therapy.[326] Mortality after 3.4 years was 33% in the insulin group and 44% (P = 0.011) in the control group.[329] DIGAMI 2 failed to demonstrate prognostic benefits. The most plausible reason for this discrepancy is that, in DIGAMI 1,[326,330] admission HbA1c decreased more (1.5%), from a higher level (9.1%), compared with 0.5% from 8.3% in DIGAMI 2.[327] In addition, the use of beta-blockade, statins and revascularization was more extensive in DIGAMI 2.

The difference in glucose levels between the control and insulin groups in the HI-5 study was small and there was no reduction in mortality among patients treated with insulin.[328] Pooled data from the three studies confirmed that insulin–glucose infusion did not reduce mortality in the absence of glucose control in patients with acute MI and DM (RR 1.07; 95% CI 0.85–1.36; P = 0.547)..[331] Since neither DIGAMI 2 nor HI-5 achieved a difference in glucose control between the intensively treated and the control groups, it is still an open question as to whether glucose lowering is beneficial.

The Heart2D compared the effects of prandial (pre-meal insulin three times daily; n = 557) vs. basal glycaemic control (long-acting insulin once or twice daily; n = 558) on cardiovascular events in patients with T2DM. Glucose targets were a PPG of 7.5 mmol/L (135 mg/dL) and an FPG of 6.7 mmol/L (121 mg/dL) respectively. The basal group had a lower mean FPG (7.0 vs. 8.1 mmol/l; P < 0.001) but a similar daily fasting/pre-meal blood glucose (7.7 vs. 7.3 mmol/l; P = 0.233) vs. the prandial group and a similar level of HbA1c. The study was stopped after an average follow-up of 963 days, due to lack of efficacy.[173]

Some registry studies have suggested that there is a J- or U-shaped relationship between PG and prognosis,[320,322,323] with the implication that hypoglycaemia, as well as hyperglycaemia, may be prognostically unfavourable. Compensatory mechanisms induced by hypoglycaemia, such as enhanced catecholamine release, may aggravate myocardial ischaemia and provoke arrhythmias.[332,333] Recent data indicate that hypoglycaemic episodes identify patients at risk for other reasons (e.g. heart failure, renal dysfunction and malnutrition) and hypoglycaemia does not remain as an independent risk factor when correcting for such variables.[334,335]

A reasonable conclusion, from DIGAMI 1,[326,330] is that DM and acute MI will benefit from glycaemic control if hyperglycaemia is significant (>10 mmol/L or >180 mg/dL). An approximation towards normoglycaemia, with less stringent targets in those with severe co-morbidities, is a reasonable goal but exact targets are still to be defined. Insulin infusion is the most efficient way to achieve rapid glucose control. Glucose management in the long-term perspective is presented elsewhere in these guidelines (Section 6.2).

7.1.8 Gaps in Knowledge.

  • The role and optimum level of glycaemic control in the outcome in ACS patients remain to be established.

  • Is it possible to reduce final infarct size by means of very early GIK administration after symptoms indicating MI?

7.1.9 Recommendations for the Management of Patients With Stable and Unstable Coronary Artery Disease and Diabetes.

7.2. Revascularization

A quarter of myocardial revascularization procedures are performed in patients with DM. Revascularization in these patients is challenged by a more diffuse atherosclerotic involvement of epicardial vessels, a higher propensity to develop re-stenosis after PCI and saphenous graft occlusion after coronary artery bypass graft surgery (CABG) and unremitting atherosclerotic progression causing new stenosis.[336] This results in a higher risk, including long-term mortality, than seen in patients without DM, irrespective of revascularization modality (Figure 7).[337] Evidence on the effect of myocardial revascularization in patients with DM has been obtained in the shifting context of a continued development of PCI, CABG and pharmacological treatments, making it difficult to establish adequate comparisons.[308,338]

7.2.1 Myocardial Revascularization in Stable and Unstable Coronary Artery Disease. Stable Coronary Artery Disease: A randomized comparison of myocardial revascularization, either with CABG or PCI, vs. optimal medical treatment (OMT)—in DM patients considered eligible for either PCI or CABG—was performed in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.[339] Once PCI or CABG had been chosen as the most adequate potential revascularization technique, patients were randomized to OMT alone or to revascularization plus OMT. After five years, no significant differences were noted in the combined endpoint of death, MI or stroke between the OMT (12%) and revascularization (12%) arms. In the surgical group, freedom from major adverse cardiac and cerebrovascular events (MACCE) was significantly higher with CABG (78%) than with OMT alone (70%, P = 0.01), but there was no difference in survival (CABG 86%; OMT 84%; P = 0.33). In the PCI group, made up of patients with less-extensive CAD than in the CABG stratum, there were no significant differences in MACCE or survival between PCI and OMT. During subsequent follow-up, 38% of the patients assigned to OMT underwent at least one revascularization for symptomatic reasons, compared with 20% in the revascularization stratum, showing that an initial conservative strategy with OMT saved about 80% of interventions over the next five years. Overall, except in specific situations such as left main coronary artery stenosis ≥50%, proximal LAD stenosis or triple vessel disease with impaired LV function, myocardial revascularization in patients with DM did not improve survival when compared with medical treatment. When transferring these results into general practice, it should be kept in mind that the results were obtained in a selected population. Patients were excluded if they required immediate revascularization or had left main coronary disease, a creatinine level >2.0 mg/dL (>177 μmol/L), HbA1c >13.0%, class III–IV heart failure or if they had undergone PCI or CABG within the previous 12 months.

Acute Coronary Syndromes: No interaction between the effect of myocardial revascularization and the presence of DM has been documented in trials on non-ST-elevation ACS management.[340–342] An early invasive strategy improved outcomes in the overall population of these studies,[303,340,342] with a greater benefit in patients with DM in the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction (TACTICS-TIMI 18) trial.[342] In STEMI patients, a pooled analysis of individual patient data (n = 6315) from 19 RCTs comparing primary PCI with fibrinolysis showed that patients with DM (n = 877; 14%) treated with reperfusion had an increased mortality, compared with those without DM. The benefits of a primary PCI, compared with fibrinolysis were, however, consistent in patients with and without DM.[343] Patients with DM had significantly delayed initiation of reperfusion treatments and longer ischaemic times, probably related to atypical symptoms causing significant delays in the time for reperfusion treatment. However, the reduction in 30-day mortality observed in PCI-treated patients was most pronounced in this group. Owing to a higher absolute risk, the NNT to save one life at 30 days was significantly lower for DM (NNT 17; 95% CI 11–28) than for non-DM patients (NNT 48; 95% CI 37–60). A subgroup analysis of DM patients included in the Occluded Artery Trial (OAT) confirmed that, as in non-DM, revascularization of an occluded infarct-related artery 3–28 days after MI does not improve outcome.[344]

7.2.2 Type of Intervention: Coronary Bypass Graft vs. Percutaneous Intervention. Higher repeat revascularization rates after PCI have been consistently found in DM patients included in RCTs comparing CABG and PCI. A meta-analysis based on individual data from 10 RCTs (7812 patients) comparing both types of revascularizations suggests a distinct survival advantage for CABG in DM patients (Figure 7:1).[337] Five-year mortality was 20% with PCI, compared with 12% with CABG (odds ratio 0.7; 95% CI 0.6–0.9), whereas no difference was found for patients without DM; the interaction between the presence of DM and type of revascularization was significant. A specific comparison of the efficacy and safety of PCI and CABG in patients with DM was performed in the Coronary Artery Revascularization in Diabetes (CARDia) trial.[345] The introduction of drug-eluting stents (DES) coincided with the enrolment period, leading to a mixed use of bare-metal stents (BMS) (31%) and DES (69%). After one year there was a non-significantly higher rate of the composite of death, MI and stroke (driven by a higher rate of MI) and significantly higher rates of repeat revascularization in the PCI group (2 vs. 12%, P < 0.001). The conclusions of the study were hampered by the limited size of the study population (n = 510).

Figure 7a.

1 Mortality in patients assigned to coronary artery bypass graft or percutaneous coronary intervention by diabetes status in an analysis of 10 randomized trials. Reproduced with permission from Hlatky et al. 337

The literature on CABG vs. PCI is confused by confounder bias in registries, the ongoing development of DES and, apart from the Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) trial, a lack of prospective RCTs. The implication is that much of the available information has to be derived from subgroup analyses in trials in populations in which patients with DM may be relatively few or selected. As a consequence of increased repeat revascularization in the SYNTAX trial,[346] performed in the DES era (using paclitaxel-eluting stents), the rate of MACCE after one year was twice as high with PCI as it was with CABG. In the pre-specified subgroup with DM, the relative risk for repeat revascularization after one year was even higher (RR 3.2; 95% CI 1.8–5.7; P < 0.001). In patients with DM and complex lesions, i.e. high SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) scores, one-year mortality was higher in the paclitaxel-eluting stent group (14% vs. 4%; P = 0.04).[347] After five years of follow-up, the rates of MACCE were significantly higher in patients with DM, when comparing PCI with CABG (PCI: 46.5% vs. CABG: 29.0%; P < 0.001) as well as for repeat revascularization (PCI: 35.3% vs. CABG: 14.6%; P < 0.001). There was no difference in the composite of all-cause death/stroke/MI (PCI: 23.9% vs. CABG: 19.1%; P = 0.26). Similar results were seen— but with somewhat fewer events—among patients without DM. It was concluded that, although PCI is a potential treatment option in patients with less complex lesions, CABG should be the revascularization choice for patients with complex anatomic disease, especially with concurrent DM.[348]

In contrast, an analysis of DM patients included in the Angina With Extremely Serious Operative Mortality Evaluation (AWESOME) randomized trial and registry, which included high-risk patients for CABG (prior CABG, recent MI, LVEF <30% or intra-aortic balloon pump treatment), showed no significant difference in three-year mortality between revascularization techniques.[349] Data obtained in recent registries support a better outcome in patients with DM treated with CABG, compared with DES, even in terms of mortality, at the expense of a higher stroke rate.[350] In an analysis of 86 244 patients ≥65 years of age undergoing CABG and 103 549 patients undergoing PCI from 2004 to 2008, four-year survival was significantly higher with surgery and the association of surgery with improved survival was most marked in insulin-treated DM.[351] The Revascularization for unprotected left main coronary artery stenosis: comparison of percutaneous (MAIN COMPARE) study reported on the long-term outcome of 1474 patients with unprotected left main stenosis, treated with DES or CABG. In this specific setting, there was a similar rate of the composite endpoint death, Q-wave MI or stroke in the PCI and CABG arms and a significantly higher rate of repeat revascularizations in the DES arm. A subgroup analysis of the study comparing patients with (n = 507; 34%) and without DM did not reveal significant interactions between treatment outcomes and the presence or absence of DM after adjustment for co-variates.[352] In an observational study from real-world patients in the Swedish Coronary Angiography and Angioplasty Registry, comprising 94 384 consecutive stent implantations, PCI with new generation DES was associated with a 38% reduced risk for clinically meaningful re-stenosis and a 23% lower death rate, compared with older DES.[353] These findings are supported by the outcome of a meta-analysis of 49 randomized controlled trials, including 50 844 patients, comparing different drug-eluting stents or drug elution with bare-metal stents.[354] The FREEDOM trial randomized 1900 patients—a majority with three-vessel disease—to treatment with CABG or PCI with sirolimus-eluting and paclitaxel-eluting stents. Newer-generation stents could be used as long as the FDA approved them. All patients were prescribed currently recommended medical therapies for the control of LDL-C, systolic BP and HbA1c. The primary results were a composite of total mortality and non-fatal MI or stroke. After a median of 3.8 years, the primary outcome occurred more frequently in the PCI group (P = 0.005), with a five-year rate of 26.6%, compared with 18.7% in the CABG group. The benefit of CABG was driven by differences in both MI (P < 0.001) and mortality (P = 0.049; Figure 7:2).

Figure 7b.

2 Kaplan-Meier estimates of the primary outcome and death. A: rates of the composite primary outcome of death, myocardial infarction or stroke and B: death from any cause truncated at five years after randomization. The P-value was calculated by means of the log-rank test on the basis of all available follow-up data. Reproduced by permission from Farkouh et al. 355

It was concluded that CABG is superior to PCI for patients with DM and advanced CAD. There was no significant interaction based on SYNTAX score, since the absolute difference in the primary end points between PCI and CABG were similar in patients with low, intermediate and high SYNTAX scores. Given the wide variability of the patients enrolled in FREEDOM, the trial represents real-world practice. Further analysis revealed that CABG was a cost-effective strategy, compared with PCI.[355,356] It can be concluded that a discussion with the patient, explaining the mortality benefit with CABG surgery, and an individualized risk assessment should be mandatory before the type of intervention is decided.[308]

7.2.3 Specific Aspects of Percutaneous and Surgical Revascularization in Diabetes Mellitus. The DIABETES trial demonstrated a 75% reduction in target vessel revascularization in DM patients treated with sirolimus-eluting stents (7%) vs. BMS (31%).[357] This finding received further support from a meta-analysis of 35 trials comparing DES with BMS,[358] which revealed a similar efficacy of sirolimus-eluting and paclitaxel-eluting stents in this regard (OR 0.29 for sirolimus; 0.38 for paclitaxel), provided that dual antiplatelet therapy after DES implantation was continued for >6 months. The risk of death associated with sirolimus-eluting stents was more than twice that associated with BMS in eight trials employing dual antiplatelet therapy for period of less than six months. In contrast, there was no increased risk associated with the use of DES in 27 trials with dual antiplatelet therapy maintained for more than six months. An analysis of registry data from the National Heart, Lung and Blood Institute Dynamic Registry revealed that, compared with BMS, DES were associated with fewer repeat revascularizations—to a similar extent in insulin-treated or non-insulin-treated DM.[359] Finally, the second-generation everolimus-eluting stents were not superior in terms of target lesion failure after one year of follow-up in a head-to-head comparison with paclitaxel-eluting stents, while zotarolimus-eluting stents were inferior to sirolimus-eluting stents in patients with DM.[360,361]

Antithrombotic treatment in DM patients undergoing coronary revascularization for stable angina or ACS is no different from those without DM.[317,362,363] Initial trials in glycoprotein IIb/IIIa inhibitors reported an interaction with DM, but this was not confirmed in the recent Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT 2) trial performed in the clopidogrel era.[364] Prasugrel is superior to clopidogrel in reducing the composite endpoint of cardiovascular death or MI or stroke without excess major bleeding. Similarly ticagrelor, in comparison with clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) trial, reduced the rate of ischaemic events in ACS patients, irrespective of the presence or absence of DM and glycaemic control, without an increase in major bleeding events.[280,282]

Patients with DM who undergo CABG usually have extensive CAD and require multiple grafts. There is no randomized evidence regarding the use of one vs. two internal thoracic artery (ITA) conduits in DM. Although observational evidence suggests that using bilateral ITA conduits improves patient outcome without compromising sternal stability, their use is still under debate, given a higher prevalence of wound infection and mediastinitis with DM.[365] A recent meta-analysis has shown that ITA harvesting by skeletonization (without the satellite veins and fascia) reduces the risk of sternal wound infection, in particular in DM patients undergoing bilateral ITA grafting,[366] although there are no randomized studies on this subject. A single-centre non-randomized study comparing CABG with bilateral ITA and PCI in DM reported improved outcomes (freedom from angina, re-intervention, or composite major adverse cardiac events) in the surgical group, but no difference in six-year survival (86% for CABG and 81% for PCI).[367] Finally, more than 50% of patients with moderate-to-poor blood glucose control after cardiac surgery may not have been diagnosed as having DM during pre-operative assessment.[368] This may lead to inadequate peri-operative glycaemic control, which is a predictor of in-hospital mortality and morbidity.

7.2.4 Myocardial Revascularization and Glucose-lowering Treatments. Although hypoglycaemic medications may influence the safety of coronary angiography, as well as early and late outcomes of revascularization with PCI or CABG, few trials have addressed interactions with myocardial revascularization in DM.

The plasma half-life of metformin is 6.2 h. There is no adequate scientific support for the frequent practice of stopping metformin 24 to 48 h prior to angiography or PCI because of a potential risk of lactic acidosis, followed by restarting treatment 48 h later. More recent recommendations are less restrictive.[308] Rather than stopping metformin treatment in all patients, a reasonable approach is to carefully monitor renal function after the procedure and to withhold metformin for 48 h if it deteriorates and until renal function has resumed its previous level.

Observational data reported concern over the use of sulphonylureas in patients treated with primary PCI for acute MI: this has not been confirmed by a post hoc analysis of the DIGAMI-2 trial, although the number of patients undergoing primary PCI in this trial was low.[369] Arrhythmias and ischaemic complications were also less frequent in patients receiving gliclazide/glimepiride.[370] Thiazolidinediones might be associated with lower re-stenosis rates after PCI with BMS,[371] but carry an increased risk of heart failure due to water retention in the kidney (see also Section 6.2.6).

No trial has demonstrated that the administration of insulin or GIK improves PCI outcome after STEMI. Observational data in patients undergoing CABG suggest that use of continuous intravenous insulin infusion to achieve moderately tight glycaemic control (6.6–9.9 mmol/L or 120–180 mg/dL) is independently associated with lower mortality and major complications than that observed after tighter (<6.6 mmol/L or <120 mg/dL) or more lenient (>9.9 mmol/L or >180 mg/dL) glycaemic control.[372] In the BARI 2D trial, outcomes were similar in patients receiving insulin sensitization vs. insulin provision to control blood glucose. In the CABG stratum, administration of insulin was associated with more cardiovascular events than insulin-sensitization medications.[339,373]

7.2.5 Gaps in Knowledge.

  • The optimal policy on metformin treatment in patients undergoing PCI is still uncertain.

  • The role and optimum level of glycaemic control in the outcome during and after myocardial revascularization remain to be established.

7.2.6 Recommendations for Coronary Revascularization of Patients With Diabetes.

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