David Fitchett, MD FRCPC FACC

David Fitchett is Director of the Cardiac Intensive Care Unit at St Michael’s Hospital, and an Associate Professor of Medicine at the University of Toronto.

He came to Toronto in 1997 after 19 years at the Royal Victoria Hospital in Montreal where he was CCU Director and Medical Director of the Heart Transplant Program.

Dr Fitchett’s investigative career has focused on arterial mechanics, heart failure, and clinical trials in acute coronary syndromes. Dr Fitchett has over 200 peer reviewed publications, abstracts, and book chapters. He is a frequently invited to be a guest speaker across Canada and has an interest in developing effective interactive teaching programs.

The Management of Acute Coronary Syndrome in Diabetics

Tuesday, March 18, 2008
8:00 AM

Download Dr. Fitchett’s complete slide set [2.06 MB PPT].

Approximately one third of admissions for acute myocardial infarction (AMI) occur in individuals with diabetes mellitus (DM). Admission rates for MI are over seven-fold higher among persons with DM than in those without DM, and three-fold higher after accounting for differences in age and gender. Diabetes shifts the risk for acute coronary syndromes (ACS) earlier by 15-20 years and abolishes female pre-menopausal protection. Patients with diabetes and ACS have worse outcomes than comparable non-diabetic individuals. Diabetes is a predictor of pre-hospital cardiac arrest, short and long-term mortality, recurrent myocardial infarction, and the development of heart failure and cardiogenic shock in patients with ACS.

Despite advances in acute cardiac care, diabetes confers almost a doubling of short and long term mortality (1;2) (3-6). Predictors of 1 year mortality in the patient with diabetes and myocardial infarction include age, female gender(7-9), blood pressure, history of prior myocardial infarction, blood glucose at the time of hospital admission, duration of diabetes, insulin therapy, and urine albumin content(10;11). Diabetes remains a major risk factor for mortality after adjustment for multiple clinical variables, extent of coronary artery disease and therapy. (JACC 2004; 43:585-91). Multiple factors contribute to the worse outcomes in the patient with diabetes and are summarized below:

Mechanisms for Adverse Outcomes in Patients with Diabetes and ACS
Pathophysiology

• – Endothelial dysfunction and decreased coronary flow reserve
• – Reduced ischemic preconditioning
• – Increased thrombogenicity
• – Sympathovagal imbalance increasing risk of arrhythmias
• – Persistence of FFA metabolism in stressed or ischemic myocardium

Clinical Associations with Adverse Outcome

• – Hypertension
• – Renal insufficiency
• – Peripheral and cerebro-vascular disease
• – Prior silent MI
• – Extent and severity of coronary disease
• – Diastolic LV dysfunction
• – Increased risk heart failure / cardiogenic shock
• – Failure to receive optimal medical treatment
• – Delayed presentation for medical care

Despite early reperfusion after myocardial infarction and similar procedural outcomes from percutaneous coronary intervention (PCI), patients with diabetes have an increased mortality from heart failure(12-14) and cardiogenic shock(15). Yet prior coronary artery bypass surgery appears to have a protective role in patients with diabetes who sustain an acute myocardial infarction(16).

Management and Care GAP (Acute Care)
Observational registries indicate that patients with diabetes and acute coronary events receive recommended treatment less frequently than similar patients without diabetes(17;18). Although there are no clinical trials that specifically address the benefit of treatment in patients with diabetes and ACS, subgroup analyses of major clinical trials and meta-analyses indicate that for most therapeutic strategies, the patient with diabetes has benefit from treatment. The Fibrinolytic Therapy Trialists meta-analysis(19) showed the mortality benefit of fibrinolysis was similar or enhanced in patients with diabetes. Despite the proven benefit of fibrinolysis there is a reduced and delayed use of any reperfusion strategy in patients with ST elevation acute myocardial infarction and diabetes(18;20;21). One reason for the lower use of thrombolysis in the patient with diabetes is the concern for intra-ocular hemorrhage. In the GUSTO 1 trial there was no intra-ocular hemorrhage in the more than 6,000 patients with diabetes(22), consequently diabetic retinopathy should not be considered to be a contraindication to fibrinolysis. Primary angioplasty when performed in a timely manner, results in a mortality benefit and reduction of (re-) infarction when compared with fibrinolysis(23) with even greater benefits in patients with diabetes.(24)

A meta-analysis(25) of patients with non ST elevation ACS examined the benefits of a strategy of routine coronary angiography and revascularization compared to a more conservative approach, and showed that death and myocardial infarction were reduced 18% by the early invasive strategy. The TACTICS-TIMI 18 study(26) included 28% patients with diabetes, and indicated that the benefit of an early invasive strategy was enhanced in the patients with diabetes. Unfortunately, despite the higher risk of an adverse outcome and the benefit from a strategy of early coronary angiography, patients with diabetes are referred less frequently for early cardiac catheterization(18).

Anti-platelet therapy in the patient with diabetes and an acute coronary syndrome has similar or enhanced benefit as compared to the overall population. In the CURE trial(27) the 22.6% of patients with diabetes had similar benefits from the combination of clopidogrel and aspirin compared to patients without diabetes. Glyco-protein IIb/IIIa inhibitors reduce the risk of death/MI before and during angioplasty in high risk patients with NSTE ACS. A meta-analysis(28) of the benefits of GP IIb/IIIa inhibitors in 6 trials with 6458 diabetic patients showed a significant reduction of mortality reduction at 30 days. In contrast, the 23,072 patients without diabetes had survival benefit. A striking mortality reduction (4.0% to 1.2% (OR 0.30; 95% CI 0.14 to 0.69) P<0.002) was observed in the 1279 patients with diabetes who received a GPIIb/IIIa inhibitor and underwent PCI during the index admission. Patients with diabetes, despite the marked benefit from treatment, receive GPIIb/IIIa less frequently than the patient without diabetes(29).

Management and Care GAP (Long-Term Care)
A long-term intensive multifactorial management strategy for the patient with diabetes, including tight blood pressure, lipid, and glycemic control, and the use of aspirin and ACE inhibition, has been shown to halve cardiovascular events when compared to a less aggressive “usual care” strategy.(30) The same study has recently reported that the intensive multifactorial management halved mortality after 13 years of follow-up. The patient with a recent myocardial infarction and diabetes is at the highest risk for recurrent ischemic events and should receive intensive multifactorial risk factor management. The patient with an acute coronary event will in addition benefit from long term treatment with beta-adrenergic blockers and dual anti-platelet therapy with both aspirin and clopidogrel for up to one year

At the time of hospital discharge, patients with diabetes and ACS are less likely to receive a beta-blocker(29), despite a greater absolute benefit (31). An analysis of pooled data(32) showed that beta-blocker treatment in patients with diabetes reduced mortality 48% compared to 33% in non-diabetic subjects. The Capricorn study(33) showed that carvedilol reduced mortality and re-infarction in the treatment of patients, with and without diabetes, and recent myocardial infarction in an era of contemporary treatment with ACE inhibition, aspirin, statins and reperfusion therapy. Beta-blockers are used less frequently in the diabetic patient following ACS, as there is concern that beta-blockade could both prolong an episode of hypoglycemia and mask hypoglycemic symptoms.

The ACC /AHA guidelines recommend that an ACE inhibitor be given within the first 24 hours of STEMI with anterior myocardial infarction, pulmonary congestion or left ventricular ejection fraction (LVEF) of less than 40%. For other patients the guidelines recommend the administration of an ACE inhibitor during convalescence for long-term vascular protection based on the results of the HOPE(34) and EUROPA(35) studies. Patients with diabetes had at least equivalent or enhanced benefit from an ACE inhibitor compared with the overall population(36). An angiotensin receptor blocker, specifically valsartan or candasartan, is recommended for patients that are intolerant of ACE inhibitors and have either clinical or radiological signs of heart failure or LVEF < 40%. In patients with diabetes and either heart failure or reduced left ventricular ejection fraction, the TRACE(37) and SMILE(38) studies with trandolapril and zofenopril respectively demonstrated that long term ACE inhibition improved clinical outcomes reducing mortality and the progression to severe heart failure(39). The VALIANT study showed non inferiority of valsartan compared with captopril in reducing mortality and recurrent myocardial infarction in patients with myocardial infarction and heart failure or reduced LV ejection fraction. In the diabetic subgroup (23%) the treatment effect of valsartan was similar to the overall group.

Why is evidence-based treatment underused in patients with diabetes and ACS? Despite worse outcomes, patients with diabetes are less likely to receive recommended evidence based treatment for the management of ACS than non-diabetic subjects. Patients with diabetes are less likely to be followed by a cardiologist(40), or to receive revascularization, thrombolysis, beta-blockers or aspirin than patients without diabetes(18;20;21;29;41;42). The reduced use of evidence based and guideline recommended treatment partially explains the unfavourable prognosis of patients with diabetes and ACS (18;20). Hence it is important that we better understand why patients with diabetes fail to receive guideline recommended treatment. Perhaps then we shall be able to encourage a better adherence to treatment that frequently has an enhanced benefit in the patient with diabetes.

Admission Hyperglycemia
Admission hyperglycemia is an independent predictor of in hospital and 6 month survival after acute MI(43-45), and a more important determinant of short-term survival than a history of diabetes. Hyperglycemia in the AMI setting is the result of the release of hormones, cytokines and free fatty acids, superimposed upon an abnormal glucometabolic state (insulin resistance and impaired insulin secretion). However admission hyperglycemia in non-diabetic patients with acute myocardial infarction is not necessarily associated with abnormal glucose tolerance or undiagnosed diabetes.(46) Furthermore in patients undergoing primary angioplasty for STE MI, admission hyperglycemia is associated with increased in-hospital mortality, whereas diabetes without admission hyperglycemia is not(47). An analysis of the CARDINAL trial(48) showed both higher baseline glucose and the failure of glucose levels to decrease in the first 24 hours after AMI predicted higher mortality in the non-diabetic patients. For every 0.6mmol/l decrease in glucose over the first 24 hours there was a 9% relative risk reduction of mortality at 30 days. Hyperglycemia increases infarction size in patients and experimental animals. Furthermore hyperglycemia increases coagulation and inflammation, impairs endothelial function and reduces ischemic reconditioning.

Glycemic control after ACS is a controversial subject The DIGAMI 1 study(49-54) demonstrated that tight glycemic control with intravenous insulin in patients with admission hyperglycemia, followed by multi-dose sub-cutaneous insulin treatment over the subsequent months resulted in a 30% reduction in one year mortality. The DIGAMI 2 study(55) failed to achieve the study goals, both in the number of patients recruited, but also in glycemic control. Despite these limitations, it did demonstrate that outcomes were closely related to glycemic control, however achieved. A recent observational study(56) suggests that individuals without known diabetes who were admitted to hospital with an acute myocardial infarction and blood glucose > 11 mmol/l and given insulin treatment had a 50% lower in-hospital and 30 day mortality than those receiving no insulin.

Although the DIGAMI trials do not allow us to distinguish between the benefits of early glycemic control and the subsequent three month multi-dose insulin therapy, other studies in critically ill patients and following coronary artery surgery(48;57;58) support the need for early glucose control. The CREATE-ECLA trial(59) showed that glucose-insulin therapy had a neutral effect on early mortality. However glucose levels on glucose and insulin treatment were significantly higher than in control subjects, and early mortality related to the average glucose level on treatment. A meta-analysis of insulin therapy in critically ill patients(60) showed that insulin therapy reduced mortality when the aim of therapy was glucose control.

The weight of evidence supports the early control of hyperglycemia in patients with acute myocardial infarction whether or not they have known diabetes. In most patients with an acute myocardial infarction who are initially not eating a normal diet, control is most rapidly achieved with an intravenous insulin regimen. In other patients a subcutaneous multi-dose insulin regimen may suffice. Aggressive glycemic control should be initiated in patients with an acute coronary syndrome and glucose levels greater than 10-11 mmol/l. However there is need for a definitive clinical trial to identify which patients will benefit, the glycemic threshold and the treatment target glucose level.

Conclusions
Patients with diabetes are at an increased risk for acute coronary events at a substantially greater mortality and morbidity. Unfortunately both acute and long-term guide-line recommended management strategies, that often have an enhanced benefit in the high-risk patient with diabetes, are less likely to be used than in the overall population. Further research is necessary to better understand this management GAP and encourage the greater application of life-saving treatment.

References

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Tailored Anti-Thrombotic and Anti-Platelet Therapy for the Patient with Acute Coronary Syndrome

Wednesday, March 19, 2008
8:30 AM

The early management of acute coronary syndromes is based upon the need to minimize myocardial injury: either as ongoing myocardial infarction or recurrent ischemic events. At the same time any management plan must minimize the risk for bleeding. Bleeding is associated with short and medium term mortality and recurrent ischemic coronary events. Recent clinical trials have indicated that a reduction of bleeding is associated with improved outcomes.

The choice of anti-thrombotic and anti-platelet treatment is determined by an assessment of risk and benefit. Assessment of bleeding risk should determine the choice of treatment and the dose of medication. The need for revascularisation and the likely timing of the procedure will also influence the choice of antithrombotic. However despite an increasing number of patients undergoing cardiac catheterization and revascularization within 24-36 hours of presentation, recent registries show that the majority of patients wait 48-72 hours. Appropriate selection of anticoagulant and antiplatelet agents will depend upon local practice.

For patients presenting with non ST segment acute coronary syndromes, the presence of ST segment depression and/or elevated biomarkers indicates higher risk and the likelihood of benefit from early revascularisation. Patients with symptoms compatible with ACS yet no objective high risk features are at indeterminate risk until further observations and testing are completed. A suggested algorithm for the management of these patients is shown below.

Factors associated with a higher risk of bleeding are:Patient

• – Female
• – Elderly
• – Asian race
• – Low body weight
• – Renal impairment
• – Hypertension
• – Prior bleed

Management

• – (early) Catheterization
• – Femoral access

Medications

• – Use of multiple agents
• – Dose
• – Choice of anticoagulant

The 2007 ACC/AHA and the 2007 ESC guidelines provide the following recommendations for the use of anticoagulation

Other factors that may influence choice of anticoagulant include

Condition	UFH	LMWH	Fondaparinux	Bivalirudin
Severe Renal Insufficiency	Caution	Avoid	Avoid	Caution
­ Bleeding risk	Neutral	Avoid	Yes	Yes
Platelets	Worst	Better	Better	Best
Early Cath Strategy	Yes	Avoid	Avoid	Yes

Dual antiplatelet therapy with ASA and clopidogrel is recommended for all patients with NSTE ACS. Benefits are achieved very early, with a reduction of recurrent ischemic events within hours of administration. The concern that the patient may need coronary bypass surgery should not influence administration of clopidogrel, as recent data indicates that < 2% of patients require coronary bypass surgery within 5 days of admission. The use of GP IIb/IIIa agents is currently reserved for patients at the highest risk with recurrent episodes of ischemia that require emergency revascularization.

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