The risk of sirolimus stent thrombosis is higher in multiple-vessel disease diabetic patients

The EVASTENT Matched-Cohort Registry investigated the frequency and causes of stent thrombosis in diabetic and nondiabetic patients after implantation of sirolimus-eluting stents.

The study population was a matched multicenter cohort registry of 1,731 patients undergoing revascularization exclusively with sirolimus stents.

The primary end point was a composite of stent thrombosis, cardiovascular death, and nonfatal myocardial infarction (major adverse cardiac events. Major events occurred in 78 patients (4.5%), cardiac death in 35 (2.1%), and stent thrombosis in 45 (2.6%): 30 definite, 23 subacute, and 22 late, including 9 at >6 months.

The 1-year stent thrombosis rate was 1.8 times higher in diabetic than in nondiabetic patients (3.2% vs. 1.7%; log rank p = 0.03), with diabetic patients with multiple-vessel disease experiencing the highest rate.

The other predictors were

• interruption of antithrombotic treatment,
• previous stroke,
• renal failure,
• lower ejection fraction,
• calcified lesion,
• length stented,
• insulin-requiring diabetes.

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Evidence of improvement of cardiovascular risk with physical activity in children with Type 1 Diabetes

Physical activity improves the cardiovascular risk profile in Children with type 1 diabetes mellitus. This includes lower lipoprotein levels and diastolic blood pressure and better glycaemic control. This is the result of a study published in the Diabetes care journal. This large multicentre trial analysed results from over 23,000 subjects. Regular physical exercise affects high-density lipoprotein (HDL) cholesterol and triglyceride levels but not total and low-density lipoprotein (LDL) cholesterol levels. Please note that the study has only shown improvement in surrogate markers of cardiovascular risk. The effect on actual outcomes was not studied. More research is necessary to demonstrate that.

QTc in type 1 diabetics

The EURODIAB Prospective Complications Study group has assessed the incidence and risk factors of prolonged QTc in people with type 1 diabetes. They studied 1,415 type 1 diabetic subjects, who had normal QTc at baseline. The QTc was reanalysed after the 7-year follow-up period. QTc >0.44 s was considered abnormally prolonged.
The predictive factors for prolonged QTc interval were female sex, A1C, and systolic blood pressure. Physical activity and BMI within the range of 21.5–23.2 kg/m2 played a protective role

Thiazolidinediones and Heart

Thiazolidinediones which include Rosiglitazone (Avandia) and Pioglitazone (Actos) are widely used all over the world to treat type 2 diabetes mellitus. They have been in the news recently, mainly due to two separate articles published in The New England Journal of Medicine and Diabetes Care.

Nissen and colleagues¹ published meta analysis of 42 trials which showed a significant increase in the risk of myocardial infarction and a borderline increase in the risk of death from cardiovascular causes. Because the use of rosiglitazone is widespread, the public health impact of this is significant.

So what is cause of this increased risk of cardiovascular events? Many reasons can contribute to this

• Mean increase in LDL cholesterol
• Increased incidence of cardiac failure. A teleo-analysis in Diabetes Care shows a significant increase in cardiac failure at high and low doses and was not limited to elderly.²
• Possible reduction in haemoglobin

The ongoing trial on the effect of rosiglitazone on cardiovascular outcomes³ will hopefully give us a clear answer.

Reference List

(1) Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med 2007; 356(24):2457-2471.

(2) Singh S, Loke YK, Furberg CD. Thiazolidinediones and Heart Failure: A Teleo-Analysis. Diabetes Care 2007.

(3) Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Dargie H et al. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol. Diabetologia 2005; 48(9):1726-1735.

Percutaneous coronary intervention (PCI)vs minimally invasive coronary artery bypass grafting

A recent meta-analysis in British Medical Journal¹compared the outcomes between minimally invasive left internal thoracic artery bypass and percutaneous coronary artery stenting as primary interventions for isolated lesions of the left anterior descending artery (LAD). The outcomes from 12 studies were analysed.

For isolated lesions of LAD, minimally invasive left internal thoracic artery bypass proved to be have less complications in the mid term. There was no significant mortality difference between the two groups.

A cost effective analysis was also published by the same investigators² which suggested that the minimally invasive left internal thoracic artery bypass may be more cost effective in the medium and long term.

On the face of it, there appears to be a clear advantage for CABG, but other factors need to be considered.

Even though drug eluting stents have revolutionised interventional cardiology, the meta-analysis has not included studies with these newer stents. It is unlikely that the drug eluting stents will match the survival benefits of CABG and brings with them the additional problems of late stent thrombosis and long term anti thrombotics. Prof. Westaby and colleagues have noted that minimally invasive CABG is rarely performed in the UK and the costs calculation was more reflective of the economics 10 years ago.³

So where do we stand regarding the debate of PCI vs CABG.

For proximal LAD lesions minimally invasive CABG results reduced re-intervention and event rates but no mortality benefit. So patient’s choice will play a significant role. Many patients will still prefer a less invasive PCI strategy.

In those patients having multivessel disease with left main stem lesion, CABG offers reduced re-intervention rates and marginally better survival. Ongoing Syntax trial will hopefully provide the answers regarding which is a clearly better strategy.⁴

References

(1) Aziz O, Rao C, Panesar SS, Jones C, Morris S, Darzi A et al. Meta-analysis of minimally invasive internal thoracic artery bypass versus percutaneous revascularisation for isolated lesions of the left anterior descending artery. BMJ 2007; 334(7594):617.

(2) Rao C, Aziz O, Panesar SS, Jones C, Morris S, Darzi A et al. Cost effectiveness analysis of minimally invasive internal thoracic artery bypass versus percutaneous revascularisation for isolated lesions of the left anterior descending artery. BMJ 2007; 334(7594):621.

(3) Westaby S, Channon K, Banning A. A sterile debate. BMJ 2007; 335(7611):111.

(4) Ong AT, Serruys PW, Mohr FW, Morice MC, Kappetein AP, Holmes DR, Jr. et al. The SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) study: design, rationale, and run-in phase. Am Heart J 2006; 151(6):1194-1204.

Should COURAGE trial change our practice?

The COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) Trial was a multi centre randomized trial involving 2287 patients who had objective evidence of myocardial ischaemia and stable coronary artery disease at 50 U.S. and Canadian centers. Study period was between 1999 and 2004. 1149 patients underwent PCI with optimal medical therapy (PCI group) and 1138 to receive optimal medical therapy alone (medical-therapy group). The primary outcome was death from any cause and nonfatal myocardial infarction during a follow-up period of 2.5 to 7.0 years (median, 4.6).

The incidence of primary events in the PCI group was 211 compared with 202 in those prescribed medical treatment alone,(no statistical significance). The median cumulative primary event rates were 19.0% in the PCI group compared with 18.5% for medical treatment (hazard ratio (HR) for the PCI group 1.05, 95% CI 0.87 to 1.27; p = 0.62). No significant differences were seen between the two groups in the composite of death, myocardial infarction and stroke, PCI vs medical treatment, respectively (20% vs 19.5%, HR = 1.05, 95% CI 0.87 to 1.27; p = 0.62), hospitalisation for acute coronary syndrome (12.4% vs 11.8%, HR = 1.07, 95% CI 0.84 to 1.37; p = 0.56) or non-fatal myocardial infarction (13.2% vs 12.3%, HR = 1.13, 95% CI 0.89 to 1.43, p = 0.33).

The authors concluded that as an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, myocardial infarction or other major cardiovascular events when added to optimal medical treatment.


So should this study lead to a reduction of percutaneous coronary intervention in clinical practice? To decide this, a number of limitations of the study should be considered.

• Of the 35,539 patients screened more than 91% were excluded. How much can we generalize the findings?
• Most of the patients received only bare metal stents >97%. At least 50% of current practice involves drug eluting stents.
• 10% were lost to follow up in both arms. Was it due to mortality? we don't know.
• In the medical treatment arm 32.6% required revascularisation by the median 4.6 years of follow-up and in the PCI arm 21.1% underwent a further revascularisation procedure.
• At least 43% had very little symptoms. In practice most patients undergo PCI for difficult to control symptoms.

Reference List

1 Franklin BA. Lessons Learned From the COURAGE Trial: Generalizability, Limitations, and Implications. Prev Cardiol 2007;10(3):117-20.

2 King SB, III. The COURAGE trial: is there still a role for PCI in stable coronary artery disease? Nat Clin Pract Cardiovasc Med 2007 Aug;4(8):410-1.

3 Boden WE, O'Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007 Apr 12;356(15):1503-16.

4 Boden WE, O'Rourke RA, Teo KK, et al. The evolving pattern of symptomatic coronary artery disease in the United States and Canada: baseline characteristics of the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial. Am J Cardiol 2007 Jan 15;99(2):208-12.