Secondary Prevention of Cardio-Vascular Disease

• NZ Guidelines Group

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• Overview

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• Treating to New Targets (TNT) trial
• Supports a lower LDL cholesterol target in stable coronary artery disease
• Comparison of the TNT trial with selected studies
• Apo B in TNT and IDEAL

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• PROVE IT
• Supports more intensive lipid lowering after acute coronary syndromes

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• Looking Beyond LDL
• Apolipoprotein-B and A1
  
  • Notes from ASEANZ 2009
  • Apo B in TNT and IDEAL
• HDL Cholesterol
• Non-HDL cholesterol Levels
• CRP in the PROVE IT trial

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• Diabetes
• New targets for management- notes from ASEANZ 2009
• Controversies- notes from ASEANZ 2009
• Macrovascular complications- more than just HbA1C- notes from ASEANZ 2009

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• Supplements
• Folic Acid

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• South Asians
  • Optimal Risk Factor Status for South Asians for Secondary Prevention
  • BMI measurement leads to underestimation of obesity

Comparison of TNT with Other Trials

To try to put the findings of the TNT trial in perspective, it is of interest to compare the benefits in terms of reduction of risk of myocardial infarction or death due to coronary heart disease in a number of primary and secondary prevention trials Not all landmark trials are included in the table below. All studies used statins vs placebo, except for the TNT trial which compared low dose vs high dose atorvatation

In the ASCOT trial, a trial comparing two different anti-hypertensive strategies, participants were further randomised to atorvastatin 10mg or to placebo. The participants had total cholesterol levels less than 6.5 mmol/l, and average total cholesterol levels of only about 5.5 mmol/l. The trial was stopped early because of the clear benefit obtained from atorvastatin therapy. Undoubtedly, the magnitude of the benefit would have been greater if the trial had continued for about five years.

When one examines the absolute risk risk reduction (in ASCOT and TNT), we might wonder which is more cost-effective:

• treat eight patients with atorvastation 10 mg daily (seven "high risk" hypertensives for primary prevention and one patient for secondary prevention provided LDL cholesterol levels are about 2.5mmol/l), a potential minimum 8.4% absolute event rate reduction over five years, or
• treat one patient for secondary prevention with atorvastatin 80mg daily to lower LDL cholesterol to 2.0mmol/l instead of 2.5mmol/l, a potential 1.6% absolute event rate reduction over five years.

I suspect most would regard the first option as being more cost-effective, yet NZ's lipid guidelines would almost certainly not recommend lipid modifying therapy for the hypertensives enrolled in the ASCOT trial.

Of course, if atorvastatin 80 mg daily costs only one and half times as much as atorvastatin 10mg daily, then both options may be equal in cost-effectiveness.

To allow comparison of different trials, the event rates for myocardial infarction or death due to coronary heart disease are presented in the table. The magnitude of benefit from lipid modifying therapy is greater when one takes into account the reduction in stroke and in need for coronary revascularisation.

It has been suggested that high-dose statins may produce benefit from mechanisms of action other than lowering of LDL cholesterol. If this is so then high dose atorvastatin may be superior to the combination of ezetimibe with simvastatin.

Whether other markers will aid the selection of patients for more intensive therapy is also an area of debate. Potential markers that might be used include apo-B, highly sensitive CRP levels, and soluble CD40 ligand. A further analysis of the PROVE-IT trial suggests that those patients that attained the dual goals of LDLC <70mg/dl (1.8mmol/l) and hs-CRP<2mg/l had the best outcome. Those patients treated with high dose atorvastatin were more likely to attain the hs-CRP target. Ideally, there will be prospective validation of this finding.

Reference:

• ASCOT Investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361: 1149–58.


• PROVE IT-TIMI 22 Investigators. Intensive versus Moderate Lipid Lowering with Statins after Acute Coronary Syndromes. N Engl J Med 2004;350:1495-504.