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Canadian Cardiovascular Congress 2006

Vancouver, British Columbia / October 21-25, 2006

According to Dr. John Deanfield, Professor of Cardiology, University College, London, UK, early risk factor modification before patients become symptomatic from cardiovascular disease (CVD) would be far more beneficial and cost-effective in the lifetime management of atherosclerosis than offering aggressive and expensive strategies when patients present with late-stage manifestations of the disease. “If you just treat symptomatic patients, you will miss the opportunity to treat a large number of people who are going to get into trouble and die from this disease outside the medical system,” he remarked. Approximately 60% of men and 40% of women will die of either a myocardial infarction (MI) or sudden death as their first presentation of atherosclerotic disease.

The proposal that atherosclerosis has a wide preclinical window is not new: intravascular ultrasound (IVUS) studies have confirmed the early onset of atherosclerosis in the coronary circulation.

The findings have shown that lesions build up in coronary arteries not by encroaching on the lumen of the artery—which they do very late in the disease, as Dr. Deanfield noted—but by expanding the arteries outwards for decades, a disease process not visualized on angiography. Importantly, autopsy studies confirm that over 85% of individuals ³50 years of age who died of non-CVD causes had significant atherosclerosis in their arteries.

The Case for Early Intervention

Another argument in favour of a “lifetime management” strategy is the interaction between classical risk factors and the arterial wall that occurs from the earliest stages of the disease. As Dr. Deanfield observed, should an individual reach the age of 50 with all the risk factors in “good shape,” that individual has approximately a 5% chance of having a stroke or MI in the next 25 years or so. Conversely, if the same individual reaches the age of 50 with two or more risk factors in less than “optimal shape,” they have a 69% lifetime risk of experiencing a CVD end point. “Preclinical interactions between risk factors and the vessel wall have a crucial role to play in driving eventual CV outcome,” he observed. Guidelines for lipid interventions and target lipid levels are helpful, but they are predicated short-term (10-year) estimates of CVD event risk and are often substantially lower than a patient’s lifetime risk.

Statin therapy has helped reduce CV event rates in adults who appear to be at risk or who have clinical evidence of CVD. Yet as Dr. Deanfield remarked, “They only reduce risk by 30% because we are introducing treatment for these risk factors too late in the natural history of this disease.” If the same agents were introduced at the age of 40 instead of 70, “you’d likely have more than twice the benefit from earlier intervention,” he added. “Early intervention leveraged late gains.” (Figure 1)

Figure 1. Benefit from Earlier Intervention

Dr. Deanfield characterized the economic impact of treating symptomatic coronary artery disease (CAD) as “staggering,” with the lion’s share of expenditures going towards the management of late clinical manifestations of atherosclerosis rather than targeting risk factors that drive disease evolution. The very risk factors that drive coronary manifestations of atherosclerosis are eminently modifiable, as the INTERHEART study showed (Lancet 2004; 364(9438):937-52). In the study, the strongest predictor of MI globally was the ApoB:ApoA1 ratio, followed by smoking and stress. Indeed, INTERHEART demonstrated that nine potentially modifiable risk factors accounted for 90% of the acute MIs in men and 94% of acute MIs in women (Figure 2).
able CVD Risk Factors

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“You’ve got to invest in your arteries just like your pensions,” Dr. Deanfield emphasized. “We know a lot about what is driving this disease and we have to tailor our approach to reduce associated morbidity and mortality from it. Otherwise, increases in risk factors in the overall population threaten to overcome all the improvements we’ve made in clinical practice in the past.”

Lifestyle Modification Pivotal

Dr. Jean-Claude Tardif, Director, Research Centre, Montreal Heart Institute, Quebec, emphasized that all CVD risk reduction should not rely solely on pharmaceutical intervention. Pivotal to reducing risk is lifestyle modification, as there is considerable evidence that changes in diet quality and quantity, increased physical activity and especially smoking cessation all exert a major impact on CVD event risk. However, the biggest challenge in initiating lifestyle change remains patient motivation.

According to Dr. Nigel Flook, Associate Clinical Professor of Family Medicine, University of Alberta, Edmonton, the right attitude is key. “We need to ask patients what their agenda is and what their priorities are and avoid the impulse of telling them what to do,” he emphasized. Physicians also need to assess at which stage patients are: pre-contemplation, in denial, prepared to act but don’t know how, action phase, maintenance phase or relapse. “By listening to what patients say and by asking open-ended questions, they will tell you where they are,” Dr. Flook explained.

Physicians can also move patients forward to the next stage by helping them identify and appreciate the personal benefits they will derive from making specific lifestyle changes, as well as identifying any barriers that may prevent them from actually going forward towards behavioural modification. Patients themselves need to be both convinced that the change they have to make will be worth it and confident that they can effect that change. According to Dr. Flook, what seems to work best is to try to get patients to identify how they would personally benefit from making a lifestyle change in a very tangible, practical way.

Smoking Cessation

The motivation to make any lifestyle change may be intensified with proper medical counselling but with a very challenging change such as smoking cessation, medication is often needed. According to findings, the selective nicotinic acetylcholine receptor partial agonist varenicline appears to significantly improve abstinence rates in recent quitters.

In one randomized controlled trial cited by Dr. Tardif, 1927 smokers were treated for 12 weeks with open-label varenicline, titrated to 1 mg b.i.d. Results showed that 64.1% did not smoke, use tobacco or nicotine replacement drugs during the last week of treatment. Of these, approximately one-third were randomized to additional treatment or placebo for another 12 weeks and then followed for 52 weeks after treatment initiation.

The main outcome measure was a carbon monoxide-confirmed continued abstinence out to week 24 and from weeks 13 to 52 of the study. During weeks 13 to 24, abstinence rates were significantly higher at 70.6% for varenicline patients compared with 49.8% for pl
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Figure 3. Rates of Maintenance of Abstinence

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For weeks 13 to 52, abstinence rates were also higher at 44% for varenicline recipients vs. 37.1% for placebo controls (P=0.0126). There was also no difference in adverse events between active treatment and placebo during the double-blind period of the trial.

“We are all struggling as practicing physicians to effect significant change in our patients,” Dr. Flook stated, “but if we can find strategies to help patients overcome barriers to change, that will increase their confidence to make that change.”

Updated Lipid Guidelines

Speaking on behalf of the Canadian working group who developed new lipid guidelines for 2006, Dr. Ruth McPherson, Professor of Medicine and Biochemistry, University of Ottawa, Ontario, acknowledged that “we’ve been a bit short-sighted only focusing on short-term risk.” Nevertheless, the updated guidelines advocate lower targets for both LDL-C as well as the total cholesterol (TC):HDL-C ratio (TC:HDL-C). For patients with established vascular disease or type 2 diabetes, target LDL-C levels should now be <2.0 mmol/L, based on results from studies such as TNT, where high-dose atorvastatin reduced the incidence of major coronary events by 22% compared with standard dose. At the same time, the TC:HDL-C ratio should be <4 in high-risk patients, Dr. McPherson stated. Optimally, LDL-C should be reduced by at least 50% relative to baseline levels. In moderate-risk patients, physicians should intervene when LDL-C is ³3.5 mmol/L or if the TC:HDL-C ratio is ³5. For low-risk patients, intervention points are LDL-C levels of ³5.0 mmol/L and a TC:HDL-C ratio of ³6.

The new guidelines also advocate up-titration of the initial statin to maximal dose and then adding a second agent, such as ezetimibe, if patients do not achieve lipid targets. Much emphasis has been placed on how statins reduce coronary events but it should not be forgotten that they also influence cerebrovascular events as well.

Questions and Answers

This question-and-answer session was conducted with Dr. Ruth McPherson, Professor of Medicine and Biochemistry, University of Ottawa, Ontario; Dr. John Deanfield, Professor of Cardiology, University College, London, UK; and Dr. Nigel Flook, Associate Clinical Professor of Family Medicine, University of Alberta, Edmonton, during the scientific sessions.

Q: How do genetics influence traditional CV risk factors?

Dr. McPherson: Most risk factors are in part genetically determined, so a Framingham 10-year risk score should be doubled in patients with a positive family history; in other words, early-onset CAD in first-degree relatives under the age of 55 in men and under the age of 65 in women.

Q: Do you think treatment guidelines which use 10-year CVD risk as a way to risk-stratify patients are undermining the benefits that appear to accrue with earlier intervention?

Dr. Deanfield: Yes, the standard types of risk factor assessment prejudice us against the treatment of young patients with risk factors at an early stage of their disease because age is the biggest driver of absolute risk. For example, the statins have been miracle drugs in reducing CVD risk, yet we’re still rather disappointed with the statins because despite their widespread use, they only reduce CVD risk by about 30%. The truth is that we are introducing treatment for these risk factors too late in the natural history of this disease—the longer you treat, the better the results.

Q: Young smokers may not realize they are at risk for CVD events. How do you encourage them to quit?

Dr. Flook: You need affective content; you need to have them explore the personal benefits of doing something like quitting smoking and why it will be meaningful for them personally. For example, young smokers appreciate the fact that their new outfit or their breath won’t smell like smoke.