Reports

Anti-diabetes Therapy Acting on the Incretin System Associated with Improvement in ß-cell Function
IL-6 Inhibition: Moving Towards Higher Remission Rates in Rheumatoid Arthritis

Optimal Risk Reduction in Diffuse Vascular Disease: Focus on Peripheral Arterial Disease

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Based on presentations from the Primary Care Today Educational Conference and Medical Exposition

Toronto, Ontario / May 8-10, 2008

Reported by:

Alan D. Bell, MD, MCFP

Humber River Regional Hospital, Toronto, Ontario

Historically, atherosclerosis was believed to be a generalized and progressive disease during which the arteries narrowed to the point where they closed off, shutting down blood flow to critical organs and triggering an acute vascular event. We now know that this is only part of the pathology behind the greatest cause of mortality worldwide. Cardiovascular (CV) events occur as a result of acute thrombus formation triggered over ruptured arterial plaque. It is the combination of plaque rupture and the formation of a thrombus within the arterial bed that leads to clinical manifestations of vascular disease, including unstable angina, myocardial infarction (MI), ischemic stroke, and worsening of peripheral vascular disease. Studies investigating culprit lesions in the coronary arteries resulting in an MI indicate that lesions most likely to rupture typically occlude less than 50% of the artery: it is not the degree of narrowing that is responsible for the acute vascular event, it is the stability of the plaque.

Thus the aim of risk reduction strategies in patients with diffuse vascular disease is to improve plaque stability and reduce thrombosis risk.

Currently, there are three distinct medical interventions that have been widely proven to achieve these goals: statins, inhibitors of the renin-aldosterone-angiotensin system (RAAS) and antiplatelet agents. As pointed out by the Canadian Cardiovascular Society (CCS) in their consensus guidelines on peripheral arterial disease (PAD) (Can J Cardiol 2005;21:997-1006), strong evidence from randomized clinical trials indicate that antiplatelet therapy, ACE inhibitors and the statins reduce the risk of future vascular events by approximately one-quarter each and their benefits appear to be independent and additive. It is therefore plausible to expect these medical interventions—together with lifestyle changes—could collectively reduce the risk of future vascular events by 75%, an observation that has enormous public health repercussions if successfully implemented.

REACH Registry

The REACH (Reduction of Atherothrombosis for Continued Health) registry reveals that risk reduction strategies are still not optimally utilized. Unlike a randomized clinical trial, a registry such as REACH tells us what real-world outcomes are in a specific patient population. REACH permits us to examine the natural history of diffuse vascular disease based on an enormous data base of 68,000 patients worldwide.

To be eligible for REACH, patients had to be at least 45 years of age and have documented disease in one of the three vascular beds. Patients were also eligible for REACH if they had multiple CV risk factors. Approximately 80% of the REACH population had manifest disease in at least one vascular bed; the remaining 20% came into REACH on the basis of multiple risk factors alone. Sixteen per cent of the symptomatic REACH registry had disease manifest in more than one vascular bed.

Coronary artery disease (CAD) was the most prominent manifestation of vascular disease in the REACH population, affecting some 45% of patients overall (Figure 1). Cerebrovascular disease affected approximately 17% of the population, while PAD affected the fewest at approximately 5%. One of the first lessons from REACH is that the distribution of CV risk factors are consistently found across all disease subpopulations. In other words, it did not matter if patients had CAD, CV disease (CVD) or PAD; the presence of known risk factors for CV disease including high blood pressure, high cholesterol levels, diabetes, obesity and smoking, were relatively evenly distributed across the three categories of disease (That said, the highest rates of hypertension were predictably among patients who had CVD, as was hypercholesterolemia among CAD patients and smoking among those with PAD). One-quarter of over 40,000 patients with CAD in REACH also had atherothrombotic disease in other vascular beds, as did 40% of those with CVD and 60% of those with PAD.

Figure 1. REACH Population Disease Characteristics


At one year, 4.2% of all REACH participants had experienced a vascular event. This translates into a 42% 10-year risk, far greater than the 20% 10-year risk considered high by the Framingham risk score.

Thus, we as clinicians should reconsider how stable patients such as those in the REACH registry really are, as they are at significant risk for a vascular event even in the short term.

The high rate of manifestations in another vascular bed in the PAD population probably reflects two realities: patients with PAD are amongst our highest-risk CV patients and we tend not to recognize PAD until diffuse vascular disease has manifest in another bed. The annual rate of the triple end point of CV death, MI or stroke in the PAD population was 5.2%. This translates into an extraordinarily high 10-year risk of 54% of having a vascular event, well above the 20% 10-year risk Framingham categorizes as high.

Regarding only the multiple risk factor population, REACH observed a 2.2% annual rate of the triple endpoint of CV death, MI or stroke. If we include hospitalization in the endpoint, the annual rate jumps to 5.3% of the same population.

Given that hospitalization for atherothrombotic events included unstable angina, a TIA or coronary artery bypass with or without stents, REACH registry patients—and those like them who we all manage—are at very real risk for vascular events and should receive prompt aggressive therapy. For patients with disease in more than one bed, one-year CV event rates were significantly higher across all disease categories than they were for patients with disease confined to a single bed. Indeed, as patients accumulated disease in an additional bed, their risk for reaching the triple endpoint roughly doubled. PAD patients were at particularly high risk to experience a vascular event over the same one-year follow-up, rivaling those with CAD for cardiac vascular events, including unstable angina and congestive heart failure.

REACH data showed that the highest event rates occurred among those whose risk factors were the least well managed. This was most prevalent in countries of Eastern Europe.

Canadian Guidelines and PAD

REACH showed us that PAD patients are among the highest risk of all vascular patients. To mitigate this risk, the first thing we can do is diagnose PAD at a stage when risk factor reduction will be more effective. Currently, approximately 27 million individuals in North America and Europe have PAD and of these, 16.5 million are asymptomatic. In other words, between 60% and 65% of PAD patients go undiagnosed as they do not present with symptomatic complaints until the disease is advanced.

To improve the diagnosis of PAD in symptomatic patients, the CCS recommends physicians take a directed history for symptoms of PAD. One very simple approach is to use the validated Edinburgh Questionnaire consisting of six questions which, when answered appropriately, can identify with 91.3% sensitivity and 99.3% specificity all patients with underlying PAD (Tabl
nburgh Questionnaire

<img1824|center>

An ABI below 0.9 is diagnostic of PAD, with values below 0.4 indicative of severe disease. The lower the ABI, the lower the survival as well, according to data presented by Diehm et al. at the European Society of Cardiology last year.

Why Focus on PAD?

Patients with PAD are at very high risk for acute vascular events. In one study (Circulation 1996;94:3026-49), 50% of PAD patients had fatal or non-fatal vascular events at five years. Another long-term follow-up of PAD patients by Criqui et al. (N Engl J Med 1992;326:381-6) showed that some 80% of patients with severe symptomatic PAD experienced fatal events by 12 years.

Given that PAD is associated with far more morbidity and mortality than is often appreciated, what can we as physicians do to reduce the risk of these hard clinical end points and improve the quality of life for our patients with PAD? Keeping in mind the diffuse nature of vascular disease, the same strategies used to reduce risk in CAD and CVD populations are entirely appropriate for those with PAD as well, with a special emphasis on smoking cessation.

The statins, RAAS inhibitors and antiplatelet therapy are the medical anchors of the overall strategy to reduce vascular risk and PAD patients should be taking all three classes of medication. For antiplatelet therapy, the CCS recommends either lifelong ASA therapy 75 to 325 mg/day or clopidogrel 75 mg/day.

There is considerable evidence supporting additional protective benefits of treating patients with diffuse vascular disease with clopidogrel over ASA alone to reduce the risk of thrombotic events. In the CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) study, for example, there was a 22.7% relative risk reduction of ischemic stroke, MI or vascular death in patients with multi-bed disease who received clopidogrel over ASA. In CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events), clopidogrel plus ASA produced a 20% relative risk reduction in MI, stroke and CV death at the end of 12 months vs. ASA alone in ACS patients, a highly statistically significant result (P=0.00009).

Although the risk of bleeding with ASA, at any given dose, plus clopidogrel is greater than with ASA alone, the actual bleeding risk is more dependent on the dose of ASA. Specifically, with regard to bleeding in the CURE trial, clopidogrel plus ASA 100 mg was safer than ASA alone at 200 to 325 mg (2.6% vs. 4% major bleeding rates).

In contrast, it is not recommended to give asymptomatic multiple-risk-factor patients dual antiplatelet therapy, as results from CHARISMA (Cardiac Arrhythmia and Risk Stratification after Myocardial Infarction) demonstrated. Patients in CHARISMA were similar to those included in the REACH registry—they had either manifest disease or multiple risk factors—all of whom received either ASA alone or ASA plus clopidogrel. Among those patients who had sustained a prior atherothrombotic event, CHARISMA showed a significant protective benefit from long-term dual antiplatelet therapy at a median follow-up of 27 months. In contrast, not only did multiple-risk-factor patients not benefit from the same dual antiplatelet strategy, but asymptomatic patients on the dual regimen had more MIs and strokes than those on ASA alone.

Non-Pharmacological Intervention

Medical therapy may be the cornerstone of risk reduction management but it must be accompanied by non- pharmacological interventions. These include dietary therapy to optimize plasma lipids, regular exercise and smoking cessation. A supervised exercise program has been demonstrated to improve claudication symptoms in patients with PAD. Patients need to be encouraged to walk with moderate intensity to the point of discomfort and beyond, rest, and then resume walking. Such an approach can be expected to provide tangible clinical benefits in as little as four weeks, reinforcing patient motivation to continue with the regimen.

Smoking cessation is more likely to be successful if associated with physician counseling and the use of pharmacologic agents, including nicotine replacement, or bupropion or varenicline. Dietary therapy can be assisted by registered dietitians with a focus on weight reduction and improved glycemic control in those with diabetes.

Summary

REACH tells us that too many of our patients with diffuse vascular disease experience an acute event within a relatively short period of follow-up. These observations argue for more aggressive risk reduction strategies in patients with CAD, CVD and PAD, as they are at risk for an event, not only in the index vascular bed but in others as well. More widespread use of proven pharmacological and non-pharmacological interventions would significantly reduce the rates of acute vascular events. As primary care physicians, we have an obligation to implement these strategies in all patients with diffuse vascular disease, regardless of where the disease is manifest.

We Appreciate Your Feedback

Please take 30 seconds to help us better understand your educational needs.