What Does ‘Best Medical Therapy’ Really Mean?

What has changed? 

During the last 20 years, major advances have been made regarding medical therapy (antiplatelet, statin, and hypertension) alongside changes in lifestyle (e.g. greater emphasis on smoking cessation). These have to be considered when planning the management of patients with carotid disease. For example, it is an indisputable fact that hypertension is now managed much better than 20 years ago with treatment goals set at stricter blood pressure thresholds than those advocated in the 1980s. Statin therapy, perhaps the single most important pharmacological advance in cardiovascular risk factor management was not available when ECST, NASCET and ACAS were recruiting. Even in the recently published ACST trial, only 30% of patients were on statin therapy when they were randomised.4 Third, there are now several new classes of antiplatelet agent some of which when administered as ‘dual’ therapy confer enhanced benefit. Accordingly, not only is there is the potential for offering improved antiplatelet activity, but there are now also therapeutic alternatives to the 10% of patients with aspirin intolerance or resistance.

Rapid access ‘best medical therapy’? 

Emerging evidence suggests that carotid endarterectomy (CEA) confers maximum benefit if it is performed within 2 weeks of onset of symptoms.5 However, few observers have considered whether rapid implementation of ‘best medical therapy’ could have just as beneficial an effect. This is largely because most clinicians believe that there is an inevitable ‘lag phase’ (lasting many months) before medical therapy can take effect. The potential importance of starting medical therapy as soon as possible was highlighted in the recently published Express Study.6 Here, the 90-day stroke rate was reduced from 10.2% to 2.1% as a consequence of simply changing clinical practices so as to minimise delays in assessment, investigation and treatment of patients with symptomatic cerebral vascular disease (Fig. 1). Medical therapy (aggressive antiplatelet, statin and anti-hypertensive therapy) was instituted in the majority of cases within 24 hours of onset of symptoms. Although this strategy also reduced delays to CEA, approximately 85% of the observed reduction in recurrent stroke was attributed to the fact that ‘best medical therapy’ had been instituted as soon as possible.6

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Fig. 1 90 day risk of stroke following presentation of initial TIA or stroke. “Before” Refers to previous treatment algorithm, “After” refers to new practice to expedite assessment and start ‘best medical treatment’.

Surgeons and ‘best medical therapy’ 

Why is it so important for the vascular surgeon/specialist to be aware of the value of improvements in medical therapy in patients with carotid stenosis? First of all, having any kind of atherosclerotic disease (coronary, cerebrovascular, renovascular, mesenteric or peripheral) indicates that there is a systemic effect on the arterial system. In other words, the patient with carotid disease is not only at risk of stroke but also of myocardial infarction and other ischemic complications. In reality, the annual risk of death/myocardial infarction is much higher than that of ipsilateral stroke in patients with asymptomatic carotid stenosis.1, 2, 7 The risk of any atherosclerotic complications (vascular death, myocardial infarction & stroke) may be as high as 7–10% per year or more.8 Put simply, it is no use simply treating a carotid stenosis by surgery or angioplasty to the exclusion of all other aspects of care.

“Best medical treatment” can be an overused and over-simplified term. This paper will review new and emerging data from the literature, predominantly relating to antiplatelet and statin therapy. All of the data and recommendations regarding medical therapy in patients with carotid disease are derived from general studies on stroke prevention, atherosclerosis prevention and (wherever possible) primary and secondary analyses from stroke prevention studies involving patients with carotid disease.

(1) Symptomatic patients with carotid stenosis 

Aspirin has been shown to reduce the risk of stroke in patients with previous cerebrovascular symptoms (TIA or stroke). The latest meta-analysis from the Anti-thrombotic Trialists Collaboration reviewed 21 placebo controlled trials (including more than 22,000 patients with previous stroke or TIA) and found that treatment with an anti-platelet agent resulted in a 22% relative risk reduction (RRR) in the combined end-point of vascular death, myocardial infarction and stroke.9 Fig. 2 summarises the principle benefits conferred by three years of antiplatelet therapy in patients who had initially presented with TIA or stroke. This meta-analysis also reviewed studies looking at different aspirin doses and observed that 75–150mg daily was just as effective as higher doses, but with fewer side effects.

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Fig. 2 Effect of antiplatelet agents on non-fatal myocardial infarction (MI), non-fatal stroke, vascular death and any death in patients with previous stroke or TIA. Bars indicate incidence in percent (mean duration of treatment 3 years).9

Several contemporary studies have also evaluated the role of alternative and/or dual antiplatelet therapy regimes. The CAPRIE Study compared aspirin 75mg daily with clopidogrel 75mg daily.10 This trial randomised more than 19,000 patients with atherosclerotic disease and demonstrated an 8.7% RRR in the combined endpoint of vascular death, myocardial infarction and stroke favouring clopidogrel. The benefit in the subset of patients with a prior history of cerebrovascular disease was similar to that of the overall, intention-to-treat population. Interestingly, patients who at randomisation had reported symptoms from more than one vascular territory (e.g. coronary, cerebrovascular and/or peripheral arterial) appeared to gain greater benefit (22% RRR).

The European Stroke Prevention Study compared aspirin to placebo, dipyridamole to placebo, aspirin+dipyridamole to placebo and aspirin alone in patients with recent stroke or TIA.11 Aspirin on its own conferred an RRR of 18% in late stroke, as compared with 16% for dipyridamole alone. The maximum benefit, however, was seen in patients randomised to combination therapy (RRR in stroke=37%).

The CHARISMA trial compared Aspirin and Clopidogrel against aspirin alone in patients with symptomatic atherosclerotic disease and those asymptomatic patients with risk factors.12 Analysing all of the patients on an intention-to-treat basis showed a non-significant 7% RRR in the risk of future ischemic events (death, myocardial infarction, and stroke). However, a secondary analysis comprising only symptomatic patients from CHARISMA revealed a 12% RRR in favour of combination therapy which just reached statistical significance.

Based on the available evidence in symptomatic patients (and without knowledge of whether they did or did not have carotid stenosis), the following recommendations can be made with reasonable certainty in symptomatic patients:

(2) Asymptomatic patients with carotid stenosis 

It is much more difficult to make recommendations based on evidence in this category of patient as they have never been subjected to scientific scrutiny. Accordingly, some have suggested that primary prophylaxis (with aspirin) may not be appropriate in every patient because the prevalence of side-effects may outweigh any clinical benefit.13 However, patients with asymptomatic carotid disease have proven atherosclerosis and a rate of ischemic events that exceeds the rate observed in persons without carotid disease.7 The European Stroke Initiative currently recommends anti-platelet therapy in patients with asymptomatic carotid disease (primarily) for the prevention of cardiac events.14

How to provide secondary prevention 

There are many types of lifestyle clinic, most linked with a service to ensure that ‘best medical therapy’ is also delivered to the patient. The following is a summary of how such a service is organised and implemented in Copenhagen. As will be seen it involves close co-operation between nurses and vascular surgeons.

The typical patient course is as follows. A newly referred patient with stroke/TIA (or aneurismal/peripheral vascular disease) is seen by a consultant who evaluates the patient's symptoms and considers whether an intervention is appropriate. Irrespective of this judgement, the patient's medication is reviewed. The nurses ensure that all patients are prescribed at least 40mg simvastatin and 75mg of aspirin. If the patient has high levels of LDL cholesterol a more potent statin may be used from the outset. The patient is then questioned about life style and given information about which modifications should be made. Thereafter, a decision is made as to whether the patient would benefit from our attending the rehabilitation clinic. This will obviously depend on which medical disciplines are already involved. For example, most diabetic/cardiac patients already attend specialist clinics and risk-factor control etc can therefore be devolved to them, thus avoiding duplication of effort. However, if the patient is not attending other clinics and if the patient is motivated, he/she is offered the chance to participate. This initiative involves a minimum of 4 visits including one at 6 weeks, 3 months, 6 months and then 1 year. On each occasion, smoking cessation advice is given and medical therapy reviewed. If blood tests show a need for an increase in dose or a change in the type of statin, the clinic nurse ensures that this happens. Using this approach, approximately 90% of patients will be taking platelet inhibitors and statins by the 2nd visit and cholesterol levels are (on average) 0.5mmol/l below national treatment targets which means that approximately 80% of patients are reaching their target. A fuller description of the methodology and results from this lifestyle service has been described in detail elsewhere.27

How might new improvements in ‘best medical therapy’ affect the evidence from the surgical trials upon which we currently base management decisions? 

As mentioned in the introduction, the trials that established that CEA conferred significant benefit were largely undertaken in an era when much of what now constitutes ‘best medical therapy’ was unavailable. Accordingly, it might not be unreasonable to speculate that were the trials to be repeated, the number of strokes observed in the medical limb of the trials would be significantly fewer. Accordingly, if one assumed that improved, modern medical care resulted in a 40% RRR in the risks of stroke observed in the medical limbs of the symptomatic and asymptomatic trials, most of the significant benefits conferred by CEA would probably disappear. This 40% figure is not unreasonable as statin therapy alone might be expected to confer a 30% RRR in the rates of stroke observed 20 years ago.

As a consequence, the available evidence from ECST, NASCET, ACAS and ACST is outdated and it is inappropriate to continue to uncritically extrapolate data to justify practice in the modern era. To this author, at least, any new trial comparing CEA with angioplasty (especially in asymptomatic patients) should also include a medical treatment limb.