The data from clinical trials have shown that the elimination of risk factors for atherosclerosis reduces cardiovascular events and improves prognosis - not only in coronary - but also in cerebrovascular and peripheral arterial occlusive disease. There are some differences concerning efficacy of distinct drugs used in secondary prevention of different atherosclerotic disease, but it seems that the effect of drugs used in prevention of atherosclerosis is much more dependent on the total cardiovascular risk and the stage of disease, rather than on its location.
Introduction
Atherosclerosis is considered a generalised disease; therefore patients with a clinical manifestation of a particular atherosclerotic disease are likely to have concomitant preclinical or clinical atherosclerotic lesions in other vascular beds. As pathomorphological characteristics of atherosclerotic plaques in different locations are similar, most probably similar or identical ethiopathogenetic mechanisms are involved in different atherosclerotic diseases. Therefore the effect of treatment of risk factors on atherosclerotic lesions in different parts of a vascular system is to be expected.
In the last decade, the data from large clinical trials have indicated that along with antiplatelet drugs, statins and ACE inhibitors prevent the progression of local disease, reduce cardiovascular events and improve the prognosis of the atherosclerotic disease. While great emphasis has been placed on the aggressive pharmacological management of coronary artery disease, less attention has been devoted to the pharmacological management of cerebrovascular and much less to peripheral arterial disease - despite their significant morbidity and mortality.
The data from subgroup analyses of clinical trials have shown that the elimination of risk factors for atherosclerosis reduces cardiovascular events and improves prognosis, not only in coronary but also in cerebrovascular and peripheral arterial occlusive disease (1). However, there are some contradictory data showing that the effect of preventive procedures is to some extent dependent on different locations of atherosclerotic disease.
Antiplatelet drugs
In patients with proven atherosclerotic disease, antiplatelet therapy provides a significant benefit. Meta-analyses of studies of antiplatelet drug therapy - primarily aspirin - conducted by the Antiplatelet Trialists’ Collaboration (which included 139,000 patients who had clinical evidence of cardiovascular disease) showed that antiplatelet drugs reduce the risk of non-fatal myocardial infarction, ischemic stroke, and death from vascular causes (2). The principal conclusion was that antiplatelet drug therapy reduces the risk for serious vascular events from 13.2% in the control group to 10.7% in the treatment group. The greatest benefit was found in coronary patients: acute MI – 30%, stable AP- 33% and unstable AP – 46% of RRR.
Antiplatelet treatment also significantly reduced recurrent ischemic stroke (22% RRR), but acute stroke was reduced only by 11 %. Among patients with peripheral arterial disease there was a 23 % reduction of serious vascular events with similar benefits in patients with intermittent claudication, those having peripheral grafting and those having peripheral angioplasty. These results show that aspirin is effective in the prevention of atherosclerotic cardiovascular events in all three mostly affected vascular beds, however the highest efficacy of aspirin was indicated in the coronary bed.
Clopidogrel is the next frequently used antiplatelet drug in secondary prevention of atherosclerosis. In the CAPRIE study where 75mg of clopidogrel was compared with 325mg of ASA, the primary outcome, a cluster of ischemic stroke, myocardial infarction or vascular death was lower in the clopidogrel group (9.8%), than in the ASA group (10.7%). The subgroup analysis showed the most significant benefit in patients with PAD. It indicates that clopidogrel is probably most convincing in PAD (3). However, although clopidogrel is recognised as slightly more effective than aspirin in preventing major atherothrombotic events in high risk patients, the size of its benefit is statistically uncertain and – mainly due to its much higher cost – clopidogrel has not been accepted as superior by regulatory authorities. Aspirin thus remains the first-line antiplatelet drug and clopidogrel as its effective alternative.
Statins
The data from clinical trials showed that treatment with statins is effective in prevention of cardiovascular events in high risk subjects and in patients with proved atherosclerotic disease. A meta-analysis of 38 primary and secondary prevention trials found that for every 10% reduction in total cholesterol, coronary heart disease mortality decreases by 15% and total mortality by 11% (4).
Several relevant randomised controlled trials (including the Scandinavian Simvastatin Survival Study (4S), Cholesterol and Recurrent Events (CARE), and Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study) confirmed that treatment with statins significantly prevents cardiovascular complications and improves prognosis in patient with ischemic heart disease (5, 6, 7).
In the Heart Protection Study (HPS), the largest statin trial, simvastatin reduced total mortality by 13%. The benefit of simvastatin was independent of baseline cholesterol and of the magnitude of the simvastatin-induced reduction in LDL. Patients with baseline LDL <2.6 mmol/L had a similar benefit to those with baseline LDL >2.6 mmol/L (8). Subgroup analyses showed that treatment with simvastatin in all investigated groups of patients with atherosclerotic disease: coronary, cerebral and peripheral, resulted in risk reduction of cardiovascular events to a comparable extent. Five years of statin treatment prevented 100 major cardiovascular events in 1000 patients with CHD, and 70 events in 1000 patients with PAD or CVD.
There is also no more doubt that statins prevent ischemic stroke. As it was shown in HPS and 4S study, treatment with simvastatin resulted in 22 – 25% risk reduction for cerebrovascular incidents. However, no effect on stroke recurrence in pre-existing cerebrovascular disease and hemorrhagic stroke was shown during statin treatment (5, 8).
Furthermore, the data from clinical trials showed that treatment with statins prevent local progression of the disease in PAD patients. In the 4S study the simvastatin treated group worsening of intermittent claudication or its new appearance was reduced by 38 % (5).
In PAD patients during statin treatment some additional, hemodynamic effects were registered and statins, independently of cholesterol reduction, improved the quality of life in those patients.
In one of the studies, patients with intermittent claudication were treated with atorvastatin 80 mg, and the prolongation of absolute claudication distance after 12 months was registered in the group of patients treated with 80 mg of atorvastatin. The effects of simvastatin on walking performance and symptoms of intermittent claudication in PAD patients with hypercholesterolemia were also investigated by Mondillo and co-workers. They found an improvement of pain–free-walking distance in PAD patients during treatment with 40mg of simvastatin already after 3 months (10).
ACE inhibitors
Evidence from large population-based studies has confirmed that hypertension increases a patient’s risk of cardiovascular disease about 2- to 3-fold. Even after adjusting to other risk factors, the presence of borderline systolic hypertension (= 160 mm Hg) alone increases the relative risk of cardiovascular events by about 1.5. Conversely, lowering of blood pressure reduces the risk of major cardiovascular events. In one study, antihypertensive treatment reduces the risk of coronary artery disease by about 15% and cerebrovascular events by about 35% (11). It was also shown that blood pressure lowering is also effective in preventing cardiovascular events in PAD patients.
In the HOPE (Heart Outcomes Prevention Evaluation) study, ramipril significantly reduced the rates of death, myocardial infarction, and stroke in a broad range of high-risk patients (12). It was also shown that ACE inhibitors effectively prevent cardiovascular incidents in patients with different atherosclerotic diseases: CHD, CVD and PAD in similar extent.
Another important finding of the HOPE study was that in the presence of peripheral arterial disease - either subclinical or clinical - ACE inhibitors substantially reduce cardiovascular morbidity and mortality. The effect was in subjects with a pathological ankle-brachial pressure index twice as large as in subjects with normal pressure index (50 vs 24 events prevented in 1000 patients). Ramipril was effective in the presence or absence of hypertension.
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Conclusion:
Preventive measures reduce cardiovascular events and local prognosis of different atherosclerotic diseases: including coronary, cerebrovascular and peripheral arterial occlusive disease. Information available from clinical trials has mostly validated the efficacy of the aggressive pharmacological management of coronary artery disease, but there are also some studies and subgroup analyses, which have shown that these measures are effective in other atherosclerotic diseases.
There are some differences concerning efficacy of distinct drugs used in secondary prevention of different types of atherosclerotic disease, but it seems that the effect of drugs used in prevention of atherosclerosis is much more dependent on the total cardiovascular risk and the stage of disease than on its location. Undoubtedly, all preventive measures including drugs are reasonable and represent the basic option for management of different types of atherosclerotic disease.
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