Does the Preventive Effect of Different Drugs Depend on Location of the Atherosclerotic Process?
By Poredos, P Jeiovnik, M K
Atherosclerosis can affect nearly any part of the arterial system. Therefore, it is considered as a generalized disease. As most probably similar or identical etiopathogenetic mechanisms are involved in different atherosclerotic diseases, a different effect of treatment of risk factors on atherosclerotic lesions in different parts of the vascular system is expected. Until now, great emphasis has been placed on the aggressive pharmacological management of coronary artery disease, less attention has been devoted to the management of cerebruvascular and much less to peripheral arterial disease, despite their significant morbidity and mortality. The data from recent trials have indicated that treatment of patients with antiplatelet drugs, statins, antihypertensive and antidiabetic drugs prevents the progression of coronary atherosclerosis, reduces cardiovascular events and improves prognosis of coronary patients. Subgroup analyses from large studies have also shown that treatment of risk factors for atherosclerosis with drugs reduces cardiovascular events and improves prognosis of cerebrovascular and peripheral arterial occlusive disease. Although some studies indicate that the effects of distinct preventive procedures are to some extent dependent on the locations of atherosclerotic disease, it seems that the success of preventive measures is mostly related to the progression of the disease or the risk of treated population and not on the treated vascular bed. [Int Angiol 2008;27:274-80]
Key words: Coronary artery disease – Cerebrovascular accidents – Peripheral vascular diseases – Risk factors – Atherosclerosis, prevention and control.
Atherosclerotic cardiovascular disease, in all its clinical manifestations, represents the leading cause of disability and mortality throughout much of the industrialized world. It encompasses a broad spectrum of disease conditions of the circulatory system that include coronary heart disease (CHD), cerebrovascular disease (CVD) and peripheral arterial disease (PAD). Epidemiological studies have identified several risk factors for atherosclerotic disease, including hypertension, hyperlipidemia, smoking, diabetes, obesity and physical inactivity.1 Therefore, treatment of risk factors and life style modification play the key role in prevention of atherosclerotic disease and its complications. Preventive measures, including pharmacotherapy, are important not only because of their impacts on morbidity and mortality rates, but also on the quality of life. In the last decade, the data from trials and subgroup analyses have indicated that treatment of patients with antiplatelet drugs, statins and ACE inhibitors prevents the progression of local disease, reduces accompanied cardiovascular events and improves prognosis of coronary, cerebrovascular and peripheral arterial occlusive disease.2,3 However, it remains an unanswered question if all these measures have similar effects in different vascular territories.
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 CVD and much less to PAD, despite their significant morbidity and mortality. According to similar or identical etiopathogenetic mechanisms, the positive effects of treatment of risk factors on atherosclerotic lesions in different parts of the vascular system are expected. However, there are some data that the effect of drugs used in prevention of cardiovascular disease is to some extent dependent on different locations of atherosclerotic disease.4
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 135 000 patients, who had clinical evidence of cardiovascular disease, showed that antiplatelet drugs significantly reduce the risk of non- fatal myocardial infarction, ischemic stroke, and death from vascular causes.4 The principal conclusion was that antiplatelet drug therapy reduced the risk of cardiovascular events from 13.2% in the control group to 10.7% in the treated group. The greatest benefit was found in coronary patients: acute myocardial infarction 30%, stable angina pectoris 33% and unstable angina pectoris 46% of relative risk reduction (RRR). Antiplatelet treatment also significantly reduced recurrent ischemic stroke (22% RRR), but acute stroke was reduced only by 11%. Among patients with PAD, there was a reduction of 23% in serious vascular events, with similar benefits in patients with intermittent claudication, those having peripheral grafting and those having angioplasty (Table I).
These results indicate that the effect of aspirin is different in different atherosclerotic diseases and also between subgroups of patients with the same atherosclerotic disease (e.g. coronary). Therefore, it seems that the protective effect of aspirin predominantly depends on the stage of the dis ease and not on the location of the atherosclerotic process. The greatest effect was shown in patients with the highest risk, which is most probably related to the structure and not to the location of atherosclerotic lesions.
Clopidogrel is the next frequently used antiplatelet drug in secondary prevention of atherosclerosis. In the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study,5 75 mg of clopidogrel were compared with 325 mg of ASA in more than 19 000 patients with recent myocardial infarction, recent ischemic stroke or PAD. The primary outcome, a cluster of ischemic stroke, myocardial infarction or vascular death was slightly lower in the clopidogrel group (9.8%) than in the ASA group (10.7%). In the CAPRIE trial, there were differences in the treatment effect among patients with different atherosclerotic diseases. Preventive effect was most expressed in the patients with PAD, the primary end point occurred at an annual rate of 4.9% in patients given aspirin, and 3.7% in patients given clopidogrel, an adjusted risk reduction (ARR) of 23.8%.
However, although clopidogrel is recognized 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 costs-clopidogrel has not been accepted as superior by regulatory authorities.
In conclusion, aspirin is effective in prevention of atherosclerotic cardiovascular events in all three most frequently affected vascular beds, but the highest efficacy of aspirin was indicated in the coronary bed, predominantly in coronary patients with the highest risk (unstable angina pectoris). Low doses of aspirin (up to 100 mg) are as effective as higher. Low doses of aspirin remain the first-line antiplatelet drug for prevention of coronary, cerebral and peripheral atherosclerotic events and clopidogrel as its effective alternative. Clopidogrel could be more effective than aspirin in highrisk patients with advanced atherosclerosis, as for example in PAD patients who typically have systemic atherosclerotic disease.
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.
Coronary artery disease and statins
Different relevant randomized controlled trials demonstrated that statin therapy in of utmost importance for patients with ischemic heart disease.6-8 A meta-analysis of 38 primary and secondary prevention trials found that for every 10% reduction in total cholesterol, CHD mortality decreases by 15% and total mortality by 11%.9 Therefore, there is no more doubt that statins prevent and improve prognosis of CVD. The data from the latest secondary prevention studies indicate that statin treatment also prevents cardiovascular events in patients with non-coronary atherosclerotic disease. The Heart Protection Study (HPS)1 the largest statin trial, compared simvastatin, 40 mg daily, with placebo in 20 536 patients.10 Simvastatin reduced total mortality by 13% (14.7% to 12.9%). 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. Myocardial infarction and stroke were significantly lower in the simvastatin group compared with placebo (8.7% vs 11.8% and 4.3% vs 5.7%, respeclively). In the subgroup of patients with peripheral artery disease only, the reduction in major vascular events was similar (P<0.0001). Therefore, 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 1 000 patients with CHD, and 70 events in 1 000 patients with PAD or CVD. The results of this very large and randomized trial support the use of the statins in patients without CAD, but other arterial disease.
The preventive effect of statins on CHD and stroke was also confirmed in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA).1! Non-fatal myocardial infarction including silent myocardial infarction, and fatal CHD was significantly lower by 36% and fatal and non-fatal stroke by 27%. However, the effect of statin on PAD did not significantly differ from that of placebo. Cerebrovascular disease only and lipid- lowenng therapy
The involvement of cholesterol in CVD and the effects of its lowering were intensively investigated in the last decade. Despite the relatively weak association between total serum cholesterol concentrations and stroke risk derived from observational data, there is no longer any doubt that statins prevent ischemic stroke. Randomized trials of statin use have shown, on average, significant reductions in stroke events in both primary and secondary prevention to 31% in all strokes, an effect which in relative terms is similar to its effects on the incidence of CAD.12 Only in the Prospective Study of Prevention in the Elderly at Risk (PROSPER)13 among patients treated with pravastatin aged 70 years and older, no reduction in strokes was noted. However, in a post-hoc analysis of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)14 data, stroke prevention was similar among 2416 patients who were older than 70 years and the remainder aged 70 years or younger (31 % vs 24% reduction). In previous trials no effect on stroke recurrence in pre- existing CVD was shown during statin treatment. However, recent Stroke Prevention by Aggressive Reduction in Cholesterol Level (SPARCL) trial confirmed benefit of statin treatment in this population.15 Treatment of patients with prior stroke or transient ischemic attack and no evidence of CHD with atorvastatin 80 mg per day was associated with significant ( 16%) relative reduction in risk of recurrent stroke. Unfortunately, there is no doubt that statin does not prevent hemorrhagic stroke. Some publications even indicated that statin treatment increases the risk for hemorrhagic stroke. These observations have raised the hypothesis that low cholesterol levels may lead to an increased susceptibility of the intracerebral arteries to shear stress and hemorrhagic stroke.16 However, several prospective studies confirmed that low cholesterol levels in serum are unlikely to lead to weakness of the intracerebral arteries and thus to be associated with hemorrhagic stroke. Accordingly, there is no reason to limit lipid-lowering therapy, since the risk, if any, only seems to affect those individuals with very low serum levels of cholesterol. Even in these subjects, the possible increased risk of hemorrhagic stroke will be outweighed by the benefits resulting from reducing the risk of CAD.
Peripheral arterial disease and lipid-lowering therapy
There are more and more data which indicate that lipid-lowering therapy might also prevent PAD itself. For example, in the Cholesterol Lowering Atherosclerosis Study (CLAS),17 angiographic assessment revealed that lipid-lowering treatment with colestipol and niacin achieved more atherosclerotic regression and less atherosclerotic progression in the femoral arteries than placebo.
The effect of dyslipidemic therapy on intermittent claudication was also investigated in two lipidlowering trials. In the Lipid Research Clinics Coronary Primary Prevention Trial,18 cholestyramine achieved a 15% reduction in claudication risk compared with placebo. In the Program on the Surgical Control of Hyperlipidemia,19 an ileal bypass, which results in an aggressive reduction of lipid levels, produced a 27% reduction in claudication risk. Retrospective analysis of data from the Scandinavian Simvastatin Survival Study (4S) supports these findings.20 It was demonstrated that over the median follow-up period of 5.4 years, the risk of new or worsening intermittent claudication was reduced by 38% in the simvastatin group compared with the placebo group.
In PAD patients statins probably had some additional, hemodynamic effects, and independently of cholesterol reduction improved the quality of life in those patients. In the Treatment of Peripheral Atherosclerotic Disease with Moderate or Intensive Lipid Lowering (TREADMILL) study 345 patients with intermittent claudication were treated with 80 mg atorvastatin for 12 months and prolongation of the claudication distance was registered.21 The effects of simvastatin on walking performance and symptoms of intermittent claudication in PAD patients with hypercholesterolemia were also investigated in an Italian study. They found improvement of the pain- free-walking distance in PAD patients during treatment with 40 mg of simvastatin already after 3 months.22
In conclusion, lipid-lowering therapy prevents progression of all three of the most frequent atherosclerotic diseases (coronary, cerebral and lower limb) and accompanying cardiovascular complications to a comparable extent. But no effect on hemorrhagic stroke was observed.
Angiotensin-converting enzyme inhibitors
Evidence from large population-based studies has confirmed that hypertension increases a patient’s risk of cardiovascular disease about two- to three-fold. Even after adjusting for other risk factors, the presence of borderline systolic hypertension alone increases the relative risk of a cardiovascular event by about 1.5.23 Conversely, lowering of blood pressure reduces the risk of major cardiovascular events, including coronary and cerebrovascular ones.24 In last decade, it was also shown that treatment of blood pressure including beta-adrenergic blocker therapy is effective in preventing cardiovascular events in PAD patients.25
Different antihypertensive drugs (diuretics, beta-blockers, angiotensin-converting enzyme [ACE]) have been shown to provide protective benefits. Recently ACE inhibitors are more and more frequently prescribed antihypertensive drugs. ACE inhibitors exert various beneficial actions on cardiac and vascular structure and function, beyond their blood pressure-lowering effects. Randomized, controlled clinical trials have shown that ACE inhibitors improve endothelial function, prevent cardiac and vascular remodeling, slow the anatomical progression of atherosclerosis in different regions of the cardiovascular system and reduce the risk of cardiovascular events and death.26
The antiatherogenic effect of the ACE inhibitor ramipril was confirmed in the HOPE study.27 The HOPE Study enrolled a total of 9 297 high-risk patients, older than 55 years, who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor. Ramipril provided significant protection against myocardial infarction, stroke and cardiovascular death. Another important finding of the HOPE study is that in the presence either subclinical or clinical of PAD, ACE inhibitors substantially reduce cardiovascular morbidity and mortality in the presence or absence of hypertension. The preventive effect of ramipril was in subjects with PAD (pathological anklebrachial pressure index) twice as large as in subjects without PAD, i.e. 50 vs 24 cardiovascular events were prevented per 1 000 treated patients in the 4.5 years of follow- up.28
In the EUROPA study that included more than 12 000 patients with stable coronary artery dis ease and other atherosclerotic diseases, perindopril in all subgroups of patients (coronary, cerebral, peripheral) caused about a 20% reduction of cardiovascular events.29 It was shown that about 50 patients need to be treated for a period of 4 years to prevent one major cardiovascular event.
Angiotensin receptor blockers also demonstrated cardiovascular benefits beyond their antihypertensive properties. Conditions favoring their use are type 2 diabetic nephropathy, diabetic microalbuminuria, proteinuria, left ventricular hypertrophy, or ACE inhibitor-related cough.30
In conclusion, both large studies (HOPE, EUROPA) as well as some smaller studies showed that ACE inhibitors effectively prevent cardiovascular incidents in patients with different atherosclerotic diseases (CHD, CVD and PAD). However, the effect is related to the global risk of the treated population. Therefore, in patients with multifocal atherosclerosis (like PAD) the greatest effect is expected.
Anti-diabetic medication
Aggressive treatment of diabetes reduces the risk of microvascular complications,31,32 but there is less evidence that it also lowers the risk of atherothrombotic events. Retrospective analysis of the Diabetes Control and Complications Trial in 1 441 type 1 diabetics aged 13-39 years at inclusion found that intensive insulin therapy, compared with conventional treatment, decreased the risk of combined major macrovascular events by more than 40%, i.e., 23 vs 40 events during follow-up of 6.5 years on average, but the result was not statistically significant (P=0.08).33 After 17 years of follow-up of the same cohort, the difference reached statistical significance: 46 cardiovascular events occurred in 31 patients among the intensively treated diabetics vs 98 events in 52 patients among the conventionally treated diabetics (P=0.02).34 In this trial, intensive therapy consisted of more daily injections of insulin treatment with an external insulin pump, whereas conventional therapy consisted of one or two daily injections of insulin. The United Kingdom Prospective Diabetes Study on 3 867 patients with type 2 diabetes found that treatment with sulphonylureas or insulin vs diet-based treatment significantly reduced the risk of myocardial infarction by 16%, but the effects on stroke, limb amputation or death were not significant.35 Recently, levels of hemoglobin A^sub 1c^ were found to be positively associated with the risk of PAD in diabetics and the association was graded and independent. Diabetic patients with poor glucose control, i.e. hemoglobin A^sub 1c^>7.5%, were more than 5 times as likely to develop intermittent claudication or have a hospitalization for PAD than patients with good glucose control, i.e. hemoglobin A^sub 1c^<6%.36 In addition to glycemic control, the mainstay of preventing macrovascular complications in diabetic patients is strict management of hypertension and dyslipidemia, administration of antiplatelet therapy and smoking cessation.37
In conclusion, the results of studies indicate that in diabetic patients intensive treatment of blood glucose level effectively prevents not only microvascular, but also macrovascular, atherothrombotic events. It seems that glycemic control irrespective of used dug lowers the risk of cardiovascular events related to different atherosclerotic diseases.
Conclusions
Different preventive measures are used to reduce cardiovascular events related to various manifestations of atherosclerotic disease, such as coronary, cerebrovascular and peripheral arterial occlusive disease. Information available from most clinical trials has already validated the efficacy of aggressive pharmacological management of coronary artery disease, but there are also subgroup analyses that have shown that these measures are effective in other atherosclerotic disease locations. There are some differences concerning the efficacy of distinct drugs used in secondary prevention of different atherosclerotic diseases. However, it seems that the effects are mostly related to the progression of the disease (structure and extent of atherosclerotic lesion) of the treated population and not to the location of atherosclerotic disease.
Received on October 3, 2007; acknowledged on October 4, 2007; accepted for publication November 13, 2007.
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P. POREDOS, M. K. JEIOVNIK
Department of Vascular Diseases, University Medical Center Ljubljana, Slovenia
Address reprint requests to: Prof. Dr. P. Poredos, Department of Vascular Disease, University Medical Center Ljubljana, Zaloska c. 007, SI-1000 Ljubljana, Slovenia. E-mail: pavel.poredos@kclj.si
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