EUROPA: EUropean Trial on Reduction Of Cardiac Events With Perindopril in Stable Coronary Artery Disease
Presenters: Kim M Fox, MD (Royal Brompton Hospital, London, UK) and Willem J Remme, MD, PhD (STICARES Cardiovascular Research Foundation, Rhoon-Rotterdam, The Netherlands)
The largest study ever conducted in patients with stable coronary disease has shown that the long-acting angiotensin-converting enzyme (ACE) inhibitor perindopril significantly reduces the risk of cardiovascular (CV) death and myocardial infarction (MI) in patients with stable coronary artery disease (CAD), including those with angina or a previous MI. The results of the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) were presented by the study co-chairmen, Professors Fox and Remme, and are published in the September 7 issue of The Lancet. On the basis of these results, the EUROPA investigators believe that the benefits of ACE inhibition have now been demonstrated to extend beyond their proven antihypertensive and anticardiac remodeling effects to the extent that perindopril should be considered for chronic therapy in all patients with coronary disease.
Landmark Study
EUROPA was a randomized, double-blind, placebo-controlled, multicenter trial designed to assess the long-term effects of ACE inhibition on the reduction of cardiac events in patients with proven CAD but with no evidence of heart failure. The long-acting ACE inhibitor perindopril was selected for the trial because of its documented anti-ischemic and atherogenic effects, its effect on CV remodeling, and its blood pressure-lowering effect.
EUROPA enrolled men and women aged ≥18 years with documented CAD as evidenced by:
Patients with clinical signs of heart failure, scheduled revascularization, hypotension, uncontrolled hypertension, recent use of ACE inhibitors or angiotensin receptor blockers, renal insufficiency, and raised serum potassium (> 5/5 mmol/L) were excluded from the study.
Objectives
The primary outcome of EUROPA was defined as the effect of perindopril on the combined endpoint of CV mortality, nonfatal acute MI, and cardiac arrest with successful resuscitation.
The secondary objectives were to assess the effect of perindopril in reducing the rate of the following events:
Trial Design
EUROPA had an initial run-in period of 4 weeks during which patients received 4 mg, then 8 mg of perindopril once daily to assess tolerance to maximum dose. This was then followed by a double-blind randomization to either perindopril 8 mg or placebo once daily for at least 3 years. If this dose was not tolerated, it could be reduced to 4 mg once daily. Patients were followed up at 3, 6, and 12 months and then every 6 months until the last patient included in the main study completed follow-up. Mean follow-up was 4.2 years.
Patient Population
EUROPA was an unprecedentedly large trial, with a total of 12,218 patients randomized by 424 centers in 24 European countries. Mean age was 60 years, and 85% were male (Table 1). Patient histories revealed that 62% had a previous MI, 55% had a previous revascularization, and 3.4% had experienced previous stroke/transient ischemic attack (TIA). Risk factors in these patients included a history of diabetes mellitus or impaired glucose tolerance in 12%, hypertension in 27%, hypercholesterolemia in 63%, and smoking in 15%.
Table 1. EUROPA: Baseline Patient Characteristics
EUROPA: Background Treatment
At study entry, 92% of the randomized patients were on platelet inhibitors, 62% on beta blockers, and 47.5% on statins, treatments appropriate for CAD at the time the trial was carried out (Table 2).
Table 2. EUROPA: Baseline Medication
EUROPA: Results
Significant Reduction in Primary Endpoint
Perindopril significantly reduced the combined primary endpoint of CV death, MI, and resuscitated cardiac arrest (P = .0003), with a 20% relative risk reduction (RRR) of 20% and an absolute risk reduction of 1.9% (Figure).
Figure. EUROPA: primary endpoint (cardiovascular death, MI, or cardiac arrest). RRR: 20% [95% CI, 9-29].
This beneficial effect of perindopril became apparent at 1 year of treatment and then continued to increase. It was seen across all predefined subgroups, including male/female; age ≤ 56 years, 57-65 years, and > 65 years; previous MI/no previous MI; previous stroke/TIA and no previous stroke/TIA; hypertension/no hypertension; and diabetes mellitus/no diabetes mellitus. Importantly, treatment benefit was seen in patients either on or not on lipid-lowering drugs, beta-blockers, and calcium channel blockers. Most patients were on platelet inhibitors.
Secondary Endpoints Also Reduced
Perindopril was associated with reductions in all secondary endpoints (Table 3), although not all were statistically significant (eg, the 11% reduction in total mortality). Significant reductions were seen in MI (fatal or nonfatal) (23.9%, P = .001) and heart failure (39.2%, P = .002). Even though defined as secondary, the EUROPA investigators believe that the heart failure effect is an especially significant finding.
Table 3. EUROPA: Secondary Endpoints
No Blood Pressure Effect?
As anticipated with an ACE inhibitor, a reduction in blood pressure was seen, but the small average 5/2 mm Hg reduction achieved with perindopril could not account for the reduction seen in CV events, the investigators believe. They suggest that the antiatherosclerotic properties of perindopril must also be considered in order to account for the result.
Absolute Benefits
The EUROPA investigators estimate from these results that perindopril 8 mg once a day prevents 1 CV death, nonfatal MI, or cardiac arrest among every 50 patients with coronary disease treated for 4 years. This means that for a country of 60 million inhabitants, such as the UK or France, treatment with perindopril over a 4-year period would prevent 50,000 MIs or CV deaths.
EUROPA vs HOPE
Prof. Fox noted that the EUROPA results extend those of the Heart Outcomes Prevention Evaluation (HOPE) trial, in which ACE inhibition with ramipril significantly reduced CV events in high-risk patients with coronary heart disease. There were important differences in the patient characteristics, however.
The HOPE patients were all aged ≥ 55 years, vs EUROPA, where one third of the patients were aged < 55 years. In addition, more HOPE patients had diabetes, hypertension, stroke, and obstructive peripheral vascular disease, and more used aspirin, beta-blockers, and lipid-lowering drugs. Major annual event rates were 40% to 80% higher in HOPE (Table 4).
Thus, as noted by Prof. Fox, the HOPE patients were a much higher-risk group than the EUROPA population, and as a result, the treatment effect seen with ramipril might not have been entirely unexpected.
Table 4. HOPE vs EUROPA: Outcomes in the Placebo Groups Standardized for 4.5 years of Follow-up
ACE Inhibitors: the New Statins?
Prof. Fox compared the story of ACE inhibitors in the treatment of CAD with that of the statins, which were investigated first in high-risk heart patients, then lower risk, then in the wider population. He believes that government regulatory bodies will respond to the evidence for ACE inhibitors in the same way, predicting that in the future, "all people with coronary disease are going to be on aspirin, a statin, and perindopril."
Official Commentary: Impact on Therapy and Future Guidelines
Asked by the ESC to comment on the EUROPA results, Sidney C Smith, MD (University of North Carolina, Chapel Hill, North Carolina, USA) predicted that they will have significant impact on therapeutic strategies and guideline recommendations for coronary heart disease.
New Indication Expected for Perindopril
EUROPA is funded by Servier, which markets perindopril in Europe and which will apply for approval of the new indication. Solvay markets perindopril in the United States
EUROPA Substudies Under Way
EUROPA includes 5 substudies, the purpose of which is to develop a better understanding of the actions of perindopril in CAD. These substudies are already under way to investigate the effects of the drug on neurohormonal activation, thrombosis, endothelium, inflammation, and coronary anatomy. In view of the known effects of ACE inhibitors in patients with diabetes, this population is being specifically investigated. The genetic characterization of the study population will be assessed.
PERTINENT (PERindopril-Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial) is evaluating the predictive value of several plasma and serum markers associated with atherosclerosis and the effects of perindopril on their levels. These markers are fibrinogen as a marker for coagulation, C-reactive protein (CRP) as a marker for inflammation, D-dimer for thrombogenesis, von Willebrand factor (vWf) for endothelial activation/coagulation, chromogranin A for neurohormonal activation, and nitric oxide synthase for endothelial function. In addition, ACE activity is measured.
This substudy has 2 parts: (1) a comparison of the effect of perindopril and placebo on these plasma markers at baseline and after 1 year of treatment in 345 patients, and (2) an evaluation of the effect of perindopril on CRP and vWf with respect to the primary and secondary CV endpoints in 1282 patients.
PERFECT (PERindopril Function of the Endothelium in Coronary artery disease Trial) will measure blood flow in the brachial artery using B-mode imaging with duplex scanning with a 7- to 10-MHz linear array transducer. Forearm circulation and flow-mediated vasodilatation of the brachial artery reflect endothelial functional changes similar to those in the coronary arteries of patients with CAD. Scanning is performed at rest, during and for 5 minutes after a 4-minute period of ischemic attack, and during and for 10 minutes after cold pressure testing. Consecutive studies are carried out during the run-in period, at the time of randomization, and at 6, 12, 24, and 36 months thereafter. At baseline and at the end of the study, nitroglycerine is administered sublingually to study nonendothelial-dependent vasodilation. Plasma levels of vWf are assessed during each study. The primary endpoint is the percentage change in the flow-mediated vasodilation of the brachial artery between baseline and 36 months and also the percentage change in neurohormonal-mediated vasoconstriction of the brachial artery.
PERSPECTIVE (PERindopril'S Prospective Effect on Coronary aTherosclerosis by angiographical and IntraVascular ultrasound Evaluation) aims to investigate the effects of perindopril administration on the progression and regression of coronary atherosclerosis using qualitative coronary angiography and intravascular ultrasound.
PERSUADE (PERindopril SUbstudy in Coronary Artery Disease and diabEtes) is examining the effects of perindopril with regard to the primary and secondary endpoints in the diabetic patients in EUROPA. The progression of diabetic nephropathy as assessed by albumin:creatinine ratio is also being investigated.
PERGENE will examine the genetic characterization of all patients in the EUROPA population. A sample of blood for DNA analysis was taken from every EUROPA patient.
According to EUROPA executive committee member Robert Ferrari, MD, PhD (University of Ferrara, Italy), results from these substudies will be available within 1 year.
References
Presenters: Kim M Fox, MD (Royal Brompton Hospital, London, UK) and Willem J Remme, MD, PhD (STICARES Cardiovascular Research Foundation, Rhoon-Rotterdam, The Netherlands)
The largest study ever conducted in patients with stable coronary disease has shown that the long-acting angiotensin-converting enzyme (ACE) inhibitor perindopril significantly reduces the risk of cardiovascular (CV) death and myocardial infarction (MI) in patients with stable coronary artery disease (CAD), including those with angina or a previous MI. The results of the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) were presented by the study co-chairmen, Professors Fox and Remme, and are published in the September 7 issue of The Lancet. On the basis of these results, the EUROPA investigators believe that the benefits of ACE inhibition have now been demonstrated to extend beyond their proven antihypertensive and anticardiac remodeling effects to the extent that perindopril should be considered for chronic therapy in all patients with coronary disease.
Landmark Study
EUROPA was a randomized, double-blind, placebo-controlled, multicenter trial designed to assess the long-term effects of ACE inhibition on the reduction of cardiac events in patients with proven CAD but with no evidence of heart failure. The long-acting ACE inhibitor perindopril was selected for the trial because of its documented anti-ischemic and atherogenic effects, its effect on CV remodeling, and its blood pressure-lowering effect.
EUROPA enrolled men and women aged ≥18 years with documented CAD as evidenced by:
Previous MI (> 3 months before screening)
Percutaneous surgical coronary revascularization (> 6 months before screening)
Angiographic evidence (≥ 70% stenosis)
Chest pain on positive exercise or stress test (men only)
Patients with clinical signs of heart failure, scheduled revascularization, hypotension, uncontrolled hypertension, recent use of ACE inhibitors or angiotensin receptor blockers, renal insufficiency, and raised serum potassium (> 5/5 mmol/L) were excluded from the study.
Objectives
The primary outcome of EUROPA was defined as the effect of perindopril on the combined endpoint of CV mortality, nonfatal acute MI, and cardiac arrest with successful resuscitation.
The secondary objectives were to assess the effect of perindopril in reducing the rate of the following events:
|
Total mortality |
Cardiac mortality |
Cardiac mortality and nonfatal acute MI |
|
Cardiac mortality, nonfatal MI, and unstable angina pectoris (UA) |
Fatal and nonfatal MI and UA |
Nonfatal MI |
|
Unstable angina |
Cardiac arrest with successful resuscitation |
Revascularization (CABG or PTCA)* |
|
Heart failure |
Stroke |
| *CABG, coronary artery bypass graft; PTCA, percutaneous transluminal coronary angioplasty |
EUROPA had an initial run-in period of 4 weeks during which patients received 4 mg, then 8 mg of perindopril once daily to assess tolerance to maximum dose. This was then followed by a double-blind randomization to either perindopril 8 mg or placebo once daily for at least 3 years. If this dose was not tolerated, it could be reduced to 4 mg once daily. Patients were followed up at 3, 6, and 12 months and then every 6 months until the last patient included in the main study completed follow-up. Mean follow-up was 4.2 years.
Patient Population
EUROPA was an unprecedentedly large trial, with a total of 12,218 patients randomized by 424 centers in 24 European countries. Mean age was 60 years, and 85% were male (Table 1). Patient histories revealed that 62% had a previous MI, 55% had a previous revascularization, and 3.4% had experienced previous stroke/transient ischemic attack (TIA). Risk factors in these patients included a history of diabetes mellitus or impaired glucose tolerance in 12%, hypertension in 27%, hypercholesterolemia in 63%, and smoking in 15%.
Table 1. EUROPA: Baseline Patient Characteristics
| Perindopril (mean ± SD) |
Placebo (mean ± SD) |
|
|---|---|---|
| Age (yrs) | 60 ± 9 | 60 ± 9 |
| Male (%) | 86 | 85 |
| Weight (kg) | 81 ± 12 | 80 ± 12 |
| Heart rate (bpm) | 68 ± 10 | 69 ± 10 |
| SBP (mm Hg) | 137 ± 16 | 137 ± 15 |
| DBP (mm Hg) | 82 ± 8 | 82 ± 8 |
| Prior MI (%) | 64.9 | 64.7 |
| Prior revascularization (%) | 54.7 | 55.2 |
| Prior stroke/TIA (%) | 3.4 | 3.3 |
| Prior heart failure (%) | 1.3 | 1.2 |
| Prior peripheral vascular disease (%) | 7.1 | 7.4 |
| Hypertension (%) | 27.0 | 27.2 |
| Diabetes mellitus (%) | 11.8 | 12.8 |
| Hypercholesterolemia (%) | 63.3 | 63.3 |
| Current smoker (%) | 15.4 | 15.1 |
| DBP, diastolic blood pressure; MI, myocardial infarction; SBP, systolic blood pressure; TIA, transient ischemic attack |
At study entry, 92% of the randomized patients were on platelet inhibitors, 62% on beta blockers, and 47.5% on statins, treatments appropriate for CAD at the time the trial was carried out (Table 2).
Table 2. EUROPA: Baseline Medication
| Perindopril (%) |
Placebo (%) |
|
|---|---|---|
| Platelet inhibitors | 91.9 | 92.7 |
| Beta-blockers | 62.0 | 61.3 |
| Lipid-lowering drugs | 57.8 | 57.3 |
| Nitrates | 42.8 | 43.0 |
| Calcium channel blockers | 31.7 | 31.0 |
| Diuretic | 9.1 | 9.4 |
| Oral anticoagulants | 4.4 | 4.2 |
Perindopril significantly reduced the combined primary endpoint of CV death, MI, and resuscitated cardiac arrest (P = .0003), with a 20% relative risk reduction (RRR) of 20% and an absolute risk reduction of 1.9% (Figure).
This beneficial effect of perindopril became apparent at 1 year of treatment and then continued to increase. It was seen across all predefined subgroups, including male/female; age ≤ 56 years, 57-65 years, and > 65 years; previous MI/no previous MI; previous stroke/TIA and no previous stroke/TIA; hypertension/no hypertension; and diabetes mellitus/no diabetes mellitus. Importantly, treatment benefit was seen in patients either on or not on lipid-lowering drugs, beta-blockers, and calcium channel blockers. Most patients were on platelet inhibitors.
Secondary Endpoints Also Reduced
Perindopril was associated with reductions in all secondary endpoints (Table 3), although not all were statistically significant (eg, the 11% reduction in total mortality). Significant reductions were seen in MI (fatal or nonfatal) (23.9%, P = .001) and heart failure (39.2%, P = .002). Even though defined as secondary, the EUROPA investigators believe that the heart failure effect is an especially significant finding.
Table 3. EUROPA: Secondary Endpoints
| Secondary endpoint | RRR (%) |
|---|---|
| Total mortality, MI, unstable angina, cardiac arrest | 14.9 |
| CV mortality and MI | 19.3 |
| CV mortality, MI, and stroke | 17.4 |
| CV mortality, MI, revascularization | 11.3 |
| CV mortality, MI, unstable angina | 15.5 |
| Fatal and nonfatal MI, unstable angina | 16.5 |
| Nonfatal and fatal MI | 23.9 |
| Total mortality | 11.0 |
| CV mortality | 13.9 |
| Unstable angina | 7.1 |
| Cardiac arrest | 45.6 |
| Stroke | 4.3 |
| Revascularization | 4.2 |
| Heart failure | 39.2 |
| CV, cardiovascular; MI, myocardial infarction; RRR, relative risk reduction |
As anticipated with an ACE inhibitor, a reduction in blood pressure was seen, but the small average 5/2 mm Hg reduction achieved with perindopril could not account for the reduction seen in CV events, the investigators believe. They suggest that the antiatherosclerotic properties of perindopril must also be considered in order to account for the result.
Absolute Benefits
The EUROPA investigators estimate from these results that perindopril 8 mg once a day prevents 1 CV death, nonfatal MI, or cardiac arrest among every 50 patients with coronary disease treated for 4 years. This means that for a country of 60 million inhabitants, such as the UK or France, treatment with perindopril over a 4-year period would prevent 50,000 MIs or CV deaths.
EUROPA vs HOPE
Prof. Fox noted that the EUROPA results extend those of the Heart Outcomes Prevention Evaluation (HOPE) trial, in which ACE inhibition with ramipril significantly reduced CV events in high-risk patients with coronary heart disease. There were important differences in the patient characteristics, however.
The HOPE patients were all aged ≥ 55 years, vs EUROPA, where one third of the patients were aged < 55 years. In addition, more HOPE patients had diabetes, hypertension, stroke, and obstructive peripheral vascular disease, and more used aspirin, beta-blockers, and lipid-lowering drugs. Major annual event rates were 40% to 80% higher in HOPE (Table 4).
Thus, as noted by Prof. Fox, the HOPE patients were a much higher-risk group than the EUROPA population, and as a result, the treatment effect seen with ramipril might not have been entirely unexpected.
Table 4. HOPE vs EUROPA: Outcomes in the Placebo Groups Standardized for 4.5 years of Follow-up
| HOPE | EUROPA | |
|---|---|---|
| Total mortality | 12.2% | 7.4% |
| CV mortality | 8.1% | 4.4% |
| Q-wave MI | 3.2% | 2.1% |
| CV, cardiovascular; MI, myocardial infarction |
Prof. Fox compared the story of ACE inhibitors in the treatment of CAD with that of the statins, which were investigated first in high-risk heart patients, then lower risk, then in the wider population. He believes that government regulatory bodies will respond to the evidence for ACE inhibitors in the same way, predicting that in the future, "all people with coronary disease are going to be on aspirin, a statin, and perindopril."
Official Commentary: Impact on Therapy and Future Guidelines
Asked by the ESC to comment on the EUROPA results, Sidney C Smith, MD (University of North Carolina, Chapel Hill, North Carolina, USA) predicted that they will have significant impact on therapeutic strategies and guideline recommendations for coronary heart disease.
New Indication Expected for Perindopril
EUROPA is funded by Servier, which markets perindopril in Europe and which will apply for approval of the new indication. Solvay markets perindopril in the United States
EUROPA Substudies Under Way
EUROPA includes 5 substudies, the purpose of which is to develop a better understanding of the actions of perindopril in CAD. These substudies are already under way to investigate the effects of the drug on neurohormonal activation, thrombosis, endothelium, inflammation, and coronary anatomy. In view of the known effects of ACE inhibitors in patients with diabetes, this population is being specifically investigated. The genetic characterization of the study population will be assessed.
PERTINENT (PERindopril-Thrombosis, InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial) is evaluating the predictive value of several plasma and serum markers associated with atherosclerosis and the effects of perindopril on their levels. These markers are fibrinogen as a marker for coagulation, C-reactive protein (CRP) as a marker for inflammation, D-dimer for thrombogenesis, von Willebrand factor (vWf) for endothelial activation/coagulation, chromogranin A for neurohormonal activation, and nitric oxide synthase for endothelial function. In addition, ACE activity is measured.
This substudy has 2 parts: (1) a comparison of the effect of perindopril and placebo on these plasma markers at baseline and after 1 year of treatment in 345 patients, and (2) an evaluation of the effect of perindopril on CRP and vWf with respect to the primary and secondary CV endpoints in 1282 patients.
PERFECT (PERindopril Function of the Endothelium in Coronary artery disease Trial) will measure blood flow in the brachial artery using B-mode imaging with duplex scanning with a 7- to 10-MHz linear array transducer. Forearm circulation and flow-mediated vasodilatation of the brachial artery reflect endothelial functional changes similar to those in the coronary arteries of patients with CAD. Scanning is performed at rest, during and for 5 minutes after a 4-minute period of ischemic attack, and during and for 10 minutes after cold pressure testing. Consecutive studies are carried out during the run-in period, at the time of randomization, and at 6, 12, 24, and 36 months thereafter. At baseline and at the end of the study, nitroglycerine is administered sublingually to study nonendothelial-dependent vasodilation. Plasma levels of vWf are assessed during each study. The primary endpoint is the percentage change in the flow-mediated vasodilation of the brachial artery between baseline and 36 months and also the percentage change in neurohormonal-mediated vasoconstriction of the brachial artery.
PERSPECTIVE (PERindopril'S Prospective Effect on Coronary aTherosclerosis by angiographical and IntraVascular ultrasound Evaluation) aims to investigate the effects of perindopril administration on the progression and regression of coronary atherosclerosis using qualitative coronary angiography and intravascular ultrasound.
PERSUADE (PERindopril SUbstudy in Coronary Artery Disease and diabEtes) is examining the effects of perindopril with regard to the primary and secondary endpoints in the diabetic patients in EUROPA. The progression of diabetic nephropathy as assessed by albumin:creatinine ratio is also being investigated.
PERGENE will examine the genetic characterization of all patients in the EUROPA population. A sample of blood for DNA analysis was taken from every EUROPA patient.
According to EUROPA executive committee member Robert Ferrari, MD, PhD (University of Ferrara, Italy), results from these substudies will be available within 1 year.
References
Fox KM, Remme WJ. Effects of an angiotensin-converting enzyme inhibitor, perindopril, on cardiovascular events in stable coronary artery disease patients (EUROPA). Presented at the ESC Congress 2003; August 30-September 3, 2003; Vienna, Austria. Hot Line I: Medical Treatment/Heart Failure, Presentation #77.
The EURopean Trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. Published online September 1, 2003.
Fox KM, Henderson JR, Bertrand ME, et al. The European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA). Eur J Heart. 1999;18(suppl J):J52-J55.
Gomma AH, Fox KM. The EUROPA trial: design, baseline demography and status of the substudies. Cardiovasc Drugs Ther. 2001;15:169-179.
The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl J Med. 2000;342:145-153.
Simoons ML, Vos J, de Feyter, et al. EUROPA substudies, confirmation of pathophysiological concepts. Eur J Heart. 1999;18(suppl J):J56-J60.
PERTINENT-PERindopril-Thrombosis, InflammatioN, Endothelial Dysfunction and Neurohormonal Activation Trial: A Sub-Study of the EUROPA Study. Cardiovasc Drugs Ther. 2003;17:83-91.
Bots ML, Remme WJ, Lüscher TF and Grobbee DE. On behalf of the EUROPA-PERFECT investigators. PERindopril-Function of the Endothelium in Coronary artery disease Trial: the PERFECT study-sub study of EUROPA: rationale and Design. Cardiovasc Drugs Ther. 2002;16:227-236.
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