EUROPA: Has Anything New Been Learned With Angiotensin‐Converting Enzyme Inhibitors?

Abstract

The European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) involved 12,218 patients with stable coronary artery disease. Patients in this trial were randomized to the angiotensin‐converting enzyme inhibitor perindopril (8 mg/d) or placebo in addition to optimized conventional therapy and followed for an average of 4 years. Perindopril reduced the primary end points of cardiovascular disease, myocardial infarction, and cardiac arrest by 20% (p=0.0003). Moreover, the angiotensin‐converting enzyme inhibitor reduced the rate of fatal and nonfatal myocardial infarction by 24% (p=0.001). The results from EUROPA complement those observed in the Heart Outcomes and Prevention Evaluation (HOPE) study and provide further support for the concept of angiotensin‐converting enzyme inhibitors conferring cardiovascular protection as a class effect.

The European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) is the largest study to date conducted in patients with stable documented coronary artery disease (CAD). This study involved 12,218 patients aged 26–89 years (mean age 60 years) from 24 European countries. Study subjects were qualified as having CAD by a history of a myocardial infarction (MI) at least 3 months before the selection visit (65%), a percutaneous or surgical coronary revascularization at least 6 months before the selection visit (55%), or angiographic evidence of at least 70% narrowing of one or more coronary arteries (61%). Male patients (85% of the study population) with a history of chest pain (4%) were also allowed study entry if they had a positive electrocardiogram, echocardiogram, or nuclear stress test. Important exclusion criteria included the presence of congestive heart failure, uncontrolled (or too low) blood pressure (BP), recent angiotensinconverting enzyme (ACE) inhibitor or angiotensin receptor blocker use, and/or a serum creatinine level >1.7mg/dL(150μmol/L). ¹

EUROPA had a run‐in period where enrolled patients received 4 mg perindopril once daily. Titration to an 8 mg once daily dose occurred during the run‐in period and at the completion of the run‐in period subjects were randomly assigned to 8 mg perindopril once daily (n=6110) or placebo (n=6108). Patients were followed for a mean follow‐up of 4.2 years. They were assessed every several months by ascertainment of cuff BP readings, serum chemistries, and renal function. The primary end point in this trial was a composite of cardiovascular (CVR) death, nonfatal MI, and cardiac arrest with successful resuscitation. Secondary end points were the composite of total mortality, nonfatal MI, hospitalization for unstable angina, and cardiac arrest with successful resuscitation; CVR mortality and nonfatal MI; the individual components of these secondary outcomes; and revascularization, stroke, and admission for heart failure. EUROPA was also one of the first trials to use the new American College of Cardiology/European Society of Cardiology definition of MI in its primary end point, which defines MI as any rise in cardiac markers, including troponin values. However, the percentage of patients diagnosed by raised troponin values (as opposed to elevations in creatine kinase‐MB values) was not reported. ²

RESULTS

Perindopril reduced the primary end point of CVR disease, MI, and cardiac arrest by 20% (p=0.0003). Moreover, the rate of fatal and nonfatal MI was reduced by 24% (p=0.001). The primary end point benefit began to appear by the 1‐year time point and increased through the course of the trial. The benefits in EUROPA were seen across all age and gender groups although the study included less than 15% women, and in those with and without hypertension or diabetes. In EUROPA there was no significant benefit of perindopril on stroke or revascularization although this may have been related to a reduced overall event rate in this population. ¹

As in the HOPE study, ³ reduction in vascular events was associated with rather small changes in BP: −5.0 mm Hg systolic and −2.0 mm Hg diastolic. Importantly, the benefits were seen in addition to other standard therapies, which included platelet inhibitors (92%), lipid‐lowering drugs (58%), and β blockers (62%). Since patients with clinically evident heart failure were excluded from this trial an unexpected finding in this population was an early and sustained reduction of heart failure, with a relative risk reduction of 39% for heart failure hospitalization over the 4‐year period of the study. At 3 years of follow‐up, 81% and 84% of patients were taking perindopril and placebo, respectively. ¹ Fewer patients were on medication after 3 years, with 48 and 49 of perindopril and placebo patients, respectively, treated at 4 years; thus, the benefit with perindopril seen at 4 years is a conservative estimate.

Why Was Perindopril Selected for This Study?

Perindopril was selected as the agent to be studied in the EUROPA study because it is a once‐a‐day ACE inhibitor whose pharmacologic pattern of lipophilicity and tissue‐ACE affinity support its offering strong tissue‐based cardiac and vascular protection. ⁴ Perindopril also seems to carry a reduced incidence rate of first‐dose hypotension although this is not likely to have been relevant to the EUROPA trial. ⁵ Several other ACE inhibitors have a similar pharmacologic profile as perindopril and thus could have easily been chosen for this trial if the choice of a study drug was not determined by the specific industry sponsorship of this trial.

Do the EUROPA Results Imply That an ACE Inhibitor Should be Required Therapy in All Patients With Stable Coronary Artery Disease and Already Receiving Best Possible Non‐ACE Inhibitor Therapy?

The answer from EUROPA is a qualified yes. However, the pretherapy BP needs to be taken into consideration before embarking on any such treatment course. It would be ill advised to simply start and/or titrate an ACE inhibitor like perindopril without some low‐end BP (with or without symptoms of hypotension) as an identifiable stopping point. To that end perindopril was surprisingly well tolerated in EUROPA with only 7% of those patients assigned to active therapy having their endtitration perindopril dose reduced from 8 to 4 mg. ¹

What Is the Relevance of the Dose of Perindopril in This Study?

The 8‐mg dose used in the EUROPA study was relatively high and was chosen to optimize the chance of there being BP‐independent cardioprotective effects. The studied dose of perindopril needs to be considered not only in the context of BP‐independent vascular effects but also for its capacity to have reduced BP. The dose‐response BP relationship for an ACE inhibitor is biphasic. At low doses the drug concentration—response relationship is fairly steep; thereafter, the concentration—response relationship flattens. ⁶ The breakpoint for a muting of any incremental BP‐lowering response to perindopril is likely to have been reached at an 8‐mg dose. ⁵ , ⁷ An 8‐mg recommended dose in a CAD population is not without some risk in that this amount of perindopril is sufficient to give rise to hypotension in susceptible subjects such as a mildly volume‐depleted, otherwise normotensive individual.

It is unclear if a 2‐ to 4‐mg dose of perindopril would have offered a graded outcomes benefit or if a dose >8 mg would have resulted in an even better outcome. The Study to Evaluate Carotid Ultrasound (SECURE) substudy of HOPE evaluated a high‐risk treatment group with both a 2.5‐ and 10‐mg dose of ramipril in parallel. Although the SECURE trial was not powered to compare the two doses of ramipril, a trend for atherosclerosis regression emerged for the 2.5‐mg treatment group compared with the 10‐mg treatment group suggesting a dose‐dependent effect. ⁸

Are There Any Comparisons to Be Made Between EUROPA and Other Trials Such as the HOPE Study?

The results of the HOPE study were of a significant enough nature to prompt the American Heart Association to include this study in its top‐10 research advances for the year 1999. The HOPE study findings were realized on top of conventional treatment and therefore viewed as being broadly applicable to clinical practice. As a result of the HOPE study many health care providers began to offer ACE inhibitor therapy to patients at risk for vascular events. ³ The HOPE study results also provided the factual basis for the continuation of additional studies, employing ACE inhibitor therapy in at‐risk patients.

Important dissimilarities between the HOPE and EUROPA trials included a much higher incidence of diabetes, peripheral vascular disease, and cerebrovascular disease in the HOPE trial and a significantly higher use of antiplatelet, statin, and β‐blocker therapies in the EUROPA study. Major annual event rates were 50%–80% higher in the HOPE study (Table). In addition, a third of the EUROPA patients were younger than age 55 years, whereas the HOPE trial exclusively studied patients older than 55 years of age. Despite these differences, the reductions in major CVR events were largely similar in both trials (24% reduction in MI rate in EUROPA vs. 20% in HOPE)

Several questions persisted in the wake of the HOPE study. Such questions included the following¹: Would a trial directed exclusively toward patients with known CAD but at a lower risk demonstrate similar benefits to those observed for the higher risk population in the HOPE study? ² Would the effects of ACE inhibition continue to be independent of a noteworthy reduction in BP? ³ Will the effects of ACE inhibition in reducing CVR events occur in a population younger than 55 years of age, the lower limit of inclusion for the HOPE trial? The results of the EUROPA trial provide a positive answer to each of these questions. This trial widens the field for application of ACE inhibitors in secondary prevention to individuals below the age of 55 years independent of their diabetes status.

What Were the Blood Pressure Considerations in EUROPA and HOPE?

In HOPE, BP (after 5 minutes of rest) was measured in duplicate by trained nurses at baseline, 1 month, 2 years, and at study conclusion. Also, in the interpretation of HOPE study findings ramipril was suggested to be taken at night therefore it is probable that its preponderant BP effect occurred during sleep and not the next day when BP readings were routinely obtained. ⁹ The role of BP reduction in the HOPE study findings remains controversial to this day. ⁹ , ¹⁰

In EUROPA patients were seen at 3, 6, and 12 months, and every 6 months thereafter. Sitting BP was recorded twice with a standard sphygmomanometer after a minimum of 5 minutes of rest. In EUROPA, perindopril was taken in the morning hours, which is important since this compound (as may be the case for other ACE inhibitors) has a time‐wise more significant BP lowering effect when taken at night. ¹¹ In EUROPA, hypertension was defined for the purpose of analysis as a systolic and diastolic BP of greater than 160 mm Hg and 95 mm Hg, respectively, or both, or prior antihypertensive therapy (present in 27% of patients). ¹

These values demarcating hypertension from nonhypertension are much higher than those in current guidelines. Unfortunately, the EUROPA investigators do not provide any analyses with correction for an antihypertensive effect, and do not detail the outcomes in patients with differing BP values at entry, particularly those with values falling between 130/80 mm Hg and 160/95 mm Hg. One EUROPA finding that argues against BP reduction being the predominant mechanism for the observed findings is that the reduction in MI was much greater than that of stroke—conflicting with a number of clinical trial observations where stroke reduction is driven by the degree of BP reduction. Alternatively, this contradictory finding may relate to the EUROPA investigators having enrolled a much younger cohort than the major antihypertensive trials.

Are the Results of EUROPA Representative of a Class Effect for All ACE Inhibitors?

Whether the findings of the HOPE study can be extrapolated to other ACE inhibitors is probably one of the first questions that arises following inspection of the EUROPA findings. In conjunction with the HOPE findings, EUROPA results now provide additional support for a class effect for ACE inhibitors in vascular protection. However, acceptance of the concept of a class effect requires a denial of the fact that ACE inhibitors are structurally and physicochemically distinct. ⁶ As much as the concept of class effect for ACE inhibitors has been championed, dose equivalence has not been established for various ACE inhibitors as to their BP‐independent effects; particularly, when highend doses are employed and/or renal failure is present in treated subjects. ¹² The latter is pertinent in that many ACE inhibitors are renally cleared and accumulate with repetitive dosing in chronic kidney disease. This makes the determination of dose equivalence unworkable if the basis for equivalence is something other than comparable reductions in BP. ⁶

Will the Results of EUROPA Modify Clinical Practice in Any Way?

The answer is a qualified yes. Effective secondary prevention strategies for patients with chronic CAD are important for several reasons. First, the dimensions of this population are large with a sizable annual growth rate. The latter is governed by the continued increase in life expectancy and the decrease in acute MI‐related death rate. Second, the risk of morbidity and death remains unacceptably high despite efforts at risk‐factor modification and treatment with aspirin, statins, and β blockers. Finally, CAD is a leading cause of death and an important contributor to global health care costs. Seemingly low‐risk patients with CAD, such as those with a remote history of MI who are otherwise asymptomatic and those with mild stable angina, will benefit from the addition of an ACE inhibitor to an optimal regimen consisting of aspirin, cholesterol‐lowering medication, and β blockers. Selection of an ACE inhibitor based on characteristics of tissue binding and/or half‐life would seem prudent based on the prior study results with ramipril and now perindopril.

ONGOING ANCILLARY STUDIES

Various substudies have been built into the EUROPA trial to evaluate the effects of perindopril in patients with diabetes, as well as to provide data on the mechanism(s) by which perindopril may reduce morbidity and mortality in CAD. ¹³

PERSUADE

The Perindopril Substudy in Coronary Artery Disease and Diabetes (PERSUADE) is examining patients (almost 1500) taking part in EUROPA who also have diabetes (12% of the study population). In addition to the objectives of the main EUROPA trial, this study will also detect the progression of diabetic nephropathy in this patient population.

PERSPECTIVE

The Perndopril's Prospective Effect on Coronary Atherosclerosis by Angiographical and Intravascular Ultrasound Evaluation (PERSPECTIVE) substudy is investigating the effects of perindopril (almost 400 patients) on the progression and regression of coronary atherosclerosis using qualitative coronary angiography and intravascular ultrasound.

PERFECT

The Perindopril Function of the Endothelium in Coronary Artery Disease Trial (PERFECT) is a nested substudy examining the effect of perindopril (almost 300 patients) on endothelial function by measuring forearm circulation and flow‐mediated vasodilatation of the brachial artery in response to administration of an 8‐mg dose of perindopril. ¹⁴

PERTINENT

The Perindopril‐Thrombosis, Inflammation, Endothelial Dysfunction and Neurohormonal Activation Trial (PERTINENT) substudy is designed to evaluate the predictive value of several plasma and serum markers associated with atherosclerosis and the effects of perindopril on their levels (almost 1300 patients). ¹⁵

PERGENE

The Perindopril and Genetic Characterization of Coronary Artery Disease Patients (PERGENE) substudy is looking at the genetic characterization of all patients in the EUROPA study population.

CONCLUSION

EUROPA is one of several megatrials that add to the expanding number of indications for ACE inhibitors. Its findings are above and beyond what might have been expected with BP reduction alone. However, it is unclear how the pharmacologic features of perindopril separate this compound from other ACE inhibitors. When the HOPE data were released and for some time thereafter the singular nature of its findings provided some basis for the lack of an ACE inhibitor class effect. Now with the EUROPA and HOPE data being so similar the concept of ACE inhibitor class effect is both rekindled and more probable.