Atherosclerosis 147 Suppl. 1 (1999) S17–S21

Evidence for the benefit of early intervention with pravastatin forsecondary prevention of cardiovascular events

Hans-Richard Arntz *Klinikum Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany

Accepted 28 June 1999

Abstract

Treatment with HMG-CoA reductase inhibitors (or statins) lowers total and LDL cholesterol and decreases the risk ofcardiovascular events. The absolute benefits are greater in patients with a higher baseline cardiovascular risk, so statins areparticularly suited to secondary prevention. Although three large studies have shown convincingly that, in patients with a historyof cardiovascular disease, simvastatin or pravastatin treatment reduces the risk of further events and lowers overall mortality,those studies have not included patients in the period immediately after an acute coronary event. They are, therefore, of limitedvalue in answering the question of when to start statin treatment. However, there are practical reasons for starting statin treatmentas early as possible, and results of clinical studies have now shown this to be a safe option for pravastatin. Early treatment withpravastatin can stabilize coronary atherosclerosis and improve endothelial function. More importantly, there is also evidence thatearly treatment with pravastatin can produce a clinical benefit a few months after the initial coronary event. © 1999 ElsevierScience Ireland Ltd. All rights reserved.

Keywords: Simvastatin; Pravastatin; Secondary CHD prevention; CARE study; LIPID study; PAIS study; RECIFE study; L-CAD study

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1. Introduction

It is well known that high plasma cholesterol concen-trations are associated with adverse cardiovascular out-comes such as angina and myocardial infarction (MI)[1–3]. It therefore seems logical that a drug that lowersplasma cholesterol will reduce the risk of those out-comes. The HMG-CoA reductase inhibitors (or statins)inhibit the conversion of 3-hydroxy-3-methylglutarateinto mevalonate, a precursor of cholesterol, and thuslead to lower plasma cholesterol (total and LDL) con-centrations, reduced triglycerides and increased HDLcholesterol [4].

There is now ample evidence that treatment withsimvastatin or pravastatin, when used for secondaryprevention, reduces the risk of further cardiovascularevents and mortality in patients with a history ofcardiovascular disease. This is true whether patients arehypercholesterolaemic (4S [5]) or have normal or onlyslightly raised cholesterol levels (CARE [6], LIPID [7]),and even applies to those without clinical evidence ofcoronary heart disease [8].

The reduction in relative risk due to pravastatintreatment is reasonably constant across a range ofabsolute risks [9], so the absolute risk reduction isgreater in patients with higher baseline risk. Thebenefits of statins should therefore be more pronouncedin secondary prevention, because patients with existingcardiovascular disease are at high risk for further car-diovascular events. Three large studies [5–7] have con-firmed that simvastatin and pravastatin do indeed leadto substantially reduced mortality in patients with exist-ing cardiovascular disease.

2. Statins for secondary prevention of coronary events

The 4S study [5] included 4444 patients with anginapectoris or previous MI and isolated hypercholesterol-aemia, with serum cholesterol in the range 5.5–8.0mmol/l, who were randomized at the earliest, 6 monthsafter MI, to treatment with simvastatin or placebo.Over the median of 5 years of follow-up, 12% of thepatients in the placebo group and 8% in the simvastatingroup died, a highly significant difference. Simvastatin* Tel.: +49-30-84452640; fax: +49-30-84452640.

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also significantly reduced cardiovascular events (fataland non-fatal), and a post-hoc analysis showed a re-duced incidence of stroke in the simvastatin group.

The benefits of pravastatin treatment for secondaryprevention also extend to patients with normal choles-terol levels, as was shown by the CARE study [6],which included 4159 subjects with a history of MI (]3months after the index MI) and a cholesterol levelbelow 6.2 mmol/l. Although the European Task ForceGuidelines [10] recommend that cholesterol levelsshould be maintained below 5.0 mmol/l, a recentlypublished normal range for serum cholesterol (i.e. arange that includes 95% of healthy subjects) has anupper limit of 6.5 mmol/l [11] so the entire populationof the CARE study would therefore fall within thenormal range for healthy subjects. The results of theCARE study showed a considerable advantage forpravastatin compared with placebo. Pravastatin-treatedpatients showed a 3% absolute reduction in the risk ofa fatal coronary event or non-fatal MI (the primaryendpoint), which corresponded to a 24% reduction inrelative risk, and similar, significant reductions in theincidence of coronary artery bypass graft (CABG)surgery, percutaneous transluminal coronary angio-plasty (PTCA), and even stroke as a pre-specified end-point (26, 23 and 31%, respectively).

Another large study has also examined the effects ofpravastatin for secondary prevention. The LIPIDstudy, the largest statin study to date [7], included 9014patients with a history of MI or hospitalization for thefirst time for unstable angina (]3 months after theindex event), and cholesterol levels at baseline in therange 4.0–7.0 mmol/l and triglycerides up to 5.0 mmol/l. The results were similar to those of the CARE study,including a significant benefit in stroke, but with theadditional finding of significantly reduced all-causemortality (22% relative risk reduction).

An important feature of the CARE and LIPID stud-ies is that they included patients whose serum choles-terol concentrations were mostly within the ‘normal’range, but still found significant benefits from prava-statin treatment. Consequently, patients at high risk ofcardiovascular events should receive treatment even inthe absence of considerable hypercholesterolaemia [10]Moreover, CARE and LIPID are the only statin studieswith stroke as a pre-specified endpoint. Both studiesshowed significant reductions in stroke and in stroke ortransient ischaemic attack (TIA).

3. Rationale for early intervention

In view of the consistent results from several largestudies, there is no doubt that simvastatin and prava-statin treatment for patients with coronary artery dis-ease saves lives. However, an important question for

the clinician treating a patient who has had an MI orunstable angina is ‘when should I start statin treat-ment?’ A limitation of the large-scale studies in sec-ondary prevention is that they have not examinedtreatment in the immediate period after the coronaryevent: treatment did not start until at least 3 months(CARE, LIPID) or 6 months (4S) after the index event.Those studies therefore do not tell us about the effect oftreatment with statins immediately after a coronaryevent.

One of the reasons why the secondary preventionstudies have included patients after a delay of severalmonths is that serum lipid levels decrease after an MI,and return to pre-infarction levels only after a period ofseveral weeks [12,13]. It is therefore difficult to obtain areliable baseline measurement of the patient’s choles-terol levels in the days after an infarction. However,cholesterol levels do not decline immediately after MI,but remain stable for about 24 h [14,15]. Cholesterolmeasurements obtained from a blood sample taken atthe time of admission to hospital, as recommended bythe revised guidelines of the Joint European Taskforce[10], could therefore provide a reliable baseline (Fig. 1).However, the results from CARE and LIPID suggestthat this post-MI fall in lipid levels may be somewhatirrelevant since patients derived benefit from pravas-tatin treatment despite having average, rather thanelevated, lipid levels.

There are good theoretical and clinical reasons forbelieving that early initiation of statin treatment wouldbe beneficial. One reason is that the absolute risk offurther events is high in the period immediately after anacute coronary event, and then gradually diminisheswith time [10]. Because statins give a constant reductionin relative risk over a wide range of absolute risks [9],the absolute benefit of statin treatment should thereforebe greatest when the absolute risk is high, in otherwords immediately after the index event.

There is also a good pragmatic reason for startingstatin treatment early. While patients are hospitalizedfor an acute coronary event, they will most probably beunder the care of a specialist, who may be in the best

Fig. 1. Implementation of evidence-based statin therapy (from Woodet al. [10])

H.-R. Arntz / Atherosclerosis 147 (1999) S17–S21 S19

position to initiate statin treatment. If treatment isdelayed for 3 months, it is more likely that statintherapy may not be considered any more by a primary-care physician [10].

A further advantage of initiating statin treatmentduring a stay in hospital is that it provides an opportu-nity to motivate patients to comply with their medica-tion regimen [16]. A subgroup analysis of data from theWOSCOPS study has confirmed convincingly the intu-itively obvious hypothesis that high compliance resultsin better outcomes [17].

In addition to their effects on plasma cholesterollevels, statins have other effects (so-called pleiotropiceffects) that are likely to be of benefit in reducingcardiovascular mortality [18,19]. Those include effectson endothelial function, the stability of atheroscleroticplaques and platelet function [20]. Although statins as aclass lead to significant reductions in cholesterol, thepleiotropic effects seem to vary among the individualdrugs. Evidence is emerging that some of thepleiotropic effects may have a clinical benefit early inthe course of treatment. For example, Crisby andNilsson [21] found that various measures of plaquestability, in specimens taken at carotid endarterectomy,were significantly improved after just 3 months in pa-tients taking pravastatin (40 mg daily) compared with acontrol group who had not taken lipid-lowering treat-ment. Such early potential clinical benefits furtherstrengthen the rationale for starting pravastatin treat-ment as soon as possible.

4. Evidence for the benefit of early intervention withpravastatin

No matter how good the theoretical arguments forstarting statin treatment early after an acute coronaryevent, definitive evidence for the benefits and safety ofso doing can only come from clinical trials designed toprovide that evidence. To date, there have been notrials on the scale of the 4S, LIPID and CARE trials inwhich statin treatment was started early, but there isgrowing evidence from smaller trials that early initia-tion of pravastatin is indeed beneficial.

Kesteloot and co-workers [22] studied 69 patientswho were randomized to pravastatin or placebo, 3 daysafter an acute MI. Pravastatin was started at 10 mg/day, and the dose was increased to 20 mg/day after 1week. Treatment continued for 3 months. The trial(known as the LAMIL study) was not designed toassess long-term outcomes, but showed that pravastatinnot only significantly reduced total and LDL choles-terol concentrations but was also well tolerated inpatients with a recent MI.

These results were confirmed by the PAIS study [23].The design was similar to the study described above,

although the inclusion criteria were slightly broader andresulted in inclusion of patients who were hospitalizedfor unstable angina as well as those with MI. Prava-statin was given at a dose of 40 mg within 48 h ofhospitalization. Again, the study was not designed toassess long-term outcomes, but it did find that prava-statin treatment was well tolerated in the populationstudied.

Early initiation of pravastatin treatment also has abeneficial effect on endothelial function. The RECIFEstudy [24] treated 60 patients with 40 mg pravastatin orplacebo before hospital discharge, a mean of 10 daysafter MI or hospitalization for unstable angina. Treat-ment was given for 6 weeks, after which endothelialfunction was assessed by high-resolution ultrasoundmeasurement of flow-mediated dilatation of thebrachial artery. Flow-mediated dilatation increased sig-nificantly by 42% in the pravastatin group, but not inthe placebo group, showing that early use of prava-statin improves endothelial function.

More robust data on the efficacy of pravastatin forearly secondary intervention have been provided by theL-CAD study [25], which included 126 patients withrecent MI and PTCA because of severe unstable anginapectoris. Patients had to have baseline LDL cholesterollevels in the range 3.4–6.5 mmol/l. Patients in thepravastatin group received 20–40 mg pravastatin daily,plus additional cholesterol-lowering treatment(cholestyramine or nicotinic acid) if necessary to reachan LDL cholesterol level below 3.4 mmol/l. By the timethis study was initiated, it was considered unethical toinclude a placebo group, so the control group receivedconventional therapy, with the choice of treatment leftto the patient’s private physician. Patients were studiedfor 2 years, and had diagnostic coronary angiographyat baseline, 6 months and 2 years. The study had thedual aims of quantifying the progression and regressionof coronary stenoses and of recording major cardiovas-cular clinical events.

The angiographic results from the L-CAD studyshowed convincingly that pravastatin had a beneficialeffect on coronary artery stenosis, with significant in-creases in minimum lumen diameter in comparison withconventional management even within 6 months oftherapy. This is important evidence that treatment withpravastatin can reverse the process of atherosclerosiswhen given immediately after an acute coronary event.More importantly, the study showed a reduced inci-dence of major cardiovascular events (acute MI, PTCA,CABG, resuscitation or cardiovascular death) in thepravastatin group, thus providing direct evidence thatearly initiation of pravastatin treatment is effective insecondary prevention. The difference between treatmentgroups was apparent a few months after the start oftreatment. By 2 years, 52% of the controls, but only

H.-R. Arntz / Atherosclerosis 147 (1999) S17–S21S20

Fig. 2. Time of initiation of statin therapy after acute coronary eventsin various studies: 4S [5]; CARE [6]; LIPID [7]; LAMIL [22]; PAIS[23]; RECIFE [24]; and L-CAD [25].

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27% of the pravastatin-treated patients had a majorevent (PB0.03).

5. Conclusions

Although the evidence for early initiation of statintreatment in secondary prevention is not as robust asthe evidence for pravastatin (\3 months) or simvas-tatin (\6 months) later after an acute coronary event,there are good reasons for starting statin treatment asearly as possible. In addition to theoretical argumentsfor early intervention, a growing body of evidence fromclinical studies shows that pravastatin treatment is safein the early period after MI or unstable angina (Fig. 2).In addition, there is encouraging evidence that earlytreatment with pravastatin can stabilize the process ofcoronary artery stenosis, improve endothelial functionand, most importantly, reduce the incidence of furthercoronary events. These results need to be confirmed bylarge-scale studies, but in the meantime it seems pru-dent to offer pravastatin treatment to patients withacute coronary syndromes as soon as possible. Becauseof the unreliability of cholesterol measurements in theperiod between 2 days and 3 months after an MI, it isimportant that a blood sample be taken for cholesterolmeasurement as soon as possible after admission tohospital. Early measurement of cholesterol and consid-eration of statin treatment should be a routine part ofthe care of patients admitted to hospital with acutecoronary syndromes.

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