Lipids and cardiovascular risk reduction – new targets, newchallenges

The last 18 months has seen the pre-

sentation and publication of several

major studies addressing the impact of

treating hyperlipidaemia, hypertension

and the combined effect on cardiovas-

cular risk. Whilst there is nothing new

in advocating this approach, there have

been significant developments with

regard to setting targets and how to

achieve them. Furthermore, it is import-

ant not to look at individual risk factors

in isolation but to look at the overall

cardiovascular risk with a view to mod-

ifying each component as part of a

comprehensive strategy. In this editorial

I will focus on the lipid trials and,

though they do overlap, I will discuss

the hypertension studies in the next

issue.

The lipid lowering trials have

focused on comparing a more aggres-

sive strategy using atorvastatin 80 mg

daily aiming for an LDL cholesterol of

1.8 mmol/L (i.e. less than 2.0 mmol/

L) with a standard approach setting a

target of 2.6 mmol/L equating

usually to a 25 to 35% LDL reduction.

They can be divided into anatomical

(1), acute (2,3), chronic (4) and

acute progressing to chronic studies

(4).

The Reversal of Atherosclerosis

with Aggressive Lipid Lowering

(REVERSAL) trial was a double blind

study comparing daily pravastatin

40 mg with atorvastatin 80 mg over

an 18 month period with the primary

endpoint percentage change in ather-

oma volume assessed using intravascu-

lar ultrasound (1). The baseline mean

LDL cholesterol of 3.89 mmol/L was

reduced to 2.85 mmol/L by pravastatin

and 2.05 mmol/L by atorvastatin.

C-reactive protein (CRP) decreased

5.25% with pravastatin and 36.4%

with atorvastatin. The primary end-

point of a change (increase) in ather-

oma volume (i.e. progression rate)

occurred in the pravastatin group

(2.7%) compared with baseline

(p ¼ 0.001) but not in the atorvastatin

group. Therefore, the more intensive

regime reduced and prevented ather-

oma progression compared with the

standard regime, which did not. In

addition, in a post-hoc analysis, after

the reduction in LDL levels was

adjusted for, the decrease in CRP was

independently significantly related to

the rate of progression (5). This does

not identify CRP as a clinical target but

confirms the need to take into account

any specific therapy’s effect on CRP as

well as the lipid profile when assessing

clinical endpoints. REVERSAL was not

a clinical endpoint trial, but it estab-

lished the basis for subsequent clinical

studies addressing morbidity and mor-

tality comparing an aggressive LDL

lowering strategy to a target of

2.0 mmol/L or less with a standard

approach to 2.6 mmol/L.

In the acute setting where plaque

inflammation might be the main target

rather than LDL lowering, though

obviously both would be considered

important, the PROVE-IT (Pravastatin

or Atorvastatin Evaluation and Infection

Therapy) study compared once more

pravastatin 40 mg with atorvastatin

80 mg daily (2). This study was

extended to 18–36 (mean 24) months

allowing a late (after 6 months) assess-

ment when LDL lowering might be

more important – in other words two

time windows (to 30 days acute; from 6

months chronic) of therapy. Over 4000

well matched patients were randomised

within 10 days of being stabilised after

presenting with an acute coronary syn-

drome (ACS). This study was designed

to establish the non-inferiority of pra-

vastatin. Pravastatin reduced the mean

LDL cholesterol to 2.46 mmol/L

and atorvastatin to 1.6 mmol/L

(p < 0.0001). There was a 16%

(p ¼ 0.005) risk reduction in the pri-

mary composite endpoint of death,

myocardial infarction, unstable angina

needing hospitalisation, stroke and

revascularisation after 30 days in favour

of atorvastatin. The study therefore

identified the superiority of atorvastatin

as the vehicle for intensive lipid lowering

soon after presentation with an ACS.

Importantly the benefit occurred in

addition to the use of good evidence-

based medicine – aspirin 93%, clopido-

grel 72%, beta blockers 85%, ACE inhi-

bitors or angiotensin II blockers 83%.

Both regimens were well tolerated with

no cases of rhabdomyolysis. A subse-

quent analysis has suggested that, in

addition to LDL cholesterol lowering, a

reduction in CRP conferred additional

independent benefit and suggested

meeting the LDL target of less than

1.8–2.0 mmol/L and CRP of less than

2 mg/L was more important in deter-

mining outcomes than the specific ther-

apy (6). PROVE-IT in addition has a

late phase. Whilst intensive early therapy

within 30 days is consistent with statin

pleiotropic effects, stable patients

beyond 6 months may be principally

affected by LDL lowering. The compo-

site endpoint for atorvastatin from 6

months to the end of the study was

9.6% vs. 13.1% for pravastatin (28%

risk reduction; p ¼ 0.003). Therefore

ACS patients should begin statin ther-

apy in hospital and be continued on

long-term therapy with a target LDL

cholesterol below 2.0 mmol/L and ide-

ally 1.8 mmol/L (7).

Specifically studying stable patients

the Treating to New Targets (TNT)

study randomised 10,001 patients

with coronary heart disease and

LDL cholesterol levels above

3.4 mmol/L to atorvastatin 10 or

80 mg daily (4). Patients were fol-

lowed for a median of 4.9 years and

the primary endpoint was first major

cardiovascular event defined as

coronary death, non fatal myocardial

infarction, resuscitation from cardiac

ª 2005 Blackwell Publishing Ltd Int J Clin Pract, June 2005, 59, 6, 617–618

EDITORIAL do i : 1 0 . 1111 / j . 1368 - 5031 . 2005 . 00552 . x

arrest or fatal or non-fatal stroke. A

run-in period of 8 weeks of atorvas-

tatin 10 mg reduced the LDL

cholesterol to less than 3.4 mmol/L,

allowing safe ethical entry into the

study, the aim of which was to

determine the efficacy and safety of

lowering LDL levels below 2.6 mmol/

L. The mean LDL levels achieved

were 2.0 mmol/L during atorvastatin

therapy at 80 mg and 2.6 mmol/L

during 10 mg of atorvastatin.

Atorvastatin 80 mg resulted in an

absolute risk reduction of a

primary event of 2.2 per cent (22%

relative risk compared with 10 mg;

p < 0.001). There was no difference

in overall mortality. Death from any

cause was less than 6% in both

groups, which is extraordinarily low

in a 5-year period and probably

reflects the use of a statin throughout

and additional non-specified evi-

dence-based medicine. As a result,

the 20 per cent reduction in CHD

deaths that occurred on 80 mg ator-

vastatin was not a large enough

number to impact on overall

mortality. In this study CRP was

not reported. There were no cases of

rhabdomyolysis and both dose levels

were well tolerated with only 0.2%

of those at 10 mg and 1.2% of

those at 80 mg having reversible

liver enzyme changes. TNT extends

the philosophy of ‘‘the lower (LDL)

the better’’ to the chronic stable

patients leading to ‘‘the more it

(LDL) is lowered the more the clin-

ical benefit’’.

We have now established that lower-

ing LDL cholesterol in acute and

chronic secondary prevention patients

to 2.0 mmol/L or less confers additional

clinical benefits as well as anatomical

benefits compared with 2.6 mmol/L.

From a previous target cholesterol of

5.0 mmol/L and LDL cholesterol of

3 mmol/L we have moved to the new

targets of 4 and 2 respectively. On the

evidence base we have, atorvastatin

currently is the safest and most

effective statin available in order to

reach these targets. While statins as a

class, depending on dose, may be able

to achieve an LDL cholesterol of

2.0 mmol/L or less each agent needs

to be tested in order to establish

individual benefit and risk (it is

simply not good enough to ride on

the coat tails of atorvastatin). The

disappointing results with simvastatin

in ACS and the withdrawal of

cerivastatin only reinforce this

approach (8). Furthermore, the

rosuvastatin emphasis on increased

potency and low cost (especially

in Asia) without clinical endpoint

data or adequate safety data at all

dose levels is not the medical

approach I consider desirable.

Statins are extremely valuable and

important drugs, and for now, as

a result of the recent trials, atorvastatin

has earned its place at the forefront

of our prescribing as it is the most

likely drug to reach the new targets

safely.

Graham Jackson

Editor

REFERENCES

1. Nissen SE, Tuzcu EM, Schoenhagen P

et al. Effect of intensive compared with

moderate lipid-lowering therapy on pro-

gression of coronary atherosclerosis.

JAMA 2004; 291: 1071–1080.

2. Cannon CP, Braunwald E, McCabe CH

et al. Intensive versus moderate lipid low-

ering with statins after acute coronary syn-

dromes. N Engl J Med 2004; 350: 1495–

504.

3. Schwartz GG, Olsson AG, Ezekowitz

MD et al. Effects of atorvastatin on

early recurrent ischemic events in acute

coronary syndromes: the MIRACL

study: a randomised controlled trial.

JAMA 2001; 285: 1711–8.

4. La Rosa JC, Grundy SM, Waters DD

et al. Intensive lipid lowering with atorvas-

tatin in patients with stable coronary dis-

ease. N Engl J Med 2005; 352: 1425–35.

5. Missen SE, Tuzcu EM, Schoenhagen P

et al. Statin therapy, LDL cholesterol, C-

Reactive protein and coronary artery dis-

ease. N Engl J Med 2005; 352: 29–38.

6. Ridker PM, Cannon CP, Morrow D

et al. C-Reactive protein levels and out-

come after statin therapy. New Engl J

Med 2005; 352: 20–28.

7. Ray KK, Cannon CP, McCabe CH

et al. Early and late benefits of high-

dose atorvastatin in patients with acute

coronary syndrome. Results from the

PROVE-IT – TIMI 22 Trial. J Am

Coll Cardiol 2005; in press.

Generic prescribing – the chaos continues

For those following this campaign, this

month’s prescription for atorvastatin

was Torvast from Italy. No dates on

the blister pack and an English sticker

across six blisters. Amlodipine was

Astudal from Spain – amlodipino besi-

lato. Same problem – no dates and

sticker across the blisters. One of my

patients who is on eleven drugs has to

have her son sort out each prescription

‘‘because they are always different and

I get so confused – I burst into tears so

he now comes to help’’. There is no

point in boasting about which political

party is going to spend what on

healthcare if we have this prescribing

chaos.

Graham JacksonEditor

618 EDITORIAL

ª 2005 Blackwell Publishing Ltd Int J Clin Pract, June 2005, 59, 6, 617–618