Expert Opinion: lipid modification

The NICE guidance on lipids recognises that some patients need more intensive therapy. By Dr Rob Butler

ABSTRACT

Robust data from randomised controlled trials have increased the role of intensive statin therapy, which was limited primarily to high-risk individuals. Then the advent of generic simvastatin caused widespread switching. The move towards generic prescribing is a laudable aim, but is constrained by its use as a cost-reduction, rather than cost-effectiveness, strategy.

Key words
Statins, intensive therapy, generic simvastatin.

The drive towards generic moderate intensity statin prescribing for all goes against much of the published data comparing moderate to intensive statin therapy. NICE recommendations on lipid modification accept that high-risk patients need more intensive therapy. The guidance has three key sections - primary prevention, secondary prevention and acute coronary syndromes (ACS). This article will consider treatment targets and intensive statin therapy.

Primary prevention
The guidance seeks to identify patients aged 40-74 years who are at increased risk of cardiovascular disease (CVD), using the 10-year Framingham risk equation. This represents the 10-year CHD risk (coronary death, ACS and angina) plus 10-year stroke/TIA risk. It makes specific recommendations regarding risk adjustment for South Asians (x1.4) and those with strong family history (x1.5 for one family member, x2 for two or more).

The guidance asks healthcare professionals to couch the risk of events and the benefit of treatment in absolute terms. It goes on to make reasonable suggestions regarding a cardioprotective diet, smoking cessation, physical activity, weight reduction and alcohol consumption.

Statin recommendations are clear - simvastatin 40mg is the preferred agent. It is relatively cheap and moderately effective, with an average reduction in cholesterol of 38 per cent from CURVES1 and STELLAR.2 However, other recommendations are more contentious, for example, the lack of a target and the lack of requirement for further measurement of cholesterol.

The 'fire and forget' strategy has a role, but my concern is regarding those patients with cholesterol levels of 8mmol/L or more, who will be unlikely to hit the conservative target of total cholesterol (TC) 5mmol/L and LDL 3mmol/L. However, even some patients with cholesterol >7mmol/L may not hit this target. Without mandating a repeat test of cholesterol, the efficacy of treatment cannot be assessed and some patients may be exposed to continuing cardiovascular risk.

It may be argued that even in primary prevention, simvastatin 40mg should be the starting therapeutic position, and if on retesting, patients do not achieve TC <5mmol/L and LDL <3mmol/L, statin treatment should be escalated. I would prefer to see this escalation of therapy: simvastatin 40mg, atorvastatin 40mg, atorvastatin 80mg and finally, atorvastatin 80mg with ezetimibe 10mg.

Rosuvastatin may prove the more potent statin in future, but as yet, the evidence base is not in its favour. Simvastatin 80mg may not be a viable alternative, because it may be associated with an increased risk of rhabdomyolysis compared to other statins.

Secondary prevention
The guidance suggests initial lipid-lowering therapy should be with simvastatin 40mg for all patients with clinical evidence of CVD (see box 1). It makes a case for more aggressive lipid-lowering targets (TC <4mmol/L, LDL <2mmol/L) than had been advised by the DoH (TC ≤5mmol/L, LDL ≤3mmol/L) and the quality framework (TC ≤5mmol/L, LDL ≤3mmol/L)

BOX 1: TARGET CHOLESTEROL LEVELS
Total cholesterolLDL
DoH≤5mmol/L≤3mmol/L
Quality framework≤5mmol/L≤3mmol/L
NICE audit standard≤5mmol/L≤3mmol/L
JBS2<4mmol/L<2mmol/L
NICE<4mmol/L<2mmol/L

However, it offers an audit standard of TC ≤5mmol/L and LDL ≤3mmol/L, which is likely to be the one picked up by the latest iteration of the quality framework, making it the de facto standard of care, which may prove a missed opportunity.

Clinicians have the opportunity to use the more intensive targets for patients with IHD (angina or ACS), cerebrovascular and peripheral vascular disease or other symptomatic atherosclerotic disease, such as hypertension.

Unfortunately, the guidance excludes patients with diabetes, which some would class as a 'symptomatic atherosclerotic disease'. Fortunately, the updated guidance for type-2 diabetes identifies all patients with type-2 diabetes as requiring lipid-lowering therapy, with a target of TC 4mmol/L and LDL 2mmol/L. Every patient with demonstrable CVD should be on a statin. The many people excluded, missed or suboptimally treated should be captured and their treatment improved. Despite arguments for more intensive lipid-lowering strategies in higher-risk individuals, there is compelling evidence to support simvastatin 40mg as better than nothing.

Acute coronary syndromes
The guidance is vague about managing ACS. Cardiovascular risk management is being driven by care pathways and protocols using clinical targets derived from various sources. In ACS patients, intensive statin therapy reduces events compared to moderate therapy and if therapy is commenced early enough, real improvements are possible.

Intensive statin therapy is accepted to include simvastatin 80mg, atorvastatin 80mg and rosuvastatin >20mg, although I only accept the latter two. The differences are well demonstrated in dose-ranging studies, such as CURVES1 and STELLAR.2 According to the data from STELLAR, only rosuvastatin 20-40mg and atorvastatin 80mg cross a mean percentage reduction in LDL of 50 per cent. Simvastatin 80mg does not reduce LDL by 50 per cent.

It is counterintuitive to accept a therapy that is 12-13 per cent less effective in reducing cholesterol levels. Data from the Cholesterol Treatment Trialists (CTT)3 collaboration meta-analysis of 14 randomised controlled trials (involving more than 90,000 patients) demonstrate a 0.2mmol/L reduction in LDL with 48 fewer cardiovascular events for every 1,000 patients treated. In other words, a 1mmol/L reduction of LDL maintained for five years will reduce cardiovascular events by 23 per cent. This was irrespective of the drug or the starting level of LDL.

Data from REVERSAL4 and ASTEROID5 suggest high-dose atorvastatin and rosuvastatin may arrest plaque progression. These studies showed for the first time that intensive statin therapy, not moderate therapy, could arrest or reverse plaque progression, an effect seen only with >50 per cent reduction in LDL. This magnitude of LDL reduction is only seen with atorvastatin 80mg or rosuvastatin >20mg.

PROVE-IT6 compared atorvastatin 80mg with pravastatin 40mg in 4,162 patients who had been hospitalised for a recent ACS, to establish the non-inferiority of pravastatin compared with atorvastatin.

This study demonstrated a reduction in the primary event rate with intensive statin therapy compared with moderate therapy (26.3 per cent pravastatin v 22.4 per cent atorvastatin p = 0.005, 95 per cent CI 5-26 per cent, NNT 26 over two years). It is this pivotal study that drives the case for intensive statin therapy in ACS patients.

The A to Z study7 was a double-blind randomised controlled trial of ACS patients who received an initial 40mg per day of simvastatin for one month, followed by 80mg per day thereafter (n = 2,265), compared with ACS patients receiving placebo for four months followed by 20mg per day of simvastatin (n = 2,232).

The reduction in major adverse cardiovascular events was a trend towards supporting intensive statin therapy and not statistically significant. This is the only examination of high-dose simvastatin in ACS patients and it failed to reach its primary endpoint, which must hamper the continued recommendation for simvastatin 80mg in the NICE guidance.

Wiviott's analysis of PROVE-IT and A to Z8 considers both trials and amalgamates their data. This is a post hoc analysis of two studies, although their excellent access to data allowed for a thorough analysis. The conclusion is that the major reasons for A to Z's apparent underperformance are premature conclusion of the study and the frequency of revascularisation.

Meta-analysis seems to suggest a strong and cogent case for intensive statin therapy in patients with a recent ACS or stable angina. The magnitude of effect with intensive statin therapy is larger for ACS patients than that seen in stable CHD. The more aggressively ACS patients are treated with early catheterisation and revascularisation strategies, the more they seem to benefit from intensive statin therapies.

Cannon et al9 reviewed data from TNT, IDEAL, A to Z and PROVE-IT. This meta-analysis investigated 27,548 patients (>100,000 patient-years) randomised to intensive versus moderate statin therapy. The combined analysis revealed a 16 per cent OR in coronary death or MI (p <0.00001) and a reduction of 16 per cent in coronary death or any cardiovascular event (p <0.00001).

A trend was also observed in cardiovascular mortality with an OR of 12 per cent (p = 0.054). This is as expected, because most studies of statins have indicated that their primary mode of action is to reduce the risk of recurrent ACS, ischaemia-driven revascularisation and stroke.

Another meta-analysis included TNT, IDEAL, A to Z and PROVE-IT, as well as VASCULAR BASIS10 and REVERSAL.4 Patients with a recent ACS benefited from a reduction in all cause mortality from 4.6 per cent to 3.5 per cent with intensive statin therapy (95 per cent CI 0.61-0.93), but this effect on all cause mortality was not seen in stable CHD patients.

The case for intensive statin therapy in ACS is clear and mandated by NICE. The debate is now about agent and dose.

- Dr Rob Butler is consultant cardiologist at the University Hospital of North Staffordshire NHS Trust, Stoke on Trent.

Competing interests: Dr Butler has received speaker fees from Pfizer, Astra Zeneca, Bristol Myers Squibb, Sanofi Aventis, Eli Lilly and Schering Plough. He has attended advisory boards for Pfizer and Takeda. His attendance at cardiology conferences has been courtesy of Boston Scientific, Medtronic and Sanofi Aventis. He has received investigator initiated research funding from Pfizer.

References
1. Jones P, Kafonek S, Laurora I et al. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study). Am J Cardiol 1998 Mar 1; 81(5): 582-7.
2. Jones PH, Davidson MH, Stein EA et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol 2003 Jul 15; 92(2): 152-60.
3. Juliard JM, Himbert D, Cristofini P et al. A matched comparison of the combination of prehospital thrombolysis and standby rescue angioplasty with primary angioplasty. Am J Cardiol 1999 Feb 1; 83(3): 305-10.
4. Nissen SE, Tuzcu EM, Schoenhagen P et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004 Mar 3; 291(9): 1071-80.
5. Nissen SE, Nicholls SJ, Sipahi I et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006 Apr 5; 295(13): 1556-65.
6. Cannon CP, Braunwald E, McCabe CH et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Eng J Med 2004 Apr 8; 350(15): 1495-504.
7. De Lemos JA, Blazing MA, Wiviott SD et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004 Sep 15; 292(11): 1307-16.
8. Wiviott SD, de Lemos JA, Cannon CP et al. A tale of two trials: a comparison of the post-acute coronary syndrome lipid-lowering trials A to Z and PROVE IT-TIMI 22. Circulation 2006 Mar 21; 113(11): 1406-14.
9. Cannon CP, Steinberg BA, Murphy SA et al. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006 Aug 1; 48(3): 438-45.
10. Stone PH, Lloyd-Jones DM, Kinlay S et al. Effect of intensive lipid lowering, with or without antioxidant vitamins, compared with moderate lipid lowering on myocardial ischemia in patients with stable coronary artery disease: the Vascular Basis for the Treatment of Myocardial Ischemia Study. Circulation 2005 Apr 12; 111(14): 1747-55.

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