Show me the Evidence for
Cholesterol Reduction - Part 2

AFCAPS/TexCAPS⁸

Beginning in May 1990 and ending in February 1993, a total of 5,608 men 45 to 73y and 997 post menopausal women 55 to 73y without prior ischemic heart disease, peripheral vascular disease, or cerebrovascular disease, with TC 4.65-6.82 mmoles/l, LDL 3.36-4.91 mmoles/l, triglycerides <4.53 mmoles/l and HDL<1.17 for men and <1.23 for women were recruited. Important exclusion criteria included uncontrolled hypertension, gross obesity (weight >50% above ideal), secondary hyperlipidemia, and diabetics on insulin or with HgA1C >10%. This was a placebo controlled intention to treat double blind trial using lovastatin 20mg with an up titration to 40mg if the LDL> 2.84 on treatment. Adjusting the dose of placebo in equal numbers of subjects preserved blinding. The primary end point was first acute major coronary event a composite of fatal or nonfatal MI, unstable angina, or sudden cardiac death. Average follow up was for 5.2 years. 71% of the lovastatin group and 63% of the placebo group followed study drug regimes. There were far more withdrawals from the placebo group because of requests to start a statin by the patient's primary doctor.

Over the 5 years, 5.5% of the placebo group developed the primary endpoint vs 3.5% in the treatment group (p=0.001 RR 0.67, RRR 33% ARR 2% NNT 50). Fatal and nonfatal MI showed a 40% reduction (p=0.002 RR 0.6 NNT 87). There was no difference statistically in fatal CV or CHD events and all cause mortality was clearly not changed in this relatively low risk group. Likely due to small numbers there was no statistical difference demonstrated for the primary end point in women, diabetics, nonsmokers or the various tertiles of HDL and LDL levels, however the trends were in the correct direction.

HPS⁹

Finally we will look at the last and biggest of the placebo controlled statin studies. This trial answered some questions and raised some more, as all good research does. The aim was to asses vascular and nonvascular mortality and major morbidity in a wide range of high risk patients with a wide range of starting cholesterol. Between July 1994 and May 1997, 20536 patients aged 40-80 (24.7% women) with a total cholesterol >3.5 mmoles/l and either established IHD, PVD, CVD or diabetes were randomized to 40mg simvastatin or placebo and followed till October 2001. Patients whose primary care physician felt needed to be on a statin were excluded from randomization. Provision was made as the study progressed to allow subjects in either group to go on a non study statin as indications for statins evolved rapidly during the course of this study. By the end of the study 85% of the simvastatin group were on a statin whilst 32% of the placebo group were on a statin. In the first year the LDL difference was 1.3, which decreased to 0.7 mmoles/l by the last year of the study. This diluted the results but the intention to treat analysis was still extremely impressive. The primary end point was all cause mortality, with fatal and nonfatal vascular events in subgroups as the secondary endpoint.

12.9% of patients in simvastatin group and 14.7% in the placebo group died (RR 0.87 RRR 0.13 ARR 1.8% NNT 56 p=0.0003). Major vascular events decreased 24% (RR 0.76 ARR 5.4% NNT 19). Stroke was decreased 25% (RR 0.75 ARR 1.4% NNT 71). Diabetics benefited to a similar extent as nondiabetics. This study was sufficiently large that all subgroup analysis were statistically significant and they were homogeneous. No matter what the initial cholesterol or LDL the simvastatin group had about a 25% reduction in major vascular events. Women did about as well as men and older subjects reduced their risk as much as younger subjects. All the above numbers are on an intention to treat basis. The authors estimate the simvastatin group to have a 35% risk reduction for major vascular events if the protocol had not been diluted.

Reduction in all cause mortality is the most powerful evidence for the efficacy of statin therapy in high risk groups. Simvastatin 40mg a day was demonstrated to be equally efficacious in all subgroups and suggests that all high risk patients with a total cholesterol >3.5 (which included a substantial number of patients with an LDL<2.5 at base line) should go on simvastatin 40 mg or its equivalent irrespective of their starting LDL. It also raises the question: must we try and get their LDL <2.5 mmoles/l even when they are on an adequate dose of a statin?

PROSPER¹⁰

2002 also saw the publication of the PROSPER trial involving 40 mg of pravastatin in 5,804 men and women aged 70-82y with a cholesterol of 4.0-9.0 mmoles/l. These subjects either had vascular disease or were at high risk due to hypertension, diabetes or smoking. 52% were women. Follow up was for 3.2 years. The primary end point was a composite of coronary death, nonfatal MI, and fatal and nonfatal stroke. Pravastatin reduced LDL by 34%. There was a 15% reduction in the primary endpoint (RR 0.85 ARR 2.1% NNT 48 p= 0.014). The more familiar end point of coronary death and nonfatal MI was reduced by 19% (RR 0.81 ARR 2.1% NNT 48 p=0.006) There was no difference in stroke or all cause mortality.

By this time atorvastatin had been available for several years. It had never been subjected to a large scale double blind placebo controlled trial because the benefit of lipid lowering had been firmly established in multiple high risk groups and placebo controlled trials could not pass ethics review. However there was an interesting trial published in a minor medical journal by researchers from Greece.

GREACE¹¹

At the time of trial design the Greek government did not cover the cost of statin therapy. The researchers designed this trial to embarrass the government into changing its stance. Interestingly this is the only trial that actually treated patients to a LDL target of 2.6 mmoles/l. 1600 consecutive patients with established CHD were randomized to atorvastatin therapy at a specialized clinic or to "usual" care (only 14% of this group got any lipid lowering therapy and only 3% got to an LDL <2.6) and followed for a mean of 3 years. The atorvastatin was titrated up to 80 mg/day to reach an LDL target <2.6. The mean dose of atorvastatin was 24 mg/day. Cholesterol was lowered 36% LDL by 46% triglycerides by 31% and HDL increased by 7%. Target was reached by 95% of patients. 24.5% of the placebo group vs 12% of the statin group developed the primary end point of recurrent CHD event or death. (RR 0.49 RRR 51% ARR 12.5 NNT 8 p<0.0001) This is a very impressive result and better than any other trails before or since. However it was not double blinded and is unclear if it was single blinded adding a possible bias to the results.

By the late 1990's it was clear that pravastatin had the most trial evidence behind it. Atorvastatin was the new kid on the block. Large scale placebo controlled trials with this new drug would be unethical so it needed to be compared to established therapies.

PROVE IT-TIMI 22¹²

Between November 2000 and December 2001, 4,162 patients (78% male, 17% diabetics, 25% prior statin use average age 58y) >18 y were enrolled within 10 days of admission for acute MI or high risk unstable angina. Cholesterol had to be <6.2 within the first 24 hrs of admission or within the last 6 months. Patients already on lipid lowering therapy had to have cholesterol <5.2 mmoles/l. Patients were randomized to 40 mg of pravastatin or 80 mg of atorvastatin (with doubling of the pravastatin dose if the LDL >3.2 on treatment) in a double blinded protocol. The dose of either drug could be halved in the event of abnormal liver enzymes, elevated CPK or myalgia. The patients were followed for 18 to 36 month. The primary endpoint was a composite of death from any cause, MI, documented unstable. angina requiring rehospitalization, revascularization > 30 days after randomization and stroke. Median LDL was 2.7 before randomization and dropped to 2.46 in the pravastatin group and 1.6 in the atorvastatin group. HDL increased 8% in the pravastatin group and 6.5% in the atorvastatin group.

The primary end point was reached in 26.3% of the pravastatin group and 22.4% of the atorvastatin group at 2 years of follow up, a 16% difference (RR 0.84 ARR 3.9% NNT 26 P=0.005). The benefit was consistent across the prespecified subgroups including men and women, patients with unstable angina or MI as the qualifying event and in diabetics and non-diabetics. The benefit was greater amongst patients with an initial LDL> 3.25 with a 34% reduction vs a 7% reduction in patients with an LDL < 3.25 mmoles/l (p=0.02 for the interaction). There was a trend to wards a reduction in all cause mortality and the composite end point of death or MI.

The rate of discontinuation either from adverse events or patient preference was 21.4% vs 22.8% at 1 year and 33% vs 30.4% at 2 years in the pravastatin vs atorvastatin groups (difference not significant). 1.1% vs 3.3% of patients developed an ALT >3X the upper limit of normal in the 2 groups (p<0.001). Investigators discontinued medication due to myalgia or rise in CPK in 2.7% vs 3.3% of cases in the 2 groups (p=0.23)

There are several lessons here. Many of the patients in the study group had starting LDL < 2.5 and they benefited more from atorvastatin, although the magnitude of the benefit was lower than those with higher starting LDLs. The median LDL on treatment was far lower than current targets in the atorvastatin group. Far more patients stopped taking the study drugs due to their preference than were told to by their investigators due to safety concerns. We see this every day in clinical practice.

Atorvastatin was compared to pravastatin in PROVE IT, it was also compared to itself in TNT, another important trial we will look at.

TNT¹³

The hypothesis of this trial was: reducing LDL to far below 2.6 mmoles/l in patients with patients with stable CHD would result in incremental benefit when compared to a group treated to conventional targets. The study design is complicated and ended up comparing 2 doses of atorvastatin not 2 different LDL targets as there were no dose adjustments after randomization.

Eligible subjects were between 35 and 75 with clinically evident CHD (prior MI, prior revascularization or objectively demonstrated angina). All lipid lowering therapy was stopped for 1 to 8 weeks. All patients with LDL between 3.4 and 6.5 and triglycerides < 6.8 entered an 8 week run in phase with atorvastatin 10mg. At the end of run in, subjects with an LDL < 3.4 were randomized in a double blind fashion to 10mg or 80mg of atorvastatin daily. They were then followed for a median of 4.9 years. 18,469 were screened, 15,464 entered the run in phase and 10,003 were randomized (81% male, 15% diabetics, average LDL 2.6 on 10 mg of atorvastatin). 5461 subjects were excluded after run in for a variety of reasons, 680 for not meeting the lipid criteria. The primary endpoint was occurrence of the first major CV event (death from CHD, non fatal non procedure related MI, resuscitation after cardiac arrest or fatal or nonfatal stroke). The study was not adequately powered to demonstrate a change in all cause mortality. During the run in phase LDL was lowered 35% to a mean of 2.6 mmoles/l and in the 80 mg group it was father lowered to a mean of 2.0 mmoles/l. These lipid levels stayed steady during the course of the study. Neither dose of atorvastatin increased HDL to a significant degree.

8.7% of the high dose group and 10.9% of the low dose group had a primary event (RR 0.79 RRR 21% ARR 2.2% NNT 45 p<0.001). Death from CHD was decreased by 20% (ARR 0.5% NNT 200) There was absolutely no difference in death from any cause in the face of reduced death from CHD. There were 127 (2.5%) deaths from non CV causes in the low dose group and 158 (3.2%) deaths in the high dose group (RR 1.25 absolute risk increase 0.7% number needed to harm-NNH 143 p=0.06). This p value is just above the threshold of significance but still this result is worrying and reminiscent of the results of the Helsinki heart study.

Adverse events occurred in 8.1% of patients given 80mg vs 5.8% given 10mg of atorvastatin. (RR 1.4 ARI 2.3% NNH 43 p<0.001) Discontinuation rates due to adverse events were 7.2% vs 5.3%. Interestingly treatment related myalgia was about 4.8% in both groups. There were 1.2% vs 0.2% rate in the high vs low dose group for persistent elevations in AST or ALT (p<0.001 NNH 100). There was no elevations in CPK >10X ULN and 2 cases of rhabdomyolisis in the high dose vs 3 cases in the low dose group. Remember randomization occurred after the screened group was tested for tolerability to 10 mg of the drug and 35% of that group excluded a proiri. Safety results in routine clinical practice are likely to be worse.

More intensive lowering of LDL was also looked at in the IDEAL trial, which compared 2 different strategies of lipid lowering (note they do not mention 2 different targets!) by comparing 20 mg simvastatin against 80 mg atorvastatin.

IDEAL¹⁵

This is a prospective randomized open label blinded endpoint classification trial design (single blind). Between March 1999 and March 2001, 9,689 patients from northern Europe < 80y with a previous MI and qualified for statin therapy according to prevalent national guidelines were screened. Exclusion criteria were known contraindication to statin therapy, previous intolerance to statins, liver enzymes > 2X ULN, nephritic syndrome, pregnancy, uncontrolled diabetes, severe CHF, triglycerides > 6.8 mmoles/l, and use of non statin lipid lowering drugs or on statins at a dose equivalent to >20 mg of simvastatin. 801 were excluded and 8888 randomized (81% male, 33% hypertensive, 12% diabetic, 74% on prior statin therapy) to 20 mg simvastatin or 80 mg atorvastatin and followed for a median of 4.8 years. If the total cholesterol was >5 mmoles/l, the dose of simvastatin could increase to 40 mg, and the dose of atorvastatin could reduce to 40 mg for adverse events. The primary endpoint was a composite of major coronary events defined as coronary death, confirmed non-fatal MI, or cardiac arrest with resuscitation. During treatment mean LDL in the simvastatin group was 2.7 mmoles/l with 23% of subjects on 40 mg, and 2.1 mmoles/l in the atorvastatin group with 13% of the subjects on 40 mg. The simvastatin treated group had a slight but statistically significant increase in HDL (numbers not reported).

10.4% of the simvastatin group and 9.3% of the atorvastatin developed the primary endpoint (RR 0.89 p=0.07). This is a non significant result. There was absolutely no difference in CHD death or all cause mortality. In the atorvastatin group nonfatal MI was reduced by 17% (RR 0.83 ARR 1.2% NNT 83 p=0.02). Any CHD event was reduced by 16% (RR 0.84 ARR 3.6% NNT 28 P<0.001). Any CV event was reduced by 16% (RR 0.84 ARR 4.3% NNT 23 P<0.001). Reassuringly there was no suggestion of an excess of non-CV deaths in the high dose atorvastatin group.

Overall adherence to the study medications was excellent with 86% of subjects on atorvastatin and 93% of the simvastatin group still on their medication at the end of the study. Interestingly an astonishingly large 95% of subjects in both groups reported an adverse event of some kind. 9.6% of the atorvastatin group stopped the study drug due to an adverse event vs 4.2% in the simvastatin group (RR 2.29 NNH 19 p<0.001). Myalgia, nausea, diarrhea, abdominal pain and elevation in liver enzymes were all higher in the atorvastatin group. A note of caution here: over 50% of the subjects were on simvastatin vs 11% on atorvastatin prior to randomization so they were pre selected as statin tolerant, mostly to simvastatin.

In summary this was essentially a negative trial, which failed to demonstrate superiority of high dose atorvastatin over lower dose simvastatin in the primary end point. Reassuringly there were no excess non CV deaths in the high dose atorvastatin group. Too bad it was not done using the HPS dose of 40 mg simvastatin.

After the results of TNT and PROVE IT the American guidelines introduced a target LDL of 1.8 mmoles/l for patients at very high risk.¹⁴ There we go again with a target lipid level and not a target statin dose. What if you do not meet the target on a maximal dose of a well studied potent statin? There is little hard point evidence to find in the literature for combination therapy with drugs like niacin, fibrates or ezetimibe. There also have been very few statin studies done to a lipid target with the vast majority of trials done treating to a dose.

Will you go wrong if you put your high risk patients on a dose of simvastatin 40 mg or equivalent dose of another statin such as atorvastatin 20 mg and not worry about the resulting LDL level? Time will tell.

- Farokh Buhariwalla CCFP

Thanks to Hector Baillie FRCP and Richard Lewanczuk FRCP for reviewing the draft copy of this article.

1. Genest J, Frohlich J, Fodor G, McPherson R (the Working Group on Hypercholesterolemia and Other Dyslipidemias). Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the 2003 update. CMAJ 2003;169(9):921-4
 
2. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet. 1994 Nov 19;344(8934):1383-9.
 
3. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998 Jul 23;339(4):229-34.
 
4. Pyörälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G, Scandinavian Simvastatin Survival Study (4S) Group. Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease: a subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997;20:614-620
 
5. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995 Nov 16;333(20):1301-7.
 
6. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med. 1996 Oct 3;335(14):1001-9.
 
7. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998 Nov 5;339(19):1349-57.
 
8. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998 May 27;279(20):1615-22.
 
9. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002 Jul 6;360(9326):7-22.
 
10. Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG; PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002 Nov 23;360(9346):1623-30.
 
11. Treatment with atorvastatin to the National Cholesterol Educational Program goal versus 'usual' care in secondary coronary heart disease prevention. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis AN, Basayannis EO, Demitriadis DS, Kontopoulos AG. Curr Med Res Opin. 2002;18(4):220-8.
 
12. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV, Hill KA, Pfeffer MA, Skene AM; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004 Apr 8;350(15):1495-504. Epub 2004 Mar 8. Erratum in: N Engl J Med. 2006 Feb 16;354(7):778.
 
13. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease.N Engl J Med. 2005 Apr 7;352(14):1425-35. Epub 2005 Mar 8.
 
14. Grundy SM, Cleeman JI, Merz CN, et al: Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004; 110: 227-39.
  
15. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, Larsen ML, Bendiksen FS, Lindahl C, Szarek M, Tsai J; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005 Nov 16;294(19):2437-45. Erratum in: JAMA. 2005 Dec 28;294(24):3092.