Cholesterol















Hyperlipidemia - Recent Landmark Trials

HPS
ASCOT
REVERSAL
PROVE-IT
CARDS
TNT
• FIELD Study
ASTEROID
JUPITER

 

 

HPS 1
The Heart Protection Study (HPS) enrolled patients 40-80 years old, with vascular disease and or diabetes and a total cholesterol > 3.5 mmol/L in whom there was uncertainty whether cholesterol lowering was indicated. Patients were randomized to treatment with simvastatin 40 mg daily or placebo and followed for five years. Simvastatin reduced cardiovascular mortality by 17%, all cause mortality by 13%, major coronary events by 27%, stroke by 25% and need for revascularization by 24%. No evidence was observed to suggest a threshold below which lowering LDL cholesterol would not reduce risk. The benefits were similar for patients < 65, 65-70, and > 70 years old. The 1263 patients age 75-80 at entry and hence age 80-85 at the end of the study derived an equivalent reduction in major vascular events of about 25% RRR: 9.2% ARR (142 vs 209, p=0.002).

Interpretation: HPS suggests that all patients with a history of coronary disease, other occlusive arterial disease, or diabetes benefit from statin therapy with simvastatin 40 mg regardless of age, gender or baseline lipid parameters. Persistent liver function abnormalities were rare 0.09% simvastatin vs 0.04% placebo (p=0.3). Similarly muscle pain symptoms and myopathy were not statistically different on statin or placebo. This suggests that monitoring of liver and muscle enzymes may not be indicated and that full dose statin therapy with simvastatin 40 mg is generally safe across the study population.

 

ASCOT 2

The ASCOT Trial enrolled patients aged 40–79 years with hypertension and at least three other cardiovascular risk factors including left-ventricular hypertrophy, other specified abnormalities on electrocardiogram, type 2 diabetes, peripheral arterial disease, previous stroke or transient ischaemic attack, male sex, age 55 years or older, microalbuminuria or proteinuria, smoking, ratio of plasma total cholesterol to HDL-cholesterol of 6 or higher, or premature family history of CHD. Patients were randomized to receive one of two anti-hypertensive regimens in a PROBE design. Additionally patients with a fasting cholesterol < 6.5 mmol/L were eligible for the Lipid Lowering Arm of ASCOT. In this arm patients were randomized to receive either atorvastatin 10 mg. or placebo. Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L (24%) and compared with placebo at 12 months, and by 1.1 mmol/L (19%) and 1.0 mmol/L after 3 years of follow-up. Atorvastatin lowered LDL by 1.2 mmol/L (35%) compared with placebo at 12 months, and by 1.0 mmol/L (29%) after 3 years of follow-up.

The planned follow-up was for an average of 5 years, the primary endpoint being non-fatal myocardial infarction and fatal CHD. Data were analysed by intention to treat. The hypertension arm of the study is still ongoing, however on Sept 2, 2002 the Lipid Lowering arm was stopped, after a mean follow-up of 3.3 years, due to benefit.

By that time, 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0.64 [95% CI 0.50–0.83], p=0.0005). This benefit emerged in the first year of follow-up. Fatal and non-fatal stroke (89 atorvastatin vs 121 placebo, 0.73 [0.56–0.96], p=0.024), total cardiovascular events (389 vs 486, 0.79 [0.69–0..0], p=0·0005), and total coronary events (178 vs 247, 0.71 [0.59–0.86], p=0.0005) were also significantly lowered. There were 185 deaths in the atorvastatin group and 212 in the placebo group (0.87 [0.71–1.06], p=0.16).

Interpretation: The reductions in major cardiovascular events with atorvastatin are large, given the short follow-up time. These findings may have implications for future lipid-lowering guidelines. ASCOT confirms and extends the benefits of lipid lowering beyond WOSCOPS and AFCAPS/TexCAPS to a primary prevention hypertensive population at moderate risk for cardiovascular events. The 36% RRR and 3.4 ARR (NNT 30) of the primary end-point (fatal CHD and non-fatal MI) is highly clinically significant. In all likelihood the benefit would have been greater had the atorvastatin dose been titrated, had both study arms not had their hypertension treated and controlled and had the planned study follow-up of 5 years been completed. ASCOT along with HPS sets the bar for a minimum therapeutic efficacy for clinical benefit, a so-called HPS/ASCOT dose equivalency of simvastatin 40 mg. or atorvastatin 10 mg. See Statin Efficacy Grid.

 

REVERSAL 3
The REVERSAL trial randomized 654 patients with symptomatic coronary artery disease, a 20% or greater stenosis by angiography, and LDL levels between 3.24 and 5.44 mmol/L to receive either pravastatin 40 mg or atorvastatin 80 mg. IVUS of a single target coronary was performed before randomization and after 18 months of treatment. Some patients withdrew, mainly because of reluctance to undergo a repeat cath for research purposes, with before and after results available for 502 patients.

Baseline low-density lipoprotein cholesterol level (mean, 3.89 mmol/L) in both treatment groups was reduced to 2.85 mmol/L in the pravastatin group and to 2.05 mmol/L in the atorvastatin group (P <.001). Intensive lipid lowering with atorvastatin 80 mg achieved a mean LDL reduction of 46.3% compared with moderate lipid lowering with pravastatin 40 mg which produced LDL reduction of 25.2%.C-reactive protein decreased 5.2% with pravastatin and 36.4% with atorvastatin (P<.001).

The primary end point was percent change in atheroma volume, which showed a 2.7% increase in the pravastatin group and a 0.4% non-significant reduction in the atorvastatin group (P= 0.02). Secondary end points including change in total atheroma volume (P= 0.02), change in percentage atheroma volume ((P=0.001), and change in atheroma volume in the most severely diseased 10-mm vessel sub-segment (P=0.01) showed progression in the pravastatin group but no change in the atorvastatin group.
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Interpretation: In patients with chronic coronary artery disease, intensive lipid-lowering treatment with atorvastatin reduced progression of coronary atherosclerosis compared with pravastatin. Compared with baseline values, patients treated with atorvastatin had no change in atheroma burden, whereas patients treated with pravastatin showed progression of coronary atherosclerosis as determined by quantitative IVUS. These differences may be related to the greater reduction in atherogenic lipoproteins and C- reactive protein in patients treated with atorvastatin. The bar or minimal LDL reduction required to arrest atherosclerotic progression appears to be ~ 45%. Whether this surrogate endpoint can be validated awaits the publication of an equivalent outcome trial.

 

PROVE-IT 4

The PROVE IT trial randomized 4162 patients within 10 days of hospitalization for acute coronary syndrome (ACS-1/3 with unstable angina, 1/3 with non-ST elevation MI and 1/3 with ST elevation MI) to either standard therapy with pravastatin 40 mg or intensive therapy with atorvastatin 80 mg. Patients had to have a baseline total cholesterol of 6.21 mmol/l or less of lipid lowering therapy or 5.18 mmol/L or less on lipid lowering therapy and be clinically stable.
Baseline median LDL cholesterol in both groups was 2.74 mmol/L in both groups. Standard lipid lowering therapy with pravastatin 40 mg achieved a mean LDL of 2.46 mmol/L. Intensive lipid lowering therapy with atorvastatin 80 mg achieved a mean LDL of 1.6 mmol/L (P<0.001). Of the 75% of patients who were statin naïve LDL fell 22% with pravastatin 40 mg and 51 % with atorvastatin 80 mg. Tolerability, discontinuation and safety of the two medications were equivalent although there was a significant difference in liver function abnormalities with atorvastatin (3.3%) vs pravastatin (1.1%, P<0.001).

The primary endpoint was time to first occurrence of a component of the primary endpoint: death from any cause, MI, hospital admission for unstable angina, PCI, CABG or stroke. Event rates for the primary endpoint at two years were 26.3% in the standard dose pravastatin group and 22.4% in the intensive dose atorvastatin group (ARR 3.9%, RRR 16%, NNT 26 patients, P=0.005). The benefit of intensive therapy with atorvastatin emerged by 30 days. The secondary endpoint of combined death due to CHD, MI or revascularization was similarly reduced from 22.3 to 19.7 % (ARR 2.6%, RRR 14 %, NNT 38, P<0.001). The risk of death, MI or urgent revascularization was similarly reduced by 25% RRR. Benefits were consistent across pre-specified subgroups including gender, unstable angina vs MII and presence or absence of diabetes. Benefit was greater amongst those with baseline LDL ≥ 3.125 mmol/L vs those with baseline LDL < 3.125 mmol/L. (RRR 34% vs. 7%, P=0.02).

Interpretation:PROVE IT–TIMI 22 validates intensive lipid lowering therapy with atorvastatin 80 mg vs standard intensive lipid lowering therapy with pravastatin 40 mg and sets the bar or minimum LDL reduction in acute coronary syndrome, unstable angina, non-ST elevation MI and ST elevation MI at ~ 50%. This study validates the utility of IVUS as a surrogate marker for cardiovascular outcome and raises the LDL reduction bar in chronic CAD to ~ 50%. The combination of the REVERSAL and PROVE-IT trials along with ALLIANCE Trial comparing intensive lipid lowering therapy with atorvastatin 80 mg vs “usual care” which showed similar results likely lead to a redefinition of the LDL target for patients with CHD, cerebrovascular disease, peripheral vascular disease and CHD equivalent disease such as diabetes. It is anticipated that the LDL target in these patients should be at least < 2.0 mmol/L and probably < 1.8 mmol/L.

 

CARDS 5

The CARDS Trial randomized 2838 patients with type 2 diabetes > 6 months and one of a history of hypertension, retinopathy, micro or macroalbuminuria or current smoking. Patients with a history of coronary artery disease, cerebral or peripheral vascular disease were excluded. Baseline LDL had to be 4.14 mmol/L or lower. Patients received either atorvastatin 10 mg or placebo. Mean follow-up was 4 years and the study was terminated 2 years early due to benefit.

The primary endpoint was the occurrence of the first of acute CHD even, either: acute MI, unstable angina, acute CHD death, resuscitated cardiac arrest, coronary revascularization or stroke. Mean baseline LDL was 3.02 mmol/L in the placebo arm and 3.04 mmol/L in the atorvastatin arm. During the treatment phase the mean LDL in the atorvastatin group was2.0 mmol/L. (40% LDL reduction from baseline).

Allocation to atorvastatin was associated with a 37% reduction in the incidence of major cardiovascular events, 36% reduction in acute coronary events, 31% in coronary revascularization events and 48% reduction in stroke. Absolute risk reductions were 3.2% in the incidence of major cardiovascular events, 1.9% reduction in acute coronary events, 0.7% in coronary revascularization events and 1.3% reduction in stroke. The NNT to prevent one major cardiovascular event was 27 patients over 4 years. The treatment benefit did not differ by pre-treatment cholesterol level. Adverse events rates were similar to placebo.

Interpretation: Treatment of type 2 diabetic patients who have comorbidities including hypertension, retinopathy albuminuria or smoking with atorvastatin 10 mg resulted in significant reductions in the rate of major cardiovascular events and in particular stroke. The 40% reduction in LDL from a baseline of 3.04 mmol/L and an achieved LDL of 2.0 mmol/L sets the bar for vascular disease prevention in this high risk population to at least 40% below initial LDL values whatever that value might be. This study confirms the findings of HPS and ASCOT-LLT in terms of minimal lipid lowering therapy and LDL target < 2 mmol/l in type 2 diabetic patients. Whether this benefit constitutes “primary prevention” in a type 2 diabetic population or “secondary prevention” in a high risk population with occult vascular disease is moot. The benefits of lipid lowering therapy in this population are clear and such should be generally applied in this patient population.

 

TNT 6

TNT randomized a total of 10,001 patients with clinicallyevident CHD and LDL cholesterol levels of less than 3.4 mmol per liter to double-blindtherapy with either 10 mg or 80 mg of atorvastatin perday. Patients were initially given open label atorvastatin 10 mg  in a run in period of 8 weeks. 5461 patients were excluded, primarily for not meeting entry criteria. Atorvastatin 10 mg lowered the LDL from a mean of 3.92 mmol/L to 2.6 mmol/L (36%). 5006 patients were randomized to receive atorvastatin 10 mg and 4995 patients received atorvastatin 80 mg. Patients were followed for a median of 4.9 years. Atorvastatin 80 mg lowered LDL to a mean of  2.0 mmol/L (50%).

The primaryend point was the occurrence of a first major cardiovascularevent, defined as death from CHD, nonfatal non-procedure-relatedmyocardial infarction, resuscitation after cardiac arrest or  fatal or nonfatal stroke.

Results: A primary event occurred in 434 patients (8.7 percent) receiving80 mg of atorvastatin, as compared with 548 patients (10.9 percent)receiving 10 mg of atorvastatin, representing an absolute reductionin the rate of major cardiovascular events of 2.2 percent anda 22 percent relative reduction in risk (hazard ratio, 0.78;95 percent confidence interval, 0.69 to 0.89; P<0.001). Therewas no difference between the two treatment groups in overallmortality.

Secondary events reductions included significant reductions in the risk of a major coronaryevent (hazard ratio, 0.80; 95 percent confidence interval, 0.69 to 0.92; P=0.002), any coronary event (hazard ratio, 0.79; 95 percent confidence interval, 0.73 to 0.86; P<0.001), a cerebrovascular event (hazard ratio, 0.77; 95 percent confidence interval, 0.64 to 0.93; P=0.007), hospitalization with a primary diagnosis of congestive heart failure (hazard ratio, 0.74; 95 percent confidence interval, 0.59 to 0.94; P=0.01), and any cardiovascular event (hazard ratio, 0.81; 95 percent confidence interval, 0.75 to 0.87; P<0.001).

The incidence of persistent elevations in liver aminotransferaselevels was 0.2 percent in the group given 10 mg of atorvastatinand 1.2 percent in the group given 80 mg of atorvastatin (P<0.001).

Interpretation: TNT validates reductions in cardiovascular events in patients with stable CHD with more intensive LDL reductions to below current CWG recommendations. The study was underpowered to detect a mortality benefit. The NNT with intensive lipid lowering versus less intensive lipid lowering in order to prevent a cardiovascular event is approximately 30 patients. The additional clinical benefit of more intensive lipid lowering in patients with stable CAD will likely result in a revision of the CWG recommendations to a LDL of  at least < 2 mmol/L and again probably < 1.8 mmol/L.

 

FIELD Study 7


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ASTEROID 8
The REVERSAL trial demonstrated slowing or halting of atherosclerosis progression with statin therapy but did not show convincing evidence of regression using percent atheroma volume (PAV), the most rigorous IVUS measure of disease progression and regression. The ASTEROID trial was designed to assess whether very intensive statin therapy could regress coronary atherosclerosis as determined by IVUS imaging. ASTEROID (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden) enrolled 507 patients in a prospective IVUS follow-up study using validated standard IVUS motorized pullback techniques. Patients received rosuvastatin 40 mg and were followed for 24 months. Each patient served as his/her own control and IVUS study interpretation was blinded and randomized as to sequencing. After 24 months, 349 patients had evaluable serial IVUS examinations.

Main Outcome Measures Two primary efficacy parameters were prespecified: the change in PAV and the change in nominal atheroma volume in the 10-mm subsegment with the greatest disease severity at baseline. A secondary efficacy variable, change in normalized total atheroma volume for the entire artery, was also prespecified.

Results The mean baseline low-density lipoprotein cholesterol (LDL-C) level of 3.4 mmol/L declined to 1.6 mmol/L, a mean reduction of 53.2% (P=.001). The median attained LDL was 1.5 mmol/L. Mean high-density lipoprotein cholesterol (HDL-C) level at baseline was 1.1 mmol/L, increasing to 1.3 mmol/L, an increase of 14.7% (P=.001).On treatment the TC/HDL ratio declined from 4.7 to 2.7 and the LDL/HDL ration declined from 3.2 to 1.3. The mean (SD) change in PAV for the entire vessel was −0.98% (3.15%), with a median of −0.79% (97.5% CI, −1.21% to −0.53%) (P=.001 vs baseline). The mean (SD) change in atheroma volume in the most diseased 10-mm subsegment was −6.1 (10.1) mm3, with a median of −5.6 mm3 (97.5% CI, −6.8 to −4.0 mm3) (P=.001 vs baseline). Change in total atheroma volume showed a 6.8% median reduction; with a mean (SD) reduction of −14.7 (25.7) mm3, with a median of −12.5 mm3 (95% CI, −15.1 to −10.5 mm3) (P=.001 vs baseline). Adverse events were infrequent and similar to other statin trials.

Interpretation Very high-intensity statin therapy using rosuvastatin 40 mg/d achieved an average LDL-C of 1.6 mmol/L, a TC/HDL ratio of 2.7 and increased HDL-C by 14.7%, resulting in significant regression of atherosclerosis for all 3 prespecified IVUS measures of disease burden. Treatment to LDL-C levels below currently accepted guidelines, when accompanied by significant HDL-C increases, can regress atherosclerosis in coronary disease patients. ASTEROID raised the bar for LDL reduction in order to achieve regression of atherosclerosis. Dual targeting yields a combination LDL reduction and HDL increase of 67%. This may require combination lipid lowering therapy to achieve in real clinical practice. Further studies are needed to determine the effect of the observed changes on clinical outcome.

 

JUPITER 9
The JUPITER Study randomized 17,802 patient's (males ≥ 50 years of age and females ≥ 60 years of age) with normal LDL levels (≤3.4 mmol) and hsCRP levels ≥ 2.0 mg per liter to receive either rosuvastatin 20 mg daily or placebo. The combined primary endpoint was the occurrence of myocardial infarction, stroke, hospitalization for unstable angina, revascularization or death from cardiovascular causes. The trial hypothesis was that patients with an elevated hsCRP were at increased risk of cardiovascular events compared with the “normal population” and would benefit from anti-inflammatory effect of LDL reduction with a statin.

Results The trial was terminated early due to therapeutic benefit. The mean follow-up was 19 months with a maximum follow-up of 5.0 years. Rosuvastatin reduced the LDL levels by 50% (from a mean baseline LDL of 2.8 mmol/L to a mean achieved LDL of 1.4 mmol/L). The hsCRP was lowered by 37% in the treatment arm. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P = 0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P = 0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P = 0.02). The beneficial effects were durable across all subgroups evaluated. There was no significant increase in myopathy or cancer with Rosuvastatin but there was a higher incidence of physician-reported diabetes.

JUPITER LDL and CRP Sub-study10 In a sub-study of the JUPITER study 15,548 patients were analyzed. Risk reduction was stratified according to LDL greater than or less than 1.8 mmol/L and hsCRP less than 2.0 mg/L and less than 1.0 mg/L. In this substudy there was greater benefit for patients achieving an LDL less than 1.8 mmol/L or an LDL reduction greater than 50%. There was incremental benefit in achieving a hsCRP less than 2.0 mg/L and even greater benefit in achieving a hsCRP less than 1.0 mg/L. Patients who achieved both an LDL less than 1.8 mmol/L and a hsCRP less than 1.0 mg/L derived the greatest benefit with a hazard reduction of 79%.

Discussion In this trial, patients with normal cholesterol who were at low cardiovascular risk aside from the presence of an elevated hsCRP benefited significantly from rosuvastatin induced LDL reduction of 50%. Whether this benefit can be extended the patient under the enrollment ages or with normal levels of hsCRP is unknown. High sensitivity CRP does appear to be a good discriminator of risk within the low risk population and an LDL reduction of 50% will likely become the new benchmark for minimum LDL reduction required to reduce cardiovascular event rates even in low risk patients. Patients who derived the greatest benefit achieved an LDL cholesterol under 1.8 mmol/L and a low hsCRP less than 1.0 mg/L. Whether these parameters should be set as therapeutic targets for an equivalent clinical population is a matter for guideline consideration.

 

 

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