NCEP GUIDELINE UPDATE
Michael Green, M.D., M.Sc.
WEEK 24
Learning Objectives:
1. Understand the results of recent CHD secondary prevention trials, which studied more
aggressive LDL lowering with statins
2. Apply the results of these trials to the decision-making for individual patients with CHD
or at very high risk for CHD
3. Thoughtfully prescribe statins alone or in combination with other lipid lowering agents
CASE ONE:
A 55 year-old man comes to see you in the office for a post-hospitalization visit. He was
hospitalized four weeks ago with an acute coronary syndrome (ACS), which represented
his initial presentation of coronary heart disease (CHD). He ruled out for a myocardial
infarction by enzymes and underwent a PTCA and stenting for a 90% LAD lesion. He has
not had any cardiac symptoms since his discharge. His past medical history included
hypertension and GERD. His medications (after his hospitalization) include aspirin 325
mg QD, clopidigrel 75 mg QD, atenolol 100 mg QD, omeprazole 40 mg QD, and
atorvastatin 10 mg QD. He does not smoke cigarettes. His father had myocardial
infarction at age 54. On physical examination, he weighs 240 lbs (BMI = 30), blood
pressure is 125/70, heart rate is 70. Lungs are clear. Cardiac exam reveals no murmurs or
extra heart sounds.
Laboratories:
Hospital
Admission
Electrolytes
Creatinine
Fasting Glucose
ALT
AST
Total Cholesterol
Triglycerides
HDL Cholesterol
LDL Cholesterol
(Calculated)
Non-HDL Cholesterol
(Calculated)
Normal
1.3
Office visit
four weeks after
admission
Second office visit 6 weeks
after your intervention in
question # 3
Normal
1.2
105
109
Normal
Normal
225
253
36
180
227
39
167
198
44
139
96
78
188
144
123
Questions:
1. What additional laboratory value would you like?
TSH, for two reasons. First, hypothyroidism is an important secondary cause of
dyslipidemia, particularly elevated LDL. More importantly, undetected (and thus
untreated) hypothyroidism increases the risk of statin-induced myopathy and
rhabdomyolysis. And we are about to contemplate either high dose statins or
combination therapy.
2. There is a consensus that we should be aggressive in the secondary prevention of
CHD. Since the risk of subsequent events is so high (20% or more in 10 years), the
absolute risk reduction [ARR] should be high (and the number needed to treat
[NNT] should be low) compared to the primary prevention of CHD, even with the
same relative risk reduction [RRR]. Regarding this patient’s lipids, are you
satisfied with his initial response to the atorvastatin or would you like to lower his
LDL further? What evidence supports your decision?
Subgroup analyses in the Heart Protection Study showed consistent relative risk
reductions regardless of baseline LDL level (including those with baseline LDL < 100
mg/dl) and regardless of age, presence of diabetes, or presence of CHD. And in the
PROVE IT study, subjects receiving more intensive LDL lowering treatment (atorvastatin
80 mg) enjoyed further risk reduction (16% RRR in composite CV endpoints) compared
to subjects receiving pravastatin 40, even though the latter attained an LDL below 100
mg/dl. Note that the NCEP update maintains that, on the basis of available evidence, the
LDL treatment goal remains < 100 mg/dl for patients with CHD or CHD equivalents. A
goal of < 70 mg/dl now represents a therapeutic option: “i.e. a reasonable clinical
strategy for persons considered to be at very high risk.” The risks of this aggressive
strategy would be the increased risks of toxicity from higher dose statins or combination
therapy.
3. How would you intervene to lower his LDL?
He has had a 31% reduction in LDL already, which is within the range of what we would
expect for 10 mg of atorvastatin. Assuming an approximate 6% additional LDL lowering
for each doubling of the dose, we might expect to reduce his LDL to 70 to 80 mg/dl with
80 mg of atorvastatin. Of course, we would progressively increase his dose (rather than
going directly to 80 mg) since many of the statin toxicities are dose related. Thus, it is
possible that we may have to combine a submaximal dose of atorvastatin with another
LDL lowering drug (ezetimibe or a resin, like colesevalam).
4. Let’s say that his risk for recurrent CHD was 22% over 10 years at an LDL of 96
mg/dl. As shown in the table, with more aggressive lipid lowering therapy, his LDL
decreases to 78 mg/dl. Estimate his 10-year CHD risk now. Calculate the RRR,
ARR, and NNT.
With this calculation, we can get a quantitative estimate of the additional benefit of
lowering the patients LDL well below 100. Extrapolating from the HPS study, the
authors of the guideline estimate that lowering LDL from 100 to 70 would achieve an
additional 30% RRR. In our patient, lowering LDL from 96 to 78 might achieve an
additional 18% RRR. An 18% RRR is the same as a RR of 0.82.
Control event rate = 0.22
Experimental event rate = 0.22 x 0.82 = 0.18
ARR = CER – EER = 0.22 – 0.18 = 0.04
NNT = 1/ARR = 1/0.04 = 25
This means that we would have to aggressively treat 25 patients to lower their LDL to 78
(vs. just lowering it to 96) to prevent 1 additional CHD event. We must then weigh this
against the risks of high dose statins or combination therapy that might be needed to
achieve it.
NOTE: This might be overestimate of benefit because the patients in HPS were not
already on statins. The pleiotropic (non-lipid) benefits of statins, achieved at the initial
dose, may not necessarily increase with increasing the dose in patients already on the
drug.
5. In addition to lipid lowering therapy, what else would you consider to reduce this
patient’s risk for recurrent CHD events?
This patient has impaired fasting glucose (IFG = 100 – 125 mg/dl) and the full metabolic
syndrome (IFG, BP > 130/85, waist circumference > 102 cm [men], triglycerides > 150
mg/dl, HDL < 40 mg/dl [men]). In addition to his insulin resistance and HTN, we can
assume that he has a proinflammatory state, a prothrombotic state, and an increased
proportion of small dense LDL particles, which are more atherogenic, and ultimately a
further increased risk of CHD. Studies have clearly shown that these abnormalities can
be reversed by lifestyle modification, including weight loss, exercise, and diet. However,
as you know, behavioral change is difficult and often not achieved. Although not the
standard of care today, some would consider using insulin-sensitizing agents (metformin
or a thiazolidenedione) in patients like this, even though he does not meet the diagnostic
criteria for type 2 diabetes mellitus.
Secondly, we should consider putting this very high risk patient on an ACE inhibitor.
While ACE inhibitors reduce cardiovascular events in several groups of patients, their
effectiveness (as demonstrated by the HOPE and EUROPA trials) in patients with
established vascular disease, preserved LV function, and no diabetes was recently called
into question by the PEACE trial. (See editorial: Pitt B, ACE inhibitors for patients with
vascular disease without left ventricular dysfunction—may they rest in PEACE? NEJM
2004;351:2115-6.)
References:
1. 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(2):227-239.