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Letters # 24, 27 and 42 recommended statin therapy for patients with ischemic heart disease (secondary prevention) based on 3 relevant randomized controlled trials (RCTs): 4S1, CARE2, and LIPID3. Letter #48 pooled the data from the 5 mostly primary prevention trials and concluded that statins have not been shown to provide an overall health benefit in patients without clinically evident atherosclerosis. This Letter summarizes the 4 latest secondary prevention statin trials and discusses 3 different dosing strategies.
Lescol Intervention Prevention Study (LIPS)4
LIPS studied the effect of 80 mg of fluvastatin compared to placebo
in 1677 patients (total cholesterol 3.5-7.0 mM) with coronary blockage following
successful completion of a percutaneous coronary intervention. Total myocardial
infarctions, RR 0.69 [0.47–1.01], and total mortality, RR 0.73 [0.48–1.10] were
not statistically significantly lower with fluvastatin than placebo. Stroke
outcomes and total serious adverse events were not reported.
PROSPER5
(described in Letter #48)
Pravastatin, 40 mg, reduced total myocardial infarction or total
stroke in the 2565 elderly (70-82 years) secondary prevention patients (total
cholesterol, 4.0–9.0 mM), RR 0.80 [0.68–0.94], ARR 4.3%, NNT 23 for 3.2 years.
GREek Atorvastatin and
Coronary-heart-disease Evaluation (GREACE)6
GREACE compared the effect of structured care using a titrated dose
of atorvastatin with ‘usual’ community care in 1600 patients (LDL cholesterol
>2.6 mM) with recent myocardial infarction or >70% stenosis of at least one
coronary artery. In the structured care group atorvastatin 10 mg/day was
increased to 80 mg if necessary to achieve an LDL of <2.6 mM. Structured care
reduced total myocardial infarction or stroke, RR 0.47 [0.34–0.65], ARR 7.0%,
NNT 14 for 3 years. Total mortality was also reduced, RR 0.58 [0.35–0.95], ARR
2.1%, NNT 48 for 3 years. Total serious adverse events were not reported.
Heart Protection Study (HPS)7
HPS, the largest statin trial, compared simvastatin, 40 mg daily,
with placebo in 20,536 patients (86% secondary prevention, total cholesterol
>3.5 mM). Simvastatin reduced total myocardial infarction or stroke, RR 0.75
[0.70–0.80], ARR 4.4%, NNT 23 for 5 years. Total mortality was also reduced RR
0.87 [0.81–0.94], ARR 1.8%, NNT 56 for 5 years. Total serious adverse events
were not reported.
The benefit of simvastatin was independent of baseline cholesterol and
independent of the magnitude of the simvastatin-induced reduction in LDL.
Patients with baseline LDL <2.6 mM had a similar benefit to those with baseline
LDL >2.6 mM.
HPS was unusual in having a pre-randomization period in which 32,145 recruited
patients were treated with simvastatin 40 mg for 4 to 6 weeks. Thirty six
percent (11,609) of these patients were dropped from the study for various
reasons: poor compliance, patient choice, side effects, etc. Because large
numbers of problematic patients were excluded, the HPS results cannot be used to
predict the safety and tolerance of simvastatin in the general population.
These 4 trials reconfirm the benefit of statins for patients with elevated cholesterol and coronary disease and expand the benefit to patients with clinically evident occlusive coronary, cerebral or peripheral vascular disease and a total cholesterol >3.5 mM. Despite the lack of reporting of total SAEs in these trials, one measure of overall health benefit, total mortality, was reduced, pooled RR 0.84 [0.79–0.88], ARR 2.1%, NNT 48 for 3 to 5 years.
What is the optimal statin dosing strategy?
RCTs comparing the morbidity and mortality of different statin dosing
strategies have not been conducted. Clinical dosing strategies can be indirectly
inferred from the 11 existing RCTs. Three of a number of possible dosing
strategies are discussed below.
“Fixed dose” strategy
Eight of eleven RCTs2-5,7,8
tested a single dose of statin. A “fixed dose” strategy based on these trials
would employ the daily dose used in the trials: atorvastatin 10 mg, fluvastatin
80 mg, pravastatin 40 mg, or simvastatin 40 mg. Advantages: based
on specific RCT evidence, limited or no cholesterol testing required, includes
all patients. Disadvantages: a fixed dose may be insufficient for
some and excessive for other patients.
“LDL target” strategy
Three RCTs treated to target based on cholesterol testing: 4S,1
AFCAPS8 and GREACE6.
In 4S the target was a total cholesterol <5.2 mM (LDL <3.8 mM). In AFCAPS the
target was an LDL <2.8 mM. In GREACE the target was an LDL of <2.6 mM. A dosing
strategy based on these trials would titrate the dose to an LDL target.
Advantages: consistent with lipid guidelines in the US/Canada9
(LDL <2.6 mM) and UK/Europe10 (LDL <3.0 mM),
prevents excessive LDL lowering if the dose is minimized to just achieve the
target. Disadvantages: optimal target is unknown, requires more
LDL testing and higher statin doses, patients with baseline LDL <2.6 mM, who
were proven to benefit in HPS7, would be
excluded.
“Average cholesterol reduction” strategy
The average reduction from baseline in total cholesterol for the
different statins was between 18 and 25% for 10 of the 11 RCTs. The one
exception is GREACE (36% reduction).6 Daily doses
of statin required to achieve the middle of this range, a 22% reduction in total
cholesterol, are approximately: fluvastatin 40 mg, pravastatin 20 mg, lovastatin
20 mg, simvastatin 10 mg, atorvastatin 5 mg or rosuvastatin 2.5 mg.11
Advantages: reduced statin doses and costs, possible reduced risk
of dose-related toxicity, includes all patients. Disadvantages:
necessitates some testing of total cholesterol.
Regardless of what dosing strategy is chosen for a particular patient, choosing higher strength statin tablets (lower price/mg) and tablet splitting, can be used to reduce the daily cost (see Table).
What is needed?
Large RCTs comparing different statin dosing strategies for secondary
prevention of cardiovascular disease are clearly needed. These trials should as
a minimum report the following outcomes: total mortality, cardiovascular serious
adverse events, other serious adverse events and total health related costs.
Statins provide a cardiovascular and total mortality benefit for patients with clinically evident occlusive vascular disease (secondary prevention) and a cholesterol of >3.5 mM.
Large RCTs are required to test different statin dosing strategies for secondary prevention before making firm recommendations.
RR = Relative Risk. CI = Confidence Interval. ARR =
Absolute Risk Reduction.
NNT = Number Needed to Treat to prevent one event.
Table. Statins, daily doses and cost comparisons
Drug |
Brand Name (formulation) |
Possible daily doses (mg) |
Cost per dose+ |
Atorvastatin | Lipitor© (tablets) | 2.5*, 5*, 10, 20, 40, 80 | $0.43, 0.86, 1.71, 2.14, 2.30, 2.30 |
Fluvastatin | Lescol© (capsules) | 20, 40, 80 | $0.82, 1.15, 2.30 |
Lovastatin | Mevacor©, generic (tablets) | 10*, 20, 40, 80 | $0.59, 1.17, 2.15, 4.30 |
Pravastatin | Pravachol©, generic (tablets) | 10, 20, 40, 80 | $1.02, 1.20, 1.45, 2.90 |
Simvastatin | Zocor©, generic (tablets) | 5, 10, 20, 40, 80 | $0.67, 1.33, 1.65, 1.65, 1.65 |
Rosuvastatin | Crestor© (tablets) | 2.5*, 5*, 10, 20, 40 | $0.37, 0.73, 1.46, 1.82, 2.13 |
* requires cutting of tablets to achieve these doses.
+ based on 2003 PharmaNet data or wholesale cost plus 7%
This Therapeutics Letter contains an assessment and synthesis of publications up to September 2003. We attempt to maintain the accuracy of the information contained in the Therapeutics Letter by extensive literature searches and verification by both the authors and the editorial board. In addition this Therapeutics Letter was submitted for review to 45 experts and primary care physicians in order to correct any identified shortcomings or inaccuracies and to ensure that the information is concise and relevant to clinicians. |
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©Therapeutics Initiative. Last updated: October 16, 2003.