Z
Zee
Guest
http://www.ti.ubc.ca/pages/letter48.htm
The Therapeutics Initiative presents critically appraised
summary evidence primarily from controlled drug trials. Such
evidence applies to patients similar to those involved in
the trails, and may not be generalizable to every patient.
We are committed to evaluate the effectiveness of our
educational activities using the Pharmacare/PharmaNet
databases without identifying individual physicians,
pharmacies or patients. The Therapeutics Initiative is
funded by the BC Ministry of Health through a 5-year grant
to the University of BC. The Therapeutics Initiative
provides evidence based advice about drug therapy, and is
not responsible for formulating or adjudicating provincial
drug policies
___________________________________________________________-
_____________________
Do Statins have a Role in Primary Prevention?
Conclusion: "...Therefore, statins have NOT BEEN SHOWN
to provide an overall health benefit in primary
prevention trials."
------------------------------------------------------------
--------------------
Click here to go to a comment regarding Therapeutics Letter
#48, posted on October 16, 2003 about the evidence of
benefit for primary prevention in women.
------------------------------------------------------------
--------------------
Two important questions regarding statin therapy are:
What is the overall health impact when statins are
prescribed for primary prevention? Should the dose of statin
be titrated to achieve target lipid levels? Three new
randomized controlled trials1-3, which help answer the first
question and one trial providing insight into the second
question have been published since our last Letter on lipid
lowering therapy (#42). This Letter addresses the first
question and the next Letter (#49) will address the second.
Estimating the overall health impact of statins in primary
prevention requires balancing possible benefits and possible
harms. In this Letter benefit is estimated by combining two
cardiovascular serious adverse events known to be reduced by
statins in secondary prevention trials: total myocardial
infarction (fatal and non-fatal)5 and total stroke (fatal
and non-fatal).6 The balance between benefit and harm
(overall health impact) is estimated by total mortality and
total serious adverse events. Serious adverse events include
any untoward medical occurrence that results in death, is
life threatening, requires hospitalization or prolongation
of hospitalization, or results in persistent or significant
disability.
Prospective Study of Pravastatin in the Elderly at Risk
(PROSPER)1 PROSPER studied the effect of pravastatin
compared to placebo in two older populations of patients:
56% primary prevention (no past or symptomatic
cardiovascular disease) and 44% secondary prevention (past
or symptomatic cardiovascular disease) (Table 1).
Pravastatin did not reduce total myocardial infarction or
total stroke in the primary prevention population, RR 0.94
[0.78 – 1.14], but did so in the secondary prevention
population, RR 0.80 [0.68 – 0.94], ARR 4.3%, NNT 23 for 3.2
years. Measures of overall health impact in the combined
populations, total mortality and total serious adverse
events, were unchanged by pravastatin as compared to
placebo, RR 0.98 [0.84 – 1.14] and 1.01 [0.96 – 1.06],
respectively.
Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT-LLT)2 ALLHAT-LLT was designed
to determine whether pravastatin compared with usual care
reduces all-cause mortality in older, moderately
hypercholesterolemic, hypertensive patients with at least
1 additional coronary heart disease risk factor. The
published data is for the whole population, 86% of which
was primary prevention. Pravastatin did not reduce total
myocardial infarction and total stroke, RR 0.91 [0.82 –
1.01]. Pravastatin also did not reduce total mortality,
RR 0.99 [.89 – 1.09]. Total serious adverse events were
not reported.
Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm
(ASCOT-LLA)3 ASCOT-LLA was designed to assess the benefits
of atorvastatin versus placebo in hypertensive patients with
average or lower-than-average cholesterol concentrations and
at least 3 other cardiovascular risk factors. The published
data is for the whole population, 82% of which was primary
prevention. The trial was originally planned for 5 years,
but was stopped after a median follow-up of 3.3 years
because of a significant reduction in cardiac events.
Atorvastatin reduced total myocardial infarction and total
stroke, RR 0.82 [0.70 – 0.96], ARR
1.2%, NNT 83. Total mortality was not significantly reduced,
RR 0.87 [.71 – 1.05]. The trial report stated that total
serious adverse events "did not differ between patients
assigned atorvastatin or placebo", but the actual numbers
of serious adverse events were not given.
What is the overall health impact when statins are
prescribed for primary prevention? To attempt to answer this
question we combined the data from the 5 mostly primary
prevention trials, the 3 above plus 2 published earlier7,8
(Table 1 & Table 2). Note that these calculations reflect a
population that is 84% primary prevention and 16% secondary
prevention. In the pooled data the statins reduced the
cardiovascular measures, total myocardial infarction and
total stroke, by 1.4% as compared to control. This value
indicates that 71 mostly primary prevention patients would
have to be treated for 3 to 5 years to prevent one such
event. This can be compared with the same pooled outcome in
4 large secondary prevention statin trials, ARR 4.8%, NNT 21
for 5 years. (Letter #42, HPS4) In the 2 trials where
serious adverse events are reported, the 1.8% absolute
reduction in myocardial infarction and stroke should be
reflected by a similar absolute reduction in total serious
adverse events; myocardial infarction and stroke are, by
definition, serious adverse events. However, this is not the
case; serious adverse events are similar in the statin
group, 44.2%, and the control group, 43.9% (Table 2). This
is consistent with the possibility that unrecognized serious
adverse events are increased by statin therapy and that the
magnitude of the increase is similar to the magnitude of the
reduction in cardiovascular serious adverse events in these
populations. This hypothesis needs to be tested by analysis
of total serious adverse event data in both past and future
statin trials. Serious adverse event data is available to
trial authors, drug companies and drug regulators. The other
measure of overall impact, total mortality, is available in
all 5 trials and is not reduced by statin therapy (Table
2).
Conclusions: If cardiovascular serious adverse events are
viewed in isolation, 71 primary prevention patients with
cardiovascular risk factors have to be treated with a
statin for 3 to 5 years to prevent one myocardial
infarction or stroke.
This cardiovascular benefit is not reflected in 2 measures
of overall health impact, total mortality and total
serious adverse events. Therefore, statins have not been
shown to provide an overall health benefit in primary
prevention trials.
------------------------------------------------------------
--------------------
RR = Relative Risk. CI = Confidence Interval. ARR =
Absolute Risk Reduction. NNT = Number Needed to Treat to
prevent one event.
MORE AT URL including charts and graphs.
B'adant
The Therapeutics Initiative presents critically appraised
summary evidence primarily from controlled drug trials. Such
evidence applies to patients similar to those involved in
the trails, and may not be generalizable to every patient.
We are committed to evaluate the effectiveness of our
educational activities using the Pharmacare/PharmaNet
databases without identifying individual physicians,
pharmacies or patients. The Therapeutics Initiative is
funded by the BC Ministry of Health through a 5-year grant
to the University of BC. The Therapeutics Initiative
provides evidence based advice about drug therapy, and is
not responsible for formulating or adjudicating provincial
drug policies
___________________________________________________________-
_____________________
Do Statins have a Role in Primary Prevention?
Conclusion: "...Therefore, statins have NOT BEEN SHOWN
to provide an overall health benefit in primary
prevention trials."
------------------------------------------------------------
--------------------
Click here to go to a comment regarding Therapeutics Letter
#48, posted on October 16, 2003 about the evidence of
benefit for primary prevention in women.
------------------------------------------------------------
--------------------
Two important questions regarding statin therapy are:
What is the overall health impact when statins are
prescribed for primary prevention? Should the dose of statin
be titrated to achieve target lipid levels? Three new
randomized controlled trials1-3, which help answer the first
question and one trial providing insight into the second
question have been published since our last Letter on lipid
lowering therapy (#42). This Letter addresses the first
question and the next Letter (#49) will address the second.
Estimating the overall health impact of statins in primary
prevention requires balancing possible benefits and possible
harms. In this Letter benefit is estimated by combining two
cardiovascular serious adverse events known to be reduced by
statins in secondary prevention trials: total myocardial
infarction (fatal and non-fatal)5 and total stroke (fatal
and non-fatal).6 The balance between benefit and harm
(overall health impact) is estimated by total mortality and
total serious adverse events. Serious adverse events include
any untoward medical occurrence that results in death, is
life threatening, requires hospitalization or prolongation
of hospitalization, or results in persistent or significant
disability.
Prospective Study of Pravastatin in the Elderly at Risk
(PROSPER)1 PROSPER studied the effect of pravastatin
compared to placebo in two older populations of patients:
56% primary prevention (no past or symptomatic
cardiovascular disease) and 44% secondary prevention (past
or symptomatic cardiovascular disease) (Table 1).
Pravastatin did not reduce total myocardial infarction or
total stroke in the primary prevention population, RR 0.94
[0.78 – 1.14], but did so in the secondary prevention
population, RR 0.80 [0.68 – 0.94], ARR 4.3%, NNT 23 for 3.2
years. Measures of overall health impact in the combined
populations, total mortality and total serious adverse
events, were unchanged by pravastatin as compared to
placebo, RR 0.98 [0.84 – 1.14] and 1.01 [0.96 – 1.06],
respectively.
Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT-LLT)2 ALLHAT-LLT was designed
to determine whether pravastatin compared with usual care
reduces all-cause mortality in older, moderately
hypercholesterolemic, hypertensive patients with at least
1 additional coronary heart disease risk factor. The
published data is for the whole population, 86% of which
was primary prevention. Pravastatin did not reduce total
myocardial infarction and total stroke, RR 0.91 [0.82 –
1.01]. Pravastatin also did not reduce total mortality,
RR 0.99 [.89 – 1.09]. Total serious adverse events were
not reported.
Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm
(ASCOT-LLA)3 ASCOT-LLA was designed to assess the benefits
of atorvastatin versus placebo in hypertensive patients with
average or lower-than-average cholesterol concentrations and
at least 3 other cardiovascular risk factors. The published
data is for the whole population, 82% of which was primary
prevention. The trial was originally planned for 5 years,
but was stopped after a median follow-up of 3.3 years
because of a significant reduction in cardiac events.
Atorvastatin reduced total myocardial infarction and total
stroke, RR 0.82 [0.70 – 0.96], ARR
1.2%, NNT 83. Total mortality was not significantly reduced,
RR 0.87 [.71 – 1.05]. The trial report stated that total
serious adverse events "did not differ between patients
assigned atorvastatin or placebo", but the actual numbers
of serious adverse events were not given.
What is the overall health impact when statins are
prescribed for primary prevention? To attempt to answer this
question we combined the data from the 5 mostly primary
prevention trials, the 3 above plus 2 published earlier7,8
(Table 1 & Table 2). Note that these calculations reflect a
population that is 84% primary prevention and 16% secondary
prevention. In the pooled data the statins reduced the
cardiovascular measures, total myocardial infarction and
total stroke, by 1.4% as compared to control. This value
indicates that 71 mostly primary prevention patients would
have to be treated for 3 to 5 years to prevent one such
event. This can be compared with the same pooled outcome in
4 large secondary prevention statin trials, ARR 4.8%, NNT 21
for 5 years. (Letter #42, HPS4) In the 2 trials where
serious adverse events are reported, the 1.8% absolute
reduction in myocardial infarction and stroke should be
reflected by a similar absolute reduction in total serious
adverse events; myocardial infarction and stroke are, by
definition, serious adverse events. However, this is not the
case; serious adverse events are similar in the statin
group, 44.2%, and the control group, 43.9% (Table 2). This
is consistent with the possibility that unrecognized serious
adverse events are increased by statin therapy and that the
magnitude of the increase is similar to the magnitude of the
reduction in cardiovascular serious adverse events in these
populations. This hypothesis needs to be tested by analysis
of total serious adverse event data in both past and future
statin trials. Serious adverse event data is available to
trial authors, drug companies and drug regulators. The other
measure of overall impact, total mortality, is available in
all 5 trials and is not reduced by statin therapy (Table
2).
Conclusions: If cardiovascular serious adverse events are
viewed in isolation, 71 primary prevention patients with
cardiovascular risk factors have to be treated with a
statin for 3 to 5 years to prevent one myocardial
infarction or stroke.
This cardiovascular benefit is not reflected in 2 measures
of overall health impact, total mortality and total
serious adverse events. Therefore, statins have not been
shown to provide an overall health benefit in primary
prevention trials.
------------------------------------------------------------
--------------------
RR = Relative Risk. CI = Confidence Interval. ARR =
Absolute Risk Reduction. NNT = Number Needed to Treat to
prevent one event.
MORE AT URL including charts and graphs.
B'adant