Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis
BMJ 2009; 338 doi: https://doi.org/10.1136/bmj.b92 (Published 16 February 2009) Cite this as: BMJ 2009;338:b92All rapid responses
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You should point out to your MD readers that “relative risk
reduction” as it applies to large groups of patients is
very different than “absolute risk reduction” as it applies
to an individual patient facing her doctor at the office.
An important statistic when facing a patient is the “number
needed to treat” to benefit 1 patient, or NNT. Pfizer used
to run an ad for Lipitor showing the results of a double
blind, placebo controlled study of 10,000 high risk (more
than 3 risk factors) patients for 5 years. Lipitor reduced
the heart attack relative risk by 50%, shown by a large
downwards facing arrow. The absolute risk reduction tells a
very different story. Heart attacks fell from 2% to 1%, for
a NNT of 100. Beyond 5 years Pfizer and all the other
makers of statins have no data. No patients would agree to
take a placebo for >5years since the populace has been
scared silly by all the hoopla about “bad” cholesterol.
Would any doctor hand a patient an Rx for Lipitor and say
“You will need to take this pill every day for the rest of
your life. But for the next 5 years there is only a 1%
chance that it will actually benefit you in any way except
for dropping the cholesterol number on the lab sheet.
Beyond 5 years we don’t know if it is still helping you
because no one has done the research on that question.”
Competing interests:
None declared
Competing interests: No competing interests
Dear Editors,
We read the article by Briel at al. [1] with interest. However, the
conclusion, that LDL-cholesterol reduction should be the primary target of
therapy requires, in our view, some clarification. The results as
presented could lead to the conclusion that there is a causal relation
between a 10 mg/dl reduction in LDL-cholesterol levels and absolute
reduction of cardiovascular endpoints. As the authors point out, this is
not a result of an intervention study aiming at different LDL-targets, but
rather an observational meta-regression which risks bias by confounding
and cannot support causal interpretation. During treatment with statins
patients with higher LDL-cholesterol values might be more likely to have a
greater reduction in serum cholesterol and at the same time a greater
reduction of cardiovascular events.
In addition, this approach ignores the pleiotropic effect of the
statins. That cannot be quantified and the results of Briel et al. do not
control for such effects. Especially in placebo-controlled trials, the
observed effect on cardiovascular outcomes could be misleadingly
attributed to the extent of the LDL reduction alone. People with CHD for
example should still be offered statins, even if the have normal LDL-
levels.
It is not disputed that statins reduce the risk of cardiovascular
morbidity and mortality regardless of both the extent of absolute
reduction of LDL cholesterol and the baseline value before therapy.
However, the results of relevant trials [2-5] comparing intensive versus
moderate statin therapy are inconsistent. Meta-analyses have shown no
significant reduction of all-cause mortality by intensive treatment
despite the achievement of noticeably lower LDL levels [6,7]. Adverse
effects were significantly higher [6]. Cannon et al. also did not find a
significant reduction of cardiovascular mortality by intensive therapy
[7]. Only combining different cardiovascular outcomes led to significant
findings in favour of aggressive LDL cholesterol reduction. The latest
results of the SEARCH trial, reported at an AHA scientific meeting in
November 2008, also showed no significant benefit of intensive therapy in
terms of the primary cardiovascular endpoint.
Even under study conditions a lot of participants in the intensive
therapy arm never achieve target LDL values – or they have to taper the
high dose because of adverse effects. One should assume that this
proportion will be even higher outside trials. To define a therapy target
that will not be reached by the majority of affected patients does not
seem to be very useful. The results of Briel et al. should not be
mistaken for a proof of beneficial effects of aggressive target-driven
statin therapy aiming for a maximum reduction of LDL cholesterol. Such
therapy may even be counterproductive, leading to an increase in dose-
dependent side effects and to frustration of patients and physicians, with
consequent adverse effects on adherence.
Recent surveys by German health insurance companies show that,
despite its undoubted efficacy, between 30-40% of patients with a known
cardiovascular disease do not get any statin at all. It seems more
important to provide these under-treated patients with at least a fixed-
dose statin therapy before we focus on further and still ambiguous issues.
1. Briel M, Ferreira-Gonzalez I, You JJ, Karanicolas PJ, Akl EA, Wu P
et al. Association between change in high density lipoprotein cholesterol
and cardiovascular disease morbidity and mortality: systematic review and
meta-regression analysis. BMJ 2009; 338: b92.
2. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R
et al. Intensive versus moderate lipid lowering with statins after acute
coronary syndromes. N Engl J Med 2004; 350(15): 1495-1504.
3. de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD et
al. Early intensive vs a delayed conservative simvastatin strategy in
patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA
2004; 292(11): 1307-1316.
4. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC et
al. Intensive lipid lowering with atorvastatin in patients with stable
coronary disease. N Engl J Med 2005; 352(14): 1425-1435.
5. Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ,
Holme I et al. High-dose atorvastatin vs usual-dose simvastatin for
secondary prevention after myocardial infarction: the IDEAL study: a
randomized controlled trial. JAMA 2005; 294(19): 2437-2445.
6. Afilalo J, Majdan AA, Eisenberg MJ. Intensive statin therapy in
acute coronary syndromes and stable coronary heart disease: a comparative
meta-analysis of randomised controlled trials. Heart 2007; 93(8): 914-921.
7. Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta-
analysis of cardiovascular outcomes trials comparing intensive versus
moderate statin therapy. J Am Coll Cardiol 2006; 48(3): 438-445.
Competing interests:
None declared
Competing interests: No competing interests
It is interesting how a statistical exercise financed by Pfizer about
HDL-cholesterol winds up suggesting that raising HDL does not matter while
lowering LDL-cholesterol does - in cardiovascular events and all-cause
deaths(1).
This study has flaws. First, the exclusion of positive studies not
fitting limiting modeling criteria, like the Coronary Drug Project
regarding niacin vs. placebo and that significantly prevented second heart
attacks with a post-study all-cause mortality benefit(2). No niacin only
study fit the inclusion criteria while niacin (very high dose vitamin B3)
is the undisputed therapy to raise HDL-cholesterol.
On the other hand, the inclusion criteria captured most LDL-lowering
controlled and dose/drug-comparison studies with the sponsor's
atorvastatin (Lipitor), a statin not raising HDL-cholesterol (ASCOT; Table
2 in ref. W40 in (1)) and that never lowered mortality in anyone (W33-W35,
56, W57 in (1)). Moreover, atorvastatin found no "event" benefit in women
(ref. W40 in (1)) as indeed no LDL-lowering study ever found a mortality
benefit in women, including statins(3).
Thirdly, there is no biological rationale for LDL adjustment when
studying HDL since HDL is a blood particle with about 80 (presumably
useful) associated proteins, while "LDL-cholesterol" represents the
concentration of a single-protein lipid transport particle of which the
composition (in trans-fats, omega-3, carotenoids, homocysteine, other)
varies widely depending upon food intakes.
Fourthly, analysis including "events" are confounded by statin's well
known "nitroglycerin mimicking" effect, promoting NO/eNOS, an unadjusted
confounder(4) that may explain, for example, much of the uniquely male non
-fatal event benefit in ASCOT.
The unspoken message of statin benefit, including total deaths, for
all is unsupported by placebo controlled studies where "Numbers Needlessly
Treated" approach infinity regarding all-cause mortality in women, and in
men regarding atorvastatin, while HDL raising niacin therapy remains an
option with trial support. vos{at}health-heart.org
1. Briel M, Ferreira-Gonzalez I, You JJ, Karanicolas PJ, Akl EA, Wu
P, et al. Association between change in high density lipoprotein
cholesterol and cardiovascular disease morbidity and mortality: systematic
review and meta-regression analysis. BMJ. 2009 Feb 16;338:b92. Medline
19221140
http://www.bmj.com/cgi/content/full/338/feb16_1/b92
2. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, Prineas RJ,
et al. Fifteen year mortality in Coronary Drug Project patients: long-term
benefit with niacin. J Am Coll Cardiol. 1986 Dec;8(6):1245-55. Medline
3782631
3. Walsh JME, Pignone M. Drug Treatment of Hyperlipidemia in Women.
JAMA. 2004;291:2243-2252. Medline 15138247
http://jama.ama-assn.org/cgi/content/full/291/18/2243
4. Laufs U. Beyond lipid-lowering: effects of statins on endothelial
nitric oxide. Eur J Clin Pharmacol. 2003 Mar;58(11):719-31. Medline
12634978
Competing interests:
None declared
Competing interests: No competing interests
Briel and 20 collaborators invested a great deal of time and
expertise to conclude that their findings, "...raises questions about the
development of therapeutic agents that increase high density lipoprotein
cholesterol." The fact that such agents have been developed probably
reflects the refusal by clinicians to recognise that blood rheology is the
system most affected by high levels of plasma cholesterol.
When plasma cholesterol levels are raised, blood viscosity increases
and red cell deformability is reduced because of an increase in the amount
of cholesterol in the red cell membrane. Agents which reduce cholesterol
levels lower blood viscosity and enhance red cell deformability so that
the flow properties of blood are increased.
In 1964, Mayer (1) reported that in both sexes, blood viscosity was
higher in those suffering from coronary heart disease than in healthy
subjects. Lowe et al (2) in 1980 reported in the Br Med J that blood
viscosity was increased in men with evidence of coronary artery disease.
Dormandy et al (3) reported in 1981 that blood samples from patients with
proven myocardial infarction showed reduced filterability ( an assessment
of red cell deformability) which fell to a minimum 7 to 16 hours after the
onset of symptoms. Lee et al (4) in 2004 reported a study of the
rheological properties of red cells from hypercholesterolemic males. They
concluded that, "...high levels of cholesterol LDL or HDL in vivo alters
the morphology and flow behaviour of blood cells that can subsequently
increase the risk of impairing function and microcirculation." As
similar findings have been reported by others, it seems strange that an
increase in HDL cholesterol could be expected to have beneficial effects.
There is sufficient published information to justify the claim that
whether viewed from the perspective of plasma cholesterol level or from
that of coronary heart disease, the active agent is altered blood
rheology. Because omega-3 fatty acids improve red cell deformability and
lower blood viscosity, the 1985 report by Kromhout et al (5) is relevant.
They found that a daily intake of about 30 grams of oily fish lowered the
incidence of heart disease by 50% in a 20 year follow-up study.
It could be noteworthy, that in the Briel et al report, there was no
clear statement which considered why cholesterol levels should be
associated with coronary heart disease.
References.
1. Mayer GA. Blood viscosity in healthy subjects and patients with
coronary heart disease. Canad Med Assn J 1964;91: 951-4.
2. Lowe GDO, Drummond M, Lorimer AR, et al. Relation between extent of
coronary artery disease and blood viscosity. Br Med J 1980; i :673-4.
3. Dormandy J, Boyd M, Ernst E. Filterability and vascular disease: 2.
Red cell filterability after myocardial infarction. Scand J Clin Invest
1981; 156 (suppl): 195-8.
4. Lee CY, Kim KC, Park HW, et al. Rheological properties of
erythrocytes from male hyper-cholesterolemia. Microvas Res 2004; 67:133-
8.
5. Kromhout D, Bosschieter EA, Coulander C, et al. The inverse relation
between fish concumption and 20 year mortality from coronary heart
disease. N Engl J Med 1985; 312: 1205-9.
Competing interests:
None declared
Competing interests: No competing interests
An increasing number of studies have addressed
the issue of cholesterol subfractions, in particular,
HDL-C and have generally found that the inverse
relationship between HDL-C and stroke is not a
consistent finding. The study from Briel (2009) showed that there is no
correlation between HDL level and the risk of cardiovascular event. The
amount of LDL is strongest predictor. The future research should also
address the type of stroke.The development of atherosclerotic
plaques and the degree of carotid atheroma has
been repeatedly related to serum lipid levels, directly
with both total and LDL-cholesterol as well
as triglycerides and inversely with HDL-CHigher HDL-C levels were thought
to be more protective against atherosclerosis ischaemic strokes as
opposed to non-atherosclerosis ischaemic strokes
Competing interests:
None declared
Competing interests: No competing interests
Relation between Lipid Modification and Outcome: Identifying the Appropriate Therapeutic Targets for Lipid Modifying Therapies
Briel et al (1) have carried out an extensive meta-analysis,
comprising nearly 300,000 participants in randomized clinical trials of
lipid modifying therapies, which failed to identify a statistically
significant association between changes in high-density lipoprotein-
cholesterol (HDL-C) levels and cardiovascular outcomes. The results of
this analysis contradict data from all major fibrate trials, that have
consistently shown a significant association between on-treatment HDL-C
increments and major reductions in cardiovascular events in both primary
and secondary prevention settings (2-4). These apparently conflicting data
can be attributed to important differences in the selected populations
among the studies. Briel et al, have chosen to focus their analysis mainly
on statin trials (n=62), which were designed to reduce LDL-C in patients
with moderately to high baseline LDL-C levels and a mean baseline HDL-C
that was in the normal range (47 mg/dL), whereas fibrate trials evaluated
the benefit of lipid modifying therapies among high-risk patients with the
common raised triglycerides-low HDL-C dyslipidaemia. Accordingly, the
results of the present meta-analysis are biased to a patient population
within which lipid modifying therapies resulted in major on-treatment LDL-
C reductions and relatively minor HDL-C increments.
To evaluate the benefit associated with on-treatment HDL-C
increments, we have carried out a subanalysis of the Bezafibrate
Infarction Prevention (BIP) Trial, comprising 3020 coronary heart disease
patients with the raised triglycerides-low HDL-C dyslipidaemia (2). Our
data demonstrate that, in this high-risk patient subset, 5 mg/dL
increments in HDL-C were independently associated a significant 27%
(p<0.001) reduction in cardiac mortality, whereas on-treatment
reductions in LDL-C did not contribute to outcome after adjustment for HDL
-C changes. The long-term survival benefit associated with of HDL-C
modification was also substantiated in an extended 16-year follow-up study
of the BIP trial (5). Furthermore, in a recent analysis of the BIP
population (6), we have shown that the benefit of raising HDL-C is related
to baseline serum levels of LDL-C. Thus, HDL-C modification was associated
with an enhanced survival benefit among patients with low baseline LDL-C
(< 130 mg/dL), whereas a significant benefit of LDL-C modification was
evident only among patients with elevated baseline LDL-C (>130 mg/dL)
(6). These results further demonstrate the substantial benefit associated
with increasing HDL-C, provided appropriate selection of patients and
therapeutic modalities.
We are concerned that the findings by Briel et al may provide
erroneous and misleading implications for an important proportion of
currently treated patients with the common raised triglycerides-low HDL-C
dyslipidaemia, who have a high risk for major cardiac events even when
their LDL-C levels are in the normal- or low-range (7). This important
subset of patients should receive a more comprehensive lipid modifying
therapeutic approach, designed also to raise HDL-C and reduce
triglycerides, rather than a narrow approach that is based solely on LDL-c
modification as suggested by Briel et al.
References
1. Briel M, Ferreira-Gonzalez I, You JJ, Karanicolas PJ, Akl EA, Wu
P, Blechacz B, Bassler D, Wei X, Sharman A, Whitt I, Alves da Silva S,
Khalid Z, Nordmann AJ, Zhou Q, Walter SD, Vale N, Bhatnagar N, O'Regan C,
Mills EJ, Bucher HC, Montori VM, Guyatt GH. Association between change in
high density lipoprotein cholesterol and cardiovascular disease morbidity
and mortality: systematic review and meta-regression analysis. BMJ.
2009;338:b92. doi: 10.1136/bmj.b92.
2. Goldenberg I, Goldbourt U, Boyco V, Behar S, Reicher-Reiss H.
Relationship between on-treatment increments in serum HDL levels and
cardiac events in patients with coronary heart disease: an extended follow
-up of the Bezafibrate Infarction Prevention Trial. Am J Cardiol.
2006;97:466-471.
3. Manninen V, Elo MO, Frick MH, Haapa K, Heinonen OP, Heinsalmi P,
Helo P, Huttunen JK, Kaitaniemi P, Koskinen P. Lipid alterations and
decline in the incidence of coronary heart disease in the Helsinki Heart
Study. JAMA 1988;260:641-651.
4. Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC,
Schaefer EJ, McNamara JR, Kashyap ML, Hershman JM, Wexler LF, Rubins HB;
VA-HIT Study Group. Veterans Affairs High-Density Lipoprotein Intervention
Trial. Relation of gemfibrozil treatment and lipid levels with major
coronary events: VA-HIT: a randomized controlled trial. JAMA 2001;285:1585
-1591.
5. Goldenberg I, Boyko V, Tennenbaum A, Tanne D, Behar S, Guetta V.
Long-term benefit of high-density lipoprotein cholesterol-raising therapy
with bezafibrate: 16-year mortality follow-up of the bezafibrate
infarction prevention trial.Arch Intern Med. 2009;169:508-514
6. Goldenberg I, Benderly M, Sidi R, Boyko V, Tenenbaum A, Tanne D,
Behar S.Relation of clinical benefit of raising high-density lipoprotein
cholesterol to serum levels of low-density lipoprotein cholesterol in
patients with coronary heart disease (from the Bezafibrate Infarction
Prevention Trial). Am J Cardiol. 2009;103:41-45
7. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM,
Kastelein JJ, Bittner V, Fruchart JC; Treating to New Targets
Investigators. HDL cholesterol, very low levels of LDL cholesterol, and
cardiovascular events. N Engl J Med 2007;357:1301-1310.
Competing interests:
None declared
Competing interests: No competing interests