Drug Treatment of Hyperlipidemia in Women

1
Drug Treatment of Hyperlipidemia in Women

• Priscilla Magaña , D.O., M.P.H.
• May 26, 2004

2
Introduction

• Coronary Heart Disease (CHD)
• Leading cause of death in the US
• ½ of all deaths from CHD occur in women
• Age is the main risk factor of CHD
• Women have a lower risk of CHD at any given age
  when compared to men
• The onset of CHD for women falls 10 years behind
  that of men
• However, by age 75, mortality among both genders
  is more similar

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Introduction

• Many more women than men have to be treated to
  prevent one CHD event, therefore the benefits
  risks of treatment may be different for men
  women
• Hyperlipidemia is one of the risk factors for CHD
  
• Many clinical trials have been done looking at
  lipid-lowering drugs on the effect of clinical
  outcomes, but many have not included
  gender-specific analyses
• Many have not even included women

4
Introduction

• This article systematically reviews the evidence
  regarding treatment of hyperlipidemia for the
  prevention of CHD events death in women
• The effect of drug treatment is also stratified
  by primary (no prior cardiovascular disease) and
  secondary (prior cardiovascular disease)
  prevention with the idea that the risks and
  benefits will differ according to the womens
  risk of CHD
• This article also performs a meta-analysis of the
  effect of drug treatment on mortality in women
• Question Does lipid-lowering therapy reduce the
  risk of outcomes in women with and without
  cardiovascular disease?

5
Methods

• The authors found 1,731 articles during their
  search dating from 1966 to 2003
• After reviewing the titles and abstracts, the
  authors reviewed the full text of 121 articles
• 21 articles met their inclusion criteria ,
  however only 9 provided results stratified by
  gender
• The principal investigators of the remaining 12
  articles were contacted and 4 were able to
  provide data on women

6
Methods

• A final 13 studies were included that met the
  following criteria
• Randomized clinical trials of outpatients w/ or
  w/o cardiovascular disease
• Had treatment duration of at least 1 year
• Classified the study population as either 1 or
  2 prevention
• Provided data on women separately from men
• Assessed the effect of lipid-lowering drug
  therapy for at least 1 clinical outcome (total
  mortality, CHD mortality, nonfatal MI, CHD
  events, or revascularization procedures)

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Methods

• Each of the 13 clinical trials was evaluated for
  quality
• Good quality studies
• Had clear appropriate inclusion and exclusion
  criteria
• Concealed randomization allocation
• Had a control placebo group
• Were double-blinded
• Had gt75 follow-up
• Fair quality studies
• did not meet the above criteria

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Critique of the Meta-Analysis

• 1. IDENTIFICATION
• Articles were derived from MEDLINE, the Cochrane
  Database, and Database of Abstracts Reviewers
• 2. SELECTION
• Articles were selected by a defined criteria
• 3. ABSTRACTION
• 2 physicians reviewed the initial search and
  excluded articles that did not meet the criteria,
  address the question, or use humans!
• 2 investigators reviewed eligible articles were
  blinded to the authors and the journal titles
• The quality of the articles was rated as good or
  fair based on a criteria

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Critique of the Meta-Analysis

• 4. ANALYSIS
• The significance level for all tests of outcome
  was set at Plt0.05
• All of the findings were assessed for
  heterogeneity using X² and q statistic with a
  critical value set at 0.10. There was no
  statistical evidence of heterogeneity
• Results of the fixed- and random-effects model
  were similar
• There was also no evidence of publication bias

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Table 1 Overview of Studies
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Table 1 contd Overview of Studies
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Overview of Studies

• The number of participants ranged from 151 to
  20,536 and 15-50 were women
• Total number of women in the trials was 17,891,
  but almost 2/3 came from 2 studies
• Ethnicity was rarely provided
• Duration of txmt ranged from 2.8 to 6.1 years
• 6 trials were classified at primary prevention
• 8 trials were classified as secondary prevention

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Overview of Studies

• 7 trials reqd mild hyperlipidemia, 4 reqd a
  range of cholesterol levels including the normal
  range, and 2 included any cholesterol level
• 2 trials looked at Clofibrate (? TG ,?
  lipoprotein lipase)
• 1 trial looked at Colestipol (binds bile acids)
• 1 trial looked at Cholestyramine (binds bile
  acids)
• 9 trials looked at Statins (Lova-, Atorva-,
  Simva-, Prava) (inhibits HMG-CoA
  reductase-?cholesterol synthesis)
• All but one trial had a placebo-control group

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Overview of Studies

• All but 2 trials were adequately blinded
• In all but one trial, follow-up was more than 75
  complete
• 9 of the trials qualified as good 4 qualified
  as fair
• The clinical outcomes evaluated were
• Total mortality
• CHD mortality
• Nonfatal MI
• CHD events
• Revascularization

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Overview of Studies

• Most trials addressed the clinical outcomes
• Some studies were not limited to primary or
  secondary prevention, thus each study was
  categorized according to the status of the
  majority of the participants
• For each outcome, the effects of lipid-lowering
  therapy were assessed separately for primary and
  secondary prevention studies

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Results Primary Prevention

• Total Mortality
• There was virtually no difference in mortality
  among women treated w/ lipid-lowering agents vs
  controls with a RR0.95 (95 CI 0.62-1.46).
• CHD Mortality
• There was virtually no difference in CHD
  mortality among treated women vs controls with
  RR1.07 (95 CI 0.47-2.40)

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Results Primary Prevention

• Nonfatal MI
• While both trials examining nonfatal MI found a
  lower risk among treated women there were only 9
  events and the difference was not significant,
  with RR0.61 (95 CI 0.22-1.68)
• Revascularization
• The single trial of revasularization found 8
  events in the treated group compared to 7 in the
  control group RR0.87 (95 CI 0.33-2.31)

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Results Primary Prevention

• CHD Events
• Based on 4 trials, the RR0.87 (95 CI 0.69-1.09)
  for CHD events among treated women vs. controls
• When the ALLHAT study was excluded from the
  results, the RR0.77 (95 CI 0.64-0.94) for CHD.
  (However, no change in mortality was seen when
  omitted)

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Results Secondary Prevention

• Total Mortality
• There was no evidence of reduced risk of
  mortality among treated women vs. controls, with
  a RR1.00 (95 CI 0.77-1.29)
• CHD Mortality
• There was evidence for a reduced risk of CHD
  death among treated women vs. controls with a
  RR0.74 (95 CI 0.55-1.00)
• This finding suggests a 26 reduced risk in CHD
  mortality, with an absolute risk reduction (ARR)
  of 1.7 (NNT59)

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Results Secondary Prevention

• Nonfatal MI
• 6 of 7 trials found a nearly 30 reduced risk of
  nonfatal MI among treated women vs. controls with
  a RR0.71 (95 CI 0.58-0.87)
• Absolute risk reduction was 3.1 (NNT32)
• Revascularization
• All 3 trials found a reduced risk in
  revascularization among treated women with a
  combined RR0.70 (95 CI 0.55-0.89)
• This finding suggests a 30 reduced risk, and a
  absolute risk reduction of 3.6 ( NNT28)

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Results Secondary Prevention

• Total CHD Events
• All 4 trials found a reduced risk of total CHD
  events among treated women with a combined
  RR0.80 (95 CI 0.71-0.91)
• This finding suggests a 20 reduced risk, and a
  absolute risk reduction of 3.8 ( NNT26)

22
Limitations

• 4 of 13 studies were of only fair quality. A
  single study, ALLHAT, which contributed 44 the
  primary prevention subjects, was unblinded, with
  a 32 crossover from controls to treatment during
  the study
• Studies were not analyzed stratified by quality
• Despite pooling multiple studies, the number of
  events in the primary prevention group remained
  small. (a total of just 21 CHD deaths and only
  15 non-fatal MIs).

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Limitations

• Only 3 secondary prevention studies, comprising
  just 4 of all the women, were treated with a
  non-statin therefore the results apply primarily
  to statins
• Drug doses were not available and therefore
  cannot be recommended
• Not all trials provided information for all of
  the types of CHD events

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Summary

• Lipid-lowering therapy was found to reduce the
  risk of CHD mortality, nonfatal MI,
  revascularization, and CHD events by 20-30 in
  women with a history of cardiovascular disease
  (secondary prevention)
• Lipid-lowering therapy was not found to reduce
  the risk of total mortality in women with a
  history of cardiovascular disease (secondary
  prevention)

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Summary

• Lipid-lowering therapy was also not found to
  reduce the risk of any outcomes in women without
  cardiovascular disease (primary prevention)
• The evidence for effectiveness in primary
  prevention appears insufficient and could be due
  to the small of events that occurred
• Better designed studies need to be conducted in
  order to address primary prevention

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Clinical Relevance

• In female patients with a history of
  cardiovascular disease, one should initiate a
  lipid-lowering drug
• In female patients without cardiovascular
  disease, the effect of lipid-lowering drugs
  remains unclear.
• Because the rate of CHD events is less in women
  than men, a larger number of women would need to
  be treated for primary prevention of a CHD event.
• Lets not forget the value of dietary change

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Future Studies

• Studies should include more women
• Studies that include both men and women should
  stratify results by gender
• Studies should be done that stratify the effects
  of lipid-lowering drugs by primary and secondary
  prevention to better understand the role these
  medications play in women without cardiovascular
  disease

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Future Studies

• Studies should have a more uniformed lipid entry
  criteria to assist in the decision-making of
  beginning a lipid-lowering drug based on lipid
  levels
• Studies should have a longer follow-up period
  since coronary events may take longer to surface
  in women

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The End