heart trials
TRANSCRIPT
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Heart diseases : an
overview on clinical trialsDR. KHALED DHIFULLAH AL-HARBY
CONSULTANT FAMILY PHYSICIAN
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14 IMPORTANT CLINICAL TRIALS
AVERT
HERS
PEPI 4 S
CARE
GISSI STRIP
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HOPE
LIPID
Oslo studyHelsinki Heart study
Framinghams study
AFCAPS/TexCAPSWomen health initiative
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HERS
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HERS Trial (1998 )
The Heart and Estrogen/Progestin replacement
2763 postmenopausal women with CHD,combined HRT or placebo, 4 years
E+P , therapy alters the risk for Ischemic
events in postmenopausal women withestablished CAD (secondary prevention).
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no significance difference in the rate ofnon-fatal MI & CHD mortality between thegroups despite significant improvement in
LDL, HDL, TG, in the treatment group there was more frequent adverse
outcomes in the HT group:
venous thromboembolic events HT 2.5%,placebo 0.9%; and gall bladder diseaseHT 6.1%, placebo 4.5%.
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2763 postmenop. + CHD
Combined HRT & placebo
4 years
HRT improved lipidbut not CHDIncrease S.E
HERS
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AVERT
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AVERT trial (1999)
RCT, 18 months follow-up (100 % )
341 patients who had been recommendedfor (PTCA) who had stable coronary heart
disease (CHD) - 177 patients wereallocated to PTCA and 164 were allocatedto atorvastatin, 80 mg per day
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Conclusion:1- aggressive lipid lowering with atrovastatin
in stable CAD patients:
- reduces ischemic events by 36 %- delays the time of first event
- safely delay percutaneous
revascularization
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341 for PTCA
177 PTCA, 164 LIPITOR
18 MONTHS
LIPITOR reducesischemia
& need for PTCA
AVERT
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PEPI
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PEPI (1995)The Postmenopausal Estrogen/Progestin Interventions
Objective: To assess pair wisedifferences between placebo, unopposedestrogen, and each of three
estrogen/progestin regimens on selectedheart disease risk factors in healthypostmenopausal women.
Design: RCT , 3 y. F/U on 875 patients
Primary Endpoints:
(HDL-C); BP; serum insulin; fibrinogen
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Conclusions:
1- Estrogen alone or in combination with aprogestin improves lipoproteins and lowersfibrinogen levels without detectable effectson insulin or blood pressure.
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2- Unopposed estrogen is the optimalregimen post-challenge for elevation ofHDL-C, but the high rate of endometrialhyperplasia restricts use to women withouta uterus.
3- In women with a uterus, CEE with cyclicMP has the most favorable effect on HDL-
C and no excess risk of endometrialhyperplasia.
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875 healthy postmenop.
Placebo, ERT, 3 HRT regimens
3 years
ERT should be usedif no uterus, CEE withCyclic MP if uterus +
PEPI
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SSSS
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SSSS trial (1994)
The Scandinavian Simvastatin Survival Study
followed 4444 patients with moderate
hypercholesterolemia (5.5-8.0 mM) whoalso had symptomatic coronary heartdisease for a median time of 5.4 years.
Patients were aged between 35 and 70years.
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treatment reduced total cholesterol by
25% and lowered low density lipoproteinby 35%.
even in patients whose initial LDL
cholesterol levels was below 4.4 mmol/l,simvastatin reduced the risk of a majorcoronary event by 35%.
6 year survival was 91.3% in thesimvastatin group against 87.6% in the
placebo group
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The treatment of 100 patients for six yearswould prevent four CHD deaths and sevennon-fatal MIs.
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4444 with mild high chol.
Simvastatin, placebo
5.4 years
Reduce T.Chol, LDL, risk of major CAD
Increase 6 y. survival
4S
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CARE
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CARE (1996)
(the Cholesterol and Recurrent Events trial)
compared pravastatin and placebo in
patients In 4000 post MI with mean TC of209 and LDL of 139
On Pravastatin 40mg/d for 5y :Decrease in
coronary events of 24%., decrease inneed for PTCA of 23% ,and decrease inneed for CABG of 26%
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conclusion
LDL concentrations
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4000 post MI
Pravastatin, placebo
5 y.
Reduce C events, need
For PTCA, CABG
CARE
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GISSI
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GISSI-prevenzione trial (1999)
o a RCT on secondary prevention, randomized1324 pt. with recent MI to one of 3 groups(Omega-3-PUFAs 1 g daily, vit E, or both)
in the framework of the Italian publichealth system
patients were invited to follow
Mediterranean dietary habits
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up to 57 lives could be saved per 1000
patients with previous myocardialinfarction treated with n-3 PUFA (1 g daily)per year.
Such a result is comparable to thatobserved in the LIPID trial, where 52 livescould be saved per 1000hypercholaesterolemic, CHD patientstreated with pravastatin for 1 year.
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1324 post MI on MDT diet
- PUVA, Vit E, both
1y.
5.7 / 1000 live saved
GISSI
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post CHD with high chol.
Pravastatin, placebo
1y.
5.2 / 1000 live saved
LIPID
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STRIP
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(STRIP) The Special Turku Coronary Risk
Factor Intervention Project
Families of 7-month-old infants (n=1062)were randomized to a control group
(n=522) or an intervention group (n=540)that received individualized dietarycounseling ( low sat. fat, low cholesterol
diet)
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conclusion:
The restriction of saturated fat and
cholesterol intake by repeated,individualized dietary counseling sinceinfancy resulted in lower serum total and
LDL cholesterol concentrations at 5 yearsof age. However, the effect was significantonly in boys.
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1062 infant
540 dietary counseling, 522 control
5 y.
Reduce T.Chol,Reduce LDL
In boys only !!!
STRIP
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Oslo
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Oslo Study: Diet and AntismokingTrial.
The trial involved 1,232 healthy men, aged40 to 49 years, at high risk for coronaryheart disease, with serum cholesterol
values in the range of 7.5 to 9.8 mmol/liter
Eighty percent of the men were dailycigarette smokers at the start of the study,
and all participants were normotensive
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A. The five years results 60 months(1981):
established the recommendation of
dietary intervention and smokingcessation to improve lipid profiles
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Results after 102 months.
The mean serum cholesterol levels in theintervention group remained unchangedthree years after the end of the trial, but
the cholesterol levels in the control groupdeclined
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1232 healthy men.
With high chol.
Dietary intervention
& smoking cessation
5 y.
Improve lipid, reduceCHD morb&mortality
Even after 3 y.
OSLO
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HOPE
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HOPE study (2000)The Heart Outcomes Prevention Evaluation Study
Effects of an angiotensin-converting-enzymeinhibitor, ramipril, on cardiovascular eventsin high-risk patients
A total of 9297 high-risk patients (55 yearsof age or older) who had evidence ofvascular disease or diabetes plus one
other cardiovascular risk factor and whowere not known to have a low ejectionfraction or heart failure
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The trial was a two-by-two factorialstudy evaluating both ramipril andvitamin E
receive ramipril (10 mg once per dayorally) or matching placebo for a mean offive years
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Conclusion
1) Ramipril significantly reduces the rates ofdeath, myocardial infarction, and stroke
in a broad range of high-risk patientswho are not known to have a low ejectionfraction or heart failure
2) no effect of vit. E on cardiovascularevents in subjects with CAD or DM over4.5 years
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9297 at risk for CAD
Ramipril , placebo
5 y.
Reduce rate of death,
MI, stroke
HOPE
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Helsinki Heart
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Helsinki Heart Study
primary-prevention trial withgemfibrozil in middle-aged men withdyslipidemia
4081 asymptomatic middle-aged men (40to 55 years of age) with primarydyslipidemia
One group (2051 men) received 600 mgof gemfibrozil twice daily, and the other(2030 men) received placebo
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Gemfibrozil caused a marked increase inHDL cholesterol and persistent reductionsin serum levels of total, low-density
lipoprotein (LDL), and non-HDLcholesterol and triglycerides
4081 t ti
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4081 asymptomaticDyslipidemeic men
2051 gemfibrozil, 2030 placebo
Same death rate
Increase HDL, reduce
LDL, TChol, TG
HH
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The womens
health
initiative
th W ' H lth I iti ti
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the Women's Health Initiative1998 - 2002
Risks and Benefits of Estrogen PlusProgestin in Healthy PostmenopausalWomen
Estrogen plus progestin component of theWomen's Health Initiative (plannedduration, 8.5 years)
16608 postmenopausal women aged 50-79 years with an intact uterus at baselinewere recruited by 40 US clinical centers
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On May 31, 2002, after a mean of 5.2
years of follow-up, the data and safetymonitoring board recommended stoppingthe trial of estrogen plus progestin vs
placebo the test statistic for invasive breast cancer
exceeded the stopping boundary for this
adverse effect and the global indexstatistic supported risks exceedingbenefits.
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Conclusion
Overall health risks exceeded benefitsfrom use of combined estrogen plusprogestin for an average 5.2-year follow-
up this regimen should not be initiated or
continued for primary prevention of CHD.
16608 healthy postmenop with
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16608 healthy postmenop with
Intact uterus
Combined HRT, placebo
Planed 8.5 y.(stopped at 5 y.)
Risks exceed benefits
WHI
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Framingham
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The Framingham study
Based on 20 years of surveillance of theFramingham cohort relating subsequentcardiovascular events to prior evidence of
diabetes, a twofold to threefold increasedrisk of clinical atherosclerotic disease wasreported
Cardiovascular mortality was actually
about as great for diabetic women as fordiabetic men
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DM vs. control
20 years
Increases 2-3 xRisk of clinical
Atherosclerotic diseases
Same in both sexes
FRAM
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AFCAPS/TexCAPS
AFCAPS/TexCAPS (1998)
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AFCAPS/TexCAPS (1998)Air Force/Texas Coronary Atherosclerosis Prevention Study
Primary prevention of acute coronaryevents with lovastatin in men andwomen with average cholesterol levels
A total of 6605 persons with average TCand LDL-C and below-average HDL-C
INTERVENTION: Lovastatin (20-40 mg
daily) or placebo in addition to a low-saturated fat, low-cholesterol diet
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After an average follow-up of 5.2 years,lovastatin reduced the incidence of firstacute major coronary events by 37%
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6605 with average chol.
Lovastatin vs. diet + placebo
5.2 y.
Reduce incidence1st major
CAD
AFCAPSTexCAPS
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