heart trials

8/9/2019 Heart Trials

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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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heart trials

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