Mrcp 2 Clinical Trial Data Mrcp 2

8/7/2019 Mrcp 2 Clinical Trial Data Mrcp 2

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MRCP 2 Clinical Trial DATA MRCP 2(w) Revision.

Clinical Trials:

4S (Scandinavian Simvastatin Survival Study)

o Chol 5.5-8 in IHD/post-MI. 33% in events with mean 25% in cholesterol.

AFCAPS/TEXCAPSo The mean total cholesterol for the trial group ( & ) was 5.71 mmol/l.

o patients were randomized to lovostatin (20-40mg daily) or placebo in addition to a low cholesterol, low

saturated fat diet

o after an average follow-up of 5.2 years

o the lovostatin group showed a significant reduction in incidence of acute major coronary events (by 37%),

unstable angina (325) and myocardial infarctions (40%).

o the beneficial effects of lovostatin therapy were evident after only one year of the study.

o lovostatin group showed a reduction in LDL cholesterol by 25% and an increase in HDL cholesterol by 6%.

o Conclusions - lovostatin therapy reduced the risk of acute coronary artery events in a trial group with

average total and LDL-cholesterols.Treatment benefits were apparent in men and women.

AIRE (Acute Infarction Ramipril Efficacy Study)

o Post MI with early clinical/CXR CCF: ramipril vs placebo (excluding NYHA IV). At 15/12 ramipril group

survival by 27%).

ATLAS (High or low doses of ACE inhibitors for heart failure?)

o chronic heart failure and an ejection fraction of 140 mmHg or diastolic blood pressure > 90 mmHg)

retinopathy

micro or macroalbuminuria

being a current smoker

o it was also required that patients had an LDL cholesterol below 4.4. mmol/l and a triglyceride level below

6.78 mmol/l to be included in the study. There were 2,838 patients in the study - about half the patients were

over 60 years of age, one third were women and about one fifth were smokers

o median LDL cholesterol at entry was 3.1 mmol/l; median HDL-cholesterol at entry was 1.4mmol/l and

median triglycerides was 1.7 mmol/l

o during the course of the four year study:

there was an absolute LDL recution of 1.2 mmol/l (p=0.0001) in the atorvastatin arm. HDL levels were

unchanged. Triglycerides were 21% (0.4 mmol/l) lower in the atorvastatin arm

127 events occurred in the placebo arm and 83 in the atorvastatin 10mg arm

patients receiving atorvastatin had 36% fewer acute coronary events, 31% fewer revascularisation

procedures and 48% fewer strokes

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all-cause mortality was reduced by 27% in the atorvastatin group

the number to needed to treat over four years in order to avoid one event is 27

no significant differences between treatments in safety, tolerability and non-CVD related deaths

Note that during the study about 9% of placebo patients started statin treatment in line with the trial

protocol. Also about 15% of patients in the atorvastatin arm stopped atorvastatin treatment. This may have

led to an underestimation of benefit of atorvastatin treatment of about 25%.

CARE (Cholesterol and Recurrent Events Trial)o High/average cholesterol post-MI 24% reduction in fatal/non-fatal coronary events.

CAST (Cardiac Arrhythmia Suppression Trial)

o Post-MI arrhythmia suppression by flecanide, encainamide & moricizine. Mortality with encainamide and

flecanide greater than placebo.

CIBIS II (Cardiac Insufficiency Bisoprolol Study II)

o EF


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GUSTO 1 (Global Utilisation of Streptokinase and t-PA for Occluded Coronary Artery at 1 year)

o Accelerated vs standard t-PA vs strep together with LMWH vs IV Hep. t-PA and IV Hep 14% better than

strep but haemorrhagic CVA.

HOPE (Heart Outcomes Prevention Evaluation)

o Patients were recruited if they:

were diabetic were 55 years or older

had a cardiovascular risk factor

did not satisfy the exclusion criteria

o The primary outcome was the combination of:

myocardial infarction

stroke

cardiovascular death A main outcome was overt nephropathy.

o Patients were randomised in a two-by-two factorial manner to:

ramipril 10 mg daily or placebo

vitamin E or placebo

o There were significant benefits for the following end-points in those patients randomised to ramipril: combined primary outcome

MI

stroke

cardiovascular death

total mortality

revascularisation

overt nephropathy

HOT (Hypertension Optimal Treatment)

o Results

lowest risk of major cardiovascular events occurred at a mean blood pressure of 139/83 mmHg lowest risk of cardiovascular mortality occurred at mean blood pressure of 140/87 mmHg

lowest risk of stroke when blood pressure lower than 142/80mm Hg

aspirin treatment reduced major cardiovascular events by 15%; aspirin treatment also reduced all

myocardial infarction by 36%; aspirin treatment did not reduce the risk of stroke

o Conclusions

first evidence for an overall benefit of low-dose aspirin in hypertensive patients

analysis of results based on achieved blood pressure indicates that optimal blood pressure is about

140/85 mmHg

IDNT (Irbesartan Diabetic Nephropathy Trial)

o 1715 type 2 diabetic patients with nephropathy receiving conventional antihypertensive drugs wererandomized to an angiotensin II receptor blocker (ARB; irbesartan),

o a calcium channel blocker (amlodipine) or placebo, and followed up for a median period of 2.6 years.

Renal protection was previously demonstrated. In this secondary analysis, treatment effects were compared

on composite cardiovascular events (cardiovascular death, myocardial infarction, congestive cardiac failure,

stroke, coronary revascularization).

o Essentially, no significant difference was found in the incidence of the composite cardiovascular endpoint

among the three groups, based on a time-to-event analysis.

o Use of an ARB and a statin together may provide a highly effective cardioprotective drug combination for

type 2 diabetic patients with nephropathy.

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ISIS 1 (International Study of Infarct Survival 1)

o 7/7 of IV atenolol during MI. 15% in 7 day mortality (mostly days 0-2). Pre-thrombolysis.


o in 5/52 vascular mortality for aspirin (23%) and strep (25%) and in combo (42%).

ISIS 3 (International Study of Infarct Survival 3)o Strep vs t-PA vs APSAC (anisoylated plasminogen streptokinase activator complex) plus aspirin vs s/c

LMWH. No change in cardiovascular mortality at day 35, but haemorrhagic CVA in t-PA arm. Improved

mortality at 1/52 with LMWH (but bleed), no difference at 1/12.


o Nitrates vs captopril vs IV Mg2+ at 5/52. Only 7% benefit seen with captopril seen at 1 year.

LIFE (Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in

hypertension study)

o revealed that treatment with losartan reduced the incidence of stroke by 25% compared to atenolol therapy

in the four year study

o patients were assigned to once-daily losartan (n=4605) or once daily atenolol (n=4588) (both therapies at

maximum doses of 100mg), to which diuretics and other antihypertensive drugs - with the exception of ACE

inhibitors, or other angiotensin II antagonists or beta blockers - could be added, as required, to normalise BP

o the trial was designed to last for at least four years and until 1040 patients had a primary cardiovascular

event (death, MI or stroke)

o there was a significant difference in the incidence of stroke with losartan (5%) and atenolol (7%) therapies

(p=0.001); the rates of cardiovascular mortality and MI were not significantly different between the groups -

however, note that the effect of losartan being the same as that of atenolol is important because it is known

that atenolol therapy reduces the risk of MI by 30% in this patient population

o in the diabetes subgroup (1195 patients, 586 treated with losartan), there was a 24% redction in risk of the

primary end point in the losartan group (p=0.031) and a 39% reduction in all-cause mortality (p=0.002)o the onset of diabetes was 25% less in the losartan arm

o losartan and atenolol had similar BP-lowering effects

MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in Heart Failure)

o EF


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doubling of serum creatinine was reduced by 25%. The risk of end stage renal disease was reduced by 28%

with losartan over an average follow-up of 3.4 years. The benefits of losartan were observed among patients,

many of whom were already receiving other therapies, such as aspirin, beta-blockers, and lipid-lowering

agents.

o Concomitant therapy with calcium-channel antagonists did not detract from the beneficial effects of

losartan. Clinically, this could mean an average delay of two years in the need for dialysis or transplantation.

There was a small, time-averaged difference in the trough blood pressure (BP) between the losartan group

and the placebo group. This small difference in BP had a beneficial effect on the renal outcomes. But,statistical analysis that corrected for these small BP differences confirmed that renal protection conferred by

losartan exceeded that attributable to any BP differences. The addition of losartan to a conventional

antihypertensive treatment regimen did not increase the incidence of adverse events. In summary, losartan

led to an improvement in renal outcomes greater than that predicted by BP reduction alone in patients with

type 2 diabetes and nephropathy.

SAVE (Survival and Ventricular Enlargement Study)

o Captopril in post-MI with EF4: pravastatin vs placebo. 22% in all cause mortality, 20% in total

cholesterol. IMPORTANT 1o PREVENTION STUDY.

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Mrcp 2 Clinical Trial Data Mrcp 2

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