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/TEXCAPS
o 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 <30%.
o there was no significant difference between the groups (low dose lisinopril, high dose lisinopril) for all
cause mortality or cardiovascular mortality
o however high dose lisinopril was more effective than low dose lisinopril for reducing the combined
endpoints of all cause mortality combined with either cardiovascular admissions to hospital, congestive heart
failure admissions to hospital, or all admissions to hospital. Also the high dose group had lower rates of
cardiovascular mortality plus cardiovascular admissions to hospital

• CARD (The Collaborative Atorvastatin Diabetes Study)

o patients were between 40 and 75 years of age and had type 2 diabetes but no history of vascular disease
o in order to be included in the trial they needed one other risk factor for CVD which could include:
♣ hypertension (systolic blood pressure >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<35%, NYHA III-IV on standard Rx. Adding bisoprolol ↓all cause mortality.

• CHARM (Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity)

o The CHARM-Preserved trial recruited 3023 patients with heart failure but no evidence of left ventricular
dysfunction. Patients were randomised to treatment with candesartan or placebo.
o There was no reduction in the primary outcome of the trial however there was a small reduction in
admissions to hospital with heart failure.
o CHARM-added:
• There had been suggestions that triple therapy with ACE inhibitor/candesartan/beta-blocker might be
dangerous. This study did not support these ideas because the small benefit of adding candesartan was also
seen in patients taking beta-blockers.

• CONSENSUS (Co-operative North Scandinavian Enalapril Survival Study)

o Use of enalapril in NYHA V CCF. 40%↓ at 6/12, 31%↓ at 1 year (due to ↑LV function).

• CONSENSUS II (Co-operative North Scandinavian Enalapril Survival Study)

o Early enalapril IV then PO after acute MI slightly ↑ mortality ?hypotension→↓coronary perfusion

• COPERNICUS (CarvedilOl ProspEctive RaNdomised Cumulative Survival Trial)

o EF<30%, NYHA III-IV, dyspnoea ± fatigue at rest/minimal exertion. Adding in carvedilol (β blocker with
some α blocking & anti-oxidant properties) ↓ all cause mortality

• DIGAMI (Intensive Insulin Therapy During and After Myocardial Infarctions in Diabetic Patients)
o The DIGAMI study showed that when insulin was started in patients whose blood glucose was >11 mmol/L
on admission, and continued for a minimum of three months, there was an absolute reduction in mortality of
11 per cent at three years.

• FRAMINGHAM
o Researchers have published more than 1,000 scientific papers based on Framingham data. Numerous
other studies were launched to answer questions raised by Framingham.
• Cigarette smoking increases the risk of heart disease.
• Switching to filtered cigarettes does not measurably reduce heart disease risk.
• Some heart attacks are "silent," or cause no pain.
• The ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol is a good predictor of risk.
• High LDL cholesterol leads to heart disease.
• High HDL cholesterol helps prevent heart disease.
• Obesity and inactivity increase the risk of heart disease.

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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 were
randomized 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.

• ISIS 2 (International Study of Infarct Survival 2)

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.

• ISIS 4 (International Study of Infarct Survival 4)

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<40%, NYHA II-IV on standard Rx. Adding in metoprolol reduced all cause mortality.

• PROGRESS (Peridopril protection against recurrent stroke study)

o investigated the efficacy of blood-pressure reduction in hyper- and normotensive patients with a history of
stroke or TIA.
o Recurrent stroke was reduced in patients randomised to anti-hypertensive treatment.
o Perindopril and indapamide therapy should be considered routinely for patients with a history of stroke or
TIA.

• RALES (Randomised Aldactone Evaluation Study)

o Adding in spiro to treat CCF (even if on ACEi) ↓morbidity & mortality. 2% ↑K+, 9% gynacomastia.

• RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan Study)
o RENAAL demonstrates that losartan, combined with conventional antihypertensive treatment as needed,
confers significant renal protection in patients with type 2 diabetes and nephropathy. The risk of the primary
endpoint (a composite of doubling of serum creatinine, end stage renal disease, or death from any cause)
was reduced by 16% with losartan, which was primarily an effect on the renal components. The risk of
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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 EF<40%. 19%↓ mortality at 3-5 yrs. ↓re-infarction and ↓HF admissions.

• SOLVED
o investigated the effect of withdrawing digoxin from patients with heart failure.
o All patients were in sinus rhythm and had stable mild to moderate heart failure treated with diuretics and
digoxin.
o The SOLVED trial provided strong evidence that digoxin controls the symptoms of heart failure in patients
treated with diuretics.
o The trial did not demonstrate any difference in mortality.

• TIMI-2 (Thrombolysis in Myocardial Infarction – Phase II)

o Trial of metoprolol after t-PA showed ↓early death rate & non fatal re-infarction rate (which was a strong
predictor of subsequent death). No outcome differences in PTCA/CABG vs t-PA group.

• UKPDS/HDS
o intensive blood glucose control by either sulphonylurea or insulin substantially reduced the risk of
microvascular complications, but not macrovascular disease (e.g. stroke, myocardial infarction), in type II
diabetics
o intensive glucose control with metformin decreased the risk of diabetes related complications in obese type
II diabetics; metformin was associated with fewer hypoglycaemic attacks and less weight gain than insulin
and sulphonylureas
o tight blood pressure control is associated with a lower risk of death and complications related to diabetes;
the correlation between blood pressure and cardiovascular disease appears to have no lower threshold - a
target blood pressure of 135/85 mmHg or less is appropriate
o captopril and atenolol were equally effective in reducing diabetic complications
o target glycosylated haemoglobin concentration should be 7.0% or less

• WOSCOPS (West Of Scotland Coronary Prevention Study)

o ♂ (45-65) with no CAD, chol>4: pravastatin vs placebo. 22%↓ in all cause mortality, 20%↓ in total
cholesterol. IMPORTANT 1o PREVENTION STUDY.