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Journal Club – Chronic illness. Hypertension Diabetes Lipids. Hypertension. HOT study - Hypertension Optimal Study - Lancet 1998;351:1755 - 18,790 patients from 26 countries (Europe, N. & S. America, Asia) - Age 50-80, mean=61 - Started 1992, ended 1997. Hot Study – con’t. Aim

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Journal Club – Chronic illness

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Journal Club – Chronic illness

  • Hypertension

  • Diabetes

  • Lipids


  • HOT study

    - Hypertension Optimal Study

    - Lancet 1998;351:1755

    - 18,790 patients from 26 countries (Europe, N. & S. America, Asia)

    - Age 50-80, mean=61

    - Started 1992, ended 1997

Hot Study – con’t


  • Assess the relationship between Major Cardiovascular (CVS) Events with 3 targets DBP

  • Assess whether low-dose Aspirin, added on anti-HT therapy, reduces CVS incidence.

    Study Design

  • Randomised, single-blinded (HT Rx) and double-blinded (Aspirin)

  • Mean years – 3.8 years follow up

HOT Study – con’t

Treatment regimen

  • HT drugs – including Felodipine 5mg QD, may add on ACEI, B-blocker, Hydrochlorothiazide if necessary.

  • Divided into 3 target groups (DBP <90, <85, <80) – each group randomised to low-dose aspirin or not.


  • The lowest incidence of major CVS events: DBP82.6

  • The lowest incidence of CVS mortality: DBP86.5

  • No BP differences whether adding Aspirin or not

  • No J-curve relationship b/w CVS events and DBP

HOT study – con’t


  • DM patients: a 51% reduction of CVS events if DBP was reduced from <90mmHg to <80mmHg.

  • Aspirin reduced major CVS events by 15% and all MI by 36%. No effect on incidence of stroke pr fatal bleeds, but non-fatal bleeds were twice as common.

HOT Study – con’t

  • Optimal calculated BP = 139/83 mmHg

  • British Hypertension Society Guidelines:

    Recommend Aspirin if 10 year CVD risk >15%

    (as calculated from Sheffield table or Joint British coronary risk chart)

SHEP Study

Systolic Hypertension in the Elderly Program


To determine if anti-HT drug treatment reduces the risk of stroke (fatal & non-fatal) in men and women with isolated systolic hypertension, aged >60.


SHEP Study – con’t

Because up until 1990, trials had only been admitting pts with high Diastolic BP, and ignoring systolic reading.

And more epidemiology studies were showing a more robust relationship b/w systolic BP and mortality, esp. in elderly

SHEP study – con’t

Study design: Randomised, double-blinded, placebo-controlled.

Patients: 4736, from US mainly. Mean age 72

SBP= 160-219 mmHg

DBP= <90 mmHg

Follow-up: 4.5 years

Treatment: Chlorthlidone, Atenolol, Respine.

SHEP study – con’t


1) Treatment group:

Average SBP=143 mmHg, DBP 68

Risk of Stroke= 5.2%

2) Placebo group:

Average SBP=155 mmHg, DBP 72

Risk of Stroke= 8.2 %

A)Relative risk (RR) of Stroke = 0.64 (p=0.0003)

B)RR of Non-fatal MI = 0.73 (p=?)

C)RR of Major CVS events = 0.68 (p=?)

SHEP study – con’t

  • Conclusion:

    - Active HT treatment was significantly associated with decreased use of CABG and PTCA in patients <75 years with IHD.

STOP Hypertension

  • Swedish Trial in Old Patients with HT

    (STOP study)


    To determine whether drug treatment of HT is beneficial in men/women aged 70-84 years, and to evaluate drug tolerance, and its effect on Cardiac, Cerebrovascular and total mortality.

STOP Study – con’t

  • Study Design

    Randomised, double-blinded, placebo-controlled.

  • Patients

    1627 men and women (812 active Rx, 815 placebo), aged 70-84 years.

  • Follow-up

    Mean = 25 months

STOP Study – con’t

  • Treatment:

    Atenolol, Metoprolol, or Pinolol, or combination of Amiloride & Hydrochlorothiazide.

    (Target BP <160/<95)

STOP Study – con’t

  • Results

    Treatment Group: mean BP 167/87 mmHg

    Placebo Group: mean BP 186/96 mmHg

    47% reduction in fatal and non-fatal strokes

    43% reduction in total mortality

    (p=0.0081and 0.0079 respectively)

    Placebo gp: 132 complication endpoints – (CHF, BP>230/120, TIA etc…)

    Treatment Gp; 40 complication endpoints only

    (The effect became more pronounced as the study progressed)

STOP Study – con’t

  • Conclusion

    -Beneficial effects of anti-HT drugs treatment were demonstrable up to age 84 (entire age range) and women were benefited at least as much as men.

  • HT treatment in elderly is cost-effective

    N.B.The study was prematurely discontinued because it was unethical to placebo group patients.

STOP 2 Study (Lancet 1999:354;1751)

Similar to STOP study (because it was really “stopped”!)

similar patients background (age 70-84), number=6614.

similar background (Swedish),

similar design (double-blinded, randomised,placebo-controlled)

But comparing the effects of 3 groups of anti-HT drugs –

1) B-blocker/Diuretics

2) Ca-antagonist +/- B-blocker

3) ACEI +/- hydrochlorothiazide

STOP 2 Study – con’t

  • Outcome measures:

    - Fatal stroke

    - Fatal MI

    - Fatal Cardiovascular disease

  • Results & Conclusion

    - Old and new antihypertensive drugs were similar in prevention of CVS mortality and major events.

Diabetes Landmark Studies

  • Diabetes Control & Complications Trial (DCCT)

  • UK Prospective Diabetes Study (UKPDS)

DCCT – Diabetes 1996;45:1289-98

In early 1990’s, the DCCT clearly showed that tight glycaemic control with intensified INSULIN therapy dramatically reduces Microvascular complications in TYPE I DM patients, but not difference in macrovascular disease

It achieved 2% reduction in median HbA1c compared with conventional therapy.


Long term follow up of these patients were published (NEJM 2000;342:381) and these benefits persist.

But it was associated with 3-fold rise in the risk of severe hypoglycaemia. This has raised the concern about the safety of intensified insulin therapy in usual clinical practice.

Until now, the DCCT results were generalised to patients with type 2 DM, without strong direct evidence in this group.


Largest Type II DM studies ever:

Started in 1977

Over 5,000 patients

The main clinical features were published in five papers

UKPDS 33 and 34 (Lancet 1998;352:837-53, 854-65)

UKPDS 38, 39, 40 (BMJ 1998;317:703-26)


Three clinically questions aimed at:

  • Intensive treatment gives a better long- term outcome?

  • Are medicines giving more benefit or harm? (Sulphonylurea – toxic?, Insulin – athrogenic?)

  • Tight BP control improves micro/macro-vascular outcomes?

UKPDS - 33

Compared the effects of intensified blood glucose control with conventional treatment over 10 years in approximately 4000 relatively young patients with newly diagnosed type 2 DM.

Design: Multicenter, randomised, controlled trial with median follow up of 10 years.

Intervention: intensive therapy vs conventional therapy

UKPDS 33 – con’t

Outcome measures: sudden death, hyper/hypo-glycaemia, CVS events, amputation, stroke, vitreous hemorrhage, angina, CHF, renal failure, blindness, etc…, death (all cause).


Median HbA1c level were significantly lowered in intensive group than in conventional group. (7.0% vs 7.9%)

25% risk reduction for microvascular complications

No difference for macrovasculat events, all-cause mortality, and DM-realted death.


  • Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 DM.

  • Results:

    Lower HbA1c level

    Reduces all-cause mortality

    Less hypoglycaemic episodes than intensive treatment group

  • Conclusion:

    Support the choice of Metformin for obese type 2 DM patients.


  • Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 DM patients.

  • Patients : 1148

  • Multicenter, RCT median FU 8.4 yrs

UKPDS 38 – con’t

  • Findings:

    Lower mean BP in tight control group

    24% reduced risks for developing any DM-related complications

    32% reduced risk of mortality

    44% reduced risk of stroke

    34% reduced risk of macrovascular disease

    37% reduced risk of microvascular disease

    56% reduction in heart failure

    NNT 10 yrs to prevent any complication=6

    NNT 10 yrs to prevent one DM-related death= 15


  • Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 DM patients

  • 1148 patients:

    758 – tight control of BP

    400 – captopril

    358 – atenolol

UKPDS 39 – con’t

  • Results:

    - Captopril and Atenolol were equally effective in controlling BP to mean 144/83

    - Both were equally effective in reducing risk of macrovascular endpoints, similar reduction in DM-related death

    - Mean weight gain in atenolol group=3.4kg vs 1.6kg


  • Cost-effectiveness of improved BP control in hypertensive type 2 DM patients

  • Conclusion:

    Tight BP control in type 2 DM patients – substantially reduced the costs of complications, increased the interval without complications, and had a cost-effectiveness ratio that compares favourably with many accepted health-care program.

Lipids Studies

  • These are well-known studies and therefore will only be mentioned briefly and given as summary:

  • Note that the outcome measures of all lipid studies are using relative risk of “coronary heart disease” because high serum lipid by itself is meaningless.

Lipid Studies

  • Secondary prevention studies:

    1) 4S study2) CARE study

    3) LIPID study4) VA-HIT

  • Primary prevention studies:

    1) Helsinki heart study2)WOSCOPS

    3) AFCAPS/TexCAPS4) BMJ –meta-analysis

Scandinavian Simvastatin Survival Study Lancet 1994;344:1383-89

  • 4444 patients, age 35-70, all had ischaemic heart disease, randomised to placebo or Simvastatin 20mg

  • T.Chol=5.5-8.0 mmol/L

  • Median FU of 5.4 years

  • Decreased cardiac mortality by 42%, all-cause mortality by 30%

  • NNT for one fatal MI = 25 over 6 years (14 for non-fatal MI)

Cholesterol And Recurrent Events (CARE)NEJM 1996;335:1001-1009

  • 4159 post-MI patients, aged 21-75, mean T.Chol = 5.4 mmol/L and LDL-C = 3.6mmol/L

  • Randomised for Pravastatin 40mg or Placebo

  • FU for 5 years

  • Results:

  • LDL-C fell by 32% and MI by 25% in treatment group

  • NNT for fatal MI =91 over 5 yrs

  • NNT for non-fatal MI = 38 over 5 yrs

Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study – NEJM 1998;339:1349

  • 9014 patients, ages 31-75 years, median T.Chol 5.66 mmol/L

  • Randomised to Pravastatin 40 mg or Placebo

  • Mean FU for 6.1 years

  • Results:

  • LDL-C fell by 25%

  • 24% reduction in CHD mortality

  • 22% reduction in all-cause mortality

VA-HIT Study (Veterans Affairs High-density lipoprotein cholesterol Intervention Trial) NEJM1999;341:410-418

  • First secondary prevention trial using Gemfibrozil (Lopid) with promising results

  • 2531 men with IHD, with mean HDL<1.0 and LDL>3.6mmol/L, TG 1.78mmol/L, Tchol 4.55mmol/L

  • Subjected to Lopid 600mg bd or placebo

  • Results:

  • HDL was 6% higher, TG 31% lower, LDL-unchanged

  • Reduction of RR for major CHD was 22%

Helsinki Heart StudyNEJM 1987;317:1237

  • Primary prevention trial with gemfibrozil in middle-aged men with dyslipidaemia.

  • 4081 men with mean T.Chol 7.51 mmol/L

  • Randomised to Lopid 600mg bd or placebo.

  • Results:

    - HDL increased by 10%, TG reduced by 35%, LDL reduced by 9%

    - Reduction of relative risk of major CHD events was 34% (esp. combined high TG & Cholesterol)

West of Scotland Coronary Prevention Study (WOSCOPS) NEJM 1995;333:1301-07

  • Primary prevention trial of 6595 middle-aged men (age 45-64), with mean cholesterol 7.06 mmol/L.

  • Randomised (double-blinded) to Pravastatin 40mg daily or placebo, mean FU 4.9 years.

  • Results:

    - LDL reduced by 26%, T.Chol by 26%.

    - Non-fatal MI reduction by 31% (RR), fatal MI by 33%, all-cause mortality reduction by 22%.

Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS) JAMA 1998;279:1615

  • 6605 patients aged 55-73, with normal or mildly elevated total or LDL cholesterol, low HDL, & no clinically CVD.

  • Randomised (double-blinded) to Lovastatin 20-40mg daily, or placebo. Mean FU for 5.2 years

  • Results:

    - LDL reduction 25%, HDL raised 6%

    - reduced incidence of MI (RR 0.6), Angina (RR 0.68), Coronary events (RR 0.75)

BMJ Meta-analysis on Primary Prevention

  • Drug treatments reduced the odds of a CHD event by 30% (95%CI 0.62-0.79) but not the odds of all cause mortality (95%CI 0.81-1.09) – even with statins.

  • Concluded that treatment with lipid lowering drugs lasting 5-7 years reduces coronary heart disease events but not all-cause mortality.

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