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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
Journal Club – Chronic illness

  • Hypertension

  • Diabetes

  • Lipids


Hypertension
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
Hot Study – con’t

Aim

  • 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 t1
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.

    Results

  • 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 t2
HOT study – con’t

Results:

  • 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 t3
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
SHEP Study

Systolic Hypertension in the Elderly Program

Aim:

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.

WHY?


Shep study con t
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 t1
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 t2
SHEP study – con’t

Results:

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 t3
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
STOP Hypertension

  • Swedish Trial in Old Patients with HT

    (STOP study)

    AIM:

    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
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 t1
STOP Study – con’t

  • Treatment:

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

    (Target BP <160/<95)


Stop study con t2
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 t3
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
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
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 Landmark Studies

  • Diabetes Control & Complications Trial (DCCT)

  • UK Prospective Diabetes Study (UKPDS)


Dcct diabetes 1996 45 1289 98
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.


DCCT

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.


Ukpds
UKPDS

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)


Ukpds1
UKPDS

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
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
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).

Results:

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.


Ukpds 34
UKPDS 34

  • 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.


Ukpds 38
UKPDS 38

  • 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
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


Ukpds 39
UKPDS 39

  • 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
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


Ukpds 40
UKPDS 40

  • 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
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
Lipid Studies

  • Secondary prevention studies:

    1) 4S study 2) CARE study

    3) LIPID study 4) VA-HIT

  • Primary prevention studies:

    1) Helsinki heart study 2)WOSCOPS

    3) AFCAPS/TexCAPS 4) BMJ –meta-analysis


Scandinavian simvastatin survival study lancet 1994 344 1383 89
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
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
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 study nejm 1987 317 1237
Helsinki Heart Study cholesterol Intervention Trial) NEJM 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
West of Scotland Coronary Prevention Study (WOSCOPS) cholesterol Intervention Trial) 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
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
BMJ Meta-analysis on Primary Prevention (AFCAPS)

  • 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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