allopurinol in angina

27
Effect of high-dose allopurinol on exercise capacity in patients with chronic stable angina Awsan Noman, MB, Donald SC Ang, MD, Simon Ogston, PhD, Chim C Lang, MD and Allan D Struthers, MD The Lancet VOLUME 375 ,ISSUE 9732 (June 2010) Copyright © 2010 Elsevier Ltd D . SUBBURAJ PROF. G.ELANGOVAN UNIT

Upload: subbu-raj

Post on 01-Jun-2015

801 views

Category:

Education


8 download

TRANSCRIPT

Page 1: Allopurinol in angina

Effect of high-dose allopurinol on exercise

capacity in patients with chronic stable angina

Awsan Noman, MB, Donald SC Ang, MD, Simon Ogston, PhD, Chim C Lang, MD

and Allan D Struthers, MD

The Lancet VOLUME 375 ,ISSUE 9732 (June 2010)

Copyright © 2010 Elsevier Ltd

D . SUBBURAJPROF. G.ELANGOVAN UNIT

Page 2: Allopurinol in angina

OLD GOUT DRUG – NEW TRICKS ON ANGINA

• XANTHINE OXIDASE INHIBITOR• Rapidly absorbed• Metabolized in liver• Active metabolite- oxypurinol ( long half life

18-20 hrs)• Adverse effects –skin rashes, hepato toxicity,

GI upset

Page 3: Allopurinol in angina

Why Allopurinol

• In experimental heart failure , allopurinol improves ‘mechano – energetic uncoupling’ in myocardium

• Decreases oxygen demand with out changing Cardiac output in pacing induced heart failure in dogs (EKYLAND 1999)

• If such an effect also occurs in man , this drug could become a new R x for ischemia

Page 4: Allopurinol in angina

Why Allopurinol

• Increase C.O without changing oxygen demand in pts with idiopathic cardio myopathy ( cappola 2001)

• Allopurinol improves endothelial function in a wide variety of cardiovascular events . ( GEORGE et all 2006)

Page 5: Allopurinol in angina

Study Design

• Design – randomized , double blind, placebo controlled, cross over study

• Dose of oral allopurinol - 100 mg od –first wk, 300 mg od - second week, and 300 mg bid during the rest of the treatment

• Primary endpoint - time to ST depression,• Secondary endpoints - total exercise

time and time to chest pain

Page 6: Allopurinol in angina

Inclusion Criteria

• Individuals (aged 18—85 years). • Angiographically documented CAD,• A positive exercise tolerance test (ETT),

• Eligible participants had to manifest ischemia (ST depression ≥1 mm compared with resting ECG) on both visits

• A history of symptoms of chronic, stable, effort-induced angina for at least 2 months.

• All concomitant antianginal drugs were allowed and continued unchanged during the study.

Page 7: Allopurinol in angina

Exclusion criteria • recent MI or ACS ( with in 2 mns)• coronary revascularisation within the previous 6

months,• LVEF < 45% ,• eGFR < 45 mL / min or creatinine > 180 mmol/mL

(n=5), • substantial valvular disease (n=1),• had gout or already on allopurinol,• arrhythmias or ECG abnormalities interfering with

ST-segment interpretation• severe hepatic disease or taking warfarin (n=6),

azathioprine (n=1), or 6-mercaptopurine.

Page 8: Allopurinol in angina

Figure 1

Source: The 6(10)60391-1)

Page 9: Allopurinol in angina

Baseline Characters

Page 10: Allopurinol in angina

Figure 4

Source: The Lancet 2010; 375:2161-2167 (DOI:10.1016/S0140-6736(10)60391-1)

Terms and Conditions

RESULTS: Time To Chest Pain

BASE LINE PLACEBO ALLOPURINOL

P VALUE

TIME TO CHEST PAIN

234 (189-382) 272 (200-421) 304 (272-421)

0.001

Page 11: Allopurinol in angina

Figure 3

total exercise time from baseline

BASE LINE ALLOPURINOL PLACEBO P VALUE

TOTAL EXERCISE TIME

301 (251-441) 393 (290-519)

307(222-420) 0.003

Page 12: Allopurinol in angina

Time To ST Depression From Baseline

BASELINE PLACEBO ALLOPURINOL P VALUE

TIME TO ST DEPRESSION

232 (182-380) 249(200-375) 298 (211-408) 0.002

Page 13: Allopurinol in angina
Page 14: Allopurinol in angina

ANGINA EPISODES PER WK

Page 15: Allopurinol in angina

BNP & CRP

• Allopurinol reduced concentrations of brain natriuretic peptide (from baseline median 84·3 pg/mL [IQR 44·8—186·0] to 65·6 pg/mL [37·0—122·7]) compared with placebo (80·4 pg/mL [40·1—132·8]; p=0·045).

• There was no significant change in concentrations of C-reactive protein from baseline (1·49 mg/L [0·48—2·88]) with allopurinol (1·47 mg/L [0·46—2·71]) or placebo (141 mg/L [0·63—2·78]; p=0·757).

Page 16: Allopurinol in angina

CONCLUSIONS

• High-dose allopurinol significantly prolonged the time to ST depression, the total exercise time, and the time to chest pain in patients with chronic stable angina during a standard exercise test, suggesting that endogenous xanthine oxidase activity contributes somehow to exercise-induced myocardial ischaemia.

• high-dose allopurinol prolongs exercise capacity in stable angina pectoris.

Page 17: Allopurinol in angina

Interpretation• Allopurinol seems to be a

useful, inexpensive, well tolerated, and safe anti-ischemic drug for patients with angina.

Page 18: Allopurinol in angina

What is the mechanism of the anti-ischaemic effect of

allopurinol? Allopurinol can reduce myocardial oxygen

consumption for a particular stroke volume. Antioxidant effect-> decrease OS ->

increase O2

Increase high energy phosphates ( ATP) Down regulates XO , up regulates NOS Improves endothelial functions -> coronary

microvascular flow

Page 19: Allopurinol in angina

ADVANTAGES OVER OTHER ANTI ANGINAL DRUS

• cost effective• 40 yrs safe records• Well tolerated • Useful in developing countries, where access

to expensive therapies such as angioplasty or newer drugs is restricted

Page 20: Allopurinol in angina

Anti ischemic effects similar to other anti anginal

drugs• eg, the absolute increase in median time to ST

depression with allopurinol was 43 s (19% increase).

• other antianginal drugs – 36 s (13%) with amlodipine– 60 s (11%) with nitrates – 12—47 s (4—14%) with phosphodiesterase inhibitors– 46 s (13·5%) with ivabradine– 50 s (15%) with atenolol and ranolazine

Page 21: Allopurinol in angina

Allopurinol could be another second agent option for angina

symptoms• the symptoms (chest pain on exertion) in chronic

stable angina is generally treated with angioplasty or beta blockers plus a second drug such as nitrates, calcium antagonists, or newer agents such as ranolazine or ivabradine

• If the second drug is ineffective, it is stopped and another second agent is tried. Allopurinol "could be another second drug to use as an option,"

Page 22: Allopurinol in angina

OTHER SIMILLAR STUDIES

Page 23: Allopurinol in angina

1.Mechanistic Insights Into the Therapeutic Use of High-Dose Allopurinol

in Angina PectorisNarasimharajapura S. Rajendra, MD*,Sheila Ireland, RGN, RM, Jacob George, MD,Jill J.F. Belch, MD, Chim

C. Lang, MD andAllan D. Struthers, MD

Conclusions: Our study demonstrates that, in optimally treated CAD patients, high-dose allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction.The former effect on OS might underpin the anti-ischemic effect of allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor allopurinol in angina)

Page 24: Allopurinol in angina

2.The Effect of Allopurinol on B-Type Natriuretic Peptide Levels in Patients with

Chronic Stable AnginaAwsan Noman; Maheshwar Pauriah; Allan D Struthers

Ninewells Hosp, Dundee, United KingdomConclusions: In patients with chronic stable angina and preserved LVSF, BNP is higher in the presence of triple-vessel CAD. In this group of patients, high dose allopurinol reduces resting and immediate post-exercise BNP. This result could be explained by (and further confirms) the previously reported anti-ischaemic effect of allopurinol.

Page 25: Allopurinol in angina

3.Allopurinol regresses left ventricular hypertrophy in chronic

kidney diseaseJULY 7, 2010 | Daniel M Keller

patients on allopurinol had a regression of the LV mass after nine months [-1.42+4.67 g/m2] compared with progression of LV mass for those patients in the placebo group [+1.28+4.45 g/m2; p=0.036]. they also found a trend toward improvement in the end-diastolic volume for those patients on allopurinol."

Page 26: Allopurinol in angina

OPT CHF TRIAL: Allopurinol - exercise capacity in CHF

NOT EFFECTIVE ??• cause exercise capacity is different in CHF &

CAD• Study population – small• Allopurinol dose used was low (300 mg)

compared to this study• Primary end point- 6 mins walk test – previous

study . Exercise tolerance test used in this study• That is why allopurinol failed to execise capacity

in heart failure

Page 27: Allopurinol in angina

Thank U

• Only antianginal drug improves survival & symptoms - beta blocker

• Allopurinol seems to have effect on mortality – large scale studies needed

• Further research is required to investigate the mechanism of this anti ischemic effect & to define the best place for allopurinol in the over all management of angina pectoris