Allopurinol in angina
Transcript of 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
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
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
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)
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
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.
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.
Figure 1
Source: The 6(10)60391-1)
Baseline Characters
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
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
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
ANGINA EPISODES PER WK
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).
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.
Interpretation• Allopurinol seems to be a
useful, inexpensive, well tolerated, and safe anti-ischemic drug for patients with 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
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
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
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,"
OTHER SIMILLAR STUDIES
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)
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.
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."
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
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