Allopurinol in angina


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  • Trial profile
  • Change in time to chest pain symptoms from baseline Data are median (IQR).
  • Change in time to ST depression from baseline Data are median (IQR).
  • Allopurinol in angina

    1. 1. D . SUBBURAJ PROF. G.ELANGOVAN UNIT <ul><li>Effect of high-dose allopurinol on exercise capacity in patients with chronic stable angina </li></ul><ul><ul><li>Awsan Noman, MB, Donald SC Ang, MD, Simon Ogston, PhD, Chim C Lang , MD and Allan D Struthers, MD </li></ul></ul><ul><li>The Lancet </li></ul><ul><li>VOLUME 375 ,ISSUE 9732 (June 2010) </li></ul>Copyright © 2010 Elsevier Ltd
    2. 2. OLD GOUT DRUG – NEW TRICKS ON ANGINA <ul><li>XANTHINE OXIDASE INHIBITOR </li></ul><ul><li>Rapidly absorbed </li></ul><ul><li>Metabolized in liver </li></ul><ul><li>Active metabolite- oxypurinol ( long half life 18-20 hrs) </li></ul><ul><li>Adverse effects –skin rashes, hepato toxicity, GI upset </li></ul>
    3. 3. Why Allopurinol <ul><li>In experimental heart failure , allopurinol improves ‘mechano – energetic uncoupling’ in myocardium </li></ul><ul><li>Decreases oxygen demand with out changing Cardiac output in pacing induced heart failure in dogs (EKYLAND 1999) </li></ul><ul><li>If such an effect also occurs in man , this drug could become a new R x for ischemia </li></ul>
    4. 4. Why Allopurinol <ul><li>Increase C.O without changing oxygen demand in pts with idiopathic cardio myopathy ( cappola 2001) </li></ul><ul><li>Allopurinol improves endothelial function in a wide variety of cardiovascular events . ( GEORGE et all 2006) </li></ul>
    5. 5. Study Design <ul><li>Design – randomized , double blind, placebo controlled, cross over study </li></ul><ul><li>Dose of oral allopurinol - 100 mg od –first wk, 300 mg od - second week, and 300 mg bid during the rest of the treatment </li></ul><ul><li>Primary endpoint - time to ST depression, </li></ul><ul><li>Secondary endpoints - total exercise time and time to chest pain </li></ul>
    6. 6. Inclusion Criteria <ul><li>Individuals (aged 18—85 years). </li></ul><ul><li>Angiographically documented CAD, </li></ul><ul><li>A positive exercise tolerance test (ETT), </li></ul><ul><ul><li>Eligible participants had to manifest ischemia (ST depression ≥1 mm compared with resting ECG) on both visits </li></ul></ul><ul><li>A history of symptoms of chronic, stable, effort-induced angina for at least 2 months. </li></ul><ul><li>All concomitant antianginal drugs were allowed and continued unchanged during the study. </li></ul>
    7. 7. Exclusion criteria <ul><li>recent MI or ACS ( with in 2 mns) </li></ul><ul><li>coronary revascularisation within the previous 6 months, </li></ul><ul><li>LVEF < 45% , </li></ul><ul><li>eGFR < 45 mL / min or creatinine > 180 mmol/mL (n=5), </li></ul><ul><li>substantial valvular disease (n=1), </li></ul><ul><li>had gout or already on allopurinol, </li></ul><ul><li>arrhythmias or ECG abnormalities interfering with ST-segment interpretation </li></ul><ul><li>severe hepatic disease or taking warfarin (n=6), azathioprine (n=1), or 6-mercaptopurine. </li></ul>
    8. 8. Figure 1 Source: The 6(10)60391-1)
    9. 9. Baseline Characters
    10. 10. 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
    11. 11. 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
    12. 12. 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
    14. 15. BNP & CRP <ul><li>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 ). </li></ul><ul><li>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 ). </li></ul>
    15. 16. CONCLUSIONS <ul><li>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 . </li></ul><ul><li>high-dose allopurinol prolongs exercise capacity in stable angina pectoris. </li></ul>
    16. 17. Interpretation <ul><li>Allopurinol seems to be a useful, inexpensive, well tolerated, and safe anti-ischemic drug for patients with angina. </li></ul>
    17. 18. What is the mechanism of the anti-ischaemic effect of allopurinol? <ul><li>Allopurinol can reduce myocardial oxygen consumption for a particular stroke volume. </li></ul><ul><li>Antioxidant effect-> decrease OS -> increase O 2 </li></ul><ul><li>Increase high energy phosphates ( ATP) </li></ul><ul><li>Down regulates XO , up regulates NOS </li></ul><ul><li>Improves endothelial functions -> coronary microvascular flow </li></ul>
    18. 19. ADVANTAGES OVER OTHER ANTI ANGINAL DRUS <ul><li>cost effective </li></ul><ul><li>40 yrs safe records </li></ul><ul><li>Well tolerated </li></ul><ul><li>Useful in developing countries, where access to expensive therapies such as angioplasty or newer drugs is restricted </li></ul>
    19. 20. Anti ischemic effects similar to other anti anginal drugs <ul><li>eg, the absolute increase in median time to ST depression with allopurinol was 43 s (19% increase). </li></ul><ul><li>other antianginal drugs </li></ul><ul><ul><li>36 s (13%) with amlodipine </li></ul></ul><ul><ul><li>  60 s (11%) with nitrates  </li></ul></ul><ul><ul><li>12—47 s (4—14%) with phosphodiesterase inhibitors </li></ul></ul><ul><ul><li>  46 s (13·5%) with ivabradine </li></ul></ul><ul><ul><li>50 s (15%) with atenolol and ranolazine </li></ul></ul>
    20. 21. Allopurinol could be another second agent option for angina symptoms <ul><li>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   </li></ul><ul><li>If the second drug is ineffective, it is stopped and another second agent is tried. Allopurinol &quot;could be another second drug to use as an option,&quot; </li></ul>
    22. 23. 1.Mechanistic Insights Into the Therapeutic Use of High-Dose Allopurinol in Angina Pectoris Narasimharajapura S. Rajendra, MD*,Sheila Ireland, RGN, RM, Jacob George, MD,Jill J.F. Belch, MD, Chim C. Lang, MD andAllan D. Struthers, MD <ul><li>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) </li></ul>
    23. 24. 2.The Effect of Allopurinol on B-Type Natriuretic Peptide Levels in Patients with Chronic Stable Angina Awsan Noman; Maheshwar Pauriah; Allan D Struthers Ninewells Hosp, Dundee, United Kingdom <ul><li>Conclusions:  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. </li></ul>
    24. 25. 3.Allopurinol regresses left ventricular hypertrophy in chronic kidney disease JULY 7, 2010 |  Daniel M Keller <ul><li>patients on allopurinol had a regression of the LV mass after nine months [-1.42 + 4.67 g/m 2 ] compared with progression of LV mass for those patients in the placebo group [+1.28 + 4.45 g/m 2 ; p=0.036 ]. they also found a trend toward improvement in the end-diastolic volume for those patients on allopurinol.&quot; </li></ul>
    25. 26. OPT CHF TRIAL: Allopurinol - exercise capacity in CHF NOT EFFECTIVE ?? <ul><li>cause exercise capacity is different in CHF & CAD </li></ul><ul><li>Study population – small </li></ul><ul><li>Allopurinol dose used was low (300 mg) compared to this study </li></ul><ul><li>Primary end point- 6 mins walk test – previous study . Exercise tolerance test used in this study </li></ul><ul><li>That is why allopurinol failed to execise capacity in heart failure </li></ul>
    26. 27. Thank U <ul><li>Only antianginal drug improves survival & symptoms - beta blocker </li></ul><ul><li>Allopurinol seems to have effect on mortality – large scale studies needed </li></ul><ul><li>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 </li></ul>