Ace inhibitor :From Venom to Drug

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  • Concomitant Use of Antihypertensive Drugs
    Antihypertensive drugs typically are very complimentary; however, there are some combinations which tend to be more favorable and are shown in this slide by the yellow lines. Although drug combinations shown by the pink line can be used, they tend to be less complimentary and frequently do not result in an additive reductions in BP.
    Reference:
    Chalmers J. The Place of Combination Therapy in the Treatment of Hypertension in 1993. Clin Exp Hypertens. 1993;15:1299-1313.
  • Ace inhibitor :From Venom to Drug

    1. 1. ACE INHIBITORS : FROM VENOM TO DRUG Dr Syed Raza MD,MRCP(UK),CCT(UK),DIP.CARD(UK),FCCCP Consultant Cardiologist
    2. 2. Objectives • Overview of ACEI • Indications and Uses • Effectiveness and • The Evidence
    3. 3. Franklin D Roosevelt – 1940s Howard Bruenn lamented in the Annals of Internal Medicine, "I have often wondered what turn the subsequent course of history might have taken if the modern methods for the control of hypertension had been available’’
    4. 4. Originally synthesized from compounds found in pit viper venom(Sir John Vane -1960s)
    5. 5. Angiotensinogen Angiotensin I Angiotensin II AT1 Receptor AT2 Receptor Bradykinin Inactive Metabolites Renin ACE ARB Non ACE ACEi(-) (-)
    6. 6. ACE Inhibitor Groups A. Sulfhydryl-containing agents: – Captopril , the first ACE inhibitor B. Dicarboxylate-containing agents: – Enalapril – Ramipril – Quinapril – Perindopril – Lisinopril – Benazepril C. Phosphonate-containing agents: – Fosinopril – Trandolapril
    7. 7. Clinical Indications for ACEI • Hypertension • CHF • Post MI • Diabetes Mellitus • Proteinuria • Vascular Disease • Post - transplant
    8. 8. Additional Benefits of ACEI • Prevention of diabetes • Prevention of stroke recurrence • Prevention of atrial fibrillation
    9. 9. How ACEI is useful in hypertension? • ACE inhibitors block the conversion of angiotensin I to angiotensin II • Lower arteriolar and renovascular resistance • Increase venous capacity, • Increase cardiac output, cardiac index and stroke volume.
    10. 10. Which antihypertensive? NICE Diabetes Clinical Guideline 66;May 2008. NICE Full Diabetes Guideline;2008 • First-line BP lowering therapy should be a once-daily, generic ACE inhibitor • Exceptions to this are: – People of African-Caribbean descent – Women for whom there is a possibility of becoming pregnant – For a person with continuing intolerance to an ACE inhibitor
    11. 11. Choice of antihypertensive agents When implementing blockade of the renin– angiotensin system start treatment with an ACE inhibitor first then move to an ARB if the ACE inhibitor is not tolerated.
    12. 12. Pharmacotherapy –BP Control • In people without CKD aim to keep the systolic blood pressure below 140 mmHg (target range 120–139 mmHg) and the diastolic blood pressure below 90 mmHg. • In people with CKD and diabetes with urinary protein excretion 1 g/24 h or more) aim to keep the systolic blood pressure below 130 mmHg (target range 120–129 mmHg) and the diastolic blood pressure below 80 mmHg
    13. 13. Fixed Drug Combination ► To achieve recommended blood pressure goals, it is often necessary to combine two or more antihypertensive agents. Is there a preferred combination?
    14. 14. Less effective Diuretics Beta Blockers ACEIs ARBs Calcium Channel Blockers α1-Receptor Blockers Particularly effective Adapted from Chalmers J. Clin Exp Hypertens. 1993;15:1299–1313. Concomitant Use of Antihypertensive Drugs
    15. 15. The Moral of the Tale As long as we reach the objective BP below 140/90 (130/80), it doesn’t matter how we get there
    16. 16. ALLHAT (JAMA 2002) “The key message from ALLHAT is that what matters most is getting blood pressure controlled’’
    17. 17. The Heart Matters – the effect of ACEI • Prevents cardiac hypertrophy • Limits infarct size • Improves cardiac function • Improves cardiac metabolism
    18. 18. ACEI in Heart Failure • ACE inhibitors are recommended to treat HF due to systolic dysfunction. • The benefit of ACE inhibitors has been demonstrated in all severities of symptomatic HF and in patients with asymptomatic left ventricular (LV) dysfunction.
    19. 19. ACE in Heart Failure: the evidence A meta-analysis evaluated five trials • Improvement in symptoms • A lower total mortality. • A lower rate of readmission for HF).
    20. 20. ACE Inhibitors for ‘Diastolic’ Heart Failure? • Guidelines for the management of heart failure focus on patients with left ventricular systolic dysfunction. • However, guidelines make no recommendation for their use in patients with heart failure and preserved left ventricular systolic function.
    21. 21. ACE inhibitors versus ARBs: comparison of practice guidelines and treatment selection • ACC/AHA Heart Failure guidelines 2005. ACE inhibitors should be prescribed to all patients with left ventricular systolic dysfunction HF (class IA recommendation). • They recommend ARBs as a "reasonable alternative" first-line therapy (class IIA recommendation).
    22. 22. ACE inhibitors versus ARBs: comparison of practice guidelines : Contd • ACEI more cost effective • ARB better tolerated than ACEI • Deciding factor may be largely patient- specific.
    23. 23. Landmark trials with ACE inhibitors in HF Trial n EF% Drug Death Hospitalisation Follow up NNT (death) CONSENSUS 1987 253 <35% (IV) enalapril 36 vs 50 reduced 1 year 6 SOLVD-P 1992 4228 <35 (I) enalapril trend to reduction reduced 4 years 104 SOLVD – T 1991 2500 < 40 (II-III) enalapril 12.3 vs 15.5 reduced 3 years 31 ATLAS 1997 3164 <35 (II-IV) lisinopril no difference reduced 4 years -
    24. 24. • The ACE inhibitor Enalapril has also been shown to reduce cardiac cachexia in patients with chronic heart failure • Cachexia is a poor prognostic sign in patients with chronic heart failure. ACE inhibitors are now used to reverse frailty and muscle wasting in elderly patients without heart failure.
    25. 25. Type 2 diabetes Management of cardiovascular risk factors Lending our patients a hand
    26. 26. Can ACEI prevent Diabetes ? • Several recent studies indicate that ACE inhibitor therapy reduces the development of type 2 diabetes in persons with essential hypertension. • HOPE, CAPPP, SOLVD, and ALLHAT • DREAM & ONTARGET = more recent
    27. 27. Path physiology • Exact mechanism is not known • ACEI reduces oxidative stress • Increases insulin sensitivity in the liver • Reduces Insulin resistance in muscles • Helps in the preservation of islet cells of pancreas
    28. 28. ACEI and the Kidneys Clinical studies have shown ACE inhibitors reduce the progress of diabetic nephropathy independently from their blood pressure- lowering effect. This action of ACE inhibitors is used in the prevention of diabetic renal failure.
    29. 29. ACEI and the Kidneys – Contd: • Decreases Proteinuria (DM and Non-DM) • Beneficial effect on permeability • Beneficial effect on size selectivity • Slow the Rate of GFR Decline
    30. 30. Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%).Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%). ** Death from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for peripheral atheroscleroticDeath from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease.artery disease. †† Behavior modification and pharmacologic therapy.Behavior modification and pharmacologic therapy. Adapted from Gaede P, et al.Adapted from Gaede P, et al. N Eng J MedN Eng J Med. 2003;348:383-393.. 2003;348:383-393. PrimaryCompositeEndpoint*(%)PrimaryCompositeEndpoint*(%) Months of Follow-UpMonths of Follow-Up 6060 4040 2020 1212 2424 3636 4848 6060 7272 8484 9696 Conventional TherapyConventional Therapy Intensive TherapyIntensive Therapy†† 20% Absolute20% Absolute Risk ReductionRisk Reduction N=160; follow-up=7.8 yearsN=160; follow-up=7.8 years Aggressive treatment ofAggressive treatment of†† :: – Microalbuminuria withMicroalbuminuria with ACEIs, ARBs, or combinationACEIs, ARBs, or combination – HypertensionHypertension – HyperglycemiaHyperglycemia – DyslipidemiaDyslipidemia – Secondary prevention of CVDSecondary prevention of CVD Intensive Multiple Risk Factor Management Patients with Type 2 Diabetes and Microalbuminuria
    31. 31. © Continuing Medical Implementation ® …...bridging the care gap Vascular Protection ACE inhibitor Trials
    32. 32. HOPE (Heart Outcome Prevention Evaluation) • 9297 Patients • Age >55 • DM + 1 other CV factor • Normal EF (>40%) • Ramipril (10mg) vs. Placebo
    33. 33. HOPE (Primary endpoints) • Death (CV) - 6.1 vs 8.1 P<0.001 RR=0.75 • MI - 9.9 vs 12.2 P<0.001 RR=0.80 • Stroke - 3.4 vs 4.9 P<0.001 RR=0.69
    34. 34. HOPE (secondary endpts.) • Death 10.4 vs 12.2 • Revascularization 16.0 vs 18.6 • Cardiac arrest 0.8 vs 1.2 • Heart Failure 7.4 vs 9.4 • DM complications 6.2 vs 7.4 * all statistically significant
    35. 35. EUROPA  Randomised 12,218 patients with stable coronary artery disease (CAD) and a broad range of risk for cardiovascular complications  Showed the benefit of long-term (mean 4.2 years) ACE-inhibition (perindopril 8 mg/day)
    36. 36. Study end points  Non Fatal MI, Cardiac arrest and CV mortalityNon Fatal MI, Cardiac arrest and CV mortality Primary endpointPrimary endpoint Secondary endpointsSecondary endpoints  Heart failureHeart failure  Revascularisation (PCI/CABG)Revascularisation (PCI/CABG)  StrokeStroke
    37. 37. Primary endpoint % CV death, MI or cardiac arrest% CV death, MI or cardiac arrest Placebo annual event rate: 2.4%Placebo annual event rate: 2.4% PerindoprilPerindopril PlaceboPlacebo p = 0.0003p = 0.0003 RRR:RRR: 20%20% YearsYears 00 22 44 66 88 1010 1212 1414 00 11 22 33 44 55
    38. 38. Primary endpoint RRR: 20% [95% CI : 9 - 29]RRR: 20% [95% CI : 9 - 29] CV death, MI or cardiac arrestCV death, MI or cardiac arrest 00 100100 200200 300300 400400 500500 600600 700700 No eventsNo events PerindoprilPerindopril (6 110)(6 110) 8.0%8.0% 488488 PlaceboPlacebo (6 108)(6 108) 9.9%9.9% 603603
    39. 39. The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial  A double-blind, placebo-controlled, randomized trial  Sponsored by the National Heart, Lung, and Blood Institute
    40. 40. Hypothesis To test whether ACE inhibitor therapy, when added to modern conventional therapy, reduces CV mortality, MI, or coronary revascularization in low-risk, stable CAD patients with normal or mildly reduced LV function.
    41. 41. Inclusion Criteria • Age ≥ 50 years • Coronary artery disease – MI, or – CABG or PCI, or – Coronary angiogram with obstruction of ≥50% luminal diameter in at least one native vessel • LVEF > 40% • Tolerated 2 week run-in of 2 mg/day trandolapril
    42. 42. Change in Systolic Blood Pressure -6 -5 -4 -3 -2 -1 0 0 1 2 3 4 5 6 Time Since Randomization (Years) PressureChange(mmHg) Placebo Trandolapril Baseline= 133±17 ∆=-1.4 ∆=-4.4, p<0.001
    43. 43. Change in Diastolic Blood Pressure -7 -6 -5 -4 -3 -2 -1 0 0 1 2 3 4 5 6 Time Since Randomization (Years) PressureChange(mmHg) Placebo Trandolapril Baseline= 78±10 ∆=-2.3 ∆=-3.6, p<0.001
    44. 44. PEACE Trial: All Death 7.2 8.1 0 2 4 6 8 10 Trandolapril Placebo • A slight reduction in all- cause death seen in the Trandolapril arm was not statistically significant All-Cause Death p = 0.13 Presented at AHA 2004
    45. 45. PEACE Trial: Primary Endpoint 3.5 5.3 6.5 12.4 3.7 5.3 7.1 12.0 0 4 8 12 16 Cardio death Nonfatal MI CABG PCI Trandolapril Placebo % Presented at AHA 2004 p=0.67 p=1.00 p=0.24 p=0.65 The individual components of the primary endpoint were also equivalent in the Trandolapril and placebo groups
    46. 46. IMAGINE •In patients at low risk of CV events after CABG, routine early initiation of ACE inhibitor therapy does not appear to improve clinical outcome up to 3 years after CABG Trial design: IMAGINE was a double-blinded, randomized, placebo-controlled trial designed to test the effects of early ACE inhibitor initiation (quinapril 10 or 20 mg/day within 7 to 10 days) after CABG in patients with preserved LV function, and no clear indication for ACE inhibitor therapy. CONCLUSION Conclusions CV death or cardiac arrest (p = 0.57) Quinapril (n = 1,280) % 0 0.2 0.4 0.6 0.5 0.4 Placeb o (n = 1,273) 0.6 0.4 0.2 0
    47. 47. THANK YOU

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