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Hypertension management- Angina IHD

Hypertension management- Angina IHD






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  • 11 Slide 11 This slide is a schematic representation of the time course effects of  - blocker therapy on the ejection fraction in patients with heart failure. The pharmacologic effect of  - blockade is characterized by relatively small, acute fluctuations in ejection fraction. During initiation of  -blockade therapy, these small fluctuations may contribute to acute exacerbation of heart failure symptoms. However, within 1 to 3 months, the biological effects (reverse remodeling) of  - blockade begin to appear and ejection fraction increases. The biologic effects of  - blockade are reversed if  - blockade is discontinued. 1 To date, the vast majority of clinical trials that have reported LVEF measurements have shown significant improvement in LVEF with  - blocker therapy. This increase in LVEF is consistent across studies, regardless of underlying cardiac cause (i.e., ischemic, idiopathic cardiomyopathy, or mixed cause) or the  - blocker studied (e.g., TOPROL-XL, carvedilol and others). These findings suggest that improvement of LVEF is a  - blocker class effect that is independent of heart failure cause. 2 Slide and Notes References 1. Eichhorn EJ. Medical therapy of chronic heart failure. Role of ACE inhibitors and beta-blockers. Cardiol Clin. 1998;16:711-725. 2. Eichorn EJ, Bristow MR. Medical therapy can improve the biological properties of the chronically failing heart. A new era in the treatment of heart failure. Circulation . 1996;94:2285-2294. 3. Eichhorn EJ. Clinical use of  -blockers in patients with heart failure. J Cardiac Fail . 2000;6:40-46.
  • Slide 10 Heart failure patients demonstrate long-term activation of the sympathetic nervous system. The level of adrenergic nervous system activation correlates with the concentration of plasma norepinephrine, as well as with levels of left ventricular filling pressures and mean right atrial pressure. 1 The extent of elevation of plasma norepinephrine concentration occurring in patients with heart failure correlates directly with the severity of left ventricular dysfunction, 2 and with cardiac mortality. 3 Measurements of plasma norepinephrine and plasma renin activity were performed in the Vasodilator-Heart Failure Trial II (V-HeFT II) to assess the effect of therapy on neuroendocrine activation and examine the response to therapy among patients with different degrees of activation. Baseline plasma norepinephrine data were grouped into three relatively homogeneous strata for analysis. Cumulative mortality between the three strata was significantly different ( P < .0001). The patients with plasma norepinephrine > 900 pg/mL had a higher mortality than those with corresponding values < 600 pg/mL or from 601 to 900 pg/mL. In these three groups mortality was directly related to increased plasma norepinephrine levels. This study thus confirms the relationship between baseline PNE values and cumulative mortality in heart failure patients. 4 Slide and Notes References 1. Leimbach WN Jr, Wallin G, Victor RG, et al. Direct evidence from intrarenal recordings for increased central sympathetic outflow in patients with heart failure. Circulation . 1986;73:913-919. 2. Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol . 1978;41:233-243. 3. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819-823. 4. Francis GS, Cohn JN, Johnson G, et al. Plasma norepinephrine, plasma renin activity, and congestive heart failure. Relations to survival and the effects of therapy in V-HeFT II. The V-HeFT VA Cooperative Studies Group. Circulation . 1993;87(suppl VI):VI-40–VI-48. 10
  • Slide Summary According to a meta-analysis of over 60 prospective studies, the risk of cardiovascular disease doubles with each rise of 20 mm Hg in systolic blood pressure (BP) and 10 mm Hg in diastolic BP. Background In a meta-analysis of 61 prospective, observational studies conducted by Lewington et al involving one million adults with no previous vascular disease at baseline, the researchers found that between the ages of 40-69 years, each incremental rise of 20 mm Hg systolic BP and 10 mm Hg diastolic BP was associated with a twofold increase in death rates from ischemic heart disease and other vascular disease. The researchers also noted that when attempting to predict vascular mortality risk from a single BP measurement, the average of systolic and diastolic BP was “slightly more informative” than either alone, and that pulse pressure was “much less informative.” The seventh report Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) notes this study result as yet more information linking hypertension to high risk for cardiovascular events. Lewington S, Clarke R, Qizilbash H, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet . 2003;361:1903-1913. JNC 7. JAMA. 2003;289:2560-2572.
  • Slide 5 Studies show that a multitude of diseases are attributable to hypertension. They include: • Heart failure • Coronary heart disease • Myocardial infarction • Left ventricular hypertrophy and failure • Aortic aneurysm • Peripheral vascular disease • Retinopathy • Hypertensive encephalopathy • Chronic kidney failure • Cerebral hemorrhage • Stroke With so many diseases linked to hypertension, prompt and effective treatments have the potential to reduce many complications. Dustan HP, et al. Arch Intern Med 1996; 156:1926-1935.
  • Partners in Healthcare Education, LLC 2009 Health-promoting lifestyle modification(s) should be applied in persons with prehypertension as primary prevention. These nonpharmacologic treatments, such as diet and exercise, should also be encouraged in patients with all stages of hypertension, as they may enhance the efficacy of antihypertensive agents and minimize risk factors associated with hypertension. While lifestyle modifications are helpful, pharmacologic therapy is usually needed to treat high BP. Most patients with hypertension require  2 antihypertensive agents to achieve goal BP (20/10 mm Hg above goal should receive pharmacologic therapy, either singly or in a fixed-dose combination.    National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure . Bethesda, Md: National Heart, Lung, and Blood Institute; 2003. NIH Publication No. 03-5233.
  • MAIN MESSAGE: BP targets for high risk individuals are lower than 140/90. In a scientific statement issued by the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention, the panel recommended the following: “ For the primary prevention of CAD in hypertension, aggressive BP lowering is appropriate, with a target BP of <120/80 mm Hg should be considered. [1] Reference 1. Rosendorff C, Black HR, Cannon CP, et al. Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease. Circulation 2007;115:2761-2788.
  • Beta blockers reduce the risk of death in individuals with known cardiovascular disease. In a meta-analysis that included 24,298 patients with stable coronary heart disease, treatment with a beta-blocker resulted in a 23% relative risk reduction in the risk of death (95% confidence interval, 0.70-0.84).
  • Numerous trials have confirmed the benefits of ß-blocker therapy in the post-MI patient. In a meta-analysis of 15 ß-blocker trials, the following risk reductions were seen: Overall mortality: 22% Sudden cardiac death: 33% Nonsudden death: 20% Nonfatal MI: 20% 1   1. Hanes DS, Weir MR. J Clin Hypertens . 2001;3:236–243.  
  • Drugs

Hypertension management- Angina IHD Hypertension management- Angina IHD Presentation Transcript

  • May not the elevation of systemic BP be anatural response to guarantee a morenormal circulation to heart, brain andkidneys (essential HTN)-Scott RW 1946Quoted in Prog. In Cardio.Diseases;2006;48(5);303-315
  • “Greatest DanGer to aMan With hiGh BP Lies inits Discovery, Becausethen soMe FooL is certainto try anD reDuce it”- Hay, Quoted inProg. In Cardio. Disease; 2006; 48(5);303-315
  • PRINCIPLES OF MANAGEMENT• Reduce myocardial oxygen consumption• Reduce bp & after load• Reduce pulse rate• Reduce platelet aggregation.• Reduce contractility• Vasodilation• Improve lv function
  • HTN+ANGINA MANAGEMENT GOALS• Relief of symptoms• CONTROL HTN TARGET LEVELS TOReduce LV massReduce deathImprove endothelial function, reducedeath, MI,HF,REVASC,CVD,CKD
  • Hemodynamic and ElectrophysiologicChanges of CCBs doneHemodynamic and Electrophysiologic effects of Calcium antagonistsNifedipine (a) Diltiazem VerapamilCoronary dilation ++ ++ +Peripheral dilation ++++ ++ +++Negative inotropic + ++ +++AV conduction +++ ++++Heart rateBlood pressure ++++ ++ +++Sinus nodedepression++ ++Cardiac output ++a- or other dihydropyridines+, minimal effect; ++++, maximal effect; , no significantchange; ,decrease; , increase
  • Calcium channel blockers• Dihydropyridine CCBs are widely used to treat hypertension and ischemicheart disease• They inhibit L-type calcium channels found in vascular smooth muscle,dilating the arterioles• Meta-analysis of several trials involving newer CCBs (amlodipine,felodipine, isradipine, nicardipine, or nisoldipine) found higher risk ofmortality compared to other antihypertensive drugs• Nifedipine– Extensively evaluated drug– Favorable effects on CV mortality or morbidity with long-lastingformulations
  • Reversal of Endothelial DysfunctionA Promising New Approach to Reduce Vascular ComplicationsSTATINSCALCIUM ANTAGONISTSACE-INHIBITORSBETA BLOCKER(Maximum clinical evidencewith Long-acting Nifedipine)(Clinical evidencewith Nebivolol)Reversal ofEndothelial DysfunctionATHEROPROTECTIONREVERSAL OF VASCULAR REMODELINGARB
  • Nifedipine XL - Reversal of Endothelial DysfunctionENCORE - I Trial(Effect of Nifedipine and Cerivastatin on recovery of Coronary Endothelialfunction)Study Design:• Randomized, Placebo-controlled, Double Blind Multi-centric Clinical Trial Carried OutAcross Europe, Israel and Australia• 800 Coronary Artery Disease Patients (Selected for Angioplasty) Randomized to 4 Groups(n=200/Group)* Placebo * Nifedipine XL (30-60mg/d)* Cerivastatin * Nifedipine XL + Cerivastatin• Coronary Endothelial Function Assessed at The Beginning andat the End of 6 Months Treatment Using Acetylcholine Testing• Blood Flow Velocity and Coronary Diameter Was Measured Using Flowmapping andQuantitative Angiography TechniquesThe ENCORE Investigators .Circulation. 2003;107:422
  • Nifedipine XL - Reversal of Endothelial DysfunctionENCORE - I Trial(Effect of Nifedipine and Cerivastatin on recovery of Coronary Endothelialfunction)Study Results:*Treatment With Nifedipine XL (Alone) Was Associated With Significant 90%Improvement in Coronary Endothelial Function as Compared to PlaceboThe ENCORE Investigators .Circulation. 2003;107:422
  • Nifedipine and athero-protection coronary calcificationstudyHypertension, 2001, 37(6), 1410-1413Aim:To detect the changes in calcium deposition score in coronary arteries of patientsusing sophisticated double-helix CT scanning(Calcium deposition score is an index of atherosclerosis and is directly proportionalto the burden of atherosclerosis)Findings:nifedipine XL was associated with significantly slower progression of coronarycalcification in 3 years as compared with diuretic treatment, despite equivalent B.P.reduction in both arms
  • Nifedipine and athero-protectionAmerican J. Cardiology, 1989.113 patients ISDN with recent onset, stable angina, followed upfor 2 years, Nifedipine v/s Propranolol v/s Progression, Steadinessand Regression of Coronary Disease* The number of stenoses with evidence of progression was significantly smaller after nifedipine.NifedipineN=39PropranololN= 36ISDNN=38No. ofpatients withprogression12 (31%) * 19(53%) 18(47%)No. ofpatients withsteadiness20(51%) 14 (39%) 17 (45%)No. ofpatients withregression7(18%) 3(8%) 3(8%)
  • Antihypertensive Efficacy Mean BloodPressureNifedipine GITSDiuretic Combination138 mmHg82 mmHg18016014012010080600 2 4 8 12 18 36 70 87 121 138 173 190 225 242mmHgYear1Year2Year3Year4WeekSystolicDiastolic176 mmHg99 mmHg
  • Angina Pectoris, Transient Ischemic Attacks(TIAs), Renal FailureIndividual Secondary Endpoints (Non-fatal) 0.4Angina pectoris TIAs Renal Failure*p = 1.0 p = 0.38Nifedipine GITSDiuretic Combination3.01.80.8 0.82.4*Decrease in estimated GFR > 25% compared to value at inclusion at 2 repeated measures00.5p = 0.10
  • CASE BASED HYPERTENSIONMANAGEMENT (CASE 1)• 65 yrs.Male• H/o anterior wall MI 6yrs.Back• Had post MI angina• CABGS 5yrs. back• SOB Class 2• BP 176/76,LVEF 35%• NON DM,CREAT.1.4
  • Effect of ACE-I in post MI patientswith HF or LV dysfunctionMortality• SAVE: 25% (placebo) vs 20% (captopril) - 19% RRR• AIRE: 23% (placebo) vs 17% (ramipril) - 27% RRR• TRACE: 42.3% (placebo) vs 34.7% (trandolapril)- 24% RRR
  • Study Patient population Randomized to ResultsACE-I-IntolerantCHARM-Alternative NYHA II-IVACE-I intolerant patientsCandesartan vs. placebo 23% RRR in primary endpoint (CVdeath + CHF hospitalize)On ACE-I,PLUS ARBCHARM-Added NYHA II-IV Candesartan vs. placebo 15% RRR in primary endpoint (CVdeath + CHF hospitalize)Val-Heft NYHA II-IV Valsartan vs. placebo No mortality difference (but 13%RRR in mortality + morbid)ACE-I vs. ARBELITE I NYHA II-IV Losartan vs. captopril 46% risk reduction in all causemortality with losartan (secondaryoutcome)ELITE II NYHA II-IV Losartan vs. captopril No mortality differenceNo difference in CHF admissionsOPTIMAAL Post MI LV dysfunction Losartan vs. captopril Trend towards better outcomesall cause mortality (p= 0.7), SCD(p=0.7), in captopril groupVALIANT Post MI LV dysfunction Valsartan vs. captopril No difference in all causemortality or CV morbidity andmortalityARB Trials
  • Eichhorn EJ, JCF. 2000;6(suppl 1):40-46.LVEFTime (months)BiologicEffectPharmacologic Effectb-BlockerInitiatedb-Blocker Discontinued00 11 33 66 88β-Blocker EffectsOn Ejection Fraction in Heart Failure
  • Mortality by Baseline PlasmaNorepinephrine Level (PNE)Francis G et al. Circulation. 1993;87(suppl VI):VI-40 - VI-48.100806040200 6 12 18 24 30 36 42 48 54 60MonthsCumulativeMortality(%)PNE > 900 pg/mLPNE > 600 and < 900 pg/mLPNE < 600 pg/mL2 YearP < .0001OverallP < .00010
  • Carvedilol Or Metoprolol European TrialCOMET17%Lancet 2003; 362: 7-13
  • Per cent of patients able to tolerate carvedilol treatment,grouped according to traditional contraindications andprecautions in prescribing a β-blocker88 85 86 8412 15 14 16020406080100Allpatients(n=795)COPD/asthma(n=89)Diabetes(n=127)PVD(n=58)Tolerated Not ToleratedPercentHeart 2000; 84:615-619
  • EPHESUS• 6642 patients:a) 3-14 days post MI,b) EF<40,c) CHF (rales, pulmonary venous congestion seenon CXR, 3rd heart sound) OR Diabetes• randomized to 25 mg eplerenone titrated upto 50 mg po qdNEJM 2003;348:1309-21
  • EPHESUS• Results:– One year mortality: 15% risk reduction (11.8% vs 13.6%)– CV death or cardiovascular hospitalizations (26% vs 30.0%)• (75% of patients on beta blockers)• adverse effects:– serious hyperkalemia (K>6) Epler- 5.5% vs plac- 3.9% (p=.002)– serious hypokalemia (K<3.5) Epler- 8.4% plac- 13.1% (p<.001)– gynecomastia- 0.5% vs 0.6%
  • Copernicus : major outcomesCarvedilol(n = 1156)placebo(n=1133)RRAll-causemortality11 % 17 % 35 %Hosp. +Mortality37 % 45 % 24 %
  • • Results:• 46% mortality placebo vs35% spironolactone (30%RRR)• adverse effects:– 10% of pts inspironolactone groupdevelopedgynecomastia.– -serious hyperkalemia(K>6) 14% vs 10% (notstatist sig)RALES
  • Spironolactone-induced reduction in systolic (dark bluecones) and diastolic blood pressure (red cones) at 6 weeks,3months, and 6months of follow-up in subjects withresistant hypertension done
  • CASE 2• Male 54 yrs obese built increased ABD girth• Angina on effort class ii• HTN BP 206/92,pulse 92/min• Coronary ANGIO OM CX 70%.PD 70% EF 55%• Advanced medical treatment and SOS PTCA withstents
  • BETA BLOCKERS IN ANGINA• Reduce myocardial oxygen consumption• Reduce heart rate• Reduce BP• Reduce double product• Reduce CAT.• Antiplatelet Effect
  • CALCIUM BLOCKERS• Decrease BP• Vasodilatation• Nefedipine felodipine and amlodipinecause tachycardia
  • Mortality benefits for ACEI trialsAMI AMI with LVD CHFTRIALACEIDose†ISIS IVcapto50x2GISSI 3lisino10SAVEcapto50x2AIRErami5x2TRACEtrandola4CONSENSUSenala40SOLVDenala20.84.74-.95.73.56-.95.78.67-.91.73.60-.89.81.68-.97.88*.79-.99.93*.87-.99RR5%CI*odds ratio †maximum daily
  • 1 2 3 4 5number at riskACE inhibitors 2995 2250 1617 892 223Placebo 2971 2184 1521 853 138time since randomization (years)cumulativemortality(%)placeboMeta-analysis of AIRE, TRACE, SAVEFlather MD, et al. Lancet 2000; 355(9215):1575 - 8126%reductionp < 0.0001ACE Inhibitors
  • CV Disease Risk Doubles withEach 20/10 mm Hg BP Increment**Individuals aged 40-70 years, starting at BP 115/75 mm Hg.CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressureCVdiseaseriskSBP/DBP (mm Hg)012345678115/75 135/85 155/95 175/105Lewington S, Cardiovascular Issues in Ageing Pilots. et al. Lancet. 2002; 60:1903-1913
  • 38Diseases Attributable toHypertensionAdapted from: Arch Intern Med 1996; 156:1926-1935.AllVascular
  • JNC VII ClassificationCategoryCategory SBP (mm Hg)SBP (mm Hg) DBP (mm Hg)DBP (mm Hg)Normal < 120 < 80Pre – hypertension 120-139 80-90HypertensionStage 1 140 – 159 90 – 99Stage 2 160 and above 100 and above
  • AA, aldosterone antagonist; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II-receptor blocker;AA, aldosterone antagonist; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II-receptor blocker; ββB,B, ßß--blocker; CCB, calcium channel blocker; MI, myocardial infarction;blocker; CCB, calcium channel blocker; MI, myocardial infarction;CAD, coronary artery disease. Chobanian AV, et al.CAD, coronary artery disease. Chobanian AV, et al. JAMA.JAMA. 2003;289(19):2560-2572.2003;289(19):2560-2572.The Seventh Report of the Joint NationalCommitteeCompellingCompellingIndicationsIndications DiureticDiuretic ßBßB ACEIACEI ARB CCBCCB AAAAHeart failureHeart failure     Post-MIPost-MI   High CAD riskHigh CAD risk    DiabetesDiabetes     Chronic kidneyChronic kidneydiseasedisease Recurrent strokeRecurrent strokepreventionprevention 
  • JNC 7: Algorithm for Treatment ofHypertensionPrehypertension (SBP 120-139 mm Hg or DBP 80-89 mm Hg)Not at Goal BP (<140/90 mm Hg, or <130/80 mm Hg forpatients with diabetes or chronic kidney disease)Without Compelling Indications With Compelling IndicationsPrehypertensionStage 1 Hypertension(SBP 140-159 or DBP 90-99 mm Hg)Thiazide-type diuretics for most;may consider ACEI, ARB, BB,CCB, or combination.Stage 2 Hypertension(SBP ≥160 or DBP ≥100 mm Hg)2-drug combinations for most(usually thiazide-type diuretics andACEI, or ARB, or BB, or CCB).Drug(s) for compelling indicationsOther antihypertensive drugs(diuretic, ACEI, ARB, BB, CCB)as needed.LIFESTYLE MODIFICATIONSIf not at goal BP, optimize dosages or add additional drugs untilgoal BP is achieved. Consider consultation with hypertension specialist.INITIAL DRUG CHOICES
  • HF of Ischemic EtiologyHF of Ischemic EtiologyHF of Ischemic EtiologyHF of Ischemic EtiologyACS - STEMIACS - STEMIACS - STEMIACS - STEMIACS – UA and NSTEMIACS – UA and NSTEMIACS – UA and NSTEMIACS – UA and NSTEMICAD and Stable AnginaCAD and Stable AnginaCAD and Stable AnginaCAD and Stable AnginaPrimary PreventionPrimary PreventionPrimary PreventionPrimary PreventionDiagnosisRosendorff et al.Rosendorff et al. Circulation.Circulation. 2007;115:2761-2788.2007;115:2761-2788.ASC: acute coronary syndrome, UA: Unstable angina, NSTEMI: Non-ST segment elevation myocardial infarction, STEMI: STsegment elevation myocardial infarction, HF: Heart failure<130/80, but consider <120/70<130/80, but consider <120/70<130/80, but consider <120/70<130/80, but consider <120/70<130/80<130/80<130/80<130/80<130/80<130/80Diabetes, Chronic Kidney Disease, CAD, CADDiabetes, Chronic Kidney Disease, CAD, CADEquivalents, or Framingham Risk ScoreEquivalents, or Framingham Risk Score ≥10%≥10%<130/80<130/80Diabetes, Chronic Kidney Disease, CAD, CADDiabetes, Chronic Kidney Disease, CAD, CADEquivalents, or Framingham Risk ScoreEquivalents, or Framingham Risk Score ≥10%≥10%Target BP (mm Hg)<140/90<140/90<140/90<140/90AHA Scientific Statement—Treatment ofHypertension in the Prevention and Management ofIschemic Heart Disease
  • Phase ofPhase ofTreatmentTreatmentAcuteAcutetreatmenttreatmentSecondarySecondarypreventionpreventionOverallOverallTotal #Total #PatientsPatients28,97028,97024,29824,29853,26853,2680.50.5 1.01.0 2.02.0RR of deathRR of deathb-blocker betterb-blocker betterRR (95% CI)RR (95% CI)Placebo betterPlacebo better0.87 (0.77-0.98)0.87 (0.77-0.98)0.77 (0.70-0.84)0.77 (0.70-0.84)0.81 (0.75-0.87)0.81 (0.75-0.87)β−blocker Evidence: Secondary PreventionAntman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP,Antman E, Braunwald E. Acute Myocardial Infarction. In: Braunwald E, Zipes DP,Libby P, eds. Heart Disease: A textbook of Cardiovascular Medicine, 6th ed.,Libby P, eds. Heart Disease: A textbook of Cardiovascular Medicine, 6th ed.,Philadelphia, PA: W.B. Sanders, 2001, 1168.Philadelphia, PA: W.B. Sanders, 2001, 1168.Summary of Secondary Prevention Trials of b-blocker TherapySummary of Secondary Prevention Trials of b-blocker TherapyCI=Confidence interval, RR=Relative riskCI=Confidence interval, RR=Relative risk
  • ––22%22% ––20%20% ––20%20%Hanes DS et al.Hanes DS et al. J Clin Hypertens (Greenwich).J Clin Hypertens (Greenwich). 2001;3(4):236-243.2001;3(4):236-243.Risk Reduction With β-Blockersin Post-MI Patients––30%30%––40%40%––20%20%––10%10%0%0%––33%33%OverallOverallmortalitymortalitySuddenSuddencardiaccardiacdeathdeathNon-suddenNon-suddendeathdeath Nonfatal MINonfatal MI15 Trials (n =18,995)15 Trials (n =18,995)
  • Carvedilol Or Metoprolol European TrialCOMETLancet 2003; 362: 7-13
  • • 2647 patient• Ischaemic or non ischaemic• Moderate to severe HF (class III NYHA)• Bisoprolol upto 10 mg day or placebo• Conventional therapy• Upto 28 months (average 16 months)Cardiac insufficiency bisoprolol studyCIBIS-IILancet 1999 353; 913
  • SURVIVAL CURVE – CIBIS II~ 30 % reduction ofall-cause mortality
  • BESTß-BLOCKER EVALUATION SURVIVAL TRIAL• N = 2708 patients• Survival in patients with moderate to severe heartfailure– NYHA III – IV– EF < 35 %
  • BEST : MAJOR OUTCOMESBucindolol(n=1263)Placebo (n=1260) Risk reductionAll cause mortality 30.2 %(Annualisedrate 14.9%)33.0% (Annualisedrate 16.6.%)8.5% (NS)Cardiovascularmortality*24.4% 27.9% 12.5% (p= 0.04)All hospitalisation 61% 64% 4.7% (NS)Heart failurehospitalisation35% 42% 16.7% (p=0.001)Progression to death/transplant31.6% 35% 10% (NS)* No significant difference in death due to heart failure, suddendeath, pump failure or myocardial infarction
  • PHARMACOLOGIC DIFFERENCESß1 Blockade ß2Blockadeα1BlockadeISA Ancillaryeffects *Carvedilol +++ +++ +++ - +++Metoprolol +++ - - - -Bisoprolol +++ - - - -Bucindolol +++ +++ - + -* Anti- oxidant, anti-endothelin, anti-proliferative
  • EVENT-FREE SURVIVAL IN THE TWO GROUPS WITH (THICK LINE)AND WITHOUT (THIN LINE) ECHOCARDIOGRAPHIC LVH AT THEBASELINEBSA INDICATES BODY SURFACE AREAProbabilityofEventFreeSurvival1009080706043210RateofEvents(per100patient-yearsBaseline LV mass > 125 g/BSABaseline LV mass < 125 g/BSAp = 0.0130 100 200 300 400 500 < 125 > 125Time to Event, week Baseline LV mass, g/BSA
  • EVENT RATE IN SUBSET WITH ECHOCARDIOGRPHICLVH ATE BASELINE VISIT0 100 200 300 400 500 Regressors Non RegressorsTime to Event, weekProbabilityofEventFreeSurvival%76543210RateofEvents(per100patient-years100908070605040Regressors (N=52)Non regressors (N=60)p = 0.002Circ. 1998, 97, 48Baseline LV mass > 125 g/BSAFollow-up mass < 125 g/BSABaseline LV mass > 125 g/BSAFollow-up mass > 125 g/BSA
  • SOME DRUGS THAT MAY CAUSEERECTILE DYSFUNCTIONGroup GroupAntihypertensive DiureticsVasodilators e.g. hydralazineCentral sympatholytics,e.g. methyldopa, clonidine,reserpineGanglion blockers e.g.guanethidineBeta-BlockersCalcium antagonistsACE inhibitorsLipid-modifying agents ClofibrateAntimicrobials Ethionamide, VidarabineCardiac-active agents DigoxinGastrointestinal agents Cimetidine
  • 43210-1-2-3-443210-1-2-3-443210-1-2-3-443210-1-2-3-4mm Hgmm HgSildenafil(n=965)Placebo(n=503)Sildenafil(n=386)Placebo(n=244)Change in SBPChange in DBPChange in SBPChange in DBPBlood pressure changes in patients not on antihypertensive therapy (top) and in those receiving1 of 5 classes of antihypertensive drugs (bottom) during concurrent treatment With sildenafil orplacebo. DBP = diastolic blood pressure; SBP = systolic blood pressure. Data on file, Pfizer Inc.B) Antihypertensive drugsA) No Antihypertensive
  • Cilnidipine – Heart Rate• Study conducted in 2920 hypertensive patients:– Treatment with cilnidipine and ARBs showedsignificant reductions in heart rate• 24-h ambulatory blood pressure monitoring studywith hypertensive patients– Reductions in heart rate significantly greater in thecilnidipine group than the amlodipine groupNagahama S, et al. Hypertens Res 2007;30:815–822
  • Effects of cilnidipine onnorepinephrine (NE) secretionCilnidipine attenuates norepinephrine release from sympatheticnerve endingsTakahara A. Cardiovascular Therapeutics 2009; 27; 124–139
  • Cilnidipine Summary of Effects• Inhibits sympathetic N-type Ca2+channels and vascular L-typeCa2+channels• Does not suppress cardiac functions at vasodilator doses– Shows antisympathetic profiles– Comparable BP reduction• Better reduction of heart rate• More vascular effect than cardio effect• Favorable effect on glucose homeostasis• Improves glomerular filtration, renal protection• Reduces proteinuria