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A Prelude to the Polypill Concept for Vascular Disease Prevention Johnny K. Lokin, MD, FPNA Stroke Services Department of Neurology & Psychiatry University.

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Presentation on theme: "A Prelude to the Polypill Concept for Vascular Disease Prevention Johnny K. Lokin, MD, FPNA Stroke Services Department of Neurology & Psychiatry University."— Presentation transcript:

1 A Prelude to the Polypill Concept for Vascular Disease Prevention Johnny K. Lokin, MD, FPNA Stroke Services Department of Neurology & Psychiatry University of Santo Tomas Hospital Johnny K. Lokin, MD, FPNA Stroke Services Department of Neurology & Psychiatry University of Santo Tomas Hospital

2 Overview Prevalence and burden of stroke in Asia and worldwide Targets in stroke prevention with multiple interventions Patient Adherence Duo Pill Polypill Concept Conclusions

3 Prevalence and burden of STROKE in Asia and worldwide

4 BURDEN OF CARDIOVASCULAR DISEASE Total Deaths million Total Deaths million Cardiovascular Disease (Heart disease & Stroke) 17 M or 30 % Cardiovascular Disease (Heart disease & Stroke) 17 M or 30 % Communicable dse, Nutritional def 30 % Communicable dse, Nutritional def 30 % Cancer 13 % Cancer 13 % Injuries 9 % Injuries 9 % Others 9 % Others 9 % Respiratory Dse - 9 % Respiratory Dse - 9 % DM - 2 %

5 AFRAMREURSEARWPREMRWORLD STROKE ,4801,0701, ,455 Isch Heart Disease ,4331, ,181 HPN Heart Dse ALL CVDS 9851,9795,0423,7973,7451,03716,585 BURDEN OF CARDIOVASCULAR DISEASE

6 BURDEN OF STROKE 15 million strokes worldwide every year Stroke is third leading cause of death in developed countries –5.5 million people die every year –5 million people left disabled every year –Commonest cause of major disability in UK 60% of patients who suffer a stroke die or become dependent WHO. The Atlas of Heart Disease and Stroke 2004.

7 Oxford Vascular Study Population based study of 2,024 vascular events in 91,106 people 918 (45%) cerebrovascular events –618 strokes/ 300 TIAs 856 (42%) coronary vascular events –159 STEMI / 316 NSTEMI –218 unstable angina / 163 sudden cardiac deaths Rothwell PM. Lancet 2005;366: BURDEN OF STROKE

8 % of STROKE DEATHS World Bank income group % of STROKE DEATHS World Bank income group 16 M first ever strokes 62 M stroke survivors 6 M deaths worldwide 16 M first ever strokes 62 M stroke survivors 6 M deaths worldwide Most of the stroke deaths (87%) occur in developing countries GLOBAL BURDEN OF STROKE

9 No per 100,000 population STROKE MORTALITY in ASIA, 2003 MacKay J and Mensah G. Atlas of Heart Disease and Stroke Geneva. WHO.

10 Incidence stable or dropping in developed countries –Halving of number of smokers & possibly better control of hypertension Auckland Regional Community Stroke Study. Stroke 2005 But, overall incidence is increasing because of aging population WHO. The Atlas of Heart Disease and Stroke BURDEN OF STROKE

11 Ischemic stroke makes up >80% of all strokes Hemorrhagic stroke 88% 12% ISCHEMIC vs HEMARRHAGIC STROKE American Heart Association Heart Disease and Stroke Statistics—2005 Update. Incidence Ischemic stroke

12 STROKE IN ASIA Intracerebral hemorrhage makes up 20–30% of all strokes in Asian populations –Chinese and Japanese studies in early 1980s –Korean, Singaporean and Filipinos in late 1990’s and early 2K Intracerebral hemorrhage in 22% of Asians vs 11% Europeans in New Zealand –Auckland Regional Community Stroke Study Feigin V, et al. Lancet Neurology 2006;5:

13 More intracranial stenosis in Asian populations –40–50% TIA / stroke patients in China and Korea have intracranial stenosis (vs 8 to 11% North America) –7% of asymptomatic villagers in rural China –13% of people with hypertension, diabetes or hyperlipidemia in Hong Kong had middle cerebral artery stenosis Wong KS, et al. Neurology 2007; 68:2031–2034; Wong KS, et al. Neurology 2007;68: STROKE IN ASIA

14 Philippines 2003 % By Questionnaire1.3 and 1.9 By History1.4 N = 4753 adults (> 20 yrs old), 17 Regions, 79 provinces Aug to Dec 2003 Results : Stroke Prevalence in the Philippines Results : Stroke Prevalence in the Philippines Slide courtesy of A. Roxas, MD Dans A. et al. Phil J Int Med; 43(3) :

15 1.3% 3.0% 6.4% 6.1% Slide courtesy of A. Roxas, MD Dans A. et al. Phil J Int Med; 43(3) : Results : Stroke Prevalence in the Philippines (by Age) Results : Stroke Prevalence in the Philippines (by Age)

16 TARGETS IN STROKE PREVENTION STROKE RISK FACTORS 80 % of premature heart disease, stroke can be prevented

17 Goldstein LB, et al. Stroke. 2001;32: Unmodifiable risk factors Modifiable risk factors Smoking Diet Sedentary lifestyle Alcohol/drug abuse Obesity CAD Atrial fibrillation Hypertension Diabetes Dyslipidemia Smoking Diet Sedentary lifestyle Alcohol/drug abuse Obesity CAD Atrial fibrillation Hypertension Diabetes Dyslipidemia Age Male sex Race Family history of stroke/TIA Prior stroke/TIA Age Male sex Race Family history of stroke/TIA Prior stroke/TIA CAD=coronary artery disease; TIA=transient ischemic attack; CHD=coronary heart disease Managing the Patient at Risk – Multiple Risk Factors Require Multiple Interventions

18 Multiple CV Risk Management Results in Dramatic Reductions in CVD 10% Reduction in BP 10% Reduction in TC + 45% Reduction in CVD = “Attention should be moved from knowing one’s BP and cholesterol concentrations to knowing one’s absolute CV risk and its determinants.” – J. Emberson et al and Jackson et al Emberson J et al. Eur Heart J. 2004;25: Jackson R et al. Lancet. 2005;365:

19 Clinical Evidence Supports Comprehensive Treatment of Multiple CV Risk Factors ASCOT: supports a new standard of care in patients with hypertension and additional CV risk factors –Low to moderate risk patients with normal to mildly elevated cholesterol levels Other studies in patients with multiple CV risk factors –VALUE: patients at high risk with hypertension Approximately 46% were on statin therapy –CARDS: patients with diabetes 84% were hypertensive 67% receiving antihypertensive treatment ASCOT: supports a new standard of care in patients with hypertension and additional CV risk factors –Low to moderate risk patients with normal to mildly elevated cholesterol levels Other studies in patients with multiple CV risk factors –VALUE: patients at high risk with hypertension Approximately 46% were on statin therapy –CARDS: patients with diabetes 84% were hypertensive 67% receiving antihypertensive treatment ASCOT=Anglo-Scandinavian Cardiac Outcomes Trial; CARDS=Collaborative AtoRvastatin Diabetes Study; VALUE=Valsartan Antihypertensive Long-term Use Evaluation. Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361: Julius et al. Lancet. 2004;363: Colhoun et al. Lancet. 2004;364:

20 19,257 hypertensive patients with ≥3 CV risk factors and no CHD amlodipine-based regimen N=9639 amlodipine-based regimen N=9639 atenolol-based regimen N=9618 atenolol-based regimen N=9618 ASCOT- BPLA 10,305 hypertensive patients (≥3 CV risk factors and no CHD) with total cholesterol ≤6.5 mmol/L (251 mg/dL) 10,305 hypertensive patients (≥3 CV risk factors and no CHD) with total cholesterol ≤6.5 mmol/L (251 mg/dL) atorvastatin 10 mg N=5168 atorvastatin 10 mg N=5168 placebo N=5137 placebo N=5137 ASCOT-LLA amlodipine-based regimen N=2584 amlodipine-based regimen N=2584 atenolol-based regimen N=2584 atenolol-based regimen N=2584 amlodipine-based regimen N=2554 amlodipine-based regimen N=2554 atenolol-based regimen N=2583 atenolol-based regimen N=2583 ASCOT-LLA 2x2 Sever PS et al. Lancet. 2003;361: The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT): A Study in Hypertensive Patients at Low to Moderate CV Risk

21 *These risk factors were used as inclusion criteria for the study. The ASCOT Investigators. Available at: Accessed: April 6, Data on file. Pfizer Inc, New York, NY. Please see prescribing information at the end of this slide presentation Hypertension Age  55 years Male Microalbuminuria/proteinuria Smoker Family history of early coronary disease Type 2 diabetes Certain ECG abnormalities Left ventricular hypertrophy Plasma TC/HDL-C ratio  6 Previous cerebrovascular events Peripheral vascular disease Patients with Risk Factor (%) ASCOT-LLA: Patient Population Routinely Seen in Clinical Practice (Hypertension Plus  3 Risk Factors for CHD*) Two of the most common additional risk factors were male sex and age ≥55 years  representative of patients frequently seen in practice

22 ASCOT-LLA: 27% RRR in Fatal and Nonfatal Stroke When Atorvastatin Added to BP Treatment Atorvastatin 10 mg (n=5168) Placebo (n=5137) Sever PS et al for the ASCOT Investigators. Lancet. 2003;361: Years HR=0.73 ( ) Trial stopped early P=.0236 Proportion of Events (%)

23 ASCOT-BPLA and -LLA Combined: Insight Into Optimal CVD Prevention End Point Amlodipine  Perindopril + Statin Atenolol  Thiazide + Placebo Relative Risk Reduction Fatal CHD and nonfatal MI % Fatal and nonfatal stroke % Rates/1000 Patient-Years The ASCOT Study Investigators. Available at: Accessed: June 30, 2006.

24 ASCOT-BPLA and -LLA Combined: Insight Into Optimal CVD Prevention ASCOT-LLA Secondary End Point: Fatal and Non-Fatal Stroke ASCOT-LLA Primary End Point: Nonfatal MI and Fatal CHD ASCOT-LLA demonstrates that adding Lipitor® (atorvastatin calcium) to an effective BP regiman results in impressive CV event reductions. Sever PS et al. Lancet. 2003;361:

25 What Are the Implications for Clinical Practice? Assessment of overall CV risk critical to maximizing CV event reduction Hypertensive patients frequently seen in clinical practice, emphasising need for comprehensive risk assessment Atorvastatin added to antihypertensive therapy results in significant benefits in low to moderate and high-risk patient populations Assessment of overall CV risk critical to maximizing CV event reduction Hypertensive patients frequently seen in clinical practice, emphasising need for comprehensive risk assessment Atorvastatin added to antihypertensive therapy results in significant benefits in low to moderate and high-risk patient populations Please see prescribing information at the end of this slide presentation.

26 RISK FACTORS % Contribution to Stroke HPN CholesBMI Smoking Physical Inactivity Alcohol Diet * Computed from risk factor prevalence & hazard size Developed Countries Developing Regions HPN CholesBMI SmokingDietPhysical Inactivity Alcohol Ezzati, M for the Comparative Risk Assessment Group Lancet 2003; 362:

27 European Stroke Initiative Discourage smoking Regular physical exercise Reduce weight (if high BMI) Low-salt, low-fat diet rich in fruits, vegetables, fiber Discourage heavy alcohol use Reduce blood pressure to <140/90 <135/80 if diabetic Initiate cholesterol- lowering therapy for high-risk patients Encourage strict control of glucose levels if diabetic Reduce blood pressure to <140/90 <135/80 if diabetic Initiate cholesterol- lowering therapy for high-risk patients Encourage strict control of glucose levels if diabetic European Stroke Initiative Executive Committee and EUSI Writing Committee. Cerebrovasc Dis 2003;16:

28 Antiplatelet Therapy after Stroke Long-term antiplatelet therapy should be prescribed to all ischemic stroke or TIA patients who aren’t prescribed anti-coagulation therapy Grade A, Level I evidence, Australian Stroke Guidelines 2007 Low dose aspirin & dipyridamole Aspirin alone or clopidogrel alone if dipyridamole- intolerant Amarenco, et al. Australian Stroke Guidelines 2007

29 Antihypertensive therapies significantly reduced risk of recurrent stroke Rashid P, et al. Stroke 2003;34: ACEI=Angiotensin-converting enzyme inhibitors. *P=.005. †P=.01. ‡P< * † ‡ –7–7 –7–7 –45 –7–7 –7–7 –32 – All Diuretics Beta-blockers ACEI ACEI + Diuretic Relative risk reduction (%)

30 Blood pressure lowering after Stroke Antihypertensive therapy should be started in all patients with stroke or TIA unless contraindicated Grade A, Level I evidence, Australian Stroke Guidelines 2007 In general aim for <140/90 mmHg; if diabetic, aim for <130/85 mmHg Most direct evidence for ACE inhibitor (  diuretic) Rashid et al. Stroke.2003;34: More recent evidence of benefit of angiotensin receptor blockers Schrader et al. Stroke 2005;36:1218

31 ASCOT-BPLA: fatal and nonfatal stroke (secondary end point) Dahlöf B et al. Lancet. 2005;366:

32 Lipid-lowering Therapy Goal Patients without diabetes: low-density lipoprotein cholesterol (LDL-C) <100 mg/dL (2.6 mmol/L) Patients with diabetes: Consider LDL-C goal of <70 mg/dL (1.8 mmol/L) Treatment If the patient is not at LDL-C goal, initiate intensive lifestyle changes Lipid-lowering therapy may be commenced at the same time as initiating the lifestyle changes Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: ; Grundy SM et al. Circulation. 2004;110: The SPARCL Investigators. N Engl J Med 2006;355: Stroke should be considered a CHD risk equivalent

33 ASCOT-LLA: fatal and nonfatal stroke (secondary end point) Sever PS et al. Lancet. 2003;361:

34

35 Lipid lowering following Stroke Therapy with a statin should be used for all patients with ischemic stroke or TIA Grade B, Level II, Australian Stroke Guidelines 2007 Statins –Good safety profile Law & Rudnicka. Am J Cardiol 2006;97:S52-60 –Well tolerated –Higher compliance if started in hospital Sannosian, et al. Arch Neurol 2006;63:1081-3

36 CONCLUSIONS Modifiable risk factors should be managed Pharmacologic options include: –Anti-thrombotic therapies –Anti-hypertensive agents –Statin therapy

37 Multiple Risk Factor Intervention Factors affecting ADHERENCE

38 Most Hypertensive Patients Need Multiple Medications for Effective Management, Yet Adherence to Concomitant Antihypertensive and Lipid- Lowering Therapy Decreases as Number of Medications Increases *Calculated for first year of concomitant therapy with antihypertensive and lipid-lowering drugs. Patients adherent if PDC  80% for both classes. PDC=proportion of days covered by antihypertensive and lipid-lowering drugs. Benner JS et al. ACC Abstract. No. of Additional Medications Median PDC* 10101010 101010 Incremental pill burden had greatest effect on adherence in patients taking the fewest medications

39 Concurrently Starting 2 Medications Improved Adherence 1-30 Days Days Days † OR for Adherence* Time Between Start of Antihypertensive and Lipid-Lowering Therapies Retrospective cohort study in a large managed-care population (N=8406). *Relative odds of being adherent with both antihypertensive and lipid-lowering therapy at any point in time. † Reference group. Chapman RH et al. Arch Intern Med. 2005;165: P<.001

40 Simplified Medication Regimen Improved Persistence Dezii CM. Manag Care. 2000;9(suppl):S2-S Patients Adherent (%) Months Since Initiation of Therapy ~20%~20% 1-pill combination therapy 2-pill therapy

41 Lower Pill Burden is Associated with Better Adherence to Antihypertensive and Lipid-Lowering Therapy As the number of preexisting* Rx meds increased, the likelihood of adequately refilling AH and LL meds decreased Number of Preexisting Rx Meds P<.001 † Reference Group Adjusted Likelihood of Being Adherent; AH and LL Rx *Preexisting is defined as the number of prescription medications a patient was taking in the year prior to initiating AH and LL medications. † Comparisons were statistically significant vs a patient taking 6+ preexisting Rx medications. Rx=prescription; meds=medications; AH=antihypertensive therapy; LL=lipid-lowering therapy. Chapman RH et al. Arch Intern Med. 2005;165: Please see prescribing information at the end of this slide presentation

42 Is Poor Adherence an Essential CV Risk Factor? Increasing pill burden decreases adherence In clinical trials, worse outcomes were attained when adherence was lower Patients need to adhere to their medications in order to effectively treat their CV risk factors –Improved adherence when starting 2 medications concurrently –Combination therapy reduces pill burden –Reduced pill burden improves adherence Nonadherence to medication increases CV risk Increasing pill burden decreases adherence In clinical trials, worse outcomes were attained when adherence was lower Patients need to adhere to their medications in order to effectively treat their CV risk factors –Improved adherence when starting 2 medications concurrently –Combination therapy reduces pill burden –Reduced pill burden improves adherence Nonadherence to medication increases CV risk

43 Multiple Risk Factor Intervention Feasibility of Single-Pill combinations “ The Duo Pill”

44 RISK FACTORS % Contribution to Stroke HPN CholesBMI Smoking Physical Inactivity Alcohol Diet * Computed from risk factor prevalence & hazard size Developed Countries Developing Regions HPN CholesBMI SmokingDietPhysical Inactivity Alcohol Ezzati, M for the Comparative Risk Assessment Group Lancet 2003; 362:

45 ENVACAR ® (amlodipine besylate/atorvastatin calcium): Optimizing CV Event Reduction by Management of Total CV Risk ENVACAR Benefits patients with hypertension plus additional CV risk factors Provides in a single pill –Proven BP-lowering of amlodipine –Proven lipid-lowering and CV event reductions of atorvastatin –Proven safety and tolerability of both parent compounds Can be easily incorporated into current CV treatment strategies May improve adherence rates, resulting in –Better rates of goal attainment –Reduced risk of having a CV event –Improved cost–benefit ratio ENVACAR Benefits patients with hypertension plus additional CV risk factors Provides in a single pill –Proven BP-lowering of amlodipine –Proven lipid-lowering and CV event reductions of atorvastatin –Proven safety and tolerability of both parent compounds Can be easily incorporated into current CV treatment strategies May improve adherence rates, resulting in –Better rates of goal attainment –Reduced risk of having a CV event –Improved cost–benefit ratio Sever PS et al for the ASCOT Investigators. Lancet. 2003;361: Julius S et al for the VALUE trial group. Lancet. 2004;363: Blank R et al. J Clin Hypertens. 2005;7: Chapman RH et al. Arch Intern Med. 2005;165: McCombs JS et al. Med Care. 1994;32: Bisognano J et al. Am J Hypertens. 2004;17: CADUET ® [SmPC 5/10]. Please see prescribing information at the end of this slide presentation. Sever PS et al for the ASCOT Investigators. Lancet. 2003;361: Julius S et al for the VALUE trial group. Lancet. 2004;363: Blank R et al. J Clin Hypertens. 2005;7: Chapman RH et al. Arch Intern Med. 2005;165: McCombs JS et al. Med Care. 1994;32: Bisognano J et al. Am J Hypertens. 2004;17: CADUET ® [SmPC 5/10]. Please see prescribing information at the end of this slide presentation.

46 ENVACAR ® (amlodipine besylate/atorvastatin calcium) Clinical Trial Program: PK Studies, AVALON and RESPOND Pharmacokinetic studies –BE studies at 5/10 and 10/80 mg –PK drug interaction at 10/80 mg AVALON (N=847) and RESPOND (N=1660) –Pivotal, double-blind, registration studies –Full safety and efficacy across the dose range –Fully characterise the PD relationship Pharmacokinetic studies –BE studies at 5/10 and 10/80 mg –PK drug interaction at 10/80 mg AVALON (N=847) and RESPOND (N=1660) –Pivotal, double-blind, registration studies –Full safety and efficacy across the dose range –Fully characterise the PD relationship 5/105/205/405/80 10/1010/2010/4010/80 1:1 1:2 1:4 1:8 1:16 PK PD BE=bioequivalency; PK=pharmacokinetics; PD=pharmacodynamics. Flack J, et al. Atheroscler Suppl. 2003;4:244. Flack J et al. J Hypertens. 2004;22(suppl 1):12S. Preston RA, et al. Am J Hypertens. 2004;17:185A. Data on file. Pfizer Inc, New York, NY.

47 Plac 227  189 AML 192  166 ATV 192  180 AML/ATV 200  171 % % Messerli, et al. J Clin Hypertens 2006;8: AVALON: Patients reaching goals for BP & LDL-C at 8 and 28 weeks Number of pts 8  28 wks Messerli, et al. J Clin Hypertens 2006;8:571-81

48 Treatment-Emergent AEs in AVALON and RESPOND Overall low rate of AEs observed in AVALON and RESPOND No unexpected differences regarding AEs observed with ENVACAR ® (amlodipine besylate/ atorvastatin calcium) from those observed with parent compounds AEs observed in ENVACAR-treated patients were easily recognisable and attributable to amlodipine or atorvastatin Overall low rate of AEs observed in AVALON and RESPOND No unexpected differences regarding AEs observed with ENVACAR ® (amlodipine besylate/ atorvastatin calcium) from those observed with parent compounds AEs observed in ENVACAR-treated patients were easily recognisable and attributable to amlodipine or atorvastatin AEs=adverse events. Flack J et al. J Hypertens. 2004;22(suppl 1):12S. Data on file. Pfizer Inc, New York, NY.

49 Side Effect Profile of Amlodipine and Atorvastatin in Combination Comparable to Amlodipine and Atorvastatin Separately ENVACAR ® (amlodipine besylate/atorvastatin calcium) AEs are similar in nature, frequency, and severity to those reported with amlodipine and atorvastatin taken separately Rate of Discontinuations due to Adverse Events Adverse Event Placebo (%, n=111) Amlodipine Only Pooled Across Dose Range (%, n=221) Atorvastatin Only Pooled Across Dose Range (%, n=443) Amlodipine with Atorvastatin Pooled Across Dose Range (%, n=885) Peripheral oedema Headache Dizziness Results of RESPOND (N=1660), a multicentre, double-blind, randomised, placebo-controlled study designed to evaluate the BP- and lipid-lowering efficacy and safety of amlodipine and atorvastatin coadministered in patients with comorbid hypertension and dyslipidaemia. Patients were randomised to receive treatment for 8 weeks and received both amlodipine 5 mg or 10 mg once daily or matching placebo, and atorvastatin 10 mg, 20 mg, 40 mg, or 80 mg once daily or matching placebo. CADUET ® [SmPC 5/10].

50 Clinical Benefit of ENVACAR ® (amlodipine besylate/atorvastatin calcium) AVALON and RESPOND Conclusions AVALON Amlodipine 5 mg and atorvastatin 10 mg more effective than single agent in reaching NCEP ATP III and JNC VI goals, respectively Simultaneous therapy safe and well tolerated in the treatment of comorbid dyslipidaemia and hypertension RESPOND Across the dose range –Effect of atorvastatin on LDL-C not modified by amlodipine –Effect of amlodipine on BP not modified by atorvastatin The combination was well tolerated –Rate of discontinuation similar to that with the parent compounds and placebo The safety profile of the combination was consistent with that seen with the parent compounds administered separately AVALON Amlodipine 5 mg and atorvastatin 10 mg more effective than single agent in reaching NCEP ATP III and JNC VI goals, respectively Simultaneous therapy safe and well tolerated in the treatment of comorbid dyslipidaemia and hypertension RESPOND Across the dose range –Effect of atorvastatin on LDL-C not modified by amlodipine –Effect of amlodipine on BP not modified by atorvastatin The combination was well tolerated –Rate of discontinuation similar to that with the parent compounds and placebo The safety profile of the combination was consistent with that seen with the parent compounds administered separately Flack J et al. J Hypertens. 2004;22(suppl 1):12S. Data on file. Pfizer Inc, New York, NY.

51 Modern treatment guidelines for HTN & dyslipidemia have introduced the concept of global CV risk Single-pill combinations of antihypertensive drugs and lipid-lowering agents increase adherence and the attainment of treatment goals For the same relative risk reduction, high-risk compared with low-risk patients experience larger absolute benefit Modern treatment guidelines for HTN & dyslipidemia have introduced the concept of global CV risk Single-pill combinations of antihypertensive drugs and lipid-lowering agents increase adherence and the attainment of treatment goals For the same relative risk reduction, high-risk compared with low-risk patients experience larger absolute benefit CONCLUSIONS

52 Can a Polypill prevent stroke?

53 CONCEPT OF POLYPILL List the risk factors for stroke and cardiovascular diseases Determine the medication/s (one or more) to treat each risk factor Create a single tablet (for optimal patient compliance) containing various combination of medications to achieve maximal benefit with minimal side-effects

54 Randomised trials: drugs to lower 3 risk factors — LDL, BP & platelet function (with aspirin) ↓ the incidence of IHD and stroke Risk Factors

55

56 Optimal Dose of Aspirin for Prevention of Stroke Treatment effect: p < Antithrombotic Trialists’ Collaboration:Br Med J 2002, 324:71-86 Meta-analysis of Aspirin (Stroke, MI, or Vascular death in high risk patients) 99% confidence interval Aspirin DoseTrials Antiplatelet (events/n) Control (events/n) Odds ratio (Cl) Antiplatelet:Control Odds reduction (SE) High (500~1,500 mg) 341,621/11,2151,930/11,23619% (3) Medium (160~325 mg) 191,526/13,2401,963/13,27326% (3) Low (75~150 mg) 12366/3,370517/3,40632% (6) Extremely low (below 75 mg) 3316/1,827354/1,82813% (8) Total653,829/29,6524,764/29,74323% (2) Antiplatelet better Antiplatelet worse % confidence interval

57 Create a Polypill Combine all necessary ingredients in a single daily pill Aim for maximal benefit with minimal adverse effects To simultaneously reduce cardiovascular risk factors regardless of pretreatment levels

58 Multiplication benefits, not merely additive effect from each agent Multiplication benefits, not merely additive effect from each agent

59 Number of life years gained free from IHD or stroke

60 Side-effects of Polypill Overall side-effects of polypill: 8 to 15% of patients 1-2% will withdraw from drug Fatal side effects < 1 in Excess risk of non-fatal major bleed (transfusion required) with aspirin cf placebo (mainly gastric) of 1.2 per 1000 person years

61 CONSTITUENTS OF SECONDARY-PREVENTION POLYPILL Version of Polypill Aspirin dose (mg) Lisinopril dose (mg) Simvastatin dose (mg) Atenolol dose (mg) Low-Dose Medium-Dose High-Dose Version of Polypill Aspirin dose (mg) Lisinopril dose (mg) Simvastatin dose (mg) Hydrochlorothiazide (mg) Low-Dose Medium-Dose High-Dose CONSTITUENTS OF PRIMARY-PREVENTION POLYPILL REFERENCE: Wald NJ and Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326:1419

62 Who should take polypill ? Pre-existing disease: heart disease, stroke, peripheral arterial disease and diabetes mellitus Those without pre-existing disease: Age > 95% of deaths from IHD and stroke occur in people > 55 years old, regardless of their risk factors. A large proportion are in those never diagnosed with any risk factor ? everyone in this group should be treated Pre-existing disease: heart disease, stroke, peripheral arterial disease and diabetes mellitus Those without pre-existing disease: Age > 95% of deaths from IHD and stroke occur in people > 55 years old, regardless of their risk factors. A large proportion are in those never diagnosed with any risk factor ? everyone in this group should be treated

63 What is new, radical and unique about Polypill? Treatment of several risk factors simultaneously, regardless of level, and without screening for them Instead of targeting people at high risk, they suggest intervention for all at increased risk (regardless of risk level) ie everyone > 55 yrs and people at any age with existing cardiovascular disease Because of the high cardiovascular risk among those > 55 yrs they believe screening for risk factors among those > 55 yrs is not necessary Treatment of several risk factors simultaneously, regardless of level, and without screening for them Instead of targeting people at high risk, they suggest intervention for all at increased risk (regardless of risk level) ie everyone > 55 yrs and people at any age with existing cardiovascular disease Because of the high cardiovascular risk among those > 55 yrs they believe screening for risk factors among those > 55 yrs is not necessary

64 Issues of Uncertainty Will the pill be too big to swallow ? Problems with formulation eg should the pill include aspirin as this is the least tolerated component If treatment is stopped due to aspirin side effects, the benefits of the other well tolerated components of the pill will be lost Hence should aspirin be prescribed separately ? Will there be additional side-effects from a pill with 6 components? Potential interaction between the different components in the pill ? Need for dosage titration ? Will the pill be too big to swallow ? Problems with formulation eg should the pill include aspirin as this is the least tolerated component If treatment is stopped due to aspirin side effects, the benefits of the other well tolerated components of the pill will be lost Hence should aspirin be prescribed separately ? Will there be additional side-effects from a pill with 6 components? Potential interaction between the different components in the pill ? Need for dosage titration ?

65 Dosing of pill ? Some components in pill may have od dosing, otherwise BID dosing ? Final cost ? 2 models: Polypill model versus the traditional model of health screening and appropriate treatment. What is the health benefit of the first versus the second in terms of reduction of cardiovascular complications, quality of life and patient motivation / compliance to medication ? Dosing of pill ? Some components in pill may have od dosing, otherwise BID dosing ? Final cost ? 2 models: Polypill model versus the traditional model of health screening and appropriate treatment. What is the health benefit of the first versus the second in terms of reduction of cardiovascular complications, quality of life and patient motivation / compliance to medication ? Issues of Uncertainty

66 Purely speculative, never tested on patients Strategy based on meta-analysis of a very large number of trials Limitations of meta analysis Publication biases which favour positive results Selection bias and confounding are troublesome Observational studies are included; high likelihood of spurious results Trials involve single risk factor intervention Potential users of polypill likely to be healthy/health conscious, Unlike the participants in those trials who are likely to be less healthy Purely speculative, never tested on patients Strategy based on meta-analysis of a very large number of trials Limitations of meta analysis Publication biases which favour positive results Selection bias and confounding are troublesome Observational studies are included; high likelihood of spurious results Trials involve single risk factor intervention Potential users of polypill likely to be healthy/health conscious, Unlike the participants in those trials who are likely to be less healthy Issues of Uncertainty

67 Empiric evidence is lacking for simultaneous intervention of several risk factors Over estimation of treatment benefit Likely benefit is less than speculated because the study compares treatment with no treatment, whereas many of the elderly with diseases are likely already to be on some treatment Empiric evidence is lacking for simultaneous intervention of several risk factors Over estimation of treatment benefit Likely benefit is less than speculated because the study compares treatment with no treatment, whereas many of the elderly with diseases are likely already to be on some treatment Issues of Uncertainty

68 CONCERNS Issues not addressed Diabetes mellitus Smoking High fat high cholesterol dietExercise ObesityStress Health promotion efforts Patient / caregiver education and encouragement Sedentary life style Industries / food establishments: less salt & fat – canned / outside food Many chronic disease are due to unhealthy life style Using pharmacologic means to treat these problems ! Issues not addressed Diabetes mellitus Smoking High fat high cholesterol dietExercise ObesityStress Health promotion efforts Patient / caregiver education and encouragement Sedentary life style Industries / food establishments: less salt & fat – canned / outside food Many chronic disease are due to unhealthy life style Using pharmacologic means to treat these problems !

69 One size fits all Some under treated, others over treated Medical treatment is individualized - each patient has a different disease profile. Proper monitoring and tailoring of treatment is essential Wrong message ‘quick fix’ with magic bullet Polypill – treating a population and not an individual ! One size fits all Some under treated, others over treated Medical treatment is individualized - each patient has a different disease profile. Proper monitoring and tailoring of treatment is essential Wrong message ‘quick fix’ with magic bullet Polypill – treating a population and not an individual ! CONCERNS

70 Like 3-in-one coffee, brew our coffee, milk and sugar Everything quick, treatment also ! Like 3-in-one coffee, brew our coffee, milk and sugar Everything quick, treatment also ! CONCERNS

71 Exercise Inactivity ↑ incidence of at least 17 unhealthy conditions, almost all of which are chronic diseases, resulting in ~ premature deaths a year ! Low level of aerobic fitness shown to be an independent and more powerful predictor of fatal cardiovascular event than other conventional risk factors Inactivity ↑ incidence of at least 17 unhealthy conditions, almost all of which are chronic diseases, resulting in ~ premature deaths a year ! Low level of aerobic fitness shown to be an independent and more powerful predictor of fatal cardiovascular event than other conventional risk factors

72 Let us not overlook…….

73 Idea of Polypill is good………. Reinforces importance of aggressive multifactorial intervention to reduce cardiovascular risk For health promotion to be effective major paradigm shifts are needed, supported by good public education and health campaigns These efforts go beyond the physician’s office and hospital pharmacy Reinforces importance of aggressive multifactorial intervention to reduce cardiovascular risk For health promotion to be effective major paradigm shifts are needed, supported by good public education and health campaigns These efforts go beyond the physician’s office and hospital pharmacy

74 To advocates of the Polypill…… Add in “User instructions” ………..take this medication daily, followed by or preceded by more than 30 minutes of moderate-to-vigorous exercise, in combination with a low-fat, low-cholesterol diet, weight management, and cessation of cigarette smoking Add in “User instructions” ………..take this medication daily, followed by or preceded by more than 30 minutes of moderate-to-vigorous exercise, in combination with a low-fat, low-cholesterol diet, weight management, and cessation of cigarette smoking SALAMAT PO !

75

76 Overall CV Risk Management is Key to Reducing Risk of CV Events Current evidence suggests that treatment of a single CV risk factor is suboptimal Reduction of overall CV risk decreases CV events greater than single risk factor reduction Current guidelines recognise the importance of total CV risk management Overall CV risk management is the ultimate goal in order to maximise CV event reduction Current evidence suggests that treatment of a single CV risk factor is suboptimal Reduction of overall CV risk decreases CV events greater than single risk factor reduction Current guidelines recognise the importance of total CV risk management Overall CV risk management is the ultimate goal in order to maximise CV event reduction

77 AVALON: Most Frequently Reported Treatment- Emergent AEs [Number (%) of Patients] COSTAR Preferred TermAmlodipine 5 mg qd + Atorvastatin 10 mg qd (N=207) Atorvastatin 10 mg qd (N=200) Amlodipine 5 mg qd (N=201) Placebo (N=239) Respiratory tract infection15(7.2)12(6.0)17(8.5)17(7.1) Headache14(6.8)20(10.0)14(7.0)24(10.0) Peripheral oedema11(5.3)1(0.5)11(5.5)5(2.1) Myalgia10(4.8)5(2.5) 5(2.1) Accidental injury8(3.9)5(2.5)3(1.5)6(2.5) Asthenia7(3.4)8(4.0)6(3.0)11(4.6) Sinusitis6(2.9)2(1.0) 2(0.8) Pain5(2.4)4(2.0)5(2.5)5(2.1) Flatulence5(2.4)6(3.0)3(1.5)6(2.5) qd=once daily; COSTAR=Coding symbols for thesaurus of adverse reaction terms. Data on file. Pfizer Inc, New York, NY.

78 RESPOND: Most Frequently Reported Treatment-Emergent AEs [Number (%) of Patients] COSTAR Preferred Term Amlodipine + Atorvastatin (any dose) (N=885) Atorvastatin (any dose) (N=443) Amlodipine (any dose) (N=221) Placebo (N=111) Peripheral oedema88 (9.9)5 (1.1)27 (12.2)3 (2.7) Headache47 (5.3)34 (7.7)11 (5.0)11 (9.9) Respiratory tract infection43 (4.9)17 (3.8)7 (3.2)5 (4.5) Abdominal pain20 (2.3)10 (2.3)2 (0.9)0 (0.0) Asthenia19 (2.1)8 (1.8)4 (1.8)3 (2.7) Constipation15 (1.7)2 (0.5)3 (1.4)1 (0.9) Rash15 (1.7)3 (0.7)1 (0.5)1 (0.9) Myalgia14 (1.6)8 (1.8)3 (1.4)2 (1.8) qd=once daily; COSTAR=Coding symbols for thesaurus of adverse reaction terms. Data on file. Pfizer Inc, New York, NY.

79 AVALON and RESPOND: Deaths and Serious Adverse Events A total of 8 deaths occurred in patients treated with either ENVACAR ® (amlodipine besylate/atorvastatin calcium) or amlodipine + atorvastatin –None of these deaths were consider by the investigator to be related to study medication There were 208 cases reporting 292 serious AEs in patients treated with either ENVACAR or amlodipine + atorvastatin –Most common serious AEs were cardiac disorders (46 cases), neoplasms (23 cases), and gastrointestinal disorders (20 cases) A total of 8 deaths occurred in patients treated with either ENVACAR ® (amlodipine besylate/atorvastatin calcium) or amlodipine + atorvastatin –None of these deaths were consider by the investigator to be related to study medication There were 208 cases reporting 292 serious AEs in patients treated with either ENVACAR or amlodipine + atorvastatin –Most common serious AEs were cardiac disorders (46 cases), neoplasms (23 cases), and gastrointestinal disorders (20 cases) Data on file. Pfizer Inc, New York, NY. Please see prescribing information at the end of this slide presentation.

80 The relationship between BP and cardiovascular risk is continuous, consistent and independent of other risk factors The ↑ the BP, the ↑ the risk – the risk of stroke increases progressively with increasing BP BP control contributes to the prevention of stroke as well as prevention & reduction of other target organ (heart, kidneys) damage Antihypt tx a/w ↓ risk of stroke and cardiovascular diseases It remains unsettled whether specific classes of antihypt drugs offer special protection against stroke in addition to their BP lowering effects HYPERTENSION

81 Epidemiological and numerous prospective studies show a positive relationship between blood homocysteine levels and stroke risk B vitamins (folate, B6 and B12) ↓ homocysteine level Insufficient data to recommend a specific treatment approach that would reduce the risk of first stroke in patients with elevated homocysteine levels Use of folic acid and B vitamins in patients with known elevated homocysteine levels may be useful given their safety and low cost Homocysteine

82 Low dose aspirin ( mg/day) = high dose ( mg/day) Hence trials of low dose aspirin More than 6 months 15 trials Healthy people (4 trials) and those with cardiovascular disease Aspirin

83 Law MR, Wald NJ, Morris JK, Jordan R. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003;326: BP – 5 main categories of drugs (thiazides, beta blockers, ACE inhibitors, angiotensin II receptor antagonists, and calcium blockers) produce similar ↓ of BP Within each dose category, BP ↓ remarkably similar for different categories of drugs No category was more effective than another; any differences between the drugs was small BP ↓ with half standard dose were ~ 20% less than those with standard dose (eg standard daily dose - atenolol 50 mg, norvasc 5 mg, lisinopril 10 mg)

84 Combination of 3 drugs from different categories have greater efficacy and fewer side effects compared to using a single drug or using 2 drugs (of different categories) i.e. better BP ↓ effect with 3 drugs Efficacy

85 Half standard dose Standard dose Thiazides2%9.9% (p<0.001) Calcium blockers1.6% 8.3% (p<0.001) Beta blockers5.5%7.5% (p=0.04) ACE Inhibitor3.9%3.9% ARBno excess of symptoms cf placebo ACE Inhibitor - cough the only S/E – no variation with dose Prevalence of adverse effects with combination therapy was less than additive ! (No potentiation of S/E from combination therapy) Side-effect profile

86 Law MR, Wald NJ, Morris JK, Jordan R. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003;326: From the average BP of 150/90 mmHg in people who have stroke, BP ↓ (20 mmHg systolic and 11 mm Hg diastolic) with 3 drugs in combination at half standard dose ↓ the incidence of IHD events by 46% and stroke by 63%

87 Epidemiological studies initially found no consistent association between cholesterol levels and overall stroke rates but were likely confounded by the inclusion of hemorrhagic as well as ischemic stroke

88 Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989;320:904–0 Kagan A, Popper JS, Rhoads GG. Factors related to stroke incidence in Hawaii Japanese men. The Honolulu Heart Study. Stroke 1980;11:14– 21. Leppala JM, Virtamo J, Fogelholm R, Albanes D, Heinoren OP. Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants. Stroke 1999;30:2535–40. Epidemiological studies initially found no consistent association between cholesterol levels and overall stroke rates but were likely confounded by the inclusion of hemorrhagic as well as ischemic stroke 3 prospective studies in men subsequently showed increases in ischemic stroke rates at higher levels of total cholesterol, particularly for levels above 240 to 270 mg/dL Epidemiological studies initially found no consistent association between cholesterol levels and overall stroke rates but were likely confounded by the inclusion of hemorrhagic as well as ischemic stroke 3 prospective studies in men subsequently showed increases in ischemic stroke rates at higher levels of total cholesterol, particularly for levels above 240 to 270 mg/dL

89 The Asia Pacific Cohort Studies Collaboration ( patients):- a 25% ↑ in ischemic stroke rates for every 1-mmol/L (38.7- mg/dL) ↑ in total cholesterol Zhang X, Patel A, Horibe H, Wu Z, Barzi F, Rodgers A, MacMahon S, Woodward M; Asia Pacific Cohort Studies Collaboration. Cholesterol, coronary heart disease, and stroke in the Asia Pacific region. Int J Epidemiol 2003;32:563–72

90 The US Women’s Pooling Project ( women):- a 25% ↑ risk of fatal ischemic stroke for each 1-mmol/L ↑ in total cholesterol in women 30 to 54 years of age Horenstein RB, Smith DE, Mosca L. Cholesterol predicts stroke mortality in the Women’s Pooling Project. Stroke 2002;33:1863–8

91 Eurostroke project ( subjects, 34% female):- a trend toward ↑ risk with 6% more cases of cerebral infarction for every 1-mmol/L ↑ in total cholesterol Bots ML, Elwood PC, Nikitin Y, Salonen JT, Freire de Concalves A, Inzitari D, Sivenius J, Benetou V, Tuomilehto J, Koudstaal PJ, Grobbee DE. Total and HDL cholesterol and risk of stroke. EUROSTROKE: a collaborative study among research centres in Europe. J Epidemiol Community Health. 2002;56(suppl 1):i19–i24

92 LDL – Statins drug of choice Statins can lower LDL by an average of 1.8 mmol/L which reduces the risk of IHD events by about 60% and stroke by 17% Law MR et al. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326: LDL – Statins drug of choice Statins can lower LDL by an average of 1.8 mmol/L which reduces the risk of IHD events by about 60% and stroke by 17% Law MR et al. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423-7

93 Stroke 2004;35: Each 10% ↓ in LDL was estimated to ↓ the risk of all strokes by about 15.6% (95% CI, 6.7 to 23.6) Stroke 2004;35: Each 10% ↓ in LDL was estimated to ↓ the risk of all strokes by about 15.6% (95% CI, 6.7 to 23.6)

94 IHD reduced by 32% Stroke reduced by 16% IHD reduced by 32% Stroke reduced by 16%

95 But….problem of compliance


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