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A Prelude to the Polypill Concept for Vascular Disease Prevention

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. Overview. Prevalence and burden of stroke in Asia and worldwide

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A Prelude to the Polypill Concept for Vascular Disease Prevention

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  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

  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 Others 9 % Cardiovascular Disease (Heart disease & Stroke) 17 M or 30 % Injuries 9 % DM - 2 % Total Deaths 2005 58 million Respiratory Dse - 9 % Cancer 13 % Communicable dse, Nutritional def 30 %

  5. 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 BURDEN OF STROKE Rothwell PM. Lancet 2005;366:1773-83

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

  9. STROKE MORTALITY in ASIA, 2003 No per 100,000 population MacKay J and Mensah G. Atlas of Heart Disease and Stroke. 2004. 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 BURDEN OF STROKE WHO. The Atlas of Heart Disease and Stroke 2004.

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

  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;5:130-139

  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 STROKE IN ASIA • Wong KS, et al. Neurology 2007; 68:2031–2034; Wong KS, et al. Neurology 2007;68:2035-2038

  14. National Nutrition and Health Survey 2003 - 2004 NNHES Results : Stroke Prevalence in the Philippines N = 4753 adults (> 20 yrs old), 17 Regions, 79 provinces Aug to Dec 2003 Dans A. et al. Phil J Int Med; 43(3) : 103 -115 Slide courtesy of A. Roxas, MD

  15. National Nutrition and Health Survey 2003 - 2004 NNHES Results : Stroke Prevalence in the Philippines (by Age) 6.4% 6.1% 3.0% 1.3% Dans A. et al. Phil J Int Med; 43(3) : 103 -115 Slide courtesy of A. Roxas, MD

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

  17. Managing the Patient at Risk – Multiple Risk Factors Require Multiple Interventions Modifiable risk factors Unmodifiable risk factors • 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 CAD=coronary artery disease; TIA=transient ischemic attack; CHD=coronary heart disease Goldstein LB, et al. Stroke. 2001;32:280-299.

  18. Multiple CV Risk Management Results in Dramatic Reductions in CVD 45% Reductionin CVD 10% Reductionin BP + 10% Reductionin TC = “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;25:484-491. Jackson R et al. Lancet. 2005;365:434-441.

  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=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;361:1149-1158. Julius et al. Lancet. 2004;363:2022-2031. Colhoun et al. Lancet. 2004;364:685-696.

  20. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT): A Study in Hypertensive Patients at Low to Moderate CV Risk 19,257 hypertensive patients with ≥3 CV risk factors and no CHD ASCOT- BPLA amlodipine-based regimen N=9639 atenolol-based regimen N=9618 10,305 hypertensive patients (≥3 CV risk factors and no CHD) with total cholesterol ≤6.5 mmol/L (251 mg/dL) ASCOT-LLA atorvastatin 10 mg N=5168 placebo N=5137 amlodipine-based regimen N=2584 atenolol-based regimen N=2584 amlodipine-based regimen N=2554 atenolol-based regimen N=2583 ASCOT-LLA 2x2 Sever PS et al. Lancet. 2003;361:1149-1158.

  21. ASCOT-LLA: Patient Population Routinely Seen in Clinical Practice (Hypertension Plus 3 Risk Factors for CHD*) 100 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 84 81 62 33 26 26 23 23 14 10 5 80 100 0 40 60 20 Patients with Risk Factor (%) Two of the most common additional risk factors were male sex and age ≥55 yearsrepresentative of patients frequently seen in practice *These risk factors were used as inclusion criteria for the study. The ASCOT Investigators. Available at: http://www.ascotstudy.org/get_doc.php?id=56. Accessed: April 6, 2006. Data on file. Pfizer Inc, New York, NY.Please see prescribing information at the end of this slide presentation.

  22. ASCOT-LLA: 27% RRR in Fatal and Nonfatal Stroke When Atorvastatin Added to BP Treatment Atorvastatin 10 mg (n=5168) Placebo (n=5137) 3 Trial stopped early P=.0236 2 Proportion of Events (%) 1 HR=0.73 (0.56-0.96) 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 5.0 Years Sever PS et al for the ASCOT Investigators. Lancet. 2003;361:1149-1158.

  23. ASCOT-BPLA and -LLA Combined: Insight Into Optimal CVD Prevention Rates/1000 Patient-Years The ASCOT Study Investigators. Available at: http://www.ascotstudy.org/get_doc.php?id=86#52. Accessed: June 30, 2006.

  24. ASCOT-BPLA and -LLA Combined: Insight Into Optimal CVD Prevention ASCOT-LLA Primary End Point: Nonfatal MI and Fatal CHD ASCOT-LLA Secondary End Point: Fatal and Non-Fatal Stroke 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;361:1149-1158.

  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 Please see prescribing information at the end of this slide presentation.

  26. RISK FACTORS% Contribution to Stroke Developed Countries Developing Regions Choles BMI Choles BMI HPN Smoking Diet HPN Smoking Diet Physical Inactivity Alcohol Physical Inactivity Alcohol * Computed from risk factor prevalence & hazard size Ezzati, M for the Comparative Risk Assessment Group Lancet 2003; 362: 271 - 280

  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 European Stroke Initiative Executive Committee and EUSI Writing Committee. Cerebrovasc Dis 2003;16:311-337.

  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 All Diuretics Beta-blockers ACEI ACEI + Diuretic 0 –7 –7 -10 -20 Relative risk reduction (%) * –24 -30 –32 † -40 ‡ –45 -50 ACEI=Angiotensin-converting enzyme inhibitors. *P=.005. †P=.01. ‡P<.00001. Rashid P, et al. Stroke 2003;34:2741-2749.

  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;34:2741-8 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;366:895-906.

  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 Stroke should be considered a CHD risk equivalent Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497; Grundy SM et al. Circulation. 2004;110:227-239. The SPARCL Investigators. N Engl J Med 2006;355:549-559.

  33. ASCOT-LLA: fatal and nonfatal stroke (secondary end point) Sever PS et al. Lancet. 2003;361:1149-1158.

  34. 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

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

  36. Multiple Risk Factor InterventionFactors affecting ADHERENCE

  37. Most Hypertensive Patients Need Multiple Medications for Effective Management, Yet Adherence to Concomitant Antihypertensive and Lipid-Lowering Therapy Decreases as Number of Medications Increases 0 1 2 8 9 10 No. of Additional Medications Median PDC* Incremental pill burden had greatest effect on adherence in patients taking the fewest medications *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 2006. Abstract.

  38. Concurrently Starting 2 Medications Improved Adherence P<.001 OR for Adherence* 1-30 Days 31-60 Days 61-90 Days† 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;165:1147-1152.

  39. Simplified Medication Regimen Improved Persistence 100 90 1-pill combination therapy 2-pill therapy 80 Patients Adherent (%) 70 ~20% 60 50 0 1 2 3 4 5 6 7 8 9 10 11 12 Months Since Initiation of Therapy Dezii CM. Manag Care. 2000;9(suppl):S2-S6.

  40. 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 3 P<.001† 2.5 P<.001† 2 P<.001† P<.001† Adjusted Likelihood of Being Adherent; AH and LL Rx 1.5 1 0.5 0 0 1 2 3.5 6+ ReferenceGroup Number of Preexisting Rx Meds *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;165:1147-1152. Please see prescribing information at the end of this slide presentation.

  41. 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

  42. Multiple Risk Factor InterventionFeasibility of Single-Pill combinations“The Duo Pill”

  43. RISK FACTORS% Contribution to Stroke Developed Countries Developing Regions Choles BMI Choles BMI HPN Smoking Diet HPN Smoking Diet Physical Inactivity Alcohol Physical Inactivity Alcohol * Computed from risk factor prevalence & hazard size Ezzati, M for the Comparative Risk Assessment Group Lancet 2003; 362: 271 - 280

  44. 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 Sever PS et al for the ASCOT Investigators. Lancet. 2003;361:1149-1158. Julius S et al for the VALUE trial group. Lancet. 2004;363:2022-2031. Blank R et al. J Clin Hypertens. 2005;7:264-273. Chapman RH et al. Arch Intern Med. 2005;165:1147-1152. McCombs JS et al. Med Care. 1994;32:214-226. Bisognano J et al. Am J Hypertens. 2004;17:676-683. CADUET® [SmPC 5/10]. Please see prescribing information at the end of this slide presentation.

  45. 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 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.

  46. AVALON: Patients reaching goals for BP & LDL-C at 8 and 28 weeks % AML192 166 Plac227189 ATV192 180 AML/ATV200 171 Number of pts828 wks Messerli, et al. J Clin Hypertens 2006;8:571-81 Messerli, et al. J Clin Hypertens 2006;8:571-81

  47. 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 AEs=adverse events. Flack J et al. J Hypertens. 2004;22(suppl 1):12S. Data on file. Pfizer Inc, New York, NY.

  48. 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 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].

  49. 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 Flack J et al. J Hypertens. 2004;22(suppl 1):12S.Data on file. Pfizer Inc, New York, NY.

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