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STUDIES ON SINGLE PILL COMBINATION SPC◼All 29 studies reported on adherence and/or persistence in patients taking SPC therapy for hypertension.. GEMINI: CONCLUSIONS ◼SPC aml/ator therapy

Ts Bs Ngô Minh Hùng Tim mạch Can thiệp – Bệnh Viện Chợ Rẫy

KINH NGHIỆM VỚI VIÊN KẾT HỢP

TỪ PHÂN TÍCH GỘP ĐẾN HỒ SƠ BỆNH NHÂN

World Health Organization Integrated management of cardiovascular risk – report of a WHO meeting, Geneva, 9–12 July 2002

Available at: http://whqlibdoc.who.int/publications/9241562242.pdf Accessed: Oct 2009

CVRFS AND HEART DISEASE

1 Expert Rev Cardiovasc Ther 2007;5(2):177-193 2 Am J Cardiol 1998;82:3Q-12Q 3 Lancet 2004;364:685-696 4 NEJM 2004;350:1495-1504 5

JAMA 2005;294:2437-2445 6 Lancet 2005;366:1267-1278 7 Expert Rev Cardiovasc Ther 2004;2(3):431-449

CVRFS AND HEART DISEASE

(2) For all other people, the use of a risk estimation system

such as SCORE is recommended to estimate total CV risk.

4 European Heart Journal (2016) 37, 2999–3058

Lewington S et al Lancet 2002;360:1903-1913.

- 12,7 triệu bệnh nhân - năm

Điều trị THA là cần thiết CVRF: HYPERTENSION

STUDIES ON SINGLE PILL COMBINATION (SPC)

◼All 29 studies reported on adherence and/or persistence in patients taking SPC therapy for hypertension

04 RCTs (14%)

25 Observational Studies (86%)

◼Sample sizes

75 to 79,958 for SPC therapy

73 to 383,269 for Free Dose Combination Therapy

Mancia G, et al J Hypertens 2015; 33:401–411 Mourad JJ, et al J Hypertens 2017; 35: 1481–1495.

edogoda SV, et al Cardiol Ther 2017; 6:91–104 Webster R, et al JAMA 2018; 320:566–579

756

4 RCTs 25 Obs645

RCTS ON SINGLE PILL COMBINATION

Mancia G, et al J Hypertens 2015; 33:401–411 Mourad JJ, et al J Hypertens 2017; 35: 1481–1495.

edogoda SV, et al Cardiol Ther 2017; 6:91–104 Webster R, et al JAMA 2018; 320:566–579

OBSERVATIONAL STUDIES ON SPC

Fleig SV, et al Adv Ther 2018; 35:353–366 Jadhav U, et al PLoS One 2014; 9:e92955.

Jung HW, et al Clin Exp Hypertens 2015; 37:482–489 Liakos CI, et al Am J Cardiovasc Drugs 2017;17:391–398.

COMBINATIONS

CHANGE IN BP AND BP CONTROL

reported the time to achieve BP control.

◼The percentage of patients who achieved target BP ranged from 25% (after1 month) [1] to 89% (after 4 months) [2].

[1] Mourad JJ, et al J Hypertens 2017; 35:1481–1495

[2] Vlachopoulos C, et al Curr Med Res Opin 2016; 32:1605–1610

◼ 16/29 studies (55%) clearly reported change in BP during the study which included all four RCTs

CHANGE IN BP AND BP CONTROL

[1] Bramlage P, et al J Clin Hypertens (Greenwich) 2018; 20:705–715; [2] Nedogoda SV, et al Cardiol Ther 2017; 6:91–104

[3] Webster R, et al JAMA 2018;320:566–579

CARDIOVASCULAR MORBIDITY AND MORTALITY

◼ There were no RCTs that investigated cardiovascular outcomes

◼ Information regarding cardiovascular outcomes with SPC therapy:

 Simons et al [1]: HR of death over 48 months SPC vs TPT was 1.83 [95% CI 1.55– 2.16] HR for discontinuation with SPC vs TPT was 1.86 (95% CI 1.74–1.99).

 Verma et al [2]: HR of death 3.4 events/100 persons vs 3.9 events/100 persons; HR

[1] Simons LA, et al Curr Med Res Opin 2017; 33:1783–1787; [2] Verma AA, et al PLoS Med 2018; 15:e1002584

[3] Tung YC, et al J Clin Hypertens (Greenwich) 2015; 17:51–58

CHD=coronary heart disease; LDL-C=low-density lipoprotein cholesterol;

Rx=drug group; PI=placebo group.

Adapted from Kastelein JJP Atherosclerosis 1999:143(suppl 1);S17-S21 Heart Protection Study Collaborative Group Lancet 2002;360:7-22 Sever PS et al Lancet 2003;361:1149-58

Colhoun HM et al Lancet 2004;364:685-96.

4S=Scandinavian Simvastatin Survival

Study AFCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study ASCOT=Anglo-Scandinavian Cardiac

Outcomes Trial CARDS=Collaborative AtoRvastatin

Diabetes Study CARE=Cholesterol and Recurrent

Events HPS=Heart Protection Study LIPID=Long-Term Intervention with Pravastatin Group in Ischaemic

Disease WOSCOPS=West of Scotland Coronary Prevention Study Group

End of Study LDL-C (mmol/L)

1.3 1.8 2.3 2.84 3.36 3.87 4.39 4.91 5.43

Secondary prevention

HPS Primary prevention

CARDS ASCOT

ELEVATED LDL-C INCREASES RISK OF CV EVENTS IN

DIFFERENT PATIENT POPULATIONS

◼ Meta-analysis CTT (Cholesterol Treatment Trialists) đã chứng minh được mối

liên hệ giữa việc giảm LDL-C một cách hiệu quả và an toàn bằng statin với giảm kết cục lâm sàng (26 thử nghiệm lâm sàng trên 170,000 bệnh nhân)

Biến cố mạch vành

 23%

Biến cố tim mạch chính 

21%

Giảm LDL-C, giảm biến cố tim mạch

Major coronary events Major vascular events

Baigent C et al Lancet 2005;366:1267–78 Lancet 2010;376:1670-81

◼Hemodynamic drugs: Single Pill for one (CVRF)

◼Hemodynamic and Metabolic drugs: Single Pill for two (CVRFs)

GOOD COMBINATIONS?

Hypertension

Drug 1: hypertensive

Drug 2: hypertensive

Anti-CVRFs

Drug 1: hypertensive

Anti-Drug 2:

Cholesterol Lowering

≥240

<130

130-139

≥160

SBP=systolic blood pressure.

Adapted from Thomas F et al Eur Heart J 2002;23:528-35.

Cholesterol Lowering

BP Lowering

Potential Benefit of Dual BP and Cholesterol Lowering on

CHD Mortality (per 100,000 Patient-Years)

TNT Endpoint (%) BP

(mm Hg)

Lipid Tertiles

<73 mg/dL

74-94 mg/dL

≥95 mg/dL

Primary Endpoint (Major CVD Events)

Adapted from Kostis J et al J Clin Hypertens 2008;10:367-76

Observational Data Show Lipid and BP Interactions

(Data From TNT Trial)

MI=myocardial infarction.

GITS=gastrointestinal therapeutic system; TC=total cholesterol.

Adapted from 1 Dahlöf B et al Lancet 2005;366:895-906 2 Sever PS et al Lancet 2003;361:1149-58

Randomized N=19,342

• 5-Year Planned Follow-up

• Primary Endpoint: Non-fatal MI

n=5168 Atorvastatin

DBP=diastolic blood pressure.

Adapted from Sever P et al Eur Heart J 2006;27:2982-88.

Atenolol + atorvastatin Atenolol + placebo

SBP

LDL-C (mg/dL) 140

3 2

1

out

Close-3 2

0

165

145 155

135

95

Amlodipine + atorvastatin Amlodipine + placebo

85

75

Blood Pressure (mm Hg)

0 1 2 3 4

90 days 2

ASCOT-LLA: 36% Reduction in Non-fatal MI and Fatal CHD

When Atorvastatin Added to BP Treatment 1

ASCOT 2x2 Analysis: Objectives

Amlodipine +

Atorvastatin

(n=2584)

Amlodipine + Placebo (n=2554)

Atenolol + Placebo (n=2583)

Atenolol + Atorvastatin (n=2584)

Adapted from Sever P et al Eur Heart J 2006;27:2982-8.

◼To evaluate the potential interaction between statins and different antihypertensive treatments (amlodipine vs

atenolol) on the primary endpoint and total CV events

and procedures

Adding Atorvastatin to Amlodipine is >3x as Effective for Reducing CHD Outcomes vs Adding Atenolol

NS=not significant.

Adapted from Sever P et al Eur Heart J 2006;27:2982-8.

Antihypertensive + atorvastatin

vs Antihypertensive + placebo

ASCOT-LLA and 2x2 Summary: CV Event Reduction

2

Adapted from 1 Sever PS et al Lancet 2003;361:1149-58 2.Sever P et al Eur Heart J 2006;27:2982-8.

▪ Observations suggest risk for future CV events was lowered most for patients in ASCOT-LLA treated with amlodipine + atorvastatin combination

SINGLE-PILL AMLODIPINE/ATORVASTATIN

(CADUET): STUDY PROGRAM

Caduet ®

administered studies

Co-Single-pill

CARPE AVALON RESPOND

GEMINI &

GEMINI (AALA) CAPABLE JEWEL CUSP TOGETHER CRUCIAL

GEMINI: CONCLUSIONS

◼SPC (aml/ator) therapy was an efficacious and safe treatment forpatient with concomitant hypertension and dyslipidemia both with andwithout additional CV risk factors or CHD, over 14 weeks of treatment

◼SPC (aml/ator) therapy increased the percentage of patients withconcomitant hypertension and dyslipidemia who achieved

treatment

SINGLE-PILL STUDIES:

GEMINI AND GEMINI-AALA

GEMINI : Blank R et al J Clin Hypertens 2005;7:264-73

GEMINI-AALA : Erdine S et al J Hum Hypertens 2009;23:196-210.

◼SPC (aml/ator) therapy when administered alone or together withother antihypertensive agents is an effective and safe means ofreducing CHD risk

Adapted from Erdine S et al J Hum Hypertens 2009;23:196-210.

*Based on the JNC 7 guidelines (JAMA 2003;289:2560-72).

**Based on the NCEP ATP III guidelines (JAMA 2001;285:2486-97).

CAPABLE: CONCLUSIONS

◼Fewer than 1% of African American patients were controlled for both goals at entry, whereas almost half were controlled at endpoint (Week 20)

◼SPC (aml/ator) therapy was well-tolerated in this African American

population

Adapted From Flack et al Mayo Clin Proc 2008;83:35-45.

Clinical Utility of Caduet in Simultaneously Achieving Blood Pressure

and Lipid End Points (CAPABLE)

JEWEL STUDY: CONCLUSIONS

◼SPC (aml/ator) was an effective and well-tolerated treatment

LDL-C goals, as recommended by local country-specific guidelines

◼The results of these studies conducted across Europe and Canada

support the use of SPC aml/ator for the management of CV risk

Adapted from Hobbs FDR et al Eur J Cardiovasc Prev Rehabil 2009;16:472-80.

International open-label studies to assess the efficacy and safety of

single-pill amlodipine/atorvastatin in attaining blood pressure and lipid targets recommended by country-specific guidelines: the JEWEL

programme

CUSP: CONCLUSIONS

in untreated patients with hypertension and dyslipidemia at week 4 and 8.

population of patients with hypertension and dyslipidemia at moderate CV risk

low-to-Adapted from Neutel JM et al J Clin Hypertens 2009;11:22-30.

*Based on the JNC 7 guidelines (JAMA 2003;289:2560-72) **Based on the NCEP ATP III guidelines (JAMA 2001; 285: 2486-97).

The use of a single-pill calcium channel blocker/statin combination in the management of hypertension and dyslipidemia: a randomized, placebo-

controlled, multicenter study

TOGETHER STUDY: CONCLUSIONS

◼SPC (aml/ator) therapy, alongside ongoing advice on TLC, is more

effective for achieving joint BP*/LDL-C** targets than amlodipine + TLC

only in primary prevention patients with hypertension and additional

CV risk factors

◼Both regimens were well tolerated, and safety profile of SPC

(aml/ator) therapy was consistent with that known for both drugs

Adapted from Grimm R et al Vasc Health Risk Manag 2010;6:261-71.

*Based on the JNC 7 guidelines (JAMA 2003;289:2560-72).

**Based on optimal goal from the NCEP ATP III guidelines (JAMA 2001;285:2486-97).

Simultaneous treatment to attain blood pressure and lipid goals and reduced CV risk burden using amlodipine/atorvastatin single-pill

therapy in treated hypertensive participants in a randomized controlled

trial

CRUCIAL STUDY: CONCLUSIONS

physicians’ usual care alone, in patients with hypertension and additional risk factors, but only mildly elevated cholesterol

SBP and total cholesterol in patients treated in the proactive intervention arm, based on single-pill therapy, compared with usual care alone

observed in earlier studies

Adapted from Zamorano J et al Curr Med Res Opin 2011;27:821-33.

The Cluster Randomized Usual Care vs Caduet Investigation

Assessing Long-Term Risk (CRUCIAL) Trial

CARPE: CADUET ADHERENCE STUDIES

CARPE-P: Adherence with single-pill therapy in Patient benefits management system

Patel BV et al Vasc Health Risk Manag 2008;4:673-81.

CARPE-M: Adherence with single-pill therapy in a Managed Care organization

Hussein MA et al Am J Cardiovasc Drugs 2010;10:193-202.

CARPE-M Events

◼ Remaining adherent with CCB and statin therapy is associated with lower risk of CV events

Chapman RH et al BMC Cardiovasc

Disord 2010;10:29.

CARPE Adherence Upgrade

◼ Patients taking amlodipine and

initiating new statin therapy have

higher adherence when switched

to single-pill vs adding statin to

their antihypertensive regimen

Chapman RH et al Patient Prefer

Adherence 2009;3:265-75.

The C ADUET A dherence R esearch P rogram and E ducation ( CARPE )

CARPE-P: Single-pill Amlodipine/Atorvastatin Therapy Improved Adherence

Adapted from Patel BV et al Vasc Health Risk Manag 2008;4:673-81.

▪ Adherence (PDC ≥0.8) was significantly higher in single-pill amlodipine/atorvastatin

cohort vs all other CCB + statin cohorts (P<0.0001)

Single-pill Amlodipine/

atorvastatin

Amlodipine + atorvastatin

CARPE-M EVENTS: Single-pill Improved Adherence Throughout

18-month Follow-up vs CCB + Statin-treated Patients

▪ Patients on SPAA were more likely to be adherent vs CCB/statin patients

(OR 4.7 [95%CI 4.22, 5.23]; P<0.001)

▪ Adherence remained higher throughout the 18-month follow-up for SPAA

SPAA (n=1537) CCB + Statin (n=17,910) P-value

CARPE-M EVENTS: Single-pill Patients had Lower CV Event Rate

Throughout Follow-up vs CCB + Statin-treated Patients

▪ Non-adherent patients and CCB/statin patients experienced higher CV

event rates than adherent and single-pill amlodipine/atorvastatin patients

▪ Being adherent to either regimen was associated with lower risk of CV

events (HR=0.77, P=0.003)

(19,447)

Adherent (4693)

Non-Adherent (14,754)

SPAA (1537)

CCB+Statin (17,910) 12-month Event Rate

Conclusions

control BP easier than baseline treatment However, for an treatment analysis, there was no significant difference between treatment arms, demonstrating the importance of adherence in the treated population.

achieving joint BP/LDL-C targets than amlodipine + TLC in primary prevention patients with hypertension and additional CV risk factors.

consistent with that known for both drugs

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