The document summarizes a clinical trial that compared the effectiveness of three drug combinations for treating hypertension in black patients in sub-Saharan Africa: amlodipine plus hydrochlorothiazide, amlodipine plus perindopril, and hydrochlorothiazide plus perindopril. The trial found that both amlodipine plus hydrochlorothiazide and amlodipine plus perindopril were more effective at reducing blood pressure than hydrochlorothiazide plus perindopril, as measured by changes in 24-hour ambulatory blood pressure and rates of controlled office blood pressure. The results provide support for guidelines recommending calcium channel blockers like amlodipine in combination with di

1. EMPERROR-PRESERVED TRIAL
JOURNAL CLUB
Fadol Mohamed, MD

2. CONTENTS
 INTRODUCTION
 ARTICLE PRESENTATION
 CONCLUSIONS, IMPLICATIONS, AND FUTURE DIRECTIONS
 GROUP DISCUSSION

3. INTRODUCTION
 Glucose is hydrophilic. We need transporter to move across membranes
 Types of Glucose transporters in the body
1. GLUTS (1,2,3 … etc) Na/ATP independent process
2. SGLT 1 (intestine, distal nephron) Na/ATP dependent  ABSORPTION
3. SGLT II (proximal tubules) Na/ATP dependent  RETENTION

4. How it works
Sodium-glucose cotransporter type 2 in the renal proximal tubule reabsorbs
approximately 90% of filtered glucose

5. SGLTII inhibitors
and Heart Failure
2019: DECLARE-TIMI 58
SGLT2 inhibitors reduce the risk of hospitalization for heart failure in patients
with T2DM
Most patients did not have heart failure at the time of enrollment

6. SGLTII inhibitors
and Heart Failure
2019
SGLT2 inhibitors reduce the risk of hospitalization for heart failure in patients with
T2DM
Most patients did not have heart failure at the time of enrollment

7. SGLTII inhibitors
and Heart Failure
2019
First SGLT II inhibitor cardiovascular outcome trial to evaluate patients with type 2
diabetes mellitus stratified by EF
• Dapagliflozin reduced HHF in patients with and without HFrEF
• Dapagliflozin reduced cardiovascular death and all-cause mortality in patients
with HFrEF.

8. SGLTII inhibitors
and Heart Failure
2020
First SGLT II inhibitor cardiovascular outcome trial to evaluate patients with type 2
diabetes mellitus stratified by EF
• Dapagliflozin reduced HHF in patients with and without HFrEF
• Dapagliflozin reduced cardiovascular death and all-cause mortality in patients
with HFrEF.

9. Non-
Pharmacologic
Therapy

10. Non-
Pharmacologic
Therapy

11. Pharmacologic
Therapy
 Medication therapy can be associated with up to:
- 50% reduction in heart failure
- 40% reduction in stroke
- 25% reduction in MI
 Should be initiated in:
 All stage II HTN
 stage 1 HTN plus:
clinical cardiovascular disease
or
10-year ASCVD risk score ≥10%

12. Primary agents
 Thiazide or thiazide-type diuretics (Chlorthalidone, HCTZ, Indapamide, Metolazone)
 ACE inhibitors (Captopril, Enalapril, Lisinopril, Perindopril, etc..)
 ARBs (Losartan, Olmesartan, Telmisartan, Valsartan)
 CCB—dihydropyridines (Amlodipine, Nicardipine SR, Nifedipine LA, Felodipine)
 CCB—nondihydropyridines (Diltiazem ER, Verapamil)

13. Secondary agents
 Direct vasodilators (Hydralazine, Minoxidil)
 Beta Blockers, Alpha-1 blockers and Central alpha2-agonist
 Diuretics—loops (Furosemide, Bumetanide, Torsemide)
 Diuretics—potassium sparing (Amiloride, Triamterene)
 Diuretics—aldosterone antagonists (Eplerenone, Spironolactone)
 Direct renin inhibitor (Aliskiren)

14. Initial Monotherapy Versus Initial Combination Drug Therapy
 Rapid titration of antihypertensives is recommended in patients with BP >20/10 mm Hg above their
target

15. Hypertension In
Patient With
Comorbidities
 Stable Ischemic Heart Disease
 Heart Failure : HFrEF and HFpEF
 Chronic Kidney Disease
 Cerebrovascular Disease
 Diabetes Mellitus

16. Special Patient
Groups
 Ethnicity related (HTN in blacks)
 Gender related (Pregnancy)
 Age related (Older persons)

17. Which Agent To
Choose for Black
Patients?
 Thiazide diuretics or CCBs are more effective in lowering BP than
are RAS inhibitors or BB
 Thiazide diuretics or CCBs are more effective in reducing CVD
events than are RAS inhibitors or alpha blockers
 RAS inhibitors are recommended in black patients with
hypertension, DM, and nephropathy, but they offer no advantage
over diuretics or CCBs in hypertensive patients with DM without
nephropathy or HF
 Combination of an RAS inhibitors (ACEi or ARB) with a CCB or
thiazide diuretic produces similar BP lowering in blacks as in other
racial or ethnic groups for blacks who do not achieve control with 3
drugs

18. ARTICLE SELECTION
https://www.ncbi.nlm.nih.gov/pubmed/30883050

19. Why is CREOLE study relevant
 In the USA, patients of African descent have a higher prevalence of
HTN, lower rates of control, and higher rates of complications than
patients of other ethnicities but are underrepresented in clinical trials
 Current recommendations suggest Thiazide diuretics or CCBs over
RAS inhibitors in black patients with uncomplicated hypertension
 Adequate BP control typically requires combinations of ≥ 2 agents
So Which Combination You Would Choose

20. ARTICLE PRESENTATION
Discussion
& Article
Critique
Results
Methods
Background

21. BACKGROUND
 Based on the preferential blood-pressure–lowering efficacy of
diuretics and calcium channel blockers as monotherapy in black
patients, Investigators hypothesized that amlodipine plus HCTZ
would be the most effective of the three combinations in
reducing the ambulatory systolic blood pressure.
 However, amlodipine plus perindopril was similarly effective in
reducing both the ambulatory systolic blood pressure and the
office blood pressure

22. Background Cont.
• Study performed in six countries in Sub-Saharan Africa which include Cameroun, Kenya, Mozambique,
Nigeria, South Africa and Uganda
• Started June 7, 2017 - Completed May 15, 2018
• Ages eligible for Study: 30 Years to 79 Years (Adult, Older Adult)
• Sexes eligible for Study: All

23. METHODOLOGY
Amlodipine 5
mg
HCTZ 12.5 mg
Amlodipine 5
mg
Perindopril 4 mg
Perindopril 4 mg
HCTZ 12.5 mg

24. Methodology Cont.
 Office BP measurements
- At randomization
- At 2-month, 4-month and 6-month visit
 Doses were doubled after 2 months
 Ambulatory BP monitoring
- At randomization
- At six months

25. Methodology Cont.
 Design: Randomized controlled trial
 Allocation: {Concealed}*.†
 Blinding: Blinded† (investigators).
 Follow-up period: 6 months.
 Setting: 10 centers in 6 sub-Saharan African countries.
 Patients: 728 black patients 30 to 79 years of age (mean age 51 y, 63% women) who had seated office systolic BP (SBP) 150
to179mmHg (no previous treatment) or 140 to 159mmHg (patients receiving monotherapy). Exclusion criteria included secondary
hypertension or history of cardiovascular disease.
 Interventions: Daily administration of (AML plus HCTZ,) (AML plus perindopril,) or (HCTZ plus perindopril.) Doses were doubled after 2
months.
 Outcomes: Primary outcome was change in 24-hour ambulatory SBP. Secondary outcomes included controlled office BP (< 140/90 mm
Hg) and treatment response (office SBP reduction > 20 mm Hg and diastolic BP reduction > 10 mm Hg).
 Patient follow-up: 96% completed the trial; 85% had ambulatory 24-hour BP measures at baseline and 6 months (intention to-treat
analysis).

26. RESULTS
 Key Findings
For black sub-Saharan African patients, blood pressure
was lowered better with amlodipine (a long-acting calcium
channel blocker) + either hydrochlorothiazide or
perindopril than with perindopril + hydrochlorothiazide
(no amlodipine).

27. Results Cont.

28. Results Cont.

29. CAVEAT
 CREOLE Trial excluded patient who have HTN with
comorbidities. (DM , HF, CKD). Compared to black
Africans, African Americans have higher rates of
hypertension with comorbidities
 CREOLE Trial did not address lifestyle modifications
(DASH diet, salt and alcohol reduction, exercise)

30. CONCLUSIONS, IMPLICATIONS, AND FUTURE
DIRECTIONS
 This study provided a high-quality evidence for current clinical guidelines that suggest use of
Amlodipine in combination with ACEi or thiazide diuretics in black patients with uncomplicated HTN and
no compelling reason to choose RAAS inhibition (e.g., heart failure, chronic kidney disease, or
proteinuria)
 This trial will inform future guidelines and raise the level of evidence for future recommendations.

31. GROUP DISCUSSION