Optimising hypertension management with the best drug combinations china tour - may 2018
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Raised blood pressure is a leading global cause of death, responsible for over 9 million deaths per year. While awareness and treatment of hypertension has increased worldwide, control rates remain low, especially in lower-income countries. Combination drug therapy is generally needed to control blood pressure, and clinical trials have demonstrated certain two-drug combinations are more effective than others. Single pill combinations may further improve adherence and blood pressure control compared to free-drug combinations. Overall, optimizing hypertension management through effective drug combinations can help reduce the global burden of cardiovascular disease.
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Optimising hypertension management with the best drug combinations china tour - may 2018
- 1. Optimising Hypertension Management with the best Drug Combinations Neil R Poulter Director Imperial Clinical Trials Unit Imperial College London UK President of the International Society of Hypertension Chinese Lecture Tour : May 2018
- 2. “Raised blood pressure continues to be the biggest contributor to the global burden of disease and to global mortality, leading to 9.4 million deaths each year.” Poulter et al. Lancet 2015
- 3. Income level n Aware (%) Treated (%) Controlled (%) High 6263 49.0 46.7 19.0 Upper Middle 18123 52.5 48.3 15.6 Lower Middle 23269 43.6 36.9 9.9 Low 10185 40.8 31.7 12.7 Total 57840 46.5 40.6 13.2 Hypertension: Awareness, Treatment & Control† by National Income: 2003 – 2009. PURE Study † <140/90 Chow et al. JAMA 2013
- 4. A SIMPLE MEASURE TO SAVE LIVES #checkyourpressure & help us to save more lives MMM18 BE PART OF IT! Please contact manager@maymeasure.com
- 5. A SIMPLE MEASURE TO SAVE LIVES #checkyourpressure COUNTRY NUMBERS (OVER 10,000) Country Total Percentage Philippines 271,883 22.6% India 240,515 20.0% China 125,239 10.4% Indonesia 69,507 5.8% Taiwan 52,606 4.4% Ukraine 45,507 3.8% Sudan 44,471 3.7% Argentina 32,353 2.7% Ivory Coast 24,563 2.0% Colombia 22,277 1.9% Venezuela 21,645 1.8% Nigeria 19,931 1.7% Angola 17,496 1.5% Cameroon 16,093 1.3% Kenya 14,863 1.2% Bangladesh 11,418 1.0% Viet Nam 10,996 0.9% Italy 10,076 0.8%
- 6. Income level n Aware (%) Treated (%) Controlled (%) High 6263 49.0 46.7 19.0 Upper Middle 18123 52.5 48.3 15.6 Lower Middle 23269 43.6 36.9 9.9 Low 10185 40.8 31.7 12.7 Total 57840 46.5 40.6 13.2 Hypertension: Awareness, Treatment & Control† by National Income: 2003 – 2009. PURE Study † <140/90 Chow et al. JAMA 2013
- 7. “Monotherapy is usually inadequate therapy” BHS IV
- 9. NICE ESH ESC ASH-ISH ‘JNC8’ A† + C§ A + C Black Black A + D* A + C C + D C + D A + D C + D Non-black Non-black A + C A + C A + D A + D C + D †: A = ACE-inhibitor or angiotensin receptor blocker §: C = Calcium channel blocker *: D = Diuretic (including thiazides or thiazide-like/type) Recommended 2-drug combinations of antihypertensive drugs
- 10. Optimal Combined Hypertension Treatment: Design R A+C A+D C+D
- 11. TRIAL VS LIFE - B + D VALUE - C + D PROGRESS - Placebo HYVET - Placebo ADVANCE - Placebo A + D Trials
- 12. A & C Trials Trial VS ASCOT - B+D ACCOMPLISH - A+D
- 13. ASCOT-BPLA: summary of all end points Dahlöf B, et al. Lancet. 2005;366:895-906. amlodipine/perindopril better atenolol/thiazide better 0.50 0.70 1.00 1.45 Primary Non-fatal MI (incl silent) + fatal CHD Secondary Non-fatal MI (exc. Silent) +fatal CHD Total coronary end point Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke Fatal and non-fatal heart failure Tertiary Silent MI Unstable angina Chronic stable angina Peripheral arterial disease Life-threatening arrhythmias New-onset diabetes mellitus New-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + stroke 2.00 Unadjusted HR (95% CI) 0.90 (0.79-1.02) 0.87 (0.76-1.00) 0.87 (0.79-0.96) 0.84 (0.78-0.90) 0.89 (0.81-0.99) 0.76 (0.65-0.90) 0.77 (0.66-0.89) 0.84 (0.66-1.05) 1.27 (0.80-2.00) 0.68 (0.51-0.92) 0.98 (0.81-1.19) 0.65 (0.52-0.81) 1.07 (0.62-1.85) 0.70 (0.63-.078) 0.85 (0.75-0.97) 0.86 (0.77-0.96) 0.84 (0.76-0.92)
- 14. ACCOMPLISH: Effects on Primary and Other End points Jamerson KA et al. N Engl J Med. 2008;359:2417-2428. Composite of death from cardiovascular causes and cardiovascular events Component Death from cardiovascular causes Myocardial infarction (fatal or nonfatal) Stroke (fatal or nonfatal) Hospitalization for unstable angina Coronary revascularization procedure Resuscitation after sudden cardiac arrest HR (95% CI) 0.80 (0.72–0.90) 0.80 (0.62–1.03) 0.78 (0.62-0.99) 0.84 (0.65-1.08) 0.75 (0.50-1.10) 0.86 (0.74–1.00) 1.75 (0.73–4.17) 0.5 1.0 2.0 Favors ACEI / HCTZ Favors CCB / ACEI Outcome P value <0.001 0.08 0.04 0.17 0.14 0.05 0.20
- 15. Step 4 Summary of antihypertensive drug treatment Aged over 55 years or black person of African or Caribbean family origin of any age Aged under 55 years C*A A + C* A + C + D Resistant hypertension A + C + D + consider further diuretic or alpha- or beta-blocker Consider seeking expert advice Step 1 Step 2 Step 3 Key A – ACE inhibitor or low-cost angiotensin II receptor blocker (ARB)1 C – Calcium-channel blocker (CCB) *D – Thiazide-like diuretic
- 16. WHICH A?
- 17. * Death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. ON-TARGET Trial: Primary Outcome*
- 18. ONTARGET: Equivalence or Non-Inferiority?
- 19. ROADMAP Trial: Design • 4447 patients with T2DM and no albuminuria • Olmesartan 40 mg vs Placebo (BP ↓ 3.1/1.9 mmHg) • 1ry Endpoint – new-onset microalbuminuria • F.U. – 3.2 years (median) NEJM 2011: 364: 907-917
- 20. ROADMAP Trial: Key Results Endpoint HR (95% CI) New microalbuminuria 0.77 (0.6 – 0.9) All cause mortality 1.70 (0.9 – 3.2) CV death 4.94 (1.4 – 17.1) - (sudden/fatal MI: 12 vs 1)
- 21. Impact of ACEI & ARBs on All Cause Mortality in the Trials Van Vark et al. Euro. Ht. J. 2012
- 22. Difference between ACE inhibitors and ARBs on mortality reductions in recent meta-analyses 1. van Vark LC, et al. Eur Heart J. 2012;33(16):2088-2097. 2. Lv J, et al. Cochrane Database Syst Rev. 2012;12:CD004136. 3. Baker WL, et al. Ann Intern Med. 2009;151(12):861-871. 4. Savarese G, et al. J Am Coll Cardiol.15;61(2):131-142.
- 23. WHICH C?
- 24. • In meta-analysis CCBs perform better especially for stroke outcomes than diuretics • CCBs less new onset diabetes • Diuretics should still be used but CCBs have a clear but modest edge (shown in 2006) NICE 2011: Treatment Algorithm Update
- 25. Q. WHICH C? ANS: AMLODIPINE WHY?: • Most effective • Longest duration • RCT evidence: ALLHAT, VALUE, ASCOT…
- 26. ADVANTAGES OF FDCs/SPCs? (Single Pill Combinations)
- 28. Full-dose Monotherapy vs four x quarter-dose combination therapy Mahmud: Hypertension: 2007 Amlod Aten Bendro
- 29. Reasons for inadequate control of BP • Ineffective drugs • Resistant hypertension • Guideline confusion • Drug costs • Drug side-effects • Poor compliance • Physician inertia
- 30. FDC and compliance ratio’s Study ID Schweizer et al. 2007 Taylor et al. 2003 Asplund et al. 1984 Gerbino et al. 2004 Dickson et al. 2008 I-V Overall (I-squared = 0.0%, p = 0.655) D+L Overall 1.08 (0.75, 1.54) 1.09 (0.80, 1.51) 1.74 (0.96, 3.15) 1.28 (0.93, 1.75) 1.29 (0.89, 1.89) 1.21 (1.03, 1.43) 1.21 (1.03, 1.43) 0.5 1.0 1.5 2.0 Favours FDCFavours free dose combination N=18,004 OR (95% CI) Odds Ratio Gupta : Hypertension : 2010
- 31. Single Pill Combinations (SPCs): Summary of Benefits • More effective and rapid BP control than monotherapy and 2 ‘free’ drugs • Reduced side effects • Enhanced adherence • Improved CV protection • More cost effective
Editor's Notes
- NEIL TO CLOSE
- 14
- NOTES FOR PRESENTERS. Key priority recommendations are identified with [KPI] in these notes. Step 3 treatment Before considering step 3 treatment, review medication to ensure step 2 treatment is at optimal or best tolerated doses. [new 2011] [1.6.16] If treatment with three drugs is required, the combination of ACE inhibitor (or angiotensin-II receptor blocker), calcium-channel blocker and thiazide-like diuretic should be used. [2006] [1.6.17] Step 4 treatment Regard clinic blood pressure that remains higher than 140/90 mmHg after treatment with the optimal or best tolerated doses of an ACE inhibitor or an ARB plus a CCB plus a diuretic as resistant hypertension, and consider adding a fourth antihypertensive drug and/or seeking expert advice. [new 2011] [1.6.18] For treatment of resistant hypertension at step 4: Consider further diuretic therapy with low-dose spironolactone4 (25 mg once daily) if the blood potassium level is 4.5 mmol/l or lower. Use particular caution in people with a reduced estimated glomerular filtration rate because they have an increased risk of hyperkalaemia. Consider higher-dose thiazide-like diuretic treatment if the blood potassium level is higher than 4.5 mmol/l. [new 2011] [1.6.19] [KPI] When using further diuretic therapy for resistant hypertension at step 4, monitor blood sodium and potassium and renal function within 1 month and repeat as required thereafter. [new 2011] [1.6.20] If further diuretic therapy for resistant hypertension at step 4 is not tolerated, or is contraindicated or ineffective, consider an alpha- or beta-blocker. [new 2011] [1.6.21] If blood pressure remains uncontrolled with the optimal or maximum tolerated doses of four drugs, seek expert advice if it has not yet been obtained. [new 2011] [1.6.22] Footnotes (1) Choose a low-cost ARB. (2) A CCB is preferred but consider a thiazide-like diuretic if a CCB is not tolerated or the person has oedema, evidence of heart failure or a high risk of heart failure. (3) Consider a low dose of spironolactone4 or higher doses of a thiazide-like diuretic. (4) At the time of publication (August 2011), spironolactone did not have a UK marketing authorisation for this indication. Informed consent should be obtained and documented. (5) Consider an alpha- or beta-blocker if further diuretic therapy is not tolerated, or is contraindicated or ineffective.
- Did the ONTARGET prove otherwise? ONTARGET was a “non-inferiority trial” that was powered to prove so. It wasn’t an “equivalence trial” which will need different settings and statistical powering. However, if it has proved anything, it is that the long acting ARB Telmisartan is not substantially worse than the short acting ACEI Ramipril. In the ARB arm in ONTARGET, there was a positive trend to increase the MI and hospitalization due to HF, despite better 24-h BP control.
- The evidence is not limited to hypertension, but spans the whole cardiovascular continuum with the results of meta-analyses including hypertensive patients, as well as those with myocardial infarction, and heart failure. ACE inhibitors have a consistently significant benefit in terms of all-cause mortality reduction through all patient profiles considered. ARBs cannot demonstrate a significant reduction in all-cause mortality in other patient profiles, especially in hypertensive patients.