By Prof. Khaled El-Rabat

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1 What is The Optimum? By Prof. Khaled El-Rabat Professor of Cardiology - Benha Faculty of Medicine

2 HT. Introduction Despite major worldwide efforts over recent decades directed at diagnosing and treating hypertension, high blood pressure (BP) still represents a leading cause of mortality, both in developing and industrialized i d countries. Reducing BP levels is associated with a significant improvement in cardiovascular and renal outcomes.

3 Introduction Recent hypertension guidelines have stressed the importance of achieving strict BP control, the aim being to lower BP below 140/90mmHg in most patients, and even below 130/90mmHg in high-risk patients with selected diseases, in particular diabetes mellitus and chronic renal insufficiency CRF.

4 CV Mortality Risk Doubles With Each 20/10 mm Hg BP Increment* CV mortality risk /75 135/85 155/95 175/105 SBP/DBP (mm Hg) *Individuals aged years, starting at BP 115/75 mm Hg. CV, cardiovascular; DBP, diastolic blood pressure; SBP, systolic blood pressure. Lewington S et al. Lancet. 2002;360: Chobanian AV et al. JAMA. 2003;289:

5 HT. Classes of Antihypertensive Drugs Currently several drug classes can be utilized in the treatment of hypertension: Thiazide diuretics, Beta (β )-blockers, Calcium channel blockers (CCB s), Angiotensin-converting enzyme (ACE) inhibitors, Angiotensin II (AII) receptor blockers, Alpha (α ) blockers and Centrally acting agents.

6 Strategy of Treatment Practice has been to begin treatment with one of these agents as monotherapy at a low dose. If this does not control blood pressure adequately then the physician is faced with three options. The first is upward drug dose titration. (Start low,go slow). In many cases increasing the dose leads to only modest increases in blood pressure response at the cost of more frequent or severe side effects.

7 Strategy of Treatment An alternative strategy is a trial of sequential monotherapy until an effective agent is found. Unfortunately there is no simple reliable method to predict which agent will work for an individual patient. The third option is to use more than one drug either as multiple individual drugs or a fixed dose combination therapy.

9 HT. Role of Combination Therapy in Reaching Blood Pressure Goals Essential hypertension is a very hetero- geneous disease and current evidence shows that it is caused by interacting multi factorial mechanisms, and this is more significant in high- risk patients. As a result,tobest treat these patients, it is necessary to use combinations of drugs with different mechanism of action. Combined therapy can be block counter regulatory mechanisms and potentiate the antihypertensive efficacy beyond the additive response of each drug alone.

10 Fig. 1. Placebo-subtracted blood pressure (BP) response to two different drugs administered separately and in combination, based on the observations made in 119 randomized placebocontrolled trials.

11 HT. Role of Combination Therapy in Reaching Blood Pressure Goals The advantages of combination therapy are well documented: 1. Increased antihypertensive efficacy as a result of combining different mechanisms of action; 2. A lesser incidence of adverse effects because of the lower doses used and the possible compensatory responses; 3. Since fixed low-dose combinations are available, the treatment simplification may optimize compliance and, secondarily, enhance BP control. 4. Starting treatment with a two-drug combination may allow BP goals to be achieved earlier than with only one antihypertensive drug.

13 Most Appropriate Drug Combinations Ideal drug combinations should not only be more effective, but also induce no more, or even fewer, adverse effects than each component given alone. Optimally, drug combinations should also provide maximal protection against target organ damage, and cardiovascular and renal complications.

14 Most Appropriate Drug Combinations In clinical practice there are numerous fixeddose antihypertensive combination regimens: Kaliuretic + Potasium sparing diuretics Beta-blockers + hydrochlorothiazide (HCTZ), Beta-blockers + Calcium channel blockers (CCB) Renin-Angiotensin System Blockers + Diuretics Renin-Angiotensin System Blockers+CCB. Less effectively: Calcium channel blockers (CCB) + Thiazid diuretics or ACEi.

15 Kaliuretic + Potassium-Sparing Diuretics The Thiazide-induced potassium deficiency is a potential cause of cardiac arrhythmias and may contribute to the development of carbohydrate intolerance and sexual impotence. There is appeal, therefore, in coadministering thiazide diuretics with a potassium- sparing diuretic (spironolactone, amiloride id or triamterene). The administration of potassium-sparing diuretics, alone or in combination, is contraindicated cated in the presence pese of renal insufficiency because of the risk of severe hyperkalaemia.

ESC-ESH Recommendations for Combining BP-lowering Drugs Diuretics Diuretics

(ARBs) -blockers Angiotensin receptor blockers (ARBs) Angiotensin-converting enzyme

channel blockers (CCBs) 2003 2007 Journal of Hypertension 2003;21:1011 53 Journal

16 ESC-ESH Recommendations for Combining BP-lowering Drugs Diuretics Diuretics -blockers Calcium channel blockers (CCBs) - blockers Angiotensin receptor blockers (ARBs) -blockers Angiotensin receptor blockers (ARBs) Angiotensin-converting enzyme (ACE) inhibitors -blockers Angiotensin-converting enzyme (ACE) inhibitors Calcium channel blockers (CCBs) Journal of Hypertension 2003;21: Journal of Hypertension 2007;25: Most rational combinations Combinations used as necessary

17 βeta-blockers plus Diuretics : During the last few years, b-blockers have lost a lot of their attraction as first choice agents in the treatment of hypertension, in particular because of an increased risk of stroke compared with other antihypertensive drugs. An increased cardiovascular mortality emerged in a meta-analysis comparing atenolol with other anti-hypertensives led the experts in the UK to withdraw beta blockers as a valuable option not only as initial, but also as add-on therapy.

18 βeta-blockers plus Diuretics : In two trials, the incidence of new onset diabetes was increased in the b- blocker arm, in which most patients received a Thiazide diuretic in addition to atenolol, suggesting that the combination of these two types of agents is particularly deleterious on insulin sensitivity. ii i The clinical benefits expected from the BP-lowering of beta-blockers may also be attenuated because these agents are not as effective as other antihypertensives t i in reducing central BP.

19 βeta-blockers plus Diuretics : In addition, b-adrenoceptor blockade may have a negative impact on global cardiovascular risk by reducing the concentration of circulating high-density lipoprotein cholesterol. These concerns probably apply to all traditional β-blockers, k but further research is warranted to assess whether they also apply to the newer vasodilating β-blockers e.g. Nebivolol.

20 βeta-blockers plus calcium channel blockers Non-dihydropyridine CCB s, such as verapamil and diltiazem, should be avoided in combination with β- blockers due to the risk of symptomatic bradycardia and atrioventricular block. Dihydropyridine CCB s have however been shown to be effective with β -blockersand are another therapeutic option in low-dose combination. β-blockers suppress renin secretion which potentiates the vasodilatory properties of CCB s and this theoretical advantage is supported by data combining felodipine plus metoprolol. Combination of a dihydropyridine such as nifedipine- with a rapid onset and short duration of effect- with a slower onset, longer lasting β-blocker like atenolol may not give optimal combined responses over the dose interval.

21 Renin-Angiotensin System Blockers+ Diuretics There is a strong rationale for coadministering an ACE inhibitor or an ARB with a diuretic i.the diuretic-induced i i d d decrease in total body sodium triggers the release of renin and the generation of angiotensin II. The diuretic-induced secondary aldosteronism is blunted during ACE inhibitor or ARB therapy, which contributes to preserve a normal potassium balance. Furthermore, the uricosuric effect of the ARB losartan offsets the thiazide induced hyperuricaemia. Mounting evidence suggests that t hyperuricaemia i is an independent d risk factor for cardiovascular and renal diseases.

22 Renin-Angiotensin System Blockers+ Diuretics ACE inhibitors and ARBs, alone or in combination with thiazide diuretics, have been shown to be equivalent or even superior to other therapeutic strategies in the prevention of cardiovascular and renal diseases. The response to ARB therapy decreased markedly with age. This age-related decline in treatment response was substantially attenuated when valsartan was coadministered with HCTZ. That indicate the initial therapy with an ACE inhibitor or ARB and a thiazide diuretic may be particularly appropriate in older patients, in whom the severity of hypertension depends mainly on SBP.

23 Fig. 2. Probability of reaching a seated systolic blood pressure (SBP)<140mmHg at the end of a7 8-week treatment with irbesartan or (HCTZ) alone, or in combination.

24 Fig. 3. Predicted mean change in systolic blood pressure (BP) at completion of an 8-week treatment with valsartan alone or coadministered with hydrochlorothiazide (HCTZ), as a function of age.the patients had stage 2 hypertension and BP responses were adjusted to a baseline systolic BP of 165mmHg.

25 HT. Renin-Angiotensin System Blockers Plus Calcium Channel Antagonists Drugs that block the renin-angiotensin system and calcium channel antagonists have both been shown to provide benefits in prospective, randomized outcome trials in hypertensive patients. Therefore, there is a strong rationale to combine these two types of agents.it is most likely that interest in this type of drug combination will grow Considerably in the coming years because of the recent publication of the ACCOMPLISH Trail.

26 The ACCOMPLISH Trial Two fixed-dose combinations used as first-line therapy have been compared very recently in a randomized, double-blind, blind, morbidity-mortality mortality trial (ACCOMPLISH) including hypertensive patients with high cardiovascular risk. The ACCOMPLISH trial was prematurely terminated by the data and safety monitoring committee after a mean follow-up of 36 months. The main finding was a relative risk reduction of 20% (p<0.001) afforded by the benazepril/ amlodipine treatment with respect to the primary composite endpoint, which consisted of a composite of fatal and non-fatal events from cardiovascular causes.

27 The ACCOMPLISH Trial The two drug regimens were equally well tolerated, except for peripheral oedema, which was encountered more frequently in the benazepril/ amlodipine group (31.3%) than in the benazepril/hctz group (13.4%), and dizziness, which was experienced more often when the ACE inhibitor was combined with HCTZ (25.4%) than with amlodipine (20.7%). The observations made in the ACCOMPLISH trial are important. It appears that combining a reninangiotensin system blocker with a long-acting calcium channel antagonist rather than with a diuretic is particularly beneficial in preventing complications such as myocardial infarction and coronary revascularization, which is not really surprising considering the known salutary effects of calcium channel antagonists in patients with coronary heart disease.

28 Fixed-Dose Combinations in HT.

29 Fixed-Dose Combinations in HT.

30 The Use of Fixed-Dose Combinations to Treat High-Risk Hypertensive Patients Treatment strategies should integrate the management of all risk factors. High-risk hypertensive patients should be aggressively treated to lower BP, if possible to below 130/80mmHg. Notably, BP control is more difficult to achieve as global cardiovascular risk increases, requiring the use of two or more antihypertensive agents in most patients. ACE inhibitors and ARBs are indicated in almost all these conditions, with calcium channel antagonists being complem- entary in the conditions not covered by ACE inhibitors and ARBs. Therefore, there is a very strong rationale to combine these two classes of antihypertensive agents to treat high-risk hypertensive patients. The coadministration of an ACE inhibitor or ARB and a thiazide diuretic is also attractive, mainly because of the resulting gain in antihypertensive efficacy.

31 Conclusions A large portion of hypertensive patients are at high cardiovascular risk because of the coexistence of increased BP with other risk factors, target organ damage and/or associated clinical conditions. Such patients require strict BP control, which usually necessitates therapy with multiple antihypertensives. The use of fixed-dose combinations for the management of hypertension appears particularly l appealing in high-risk h i hypertensive.

32 Conclusions However, the need still exists to individualize therapy in such patients. In a given patient, this could be achieved with an ACE inhibitor or ARB coadministered with a calcium channel antagonist, but in another patient by an ACE inhibitor or ARB combined with a diuretic.

Hypertension. Does it Matter What Medications We Use? Nishant K. Sekaran, M.D. M.Sc. Intermountain Heart Institute

Hypertension. Does it Matter What Medications We Use? Nishant K. Sekaran, M.D. M.Sc. Intermountain Heart Institute Hypertension Does it Matter What Medications We Use? Nishant K. Sekaran, M.D. M.Sc. Intermountain Heart Institute Hypertension 2017 Classification BP Category Systolic Diastolic Normal 120 and 80 Elevated