1	"Prof." Prof. Esther Paran Hypertension Unit and Research Laboratory Soroka University Hospital Ben-Gurion University
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3	Fixed combination האם זה טוב?
4	Algorithm for Treatment of Hypertension
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10	Failure of Single-Drug Regimen Most drugs only reduce SBP 7~13 mmHg DBP 4~8 mmHg
11	Patients reaching BP goals
12	Physicians consistently overestimate the control rate
13	Monotherapy versus Combination Therapy Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number of hypertensive patients Use of more than one agent is necessary to achieve target BP in the majority of patients. A vast array of effective and well tolerated combinations is available Monotherapy could be the initial treatment for a mild BP elevation with a low or moderate total CV risk. A combination of two drugs at low doses should be preferred as first step treatment when initial BP is in the grade 2 or 3 range or total CVrisk is high or very high
14	Monotherapy versus Combination Therapy Fixed combination of two drugs can simplify treatment schedule and favour compliance In several patients BP control is not achieved by two drugs and a combination of three of more drugs is required In uncomplicated hypertensives and in the elderly, antihypertensive therapy should normally be initiated gradually. In high risk hypertensives, goal blood pressure should be achieved more promptly, which favours initial combination therapy and quicker adjustment of doses
15	Possible combinations between some classes of antihypertensive drugs
16	Combination Therapies b-adrenergic blockers and diuretics ACE inhibitors and diuretics Angiotensin II receptor antagonists (ARBs) and diuretics Calcium antagonists and ACE inhibitors Calcium antagonists and ARBs Renin inhibitors and diuretics
17	Choice of Antihypertensive Drugs The main benefits of antihypertensive therapy are due to lowering of BP per se
18	Treatment of Hypertension Classic “First Line” Drug Groups Angiotensin Converting Enzyme Inhibitors [ACEi] Angiotensin II Receptor Blockers [ARB] Beta-adrenergic Receptor Blockers [BB] Calcium Channel Blockers [CCB] Diuretics – Thiazide type [HCTZ]
19	Combination treatment האם יש צורך בצרופי תרופות? האם צריך להתחיל טיפול, fixed combination ? האם הצרוף יעיל יותר מכל מרכיביו? האם ACE&HCTZ מהווה צרוף היעיל ? האם ACE&CCB מהווה צרוף היעיל ? יש עדיפות לאחד הצירופים?
20	ACEIs and ARBs Yield Reduction in Cardiovascular Morbidity and Mortality
21	Key benefits adding HCTZ to ACE -I Increased effectiveness without decreased tolerability Very high response rate Reliable blood pressure control for 24 hours with a simple dosing regimen (single daily dose) No negative metabolic effects Alleviation of diuretic-induced hypokalemia
22	Combination Drug Therapy In Hypertension
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24	Blood pressure lowering efficacy of angiotensin receptor blockers for primary hypertension
25	ACE or ARB & Diuretics
26	Combination treatment האם יש צורך בצרופי תרופות? האם צריך להתחיל טיפול, fixed combination ? האם הצרוף יעיל יותר מכל מרכיביו? האם ACE&HCTZ מהווה צרוף היעיל ? האם ACE&CCB מהווה צרוף היעיל ? יש עדיפות לאחד הצירופים?
27	Combination of ACE&CCB לפני הדיון בצירוף, נדון במרכיבים: ACE כבר הזכרנו CCBs הם המרכיב החדש בצירוף מה תרומתם?
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39	Literature
40	"The amlodipine group showed a..." The amlodipine group showed a significant decrease in IMT compared to the ARB group (0.046 [S.E. 0.161] mm vs. 0.080 [S.E. 0.255] mm, P < 0.05). These results suggest that amlodipine has an inhibitory effect on early atherosclerotic process, ARBs do not have any effect on IMT in hypertensive patients with type 2 diabetes.
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51	Combination treatment האם יש צורך בצרופי תרופות? האם צריך להתחיל טיפול, fixed combination ? האם הצרוף יעיל יותר מכל מרכיביו? האם ACE&HCTZ מהווה צרוף היעיל ? האם ACE&CCB מהווה צרוף היעיל ? יש עדיפות לאחד הצירופים?
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53	Fatal and non-fatal stroke
54	Unstable angina
55	New-onset diabetes mellitus
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58	The ACCOMPLISH Trial
59	Avoiding Cardiovascular Events through COMbination Therapy in Patients LIving with Systolic Hypertension
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61	ACCOMPLISH: Design
62	ACCOMPLISH: Effect of Initial Combination Therapy on SBP Over Time
63	ACCOMPLISH: Exceptional Control Rates with Initial Combination Therapy
64	Systolic Blood Pressure Over Time
65	Kaplan Meier for Primary Endpoint
66	Primary and Other Endpoints
67	"In this trial," In this trial, benazepril plus amlodipine produced better outcomes than did benazepril plus hydrochlorothiazide, despite similar efficacy in reducing blood pressure. These findings challenge the preference for thiazide diuretics contained in recommendations from some organizations, as well as the notion that all thiazide diuretics are the same. The author of a related editorial does not endorse a particular strategy. This study engender some controversy about the best approach to hypertension control in high-risk patients.
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69	Conclusion האם יש עוררים על המסקנות של ACOMPLISH או היתרון של ברור? ACE/CCB
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71	Putting ACCOMPLISH study into perspective Both benazepril and HCTZ are not true once daily drugs Amlodipine is one of the longest-acting antihypertensive agents Most of the clinical evidence supporting diuretics based on studies using chlorothalidone HCTZ is the most commonly subscribed diuretic and available in most of the fixed combinations Chlorothalidone and HCTZ differ in potency and in the duration of action
72	Putting ACCOMPLISH study into perspective Chlorothalidone half life is 38-50 h vs 8-15 h in HCTZ Which raises questions about differences between the groups regarding nighttime BP control In studies as ALLHAT and SHEP chlorothalidone was used as effective monotherapy in dose of 12.5-25 mg to achieve BP reduction > 15 mmHg Similar reduction of BP require 25 mg HCTZ Probably we are using too low doses of HCTZ??
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74	תודה על תשומת הלב