Epidemiology and treatment of hypertension Note the first part of this presentation on risk-based assessment of BP treatment has been provided by Professor Rod Jackson, Head of Division of Community Health Faculty of Medical & Health Sciences University of Auckland

Part 1 n Defining ‘hypertension’ and making decisions based on cardiovascular risk

Argument 1. There is no clinically relevant entity that can be defined by a mildly raised blood pressure. 2. A mildly raised blood pressure level is not a major determinant of which patients benefit from blood pressure lowering

what is mild hypertension?

SBP (mmHg) Systolic blood pressure distribution: Framingham Study participants years top x%??

??

??

Definitions of mild hypertension & prevalence

?? ≥130/80

what is mild hypertension? n it’s the wrong question

who benefits from blood pressure lowering?

Meta-analysis of RCTs of BP lowering drugs: 15,559 patients, SBP diff 17 mmHg, DBP diff 9 mmHg, follow-up 4.1 years (≥ 60 years) Endpoint Odds ratio (Relative risk red.) Stroke morbidity 35 % Stroke mortality 36 % CHD mortality 25 % CHD morbidity 15 % Insua et al Ann Intern Med 1994;121:355-62

Stroke and blood pressure lowering: subgroup analysis from 17 RCTs Trial % Events Relative risk red. group control treatment Some ≥ 110, 6.5 % 4.6 %32 % all ≤ 115 All entry 2.2 % 1.3 %39% DBP < MacMahon & Rogers J Vasc Med Biol 1993;4: Some or all 8.2 % 4.7 %45 % ≥ 115

Stroke and blood pressure lowering: subgroup analysis from 17 RCTs Trial % Events Odds ratio (Relative risk red.) group control treatment Older 7.0 % 4.6 %34 % patients Younger 2.3 % 1.3 %43 % patients º prev. 3.2 % 2.0 %38 % 2º prev % 18.8 %38 % MacMahon & Rogers J Vasc Med Biol 1993;4:265-71

Stroke and blood pressure lowering: subgroup analysis from 17 RCTs Trial % Events Odds ratio (Relative risk red.) group control treatment Older 7.0 % 4.6 %34 % patients Younger 2.3 % 1.3 %43 % patients º prev. 3.2 % 2.0 %38 % 2º prev % 18.8 %38 % MacMahon & Rogers J Vasc Med Biol 1993;4: % 2.4% 1.2% 8.5%

which patients should be treated? n “individual treatment can only be justified if there is individual benefit” n “only absolute benefits are relevant to patients”

PSC Lancet 1995;346: (45 prospective studies: 450,000 people 13,000 events)

PSC Lancet 1995;346:

SBP high chol gluc intol cigarettes LVH CVD risk per 1000 in 8 years Absolute risk of CVD risk in 40 year old men by SBP and other risk factors, Framingham, USA

/ /95 140/85 120/75 180/ /95 140/85 120/75 180/ /95 140/85 120/75 180/ /95 140/85 120/75 180/ /95 140/85 120/75 180/ /95 140/85 120/75 180/ /95 140/85 120/75 180/ /95 140/85 120/ NonsmokerSmokerNonsmokerSmoker WOMEN AGE 70 AGE 50 AGE 40 DiabetesNoDiabetes Ratio of Total Cholesterol:HDL AGE 60

/ /95 140/85 120/75 180/ /95 140/85 120/ NonsmokerSmokerNonsmokerSmoker AGE 70 DiabetesNoDiabetes Ratio of Total Cholesterol:HDL

CVD risk & NNTs 5yr CVD risk5 yr NNT* > 30%< % % * assumes 33% RRR

50 yr old woman BP 160/95 mmHg non smoker TC 240 mg/dl HDLC 62 mg/dl BMI 25 no Hx CVD 60 yr old man BP 148/ 88 mmHg smoker TC 240 mg/dl HDLC 38 mg/dl BMI 25 no Hx CVD is BP lowering therapy indicated ?

50 yr old woman BP 160/95 mmHg non smoker TC 240 mg/dl HDLC 62 mg/dl 60 yr old man BP 148/ 88 mmHg smoker TC 240 mg/dl HDLC 38 mg/dl is BP lowering therapy indicated ? 5 yr absolute CVD risk: 4% 5 yr NNT: 72 5 yr absolute CVD risk: 24% 5 yr NNT: 12

50/60 yr old woman non smoker TC 240 mmol/L HDLC 60 mmol/L No diabetes SBP mmHg: yr NNT:90 / 5070 / 4260 / 37

To treat or not to treat “mild hypertension” “treat risk not blood pressure” “only absolute risks and benefits are relevant to patients” “the payer should choose the threshold”

Part 2 Pharmacological considerations in hypertension management Sue Hill and David Henry Discipline of Clinical Pharmacology

Factors that influence blood pressure n sympathetic nervous system n total peripheral resistance –mainly arterioles n intravascular volume (renin- angiotensin) –renal excretion n atheroma, thrombosis

things that alter vascular resistance n vascular smooth muscle –mediators from sympathetic nerves and vascular endothelium –calcium dependent –contraction due to  intracellular calcium –relaxation due to  calcium entry or  cGMP, cAMP n depends on intact endothelium n complex, interdependent biochemical reactions

drugs that will reduce vascular resistance n nitric oxide, nitrates n  - antagonists n  - antagonists n Calcium channel blockers n angiotensin II antagonsists n (lots more)

other mechanisms to remember n central control - –methyldopa, ganglion blocking drugs n renal excretion of sodium and water –diuretics, spironolactone

drugs we use for hypertension n  - blockers n thiazide diuretics n Calcium channel blockers n angiotensin converting enzyme inhibitors n ( others - alphamethyldopa, reserpine, hydralazine, prazosin )

thiazide diuretics n ACTION: increase sodium and water excretion by decreasing reabsorption of sodium and chloride in the distal tubule (later effect on vessels) n EFFECT lowers blood pressure- over several days decreases complications, morbidity and mortality ( good clinical trials) n Side effects: –metabolic effects: diabetes, gout, low Na, K, impotence

 - adrenoceptor antagonists n ACTION: –effects on heart (  1 ) and smooth muscle (  2 ) via noradrenaline –lowers BP: reduces cardiac output reduces renin release reduces central sympathetic activity effect on pre-synaptic noradrenaline release –nonselective antagonist = propranolol –relatively selective  1 = metoprolol, atenolol –mixed agonist/antagonist - oxprenolol

 - adrenoceptor antagonists n EFFECT lowers blood pressure - over several days decreases complications, mortality and morbidity (good clinical trials) n SIDE EEFECTS –bronchospasm, fatigue, bad dreams, cold extremities –worsening cardiac failure, heart block –hypoglyacaemia

ACE-inhibitors n ACTION –inhibits conversion of angiotensin I to angiotensin II - effects on vasculature in kidney, brain, heart –vasodilator –eg: captopril, enalapril, lisinopril, ramipril n EFFECTS –lower blood pressure- relatively rapidly –effect on mortality, morbidity and complications?? –Reduces mortality in cardiac failure, post-AMI; good clinical trials

ACE-inhibitors n SIDE EFFECTS: –cough, rash, taste disturbances –renal failure, neutropenia, proteinuria n COST –relatively expensive

Angiotensin II antagonists n losarten, ibersarten, candesarten n actions similar to ACE inhibitors n effects – lower blood pressure- relatively rapidly –effects on clinical outcomes? n Side effects: –rash, cough n cost: expensive

calcium antagonists n ACTION: –three classes: verapamil, dihydropyridines, benzothiazepines –block calcium entry into cells by preventing opening of voltage gated calcium channels –act on heart and smooth muscle, depending on type –vasodilator effect (mainly dihydropyridines) –two forms - immediate and slow release n EFFECTS –lower blood pressure - can be rapid –mortality, morbidity, complications??

Calcium antagonists n SIDE EFFECTS –flushing, headache, ankle swelling, constipation –heart block, worsening cardiac failure

choices n BENEFITS –short-term –long term n RISKS –side-effects –lack of beneficial effect ( unnecessary medication)

issues n Preventive versus curative treatment n need for joint decision making n use of drugs with clinical effects versus elegant pharmacologically active molecules n benefits versus risks!!

terms n agonist, partial agonist n receptor n antagonist, competitive antagonist n ligand n affinity n mediators n tolerance