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Hypertension-so what has changed? Review of ASCOT and NICE Guidelines

Hypertension-so what has changed? Review of ASCOT and NICE Guidelines. Cardiovascular Study day Cheltenham Racecourse 10 th October 2006 Dr Jim Moore. ASCOT- BPLA: Rationale.

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Hypertension-so what has changed? Review of ASCOT and NICE Guidelines

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  1. Hypertension-so what has changed?Review of ASCOT and NICE Guidelines Cardiovascular Study day Cheltenham Racecourse 10th October 2006 Dr Jim Moore

  2. ASCOT- BPLA: Rationale • Insufficient outcome data on newer types of BP-lowering agents, especially in specific combination treatment regimens • Less-than-expected CHD prevention using standard therapy

  3. Patient inclusion criteria • Screening and baseline BP • 160/100 mm Hg untreated •  140/90 mm Hg following treatment with 1 or more drugs • Age 40-79 years • Primary Prevention-No previous MI or current clinical CHD •  3 CV risk factors e.g. male sex, age  55 yr, smoking [Annual CHD event rate 0.9% per year]

  4. ASCOT- BPLA Primary Objective To compare the effect on non-fatal myocardial infarction (MI) and fatal CHD of the standard antihypertensive regimen (-blocker ± diuretic) with a more contemporary regimen (CCB ± ACE inhibitor)

  5. Treatment algorithm to BP targets < 140/90 mm Hg or < 130/80 mm Hg in patients with diabetes amlodipine 5-10 mg atenolol 50-100 mg add add bendroflumethiazide-K 1.25-2.5 mg perindopril 4-8 mg add doxazosin GITS 4-8 mg add additional drugs, eg, moxonidine/spironolactone

  6. Systolic and diastolic blood pressure atenolol  thiazide amlodipine  perindopril 180 164.1 SBP 160 163.9 Mean difference 2.7 137.7 140 136.1 mm Hg 120 DBP 94.8 100 Mean difference 1.9 94.5 79.2 80 77.4 60 Last visit Baseline 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 Time (years)

  7. Primary end point: Non-fatal MI, fatal CHD % 5.0 10% Atenolol  thiazide (No. of events =474) 4.0 Amlodipine  perindopril (No. of events = 429) 3.0 Cumulative Events 2.0 HR = 0.90 (0.79­1.02)p = 0.1052 1.0 Years 0.0 0.0 1.0 2.0 3.0 4.0 5.0 Number at risk Amlodipine  perindopril 9639 9475 9337 9168 8966 7863 Atenolol  thiazide9618 9470 9290 9083 8858 7743

  8. Fatal and non-fatal stroke % 5.0 Atenolol  thiazide (No. of events 422) 23% 4.0 3.0 Cumulative Events Amlodipine  perindopril (No. of events 327) 2.0 HR = 0.77 (0.66­0.89) p = 0.0003 1.0 0.0 Years 3.0 1.0 2.0 0.0 4.0 5.0 Number at risk Amlodipine  perindopril 9639 9483 9331 9156 8972 7863 Atenolol  thiazide9618 9461 9274 9059 8843 7720

  9. Total CV events and procedures % 18.0 Atenolol  thiazide (No. of events 1602) 16% 16.0 14.0 12.0 Amlodipine  perindopril (No. of events 1362) 10.0 Cumulative Events 8.0 6.0 4.0 HR = 0.84 (0.78­0.90) p< 0.0001 2.0 0.0 Years 1.0 2.0 0.0 3.0 4.0 5.0 Number at risk Amlodipine  perindopril 9639 9277 8957 8646 8353 7207 Atenolol  thiazide9618 9210 8848 8465 8121 6977

  10. All-cause mortality % 10.0 Atenolol  thiazide (No. of events 820) 8.0 11% 6.0 Cumulative Events Amlodipine  perindopril (No. of events 738) 4.0 HR = 0.89 (0.81­0.99)p = 0.0247 2.0 0.0 Years 0.0 1.0 2.0 3.0 4.0 5.0 Number at risk Amlodipine  perindopril 9639 9544 9441 9332 9167 8078 Atenolol  thiazide9618 9532 9415 9261 9085 7975

  11. New-onset diabetes mellitus % 10.0 Atenolol  thiazide (No. of events = 799) 8.0 30% 6.0 Cumulative Events Amlodipine  perindopril (No. of events = 567) 4.0 HR = 0.70 (0.63­0.78) p < 0.0001 2.0 0.0 Years 0.0 3.0 4.0 5.0 1.0 2.0 Number at risk Amlodipine  perindopril 9639 9383 9165 8966 8726 7618 Atenolol  thiazide9618 9295 9014 8735 8455 7319

  12. Unadjusted Hazard ratio (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) Summary of all end points PrimaryNon-fatal MI (incl silent) + fatal CHD SecondaryNon-fatal MI (exc. Silent) +fatal CHD Total coronary end pointTotal CV event and proceduresAll-cause mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal heart failure TertiarySilent MI Unstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset diabetes mellitusNew-onset renal impairment Post hoc Primary end point + coronary revasc procs CV death + MI + stroke 1.00 1.45 2.00 0.50 0.70 Atenolol  thiazide better Amlodipine  perindopril better The area of the blue square is proportional to the amount of statistical information

  13. Variables which differed significantly (baseline - final visit) between treatment regimens

  14. Summary • No temporal association between BP differences and event rate differences • SMM for SBP and updated Cox regression analyses suggested BP accounted for about 15% of coronary differences and 30% of stroke differences • Full multivariate adjustment accounted for about 50% of coronary differences (mainly HDL-C differences) and 40% of stroke differences

  15. Conclusions • These analyses are compatible with the possibility that CV event differences were explained by the variables considered • BP differences unlikely single explanation • Residual differences, albeit non-significant, are large especially for stroke • ASCOT provides implications for optimal CV prevention independent of these analyses

  16. Final conclusions • Amlodipine  perindopril based therapy confers an advantage over atenolol  thiazide based therapy on all major CV end points, all-cause mortality and new-onset diabetes • Irrespective of the reasons for benefit, the amlodipine  perindopril regimen should be preferred to the standard regimen of atenolol  thiazide for most patients with hypertension • Compared with standard antihypertensive therapy without statin therapy, the amlodipine  perindopril regimen plus atorvastatin reduced coronary and stroke events by almost 50%

  17. What stops us from doing better?

  18. Why revise NICE Hypertension guideline of August 2004? • Number of trials published in 2004 or later whose data was not available for consideration : ASCOT , PHYLLIS, VALUE and JMIC-B. • Evidence from these trials raised doubts about the original NICE recommendation (2004) of using low dose thiazide as first line therapy with beta blocker added in as second line agent in hypertension. • Clinical outcomes data for drug therapy in younger patients (under 55 age group) was limited .

  19. General conclusions • Patients age and ethnicity influence their “Renin” status and thus the blood pressure lowering response to initial antihypertensive therapy • Evidence suggested that calcium channel blockers and thiazide diuretics were first line treatment most likely to confer benefit in most patients but people under 55 years old poorly represented in trials. • Combining drug therapy based on pathophysiological reasoning as lack of robust evidence if BP not controlled with single agent although most patients will require multiple drug therapy! • Change in recommendations for beta blockers . • Updated NICE/BHS treatment algorithm

  20. “New” NICE Recommendations (2006) • In hypertensives aged 55years or over or in black patients of any age,the first choice for initial therapy is a Ca channel blocker (CCB) or thiazide type diuretic. • In hypertensives younger than age 55years ,the first choice for initial therapy is an ACE inhibitor (or ARB) • If initial therapy is with a CCB or thiazide and a second drug is required then add an ACE inhibitor( or ARB).If initial therapy is with an ACE then add a CCB or thiazide. • If treatment with three drugs are reqired then use an ACE(or ARB),CCB and thiazide. • If BP uncontrolled on three drugs then consider either fourth drug and/or seek expert advice. • If a fourth drug required then consider : higher dose of thiazide or additional diuretic or beta blocker or selective alpha blocker • If blood pressure uncontrolled on adequate doses of four drugs and expert advice not already obtained ,this should now be sought.

  21. Recommendations relating to Beta-blockers • No longer recommended as first line therapy but may be considered in younger people particularly : a) if intolerant/contraindication to ACE/ARB or b) if woman of child-bearing potential or c) if patient with evidence of high sympathetic drive • Trials show clinical benefit less likely (particularly for CVA) and higher incidence of diabetes. • Most research evidence relates to atenolol but recommendations relate to ALL beta-blockers despite absence of substantial data on other drugs in this class • Compelling indications remain for IHD(post MI or symptomatic angina) • If used as first line therapy then if a second drug is required then use calcium channel blocker ( not thiazide) • Consider options in patients on thiazide /beta-blocker combination • In patients whose BP is well controlled with a regimen which includes a beta-blocker ,long term management should be considered as part of their routine review.In these patients there is no absolute need to replace the beta-blocker with an alternative agent. • When a beta-blocker is withdrawn the dose should be stepped down gradually.

  22. “High renin” hypertension Under 55 years old White/Caucasian Drugs that block the Renin-angiotensin system (A ) are more effective and ACE inhibitors (or ARB’s) should be chosen as initial therapy. “Low renin” hypertension Age 55 years or older Black(African descent) Calcium channel blockers or diuretics (C or D) are more effective and should be chosen as first line therapy Renin status and hypertension

  23. Existing NICE Recommendations(2004) • Offer anti-hypertensive drug therapy to patient with : a)Persistent raised BP of 160/100 or more b)High risk of CVD (10year CVD risk of 20% or existing CVD or Target organ damage ) with a persistent BP of greater than 140/90. • Provide patient information re treatment to allow informed choice • Offer drug therapy ,adding different drugs if necessary to achieve a target of 140/90 or until further treatment is inappropriate or declined. • Offer patients with Isolated Systolic Hypertension (ISH) same treatment as those with both raised systolic and diastolic blood pressure. • Offer patients over the age of 80 years the same treatment as those over 55 taking into account any comorbidity and any existing burden of drug use • Where possible recommend use of drugs taken only once per day • Prescribe non-proprietary drugs where appropriate to minimise prescribing costs.

  24. Thank You !

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