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Implications of ASCOT Results for ALLHAT Conclusions

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Implications of ASCOT Results for ALLHAT Conclusions

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    1. 1 Implications of ASCOT Results for ALLHAT Conclusions

    2. 2 Overall Implications ASCOT was not a comparison of initial treatment with newer drugs versus thiazide diuretic-based treatment—therefore, no change in ALLHAT conclusions. Differences in fatal/non-fatal events largely due to lesser BP reduction with ß-blocker-based regimen.

    3. 3 ASCOT Aim To compare a treatment regimen of newer antihypertensive drugs (CCB ? ACEI) with a traditional regimen (ß-blocker ? diuretic) for primary prevention of CHD.

    4. 4 ASCOT Design Prospective, randomized, open-label, blinded endpoint (PROBE) Randomization to CCB or ß-blocker Add-on drugs ACEI (CCB arm) or diuretic (ß-blocker arm) Primary endpoint: Nonfatal MI + fatal CHD 19,257 participants Mean follow-up: 5.4 years

    5. 5 ASCOT Inclusions Blood pressure: Screening and baseline SBP =160 and/or DBP =100 mm Hg untreated, or Baseline SBP =140 and/or DBP = 90 mm Hg following treatment with 1 or more drugs Age 40-79 years No previous MI or current clinical CHD 3 or more risk factors for a future CV event

    6. 6 ASCOT Exclusions Previous MI Currently treated angina CVA within 3 months Fasting TG >400 mg/dl Heart failure Uncontrolled arrhythmias Clinically important hematological or biochemical abnormality on routine screening

    7. 7 ASCOT Outcomes No significant difference in primary CHD outcome. Stopped early due to reduction in total mortality in amlodipine-based treatment arm. Final result 11% reduction in total mortality, p=0.02

    8. 8 ASCOT Secondary Outcomes CV mortality reduced 24%, p=0.001 Total coronary events reduced 13%, p=0.007 fatal CHD + non-fatal MI (symptomatic and silent) + chronic stable angina + unstable angina + fatal and non-fatal heart failure Stroke reduced 23%, p=0.0003 CV events/procedures reduced 16%, p<0.0001 Fatal & nonfatal HF non-significantly lower by 16% (p=0.13)

    9. 9 Other ASCOT Results 2nd step medications: 58% of amlodipine person-yrs on perindopril 66% of atenolol person-yrs on bendroflumethiazide 2.7 mm Hg mean SBP difference favoring amlodipine (5.9 mm Hg at 3 months) HDL lower and TG higher in ß-blocker arm New onset DM reduced 30% with amlodipine, p<0.0001 (absolute difference 5 per 1000 person-years) 98.5% of participants with complete information at end of trial FROM THE ASCOT FINAL PAPER: At the final visit, patients on the amlodipine-based regimen had significantly higher mean pulse rate (11ˇ2 bpm [SD 12ˇ2]; p0ˇ0001) and HDL-cholesterol (0ˇ1 mmol/L [0ˇ4]; p0ˇ0001), and significantly lower BMI (0ˇ3 kg/m2 [4ˇ9]; p=0ˇ0001), triglycerides (0ˇ3 mmol/L [1ˇ0]; p0ˇ0001), serum creatinine (5ˇ3 mol/L [26ˇ2]; p0ˇ0001), and glucose (0ˇ20 mmol/L [2ˇ08]; p0ˇ0001) than did those on the atenolol-based regimen. There were no significant differences in either LDL-cholesterol or total-cholesterol concentrations. The primary endpoint At the final visit, patients on the amlodipine-based regimen had significantly higher mean pulse rate (11ˇ2 bpm [SD 12ˇ2]; p0ˇ0001) and HDL-cholesterol (0ˇ1 mmol/L [0ˇ4]; p0ˇ0001), and significantly lower BMI (0ˇ3 kg/m2 [4ˇ9]; p=0ˇ0001), triglycerides (0ˇ3 mmol/L [1ˇ0]; p0ˇ0001), serum creatinine (5ˇ3 mol/L [26ˇ2]; p0ˇ0001), and glucose (0ˇ20 mmol/L [2ˇ08]; p0ˇ0001) than did those on the atenolol-based regimen. There were no significant differences in either LDL-cholesterol or total-cholesterol concentrations. FROM THE ASCOT FINAL PAPER: At the final visit, patients on the amlodipine-based regimen had significantly higher mean pulse rate (11ˇ2 bpm [SD 12ˇ2]; p0ˇ0001) and HDL-cholesterol (0ˇ1 mmol/L [0ˇ4]; p0ˇ0001), and significantly lower BMI (0ˇ3 kg/m2 [4ˇ9]; p=0ˇ0001), triglycerides (0ˇ3 mmol/L [1ˇ0]; p0ˇ0001), serum creatinine (5ˇ3 mol/L [26ˇ2]; p0ˇ0001), and glucose (0ˇ20 mmol/L [2ˇ08]; p0ˇ0001) than did those on the atenolol-based regimen. There were no significant differences in either LDL-cholesterol or total-cholesterol concentrations. The primary endpoint At the final visit, patients on the amlodipine-based regimen had significantly higher mean pulse rate (11ˇ2 bpm [SD 12ˇ2]; p0ˇ0001) and HDL-cholesterol (0ˇ1 mmol/L [0ˇ4]; p0ˇ0001), and significantly lower BMI (0ˇ3 kg/m2 [4ˇ9]; p=0ˇ0001), triglycerides (0ˇ3 mmol/L [1ˇ0]; p0ˇ0001), serum creatinine (5ˇ3 mol/L [26ˇ2]; p0ˇ0001), and glucose (0ˇ20 mmol/L [2ˇ08]; p0ˇ0001) than did those on the atenolol-based regimen. There were no significant differences in either LDL-cholesterol or total-cholesterol concentrations.

    10. 10 ASCOT Conclusion Amlodipine-based therapy confers an advantage over atenolol-based therapy on some major CV end points, all-cause mortality and new-onset diabetes.

    11. 11 ASCOT vs ALLHAT

    12. 12 ASCOT Atenolol-based regimen inferior to amlodipine-based regimen. ß-blockers are also inferior to ARBs based on the LIFE study.1 ß-blockers are also inferior to diuretics for CHD, especially in this age group.2 Reminder - In ASCOT, different add-on drugs in the two arms make comparison of initial agent difficult Reminder - In ASCOT, different add-on drugs in the two arms make comparison of initial agent difficult

    13. 13 ALLHAT Results Compared amlodipine vs chlorthalidone Add-on drugs and achieved BP were similar No difference in CHD outcome or stroke 1/3 higher rates of HF with amlodipine

    14. 14 Comments - Design PROBE (open-label) design ? bias? Even for total mortality, concomitant interventions can introduce confounding, and were not reported. Randomization not to newer vs older drugs but to CCB vs ß-blocker with ACEI & diuretic as step-up.

    15. 15 Comments - Endpoints CV endpoints in ASCOT include soft outcomes (e.g., chronic stable angina, revascularization, PVD, etc.). Reporting was not blinded How might have amlodipine’s anti-anginal properties affected the results? No difference in major CHD Difference for total coronary events

    16. 16 Comments - Conclusions ß-blocker should not be used as initial therapy in uncomplicated hypertension. Inferior to ARB in LIFE, inferior to CCB in ASCOT, and inferior to diuretic in MRC in Elderly ß-blocker inferior to thiazide diuretic in meta-analysis (Psaty BM, Lumley T, Furberg CD, et al. JAMA. 2003;289:2534-2544.)

    17. 17 Conclusions from new meta-analysis of beta-blocker trials

    18. 18 Comments - Conclusions Amlodipine has shown comparable CVD reduction vs diuretic except for HF (ALLHAT, others). Amlodipine superior to ACEI in ALLHAT for stroke and combined CVD (especially in Blacks and women), and inferior for HF. Amlodipine superior to ARB for fatal and nonfatal MI (VALUE).

    19. 19 Dose of Thiazide-type Diuretic in ASCOT Dose of thiazide-type diuretic used (BFMZ 1.25-2.5 mg/day) was lower than that in any positive CVD outcome trial. MRC trial of treatment of mild HTN: BFMZ dosage was 10 mg daily. Evidence evaluating benefit of such thiazide-type diuretic doses (equivalent to 12.5 mg/day or less of HCTZ) on clinical outcomes is not available.

    20. 20 Comments - Unknowns Because study population mostly white men, application to women and Black patients is unknown. Although potassium supplements routinely given with diuretic, adequacy of treatment for hypokalemia not reported.

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