Cardiovascular Outcomes in Hypertensives with CHD Randomized to Amlodipine versus Lisinopril in ALLHAT Frans Leenen MD, PhD, Chuke Nwachuku MA, MPH, Dr.

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Cardiovascular Outcomes in Hypertensives with CHD Randomized to Amlodipine versus Lisinopril in ALLHAT Frans Leenen MD, PhD, Chuke Nwachuku MA, MPH, Dr PH, William Cushman MD, Henry Black MD, Lara Simpson MS, Barry Davis MD, PhD. For the ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung and Blood Institute (NHLBI) in collaboration with the Department of Veterans Affairs U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute ALLHAT

Background ALLHAT * In the 90’s several mainly observational studies reported unfavorable cardiovascular outcomes on therapy with DHP-CCB’s in patients with CHD. * Placebo-controlled RCT’s such as HOPE or EUROPA (but not PEACE) concluded that (hypertensive) patients with CHD show benefits from ACE-inhibitor therapy beyond that expected from BP lowering per se. on the other hand:

Objective of Present Post-Hoc Analysis ALLHAT Comparison of cardiovascular and other outcomes among 18,102 patients with or without CHD at baseline randomized to the ACE-inhibitor lisinopril or the DHP-CCB amlodipine.

42,418 high-risk hypertensive patients 90% previously treated 10% untreated STEP 1 AGENTS Chlorthalidone mg Amlodipine mg Lisinopril mg Doxazosin 1-8 mg N=15,255 N=9,048 N=9,054 N=9,061 STEP 2 AND 3 AGENTS (5 years) Atenolol 28.0% Clonidine 10.6% Reserpine 4.3% Hydralazine 10.9% Hypertension Trial ALLHAT

CHD at Baseline ALLHAT “known prior MI, angina, primary cardiac arrest, coronary artery stenosis >50%, reversible perfusion defect, or major coronary revascularization procedure”

Baseline Characteristics by CHD at Baseline CHD at BaselineNo CHD at Baseline Aml (n=2202) Lis (n=2270) Aml (n=6777) Lis (n=6715) SBP/DBP, mean145/83146/83147/84 Age in yrs, mean On antihypertensive meds (%) Type 2 diabetes (%) Cigarette smoker (%) Female (%) Blacks (%)24 39 On aspirin (%) ALLHAT

Y Y2Y4Y1BL Mean # of Meds: AmlodipineCHD at BL No CHD at BL LisinoprilCHD at BL No CHD at BL mmHg BP Δ =1.1 Δ =1.5 Δ =1.0Δ = Amlodipine - CHD at BL Amlodipine - No CHD at BL Lisinopril - CHD at BL Lisinopril - No CHD at BL mmHg BP Δ =1.5 Δ =0.8 Δ =1.8 Δ =1.2 Baseline and Follow-up BPs by CHD at BL ALLHAT

Events – L vs. A Relative Risk and 95% Confidence Intervals Favors Lisinopril Favors Amlodipine PAD1.19 ( ) Revascularization1.00 ( ) Angina1.09 ( ) HF0.87 ( ) GI Bleed1.20 ( ) Cancer1.01 ( ) ESRD0.99 ( ) Combined CVD1.06 ( ) Stroke1.23 ( ) Combined CHD1.04 ( ) Death1.05 ( ) CHD1.01 ( ) ALLHAT p=0.047 p=0.045

Cumulative Event Rates for Primary Endpoint by CHD at Baseline and Treatment Group ALLHAT Years to Primary Endpoint Amlodipine Lisinopril No CHD at BL Cumulative CHD Rate Years to Primary Endpoint Amlodipine Lisinopril CHD at BL RR (95%CI)P value L/A1.15 ( )0.06 RR (95%CI)P value L/A0.99 ( )0.92

Secondary Endpoints: Lisinopril versus Amlodipine ALLHAT CHD at BLNo CHD at BL RR (95% CI)P valueRR (95% CI)P value Combined CHD1.07 ( ) ( )0.64 All-Cause Mortality1.15 ( ) ( )0.78 ESRD0.92 ( ) ( )0.99

Cumulative Event Rates for Stroke by CHD at Baseline and Treatment Group ALLHAT RR (95%CI)P value L/A1.31 ( )0.04 RR (95%CI)P value L/A1.20 ( ) Years to Stroke Amlodipine Lisinopril No CHD at BL Cumulative Sstroke Rate Years to Stroke Amlodipine Lisinopril CHD at BL

Cumulative Event Rates for Heart Failure by CHD at Baseline and Treatment Group ALLHAT RR (95%CI)P value L/A0.91 ( )0.31 RR (95%CI)P value L/A0.85 ( ) Years to HF Amlodipine Lisinopril No CHD at BL Cumulative HF Rate Years to HF Amlodipine Lisinopril CHD at BL

Cumulative Event Rates for Angina by CHD at Baseline and Treatment Group ALLHAT RR (95%CI)P value L/A0.99 ( )0.87 RR (95%CI)P value L/A1.17 ( ) Years to Angina Amlodipine Lisinopril No CHD at BL Cumulative ANG Rate Years to Angina Amlodipine Lisinopril CHD at BL

Cumulative Event Rates for PAD by CHD at Baseline and Treatment Group ALLHAT RR (95%CI)P value L/A0.93 ( )0.58 RR (95%CI)P value L/A1.39 ( ) Cumulative PAD Rate Years to PAD Amlodipine Lisinopril CHD at BL Years to PAD Amlodipine Lisinopril No CHD at BL

Combined CVD ALLHAT RR (95%CI)P value L/A1.03 ( )0.54 RR (95%CI)P value L/A1.08 ( ) Cumulative CCVD Rate Years to CCVD Amlodipine Lisinopril CHD at BL Years to CCVD Amlodipine Lisinopril No CHD at BL

Summary ALLHAT Lisinoprilvs.Amlodipine CHD at baselineNo CHD at baseline CHD, mortality, ESRD similar Stroke+31%+20% HF Angina PAD -9% -1% -7% -15% +17% (p=0.07 for interaction) +39% (p=0.02 for interaction) Treated SBP levelsimilar+ 1-2 mmHg Combined CVD+3%+8%

Conclusion ALLHAT In hypertensive patients with CHD, lisinopril and amlodipine – based treatment provides equivalent BP control and equivalent rates for most outcomes. Patients with and without CHD have similar higher stroke rates and lower HF rates on lisinopril versus amlodipine. This post-hoc analysis provides no evidence for specific benefits by ACE-inhibitor based treatment in patients with CHD.

Events for CHD by Race Relative Risk and 95% Confidence Intervals Revascularization Combined CVD Combined CHD Non-Blacks Favors Lisinopril Favors Amlodipine PAD0.98 ( ) 1.00 ( ) Angina0.99 ( ) HF0.90 ( ) GI Bleed1.00 ( ) Cancer1.03 ( ) ESRD 0.65 ( ) 1.03 ( ) Stroke1.20 ( ) 1.07 ( ) Death1.15 ( ) CHD1.08 ( ) Blacks Favors Lisinopril Favors Amlodipine ( ) 1.17 ( ) 0.98 ( ) 0.95 ( ) 1.20 ( ) 0.92 ( ) 1.72 ( ) 1.02 ( ) 1.63 ( ) 1.06 ( ) 1.14 ( ) 0.95 ( ) ALLHAT

Non-Blacks Favors Lisinopril Favors Amlodipine PAD1.35 ( ) Revascularization0.95 ( ) Angina1.12 ( ) HF0.83 ( ) GI Bleed1.27 ( ) Cancer0.95 ( ) ESRD0.97 ( ) Combined CVD1.02 ( ) Stroke1.00 ( ) Combined CHD0.97 ( ) Death0.96 ( ) CHD0.91 ( ) Blacks Favors Lisinopril Favors Amlodipine ( ) 1.08 ( ) 1.24 ( ) 0.87 ( ) 1.30 ( ) 1.10 ( ) 1.03 ( ) 1.16 ( ) 1.48 ( ) 1.14 ( ) 1.08 ( ) 1.17 ( ) Events for No CHD by Race Relative Risk and 95% Confidence Intervals ALLHAT

Events for Non-Blacks by CHD Status Relative Risk and 95% Confidence Intervals

ALLHAT Events for Blacks by CHD Status Relative Risk and 95% Confidence Intervals

Outcomes L vs. A: RR and 95% Confidence Intervals CHD at Baseline Favors Lisinopril Favors Amlodipine PAD 0.93 ( ) Revascularization 1.03 ( ) Angina 0.99 ( ) HF 0.91 ( ) GI Bleed 1.05 ( ) Cancer 1.01 ( ) ESRD 0.92 ( ) Combined CVD 1.03 ( ) Stroke 1.31 ( ) Combined CHD 1.07 ( ) Death 1.15 ( ) CHD 1.05 ( ) No CHD at Baseline Favors Lisinopril Favors Amlodipine ( ) 0.98 ( ) 1.17 ( ) 0.85 ( ) 1.28 ( ) 1.01 ( ) 1.00 ( ) 1.07 ( ) 1.20 ( ) 1.02 ( ) 1.01 ( ) 0.99 ( ) ALLHAT

Outcomes A vs. C: RR and 95% Confidence Intervals No CHD at Baseline Favors Amlodipine Favors Chlorthalidone ( ) 1.08 ( ) 0.99 ( ) 1.48 ( ) 0.88 ( ) 1.06 ( ) 1.23 ( ) 1.05 ( ) 0.96 ( ) 1.02 ( ) 0.99 ( ) 1.01 ( ) CHD at Baseline Favors Amlodipine Favors Chlorthalidone PAD 1.04 ( ) Revascularization 1.16 ( ) Angina 1.10 ( ) HF 1.29 ( ) GI Bleed 1.00 ( ) Cancer 0.92 ( ) ESRD 0.88 ( ) Combined CVD 1.07 ( ) Stroke 0.90 ( ) Combined CHD 1.02 ( ) Death 0.89 ( ) CHD 0.95 ( ) ALLHAT

Outcomes A vs. C in Blacks: RR and 95% Confidence Intervals CHD at Baseline in Blacks Favors Amlodipine Favors Chlorthalidone PAD 1.18 ( ) Revascularization 1.37 ( ) Angina 1.08 ( ) HF 1.47 ( ) GI Bleed 0.94 ( ) Cancer 1.07 ( ) ESRD 0.70 ( ) Combined CVD 1.16 ( ) Stroke 0.89 ( ) Combined CHD 1.19 ( ) Death 0.96 ( ) CHD 1.19 ( ) No CHD at Baseline in Blacks Favors Amlodipine Favors Chlorthalidone ( ) 0.97 ( ) 1.10 ( ) 1.53 ( ) 1.01 ( ) 0.95 ( ) 1.27 ( ) 1.05 ( ) 0.96 ( ) 1.00 ( ) 0.99 ( ) 0.95 ( ) ALLHAT

Outcomes A vs. C in Non-Blacks: RR and 95% Confidence Intervals CHD at Baseline in Non-Blacks Favors Amlodipine Favors Chlorthalidone PAD1.00 ( ) Revascularization1.12 ( ) Angina1.11 ( ) HF1.24 ( ) GI Bleed1.03 ( ) Cancer0.87 ( ) ESRD1.96 ( ) Combined CVD1.04 ( ) Stroke0.90( ) Combined CHD0.98 ( ) Death0.87 ( ) CHD0.89 ( ) No CHD at Baseline in Non-Blacks Favors Amlodipine Favors Chlorthalidone ( ) 1.12 ( ) 0.94 ( ) 1.44 ( ) 0.80 ( ) 1.13 ( ) 1.18 ( ) 1.05 ( ) 0.95 ( ) 1.02 ( ) 0.99 ( ) 1.04 ( ) ALLHAT

Outcomes L vs. C: RR and 95% Confidence Intervals No CHD at Baseline Favors Lisinopril Favors Chlorthalidone ( ) 1.06 ( ) 1.16 ( ) 1.25 ( ) 1.13 ( ) 1.06 ( ) 1.23 ( ) 1.12 ( ) 1.15 ( ) 1.04 ( ) 1.01 ( ) 1.00 ( ) CHD at Baseline Favors Lisinopril Favors Chlorthalidone PAD 0.96 ( ) Revascularization 1.18 ( ) Angina 1.09 ( ) HF 1.18 ( ) GI Bleed 1.06 ( ) Cancer 0.93 ( ) ESRD 0.80 ( ) Combined CVD 1.10 ( ) Stroke 1.17 ( ) Combined CHD 1.09 ( ) Death 1.02 ( ) CHD 1.00 ( ) ALLHAT

Outcomes L vs. C in Blacks: RR and 95% Confidence Intervals CHD at Baseline in Blacks Favors Lisinopril Favors Chlorthalidone PAD 0.90 ( ) Revascularization 1.59( ) Angina 1.06 ( ) HF 1.39 ( ) GI Bleed 1.13 ( Cancer 1.00 ( ) ESRD 1.21 ( ) Combined CVD 1.18 ( ) Stroke 1.45 ( ) Combined CHD 1.26 ( ) Death 1.10 ( ) CHD 1.14 ( ) No CHD at Baseline in Blacks Favors Lisinopril Favors Chlorthalidone ( ) 1.05 ( ) 1.37 ( ) 1.34 ( ) 1.32 ( ) 1.04 ( ) 1.30 ( ) 1.22 ( ) 1.43 ( ) 1.14 ( ) 1.07 ( ) 1.11 ( ) ALLHAT

Outcomes L vs. C in Non-Blacks: RR and 95% Confidence Intervals No CHD at Baseline in Non-Blacks Favors Lisinopril Favors Chlorthalidone ( ) 1.07 ( ) 1.06 ( ) 1.19 ( ) 1.02 ( ) 1.08 ( ) 1.15 ( ) 1.07 ( ) 0.95 ( ) 0.99 ( ) 0.96 ( ) 0.94 ( ) CHD at Baseline in Non-Blacks Favors Lisinopril Favors Chlorthalidone PAD0.98 ( ) Revascularization1.12 ( ) Angina1.10 ( ) HF1.12 ( ) GI Bleed1.03 ( ) Cancer0.91 ( ) ESRD 0.63 ( ) Combined CVD1.08 ( ) Stroke1.08 ( ) Combined CHD1.05 ( ) Death1.00 ( ) CHD0.97( ) ALLHAT