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Cliff Rutter 1/31/13

Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT) ALLHAT Collaborative Research Group. JAMA. 2000; 283(15):1967-75.
Background Beta blockers and diuretics were the only agents that were shown to decrease hypertension related cardiovascular disease (CVD) Newer agents had been approved to lower blood pressure but no studies examined their effects on CVD mortality and morbidity o ACE inhibitors, Alpha blockers, and calcium channel antagonists These new agents are more expensive than diuretics and beta blockers but have not demonstrated equivalent outcomes Objective To compare the effect of doxazosin with chlorthalidone on incidence of CVD in hypertensive patients Methods Patient population Inclusion criteria: o Adults > 55 years of age o Systolic BP > 140 mmHg and/or Diastolic BP > 90 mmHg OR taking medication for hypertension o Have at least 1 additional risk factor for CVD Previous MI/stroke Left ventricular hypertrophy History of type 2 diabetes Current smoking Low HDL Exclusion criteria: o Symptomatic MI/stroke within previous 6 months o Symptomatic HF or EF < 35% o Angina in previous 6 months o Serum creatinine > 2 mg/dL o Requirement for study drugs other than hypertension o Requirement for > 2 antihypertensive drugs to achieve satisfactory BP control o Contraindications to study medications o Factors suggesting low compliance with protocol o Diseases likely to lead to non-CVD death over the course of the study o SBP > 180 mmHg or DBP > 110 mmHg on two separate readings during screening Study design Multicenter, double-blind, randomized, active comparator-controlled trial Study participants were randomly assigned in a 1.7:1:1:1 ratio to one of four groups o Chlorthalidone o Doxazosin o Lisinopril o Amlodipine The treatment goal for all four arms was BP <140/90 mmHg The therapeutic goal was to achieve BP control with the lowest possible dosage of study drug All medications were encapsulated and identical in appearance Doxazosin doses were 2 mg/day, 4 mg/day, and 8 mg/day 1

Cliff Rutter 1/31/13 o Chlorthalidone equivalent doses were 12.5 mg/day, 12.5 mg/day, and 25 mg/day If BP goal was not achieved with the maximum tolerated doses of study drugs, an open label step 2 or step 3 agent could be added to the patients regimen o Step 2 agents Atenolol 25-100 mg/day Reserpine 0.05-0.2 mg/day Clonidine 0.1-0.3 mg/day o Step 3 agents Hydralazine 25-100 mg BID After initial titration visits, patients were seen every 3 months during the first year of follow up and every 4 months thereafter Statistical analysis Primary outcome: o Composite of fatal CHD and nonfatal MI Secondary endpoints: o All-cause mortality o Combined CHD CHD death, nonfatal MI, revascularization procedures, and hospitalized angina o Stroke o Combined CVD CHD death, nonfatal MI, stroke, revascularization procedures, angina, CHF, and peripheral arterial disease o Individual components of combined outcomes Results (Table 1, Figure 1) Primary outcomes o CHD and nonfatal MI No significant difference (p = 0.71; RR 1.03; 95% CI 0.9-1.17) Secondary outcomes o All-cause mortality No significant difference (p = 0.56; RR 1.03; 95% CI 0.9-1.15) o Combined CHD RR = 1.1 (95% CI 1-1.12); p = 0.05 o Stroke RR = 1.19 (95% CI 1.01-1.4); p = 0.04 o Combined CVD RR = 1.25 (95% CI 1.17-1.33); p <0.001 CHF RR = 2.04 (95% CI 1.79 2.32); p < 0.001 Coronary revascularization RR = 1.15 (95% CI 1-1.32); p = 0.05 Angina RR = 1.16 (95% CI 1.05-1.27); p <0.001 PAD Not significant (p = 0.5) Authors conclusions Doxazosin arm terminated early due to doubling of CHF risk in doxazosin treated patients Chlorthalidone is superior to doxazosin as the first line choice antihypertensive agent for monotherapy Strengths Large study population with balanced demographics Independent sponsor Extensive monitoring medication adherence, therapy changes Weaknesses Ended early Student conclusion Chlorthalidone and doxazosin are similar in lowering blood pressure but chlorthalidone is significantly better at preventing CVD, especially CHF

Cliff Rutter 1/31/13 Table 1

Figure 1