The rationale and design of ALLHAT are described in detail elsewhere . Briefly, those eligible for randomization had systolic blood pressure (SBP) of at least 140 mm Hg and/or diastolic blood pressure of at least 90 mm Hg, or took medication for hypertension, and had at least one other risk factor for CHD events. Risk factors included previous MI or stroke, left ventricular hypertrophy by electrocardiogram or echocardiogram, history of type 2 diabetes, current cigarette smoking, and low high-density lipoprotein (HDL) level.
The primary endpoint of the blood pressure (BP) trial is the composite of nonfatal MI and fatal CHD. The four protocol-defined secondary clinical outcomes are all-cause mortality, combined CHD (including CHD death, nonfatal MI, coronary revascularization procedures and hospitalized angina), stroke, and combined CVD (including CHD death, nonfatal MI, stroke, coronary revascularization procedures, angina treated in the hospital or as an outpatient, lower extremity peripheral arterial disease treated in the hospital or with outpatient revascularization, and HF, fatal or treated in the hospital or as an outpatient).
The validation of HF diagnosis entailed answering several questions:
1. Did HF cases meet ALLHAT diagnostic criteria?
2. Were baseline characteristics and medical management for HF cases as expected and similar across the drug groups?
3. Were prevalence and severity of systolic dysfunction as expected and similar across drug groups?
4. Were case-fatality rates as expected and similar across drug groups?
Unless otherwise specified, all data for these analyses were collected as of December, 1999.
Heart Failure Diagnosis
At each follow-up clinic visit the occurrence of study clinical events was assessed, and, if identified by the clinical investigator, reported on an endpoint form. For each event involving hospitalization, a hospital discharge summary or expiration summary was to be submitted, and for each death a death certificate was required. Endpoint forms and supporting documentation were reviewed at the ALLHAT Clinical Trials Center (CTC) for accuracy and appropriateness. When a discrepancy or ambiguity was found, the CTC sent a written query to the Principal Investigator, who retained the final word concerning the diagnosis or cause of death. A random 10% sample of strokes, nonfatal MIs and CHD deaths was selected for blinded quality control evaluation by the ALLHAT Endpoints Subcommittee; for these cases additional documentation was requested.
No such routine Endpoints Subcommittee quality control was initially planned for reported HF. However, the Subcommittee was subsequently called upon to evaluate a random sample of reported fatal and hospitalized nonfatal HF events. As this occurred prior to the termination of the doxazosin arm, neither the chair nor the members of the Subcommittee was informed of the major reason for this review, namely, the trend toward a higher HF event rate in the doxazosin group compared to the chlorthalidone group. The Subcommittee was told that the review was undertaken at the request of the DSMB to address the reliability and validity of reported HF events. This evaluation consisted of fifty events, evenly distributed across the four treatment groups, reported as fatal or hospitalized nonfatal HF and with protocol-required documentation (discharge summary for hospitalized events, death certificates for deaths). Additional material was not requested, since this would have posed an undue burden on the clinical site staff and would have risked raising questions about emerging differences among treatment groups.
The ALLHAT definition of HF, used previously in the Systolic Hypertension in the Elderly Program (SHEP) , includes "patients with clear-cut signs or symptoms of left or right ventricular dysfunction that cannot be attributed to other causes..." The diagnosis of HF must include at least one of four stated symptoms [paroxysmal nocturnal dyspnea, dyspnea at rest, New York Heart Classification functional class III (for definition see Additional Information, Item 1), or orthopnea], and one of seven stated signs (rales, 2+ or greater ankle edema, tachycardia of 120 beats/minute or more after five minutes at rest, cardiomegaly by chest x-ray, chest x-ray characteristic of HF, S3 gallop, or jugular venous distention). Since lower extremity edema or exertional dyspnea may be due to non-cardiac causes, the presence of either of these alone, without other indications of heart failure, is not sufficient for a diagnosis of HF. Study guidelines caution against a hasty HF diagnosis in patients with severe pulmonary disease, including chronic obstructive pulmonary disease (COPD), pneumonia, or other severe, documented lung disease.
Baseline Characteristics and Medical Management
Baseline characteristics of chlorthalidone and doxazosin participants were compared. These analyses were stratified by HF outcome: 1) fatal and hospitalized HF; 2) treated, non-hospitalized HF; and, 3) no HF.
Post-HF event medical management may provide additional evidence of the physicians' confidence in the HF diagnosis. The post-event use of open-label diuretics, ACE-inhibitors, and beta-blockers, i.e., accepted treatments for HF [6–9], was compared between doxazosin and chlorthalidone groups, as was the proportion in each group of those who remained on assigned blinded medication after the event. (For study guidelines regarding the use and reporting of open-label medicines of the same class as the blinded drugs, see Additional Information, Items 2 and 3.)
Ejection Fraction Review
A CTC physician plus non-medical staff reviewed in a blinded fashion 361 hospitalized HF events (representing 278 participants) for ejection fraction data: looking for whether an ejection fraction was measured, the method utilized, and the measurement. Results, tabulated by randomization groups, reflected data that had been collected up to July, 1999, the time of the review.
Case-Fatality Rates and Causes of Death
As a measure of the diagnostic validity and severity of HF and comparability between drug groups, time-from-event-to-death analyses of participants with hospitalized or treated HF were compared between the two groups. Causes of death of such participants were also compared in the doxazosin and chlorthalidone groups.
Data were analyzed according to participants' randomization assignments and HF outcome status, regardless of subsequent medication adherence. The Kaplan-Meier method was utilized in calculating cumulative event rates. Descriptive statistics by treatment groups were presented for baseline characteristics, HF ascertainment, ejection fractions and use of HF medications. Comparability of baseline characteristics of the treatment and HF outcome groups was ascertained by the χ2 test for categorical variables and standard normal (z) test for continuous variables.