Paired studies suggests that thiazide diuretics should be the first-choice medication for hypertension but that the value of statin therapy in the primary-care setting for moderate hypercholesterolemia is less clear-cut, according to articles in the December 18th issue of The Journal of the American Medical Association (JAMA).

In the first report, researchers concluded that thiazide diuretic agents were equally good or better at reducing blood pressure in hypertensive patients and preventing coronary events than angiotensin converting enzyme inhibitors or calcium channel blockers.

According to background information, antihypertensive therapies have included diuretics and beta blockers, as well as several newer classes of agents such as angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers. Over the past decade, major placebo-controlled trials have documented that ACE inhibitors and calcium channel blockers reduce cardiovascular events in individuals with hypertension. However, their relative value compared with older, less expensive agents such as diuretics and beta blockers was unclear.

Jackson T. Wright, Jr., M.D., Ph.D., Barry R. Davis, M.D., Ph.D., and fellow investigators for the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) conducted a randomized, double-blind clinical trial to determine whether the occurrence of fatal heart disease or nonfatal myocardial infarction is lower for high-risk patients with hypertension treated with a calcium channel blocker (amlodipine, 2.5 to 10 mg/d, 9,048 patients) or an ACE inhibitor (lisinopril, 10 to 40 mg/d, 9,054 patients), with each compared with thiazide diuretic treatment (chlorthalidone, 12.5 to 25 mg/d, 15,255 patients).

The trial was conducted from February 1994 through March 2002 and included 33,357 participants aged 55 years or older with hypertension and at least one other risk factor for coronary heart disease. Follow-up was approximately four to eight years.

The researchers found that the primary outcome of combined fatal coronary event or non-fatal myocardial infarction occurred in 2,956 participants.

"Neither amlodipine [6-year rate, 11.3 percent] nor lisinopril [6-year rate, 11.4 percent] was superior to chlorthalidone [6-year rate, 11.5 percent] in preventing major coronary events or in increasing survival," the authors wrote.

"Chlorthalidone was superior to amlodipine (by about 25 percent) in preventing heart failure overall and for hospitalized or fatal cases, although it did not differ from amlodipine in overall prevention of cardiovascular disease. Chlorthalidone was superior to lisinopril in lowering blood pressure and in preventing aggregate cardiovascular events, principally stroke, heart failure, angina, and coronary revascularization."

"In conclusion, the results of the trial [ALLHAT] indicate that thiazide-type diuretics should be considered first for pharmacologic therapy in patients with hypertension. They are unsurpassed in lowering blood pressure, reducing clinical events, and tolerability, and they are less costly. Since a large proportion of participants required more than one drug to control their blood pressure, it is reasonable to infer that a diuretic be included in all multidrug regimens, if possible. Although diuretics already play a key role in most antihypertensive treatment recommendations, the study findings [of ALLHAT] should be carefully evaluated by those responsible for clinical guidelines and be widely applied in patient care."

In an accompanying editorial, Lawrence J. Appel, M.D., M.P.H., wrote that "quite simply, [ALLHAT] is one of the most important trials of antihypertensive drug therapy. For decades, experts have passionately debated which class of drugs should be initial therapy for hypertension. Resolution of this issue, which has enormous clinical, public health, and economic implications, comes at a time of intense pressure to reduce health care costs while improving clinical outcomes. In this setting, the ALLHAT results, reported in this issue of The Journal, are particularly noteworthy, because there is no cost-quality tradeoff; the most effective therapy was also the least expensive."

He added that the trial results are robust, unambiguous, and generalizable, especially to the broad population of patients with stage 1 or 2 hypertension. Approximately 50 percent of the North American participants were women, and 35 percent were black.

In the second report, researchers concluded that pravastatin use did not reduce the mortality rate or incidence of coronary events in patients with moderately elevated cholesterol and well-controlled hypertension when compared with usual primary care.

According to background information, many of the original studies evaluating statin therapy were too small to assess all-cause mortality or outcomes in important patient subgroups. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial evaluated the impact of sustained cholesterol reductions on deaths in an older population with hypertension and moderately high cholesterol and at least one other coronary risk factor: It employed use of pravastatin in all patients versus usual care--- care that could include statin therapy if the patient's individual physician chose to prescribe it.

The statin study (ALLHAT-LLT) was a randomized, non-blinded trial conducted from February 1994 through March 2002 at 513 North American clinical centers. Jeffrey L. Probstfield, M.D., Barry R. Davis, M.D., Ph.D., and colleagues enrolled 10,355 people aged 55 or older with high low-density lipoprotein cholesterol levels (120 to 180 mg/dL). All participants were also enrolled in ALLHAT, the study comparing treatments for hypertension. The average age of the participants was 66 years, and 49 percent were women. Fourteen percent had a history of coronary heart disease and 35 percent of participants had type II diabetes. Of the participants, 5,170 were assigned to the pravastatin group (40 mg/day) and 5,185 were assigned to usual care.

Participants were followed up for an average of 4.8 years. During the course of the trial, 32 percent of the usual care patients with coronary heart disease and 29 percent of participants without coronary heart disease started taking cholesterol-lowering drugs. At the fourth year, total cholesterol levels were reduced by 17 percent with pravastatin versus 8 percent with usual care. Among the random sample of participants who had their low-density lipoprotein cholesterol levels assessed, levels were reduced by 28 percent with pravastatin versus 11 percent with usual care.

The researchers found that death rates were similar for the two groups, with 6-year death rates of 14.9 percent for pravastatin and 15.3 percent with usual care. The rate of events related to coronary heart disease such as myocardial infarction and stroke were not significantly different between the two groups, with 6-year event rates of 9.3 percent for pravastatin and 10.4 percent for usual care.

"ALLHAT-LLT demonstrated no significant difference between pravastatin and usual care groups in all-cause mortality or combined fatal and nonfatal coronary heart disease," the authors wrote. "However, in the context of the modest cholesterol differential, the results are consistent with the evidence from other large trials. Indeed, the overall findings from the nine large long-term statin trials (including ALLHAT-LLT) leave little doubt regarding the broad efficacy and safety of this treatment in the prevention and treatment of atherosclerotic cardiovascular disease. In the absence of evidence for increases in any category of noncardiovascular mortality, the ALLHAT-LLT results should be interpreted as consistent with current recommendations for cholesterol control in the prevention and treatment of cardiovascular disease. These results emphasize the need for obtaining an adequate reduction in low-density lipoprotein cholesterol in clinical practice when lipid-lowering therapy is implemented."

In an accompanying editorial, Richard C. Pasternak, M.D. discussed factors that may have contributed to the similarity between the outcomes of the pravastatin and usual care groups.

"By Year 6 of the study, only 70.3 percent of patients in the treatment group were still taking the protocol-specified 40 mg of pravastatin, whereas 28.5 percent of the usual care group was receiving a lipid-lowering drug (26.1 percent received a statin)," wrote Dr. Pasternak. Studies supporting the use of statins were published early during the course of the trial [ALLHAT-LLT], increasing the number of physicians prescribing statins for patients in the usual care group, particularly those at the highest risk of heart disease.

Another issue he noted was that "because of reduced adherence and the large degree of crossover, the difference in total cholesterol and the apparent difference in low-density lipoprotein cholesterol between the two groups were modest and substantially less than the differences reported in other statin trials."

"Physicians might be tempted to conclude that this large study demonstrates that statins do not work; however, it is well known that they do," stated Dr. Pasternak. "Rather, it appears that statins may be less effective in the primary care setting in which they were used in ALLHAT-LLT. Statins have been proven efficacious in a wide array of primary and secondary prevention randomized, blinded, controlled trials. ALLHAT-LLT shows that the effectiveness may be limited in a setting that more closely mirrors clinical practice."

"Until routine practice becomes closer to the conditions achieved in randomized clinical trials, there will continue to be a gap between optimal care based on the best knowledge and actual care in clinical practice," Dr. Pasternak writes.