Blood Pressure Treatment for Stroke Patients: What Should Be the First Line?
Abstract & Commentary
Source: Major outcomes in high-risk hypertensive patients randomized to angiotensin converting enzyme inhibitor or calcium channel blocker vs. diuretic. The antihypertensive and lipid lowering treatment to prevent heart attack trial (ALLHAT). JAMA. 2002;288:2981-2997.
The publication of the ALLHAT trial received much publicity not only in medical circles but was also front-page news in the Wall Street Journal. This trial was a significant blow to the pharmaceutical industry, and it convincingly showed that inexpensive diuretic medications had superiority over highly marketed ACE inhibitors and calcium channel blockers for the treatment of hypertension.
ALLHAT included more than 33,000 participants with hypertension and 1 other vascular problem such as prior myocardial infarction or stroke, diabetes, smoking, and hyperlipidemia. Subjects, not previously treated for their blood pressure, were randomly assigned to a regimen of diuretic (chlorthalidone), ACE inhibitor (lisinopril), or calcium channel blocker (amlodipine). Additional drugs such as atenolol were added in an open-label format. There were no differences between the 3 treatment regimens in the primary outcome measure of fatal or nonfatal MI. Perhaps more importantly, chlorthalidone was about 20% superior to lisinopril in preventing stroke; it was a stronger antihypertensive and even appeared to produce less congestive heart failure than lisinopril, a disorder thought optimally treated with ACE inhibition. Chlorthalidone was also superior to lisinopril when all vascular disorders (MI, stroke, and peripheral vascular disease) were lumped together.
Commentary
How should neurologists interpret these results? Within the past 2 years there have been important reports in the stroke literature suggesting that ACE inhibitors should be considered a crucial part of any drug cocktail for the "post-stroke" patient. Both the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) and Heart Outcomes Prevention Evaluation (HOPE) trial suggested that ACE inhibition provided about a 30% relative risk reduction of recurrent stroke independent of any effects on blood pressure. How should these trials now be viewed? Interestingly, the PROGRESS study, largely heralded as an ACE inhibitor trial, also included the diuretic indapamide. Deeper analysis of PROGRESS indicates that a large portion of benefit ascribed to the treatment regimen may have been explained by the inclusion of indapamide. While patients treated with the combination of perindopril and indapamide had reduced stroke risk over placebo patients, those treated only with perindopril had minimal blood pressure reductions and no significant decrease in stroke.
ALLHAT was a nearly flawless study methodologically, but it is nevertheless open to deeper analysis as well. Nearly one-third of the ALLHAT participants were black, an overall plus, reflecting an ethnically diverse patient pool. It is well known, however, that hypertension in blacks is caused by a hyper-reninemic state and that this pathophysiology is optimally treated with diuresis. Indeed, in subgroup analysis, blacks in ALLHAT on ACE inhibitors had suboptimally controlled blood pressures and higher incidences of stroke/MI. In contrast, the relative risk of stroke for whites on ACE inhibitors compared to diuretic was 1.00, reflecting overall clinical equivalence. Physicians treating primarily white populations may need to take these differences into account.
Much of the publicity surrounding ALLHAT was financial, critical of trends toward more expensive drugs driven by pharmaceutical detail men. The cost issues, however, are not cut and dry. Diuretics are inexpensive, but there are also off-patent ACE inhibitors available such as captopril, enalapril, and lisinopril. Angiotensin receptor blockers are expensive and should only be used when standard ACE inhibitors cannot be tolerated.
In conclusion, ACE inhibitors and diuretics are both appropriate first-line blood pressure therapies for stroke patients. Ultimately, since many of our patients require combination therapy with both of these drugs, head-to-head comparisons may be less important than an emphasis on continued careful diligence to strict blood pressure control. — Alan Z. Segal
Dr. Segal is Assistant
Editor of Neurology Alert; Assistant Professor, Department of Neurology
at Weill-Cornell Medical College; and Attending Neurologist at New York Presbyterian
Hospital.
The publication of the ALLHAT trial received much publicity not only in medical circles but was also front-page news in the Wall Street Journal. This trial was a significant blow to the pharmaceutical industry, and it convincingly showed that inexpensive diuretic medications had superiority over highly marketed ACE inhibitors and calcium channel blockers for the treatment of hypertension.
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