- Email: [email protected]
Response to Poulter & Williams #13308R: In reply
1172
LETTER TO THE EDITOR
In Reply: Drs. Poulter and Williams offer an appraisal of the ALLHAT study1 and raise many questions that, in their view, must be addressed before the results of ALLHAT become the basis for “policy decisions.” Their concerns are probably held by many who were surprised or even disappointed by the ALLHAT publication. At issue are not the results of ALLHAT, but how they should be interpreted with regard to the need to change advice and guidelines for treatment of hypertension. Drs. Poulter and Williams’ criticisms fall into two categories. First, the results of ALLHAT can be explained by differences in systolic pressure between the two groups. Thus, doxazosin is not a less effective agent but, rather it was used less effectively, as somehow in the doubleblinded trial, the control of blood pressure was not achieved as well by the treaters. Second, the diuretic chlorthalidone “masked” latent heart failure, whereas doxazosin had no such action. Because cardiovascular mortality was similar for the two cohorts, the diagnosis of heart failure has no real significance. We find it curious that Drs. Poulter and Williams have ignored the intent and design for ALLHAT,2 which clearly guide how its results are to be interpreted. By 1990, it was evident that newer drug classes (calcium blockers, angiotensin converting enzyme (ACE) inhibitors, and ␣-blockers) had not been directly compared to older, successful strategies (diuretic and -blocker– based therapy) for treatment of hypertension in groups likely to benefit from antihypertensive therapy (at high risk) and treated by primary care physicians, who care for nearly all of the very large hypertensive population in developed nations. ALLHAT was conceived as a large, multicenter, double-blind trial to address these issues. The “gold standard” therapy, chlorthalidone, had proven its value in SHEP3 and was the benchmark against which the three other drugs would be compared: an ACE inhibitor (lisinopril), a calcium blocker (amlodipine), and an ␣-blocker (doxazosin). Although planned for a longer follow-up period of 6 years, provisions were made for ongoing assessment in case one or more groups diverged from the other cohorts. This indeed took place and those who monitored the study, after due consideration, recommended that the doxazosin treatment arm be discontinued, but that the other arms be continued. At this point, there was a highly significant 25% higher incidence of cardiovascular events in the group assigned to doxazosin, compared with that given chlorthalidone. The results were presented at a national meeting and published shortly thereafter. Further analysis of ALLHAT has shown that the criteria for an event, heart failure, was equally applied to both cohorts, and that the case-fatality for this diagnosis on follow-up was similarly high for both groups.4 In ALLHAT, heart failure was a serious consequence, not a trivial occurrence. What inferences should be drawn from ALLHAT, and to whom should these be addressed? On the evidence, one conclusion must be that doxazosin, as monotherapy, is clearly inferior to the diuretic for the very large fraction of
AJH–November 2001–VOL. 14, NO. 11, PART 1
hypertensive patients who are similar to those enrolled in ALLHAT. Why this is so may be debated, and the many post hoc subgroup analyses requested by Drs. Poulter and Williams should stimulate discussion and, perhaps, some innovative research. One would like to know why, in a double-blind study, those treated with doxazosin could not achieve the same level of on-treatment systolic pressure, and why fewer patients remained on doxazosin therapy. Nonetheless, these observations may not explain the outcomes, and they only reinforce the overall conclusion that doxazosin is less effective, no matter what the unknown mechanism. All those who treat hypertension, especially primary care physicians, need to know these facts and manage their patients accordingly. Our view is that the ALLHAT findings fully justify changes in policy and rewriting of guidelines. There are unanswered questions. Does doxazosin (or do other ␣-blockers) provide any benefit in combination with other drug classes, as add-on treatment? When added in combination to treat refractory hypertension and lower blood pressure is achieved,5 are outcomes improved? Doxazosin may still have a role to play in the management of hypertension; that role is now a minor one. For safety’s sake, it’s time to make this widely known. LAWRENCE R. KRAKOFF Englewood Hospital & Medical Center Englewood, New Jersey Mount Sinai School of Medicine New York, New York MICHAEL H. ALDERMAN Albert Einstein College of Medicine Bronx, New York PII S0895-7061(01)02244-0 Address correspondence and reprint requests to Dr. Lawrence R. Krakoff, Chief of Medicine, Englewood Hospital, 30 Eagle Street, Englewood, NJ 07631.
References 1.
2.
3.
4.
5.
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2000;283:1967–1975 Davis B, Gordon DJ, Furberg CD, Wright JT Jr, Cushman WC, Grimm RH, LaRosa JC, Whelton PK, Perry HM, Alderman MH, Ford CE, Oparil S, Francis CK, Proschan M, Pressel S, Black HR, Hawkins CM: Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens 1996;9:342–360. SHEP Cooperative Research Group: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255–3264. Piller LB, Davis BR, Cutler JA, Cushman WC, Probstfield JL, Williamson JD, Leenen FH, Golden JS, Randell O, Wright JT, Wright JT: Validation of heart failure events in ALLHAT participants assigned to doxazosin. Am J Hypertens 2001;14:180A. Black HR, Sollins JS, Garofalo JL: The addition of doxazosin to the therapeutic regimen of hypertensive patients inadequately controlled with other antihypertensive medications: a randomized, placebo-controlled study. Am J Hypertens 2000;13:468– 474.
LETTER TO THE EDITOR
In Reply: Drs. Poulter and Williams offer an appraisal of the ALLHAT study1 and raise many questions that, in their view, must be addressed before the results of ALLHAT become the basis for “policy decisions.” Their concerns are probably held by many who were surprised or even disappointed by the ALLHAT publication. At issue are not the results of ALLHAT, but how they should be interpreted with regard to the need to change advice and guidelines for treatment of hypertension. Drs. Poulter and Williams’ criticisms fall into two categories. First, the results of ALLHAT can be explained by differences in systolic pressure between the two groups. Thus, doxazosin is not a less effective agent but, rather it was used less effectively, as somehow in the doubleblinded trial, the control of blood pressure was not achieved as well by the treaters. Second, the diuretic chlorthalidone “masked” latent heart failure, whereas doxazosin had no such action. Because cardiovascular mortality was similar for the two cohorts, the diagnosis of heart failure has no real significance. We find it curious that Drs. Poulter and Williams have ignored the intent and design for ALLHAT,2 which clearly guide how its results are to be interpreted. By 1990, it was evident that newer drug classes (calcium blockers, angiotensin converting enzyme (ACE) inhibitors, and ␣-blockers) had not been directly compared to older, successful strategies (diuretic and -blocker– based therapy) for treatment of hypertension in groups likely to benefit from antihypertensive therapy (at high risk) and treated by primary care physicians, who care for nearly all of the very large hypertensive population in developed nations. ALLHAT was conceived as a large, multicenter, double-blind trial to address these issues. The “gold standard” therapy, chlorthalidone, had proven its value in SHEP3 and was the benchmark against which the three other drugs would be compared: an ACE inhibitor (lisinopril), a calcium blocker (amlodipine), and an ␣-blocker (doxazosin). Although planned for a longer follow-up period of 6 years, provisions were made for ongoing assessment in case one or more groups diverged from the other cohorts. This indeed took place and those who monitored the study, after due consideration, recommended that the doxazosin treatment arm be discontinued, but that the other arms be continued. At this point, there was a highly significant 25% higher incidence of cardiovascular events in the group assigned to doxazosin, compared with that given chlorthalidone. The results were presented at a national meeting and published shortly thereafter. Further analysis of ALLHAT has shown that the criteria for an event, heart failure, was equally applied to both cohorts, and that the case-fatality for this diagnosis on follow-up was similarly high for both groups.4 In ALLHAT, heart failure was a serious consequence, not a trivial occurrence. What inferences should be drawn from ALLHAT, and to whom should these be addressed? On the evidence, one conclusion must be that doxazosin, as monotherapy, is clearly inferior to the diuretic for the very large fraction of
AJH–November 2001–VOL. 14, NO. 11, PART 1
hypertensive patients who are similar to those enrolled in ALLHAT. Why this is so may be debated, and the many post hoc subgroup analyses requested by Drs. Poulter and Williams should stimulate discussion and, perhaps, some innovative research. One would like to know why, in a double-blind study, those treated with doxazosin could not achieve the same level of on-treatment systolic pressure, and why fewer patients remained on doxazosin therapy. Nonetheless, these observations may not explain the outcomes, and they only reinforce the overall conclusion that doxazosin is less effective, no matter what the unknown mechanism. All those who treat hypertension, especially primary care physicians, need to know these facts and manage their patients accordingly. Our view is that the ALLHAT findings fully justify changes in policy and rewriting of guidelines. There are unanswered questions. Does doxazosin (or do other ␣-blockers) provide any benefit in combination with other drug classes, as add-on treatment? When added in combination to treat refractory hypertension and lower blood pressure is achieved,5 are outcomes improved? Doxazosin may still have a role to play in the management of hypertension; that role is now a minor one. For safety’s sake, it’s time to make this widely known. LAWRENCE R. KRAKOFF Englewood Hospital & Medical Center Englewood, New Jersey Mount Sinai School of Medicine New York, New York MICHAEL H. ALDERMAN Albert Einstein College of Medicine Bronx, New York PII S0895-7061(01)02244-0 Address correspondence and reprint requests to Dr. Lawrence R. Krakoff, Chief of Medicine, Englewood Hospital, 30 Eagle Street, Englewood, NJ 07631.
References 1.
2.
3.
4.
5.
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2000;283:1967–1975 Davis B, Gordon DJ, Furberg CD, Wright JT Jr, Cushman WC, Grimm RH, LaRosa JC, Whelton PK, Perry HM, Alderman MH, Ford CE, Oparil S, Francis CK, Proschan M, Pressel S, Black HR, Hawkins CM: Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens 1996;9:342–360. SHEP Cooperative Research Group: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;265:3255–3264. Piller LB, Davis BR, Cutler JA, Cushman WC, Probstfield JL, Williamson JD, Leenen FH, Golden JS, Randell O, Wright JT, Wright JT: Validation of heart failure events in ALLHAT participants assigned to doxazosin. Am J Hypertens 2001;14:180A. Black HR, Sollins JS, Garofalo JL: The addition of doxazosin to the therapeutic regimen of hypertensive patients inadequately controlled with other antihypertensive medications: a randomized, placebo-controlled study. Am J Hypertens 2000;13:468– 474.