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Hypertension detection and follow-up program: An alternative interpretation
FORUM--LETTERS TO THE EDITOR
HEMODYNAMIC EVALUATION OF VASODILATOR DRUG THERAPY IN PRIMARY PULMONARY HYPERTENSION To the Editor: In 1951 Dresdale et al. 1described the clinical and hemodynamic findings of primary pulmonary hypertension (PPH). The cause of this condition is unknown and is characterized by an unfavorable clinical course, with the results of medical t r e a t m e n t being usually unsatisfactory. Recent studies have demonstrated t h a t the systemic vasodilators may produce hemodynamic improvement in patients with pulmonary hypertension. ~-4 Our present study examines the hemodynamic changes t h a t occurred in three P P H patients who were treated with intravenous phentolamine. In addition, one of these patients was given a number of drugs and the hemodynamic effects of these agents were evaluated. Three patients with P P H had right heart catheterization. Cardiac output (CO) was obtained by the Fick method. All patients received 5 mg phentolamine intravenously at 0.3 mg/ min. A Swan-Ganz catheter was left in place in patient No. 3 and during the next 24 hours he received 50 and then 150 mg of diazoxide, an infusion of isoproterenol 1 pg/min for 5 minutes, 1/15o grain sublingual nitroglycerin, an infusion of 20 mg hydralazine over 20 minutes, and inhalation of 70% oxygen for 30 minutes. In the first patient, pulmonary artery (PA) mean pressure fell from control of 45 m m Hg to post-phentolamine of 41 mm Hg, PA wedge mean remained at 2 m m Hg, CO increased from 3.44 to 4.01 L/min, and the pulmonary vascular resistance (PVR) fell from 1005 to 775 dynes-sec-cm 5. In the second patient, PA pressure fell from 57 to 48 m m Hg, PA wedge mean remained at 0 m m Hg, CO increased from 2.50 to 3.10 L/min, and PVR fell from 1807 to 1230 dynes-sec-cm -~. In the third patient, the PA mean pressure fell from 72 to 68 m m Hg, PA wedge pressure fell from 10 to 9 m m Hg, CO declined from 2.80 to 2.20 L/min, and PVR increased from 1757 to 2124 dynes-sec-cm -5. In patient No. 3, diazoxide produced progressive increase in PA pressure; 70% oxygen was without effect; isoproterenol increased heart rate, CO, and PA pressure; nitroglycerin increased CO but did not change PA pressure; while hydralazine substantially increased CO and PA pressure. Phentolamine was administered to the three patients because it is an afterload reducing agent s and a PA dilator. ~ Patients No. 1 and 2 responded to phentolamine by decreased PVR and PA pressure with increased CO. However, patient No. 3 responded to phentolamine by increased PVR with decreased CO and PA pressure. This patient had extreme elevation of PA pressure, and presumably was at a later stage in the disease process. Similarly diazoxide, 70% oxygen, isoproterenol, nitroglycerin, and hydralazine produced either a minimal change or an increase in PA pressure. Based on this experience, it is reasonable to perform a right heart catheterization on patients with P P H to evaluate pulmonary vascular responsiveness to vasodilators. Any desire to empirically treat pulmonary hypertensive patients with vasodilators should be negated; hemodynamic change may be the only evidence of improvement. Lawrence Gould, M.D. A. B. Chokshi, M.D. S. Patel, M.D. G. I. Gomes, M.D. Department of Medicine The Methodist Hospital 506-6th Street Brooklyn, N.Y. 11215
300
REFERENCES 1. Dreedale DT, Schultz M, Michtom RJ: Primary pulmonary hypertension. I. Clinical and hemodynamic study. Am J Med 11:686, 1951. 2. Rubin LJ, Peter RH: Oral hydralazine therapy for primary pulmonary hypertension. N Engl J Med 302:69, 1980. 3. Knapp E, Gweiner R: Reduction of pulmonary hypertension by nitroprusside. I n t J Clin Pharmacol Biopharmacol 15:75, 1977. 4. Gould L, Zahir M, DeMartino A, Gomprecht RF: Hemodynamic effects of phentolamine in chronic obstructive pulmonary disease. Br Heart J 33:445, 1971. 5. Gould L, Zahir M, Ettinger S: Phentolamine and cardiovascular performance. Br Heart J 31:154, 1969. 6. Gould L, Reddy CVR: Phentolamine. AM HEART J 92:397, 1976.
HYPERTENSION DETECTION AND FOLLOW-UP PROGRAM: AN ALTERNATIVE INTERPRETATION To the Editor: The report of the Hypertension Detection and Follow-up Program (HDFP) ' showed a decrease of 5-year mortality from all causes of 16.9% in the Stepped Care (SC) patients compared to the Referred Care (RC) patients. In stratum I (entry diastolic pressure 90 to 104 m m Hg), there was a decrease of 20.3% iu overall mortality in SC compared to RC. Despite a disclaimer t h a t other factors may be responsible, the report states " t h u s for the first time, with the large sample size of H D F P evidence has been obtained on the efficacy of antihypertensive pharmacologic treatment for adults with mild blood pressure elevation." The H D F P results and conclusions are in striking contrast to the results and conclusions of the Veterans Administration (VA) Cooperative Study 2 and the U.S. Public Health Service (PHS) Hospitals Cooperative S t u d y / w h i c h found no significant reduction in morbidity or mortality as a result of drug t r e a t m e n t in patients with entry diastolic pressure of 90 to 104 m m Hg. I t is worthwhile, therefore, to examine the design of these three studies to see if an explanation can be found for the different results obtained. The VA study was double-blind and placebo-controlled. Average duration of follow-up was 3.3 years for placebo-controlled patients and 3.2 years for drug-treated patients. In the PHS study patients were followed for 7 to 10 years, with an average of 8 years. In both studies, the placebo-controlled and drug-treatment groups received identical care, except for antihypertensive drugs. Both the VA study and the PHS study showed no significant difference in the frequency of complications or deaths in patients with entry blood pressure 90 to 104 m m Hg diastolic. A significant decrease in complications and deaths was found in the VA study in drug treatment patients with entry diastolic pressure 105 to 114 mm. Hg. The H D F P was not a double-blind, placebo-controlled study. It compared care given in special centers with care given in community hospitals, clinics, and physician's offices. The endpoint was overall 5-year mortality. A majority of patients in both SC and RC groups received drugs, but other aspects of t r e a t m e n t were different in the two groups. SC patients received intensive supportive care. They were a part of a team effort, the sole purpose of which was to keep them under antihypertensive care.
Volume 102 Number 2
T a b l e I. H D F P
Letters to the Editor
d i a s t o l i c b l o o d p r e s s u r e r e s p o n s e b y s t r a t a ( m m Hg)
Stratum I Entry DBP: 96.4
RxDBP ADBP %A
301
Stratum II Entry DBP: 108.7
Stratum III Entry DBP: 122.3
SC
RC
SC
RC
SC
RC
86.4-83.4 9.9-12.9 10.2-13.4
91.9-87.8 4.5-8.6 4.6-8.9
89.1-85.0 19.3-23.4 17.8-21.6
97.4-90.7 11.3-18,0 10.4-16.5
93.5-87.1 28.2-34.6 23.1-28.4
103.1-94.2 19.2-28.1 15.7-23.0
RxDBP = mean resting diastolic blood pressure (years 1, 2, 4, and 5 of study); ADBP = change in diastolic blood pressure; %h = percent change in diastolic blood pressure. Patients who failed to keep appointments were called to reschedule. In some of the SC clinics, vans transported patients to and from clinics. In others, baby-sitters were provided for women patients with small children. Arrangements were made in some SC clinics to make certain t h a t employed patients could attend without a loss of pay. The SC patients were the beneficiaries of an intensive psychologic and social support system provided by a dedicated and effective staff throughout the 5-year follow-up period. RC patients were referred to their usual source of health care, The variety of facilities and services included clinics in large hospitals for the indigent, as well as the offices of physicians in practice. H D F P patients were classified by entry diastolic pressure as in the VA study: stratum I, 90 to 104 mm. Hg; stratum II, 105 to 114 mm. Hg; and stratum III, _> 115 m m Hg. Mortality was less in SC compared to RC by 20% in stratum I, 13% in stratum II, and 7.3% in stratum III. The differences in strata II and III were not statistically significant. The decreased mortality in SC compared to RC is attributed to lower diastolic pressures maintained through the 5-year study period. These were reported for years, 1, 2, 4, and 5. Diastolic pressure was reduced below entry level by 10.2% to 13.4% in SC and from 4.6% to 8.9% in RC. T r e a t m e n t diastolic pressures averaged from 5.4 to 4.3 m m Hg lower for SC than RC in stratum I. This modest difference in treatment diastolic pressure does not seem of sufficient magnitude to explain a decrease of mortality of 20% over a 5-year period. Data from strata II and III suggest t h a t the difference in the magnitude of blood pressure reduction is not the cause of the reduced mortality of SC vs RC in stratum I. In strata I! and III the differences in treatment diastolic pressure of SC vs RC expressed in absolute terms or in percentage of entry values were greater than those of stratum I (Table I). Despite greater reductions in blood pressure, the differences in mortality were smaller and not significant. The data from the PHS study also suggest t h a t the difference in mortality between SC and RC in stratum I was not due to the difference in diastolic pressure. In the PHS study the difference in diastolic pressure between the drug t r e a t m e n t group and the control group averaged 10 mm Hg for the 8-year follow-up period. This must be compared with the difference of only 5.4 to 4.3 mm Hg in SC vs RC noted in stratum I of HDFP. Despite the greater blood pressure difference in the PHS study applied over a longer period of follow-up, there was no significant difference in morbidity or mortality. An alternative hypothesis is therefore suggested to reconcile the findings of H D F P study with those of VA and PHS studies: the strong support system given SC patients was the principal cause of the decreased mortality observed in stratum I. Strong support system was available only to SC patients. Its favorable effect on mortality in SC was greatest in stratum I because drug therapy is relatively ineffective at diastolic pressures of 90 to 104 mm Hg. In strata II and III, on the other hand, with progressively
higher entry diastolic pressures drug treatment was effective and was an increasingly powerful factor in both SC and RC 4 This diluted the influence of the strong support system progressively in patients with higher entry diastolic pressure and is consistent with the diminishing difference in mortality of 20.3%, 13%, and 7.2% in strata I, II, and III, respectively. The reduced effect of the strong support system with increasing entry diastolic pressure may also be responsible for differences in mortality reported at different levels within stratum I. The difference in mortality for SC vs RC was 22% for substratum 90 to 94 mm Hg, 23% for substratrum 95 to 99 m m Hg, and 14% for substratrum 100 to 104 mm Hg. These figures within stratum I suggest t h a t the dilution of the effect of the strong support system began at entry diastolic of 100 to 104 mm Hg. This supports the idea t h a t under the conditions of HDFP, antihypertensive drug therapy exerted a favorable influence on mortality at entry diastolic ___ 100 mm Hg. From the above observations, it is concluded t h a t (1) the design of H D F P and the data reported do not support the conclusion that antihypertensive drug therapy caused the 20% decrease in mortality in stratum I SC patients; (2) it is suggested t h a t the strong support system which was available only to SC patients caused the decreased mortality in SC vs RC in stratum I; and (3) the decreased difference in mortality of SC vs RC within the substrata of stratum I and in strata II and III suggests t h a t drug treatment was effective in reducing mortality at entry diastolic ---- 100 mm Hg. George N. Aagaard, M.D. Division of Clinical Pharmacology Department of Medicine-RG20 University of Washington School of Medicine Seattle, WA 98195 REFERENCES
1. Hypertension Detection and Follow-up Program Cooperative Group: Five-year findings of the hypertension detection and follow-up program. 1. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 242:2562, 1979. 2. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 m m Hg. JAMA 213:1143, 1970. 3. U.S. Public Health Service Hospitals Cooperative Study Group: Treatment of mild hypertension. Results of a tenyear intervention trial. Circ Res 40(suppl I):98, 1977. 4. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 m m Hg. JAMA 202:116, 1967.
HEMODYNAMIC EVALUATION OF VASODILATOR DRUG THERAPY IN PRIMARY PULMONARY HYPERTENSION To the Editor: In 1951 Dresdale et al. 1described the clinical and hemodynamic findings of primary pulmonary hypertension (PPH). The cause of this condition is unknown and is characterized by an unfavorable clinical course, with the results of medical t r e a t m e n t being usually unsatisfactory. Recent studies have demonstrated t h a t the systemic vasodilators may produce hemodynamic improvement in patients with pulmonary hypertension. ~-4 Our present study examines the hemodynamic changes t h a t occurred in three P P H patients who were treated with intravenous phentolamine. In addition, one of these patients was given a number of drugs and the hemodynamic effects of these agents were evaluated. Three patients with P P H had right heart catheterization. Cardiac output (CO) was obtained by the Fick method. All patients received 5 mg phentolamine intravenously at 0.3 mg/ min. A Swan-Ganz catheter was left in place in patient No. 3 and during the next 24 hours he received 50 and then 150 mg of diazoxide, an infusion of isoproterenol 1 pg/min for 5 minutes, 1/15o grain sublingual nitroglycerin, an infusion of 20 mg hydralazine over 20 minutes, and inhalation of 70% oxygen for 30 minutes. In the first patient, pulmonary artery (PA) mean pressure fell from control of 45 m m Hg to post-phentolamine of 41 mm Hg, PA wedge mean remained at 2 m m Hg, CO increased from 3.44 to 4.01 L/min, and the pulmonary vascular resistance (PVR) fell from 1005 to 775 dynes-sec-cm 5. In the second patient, PA pressure fell from 57 to 48 m m Hg, PA wedge mean remained at 0 m m Hg, CO increased from 2.50 to 3.10 L/min, and PVR fell from 1807 to 1230 dynes-sec-cm -~. In the third patient, the PA mean pressure fell from 72 to 68 m m Hg, PA wedge pressure fell from 10 to 9 m m Hg, CO declined from 2.80 to 2.20 L/min, and PVR increased from 1757 to 2124 dynes-sec-cm -5. In patient No. 3, diazoxide produced progressive increase in PA pressure; 70% oxygen was without effect; isoproterenol increased heart rate, CO, and PA pressure; nitroglycerin increased CO but did not change PA pressure; while hydralazine substantially increased CO and PA pressure. Phentolamine was administered to the three patients because it is an afterload reducing agent s and a PA dilator. ~ Patients No. 1 and 2 responded to phentolamine by decreased PVR and PA pressure with increased CO. However, patient No. 3 responded to phentolamine by increased PVR with decreased CO and PA pressure. This patient had extreme elevation of PA pressure, and presumably was at a later stage in the disease process. Similarly diazoxide, 70% oxygen, isoproterenol, nitroglycerin, and hydralazine produced either a minimal change or an increase in PA pressure. Based on this experience, it is reasonable to perform a right heart catheterization on patients with P P H to evaluate pulmonary vascular responsiveness to vasodilators. Any desire to empirically treat pulmonary hypertensive patients with vasodilators should be negated; hemodynamic change may be the only evidence of improvement. Lawrence Gould, M.D. A. B. Chokshi, M.D. S. Patel, M.D. G. I. Gomes, M.D. Department of Medicine The Methodist Hospital 506-6th Street Brooklyn, N.Y. 11215
300
REFERENCES 1. Dreedale DT, Schultz M, Michtom RJ: Primary pulmonary hypertension. I. Clinical and hemodynamic study. Am J Med 11:686, 1951. 2. Rubin LJ, Peter RH: Oral hydralazine therapy for primary pulmonary hypertension. N Engl J Med 302:69, 1980. 3. Knapp E, Gweiner R: Reduction of pulmonary hypertension by nitroprusside. I n t J Clin Pharmacol Biopharmacol 15:75, 1977. 4. Gould L, Zahir M, DeMartino A, Gomprecht RF: Hemodynamic effects of phentolamine in chronic obstructive pulmonary disease. Br Heart J 33:445, 1971. 5. Gould L, Zahir M, Ettinger S: Phentolamine and cardiovascular performance. Br Heart J 31:154, 1969. 6. Gould L, Reddy CVR: Phentolamine. AM HEART J 92:397, 1976.
HYPERTENSION DETECTION AND FOLLOW-UP PROGRAM: AN ALTERNATIVE INTERPRETATION To the Editor: The report of the Hypertension Detection and Follow-up Program (HDFP) ' showed a decrease of 5-year mortality from all causes of 16.9% in the Stepped Care (SC) patients compared to the Referred Care (RC) patients. In stratum I (entry diastolic pressure 90 to 104 m m Hg), there was a decrease of 20.3% iu overall mortality in SC compared to RC. Despite a disclaimer t h a t other factors may be responsible, the report states " t h u s for the first time, with the large sample size of H D F P evidence has been obtained on the efficacy of antihypertensive pharmacologic treatment for adults with mild blood pressure elevation." The H D F P results and conclusions are in striking contrast to the results and conclusions of the Veterans Administration (VA) Cooperative Study 2 and the U.S. Public Health Service (PHS) Hospitals Cooperative S t u d y / w h i c h found no significant reduction in morbidity or mortality as a result of drug t r e a t m e n t in patients with entry diastolic pressure of 90 to 104 m m Hg. I t is worthwhile, therefore, to examine the design of these three studies to see if an explanation can be found for the different results obtained. The VA study was double-blind and placebo-controlled. Average duration of follow-up was 3.3 years for placebo-controlled patients and 3.2 years for drug-treated patients. In the PHS study patients were followed for 7 to 10 years, with an average of 8 years. In both studies, the placebo-controlled and drug-treatment groups received identical care, except for antihypertensive drugs. Both the VA study and the PHS study showed no significant difference in the frequency of complications or deaths in patients with entry blood pressure 90 to 104 m m Hg diastolic. A significant decrease in complications and deaths was found in the VA study in drug treatment patients with entry diastolic pressure 105 to 114 mm. Hg. The H D F P was not a double-blind, placebo-controlled study. It compared care given in special centers with care given in community hospitals, clinics, and physician's offices. The endpoint was overall 5-year mortality. A majority of patients in both SC and RC groups received drugs, but other aspects of t r e a t m e n t were different in the two groups. SC patients received intensive supportive care. They were a part of a team effort, the sole purpose of which was to keep them under antihypertensive care.
Volume 102 Number 2
T a b l e I. H D F P
Letters to the Editor
d i a s t o l i c b l o o d p r e s s u r e r e s p o n s e b y s t r a t a ( m m Hg)
Stratum I Entry DBP: 96.4
RxDBP ADBP %A
301
Stratum II Entry DBP: 108.7
Stratum III Entry DBP: 122.3
SC
RC
SC
RC
SC
RC
86.4-83.4 9.9-12.9 10.2-13.4
91.9-87.8 4.5-8.6 4.6-8.9
89.1-85.0 19.3-23.4 17.8-21.6
97.4-90.7 11.3-18,0 10.4-16.5
93.5-87.1 28.2-34.6 23.1-28.4
103.1-94.2 19.2-28.1 15.7-23.0
RxDBP = mean resting diastolic blood pressure (years 1, 2, 4, and 5 of study); ADBP = change in diastolic blood pressure; %h = percent change in diastolic blood pressure. Patients who failed to keep appointments were called to reschedule. In some of the SC clinics, vans transported patients to and from clinics. In others, baby-sitters were provided for women patients with small children. Arrangements were made in some SC clinics to make certain t h a t employed patients could attend without a loss of pay. The SC patients were the beneficiaries of an intensive psychologic and social support system provided by a dedicated and effective staff throughout the 5-year follow-up period. RC patients were referred to their usual source of health care, The variety of facilities and services included clinics in large hospitals for the indigent, as well as the offices of physicians in practice. H D F P patients were classified by entry diastolic pressure as in the VA study: stratum I, 90 to 104 mm. Hg; stratum II, 105 to 114 mm. Hg; and stratum III, _> 115 m m Hg. Mortality was less in SC compared to RC by 20% in stratum I, 13% in stratum II, and 7.3% in stratum III. The differences in strata II and III were not statistically significant. The decreased mortality in SC compared to RC is attributed to lower diastolic pressures maintained through the 5-year study period. These were reported for years, 1, 2, 4, and 5. Diastolic pressure was reduced below entry level by 10.2% to 13.4% in SC and from 4.6% to 8.9% in RC. T r e a t m e n t diastolic pressures averaged from 5.4 to 4.3 m m Hg lower for SC than RC in stratum I. This modest difference in treatment diastolic pressure does not seem of sufficient magnitude to explain a decrease of mortality of 20% over a 5-year period. Data from strata II and III suggest t h a t the difference in the magnitude of blood pressure reduction is not the cause of the reduced mortality of SC vs RC in stratum I. In strata I! and III the differences in treatment diastolic pressure of SC vs RC expressed in absolute terms or in percentage of entry values were greater than those of stratum I (Table I). Despite greater reductions in blood pressure, the differences in mortality were smaller and not significant. The data from the PHS study also suggest t h a t the difference in mortality between SC and RC in stratum I was not due to the difference in diastolic pressure. In the PHS study the difference in diastolic pressure between the drug t r e a t m e n t group and the control group averaged 10 mm Hg for the 8-year follow-up period. This must be compared with the difference of only 5.4 to 4.3 mm Hg in SC vs RC noted in stratum I of HDFP. Despite the greater blood pressure difference in the PHS study applied over a longer period of follow-up, there was no significant difference in morbidity or mortality. An alternative hypothesis is therefore suggested to reconcile the findings of H D F P study with those of VA and PHS studies: the strong support system given SC patients was the principal cause of the decreased mortality observed in stratum I. Strong support system was available only to SC patients. Its favorable effect on mortality in SC was greatest in stratum I because drug therapy is relatively ineffective at diastolic pressures of 90 to 104 mm Hg. In strata II and III, on the other hand, with progressively
higher entry diastolic pressures drug treatment was effective and was an increasingly powerful factor in both SC and RC 4 This diluted the influence of the strong support system progressively in patients with higher entry diastolic pressure and is consistent with the diminishing difference in mortality of 20.3%, 13%, and 7.2% in strata I, II, and III, respectively. The reduced effect of the strong support system with increasing entry diastolic pressure may also be responsible for differences in mortality reported at different levels within stratum I. The difference in mortality for SC vs RC was 22% for substratum 90 to 94 mm Hg, 23% for substratrum 95 to 99 m m Hg, and 14% for substratrum 100 to 104 mm Hg. These figures within stratum I suggest t h a t the dilution of the effect of the strong support system began at entry diastolic of 100 to 104 mm Hg. This supports the idea t h a t under the conditions of HDFP, antihypertensive drug therapy exerted a favorable influence on mortality at entry diastolic ___ 100 mm Hg. From the above observations, it is concluded t h a t (1) the design of H D F P and the data reported do not support the conclusion that antihypertensive drug therapy caused the 20% decrease in mortality in stratum I SC patients; (2) it is suggested t h a t the strong support system which was available only to SC patients caused the decreased mortality in SC vs RC in stratum I; and (3) the decreased difference in mortality of SC vs RC within the substrata of stratum I and in strata II and III suggests t h a t drug treatment was effective in reducing mortality at entry diastolic ---- 100 mm Hg. George N. Aagaard, M.D. Division of Clinical Pharmacology Department of Medicine-RG20 University of Washington School of Medicine Seattle, WA 98195 REFERENCES
1. Hypertension Detection and Follow-up Program Cooperative Group: Five-year findings of the hypertension detection and follow-up program. 1. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 242:2562, 1979. 2. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 m m Hg. JAMA 213:1143, 1970. 3. U.S. Public Health Service Hospitals Cooperative Study Group: Treatment of mild hypertension. Results of a tenyear intervention trial. Circ Res 40(suppl I):98, 1977. 4. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 m m Hg. JAMA 202:116, 1967.