E-DRUG: New U.S. Blood Pressure guidelines (2)
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Dear Colleagues:
The E-Drug posting announcing the release of The Sixth Report of the Joint
National Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure (JNC VI) contained the following statement: ". . . JNC
VI suggests that certain long-acting calcium channel blockers _ including
long-acting nifedipine _ are alternate choices for older patients with
isolated systolic hypertension (ISH), the most common form of hypertension
in the elderly."
This recommendation was extrapolated from the results of the SYST-EUR (1),
a study involving the dihydropyridine calcium channel blocker (CCB)
nitrendipine, a drug not approved for use in the US. SYST-EUR provides
scientific evidence that one agent in the class of at least 35 CCBs, a
class of agents that has been on the market more than three decades,
conveys a health benefit to patients with ISH. However, there are a number
of issues with this trial that should be considered.
SYST-EUR enrolled 4,695 patients, who were followed for an average of two
years. The proportion of patients given additional enalapril and
hydrochlorothiazide makes it difficult to attribute the benefit solely to
nitrendipine. A major problem in SYST-EUR is the large number of enrolled
patients (237) lost to follow-up. This number is almost twice the total
number of stroke events in the trial (124 -- 77 vs 47 strokes) and is up to
100 times the typical number of lost to follow up participants in major
trials in the US and northern Europe. Although the reported reduction in
stroke risk is similar in SYST-EUR and in the Systolic Hypertension in the
Elderly Program (SHEP) published in 1991(2). The 29 % reduction (not
statistically significant) in risk of congestive heart failure in SYST-EUR
is approximately half that observed in the recent reanalysis of SHEP,
(49%).(3) This is particularly important from a public health perspective,
since heart failure is the most common clinical complication of ISH.
SYST-EUR subjects who were randomized to receive only placebo have now
been offered active treatment. Under what circumstances would patients
fully informed of the SHEP results knowingly choose a probability of no
treatment, with an increased risk of stroke, and then accept active
treatment at the completion of the study? SYST-EUR's use of a placebo
group would be considered unethical in North America and most of Western
Europe, since diuretics are of proven benefit in the treatment if ISH. A
proper design from the public health point of view would have been a direct
comparison of nitrendipine to low-dose diuretics. SYST-EUR appears to have
violated major international ethical standards of conducting human research
by withholding an effective treatment from the control group. The World
Medical Association's 1975 Declaration of Helsinki states that "In any
medical study, every patient - including those of a control group, if any -
should be assured of the best proven diagnostic and therapeutic method."(4)
It is suggested in the Organization and Methods the recommendations of JNC
VI are evidence based. Careful readers must evaluate SYS-EUR for
themselves and decide if its' results warrant extrapolation to the general
population of elderly with ISH. The debate on the long term safety of the
CCBs will continue until long-term clinical trials are completed that can
identify important differences between antihypertensive agents using
clinically relevant outcomes.
REFERENCES
1. Staessen JA, Fagard R, Lutgarde T, Celis H, Arabidze GG, Birkenh�ger
WH, et al. Randomized double-blind comparison of placebo and active
treatment for older patients with isolated systolic hypertension. Lancet
1997; 350:757-764.
2. SHEP Cooperative Research. 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.
3. Kostis JB, Davis BR, Cutler J, et al. Prevention of heart failure by
antihypertensive drug treatment in older persons with isolated systolic
hypertension. JAMA. 1997;278:212-216.
4. World Medical Association Declaration of Helsinki: recommendations
guiding physicians in biomedical research involving human subjects. Adopted
by the 18 th World Medical Assembly, Helsinki, 1964 and revised by the 29
th World Medical Assembly, Tokyo, 1975, the 35 th World Medical Assembly,
Venice, 1983 and the 41 st World Medical Assembly, Hong Kong, 1989.
Larry D. Sasich, Pharm.D., M.P.H., FASHP
Research Analyst
Public Citizen Health Research Group
1600 20th Street, NW
Washington, DC, USA
Phone: 202-588-7782
FAX: 202-588-7796
Email: lsasich@citizen.org